[ { "id": "https://authors.library.caltech.edu/records/rjrx5-9bm15", "eprint_status": "archive", "datestamp": "2023-10-13 16:53:45", "lastmod": "2024-01-09 22:23:51", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Wu-Woods-Natalie-J", "name": { "family": "Wu-Woods", "given": "Natalie J." }, "orcid": "0000-0001-5070-9091" }, { "id": "Barlow-Jacob-T", "name": { "family": "Barlow", "given": "Jacob T." }, "orcid": "0000-0002-1842-4835" }, { "id": "Trigodet-Florian", "name": { "family": "Trigodet", "given": "Florian" }, "orcid": "0000-0002-4933-2896" }, { "id": "Shaw-Dustin-G", "name": { "family": "Shaw", "given": "Dustin G." }, "orcid": "0000-0003-3961-7588" }, { "id": "Romano-Anna-E", "name": { "family": "Romano", "given": "Anna E." }, "orcid": "0000-0002-7148-0668" }, { "id": "Jabri-Bana", "name": { "family": "Jabri", "given": "Bana" }, "orcid": "0000-0001-7427-4424" }, { "name": { "family": "Eren", "given": "A. Murat" }, "orcid": "0000-0001-9013-4827" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Microbial-enrichment method enables high-throughput metagenomic characterization from host-rich samples", "ispublished": "pub", "full_text_status": "public", "keywords": "Cell Biology; Molecular Biology; Biochemistry; Biotechnology", "note": "
\u00a9 The Author(s), under exclusive licence to Springer Nature America, Inc. 2023.
\n\nWe acknowledge assistance with animal experiments from Caltech Office of Laboratory Animal Research. We thank M. Ratanapanichkich (California Institute of Technology) for assistance on manual refinement of metagenomic bins and feedback on figure design. We thank A. Carter (California Institute of Technology) for assistance with Quant-seq library preparation, ddPCR measurements and feedback during manuscript preparation. We thank M. Cooper (California Institute of Technology) for identifying appropriate statistical tests, guidance during Quant-seq analysis and feedback on figure design. We thank S. R. Bogatyrev for preliminary investigations, discussions and advice. We thank O. Pradhan (California Institute of Technology) and R. Akana (California Institute of Technology) for advice and feedback during manuscript preparation. We thank B. McDonald (University of Chicago) for providing his expertise and advice on clinical sample collection and processing. We thank A. Wang (University of Chicago) for her assistance in the processing of the human tissue for Figs. 3\u20136. We thank N. Shelby (California Institute of Technology) for contributions to writing and editing this manuscript. This work was funded in part by a grant from the Kenneth Rainin Foundation (grant no. 2018-1207 to R.F.I.), the Army Research Office Multidisciplinary University Research Initiative (grant no. W911NF-17-1-0402 to R.F.I.), the Jacobs Institute for Molecular Engineering for Medicine, a NIH NIDDK grant (no. RC2 DK133947 to R.F.I. and B.J.), a National Science Foundation Graduate Research Fellowship (grant no. DGE\u20101745301 to N.J.W.-W.), and a National Institutes of Health Biotechnology Leadership Pre-doctoral Training Program fellowship from Caltech's Donna and Benjamin M. Rosen Bioengineering Center (grant no. T32GM112592, to J.T.B.), a Helmsley Foundation grant (to F.T.), a NIH NIDDK grant (no. RC2 DK122394, to F.T.), a F30 (grant no. 5F30DK121470, to D.G.S.), a R01 (grant no. DK067180, to B.J.) and the Digestive Diseases Research Core Center grant no. P30 DK42086 at the University of Chicago (to B.J.). The funders had no role in the design of the study, the collection, analysis and interpretation of data, nor in writing the manuscript.
\n\nThese authors contributed equally: Natalie J. Wu-Woods, Jacob T. Barlow.
N.J.W.-W. and J.T.B. conceived and optimized MEM. J.T.B. designed sample collection and analyzed 16S sequencing. D.G.S. codesigned and performed human biopsy collection. N.J.W.-W. and F.T. analyzed shotgun sequencing. A.E.R. performed library preparation. R.F.I. contributed to the design and implementation of the study and to obtaining funding. A.M.E. oversaw the bioinformatic analysis, contributed to the design and implementation of the study and to obtaining funding. B.J. supervised the clinical work, contributed to the design and implementation of the study and to obtaining funding. All authors edited the manuscript. A detailed author contribution statement is available in the Supplementary Information.
\n\nThe datasets generated and analyzed during the current study are available at CaltechDATA, https://doi.org/10.22002/gx69z-wec80. Microbial sequencing data are available at NCBI Accession no. PRJNA991155. Sequencing data from human samples have been host scrubbed using STAT78 sra-human-scrubber (https://github.com/ncbi/sra-human-scrubber) followed by alignment to CHM13 (ref. 79). Source data are provided with this paper.
\n\nThe code used in data processing and analysis is available at CaltechDATA, https://doi.org/10.22002/gx69z-wec80.
\n\nThe work in this paper is the subject of a patent application filed by Caltech (R.F.I., N.J.W.-W., J.T.B. and A.E.R.). The other authors declare no competing interests.
", "abstract": "Host\u2013microbe interactions have been linked to health and disease states through the use of microbial taxonomic profiling, mostly via 16S ribosomal RNA gene sequencing. However, many mechanistic insights remain elusive, in part because studying the genomes of microbes associated with mammalian tissue is difficult due to the high ratio of host to microbial DNA in such samples. Here we describe a microbial-enrichment method (MEM), which we demonstrate on a wide range of sample types, including saliva, stool, intestinal scrapings, and intestinal mucosal biopsies. MEM enabled high-throughput characterization of microbial metagenomes from human intestinal biopsies by reducing host DNA more than 1,000-fold with minimal microbial community changes (roughly 90% of taxa had no significant differences between MEM-treated and untreated control groups). Shotgun sequencing of MEM-treated human intestinal biopsies enabled characterization of both high- and low-abundance microbial taxa, pathways and genes longitudinally along the gastrointestinal tract. We report the construction of metagenome-assembled genomes directly from human intestinal biopsies for bacteria and archaea at relative abundances as low as 1%. Analysis of metagenome-assembled genomes reveals distinct subpopulation structures between the small and large intestine for some taxa. MEM opens a path for the microbiome field to acquire deeper insights into host\u2013microbe interactions by enabling in-depth characterization of host-tissue-associated microbial communities.
", "date": "2023-10-12", "date_type": "published", "publication": "Nature Methods", "publisher": "Nature Publishing Group", "issn": "1548-7091", "official_url": "https://authors.library.caltech.edu/records/rjrx5-9bm15", "funders": { "items": [ { "grant_number": "2018-1207" }, { "grant_number": "W911NF-17-1-0402" }, { "grant_number": "RC2 DK133947" }, { "grant_number": "DGE\u20101745301" }, { "grant_number": "T32GM112592" }, {}, { "grant_number": "RC2 DK122394" }, { "grant_number": "5F30DK121470" }, { "grant_number": "DK067180" }, { "grant_number": "P30 DK42086" } ] }, "local_group": { "items": [ { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" }, { "id": "Rosen-Bioengineering-Center" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1038/s41592-023-02025-4", "primary_object": { "basename": "41592_2023_2025_Fig11_ESM.jpg", "url": "https://authors.library.caltech.edu/records/rjrx5-9bm15/files/41592_2023_2025_Fig11_ESM.jpg" }, "related_objects": [ { "basename": "41592_2023_2025_MOESM11_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/rjrx5-9bm15/files/41592_2023_2025_MOESM11_ESM.xlsx" }, { "basename": "41592_2023_2025_MOESM12_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/rjrx5-9bm15/files/41592_2023_2025_MOESM12_ESM.xlsx" }, { "basename": "41592_2023_2025_MOESM4_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/rjrx5-9bm15/files/41592_2023_2025_MOESM4_ESM.xlsx" }, { "basename": "41592_2023_2025_Fig10_ESM.jpg", "url": "https://authors.library.caltech.edu/records/rjrx5-9bm15/files/41592_2023_2025_Fig10_ESM.jpg" }, { "basename": "41592_2023_2025_Fig8_ESM.jpg", "url": "https://authors.library.caltech.edu/records/rjrx5-9bm15/files/41592_2023_2025_Fig8_ESM.jpg" }, { "basename": "41592_2023_2025_MOESM1_ESM.pdf", "url": "https://authors.library.caltech.edu/records/rjrx5-9bm15/files/41592_2023_2025_MOESM1_ESM.pdf" }, { "basename": "41592_2023_2025_MOESM10_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/rjrx5-9bm15/files/41592_2023_2025_MOESM10_ESM.xlsx" }, { "basename": "41592_2023_2025_MOESM5_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/rjrx5-9bm15/files/41592_2023_2025_MOESM5_ESM.xlsx" }, { "basename": "41592_2023_2025_MOESM9_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/rjrx5-9bm15/files/41592_2023_2025_MOESM9_ESM.xlsx" }, { "basename": "41592_2023_2025_MOESM14_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/rjrx5-9bm15/files/41592_2023_2025_MOESM14_ESM.xlsx" }, { "basename": "41592_2023_2025_MOESM15_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/rjrx5-9bm15/files/41592_2023_2025_MOESM15_ESM.xlsx" }, { "basename": "41592_2023_2025_MOESM6_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/rjrx5-9bm15/files/41592_2023_2025_MOESM6_ESM.xlsx" }, { "basename": "41592_2023_2025_MOESM7_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/rjrx5-9bm15/files/41592_2023_2025_MOESM7_ESM.xlsx" }, { "basename": "41592_2023_2025_MOESM8_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/rjrx5-9bm15/files/41592_2023_2025_MOESM8_ESM.xlsx" }, { "basename": "41592_2023_2025_Fig7_ESM.jpg", "url": "https://authors.library.caltech.edu/records/rjrx5-9bm15/files/41592_2023_2025_Fig7_ESM.jpg" }, { "basename": "41592_2023_2025_Fig9_ESM.jpg", "url": "https://authors.library.caltech.edu/records/rjrx5-9bm15/files/41592_2023_2025_Fig9_ESM.jpg" }, { "basename": "41592_2023_2025_MOESM13_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/rjrx5-9bm15/files/41592_2023_2025_MOESM13_ESM.xlsx" } ], "resource_type": "article", "pub_year": "2023", "author_list": "Wu-Woods, Natalie J.; Barlow, Jacob T.; et el." }, { "id": "https://authors.library.caltech.edu/records/7j7m9-fec46", "eprint_status": "archive", "datestamp": "2023-11-15 17:22:40", "lastmod": "2024-01-09 22:22:26", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Ji-Jenny", "name": { "family": "Ji", "given": "Jenny" }, "orcid": "0000-0002-7901-5605" }, { "id": "Winnett-Alexander-Viloria", "name": { "family": "Viloria Winnett", "given": "Alexander" }, "orcid": "0000-0002-7338-5605" }, { "id": "Shelby-Natasha", "name": { "family": "Shelby", "given": "Natasha" }, "orcid": "0000-0001-9097-3663" }, { "id": "Reyes-Jessica-A", "name": { "family": "Reyes", "given": "Jessica A." }, "orcid": "0000-0002-5507-7633" }, { "id": "Schlenker-Noah-W", "name": { "family": "Schlenker", "given": "Noah W." }, "orcid": "0000-0002-8581-4403" }, { "id": "Davich-Hannah", "name": { "family": "Davich", "given": "Hannah" }, "orcid": "0000-0001-6880-3086" }, { "id": "Caldera-Saharai", "name": { "family": "Caldera", "given": "Saharai" }, "orcid": "0000-0001-5057-9186" }, { "id": "Tognazzini-Colten", "name": { "family": "Tognazzini", "given": "Colten" }, "orcid": "0000-0002-2754-3588" }, { "id": "Goh-Ying-Ying", "name": { "family": "Goh", "given": "Ying-Ying" }, "orcid": "0000-0001-5136-7214" }, { "id": "Feaster-Matthew", "name": { "family": "Feaster", "given": "Matt" }, "orcid": "0000-0001-9966-2845" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Index cases first identified by nasal-swab rapid COVID-19 tests had more transmission to household contacts than cases identified by other test types", "ispublished": "pub", "full_text_status": "public", "keywords": "Multidisciplinary", "note": "\u00a9 2023 Ji et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
\n\nWe thank the University of California, Los Angeles, Office of Advanced Research Computing, Statistical Methods and Data Analytics Group for recommendations on statistical methodology and implementation, and Dr. Andy Lin for guidance designing the analysis and feedback on the manuscript.
\n\nThis study is based on research funded in part by the Bill & Melinda Gates Foundation (INV-023124). The findings and conclusions contained within are those of the authors and do not necessarily reflect positions or policies of the Bill & Melinda Gates Foundation. This study was also funded in part by grants from the Ronald and Maxine Linde Center for New Initiatives at the California Institute of Technology (to RFI), a grant from the Jacobs Institute for Molecular Engineering for Medicine at the California Institute of Technology (to RFI), a DGSOM Geffen Fellowship at the University of California, Los Angeles (to AVW), and the John Stauffer Charitable Trust SURF Fellowship at the California Institute of Technology (to JJ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There was no additional external funding received for this study.
\n\nRaw data are available at CaltechDATA: https://doi.org/10.22002/csh5w-rf132.
\n\nI have read the journal's policy and the authors of this manuscript have the following competing interests: R.F.I. is a cofounder, consultant, and a director and has stock ownership of Talis Biomedical Corp. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other co-authors report no competing interests.
", "abstract": "At-home rapid COVID-19 tests in the U.S. utilize nasal-swab specimens and require high viral loads to reliably give positive results. Longitudinal studies from the onset of infection have found infectious virus can present in oral specimens days before nasal. Detection and initiation of infection-control practices may therefore be delayed when nasal-swab rapid tests are used, resulting in greater transmission to contacts. We assessed whether index cases first identified by rapid nasal-swab COVID-19 tests had more transmission to household contacts than index cases who used other test types (tests with higher analytical sensitivity and/or non-nasal specimen types). In this observational cohort study, 370 individuals from 85 households with a recent COVID-19 case were screened at least daily by RT-qPCR on one or more self-collected upper-respiratory specimen types. A two-level random intercept model was used to assess the association between the infection outcome of household contacts and each covariable (household size, race/ethnicity, age, vaccination status, viral variant, infection-control practices, and whether a rapid nasal-swab test was used to initially identify the household index case). Transmission was quantified by adjusted secondary attack rates (aSAR) and adjusted odds ratios (aOR). An aSAR of 53.6% (95% CI 38.8\u201368.3%) was observed among households where the index case first tested positive by a rapid nasal-swab COVID-19 test, which was significantly higher than the aSAR for households where the index case utilized another test type (27.2% 95% CI 19.5\u201335.0%, P = 0.003 pairwise comparisons of predictive margins). We observed an aOR of 4.90 (95% CI 1.65\u201314.56) for transmission to household contacts when a nasal-swab rapid test was used to identify the index case, compared to other test types. Use of nasal-swab rapid COVID-19 tests for initial detection of infection and initiation of infection control may be less effective at limiting transmission to household contacts than other test types.", "date": "2023-10", "date_type": "published", "publication": "PLOS ONE", "volume": "18", "number": "10", "publisher": "Public Library of Science", "pagerange": "e0292389", "issn": "1932-6203", "official_url": "https://authors.library.caltech.edu/records/7j7m9-fec46", "funders": { "items": [ { "agency": "Bill & Melinda Gates Foundation", "grant_number": "INV-023124" }, { "agency": "Ronald and Maxine Linde Center for New Initiatives at the California Institute of Technology" }, { "agency": "Jacobs Institute for Molecular Engineering for Medicine at the California Institute of Technology" }, {}, { "agency": "John Stauffer Charitable Trust SURF Fellowship at the California Institute of Technology" } ] }, "local_group": { "items": [ { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1371/journal.pone.0292389", "pmcid": "PMC10553276", "primary_object": { "basename": "pone.0292389.pdf", "url": "https://authors.library.caltech.edu/records/7j7m9-fec46/files/pone.0292389.pdf" }, "related_objects": [ { "basename": "pone.0292389.s001.pdf", "url": "https://authors.library.caltech.edu/records/7j7m9-fec46/files/pone.0292389.s001.pdf" } ], "resource_type": "article", "pub_year": "2023", "author_list": "Ji, Jenny; Viloria Winnett, Alexander; et el." }, { "id": "https://authors.library.caltech.edu/records/4rjkx-r3m91", "eprint_status": "archive", "datestamp": "2023-09-27 22:44:38", "lastmod": "2024-01-09 22:22:30", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Poceviciute-Roberta", "name": { "family": "Poceviciute", "given": "Roberta" }, "orcid": "0000-0002-6649-2170" }, { "id": "Bogatyrev-Said-R", "name": { "family": "Bogatyrev", "given": "Said R." }, "orcid": "0000-0003-0486-9451" }, { "id": "Romano-Anna-E", "name": { "family": "Romano", "given": "Anna E." }, "orcid": "0000-0002-7148-0668" }, { "id": "Dilmore-Amanda-H", "name": { "family": "Dilmore", "given": "Amanda H." }, "orcid": "0000-0001-6493-7116" }, { "id": "Mondrag\u00f3n-Palomino-Octavio", "name": { "family": "Mondrag\u00f3n-Palomino", "given": "Octavio" }, "orcid": "0000-0003-1129-4932" }, { "id": "Takko-Heli", "name": { "family": "Takko", "given": "Heli" }, "orcid": "0000-0003-2544-409X" }, { "id": "Pradhan-Ojas", "name": { "family": "Pradhan", "given": "Ojas" }, "orcid": "0000-0002-5678-4081" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Quantitative whole-tissue 3D imaging reveals bacteria in close association with mouse jejunum mucosa", "ispublished": "pub", "full_text_status": "public", "keywords": "Applied Microbiology and Biotechnology; Microbiology; Biotechnology", "note": "\u00a9 The Author(s) 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
\n\nWe thank the Caltech Office of Laboratory Animal Resources as well as the veterinary technicians at the animal facilities for animal care, personnel training, and resources. We thank Biological Imaging Facility at Caltech (including Andres Collazo, Giada Spigolon, and Steven Wilbert) for resources, training, and technical support. We thank Brett Finley (University of British Columbia) and Prof. Emma Allen Vercoe (University of Guelph) for providing bacterial isolates. We thank Prof. Jared Leadbetter and Prof. Sarkis Mazmanian for providing feedback on study design. We thank Justin Bois for introduction to data analysis in Python. We thank Emily Savela, Mary Arrastia, and Eugenia Khorosheva for reviewing and filing Institutional Biosafety Committee paperwork. We thank Jacob T. Barlow for processing sequencing data. We thank Joanne Lau for maintaining anaerobic chambers for bacterial culture. We also thank Natasha Shelby for contributions to writing and editing this manuscript. This work was supported in part by the Kenneth Rainin Foundation (2018-1207), Army Research Office Multidisciplinary University Research Initiative (W911NF-17-1-0402), Defense Advanced Research Projects Agency (HR0011-17-2-0037), and the Jacobs Institute for Molecular Engineering for Medicine. OMP was supported by a Burroughs Welcome Fund Career Award at the Scientific Interface (ID# 106969). The funders had no role in the design of the study, the collection, analysis, and interpretation of data, nor in writing the manuscript.
\n\nRP Conception, animal study execution, sample collection, sample processing for imaging, imaging, data analysis, figure generation, manuscript preparation. SRB Tail cup study implementation. sample collection. AER RT-qPCR, dPCR, and sequencing data acquisition. AHD dPCR data acquisition. OMP Preliminary imaging and sequencing. HT Preliminary image analysis. OJ Management of histopathology data acquisition. RFI Project supervision and administration, acquisition of funding, manuscript review and editing. All authors read and approved the final manuscript. See Supplementary Information for detailed author contributions.
\n\nSupplementary Data 1\u20134, all raw data, data analysis scripts, and the new HCR v3.0 rRNA probe sequences from this publication are available at Caltech DATA at https://doi.org/10.22002/zg1d3-k3b49.
\n\nRFI is an inventor on a series of patents licensed by the University of Chicago to Bio-Rad Laboratories Inc. in the context of dPCR.
", "abstract": "Because the small intestine (SI) epithelium lacks a thick protective mucus layer, microbes that colonize the thin SI mucosa may exert a substantial effect on the host. For example, bacterial colonization of the human SI may contribute to environmental enteropathy dysfunction (EED) in malnourished children. Thus far, potential bacterial colonization of the mucosal surface of the SI has only been documented in disease states, suggesting mucosal colonization is rare, likely requiring multiple perturbations. Furthermore, conclusive proof of bacterial colonization of the SI mucosal surface is challenging, and the three-dimensional (3D) spatial structure of mucosal colonies remains unknown. Here, we tested whether we could induce dense bacterial association with jejunum mucosa by subjecting mice to a combination of malnutrition and oral co-gavage with a bacterial cocktail (E. coli and Bacteroides spp.) known to induce EED. To visualize these events, we optimized our previously developed whole-tissue 3D imaging tools with third-generation hybridization chain reaction (HCR v3.0) probes. Only in mice that were malnourished and gavaged with the bacterial cocktail did we detect dense bacterial clusters surrounding intestinal villi suggestive of colonization. Furthermore, in these mice we detected villus loss, which may represent one possible consequence that bacterial colonization of the SI mucosa has on the host. Our results suggest that dense bacterial colonization of jejunum mucosa is possible in the presence of multiple perturbations and that whole-tissue 3D imaging tools can enable the study of these rare events.
", "date": "2023-09-07", "date_type": "published", "publication": "npj Biofilms and Microbiomes", "volume": "9", "publisher": "Nature Publishing Group", "pagerange": "64", "issn": "2055-5008", "official_url": "https://authors.library.caltech.edu/records/4rjkx-r3m91", "funders": { "items": [ { "grant_number": "2018-1207" }, { "grant_number": "W911NF-17-1-0402" }, { "grant_number": "HR0011-17-2-0037" }, { "grant_number": "106969" } ] }, "local_group": { "items": [ { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1038/s41522-023-00423-2", "pmcid": "PMC10485000", "primary_object": { "basename": "s41522-023-00423-2.pdf", "url": "https://authors.library.caltech.edu/records/4rjkx-r3m91/files/s41522-023-00423-2.pdf" }, "related_objects": [ { "basename": "41522_2023_423_MOESM2_ESM.pdf", "url": "https://authors.library.caltech.edu/records/4rjkx-r3m91/files/41522_2023_423_MOESM2_ESM.pdf" }, { "basename": "41522_2023_423_MOESM3_ESM.mp4", "url": "https://authors.library.caltech.edu/records/4rjkx-r3m91/files/41522_2023_423_MOESM3_ESM.mp4" } ], "resource_type": "article", "pub_year": "2023", "author_list": "Poceviciute, Roberta; Bogatyrev, Said R.; et el." }, { "id": "https://authors.library.caltech.edu/records/k79gc-vkp02", "eprint_id": 122011, "eprint_status": "archive", "datestamp": "2023-11-07 23:00:29", "lastmod": "2024-01-09 22:21:30", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Winnett-Alexander-Viloria", "name": { "family": "Winnett", "given": "Alexander Viloria" } }, { "id": "Akana-Reid", "name": { "family": "Akana", "given": "Reid" } }, { "id": "Shelby-Natasha", "name": { "family": "Shelby", "given": "Natasha" } }, { "id": "Davich-Hannah", "name": { "family": "Davich", "given": "Hannah" } }, { "id": "Caldera-Saharai", "name": { "family": "Caldera", "given": "Saharai" } }, { "id": "Yamada-Taikun", "name": { "family": "Yamada", "given": "Taikun" } }, { "id": "Reyna-John-Raymond-B", "name": { "family": "Reyna", "given": "John Raymond B." } }, { "id": "Romano-Anne-E", "name": { "family": "Romano", "given": "Anna E." } }, { "id": "Carter-Alyssa-M", "name": { "family": "Carter", "given": "Alyssa M." } }, { "id": "Kim-Mi-Kyung", "name": { "family": "Kim", "given": "Mi Kyung" } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" } }, { "id": "Tognazzini-Colten", "name": { "family": "Tognazzini", "given": "Colten" } }, { "id": "Feaster-Matthew", "name": { "family": "Feaster", "given": "Matthew" } }, { "id": "Goh-Ying-Ying", "name": { "family": "Goh", "given": "Ying-Ying" } }, { "id": "Chew-Yap-Ching", "name": { "family": "Chew", "given": "Yap Ching" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Daily SARS-CoV-2 Nasal Antigen Tests Miss Infected and Presumably Infectious People Due to Viral Load Differences among Specimen Types", "ispublished": "pub", "full_text_status": "public", "keywords": "Infectious Diseases; Cell Biology; Microbiology (medical); Genetics; General Immunology and Microbiology; Ecology; Physiology", "note": "\u00a9 2023 Viloria Winnett et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. \n\nWe sincerely thank the study participants for making this work possible. We thank Lauriane Quenee, Grace Fisher-Adams, Junie Hildebrandt, Megan Hayashi, RuthAnne Bevier, Chantal D'Apuzzo, Ralph Adolphs, Victor Rivera, Steve Chapman, Gary Waters, Leonard Edwards, Gaylene Ursua, Cynthia Ramos, and Shannon Yamashita for their assistance and advice on study implementation and/or administration. We thank Jessica Leong, Ojas Pradhan, Si Hyung Jin, Emily Savela, Bridget Yang, Ekta Patel, Hsiuchen Chen, Paresh Samantaray, Zeynep Turan, Cindy Kim, Trinity Lee, Vanessa Mechan, Katherine Stiefel, Rosie Zedan, Rahulijeet Chadha, Minkyo Lee, and Jenny Ji for volunteering their time to help with this study. We thank Prabhu Gounder, Tony Chang, Jennifer Howes, and Nari Shin for their support with recruitment. Finally, we thank all the case investigators and contact tracers at the Pasadena Public Health Department and Caltech Student Wellness Services for their efforts in study recruitment and their work in the pandemic response. \n\nR.F.I. is a cofounder, consultant, and director and has stock ownership of Talis Biomedical Corp. All other authors declare that they have no competing interests. \n\nConceptualization, M.F., Y.-Y.G., R.F.I., N.S., and A.V.W. Methodology, R.A., N.S., and A.V.W. Investigation, R.A., A.M.C., Y.C.C., S.C., H.D., M.K.K., J.R.B.R., A.E.R., N.S., A.V.W., and T.Y. Visualization, R.A., N.S., and A.V.W. Funding acquisition, R.F.I. and A.V.W. Project administration, R.F.I. and N.S. Supervision, Y.C.C. and R.F.I. Writing \u2013 original draft, R.A., N.S., and A.V.W. Writing \u2013 review & editing, R.A., A.M.C., R.F.I., A.E.R., N.S., and A.V.W. Detailed author contributions are given in the supplemental material. \n\nThis work was supported in part by a grant from the Ronald and Maxine Linde Center for New Initiatives at the California Institute of Technology (to R.F.I.) and the Jacobs Institute for Molecular Engineering for Medicine at the California Institute of Technology (to R.F.I.). A.V.W. is supported by a UCLA DGSOM Geffen Fellowship.", "abstract": "In a recent household transmission study of SARS-CoV-2, we found extreme differences in SARS-CoV-2 viral loads among paired saliva, anterior nares swab (ANS), and oropharyngeal swab specimens collected from the same time point. We hypothesized these differences may hinder low-analytical-sensitivity assays (including antigen rapid diagnostic tests [Ag-RDTs]) by using a single specimen type (e.g., ANS) from reliably detecting infected and infectious individuals. We evaluated daily at-home ANS Ag-RDTs (Quidel QuickVue) in a cross-sectional analysis of 228 individuals and a longitudinal analysis (throughout infection) of 17 individuals enrolled early in the course of infection. Ag-RDT results were compared to reverse transcription-quantitative PCR (RT-qPCR) results and high, presumably infectious viral loads (in each, or any, specimen type). The ANS Ag-RDT correctly detected only 44% of time points from infected individuals on cross-sectional analysis, and this population had an inferred limit of detection of 7.6\u2009\u00d7\u200910\u2076 copies/mL. From the longitudinal cohort, daily Ag-RDT clinical sensitivity was very low (<3%) during the early, preinfectious period of the infection. Further, the Ag-RDT detected \u226463% of presumably infectious time points. The poor observed clinical sensitivity of the Ag-RDT was similar to what was predicted based on quantitative ANS viral loads and the inferred limit of detection of the ANS Ag-RDT being evaluated, indicating high-quality self-sampling. Nasal Ag-RDTs, even when used daily, can miss individuals infected with the Omicron variant and even those presumably infectious. Evaluations of Ag-RDTs for detection of infected or infectious individuals should be compared with a composite (multispecimen) infection status to correctly assess performance.\n\nImportance:\nWe reveal three findings from a longitudinal study of daily nasal antigen rapid diagnostic test (Ag-RDT) evaluated against SARS-CoV-2 viral load quantification in three specimen types (saliva, nasal swab, and throat swab) in participants enrolled at the incidence of infection. First, the evaluated Ag-RDT showed low (44%) clinical sensitivity for detecting infected persons at all infection stages. Second, the Ag-RDT poorly detected (\u226463%) time points that participants had high and presumably infectious viral loads in at least one specimen type. This poor clinical sensitivity to detect infectious individuals is inconsistent with the commonly held view that daily Ag-RDTs have near-perfect detection of infectious individuals. Third, use of a combination nasal-throat specimen type was inferred by viral loads to significantly improve Ag-RDT performance to detect infectious individuals.", "date": "2023-07", "date_type": "published", "publication": "Microbiology Spectrum", "volume": "11", "number": "4", "publisher": "American Society for Microbiology", "pagerange": "e01295-23", "id_number": "CaltechAUTHORS:20230628-344482000.1", "issn": "2165-0497", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20230628-344482000.1", "funders": { "items": [ { "agency": "Ronald and Maxine Linde Center for New Initiatives" }, { "agency": "Jacobs Institute for Molecular Engineering for Medicine" }, { "agency": "UCLA" } ] }, "local_group": { "items": [ { "id": "COVID-19" }, { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1128/spectrum.01295-23", "pmcid": "PMC10434058", "primary_object": { "basename": "spectrum.01295-23-s0001.pdf", "url": "https://authors.library.caltech.edu/records/k79gc-vkp02/files/spectrum.01295-23-s0001.pdf" }, "related_objects": [ { "basename": "spectrum.01295-23.pdf", "url": "https://authors.library.caltech.edu/records/k79gc-vkp02/files/spectrum.01295-23.pdf" } ], "resource_type": "article", "pub_year": "2023", "author_list": "Winnett, Alexander Viloria; Akana, Reid; et el." }, { "id": "https://authors.library.caltech.edu/records/8xx2v-fk653", "eprint_id": 120367, "eprint_status": "archive", "datestamp": "2023-08-20 16:38:33", "lastmod": "2023-12-22 23:34:21", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Winnett-Alexander-Viloria", "name": { "family": "Winnett", "given": "Alexander Viloria" }, "orcid": "0000-0002-7338-5605" }, { "id": "Akana-Reid", "name": { "family": "Akana", "given": "Reid" }, "orcid": "0000-0003-4422-587X" }, { "id": "Shelby-Natasha", "name": { "family": "Shelby", "given": "Natasha" }, "orcid": "0000-0001-9097-3663" }, { "id": "Davich-Hannah", "name": { "family": "Davich", "given": "Hannah" }, "orcid": "0000-0001-6880-3086" }, { "id": "Caldera-Saharai", "name": { "family": "Caldera", "given": "Saharai" }, "orcid": "0000-0001-5057-9186" }, { "id": "Yamada-Taikun", "name": { "family": "Yamada", "given": "Taikun" } }, { "id": "Reyna-John-Raymond-B", "name": { "family": "Reyna", "given": "John Raymond B." } }, { "id": "Romano-Anne-E", "name": { "family": "Romano", "given": "Anna E." }, "orcid": "0000-0002-7148-0668" }, { "id": "Carter-Alyssa-M", "name": { "family": "Carter", "given": "Alyssa M." }, "orcid": "0000-0002-2776-9421" }, { "id": "Kim-Mi-Kyung", "name": { "family": "Kim", "given": "Mi Kyung" } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" }, "orcid": "0000-0003-1021-1234" }, { "id": "Tognazzini-Colten", "name": { "family": "Tognazzini", "given": "Colten" }, "orcid": "0000-0002-2754-3588" }, { "id": "Feaster-Matthew", "name": { "family": "Feaster", "given": "Matthew" }, "orcid": "0000-0001-9966-2845" }, { "id": "Goh-Ying-Ying", "name": { "family": "Goh", "given": "Ying-Ying" }, "orcid": "0000-0001-5136-7214" }, { "id": "Chew-Yap-Ching", "name": { "family": "Chew", "given": "Yap Ching" }, "orcid": "0000-0002-1686-6541" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Extreme differences in SARS-CoV-2 viral loads among respiratory specimen types during presumed pre-infectious and infectious periods", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 The Author(s) 2023. Published by Oxford University Press on behalf of National Academy of Sciences. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. \n\nThe authors thank the study participants for making this work possible. The authors thank Lauriane Quenee, Grace Fisher-Adams, Junie Hildebrandt, Megan Hayashi, RuthAnne Bevier, Chantal D'Apuzzo, Ralph Adolphs, Victor Rivera, Steve Chapman, Gary Waters, Leonard Edwards, Gaylene Ursua, Cynthia Ramos, and Shannon Yamashita for their assistance and advice on study implementation and/or administration. They thank Jessica Leong, Ojas Pradhan, Si Hyung Jin, Emily Savela, Bridget Yang, Ekta Patel, Hsiuchen Chen, Paresh Samantaray, Zeynep Turan, Cindy Kim, Trinity Lee, Vanessa Mechan, Katherine Stiefel, Rosie Zedan, Rahulijeet Chadha, Minkyo Lee, and Jenny Ji for volunteering their time to help with this study. The authors thank Prabhu Gounder, Tony Chang, Jennifer Howes, and Nari Shin for their support with recruitment. Finally, the authors thank all the case investigators and contact tracers at the Pasadena Public Health Department and Caltech Student Wellness Services for their efforts in study recruitment and their work in the pandemic response. This manuscript was posted on the preprint server medRxiv at https://www.medrxiv.org/content/10.1101/2022.07.13.22277113v2. \n\nThis work was funded in part by a grant from the Ronald and Maxine Linde Center for New Initiatives at the California Institute of Technology (to RFI), a grant from the Jacobs Institute for Molecular Engineering for Medicine at the California Institute of Technology (to RFI), and a DGSOM Geffen Fellowship at the University of California, Los Angeles (to AVW). \n\nAuthor contributions. Detailed author contributions are in the Supplement. \n\nConceptualization: A.V.W., N.S., M.F., Y-Y.G., R.F.I.; methodology: A.V.W., R.A., N.S.; investigation: A.V.W., R.A., N.S., S.C., H.D., M.K.K., J.R.B.R., T.Y., A.E.R., A.M.C., Y.C.C.; visualization: A.V.W., R.A., N.S.; funding acquisition: A.V.W., R.F.I.; project administration: N.S., R.F.I.; supervision: Y.C.C., R.F.I.; writing\u2014original draft: A.V.W., R.A., N.S. writing\u2014review and editing: A.V.W., R.A., N.S., A.E.R., A.M.C., R.F.I. \n\nData availability. The data underlying the results presented in the study can be accessed at CaltechDATA: https://data.caltech.edu/records/20223. \n\nA.V.W., R.A., and N.S. authors contributed equally to this report. Order of co-first authorship was determined by extent of contributions; see detailed Author Contributions statement in the supplement. \n\nCompeting interest: R.F.I. is a co-founder, consultant, and director for and has stock ownership in Talis Biomedical Corporation. All other authors report no potential conflicts.\n\nPublished - pgad033.pdf
Supplemental Material - pgad033_supplementary_data.zip
", "abstract": "SARS-CoV-2 viral-load measurements from a single-specimen type are used to establish diagnostic strategies, interpret clinical-trial results for vaccines and therapeutics, model viral transmission, and understand virus\u2013host interactions. However, measurements from a single-specimen type are implicitly assumed to be representative of other specimen types. We quantified viral-load timecourses from individuals who began daily self-sampling of saliva, anterior-nares (nasal), and oropharyngeal (throat) swabs before or at the incidence of infection with the Omicron variant. Viral loads in different specimen types from the same person at the same timepoint exhibited extreme differences, up to 109 copies/mL. These differences were not due to variation in sample self-collection, which was consistent. For most individuals, longitudinal viral-load timecourses in different specimen types did not correlate. Throat-swab and saliva viral loads began to rise as many as 7 days earlier than nasal-swab viral loads in most individuals, leading to very low clinical sensitivity of nasal swabs during the first days of infection. Individuals frequently exhibited presumably infectious viral loads in one specimen type while viral loads were low or undetectable in other specimen types. Therefore, defining an individual as infectious based on assessment of a single-specimen type underestimates the infectious period, and overestimates the ability of that specimen type to detect infectious individuals. For diagnostic COVID-19 testing, these three single-specimen types have low clinical sensitivity, whereas a combined throat\u2013nasal swab, and assays with high analytical sensitivity, was inferred to have significantly better clinical sensitivity to detect presumed pre-infectious and infectious individuals.", "date": "2023-03", "date_type": "published", "publication": "PNAS Nexus", "volume": "2", "number": "3", "publisher": "Oxford University Press", "pagerange": "pgad033", "id_number": "CaltechAUTHORS:20230323-759607000.4", "issn": "2752-6542", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20230323-759607000.4", "funders": { "items": [ { "agency": "Ronald and Maxine Linde Center for New Initiatives" }, { "agency": "Jacobs Institute for Molecular Engineering for Medicine" }, { "agency": "UCLA" } ] }, "local_group": { "items": [ { "id": "COVID-19" }, { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1093/pnasnexus/pgad033", "pmcid": "PMC10013338", "primary_object": { "basename": "pgad033.pdf", "url": "https://authors.library.caltech.edu/records/8xx2v-fk653/files/pgad033.pdf" }, "related_objects": [ { "basename": "pgad033_supplementary_data.zip", "url": "https://authors.library.caltech.edu/records/8xx2v-fk653/files/pgad033_supplementary_data.zip" } ], "resource_type": "article", "pub_year": "2023", "author_list": "Winnett, Alexander Viloria; Akana, Reid; et el." }, { "id": "https://authors.library.caltech.edu/records/0mjqz-64458", "eprint_id": 118971, "eprint_status": "archive", "datestamp": "2023-08-22 18:35:42", "lastmod": "2023-12-22 23:42:01", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Carter-Alyssa-M", "name": { "family": "Carter", "given": "Alyssa M." }, "orcid": "0000-0002-2776-9421" }, { "id": "Winnett-Alexander-Viloria", "name": { "family": "Winnett", "given": "Alexander Viloria" }, "orcid": "0000-0002-7338-5605" }, { "id": "Romano-Anne-E", "name": { "family": "Romano", "given": "Anna E." }, "orcid": "0000-0002-7148-0668" }, { "id": "Akana-Reid", "name": { "family": "Akana", "given": "Reid" }, "orcid": "0000-0003-4422-587X" }, { "id": "Shelby-Natasha", "name": { "family": "Shelby", "given": "Natasha" }, "orcid": "0000-0001-9097-3663" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Laboratory Evaluation Links Some False-Positive COVID-19 Antigen Test Results Observed in a Field Study to a Specific Lot of Test Strips", "ispublished": "pub", "full_text_status": "public", "keywords": "Infectious Diseases; Oncology", "note": "\u00a9 The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. \n\nWe thank the study participants for making this work possible. We thank Study Coordinators Saharai Caldera for suggesting the laboratory evaluation and both Saharai and Hannah Davich for removing lot 152000 from circulation in the study. We thank Taikun Yamada, John Raymond B. Reyna, Paolo Piatti and Yap Ching Chew for performing and verifying the validity of RT-qPCR results as previously reported. Finally, we thank all the case investigators and contact tracers at the Pasadena Public Health Department and Caltech Student Wellness Services for their efforts in study recruitment and their work in the pandemic response. \n\nThis work was supported by the Ronald and Maxine Linde Center for New Initiatives at the California Institute of Technology and the Jacobs Institute for Molecular Engineering for Medicine at the California Institute of Technology. A UCLA DGSOM Geffen Fellowship to AVW. \n\nData Availability: The data underlying the results presented in the study are available at CaltechDATA at: https://doi.org/10.22002/fmz6a-0x036.\n\nAlyssa M. Carter and Alexander Viloria Winnett contributed equally to this manuscript.\n\nPublished - ofac701.pdf
Supplemental Material - ofac701_supplementary_data.pdf
", "abstract": "During a household-transmission field study using COVID-19 antigen rapid diagnostic tests (Ag-RDT), a common test strip lot was identified among three participants with false-positive results. In blinded laboratory evaluation, this lot, exhibited a significantly higher false-positive rate than other lots. Because a positive Ag-RDT result often prompts action, reducing lot-specific false positives can maintain confidence and actionability of true-positive Ag-RDT results.", "date": "2023-01-30", "date_type": "published", "publication": "Open Forum Infectious Diseases", "volume": "10", "number": "1", "publisher": "Oxford University Press", "pagerange": "Art. No. ofac701", "id_number": "CaltechAUTHORS:20230130-263514000.2", "issn": "2328-8957", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20230130-263514000.2", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Ronald and Maxine Linde Center for New Initiatives" }, { "agency": "Jacobs Institute for Molecular Engineering for Medicine" }, { "agency": "UCLA" } ] }, "local_group": { "items": [ { "id": "COVID-19" }, { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1093/ofid/ofac701", "pmcid": "PMC9887260", "primary_object": { "basename": "ofac701.pdf", "url": "https://authors.library.caltech.edu/records/0mjqz-64458/files/ofac701.pdf" }, "related_objects": [ { "basename": "ofac701_supplementary_data.pdf", "url": "https://authors.library.caltech.edu/records/0mjqz-64458/files/ofac701_supplementary_data.pdf" } ], "resource_type": "article", "pub_year": "2023", "author_list": "Carter, Alyssa M.; Winnett, Alexander Viloria; et el." }, { "id": "https://authors.library.caltech.edu/records/sh6x3-qaj93", "eprint_id": 118970, "eprint_status": "archive", "datestamp": "2023-08-22 18:42:31", "lastmod": "2023-12-22 23:10:33", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Earley-Zachary-M", "name": { "family": "Earley", "given": "Zachary M." }, "orcid": "0000-0001-9748-7262" }, { "id": "Lisicka-Wioletta", "name": { "family": "Lisicka", "given": "Wioletta" }, "orcid": "0000-0003-2623-5185" }, { "id": "Sifakis-Joseph-J", "name": { "family": "Sifakis", "given": "Joseph J." } }, { "id": "Aguirre-Gamboa-Ra\u00fal", "name": { "family": "Aguirre-Gamboa", "given": "Ra\u00fal" }, "orcid": "0000-0003-2505-3574" }, { "id": "Kowalczyk-Anita", "name": { "family": "Kowalczyk", "given": "Anita" }, "orcid": "0000-0002-4217-8857" }, { "id": "Barlow-Jacob-T", "name": { "family": "Barlow", "given": "Jacob T." }, "orcid": "0000-0002-1842-4835" }, { "id": "Shaw-Dustin-G", "name": { "family": "Shaw", "given": "Dustin G." }, "orcid": "0000-0003-3961-7588" }, { "id": "Discepolo-Valentina", "name": { "family": "Discepolo", "given": "Valentina" }, "orcid": "0000-0001-6158-0545" }, { "id": "Tan-Ineke-L", "name": { "family": "Tan", "given": "Ineke L." }, "orcid": "0000-0001-8159-2367" }, { "id": "Gona-Saideep", "name": { "family": "Gona", "given": "Saideep" }, "orcid": "0000-0002-7469-2607" }, { "id": "Ernest-Jordan-B", "name": { "family": "Ernest", "given": "Jordan D." }, "orcid": "0000-0003-0857-217X" }, { "id": "Matzinger-Polly", "name": { "family": "Matzinger", "given": "Polly" } }, { "id": "Barreiro-Luis-B", "name": { "family": "Barreiro", "given": "Luis B." }, "orcid": "0000-0001-9456-367X" }, { "id": "Morgun-Andrey", "name": { "family": "Morgun", "given": "Andrey" }, "orcid": "0000-0002-8924-6108" }, { "id": "Bendelac-Albert", "name": { "family": "Bendelac", "given": "Albert" }, "orcid": "0000-0003-1859-206X" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Shulzhenko-Natalia", "name": { "family": "Shulzhenko", "given": "Natalia" }, "orcid": "0000-0003-0077-8456" }, { "id": "Riesenfeld-Samantha-J", "name": { "family": "Riesenfeld", "given": "Samantha J." }, "orcid": "0000-0001-9144-021X" }, { "id": "Jabri-Bana", "name": { "family": "Jabri", "given": "Bana" } } ] }, "title": "GATA4 controls regionalization of tissue immunity and commensal-driven immunopathology", "ispublished": "pub", "full_text_status": "public", "keywords": "Infectious Diseases; Immunology; Immunology and Allergy", "note": "\u00a9 2022 Elsevier. \n\nWe would like to thank the patients and their family members, as well as the University of Chicago Celiac Disease Center, for supporting our research. We would like to thank Drs. Sonia Kupfer, Carol Semrad, Ritu Verma, Hilary Jericho, and Ian Wilson from the Celiac Disease Center for consenting and recruiting patients. We would like to thank Joaqu\u00edn Sanz Rem\u00f3n for his help with the general transcriptional analysis of celiac disease and control patient biopsies. We thank Drs. Kenya Honda and Gabriel Nu\u00f1ez for providing rat SFB and \u0394EAE C.\u00a0rodentium, respectively. We thank Ivaylo Ivanov for providing SFB TCR transgenic mice and for helpful discussions. We thank Steven Erickson from Dr. Albert Bendelac's lab for generating IgA- and Jh-deficient mice using CRISPR-Cas technologies based on previously published mouse models.24,55 We thank Betty Theriault, Kristin Kolar, and the entire Gnotobiotic Research Animal Facility at the University of Chicago for their help with the experiments involving gnotobiotic mice. We thank Yimei Chen and Tera Lavoie of the Advanced Electron Microscopy Core at University of Chicago for their help with transmission electron microscopy. We thank the Human Tissue Resource Center, the Integrated Light Microscopy Core Facility, Flow Cytometry Facility, and the Genomics Facility at the University of Chicago for their technical support. We thank Toufic Mayassi and Cezary Ciszewski for the thoughtful discussions and insightful comments. Finally, we thank Valerie Abadie for a critical reading of the manuscript and help with the graphical abstract. This work was supported by the National Institutes of Health via T32 AI007090 to Z.M.E., T32 GM007281 to D.G.S., U01AI109695 to A.M., U01 AI125250 to A.B., R01 AI144094 to A.B., R01DK103761 to N.S., R01 DK067180 to B.J., and the Digestive Diseases Research Core Center C-IID P30 DK42086 at the University of Chicago to B.J.\n\nAuthor contributions:\n\nZ.M.E. and B.J. conceived the study and designed the experiments. S.J.R. designed and oversaw computational analysis of the RNA-seq data with input from Z.M.E., B.J., J.J.S., and R.A.-G. Based on their previously published work and studies performed in gnotobiotic mice, N.S., A.M., and P.M. put forward the concept that absence of GATA4 in epithelial cells was driving inflammatory immune responses in the jejunum in a microbiota-dependent manner. Z.M.E., W.L., A.K., D.G.S., J.D.E., and J.T.B. performed the experiments. Z.M.E., W.L., J.J.S, R.A.-G., J.T.B., and S.J.R. analyzed and interpreted the data. J.J.S. performed computational analysis of mouse RNA-seq data, and R.A.-G. performed computational analysis of human RNA-seq data. J.T.B. performed the 16S sequencing and analysis. D.G.S. and V.D. created the RNA-seq libraries, and S.G. performed the DNA alignments. P.M. supervised an initial microarray transcriptional analysis. I.L.T contributed to and L.B.B. supervised RNA-seq analysis of human celiac disease patients. R.F.I. supervised the 16S analysis. A.B. supervised the IgA experiments. Z.M.E., S.J.R., and B.J. wrote the manuscript. W.L., J.J.S, J.T.B., R.F.I., A.M., N.S., and A.B. edited the manuscript. R.F.I., A.M., A.B., N.S., and B.J. acquired funds to support the work, and B.J. directed the study. \n\nData and code availability. All the data supporting the findings of the article are available within the main text or supplementary information. The published article includes datasets generated during this study. Original RNA-seq data has been deposited in GEO: GSE205743. Original 16S rRNA sequencing datasets analyzed in this study are available at the NCBI BioProject: PRJNA797871. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request. Original code for analyzing these datasets have been deposited in Zenodo and is publicly available. DOIs are listed in the key resources table. \n\nThe authors declare no competing interests. \n\nWe support inclusive, diverse, and equitable conduct of research.", "abstract": "There is growing recognition that regionalization of bacterial colonization and immunity along the intestinal tract has an important role in health and disease. Yet, the mechanisms underlying intestinal regionalization and its dysregulation in disease are not well understood. This study found that regional epithelial expression of the transcription factor GATA4 controls bacterial colonization and inflammatory tissue immunity in the proximal small intestine by regulating retinol metabolism and luminal IgA. Furthermore, in mice without jejunal GATA4 expression, the commensal segmented filamentous bacteria promoted pathogenic inflammatory immune responses that disrupted barrier function and increased mortality upon Citrobacter rodentium infection. In celiac disease patients, low GATA4 expression was associated with metabolic alterations, mucosal Actinobacillus, and increased IL-17 immunity. Taken together, these results reveal broad impacts of GATA4-regulated intestinal regionalization on bacterial colonization and tissue immunity, highlighting an elaborate interdependence of intestinal metabolism, immunity, and microbiota in homeostasis and disease.", "date": "2023-01-10", "date_type": "published", "publication": "Immunity", "volume": "56", "number": "1", "publisher": "Cell Press", "pagerange": "43-57.e10", "id_number": "CaltechAUTHORS:20230130-262818000.1", "issn": "1074-7613", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20230130-262818000.1", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH Predoctoral Fellowship", "grant_number": "T32 AI007090" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "T32 GM007281" }, { "agency": "NIH", "grant_number": "U01 AI109695" }, { "agency": "NIH", "grant_number": "U01 AI125250" }, { "agency": "NIH", "grant_number": "R01 AI144094" }, { "agency": "NIH", "grant_number": "R01 DK103761" }, { "agency": "NIH", "grant_number": "R01 DK067180" }, { "agency": "NIH", "grant_number": "P30 DK42086" } ] }, "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1016/j.immuni.2022.12.009", "resource_type": "article", "pub_year": "2023", "author_list": "Earley, Zachary M.; Lisicka, Wioletta; et el." }, { "id": "https://authors.library.caltech.edu/records/00s15-xar08", "eprint_id": 117825, "eprint_status": "archive", "datestamp": "2023-10-25 15:58:49", "lastmod": "2024-01-09 22:23:46", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Winnett-Alexander-Viloria", "name": { "family": "Winnett", "given": "Alexander Viloria" }, "orcid": "0000-0002-7338-5605" }, { "id": "Porter-Michael-K", "name": { "family": "Porter", "given": "Michael K." }, "orcid": "0000-0002-0777-7563" }, { "id": "Romano-Anne-E", "name": { "family": "Romano", "given": "Anna E." }, "orcid": "0000-0002-7148-0668" }, { "id": "Savela-Emily-S", "name": { "family": "Savela", "given": "Emily S." }, "orcid": "0000-0001-9614-4276" }, { "id": "Akana-Reid", "name": { "family": "Akana", "given": "Reid" }, "orcid": "0000-0003-4422-587X" }, { "id": "Shelby-Natasha", "name": { "family": "Shelby", "given": "Natasha" }, "orcid": "0000-0001-9097-3663" }, { "id": "Reyes-Jessica-A", "name": { "family": "Reyes", "given": "Jessica A." }, "orcid": "0000-0002-5507-7633" }, { "id": "Schlenker-Noah-W", "name": { "family": "Schlenker", "given": "Noah W." }, "orcid": "0000-0002-8581-4403" }, { "id": "Cooper-Matthew-M", "name": { "family": "Cooper", "given": "Matthew M." }, "orcid": "0000-0002-5868-5159" }, { "id": "Carter-Alyssa-M", "name": { "family": "Carter", "given": "Alyssa M." }, "orcid": "0000-0002-2776-9421" }, { "id": "Ji-Jenny", "name": { "family": "Ji", "given": "Jenny" }, "orcid": "0000-0002-7901-5605" }, { "id": "Barlow-Jacob-T", "name": { "family": "Barlow", "given": "Jacob T." }, "orcid": "0000-0002-1842-4835" }, { "id": "Tognazzini-Colten", "name": { "family": "Tognazzini", "given": "Colten" }, "orcid": "0000-0002-2754-3588" }, { "id": "Feaster-Matthew", "name": { "family": "Feaster", "given": "Matthew" }, "orcid": "0000-0001-9966-2845" }, { "id": "Goh-Ying-Ying", "name": { "family": "Goh", "given": "Ying-Ying" }, "orcid": "0000-0001-5136-7214" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Morning SARS-CoV-2 Testing Yields Better Detection of Infection Due to Higher Viral Loads in Saliva and Nasal Swabs upon Waking", "ispublished": "pub", "full_text_status": "public", "keywords": "Infectious Diseases; Cell Biology; Microbiology (medical); Genetics; General Immunology and Microbiology; Ecology; Physiology", "note": "We sincerely thank the study participants for making this work possible. We thank Lauriane Quenee, Grace Fisher-Adams, Junie Hildebrandt, Megan Hyashi, RuthAnne Bevier, Chantal D'Apuzzo, Ralph Adolphs, Victor Rivera, Steve Chapman, Gary Waters, Leonard Edwards, Gaylene Ursua, Cynthia Ramos, and Shannon Yamashita for their assistance and advice on study implementation and/or administration. We thank Jessica Leong, Jessica Slagle, Mika Walton, Angel Navarro, Daniel Brenner, Ojas Pradhan, Si Hyung Jin, and Mary Arrastia for volunteering their time to help with this study. We thank Angie Cheng, Susan Magdaleno, Christian Kis, Monica Herrera, and Zaina Lemeir for technical discussions regarding saliva extraction and detection. We thank Jennifer Fulcher, Debika Bhattacharya, and Matthew Bidwell Goetz for their ideas on potential study populations and early study design. We thank Omai Garner and David Beenhouwer for providing materials for initial nasal swab validation. We thank Martin Hill, Alma Sanchez, Scott Kim, Debbie Noble, Nina Paddock, Whitney Harrison, Emily Holman, Isaac Turner, Vivek Desai, Luke Wade, Tom Mayell, Stu Miller, Jennifer Howes, and Nari Shin for their support with recruitment. We thank Allison Rhines, Karen Heichman, and Dan Wattendorf for valuable discussions and guidance. We thank David Prober for discussions of circadian rhythms and feedback on the manuscript. Finally, we thank all the case investigators and contact tracers at the Pasadena Public Health Department, the City of Long Beach Department of Health & Human Services, and Caltech Student Wellness Services for their efforts in study recruitment and their work in the pandemic response.\n\nR.F.I. is a cofounder, consultant, and a director and has stock ownership of Talis Biomedical Corp.\n\nThis study is based on research funded in part by the Bill & Melinda Gates Foundation (INV-023124). The findings and conclusions contained within are those of the authors and do not necessarily reflect positions or policies of the Bill & Melinda Gates Foundation. This work was also funded by the Ronald and Maxine Linde Center for New Initiatives at the California Institute of Technology and the Jacobs Institute for Molecular Engineering for Medicine at the California Institute of Technology. A.V.W. is supported by a UCLA DGSOM Geffen Fellowship, and M.M.C. is supported by a Caltech Graduate Student Fellowship.", "abstract": "Optimizing specimen collection methods to achieve the most reliable SARS-CoV-2 detection for a given diagnostic sensitivity would improve testing and minimize COVID-19 outbreaks. From September 2020 to April 2021, we performed a household-transmission study in which participants self-collected specimens every morning and evening throughout acute SARS-CoV-2 infection. Seventy mildly symptomatic participants collected saliva, and of those, 29 also collected nasal swab specimens. Viral load was quantified in 1,194 saliva and 661 nasal swab specimens using a high-analytical-sensitivity reverse transcription-quantitative PCR (RT-qPCR) assay. Viral loads in both saliva and nasal swab specimens were significantly higher in morning-collected specimens than in evening-collected specimens after symptom onset. This aspect of the biology of SARS-CoV-2 infection has implications for diagnostic testing. We infer that morning collection would have resulted in significantly improved detection and that this advantage would be most pronounced for tests with low to moderate analytical sensitivity. Collecting specimens for COVID-19 testing in the morning offers a simple and low-cost improvement to clinical diagnostic sensitivity of low- to moderate-analytical-sensitivity tests.\n\nImportance: Our findings suggest that collecting saliva and nasal swab specimens in the morning immediately after waking yields higher SARS-CoV-2 viral loads than collection later in the day. The higher viral loads from morning specimen collection are predicted to significantly improve detection of SARS-CoV-2 in symptomatic individuals, particularly when using moderate- to low-analytical-sensitivity COVID-19 diagnostic tests, such as rapid antigen tests.", "date": "2022-12-21", "date_type": "published", "publication": "Microbiology Spectrum", "volume": "10", "number": "6", "publisher": "American Society for Microbiology", "pagerange": "e03873-22", "id_number": "CaltechAUTHORS:20221110-430693700.10", "issn": "2165-0497", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20221110-430693700.10", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Bill and Melinda Gates Foundation", "grant_number": "INV-023124" }, { "agency": "Ronald and Maxine Linde Center for New Initiatives" }, { "agency": "Jacobs Institute for Molecular Engineering for Medicine" }, { "agency": "UCLA" }, { "agency": "Caltech" } ] }, "local_group": { "items": [ { "id": "COVID-19" }, { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1128/spectrum.03873-22", "pmcid": "PMC9769854", "primary_object": { "basename": "jhaveri-et-al-2022-morning-sars-cov-2-testing-yields-better-detection-of-infection-due-to-higher-viral-loads-in-saliva.pdf", "url": "https://authors.library.caltech.edu/records/00s15-xar08/files/jhaveri-et-al-2022-morning-sars-cov-2-testing-yields-better-detection-of-infection-due-to-higher-viral-loads-in-saliva.pdf" }, "related_objects": [ { "basename": "spectrum.03873-22-s0001.pdf", "url": "https://authors.library.caltech.edu/records/00s15-xar08/files/spectrum.03873-22-s0001.pdf" } ], "resource_type": "article", "pub_year": "2022", "author_list": "Winnett, Alexander Viloria; Porter, Michael K.; et el." }, { "id": "https://authors.library.caltech.edu/records/f4njc-jvc50", "eprint_id": 114509, "eprint_status": "archive", "datestamp": "2023-08-22 15:13:42", "lastmod": "2023-12-22 23:08:02", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Mondrag\u00f3n-Palomino-Octavio", "name": { "family": "Mondrag\u00f3n-Palomino", "given": "Octavio" }, "orcid": "0000-0003-1129-4932" }, { "id": "Poceviciute-Roberta", "name": { "family": "Poceviciute", "given": "Roberta" }, "orcid": "0000-0002-6649-2170" }, { "id": "Lignell-Antti", "name": { "family": "Lignell", "given": "Antti" }, "orcid": "0000-0001-7664-5583" }, { "id": "Griffiths-Jessica-A", "name": { "family": "Griffiths", "given": "Jessica A." }, "orcid": "0000-0002-5586-1567" }, { "id": "Takko-Heli", "name": { "family": "Takko", "given": "Heli" }, "orcid": "0000-0003-2544-409X" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Three-dimensional imaging for the quantification of spatial patterns in microbiota of the intestinal mucosa", "ispublished": "pub", "full_text_status": "public", "keywords": "microbiota; quantitative biogeography; tissue clearing", "note": "\u00a9 2022 the Author(s). Published by PNAS.\nThis open access article is distributed under Creative\nCommons Attribution License 4.0 (CC BY).\n\nEdited by Jeffrey Gordon, Washington University in St. Louis School of Medicine, St. Louis, MO; received October 18, 2021; accepted March 7, 2022. Published April 27, 2022.\n\nThis work was funded, in part, by a Burroughs Wellcome\nFund Career Award at the Scientific Interface (ID#1016969, to O.M.-P.), a Biology & Biological Engineering divisional fellowship (to O.M.-P.), a seeding grant from Caltech's\nCenter for Environmental Microbial Interactions, Army Research Office Multidisciplinary University Research Initiative Contract W911NF-17-1-0402, Defense\nAdvanced Research Projects Agency Award HR0011-17-2-0037, an Innovator Award from the Kenneth Rainin Foundation (Grant 2018-1207), and the Jacobs Institute for Molecular Engineering for Medicine. We thank Said Bogatyrev for\nsharing his expertise and advice, and help with the administration of antibiotics to mice, as well as processing fecal samples for quantitative sequencing. We acknowledge\ntechnical advice from Nick Flytzanis, Ben Deverman, and Ken Chan. We thank Andres Collazo and Giada Spigolon at the Beckman Institute Biological Imaging Facility for help with imaging. We thank the veterinarians and Office of\nLaboratory Animal Research staff for their assistance with animal experiments, Elaine Hsiao for providing Akkermansia muciniphila, and Natasha Shelby for contributions\nto writing and editing this manuscript. O.M.-P. thanks Jeff Hasty and Lev Tsimring of the BioCircuits Institute at University of California San Diego for the\ngenerous space and resources provided to complete this manuscript.\n\nData Availability:\nRaw data have been deposited in CaltechDATA (https://data.caltech.edu/20077) (58).\n\nAuthor contributions: \nO.M.-P., R.P., J.A.G., and R.F.I.\ndesigned research; O.M.-P., R.P., J.A.G., and H.T.\nperformed research; O.M.-P., R.P., J.A.G., and H.T.\ncontributed new reagents/analytic tools; O.M.-P., R.P.,\nA.L., J.A.G., and H.T. analyzed data; O.M.-P. and R.F.I.\nwrote the paper; O.M.-P. and R.F.I. conceived the\nstudy; and R.F.I. supervised the research.\n\nThe authors declare no competing interest.\n\nThis article is a PNAS Direct Submission.\n\nThis article contains supporting information online at\nhttp://www.pnas.org/lookup/suppl/doi:10.1073/pnas.\n2118483119/-/DCSupplemental.\n\nPublished - pnas.2118483119.pdf
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Supplemental Material - pnas.2118483119.sm04.mp4
", "abstract": "Improving our understanding of host\u2013microbe relationships in the gut requires the ability to both visualize and quantify the spatial organization of microbial communities in their native orientation with the host tissue. We developed a systematic procedure to quantify the three-dimensional (3D) spatial structure of the native mucosal microbiota in any part of the intestines with taxonomic and high spatial resolution. We performed a 3D biogeographical analysis of the microbiota of mouse cecal crypts at different stages of antibiotic exposure. By tracking eubacteria and four dominant bacterial taxa, we found that the colonization of crypts by native bacteria is a dynamic and spatially organized process. Ciprofloxacin treatment drastically reduced bacterial loads and eliminated Muribaculaceae (or all Bacteroidetes entirely) even 10 d after recovery when overall bacterial loads returned to preantibiotic levels. Our 3D quantitative imaging approach revealed that the bacterial colonization of crypts is organized in a spatial pattern that consists of clusters of adjacent colonized crypts that are surrounded by unoccupied crypts, and that this spatial pattern is resistant to the elimination of Muribaculaceae or of all Bacteroidetes by ciprofloxacin. Our approach also revealed that the composition of cecal crypt communities is diverse and that Lactobacilli were found closer to the lumen than Bacteroidetes, Ruminococcaceae, and Lachnospiraceae, regardless of antibiotic exposure. Finally, we found that crypts communities with similar taxonomic composition were physically closer to each other than communities that were taxonomically different.", "date": "2022-05-03", "date_type": "published", "publication": "Proceedings of the National Academy of Sciences", "volume": "119", "number": "18", "publisher": "National Academy of Sciences", "pagerange": "Art. No. e2118483119", "id_number": "CaltechAUTHORS:20220428-203848852", "issn": "0027-8424", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20220428-203848852", "funders": { "items": [ { "agency": "Burroughs Wellcome Fund", "grant_number": "1016969" }, { "agency": "Caltech Division of Biology and Biological Engineering" }, { "agency": "Caltech Center for Environmental Microbial Interactions (CEMI)" }, { "agency": "Army Research Office (ARO)", "grant_number": "W911NF-17-1-0402" }, { "agency": "Defense Advanced Research Projects Agency (DARPA)", "grant_number": "HR0011-17-2-0037" }, { "agency": "Kenneth Rainin Foundation", "grant_number": "2018-1207" }, { "agency": "Jacobs Institute for Molecular Engineering for Medicine" } ] }, "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1073/pnas.2118483119", "pmcid": "PMC9171773", "primary_object": { "basename": "pnas.2118483119.pdf", "url": "https://authors.library.caltech.edu/records/f4njc-jvc50/files/pnas.2118483119.pdf" }, "related_objects": [ { "basename": "pnas.2118483119.sapp.pdf", "url": "https://authors.library.caltech.edu/records/f4njc-jvc50/files/pnas.2118483119.sapp.pdf" }, { "basename": "pnas.2118483119.sm01.mp4", "url": "https://authors.library.caltech.edu/records/f4njc-jvc50/files/pnas.2118483119.sm01.mp4" }, { "basename": "pnas.2118483119.sm02.mp4", "url": "https://authors.library.caltech.edu/records/f4njc-jvc50/files/pnas.2118483119.sm02.mp4" }, { "basename": "pnas.2118483119.sm03.mp4", "url": "https://authors.library.caltech.edu/records/f4njc-jvc50/files/pnas.2118483119.sm03.mp4" }, { "basename": "pnas.2118483119.sm04.mp4", "url": "https://authors.library.caltech.edu/records/f4njc-jvc50/files/pnas.2118483119.sm04.mp4" } ], "resource_type": "article", "pub_year": "2022", "author_list": "Mondrag\u00f3n-Palomino, Octavio; Poceviciute, Roberta; et el." }, { "id": "https://authors.library.caltech.edu/records/r8qh8-y4065", "eprint_id": 108641, "eprint_status": "archive", "datestamp": "2023-08-20 06:53:20", "lastmod": "2023-12-22 23:44:25", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Savela-Emily-S", "name": { "family": "Savela", "given": "Emily S." }, "orcid": "0000-0001-9614-4276" }, { "id": "Winnett-Alexander-Viloria", "name": { "family": "Winnett", "given": "Alexander Viloria" }, "orcid": "0000-0002-7338-5605" }, { "id": "Romano-Anna-E", "name": { "family": "Romano", "given": "Anna E." }, "orcid": "0000-0003-1871-1727" }, { "id": "Porter-Michael-K", "name": { "family": "Porter", "given": "Michael K." }, "orcid": "0000-0002-0777-7563" }, { "id": "Shelby-Natasha", "name": { "family": "Shelby", "given": "Natasha" }, "orcid": "0000-0001-9097-3663" }, { "id": "Akana-Reid", "name": { "family": "Akana", "given": "Reid" }, "orcid": "0000-0003-4422-587X" }, { "id": "Ji-Jenny", "name": { "family": "Ji", "given": "Jenny" }, "orcid": "0000-0002-7901-5605" }, { "id": "Cooper-Matthew-M", "name": { "family": "Cooper", "given": "Matthew M." }, "orcid": "0000-0002-5868-5159" }, { "id": "Schlenker-Noah-W", "name": { "family": "Schlenker", "given": "Noah W." }, "orcid": "0000-0002-8581-4403" }, { "id": "Reyes-Jessica-A", "name": { "family": "Reyes", "given": "Jessica A." }, "orcid": "0000-0002-5507-7633" }, { "id": "Carter-Alyssa-M", "name": { "family": "Carter", "given": "Alyssa M." }, "orcid": "0000-0002-2776-9421" }, { "id": "Barlow-Jacob-T", "name": { "family": "Barlow", "given": "Jacob T." }, "orcid": "0000-0002-1842-4835" }, { "id": "Tognazzini-Colten", "name": { "family": "Tognazzini", "given": "Colten" } }, { "id": "Feaster-Matthew", "name": { "family": "Feaster", "given": "Matthew" }, "orcid": "0000-0001-9966-2845" }, { "id": "Goh-Ying-Ying", "name": { "family": "Goh", "given": "Ying-Ying" }, "orcid": "0000-0001-5136-7214" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Quantitative SARS-CoV-2 Viral-Load Curves in Paired Saliva Samples and Nasal Swabs Inform Appropriate Respiratory Sampling Site and Analytical Test Sensitivity Required for Earliest Viral Detection", "ispublished": "pub", "full_text_status": "public", "keywords": "RT-qPCR, COVID-19, case-ascertained, diagnostics, household study,\nlongitudinal sampling, nasal swab, presymptomatic, saliva, surveillance, transmission", "note": "\u00a9 2022 Savela et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. \n\nReceived 24 August 2021; Returned for modification 21 September 2021; Accepted 10 December 2021; Accepted manuscript posted online 15 December 2021; Published 16 February 2022. \n\nWe thank Lauriane Quenee, Junie Hildebrandt, Grace Fisher-Adams, RuthAnne Bevier, Chantal D'Apuzzo, Ralph Adolphs, Victor Rivera, Steve Chapman, Gary Waters, Leonard Edwards, Gaylene Ursua, Cynthia Ramos, and Shannon Yamashita for their assistance and advice on study implementation and/or administration. We thank Jessica Leong, Jessica Slagle, Mika Walton, Angel Navarro, Daniel Brenner, and Ojas Pradhan for volunteering their time to help with this study, Si Hyung Jin for helping with a literature review, and Mary Arrastia for providing biosafety support. We thank Maira Phelps, Lienna Chan, Lucy Li, Dan Lu, and Amy Kistler at the Chan Zuckerberg Biohub for performing SARS-CoV-2 sequencing. We thank Angie Cheng, Susan Magdaleno, Christian Kis, Monica Herrera, and Zaina Lemeir for technical discussions regarding saliva extraction and ddPCR detection. We thank Jennifer Fulcher, Debika Bhattacharya, and Matthew Bidwell Goetz for their ideas on potential study populations and early study design. We thank Omai Garner and David Beenhouwer for providing materials for initial nasal-swab validation. We thank Martin Hill, Alma Sanchez, Scott Kim, Debbie Noble, Nina Paddock, Whitney Harrison, Emily Holman, Isaac Turner, Vivek Desai, Luke Wade, Tom Mayell, Stu Miller, and Jennifer Howes for their support with recruitment. We thank Allison Rhines, Karen Heichman, and Dan Wattendorf for valuable discussions. Finally, we thank all the case investigators and contact tracers at the Pasadena Public Health Department and the City of Long Beach Department of Health & Human Services for their efforts in study recruitment and their work in the pandemic response. \n\nR.F.I. is a cofounder, consultant, and a director and has stock ownership of Talis Biomedical Corp. In addition, R.F.I. is an inventor on a series of patents licensed by the University of Chicago to Bio-Rad Laboratories, Inc., in the context of ddPCR. \n\nThis study is based on research funded in part by the Bill & Melinda Gates Foundation (INV-023124). The findings and conclusions contained within are those of the authors and do not necessarily reflect positions or policies of the Bill & Melinda Gates Foundation. This work was also funded by the Ronald and Maxine Linde Center for New Initiatives at the California Institute of Technology and the Jacobs Institute for Molecular Engineering for Medicine at the California Institute of Technology. A.V.W. is supported by a National Institutes of Health NIGMS predoctoral training grant (GM008042) and a UCLA DGSOM Geffen fellowship; M.M.C. is supported by a Caltech graduate student fellowship, and M.K.P. and J.T.B. are each partially supported by a National Institutes of Health Biotechnology Leadership Predoctoral Training Program (BLP) fellowship from Caltech's Donna and Benjamin M. Rosen Bioengineering Center (T32GM112592).\n\nPublished - jcm.01785-21.pdf
Submitted - 2021.04.02.21254771v2.full.pdf
Supplemental Material - jcm.01785-21-s0001.pdf
", "abstract": "Early detection of SARS-CoV-2 infection is critical to reduce asymptomatic and presymptomatic transmission, curb the spread of variants, and maximize treatment efficacy. Low-analytical-sensitivity nasal-swab testing is commonly used for surveillance and symptomatic testing, but the ability of these tests to detect the earliest stages of infection has not been established. In this study, conducted between September 2020 and June 2021 in the greater Los Angeles County, California, area, initially SARS-CoV-2-negative household contacts of individuals diagnosed with COVID-19 prospectively self-collected paired anterior-nares nasal-swab and saliva samples twice daily for viral-load quantification by high-sensitivity reverse-transcription quantitative PCR (RT-qPCR) and digital-RT-PCR assays. We captured viral-load profiles from the incidence of infection for seven individuals and compared diagnostic sensitivities between respiratory sites. Among unvaccinated persons, testing saliva with a high-analytical-sensitivity assay detected infection up to 4.5\u2009days before viral loads in nasal swabs reached concentrations detectable by low-analytical-sensitivity nasal-swab tests. For most participants, nasal swabs reached higher peak viral loads than saliva but were undetectable or at lower loads during the first few days of infection. High-analytical-sensitivity saliva testing was most reliable for earliest detection. Our study illustrates the value of acquiring early (within hours after a negative high-sensitivity test) viral-load profiles to guide the appropriate analytical sensitivity and respiratory site for detecting earliest infections. Such data are challenging to acquire but critical to designing optimal testing strategies with emerging variants in the current pandemic and to respond to future viral pandemics.", "date": "2022-02", "date_type": "published", "publication": "Journal of Clinical Microbiology", "volume": "60", "number": "2", "publisher": "American Society for Microbiology", "pagerange": "Art. No. e01785-21", "id_number": "CaltechAUTHORS:20210407-080559241", "issn": "0095-1137", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210407-080559241", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Bill and Melinda Gates Foundation", "grant_number": "INV-023124" }, { "agency": "Ronald and Maxine Linde Center for New Initiatives" }, { "agency": "Jacobs Institute for Molecular Engineering for Medicine" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "GM008042" }, { "agency": "UCLA" }, { "agency": "Caltech" }, { "agency": "Donna and Benjamin M. Rosen Bioengineering Center" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "T32GM112592" } ] }, "local_group": { "items": [ { "id": "COVID-19" }, { "id": "Rosen-Bioengineering-Center" }, { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1128/JCM.01785-21", "pmcid": "PMC8849374", "primary_object": { "basename": "2021.04.02.21254771v2.full.pdf", "url": "https://authors.library.caltech.edu/records/r8qh8-y4065/files/2021.04.02.21254771v2.full.pdf" }, "related_objects": [ { "basename": "jcm.01785-21-s0001.pdf", "url": "https://authors.library.caltech.edu/records/r8qh8-y4065/files/jcm.01785-21-s0001.pdf" }, { "basename": "jcm.01785-21.pdf", "url": "https://authors.library.caltech.edu/records/r8qh8-y4065/files/jcm.01785-21.pdf" } ], "resource_type": "article", "pub_year": "2022", "author_list": "Savela, Emily S.; Winnett, Alexander Viloria; et el." }, { "id": "https://authors.library.caltech.edu/records/nepdr-6d707", "eprint_id": 104955, "eprint_status": "archive", "datestamp": "2023-08-22 12:58:06", "lastmod": "2023-12-22 23:34:06", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Arrastia-Mary-V", "name": { "family": "Arrastia", "given": "Mary V." }, "orcid": "0000-0002-0723-3574" }, { "id": "Jachowicz-Joanna-W", "name": { "family": "Jachowicz", "given": "Joanna W." }, "orcid": "0000-0002-1599-682X" }, { "id": "Ollikainen-Noah", "name": { "family": "Ollikainen", "given": "Noah" }, "orcid": "0000-0002-1174-2400" }, { "id": "Curtis-Matthew-S", "name": { "family": "Curtis", "given": "Matthew S." }, "orcid": "0000-0002-9662-3266" }, { "id": "Lai-Charlotte", "name": { "family": "Lai", "given": "Charlotte" } }, { "id": "Quinodoz-Sofia-A", "name": { "family": "Quinodoz", "given": "Sofia A." }, "orcid": "0000-0003-1862-5204" }, { "id": "Selck-David-A", "name": { "family": "Selck", "given": "David A." }, "orcid": "0000-0002-0591-4165" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Guttman-M", "name": { "family": "Guttman", "given": "Mitchell" }, "orcid": "0000-0003-4748-9352" } ] }, "title": "Single-cell measurement of higher-order 3D genome organization with scSPRITE", "ispublished": "pub", "full_text_status": "public", "keywords": "Biological techniques; Cell biology; Molecular biology; Stem cells", "note": "\u00a9 2021 Nature Publishing Group. \n\nReceived 20 July 2020; Accepted 25 June 2021; Published 23 August 2021. \n\nWe would like to thank F. Gao from Caltech's Bioinformatics Resource Center and I. Antoshechkin from Caltech's Millard and Muriel Jacobs Genetics and Genomics Laboratory for assistance. We would also like to thank C. Chen, V. Trinh, E. Detmar, E. Soehalim, A. Narayanan and I. Goronzy for their contributions in helping develop scSPRITE and analysis. We would like to thank M. Thompson's laboratory for allowing us to use their MiSeq instrument and the ENCODE Consortium and the ENCODE production laboratory of B. Ren (University of California, San Diego) for making their data publicly available. We also thank N. Shelby and S. Hiley for contributions to the writing and editing this manuscript and I.-M. Strazhnik for helping with illustrations. Funding: This work was funded by the National Institutes of Health 4DN Program (U01 DA040612 and U01 HL130007), the National Human Genome Research Institute Genomics of Gene Regulation Program (U01 HG007910), the New York Stem Cell Foundation (NYSCF-R-I13), the Sontag Foundation and funds from Caltech. M.V.A. and S.A.Q. were funded by a National Science Foundation Graduate Research Fellowship Program fellowship. M.V.A. was additionally funded by the Earle C. Anthony Fellowship (Caltech). M. Guttman is an NYSCF-Robertson Investigator. \n\nData availability: The datasets (Figs. 1\u20135 and Extended Data Figs. 1\u22125) generated and analyzed in the current study are available in the Gene Expression Omnibus repository under accession number GSE154353 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE154353). \n\nCode availability: scSPRITE software is available at https://github.com/caltech-bioinformatics-resource-center/Guttman_Ismagilov_Labs. \n\nThese authors contributed equally: Mary V. Arrastia, Joanna W. Jachowicz. \n\nAuthor Contributions: M.V.A. conducted the experiments to develop and validate the method, conceptualized and performed the analyses and wrote the manuscript. J.W.J. contributed to and supervised the experiments to develop and validate the method, conceptualized and performed the analyses and wrote the manuscript. N.O. conceptualized and performed analysis to validate the method, developed the pipeline for the workup of scSPRITE sequencing data and contributed to writing the manuscript. M.S.C. contributed to the experiments to develop the method. C.A.L. developed a pipeline to sort cells by cell-specific barcodes. S.A.Q. contributed to the experiments to develop and validate the method. D.A.S. contributed to conceptualize scSPRITE and to the experiments to develop the method. R.F.I. conceptualized scSPRITE and supervised the experiments and the analysis to develop the method. M.G. conceptualized scSPRITE, supervised the experiments and the analysis to validate the method and wrote the manuscript. For detailed author contributions, please see Supplementary Note 5. \n\nCompeting interests: This paper is the subject of a patent application filed by Caltech. R.F.I. has a financial interest in Talis Biomedical Corp. S.A.Q. and M.G. are inventors on a patent owned by Caltech on SPRITE. The remaining authors declare no competing financial interests. \n\nPeer review information: Nature Biotechnology thanks Andrew Adey and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.\n\nSubmitted - 2020.08.11.242081v1.full.pdf
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", "abstract": "Although three-dimensional (3D) genome organization is central to many aspects of nuclear function, it has been difficult to measure at the single-cell level. To address this, we developed 'single-cell split-pool recognition of interactions by tag extension' (scSPRITE). scSPRITE uses split-and-pool barcoding to tag DNA fragments in the same nucleus and their 3D spatial arrangement. Because scSPRITE measures multiway DNA contacts, it generates higher-resolution maps within an individual cell than can be achieved by proximity ligation. We applied scSPRITE to thousands of mouse embryonic stem cells and detected known genome structures, including chromosome territories, active and inactive compartments, and topologically associating domains (TADs) as well as long-range inter-chromosomal structures organized around various nuclear bodies. We observe that these structures exhibit different levels of heterogeneity across the population, with TADs representing dynamic units of genome organization across cells. We expect that scSPRITE will be a critical tool for studying genome structure within heterogeneous populations.", "date": "2022-01", "date_type": "published", "publication": "Nature Biotechnology", "volume": "40", "number": "1", "publisher": "Nature Publishing Group", "pagerange": "64-73", "id_number": "CaltechAUTHORS:20200813-130113364", "issn": "1087-0156", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200813-130113364", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "U01 DA040612" }, { "agency": "NIH", "grant_number": "U01 HL130007" }, { "agency": "NIH", "grant_number": "U01 HG007910" }, { "agency": "New York Stem Cell Foundation", "grant_number": "NYSCF-R-I13" }, { "agency": "Sontag Foundation" }, { "agency": "Caltech Earle C. Anthony Fellowship" }, { "agency": "NSF Graduate Research Fellowship", "grant_number": "DGE\u20101144469" } ] }, "local_group": { "items": [ { "id": "Millard-and-Muriel-Jacobs-Genetics-and-Genomics-Laboratory" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1038/s41587-021-00998-1", "primary_object": { "basename": "41587_2021_998_Fig7_ESM.webp", "url": "https://authors.library.caltech.edu/records/nepdr-6d707/files/41587_2021_998_Fig7_ESM.webp" }, "related_objects": [ { "basename": "41587_2021_998_Fig8_ESM.webp", "url": "https://authors.library.caltech.edu/records/nepdr-6d707/files/41587_2021_998_Fig8_ESM.webp" }, { "basename": "41587_2021_998_MOESM2_ESM.pdf", "url": "https://authors.library.caltech.edu/records/nepdr-6d707/files/41587_2021_998_MOESM2_ESM.pdf" }, { "basename": "2020.08.11.242081v1.full.pdf", "url": "https://authors.library.caltech.edu/records/nepdr-6d707/files/2020.08.11.242081v1.full.pdf" }, { "basename": "41587_2021_998_Fig6_ESM.webp", "url": "https://authors.library.caltech.edu/records/nepdr-6d707/files/41587_2021_998_Fig6_ESM.webp" }, { "basename": "41587_2021_998_MOESM1_ESM.pdf", "url": "https://authors.library.caltech.edu/records/nepdr-6d707/files/41587_2021_998_MOESM1_ESM.pdf" }, { "basename": "41587_2021_998_MOESM3_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/nepdr-6d707/files/41587_2021_998_MOESM3_ESM.xlsx" }, { "basename": "41587_2021_998_Fig10_ESM.webp", "url": "https://authors.library.caltech.edu/records/nepdr-6d707/files/41587_2021_998_Fig10_ESM.webp" }, { "basename": "41587_2021_998_Fig9_ESM.webp", "url": "https://authors.library.caltech.edu/records/nepdr-6d707/files/41587_2021_998_Fig9_ESM.webp" } ], "resource_type": "article", "pub_year": "2022", "author_list": "Arrastia, Mary V.; Jachowicz, Joanna W.; et el." }, { "id": "https://authors.library.caltech.edu/records/tmw0j-mph48", "eprint_id": 111829, "eprint_status": "archive", "datestamp": "2023-08-22 11:54:59", "lastmod": "2023-12-22 23:33:09", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Barlow-Jacob-T", "name": { "family": "Barlow", "given": "Jacob T." }, "orcid": "0000-0002-1842-4835" }, { "id": "Leite-Gabriela", "name": { "family": "Leite", "given": "Gabriela" }, "orcid": "0000-0001-5772-7735" }, { "id": "Romano-Anna-E", "name": { "family": "Romano", "given": "Anna E." }, "orcid": "0000-0003-1871-1727" }, { "id": "Sedighi-Rashin", "name": { "family": "Sedighi", "given": "Rashin" } }, { "id": "Chang-Christine", "name": { "family": "Chang", "given": "Christine" }, "orcid": "0000-0003-0179-7800" }, { "id": "Celly-Shreya", "name": { "family": "Celly", "given": "Shreya" }, "orcid": "0000-0002-5896-457X" }, { "id": "Rezaie-Ali", "name": { "family": "Rezaie", "given": "Ali" }, "orcid": "0000-0002-0106-372X" }, { "id": "Mathur-Ruchi", "name": { "family": "Mathur", "given": "Ruchi" }, "orcid": "0000-0003-1053-6557" }, { "id": "Pimentel-Mark", "name": { "family": "Pimentel", "given": "Mark" }, "orcid": "0000-0002-0619-5115" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Quantitative sequencing clarifies the role of disruptor taxa, oral microbiota, and strict anaerobes in the human small-intestine microbiome", "ispublished": "pub", "full_text_status": "public", "keywords": "Duodenum; Saliva; HACEK; Human small intestinal microbiome; IBS; SIBO; Enterobacteriaceae; Lactobacillus; Constipation; Bloating", "note": "\u00a9 The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. \n\nReceived 15 June 2021; Accepted 14 September 2021; Published 02 November 2021. \n\nWe thank the Caltech Bioinformatics Resource Center for assistance with statistical analyses, Jenny Ji for related analyses and Natasha Shelby for contributions to writing and editing this manuscript. We acknowledge OpenMoji for use of the saliva and stool graphics in Fig. 1. We thank Stacy Weitsman, Walter Morales and Maria Jesus Villanueva-Milan from MAST for assistance with sample processing and data curation from the REIMAGINE study. We also thank the Gastroenterology team at Cedars-Sinai Medical Center for assistance with patient recruitment and endoscopy procedures. \n\nThis work was supported in part by the Kenneth Rainin Foundation (2018-1207), the Jacobs Institute for Molecular Engineering for Medicine, and a National Institutes of Health Biotechnology Leadership Pre-doctoral Training Program (BLP) fellowship from Caltech's Donna and Benjamin M. Rosen Bioengineering Center (T32GM112592, to J.T.B.). The funders had no role in the design of the study, the collection, analysis, and interpretation of data, nor in writing the manuscript. \n\nJacob T. Barlow and Gabriela Leite contributed equally to this work. \n\nAuthor Contributions: Conceptualization, J.T.B., G.L., R.M., M.P., and R.F.I.. Methodology, J.T.B., G.L., S.C., R.S., C.C.. Formal analysis, J.T.B.. Investigation, J.T.B, G.L., and A.E.R. Resources, G.L. Data curation, J.T.B., and G.L. Writing\u2014original draft, J.T.B. Writing\u2014review and editing, J.T.B., G.L., A.R., R.M., M.P., and R.F.I. Visualization, J.T.B. Supervision, M.P., and R.F.I. The author(s) read and approved the final manuscript. \n\nEthics approval and consent to participate: The study was reviewed and approved by the Cedars-Sinai Medical Center IRB (Protocol #00035192). All participants provided written informed consent prior to participation. \n\nConsent for publication: Not applicable. \n\nCompeting interests: The quantitative sequencing technology described in this publication is the subject of a patent application filed by Caltech. R.F.I. receives patent royalties from Bio-Rad related to droplet digital PCR.\n\nPublished - s40168-021-01162-2.pdf
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", "abstract": "Background: Upper gastrointestinal (GI) disorders and abdominal pain afflict between 12 and 30% of the worldwide population and research suggests these conditions are linked to the gut microbiome. Although large-intestine microbiota have been linked to several GI diseases, the microbiota of the human small intestine and its relation to human disease has been understudied. The small intestine is the major site for immune surveillance in the gut, and compared with the large intestine, it has greater than 100 times the surface area and a thinner and more permeable mucus layer. \n\nResults: Using quantitative sequencing, we evaluated total and taxon-specific absolute microbial loads from 250 duodenal-aspirate samples and 21 paired duodenum-saliva samples from participants in the REIMAGINE study. Log-transformed total microbial loads spanned 5 logs and were normally distributed. Paired saliva-duodenum samples suggested potential transmission of oral microbes to the duodenum, including organisms from the HACEK group. Several taxa, including Klebsiella, Escherichia, Enterococcus, and Clostridium, seemed to displace strict anaerobes common in the duodenum, so we refer to these taxa as disruptors. Disruptor taxa were enriched in samples with high total microbial loads and in individuals with small intestinal bacterial overgrowth (SIBO). Absolute loads of disruptors were associated with more severe GI symptoms, highlighting the value of absolute taxon quantification when studying small-intestine health and function. \n\nConclusion: This study provides the largest dataset of the absolute abundance of microbiota from the human duodenum to date. The results reveal a clear relationship between the oral microbiota and the duodenal microbiota and suggest an association between the absolute abundance of disruptor taxa, SIBO, and the prevalence of severe GI symptoms.", "date": "2021-11-02", "date_type": "published", "publication": "Microbiome", "volume": "9", "publisher": "Springer", "pagerange": "Art. No. 214", "id_number": "CaltechAUTHORS:20211110-202208524", "issn": "2049-2618", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20211110-202208524", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Kenneth Rainin Foundation", "grant_number": "2018-1207" }, { "agency": "Jacobs Institute for Molecular Engineering for Medicine" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "T32GM112592" } ] }, "local_group": { "items": [ { "id": "Rosen-Bioengineering-Center" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1186/s40168-021-01162-2", "pmcid": "PMC8561862", "primary_object": { "basename": "s40168-021-01162-2.pdf", "url": "https://authors.library.caltech.edu/records/tmw0j-mph48/files/s40168-021-01162-2.pdf" }, "related_objects": [ { "basename": "40168_2021_1162_MOESM2_ESM.docx", "url": "https://authors.library.caltech.edu/records/tmw0j-mph48/files/40168_2021_1162_MOESM2_ESM.docx" }, { "basename": "40168_2021_1162_MOESM3_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/tmw0j-mph48/files/40168_2021_1162_MOESM3_ESM.xlsx" } ], "resource_type": "article", "pub_year": "2021", "author_list": "Barlow, Jacob T.; Leite, Gabriela; et el." }, { "id": "https://authors.library.caltech.edu/records/6ez4q-hx548", "eprint_id": 114693, "eprint_status": "archive", "datestamp": "2023-08-20 05:51:57", "lastmod": "2023-12-22 23:31:07", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Ji-Jenny", "name": { "family": "Ji", "given": "Jenny" }, "orcid": "0000-0002-7901-5605" }, { "id": "Winnett-Alexander", "name": { "family": "Winnett", "given": "Alexander" }, "orcid": "0000-0002-7338-5605" }, { "id": "Shelby-Natasha", "name": { "family": "Shelby", "given": "Natasha" }, "orcid": "0000-0001-9097-3663" }, { "id": "Reyes-Jessica-A", "name": { "family": "Reyes", "given": "Jessica A." }, "orcid": "0000-0002-5507-7633" }, { "id": "Akana-Reid", "name": { "family": "Akana", "given": "Reid" }, "orcid": "0000-0003-4422-587X" }, { "id": "Schlenker-Noah-W", "name": { "family": "Schlenker", "given": "Noah W." }, "orcid": "0000-0002-8581-4403" }, { "id": "Savela-Emily-S", "name": { "family": "Savela", "given": "Emily S." }, "orcid": "0000-0001-9614-4276" }, { "id": "Romano-Anna-E", "name": { "family": "Romano", "given": "Anna" }, "orcid": "0000-0003-1871-1727" }, { "id": "Porter-Michael-K", "name": { "family": "Porter", "given": "Michael K." }, "orcid": "0000-0002-0777-7563" }, { "id": "Carter-Alyssa-M", "name": { "family": "Carter", "given": "Alyssa M." }, "orcid": "0000-0002-2776-9421" }, { "id": "Cooper-Matthew-M", "name": { "family": "Cooper", "given": "Matthew M." }, "orcid": "0000-0002-5868-5159" }, { "id": "Barlow-Jacob-T", "name": { "family": "Barlow", "given": "Jacob T." }, "orcid": "0000-0002-1842-4835" }, { "id": "Tognazzini-Colten", "name": { "family": "Tognazzini", "given": "Colten" } }, { "id": "Feaster-Matthew", "name": { "family": "Feaster", "given": "Matthew" }, "orcid": "0000-0001-9966-2845" }, { "id": "Goh-Ying-Ying", "name": { "family": "Goh", "given": "Ying-Ying" }, "orcid": "0000-0001-5136-7214" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Modulating Factors of Household Transmission of SARS\u2011CoV\u20112 in a Community-Based Study", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2021 American Society of Tropical Medicine and Hygiene. \n\nMeeting abstract 0975.", "abstract": "[no abstract]", "date": "2021-11", "date_type": "published", "publication": "American Journal of Tropical Medicine and Hygiene", "volume": "105", "number": "5", "publisher": "American Society of Tropical Medicine and Hygiene", "pagerange": "313", "id_number": "CaltechAUTHORS:20220512-142847077", "issn": "0002-9637", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20220512-142847077", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "local_group": { "items": [ { "id": "COVID-19" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.4269/ajtmh.abstract2021", "resource_type": "article", "pub_year": "2021", "author_list": "Ji, Jenny; Winnett, Alexander; et el." }, { "id": "https://authors.library.caltech.edu/records/en9tt-2np72", "eprint_id": 110773, "eprint_status": "archive", "datestamp": "2023-08-22 11:09:52", "lastmod": "2023-12-22 23:10:27", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Olson-Christine-A", "name": { "family": "Olson", "given": "Christine A." }, "orcid": "0000-0002-5382-1393" }, { "id": "I\u00f1iguez-Alonso-J", "name": { "family": "I\u00f1iguez", "given": "Alonso J." }, "orcid": "0000-0002-4869-3278" }, { "id": "Yang-Grace-E", "name": { "family": "Yang", "given": "Grace E." }, "orcid": "0000-0001-8346-908X" }, { "id": "Fang-Ping", "name": { "family": "Fang", "given": "Ping" }, "orcid": "0000-0003-4379-3787" }, { "id": "Pronovost-Geoffrey-N", "name": { "family": "Pronovost", "given": "Geoffrey N." } }, { "id": "Jameson-Kelly-G", "name": { "family": "Jameson", "given": "Kelly G." }, "orcid": "0000-0002-9972-9138" }, { "id": "Rendon-Tomiko-K", "name": { "family": "Rendon", "given": "Tomiko K." } }, { "id": "Paramo-Jorge", "name": { "family": "Paramo", "given": "Jorge" } }, { "id": "Barlow-Jacob-T", "name": { "family": "Barlow", "given": "Jacob T." }, "orcid": "0000-0002-1842-4835" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Hsiao-Elaine-Y-Bio", "name": { "family": "Hsiao", "given": "Elaine Y." }, "orcid": "0000-0002-1633-588X" } ] }, "title": "Alterations in the gut microbiota contribute to cognitive impairment induced by the ketogenic diet and hypoxia", "ispublished": "pub", "full_text_status": "public", "keywords": "microbiota; Bilophila; hippocampus; brain; cognition; neuroimmune", "note": "\u00a9 2021 Elsevier. \n\nReceived 21 January 2021, Revised 17 May 2021, Accepted 12 July 2021, Available online 5 August 2021. \n\nWe thank members of the Hsiao laboratory for their critical review of the manuscript; Dr. Alcino Silva for helpful advice regarding behavioral testing; Drs. Thomas O'Dell and Walter Babiec for critical training and advice on hippocampal electrophysiology; Irina Zhuravka of the UCLA Behavioral Testing Core for behavioral assay training; Dr. Matteo Pellegrini (UCLA) for helpful advice regarding analysis of RNA sequencing data; Drs. Suzanne Devkota and Connie Ha (Cedars, Sinai) for generously supplying Bilophila wadsworthia; Dr. Said Bogatryev for assistance with experiments for digital PCR and serum IFNg measurements; and Dr. Timothy O'Sullivan for allowing usage of his Attune NxT flow cytometer. This work was supported by funds from an NIH Ruth L. Kirschstein National Research Service Award (#F31 AG064844) and UCLA Dissertation Year Fellowship to C.A.O., Weston Family Foundation Fellowship to P.F., the Ruth L. Kirschstein National Research Service Award (#F31 HD101270) to G.N.P., the Ruth L. Kirschstein National Research Service Award (#F31 NS118966) to K.G.J., and Army Research Office Multidisciplinary University Research Initiative (W911NF-17-1-0402 to E.Y.H. and R.F.I.). E.Y.H. is a New York Stem Cell Foundation \u2013 Robertson investigator. This research was supported in part by the New York Stem Cell Foundation. This project has been made possible in part by grant number 2018-191860 from the Chan Zuckerberg Initiative DAF, an advised fund of Silicon Valley Community Foundation. \n\nAuthor contributions. C.A.O., A.J.I., G.E.Y., P.F., G.N.P., K.G.J, and J.T.B.performed the experiments and analyzed the data. C.A.O., A.J.I., R.F.I., and E.Y.H. designed the study. C.A.O. and E.Y.H wrote the manuscript. All authors discussed the results and commented on the manuscript. \n\nThe authors declare no competing interests. \n\nInclusion and diversity. We worked to ensure sex balance in the selection of non-human subjects. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. \n\nData and code availability. 16S rRNA gene sequencing data and metadata are available through QIITA repository (https://qiita.ucsd.edu/) with the study accession # 13510. Hippocampal transcriptomic data are available on through Gene Expression Omnibus repository (https://www.ncbi.nlm.nih.gov/geo/) with the identification number # GSE163099.\n\nSupplemental Material - 1-s2.0-S1931312821003371-mmc1.pdf
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", "abstract": "Many genetic and environmental factors increase susceptibility to cognitive impairment (CI), and the gut microbiome is increasingly implicated. However, the identity of gut microbes associated with CI risk, their effects on CI, and their mechanisms remain unclear. Here, we show that a carbohydrate-restricted (ketogenic) diet potentiates CI induced by intermittent hypoxia in mice and alters the gut microbiota. Depleting the microbiome reduces CI, whereas transplantation of the risk-associated microbiome or monocolonization with Bilophila wadsworthia confers CI in mice fed a standard diet. B. wadsworthia and the risk-associated microbiome disrupt hippocampal synaptic plasticity, neurogenesis, and gene expression. The CI is associated with microbiome-dependent increases in intestinal interferon-gamma (IFNg)-producing Th1 cells. Inhibiting Th1 cell development abrogates the adverse effects of both B. wadsworthia and environmental risk factors on CI. Together, these findings identify select gut bacteria that contribute to environmental risk for CI in mice by promoting inflammation and hippocampal dysfunction.", "date": "2021-09-08", "date_type": "published", "publication": "Cell Host and Microbe", "volume": "29", "number": "9", "publisher": "Cell Press", "pagerange": "1378-1392", "id_number": "CaltechAUTHORS:20210908-171123816", "issn": "1931-3128", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210908-171123816", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH Postdoctoral Fellowship", "grant_number": "F31 AG064844" }, { "agency": "UCLA" }, { "agency": "Weston Family Foundation" }, { "agency": "NIH Postdoctoral Fellowship", "grant_number": "F31 HD101270" }, { "agency": "NIH Postdoctoral Fellowship", "grant_number": "F31 NS118966" }, { "agency": "Army Research Office (ARO)", "grant_number": "W911NF-17-1-0402" }, { "agency": "New York Stem Cell Foundation" }, { "agency": "Chan-Zuckerberg Initiative", "grant_number": "2018-191860" } ] }, "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1016/j.chom.2021.07.004", "pmcid": "PMC8429275", "primary_object": { "basename": "1-s2.0-S1931312821003371-mmc1.pdf", "url": "https://authors.library.caltech.edu/records/en9tt-2np72/files/1-s2.0-S1931312821003371-mmc1.pdf" }, "related_objects": [ { "basename": "1-s2.0-S1931312821003371-mmc2.xlsx", "url": "https://authors.library.caltech.edu/records/en9tt-2np72/files/1-s2.0-S1931312821003371-mmc2.xlsx" }, { "basename": "1-s2.0-S1931312821003371-mmc3.xlsx", "url": "https://authors.library.caltech.edu/records/en9tt-2np72/files/1-s2.0-S1931312821003371-mmc3.xlsx" }, { "basename": "1-s2.0-S1931312821003371-mmc4.xlsx", "url": "https://authors.library.caltech.edu/records/en9tt-2np72/files/1-s2.0-S1931312821003371-mmc4.xlsx" }, { "basename": "1-s2.0-S1931312821003371-mmc5.xlsx", "url": "https://authors.library.caltech.edu/records/en9tt-2np72/files/1-s2.0-S1931312821003371-mmc5.xlsx" } ], "resource_type": "article", "pub_year": "2021", "author_list": "Olson, Christine A.; I\u00f1iguez, Alonso J.; et el." }, { "id": "https://authors.library.caltech.edu/records/3mzpv-c6728", "eprint_id": 109729, "eprint_status": "archive", "datestamp": "2023-08-22 10:33:48", "lastmod": "2023-12-22 23:35:13", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Wu-Wei-Li", "name": { "family": "Wu", "given": "Wei-Li" }, "orcid": "0000-0003-2610-1881" }, { "id": "Adame-Mark-D", "name": { "family": "Adame", "given": "Mark D." } }, { "id": "Liou-Chia-Wei", "name": { "family": "Liou", "given": "Chia-Wei" }, "orcid": "0000-0002-9003-4065" }, { "id": "Barlow-Jacob-T", "name": { "family": "Barlow", "given": "Jacob T." }, "orcid": "0000-0002-1842-4835" }, { "id": "Lai-Tzu-Ting", "name": { "family": "Lai", "given": "Tzu-Ting" } }, { "id": "Sharon-Gil", "name": { "family": "Sharon", "given": "Gil" }, "orcid": "0000-0002-4605-9943" }, { "id": "Schretter-Catherine-E", "name": { "family": "Schretter", "given": "Catherine E." }, "orcid": "0000-0002-3957-6838" }, { "id": "Needham-Brittany-D", "name": { "family": "Needham", "given": "Brittany D." }, "orcid": "0000-0002-0280-1886" }, { "id": "Wang-Madelyn-I", "name": { "family": "Wang", "given": "Madelyn I." }, "orcid": "0000-0001-7576-1179" }, { "id": "Tang-Weiyi", "name": { "family": "Tang", "given": "Weiyi" }, "orcid": "0000-0002-1279-1001" }, { "id": "Ousey-James", "name": { "family": "Ousey", "given": "James" }, "orcid": "0000-0003-4886-0053" }, { "id": "Lin-Yuan-Yuan", "name": { "family": "Lin", "given": "Yuan-Yuan" } }, { "id": "Yao-Tzu-Hsuan", "name": { "family": "Yao", "given": "Tzu-Hsuan" } }, { "id": "Abdel-Haq-Reem", "name": { "family": "Abdel-Haq", "given": "Reem" }, "orcid": "0000-0002-7418-5736" }, { "id": "Beadle-Keith", "name": { "family": "Beadle", "given": "Keith" }, "orcid": "0000-0002-5695-6461" }, { "id": "Gradinaru-V", "name": { "family": "Gradinaru", "given": "Viviana" }, "orcid": "0000-0001-5868-348X" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Mazmanian-S-K", "name": { "family": "Mazmanian", "given": "Sarkis K." }, "orcid": "0000-0003-2713-1513" } ] }, "title": "Microbiota regulate social behaviour via stress response neurons in the brain", "ispublished": "pub", "full_text_status": "public", "keywords": "Microbial communities; Emotion", "note": "\u00a9 The Author(s), under exclusive licence to Springer Nature Limited 2021. \n\nReceived 05 January 2019; Accepted 25 May 2021; Published 30 June 2021. \n\nWe thank H.-N. Huang for support and planning in the initial staged of this study; H. Chu, J. Boktor, members of the Mazmanian laboratory and B. E. Deverman for critically reviewing the manuscript; Y. Garcia-Flores for administrative assistance; T. M. Thron, OLAR at Caltech, and LAC at NCKU for animal husbandry; D. J. Anderson and L. C. Hsieh-Wilson for stereotaxic instruments; L.-C. Lo and H. Huang for technical assistance; and J.-W. Chen for biological materials. M. Costa-Mattioli, M. Sgritta and K. Imanbayev provided advice on vagotomy. The BIF at Caltech provided use of confocal microscopes. The CLOVER Center at Caltech provided viral vectors. This work was supported by funds from the Ministry of Science and Technology in Taiwan (MOST 107-2320-B-006-072-MY3; 108-2321-B-006-025-MY2; 109-2314-B-006-046), the Higher Education Sprout Project, Ministry of Education to the Headquarters of University Advancement (NCKU) to W.-L.W.; an NIH Biotechnology Leadership Pre-doctoral Training Program (BLP) Fellowship (T32GM112592) to J.T.B.; the National Science Foundation Graduate Research Fellowship Program (NSF GRFP No. DGE-1745301) to J.O.; a grant from the Jacobs Institute for Molecular Engineering for Medicine (Caltech), the Kenneth Rainin Foundation Innovator Award (2018-1207) to R.F.I.; and Lynda and Blaine Fetter, Charlie Trimble, the Heritage Medical Research Institute, and the NIH (MH100556) to S.K.M. \n\nData availability: All data generated and analysed during this study are included in this published article and its Supplementary Information files. Raw data for 16S rRNA gene sequencing and data analysis have been deposited in the ENA database under BioProject PRJNA632893. Source data are provided with this paper. \n\nAuthor Contributions: W.-L.W., M.D.A., C.-W.L., J.T.B., T.-T.L., G.S., C.E.S., M.I.W., W.T., J.O., Y.-Y.L., T.-H.Y. and R.A.-H. performed the experiments and/or analysed data. J.T.B., G.S., B.D.N. and R.F.I. provided consultations regarding microbiome analysis. K.B. and V.G. provided novel viral vectors. W.-L.W. and S.K.M. designed the research. S.K.M. supervised the research. W.-L.W. and S.K.M. integrated the data, interpreted the results, and wrote the manuscript. All authors discussed the results and commented on the manuscript. \n\nCompeting interests: W-L.W., M.D.A., B.D.N., and S.K.M. have filed a provisional patent on this work. All other authors declare no competing interests. \n\nPeer review information: Nature thanks Ioana Carcea and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.\n\nAccepted Version - nihms-1723165.pdf
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", "abstract": "Social interactions among animals mediate essential behaviours, including mating, nurturing, and defence. The gut microbiota contribute to social activity in mice, but the gut\u2013brain connections that regulate this complex behaviour and its underlying neural basis are unclear. Here we show that the microbiome modulates neuronal activity in specific brain regions of male mice to regulate canonical stress responses and social behaviours. Social deviation in germ-free and antibiotic-treated mice is associated with elevated levels of the stress hormone corticosterone, which is primarily produced by activation of the hypothalamus\u2013pituitary\u2013adrenal (HPA) axis. Adrenalectomy, antagonism of glucocorticoid receptors, or pharmacological inhibition of corticosterone synthesis effectively corrects social deficits following microbiome depletion. Genetic ablation of glucocorticoid receptors in specific brain regions or chemogenetic inactivation of neurons in the paraventricular nucleus of the hypothalamus that produce corticotrophin-releasing hormone (CRH) reverse social impairments in antibiotic-treated mice. Conversely, specific activation of CRH-expressing neurons in the paraventricular nucleus induces social deficits in mice with a normal microbiome. Via microbiome profiling and in vivo selection, we identify a bacterial species, Enterococcus faecalis, that promotes social activity and reduces corticosterone levels in mice following social stress. These studies suggest that specific gut bacteria can restrain the activation of the HPA axis, and show that the microbiome can affect social behaviours through discrete neuronal circuits that mediate stress responses in the brain.", "date": "2021-07-15", "date_type": "published", "publication": "Nature", "volume": "595", "number": "7867", "publisher": "Nature Publishing Group", "pagerange": "409-414", "id_number": "CaltechAUTHORS:20210706-202344110", "issn": "0028-0836", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210706-202344110", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Ministry of Science and Technology (Taipei)", "grant_number": "107-2320-B-006-072-MY3" }, { "agency": "Ministry of Science and Technology (Taipei)", "grant_number": "108-2321-B-006-025-MY2" }, { "agency": "Ministry of Science and Technology (Taipei)", "grant_number": "109-2314-B-006-046" }, { "agency": "Ministry of Education (China)" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "T32GM112592" }, { "agency": "NSF Graduate Research Fellowship", "grant_number": "DGE-1745301" }, { "agency": "Jacobs Institute for Molecular Engineering for Medicine" }, { "agency": "Kenneth Rainin Foundation", "grant_number": "2018-1207" }, { "agency": "Lynda and Blaine Fetter" }, { "agency": "Charlie Trimble" }, { "agency": "Heritage Medical Research Institute" }, { "agency": "NIH", "grant_number": "MH100556" } ] }, "local_group": { "items": [ { "id": "Heritage-Medical-Research-Institute" }, { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" }, { "id": "Tianqiao-and-Chrissy-Chen-Institute-for-Neuroscience" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1038/s41586-021-03669-y", "pmcid": "PMC8346519", "primary_object": { "basename": "41586_2021_3669_Fig7_ESM.webp", "url": 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"basename": "41586_2021_3669_MOESM3_ESM.mov", "url": "https://authors.library.caltech.edu/records/3mzpv-c6728/files/41586_2021_3669_MOESM3_ESM.mov" }, { "basename": "41586_2021_3669_MOESM6_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/3mzpv-c6728/files/41586_2021_3669_MOESM6_ESM.xlsx" }, { "basename": "41586_2021_3669_MOESM7_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/3mzpv-c6728/files/41586_2021_3669_MOESM7_ESM.xlsx" }, { "basename": "41586_2021_3669_Fig12_ESM.webp", "url": "https://authors.library.caltech.edu/records/3mzpv-c6728/files/41586_2021_3669_Fig12_ESM.webp" } ], "resource_type": "article", "pub_year": "2021", "author_list": "Wu, Wei-Li; Adame, Mark D.; et el." }, { "id": "https://authors.library.caltech.edu/records/74gj8-w4649", "eprint_id": 104959, "eprint_status": "archive", "datestamp": "2023-08-19 22:56:13", "lastmod": "2023-12-22 23:45:10", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Khazaei-Tahmineh", "name": { "family": "Khazaei", "given": "Tahmineh" }, "orcid": "0000-0002-4743-2383" }, { "id": "Williams-Rory-L", "name": { "family": "Williams", "given": "Rory L." }, "orcid": "0000-0003-2605-5790" }, { "id": "Bogatyrev-Said-R", "name": { "family": "Bogatyrev", "given": "Said R." }, "orcid": "0000-0003-0486-9451" }, { "id": "Doyle-J-C", "name": { "family": "Doyle", "given": "John C." }, "orcid": "0000-0002-1828-2486" }, { "id": "Henry-Christopher-S", "name": { "family": "Henry", "given": "Christopher S." }, "orcid": "0000-0001-8058-9123" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Metabolic multistability and hysteresis in a model aerobe-anaerobe microbiome community", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). \n\nSubmitted 30 October 2019; Accepted 26 June 2020; Published 12 August 2020. \n\nWe thank J. Nielsen (Chalmers University of Technology), R. Murray (Caltech), J. Leadbetter (Caltech), and E. Hsiao (UCLA) for helpful discussions. We thank R. Poceviciute (Caltech) for imaging samples, K. Winzey (Caltech) for performing dPCR analysis of samples, and N. Shelby for contributions to writing and editing this manuscript. \n\nThis work was supported, in part, by Army Research Office (ARO) MURI contract no. W911NF-17-1-0402, NSF Emerging Frontiers in Research and Innovation (EFRI) grant 1137089A, NSERC fellowship PGSD3-438474-2013 (to T.K.), and the Center for Environmental Microbial Interactions (CEMI). This work was also supported by the Millard and Muriel Jacobs Genetics and Genomics Laboratory at Caltech, and we thank director I. Antoshechkin for assistance. \n\nAuthor contributions: T.K., S.R.B., J.C.D., C.S.H., and R.F.I. conceptualized the study. T.K. and C.S.H. contributed to the computational investigation. T.K., R.L.W., and R.F.I. contributed to the experimental investigation. T.K. wrote the manuscript, and all authors contributed to the final submission of the manuscript. See the Supplementary Materials for detailed contribution statements. \n\nThe authors declare that they have no competing interests. \n\nData and materials availability: All associated raw sequencing data have been deposited in the Sequence Read Archive (Bio-Project Accession Number PRJNA580293). All other data are publicly available at CaltechDATA, https://data.caltech.edu/records/1382.\n\nPublished - eaba0353.full.pdf
Supplemental Material - aba0353_SM.pdf
", "abstract": "Major changes in the microbiome are associated with health and disease. Some microbiome states persist despite seemingly unfavorable conditions, such as the proliferation of aerobe-anaerobe communities in oxygen-exposed environments in wound infections or small intestinal bacterial overgrowth. Mechanisms underlying transitions into and persistence of these states remain unclear. Using two microbial taxa relevant to the human microbiome, we combine genome-scale mathematical modeling, bioreactor experiments, transcriptomics, and dynamical systems theory to show that multistability and hysteresis (MSH) is a mechanism describing the shift from an aerobe-dominated state to a resilient, paradoxically persistent aerobe-anaerobe state. We examine the impact of changing oxygen and nutrient regimes and identify changes in metabolism and gene expression that lead to MSH and associated multi-stable states. In such systems, conceptual causation-correlation connections break and MSH must be used for analysis. Using MSH to analyze microbiome dynamics will improve our conceptual understanding of stability of microbiome states and transitions between states.", "date": "2020-08-12", "date_type": "published", "publication": "Science Advances", "volume": "6", "number": "33", "publisher": "American Association for the Advancement of Science", "pagerange": "Art. No. eaba0353", "id_number": "CaltechAUTHORS:20200813-144241318", "issn": "2375-2548", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200813-144241318", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Army Research Office (ARO)", "grant_number": "W911NF-17-1-0402" }, { "agency": "NSF", "grant_number": "EFMA-1137089A" }, { "agency": "Natural Sciences and Engineering Research Council of Canada (NSERC)", "grant_number": "PGSD3-438474-2013" }, { "agency": "Caltech Center for Environmental Microbial Interactions (CEMI)" }, { "agency": "Millard and Muriel Jacobs Genetics and Genomics Laboratory" } ] }, "local_group": { "items": [ { "id": "Millard-and-Muriel-Jacobs-Genetics-and-Genomics-Laboratory" }, { "id": "Caltech-Center-for-Environmental-Microbial-Interactions-(CEMI)" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1126/sciadv.aba0353", "pmcid": "PMC7423363", "primary_object": { "basename": "aba0353_SM.pdf", "url": "https://authors.library.caltech.edu/records/74gj8-w4649/files/aba0353_SM.pdf" }, "related_objects": [ { "basename": "eaba0353.full.pdf", "url": "https://authors.library.caltech.edu/records/74gj8-w4649/files/eaba0353.full.pdf" } ], "resource_type": "article", "pub_year": "2020", "author_list": "Khazaei, Tahmineh; Williams, Rory L.; et el." }, { "id": "https://authors.library.caltech.edu/records/6famx-f0654", "eprint_id": 101678, "eprint_status": "archive", "datestamp": "2023-08-19 21:30:45", "lastmod": "2023-12-22 23:33:07", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Barlow-Jacob-T", "name": { "family": "Barlow", "given": "Jacob T." }, "orcid": "0000-0002-1842-4835" }, { "id": "Bogatyrev-Said-R", "name": { "family": "Bogatyrev", "given": "Said R." }, "orcid": "0000-0003-0486-9451" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "A Quantitative Sequencing Framework for Absolute Abundance Measurements of Mucosal and Lumenal Microbial Communities", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. \n\nReceived 15 March 2020; Accepted 20 April 2020; Published 22 May 2020. \n\nThis work was supported in part by the Kenneth Rainin Foundation (2018\u20131207), the Army Research Office (ARO) Multidisciplinary University Research Initiative (MURI #W911NF-17-1-0402), and a National Institutes of Health Biotechnology Leadership Pre-doctoral Training Program (BLP) fellowship from Caltech's Donna and Benjamin M. Rosen Bioengineering Center (T32GM112592, to J.T.B.). We thank Elaine Hsiao and Christine Olson for helpful discussions and input on the experimental design and diets; we thank the Caltech Bioinformatics Resource Center for assistance with statistical analyses; we acknowledge the Caltech animal facility for experimental resources; we thank the Caltech Office of Laboratory Animal Resources and the veterinary technicians at Caltech for technical support; and Natasha Shelby for contributions to writing and editing this manuscript. \n\nData availability: The complete sequencing data generated during this study are available in the National Center for Biotechnology Information Sequence Read Archive repository under study accession number PRJNA575097. Raw data for all figures are provided as Source data file. \n\nAuthor Contributions: J.T.B. validated limits of digital PCR assay with mock microbial communities in germ-free tissues; designed, performed, and analyzed experiments to validate accuracy of quantitative sequencing with dPCR anchoring; established the quantitative limits of an individual taxon's absolute abundance; conducted the ketogenic animal study; analyzed all data; created all figures; and wrote the paper. S.R.B. co-developed the idea of quantitative sequencing with dPCR anchoring for absolute quantification of total microbial loads and taxa absolute abundances in lumenal and mucosal samples; contributed the method for quantitative sequencing with dPCR anchoring in lumenal and mucosal samples; contributed ideas and provided support for animal study design; contributed ideas for data-analysis and representation. R.F.I. contributed to study design and manuscript preparation. \n\nThe authors declare no competing interests.\n\nPublished - s41467-020-16224-6.pdf
Submitted - 2020.02.28.970087v1.full.pdf
Supplemental Material - 41467_2020_16224_MOESM1_ESM.pdf
Supplemental Material - 41467_2020_16224_MOESM2_ESM.pdf
Supplemental Material - 41467_2020_16224_MOESM3_ESM.zip
Erratum - s41467-020-17055-1.pdf
", "abstract": "A fundamental goal in microbiome studies is determining which microbes affect host physiology. Standard methods for determining changes in microbial taxa measure relative, rather than absolute abundances. Moreover, studies often analyze only stool, despite microbial diversity differing substantially among gastrointestinal (GI) locations. Here, we develop a quantitative framework to measure absolute abundances of individual bacterial taxa by combining the precision of digital PCR with the high-throughput nature of 16S rRNA gene amplicon sequencing. In a murine ketogenic-diet study, we compare microbial loads in lumenal and mucosal samples along the GI tract. Quantitative measurements of absolute (but not relative) abundances reveal decreases in total microbial loads on the ketogenic diet and enable us to determine the differential effects of diet on each taxon in stool and small-intestine mucosa samples. This rigorous quantitative microbial analysis framework, appropriate for diverse GI locations enables mapping microbial biogeography of the mammalian GI tract and more accurate analyses of changes in microbial taxa in microbiome studies.", "date": "2020-05-22", "date_type": "published", "publication": "Nature Communications", "volume": "11", "publisher": "Nature Publishing Group", "pagerange": "Art. No. 2590", "id_number": "CaltechAUTHORS:20200303-103834329", "issn": "2041-1723", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200303-103834329", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Kenneth Rainin Foundation", "grant_number": "2018-1207" }, { "agency": "Army Research Office (ARO)", "grant_number": "W911NF-17-1-0402" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "T32GM112592" } ] }, "local_group": { "items": [ { "id": "Rosen-Bioengineering-Center" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1038/s41467-020-16224-6", "pmcid": "PMC7244552", "primary_object": { "basename": "41467_2020_16224_MOESM1_ESM.pdf", "url": "https://authors.library.caltech.edu/records/6famx-f0654/files/41467_2020_16224_MOESM1_ESM.pdf" }, "related_objects": [ { "basename": "41467_2020_16224_MOESM2_ESM.pdf", "url": "https://authors.library.caltech.edu/records/6famx-f0654/files/41467_2020_16224_MOESM2_ESM.pdf" }, { "basename": "41467_2020_16224_MOESM3_ESM.zip", "url": "https://authors.library.caltech.edu/records/6famx-f0654/files/41467_2020_16224_MOESM3_ESM.zip" }, { "basename": "s41467-020-16224-6.pdf", "url": "https://authors.library.caltech.edu/records/6famx-f0654/files/s41467-020-16224-6.pdf" }, { "basename": "s41467-020-17055-1.pdf", "url": "https://authors.library.caltech.edu/records/6famx-f0654/files/s41467-020-17055-1.pdf" }, { "basename": "2020.02.28.970087v1.full.pdf", "url": "https://authors.library.caltech.edu/records/6famx-f0654/files/2020.02.28.970087v1.full.pdf" } ], "resource_type": "article", "pub_year": "2020", "author_list": "Barlow, Jacob T.; Bogatyrev, Said R.; et el." }, { "id": "https://authors.library.caltech.edu/records/hh1ak-4sk21", "eprint_id": 101382, "eprint_status": "archive", "datestamp": "2023-08-22 04:57:23", "lastmod": "2023-12-22 23:10:31", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Yu-Ziqing", "name": { "family": "Yu", "given": "Ziqing" } }, { "id": "Lyu-Weiyuan", "name": { "family": "Lyu", "given": "Weiyuan" } }, { "id": "Yu-Mengchao", "name": { "family": "Yu", "given": "Mengchao" }, "orcid": "0000-0002-2535-429X" }, { "id": "Wang-Qian", "name": { "family": "Wang", "given": "Qian" } }, { "id": "Qu-Haijun", "name": { "family": "Qu", "given": "Haijun" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Han-Xu", "name": { "family": "Han", "given": "Xu" } }, { "id": "Lai-Dongmei", "name": { "family": "Lai", "given": "Dongmei" }, "orcid": "0000-0003-3810-2136" }, { "id": "Shen-Feng", "name": { "family": "Shen", "given": "Feng" }, "orcid": "0000-0002-4709-330X" } ] }, "title": "Self-partitioning SlipChip for slip-induced droplet formation and human papillomavirus viral load quantification with digital LAMP", "ispublished": "pub", "full_text_status": "public", "keywords": "Lab on a chip; Digital PCR; Droplet; Point-of-care; Microfluidics", "note": "\u00a9 2020 Published by Elsevier B.V. \n\nReceived 23 October 2019, Revised 5 February 2020, Accepted 17 February 2020, Available online 18 February 2020. \n\nWe thank Dr. Rebecca R. Pompano and Ms. Jing Ling for editing the manuscript. This work is supported by the National Natural Science Foundation of China (no. 21705109), the Innovation Research Plan supported by Shanghai Municipal Education Commission (no. ZXWF082101), the Natural Science Foundation of Shanghai (no. 19ZR1475900), the interdisciplinary program of Shanghai Jiao Tong University (no. YG2015ZD11), and supported by Shanghai Jiao Tong University Scientific and Technological Innovation Funds. \n\nZ. Y., W. L., M. Y., and Q. W. contributed equally. \n\nCRediT authorship contribution statement\nZiqing Yu: Formal analysis, Writing - original draft. Weiyuan Lyu: Writing - original draft. Mengchao Yu: Formal analysis, Writing - original draft. Qian Wang: Writing - original draft. Haijun Qu: Formal analysis, Writing - original draft. Rustem F. Ismagilov: Conceptualization, Writing - original draft. Xu Han: Writing - original draft. Dongmei Lai: Writing - original draft. Feng Shen: Conceptualization, Writing - original draft. \n\nThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\n\nSupplemental Material - 1-s2.0-S0956566320301044-mmc1.docx
", "abstract": "Human papillomavirus (HPV) is one of the most common sexually transmitted infections worldwide, and persistent HPV infection can cause warts and even cancer. Nucleic acid analysis of HPV viral DNA can be very informative for the diagnosis and monitoring of HPV. Digital nucleic acid analysis, such as digital PCR and digital isothermal amplification, can provide sensitive detection and precise quantification of target nucleic acids, and its utility has been demonstrated in many biological research and medical diagnostic applications. A variety of methods have been developed for the generation of a large number of individual reaction partitions, a key requirement for digital nucleic acid analysis. However, an easily assembled and operated device for robust droplet formation without preprocessing devices, auxiliary instrumentation or control systems is still highly desired. In this paper, we present a self-partitioning SlipChip (sp-SlipChip) microfluidic device for the slip-induced generation of droplets to perform digital loop-mediated isothermal amplification (LAMP) for the detection and quantification of HPV DNA. In contrast to traditional SlipChip methods, which require the precise alignment of microfeatures, this sp-SlipChip utilized a design of \"chain-of-pearls\" continuous microfluidic channel that is independent of the overlapping of microfeatures on different plates to establish the fluidic path for reagent loading. Initiated by a simple slipping step, the aqueous solution can robustly self-partition into individual droplets by capillary pressure-driven flow. This advantage makes the sp-SlipChip very appealing for the point-of-care quantitative analysis of viral load. As a proof of concept, we performed digital LAMP on an sp-SlipChip to quantify human papillomaviruses (HPVs) 16 and 18 and tested this method with fifteen anonymous clinical samples.", "date": "2020-05-01", "date_type": "published", "publication": "Biosensors and Bioelectronics", "volume": "155", "publisher": "Elsevier", "pagerange": "Art. No. 112107", "id_number": "CaltechAUTHORS:20200219-114918172", "issn": "0956-5663", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200219-114918172", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "National Natural Science Foundation of China", "grant_number": "21705109" }, { "agency": "Shanghai Municipal Education Commission", "grant_number": "ZXWF082101" }, { "agency": "Natural Science Foundation of Shanghai", "grant_number": "19ZR1475900" }, { "agency": "Shanghai Jiao Tong University", "grant_number": "YG2015ZD11" } ] }, "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1016/j.bios.2020.112107", "primary_object": { "basename": "1-s2.0-S0956566320301044-mmc1.docx", "url": "https://authors.library.caltech.edu/records/hh1ak-4sk21/files/1-s2.0-S0956566320301044-mmc1.docx" }, "resource_type": "article", "pub_year": "2020", "author_list": "Yu, Ziqing; Lyu, Weiyuan; et el." }, { "id": "https://authors.library.caltech.edu/records/e8d7z-m7780", "eprint_id": 101668, "eprint_status": "archive", "datestamp": "2023-08-19 21:00:27", "lastmod": "2023-12-22 23:38:00", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Rolando-Justin-C", "name": { "family": "Rolando", "given": "Justin C." }, "orcid": "0000-0001-8948-319X" }, { "id": "Jue-Erik", "name": { "family": "Jue", "given": "Erik" }, "orcid": "0000-0001-7585-3794" }, { "id": "Barlow-Jacob-T", "name": { "family": "Barlow", "given": "Jacob T." }, "orcid": "0000-0002-1842-4835" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Real-time kinetics and high-resolution melt curves in single-molecule digital LAMP to differentiate and study specific and non-specific amplification", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2020 The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. \n\nReceived October 04, 2019; Revised January 08, 2020; Editorial Decision February 04, 2020; Accepted February 06, 2020. Published: 27 February 2020. \n\nData Availability: The complete sequencing data generated during this study are available in the National Center for Biotechnology Information Sequence Read Archive repository with the BioProject ID: PRJNA574638. \n\nThe MATLAB script described here has been deposited in the open-access online repository GitHub and may be accessed using the following direct link: https://github.com/IsmagilovLab/Digital_NAAT_2Ch_MeltCurve_Analyzer. \n\nThis project benefited from the use of instrumentation at the Jim Hall Design and Prototyping Lab and the Millard and Muriel Jacobs Genetics and Genomics Laboratory. We thank Daan Witters and Pedro Ojeda for initial selection of CT primers, Eric Liaw for helpful discussions of error propagation and Natasha Shelby for help with writing and editing this manuscript. \n\nFunding: Defense Threat Reduction Agency (DTRA) Award [MCDC-18-01-01-007, W15QKN-16-9-1002]; Burroughs Wellcome Fund Innovation in Regulatory Science Award; National Institutes of Health Biotechnology Leadership Pre-doctoral Training Program (BLP) Fellowship [T32GM112592 to J.T.B.]; National Science Foundation Graduate Research Fellowships [DGE-1144469 to E.J.]; and the Joseph J. Jacobs Institute for Molecular Engineering for Medicine (Caltech). Funding for open access charge: DTRA [W15QKN-16-9-1002]. \n\nConflict of interest statement. The content of this manuscript is the subject of a patent application filed by Caltech.\n\nPublished - gkaa099.pdf
Supplemental Material - gkaa099_supplemental_files.zip
", "abstract": "Isothermal amplification assays, such as loop-mediated isothermal amplification (LAMP), show great utility for the development of rapid diagnostics for infectious diseases because they have high sensitivity, pathogen-specificity and potential for implementation at the point of care. However, elimination of non-specific amplification remains a key challenge for the optimization of LAMP assays. Here, using chlamydia DNA as a clinically relevant target and high-throughput sequencing as an analytical tool, we investigate a potential mechanism of non-specific amplification. We then develop a real-time digital LAMP (dLAMP) with high-resolution melting temperature (HRM) analysis and use this single-molecule approach to analyze approximately 1.2 million amplification events. We show that single-molecule HRM provides insight into specific and non-specific amplification in LAMP that are difficult to deduce from bulk measurements. We use real-time dLAMP with HRM to evaluate differences between polymerase enzymes, the impact of assay parameters (e.g. time, rate or florescence intensity), and the effect background human DNA. By differentiating true and false positives, HRM enables determination of the optimal assay and analysis parameters that leads to the lowest limit of detection (LOD) in a digital isothermal amplification assay.", "date": "2020-04-17", "date_type": "published", "publication": "Nucleic Acids Research", "volume": "48", "number": "7", "publisher": "Oxford University Press", "pagerange": "Art. No. e42", "id_number": "CaltechAUTHORS:20200302-155937790", "issn": "0305-1048", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200302-155937790", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Defense Threat Reduction Agency (DTRA)", "grant_number": "MCDC-18-01-01-007" }, { "agency": "Defense Threat Reduction Agency (DTRA)", "grant_number": "W15QKN-16-9-1002" }, { "agency": "Burroughs Wellcome Fund" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "T32GM112592" }, { "agency": "NSF Graduate Research Fellowship", "grant_number": "DGE-1144469" }, { "agency": "Jacobs Institute for Molecular Engineering for Medicine" } ] }, "local_group": { "items": [ { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1093/nar/gkaa099", "pmcid": "PMC7144905", "primary_object": { "basename": "gkaa099.pdf", "url": "https://authors.library.caltech.edu/records/e8d7z-m7780/files/gkaa099.pdf" }, "related_objects": [ { "basename": "gkaa099_supplemental_files.zip", "url": "https://authors.library.caltech.edu/records/e8d7z-m7780/files/gkaa099_supplemental_files.zip" } ], "resource_type": "article", "pub_year": "2020", "author_list": "Rolando, Justin C.; Jue, Erik; et el." }, { "id": "https://authors.library.caltech.edu/records/zn887-tf656", "eprint_id": 102007, "eprint_status": "archive", "datestamp": "2023-08-19 20:36:38", "lastmod": "2023-12-22 23:37:49", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Schoepp-Nathan-G", "name": { "family": "Schoepp", "given": "Nathan G." }, "orcid": "0000-0002-2406-3693" }, { "id": "Liaw-Eric-J", "name": { "family": "Liaw", "given": "Eric J." }, "orcid": "0000-0003-2244-8335" }, { "id": "Winnett-A", "name": { "family": "Winnett", "given": "Alexander" }, "orcid": "0000-0002-7338-5605" }, { "id": "Savela-Emily-S", "name": { "family": "Savela", "given": "Emily S." }, "orcid": "0000-0001-9614-4276" }, { "id": "Garner-Omai-B", "name": { "family": "Garner", "given": "Omai B." }, "orcid": "0000-0002-7366-2692" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Differential DNA accessibility to polymerase enables 30-minute phenotypic \u03b2-lactam antibiotic susceptibility testing of carbapenem-resistant Enterobacteriaceae", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2020 Schoepp et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. \n\nReceived: July 3, 2019; Accepted: February 14, 2020; Published: March 19, 2020. \n\nWe thank Sukantha Chandrasekaran, Shelley Miller, Romney Humphries, Marisol Trejo, Catherine Le, and Lyna Chheang at the UCLA Clinical Microbiology Laboratory for providing isolates and clinical urine samples and for discussion of gold-standard practices. We thank Jennifer Dien Bard at the Keck School of Medicine of USC for performing Cepheid Xpert Carba-R tests. We also thank Natasha Shelby for help with writing and editing this manuscript. \n\nData Availability Statement: The authors declare that all the data supporting these findings are available within the article and its Supporting Information. \n\nThis work was funded in part by the Defense Threat Reduction Agency (DTRA) award MCDC-18-01-01-007; an effort sponsored by the U.S. Government under Other Transaction number W15QKN-16-9-1002 between the MCDC, and the Government. The U.S. Government is authorized to reproduce and distribute reprints for Governmental purposes notwithstanding any copyright notation thereon. The views and conclusions contained herein are those of the authors and should not be interpreted as necessarily representing the official policies or endorsements, either expressed or implied, of the U.S. Government. This work was also supported by a Burroughs Wellcome Fund Innovation in Regulatory Science Award, an NIH National Research Service Award (NRSA) [5T32GM07616NSF] (to N.G.S.), NIH NIGMS Predoctoral Training Grants (GM008042) to A.W. and E.J.L., a grant from the Joseph J. Jacobs Institute for Molecular Engineering for Medicine, and a fellowship (to E.S.S.) from Joan and Jerry Doren. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. \n\nCompeting interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: The technology described in this publication is the subject of a patent application filed by Caltech. R.F.I. has a financial interest in Talis Biomedical Corp. \n\nAuthor Contributions:\nConceptualization: Nathan G. Schoepp, Eric J. Liaw, Emily S. Savela, Rustem F. Ismagilov.\nData curation: Nathan G. Schoepp.\nFormal analysis: Nathan G. Schoepp, Alexander Winnett, Emily S. Savela.\nFunding acquisition: Nathan G. Schoepp, Alexander Winnett, Rustem F. Ismagilov.\nInvestigation: Nathan G. Schoepp, Eric J. Liaw, Alexander Winnett.\nMethodology: Nathan G. Schoepp, Eric J. Liaw, Alexander Winnett, Emily S. Savela, Rustem\nF. Ismagilov.\nProject administration: Rustem F. Ismagilov.\nResources: Omai B. Garner, Rustem F. Ismagilov.\nSupervision: Rustem F. Ismagilov.\nValidation: Nathan G. Schoepp, Alexander Winnett.\nVisualization: Nathan G. Schoepp.\nWriting \u2013 original draft: Nathan G. Schoepp, Eric J. Liaw.\nWriting \u2013 review & editing: Nathan G. Schoepp, Alexander Winnett, Emily S. Savela, Omai\nB. Garner, Rustem F. Ismagilov.\n\nPublished - journal.pbio.3000652.pdf
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", "abstract": "The rise in carbapenem-resistant Enterobacteriaceae (CRE) infections has created a global health emergency, underlining the critical need to develop faster diagnostics to treat swiftly and correctly. Although rapid pathogen-identification (ID) tests are being developed, gold-standard antibiotic susceptibility testing (AST) remains unacceptably slow (1\u20132 d), and innovative approaches for rapid phenotypic ASTs for CREs are urgently needed. Motivated by this need, in this manuscript we tested the hypothesis that upon treatment with \u03b2-lactam antibiotics, susceptible Enterobacteriaceae isolates would become sufficiently permeabilized, making some of their DNA accessible to added polymerase and primers. Further, we hypothesized that this accessible DNA would be detectable directly by isothermal amplification methods that do not fully lyse bacterial cells. We build on these results to develop the polymerase-accessibility AST (pol-aAST), a new phenotypic approach for \u03b2-lactams, the major antibiotic class for gram-negative infections. We test isolates of the 3 causative pathogens of CRE infections using ceftriaxone (CRO), ertapenem (ETP), and meropenem (MEM) and demonstrate agreement with gold-standard AST. Importantly, pol-aAST correctly categorized resistant isolates that are undetectable by current genotypic methods (negative for \u03b2-lactamase genes or lacking predictive genotypes). We also test contrived and clinical urine samples. We show that the pol-aAST can be performed in 30 min sample-to-answer using contrived urine samples and has the potential to be performed directly on clinical urine specimens.", "date": "2020-03-19", "date_type": "published", "publication": "PLoS Biology", "volume": "18", "number": "3", "publisher": "Public Library of Science", "pagerange": "Art. No. 3000652", "id_number": "CaltechAUTHORS:20200320-065850359", "issn": "1545-7885", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200320-065850359", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Defense Threat Reduction Agency (DTRA)", "grant_number": "MCDC-18-01-01-007" }, { "agency": "Defense Threat Reduction Agency (DTRA)", "grant_number": "W15QKN-16-9-1002" }, { "agency": "Burroughs Wellcome Fund" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "5T32GM07616NSF" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "GM008042" }, { "agency": "Joseph J. Jacobs Institute for Molecular Engineering for Medicine" }, { "agency": "Joan and Jerry Doren" } ] }, "local_group": { "items": [ { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1371/journal.pbio.3000652", "pmcid": "PMC7081982", "primary_object": { "basename": "journal.pbio.3000652.pdf", "url": "https://authors.library.caltech.edu/records/zn887-tf656/files/journal.pbio.3000652.pdf" }, "related_objects": [ { "basename": "journal.pbio.3000652.s001.xlsx", "url": "https://authors.library.caltech.edu/records/zn887-tf656/files/journal.pbio.3000652.s001.xlsx" }, { "basename": "journal.pbio.3000652.s002.xlsx", "url": "https://authors.library.caltech.edu/records/zn887-tf656/files/journal.pbio.3000652.s002.xlsx" }, { "basename": "journal.pbio.3000652.s004.xlsx", "url": "https://authors.library.caltech.edu/records/zn887-tf656/files/journal.pbio.3000652.s004.xlsx" }, { "basename": "journal.pbio.3000652.s005.csv", "url": "https://authors.library.caltech.edu/records/zn887-tf656/files/journal.pbio.3000652.s005.csv" }, { "basename": "journal.pbio.3000652.s008.pdf", "url": "https://authors.library.caltech.edu/records/zn887-tf656/files/journal.pbio.3000652.s008.pdf" }, { "basename": "journal.pbio.3000652.s003.xlsx", "url": "https://authors.library.caltech.edu/records/zn887-tf656/files/journal.pbio.3000652.s003.xlsx" }, { "basename": "journal.pbio.3000652.s006.xlsx", "url": "https://authors.library.caltech.edu/records/zn887-tf656/files/journal.pbio.3000652.s006.xlsx" }, { "basename": "journal.pbio.3000652.s007.tif", "url": "https://authors.library.caltech.edu/records/zn887-tf656/files/journal.pbio.3000652.s007.tif" } ], "resource_type": "article", "pub_year": "2020", "author_list": "Schoepp, Nathan G.; Liaw, Eric J.; et el." }, { "id": "https://authors.library.caltech.edu/records/fhhh2-xg437", "eprint_id": 102004, "eprint_status": "archive", "datestamp": "2023-08-19 20:36:21", "lastmod": "2023-12-22 23:37:46", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Savela-E-S", "name": { "family": "Savela", "given": "Emily S." }, "orcid": "0000-0001-9614-4276" }, { "id": "Schoepp-N-G", "name": { "family": "Schoepp", "given": "Nathan G." }, "orcid": "0000-0002-2406-3693" }, { "id": "Cooper-M-M", "name": { "family": "Cooper", "given": "Matthew M." }, "orcid": "0000-0002-5868-5159" }, { "id": "Rolando-J-C", "name": { "family": "Rolando", "given": "Justin C." }, "orcid": "0000-0001-8948-319X" }, { "id": "Klausner-J-D", "name": { "family": "Klausner", "given": "Jeffrey D." }, "orcid": "0000-0002-6922-7364" }, { "id": "Soge-O-O", "name": { "family": "Soge", "given": "Olusegun O." }, "orcid": "0000-0002-8504-2319" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Surfactant-enhanced DNA accessibility to nuclease accelerates phenotypic \u03b2-lactam antibiotic susceptibility testing of Neisseria gonorrhoeae", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2020 Savela et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. \n\nReceived: June 29, 2019; Accepted: February 14, 2020; Published: March 19, 2020.\n\nWe thank Adam Sukhija-Cohen, Sherrelle Banks, Matt Santos, and Yancy Granados at the AIDS Healthcare Foundation for their technical assistance with the clinical study and patient enrollment. We thank Peera Hemarajata at the UCLA Clinical Microbiology Laboratory for providing isolates and for discussion of gold-standard practices. We also thank Natasha Shelby for help with writing and editing this manuscript. \n\nData Availability Statement: The authors declare that all the data supporting these findings are available within the article and its supplemental files. \n\nThis work was funded in part by the Department of Health and Human Services (HHS) Office of the Assistant Secretary for Preparedness and Response (ASPR) and the Wellcome Trust under the CARB-X program (federal award number IDSEP160030-02); the content is solely the responsibility of the authors and does not necessarily represent the official views of the Department of HHS Office of the ASPR. This CARB-X project is a collaboration between Talis Biomedical Corp. and Caltech. This work was also supported by a Burroughs Wellcome Fund Innovation in Regulatory Science Award (1014981), an NIH National Research Service Award (NRSA) [5T32GM07616NSF] (to NGS), a grant from the Joseph J. Jacobs Institute for Molecular Engineering for Medicine, and a fellowship (to ESS) from Joan and Jerry Doren. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. \n\nCompeting interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: The technology described in this publication is the subject of a patent application filed by Caltech. RFI has a financial interest in Talis Biomedical Corp. Caltech is a sub-awardee to Talis Biomedical Corp. on the CARB-X grant that partially funded this work. \n\nWe thank Adam Sukhija-Cohen, Sherrelle Banks, Matt Santos, and Yancy Granados at the AIDS Healthcare Foundation for their technical assistance with the clinical study and patient enrollment. We thank Peera Hemarajata at the UCLA Clinical Microbiology Laboratory for providing isolates and for discussion of gold-standard practices. We also thank Natasha Shelby for help with writing and editing this manuscript. \n\nAuthor Contributions:\nConceptualization: Emily S. Savela, Nathan G. Schoepp, Rustem F. Ismagilov.\nData curation: Emily S. Savela, Nathan G. Schoepp, Justin C. Rolando.\nFormal analysis: Emily S. Savela, Nathan G. Schoepp, Matthew M. Cooper, Justin C. Rolando.\nFunding acquisition: Nathan G. Schoepp, Rustem F. Ismagilov.\nInvestigation: Emily S. Savela, Nathan G. Schoepp, Matthew M. Cooper.\nMethodology: Emily S. Savela, Nathan G. Schoepp.\nProject administration: Rustem F. Ismagilov.\nResources: Jeffrey D. Klausner, Olusegun O. Soge, Rustem F. Ismagilov.\nSupervision: Rustem F. Ismagilov\nValidation: Emily S. Savela, Nathan G. Schoepp, Matthew M. Cooper.\nVisualization: Emily S. Savela, Nathan G. Schoepp.\nWriting \u2013 original draft: Emily S. Savela, Nathan G. Schoepp.\nWriting \u2013 review & editing: Emily S. Savela, Nathan G. Schoepp, Matthew M. Cooper, Jeffrey\nD. Klausner, Olusegun O. Soge, Rustem F. Ismagilov.\n\nPublished - journal.pbio.3000651.pdf
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", "abstract": "Rapid antibiotic susceptibility testing (AST) for Neisseria gonorrhoeae (Ng) is critically needed to counter widespread antibiotic resistance. Detection of nucleic acids in genotypic AST can be rapid, but it has not been successful for \u03b2-lactams (the largest antibiotic class used to treat Ng). Rapid phenotypic AST for Ng is challenged by the pathogen's slow doubling time and the lack of methods to quickly quantify the pathogen's response to \u03b2-lactams. Here, we asked two questions: (1) Is it possible to use nucleic acid quantification to measure the \u03b2-lactam susceptibility phenotype of Ng very rapidly, using antibiotic-exposure times much shorter than the 1- to 2-h doubling time of Ng? (2) Would such short-term antibiotic exposures predict the antibiotic resistance profile of Ng measured by plate growth assays over multiple days? To answer these questions, we devised an innovative approach for performing a rapid phenotypic AST that measures DNA accessibility to exogenous nucleases after exposure to \u03b2-lactams (termed nuclease-accessibility AST [nuc-aAST]). We showed that DNA in antibiotic-susceptible cells has increased accessibility upon exposure to \u03b2-lactams and that a judiciously chosen surfactant permeabilized the outer membrane and enhanced this effect. We tested penicillin, cefixime, and ceftriaxone and found good agreement between the results of the nuc-aAST after 15\u201330 min of antibiotic exposure and the results of the gold-standard culture-based AST measured over days. These results provide a new pathway toward developing a critically needed phenotypic AST for Ng and additional global-health threats.", "date": "2020-03-19", "date_type": "published", "publication": "PLoS Biology", "volume": "18", "number": "3", "publisher": "Public Library of Science", "pagerange": "Art. No. 3000651", "id_number": "CaltechAUTHORS:20200319-141031875", "issn": "1545-7885", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200319-141031875", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Department of Health and Human Services" }, { "agency": "Wellcome Trust", "grant_number": "IDSEP160030-02" }, { "agency": "Burroughs Wellcome Fund", "grant_number": "1014981" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "5T32GM07616NSF" }, { "agency": "Joseph J. Jacobs Institute for Molecular Engineering for Medicine" }, { "agency": "Joan and Jerry Doren" } ] }, "local_group": { "items": [ { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1371/journal.pbio.3000651", "pmcid": "PMC7081974", "primary_object": { "basename": "journal.pbio.3000651.s010.xlsx", "url": "https://authors.library.caltech.edu/records/fhhh2-xg437/files/journal.pbio.3000651.s010.xlsx" }, "related_objects": [ { "basename": "journal.pbio.3000651.s016.xlsx", "url": "https://authors.library.caltech.edu/records/fhhh2-xg437/files/journal.pbio.3000651.s016.xlsx" }, { "basename": "journal.pbio.3000651.s001.tif", "url": "https://authors.library.caltech.edu/records/fhhh2-xg437/files/journal.pbio.3000651.s001.tif" }, { "basename": "journal.pbio.3000651.s002.tif", "url": "https://authors.library.caltech.edu/records/fhhh2-xg437/files/journal.pbio.3000651.s002.tif" }, { "basename": "journal.pbio.3000651.s004.tif", "url": "https://authors.library.caltech.edu/records/fhhh2-xg437/files/journal.pbio.3000651.s004.tif" }, { "basename": "journal.pbio.3000651.s007.xlsx", "url": "https://authors.library.caltech.edu/records/fhhh2-xg437/files/journal.pbio.3000651.s007.xlsx" }, { "basename": "journal.pbio.3000651.s009.xlsx", "url": "https://authors.library.caltech.edu/records/fhhh2-xg437/files/journal.pbio.3000651.s009.xlsx" }, { "basename": "journal.pbio.3000651.s021.xlsx", "url": "https://authors.library.caltech.edu/records/fhhh2-xg437/files/journal.pbio.3000651.s021.xlsx" }, { "basename": "journal.pbio.3000651.s011.xlsx", "url": "https://authors.library.caltech.edu/records/fhhh2-xg437/files/journal.pbio.3000651.s011.xlsx" }, { "basename": "journal.pbio.3000651.s012.xlsx", "url": "https://authors.library.caltech.edu/records/fhhh2-xg437/files/journal.pbio.3000651.s012.xlsx" }, { "basename": "journal.pbio.3000651.s017.pdf", "url": "https://authors.library.caltech.edu/records/fhhh2-xg437/files/journal.pbio.3000651.s017.pdf" }, { "basename": "journal.pbio.3000651.s018.xlsx", "url": "https://authors.library.caltech.edu/records/fhhh2-xg437/files/journal.pbio.3000651.s018.xlsx" }, { "basename": "journal.pbio.3000651.s020.xlsx", "url": "https://authors.library.caltech.edu/records/fhhh2-xg437/files/journal.pbio.3000651.s020.xlsx" }, { "basename": "journal.pbio.3000651.s003.tif", "url": "https://authors.library.caltech.edu/records/fhhh2-xg437/files/journal.pbio.3000651.s003.tif" }, { "basename": "journal.pbio.3000651.s014.xlsx", "url": "https://authors.library.caltech.edu/records/fhhh2-xg437/files/journal.pbio.3000651.s014.xlsx" }, { "basename": "journal.pbio.3000651.s015.xlsx", "url": "https://authors.library.caltech.edu/records/fhhh2-xg437/files/journal.pbio.3000651.s015.xlsx" }, { "basename": "journal.pbio.3000651.s019.xlsx", "url": "https://authors.library.caltech.edu/records/fhhh2-xg437/files/journal.pbio.3000651.s019.xlsx" }, { "basename": "journal.pbio.3000651.pdf", "url": "https://authors.library.caltech.edu/records/fhhh2-xg437/files/journal.pbio.3000651.pdf" }, { "basename": "journal.pbio.3000651.s005.xlsx", "url": "https://authors.library.caltech.edu/records/fhhh2-xg437/files/journal.pbio.3000651.s005.xlsx" }, { "basename": "journal.pbio.3000651.s006.xlsx", "url": "https://authors.library.caltech.edu/records/fhhh2-xg437/files/journal.pbio.3000651.s006.xlsx" }, { "basename": "journal.pbio.3000651.s008.xlsx", "url": "https://authors.library.caltech.edu/records/fhhh2-xg437/files/journal.pbio.3000651.s008.xlsx" }, { "basename": "journal.pbio.3000651.s013.xlsx", "url": "https://authors.library.caltech.edu/records/fhhh2-xg437/files/journal.pbio.3000651.s013.xlsx" } ], "resource_type": "article", "pub_year": "2020", "author_list": "Savela, Emily S.; Schoepp, Nathan G.; et el." }, { "id": "https://authors.library.caltech.edu/records/ahsp6-e8a25", "eprint_id": 101255, "eprint_status": "archive", "datestamp": "2023-08-19 19:57:26", "lastmod": "2023-12-22 23:37:51", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Bogatyrev-S-R", "name": { "family": "Bogatyrev", "given": "Said R." }, "orcid": "0000-0003-0486-9451" }, { "id": "Rolando-J-C", "name": { "family": "Rolando", "given": "Justin C." }, "orcid": "0000-0001-8948-319X" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Self-reinoculation with fecal flora changes microbiota density and composition leading to an altered bile-acid profile in the mouse small intestine", "ispublished": "pub", "full_text_status": "public", "keywords": "Microbial quantification, Metabolomics analyses, Mouse models, Small intestine microbiota, Bile acids, Deconjugation, Coprophagy, Microbial colonization, 16S rRNA gene amplicon sequencing", "note": "\u00a9 2020 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. \n\nReceived: 26 September 2019; Accepted: 5 January 2020; Published online: 12 February 2020. \n\nWe thank Karen Lencioni, Janet Baer, the Caltech Office of Laboratory Animal Resources, veterinary technicians at the Church Animal Facility for experimental resources. We thank Liang Ma for the introduction to 16S rRNA gene amplicon sequencing, Heidi Klumpe for her assistance with the preliminary MPN experiments, and Justin Bois for the introduction to data analysis in Python. S.R.B. would like to thank Kimberly Zhou for the personal feedback on the project and inspiration. This project benefited from the use of instrumentation made available by the Caltech Environmental Analysis Center and technical support from Nathan Dalleska. We thank Natasha Shelby for contributions to writing and editing this manuscript. \n\nAvailability of data and materials: The datasets supporting the conclusions of this article are included within the article and its additional files. Sequencing data (paired end reads in FASTQ) and a manifest file for analysis in Qiime2 are available under a CC-BY license via CaltechDATA: https://doi.org/10.22002/D1.1295. Supplementary Information includes a zip file containing all sequencing sample metadata, numerical microbial quantification data (16S copies from the main study + MPN from the pilot study), Qiime2 sequencing output data, PICRUSt2 output data, numerical bile acid analysis data, numerical body weight data, numerical food intake data, and analytical scripts (iPython Notebooks) for all figures and statistical analyses in the manuscript. \n\nThis work was supported in part by a Kenneth Rainin Foundation Innovator Award (2018\u20131207), Army Research Office (ARO) Multidisciplinary University Research Initiative (MURI) contract #W911NF-17-1-0402, and the Jacobs Institute for Molecular Engineering for Medicine. National Science Foundation (NSF) Emerging Frontiers in Research and Innovation Award Grant 1137089. The funders had no role in the design of the study, collection, analysis or interpretation of data, nor in the writing of the manuscript. \n\nAuthor Contributions: SRB Conception, mouse tail cup development, animal study execution, animal study sample processing for quantitative 16S rRNA gene amplicon sequencing, quantitative 16S rRNA gene amplicon sequencing and data analysis, animal study sample processing for metabolomic analysis, bile acid metabolomics data analysis, manuscript preparation. JCR Metabolomics method development and validation, animal study sample processing for metabolomic analysis, UPLC-MS instrument setup and sample analysis, chromatography and mass spectra data analysis. RFI Project supervision and administration, acquisition of funding, manuscript review and editing. All authors read and approved the final manuscript. \n\nEthics approval and consent to participate: All animal handling and procedures were performed in accordance with the California Institute of Technology (Caltech) Institutional Animal Care and Use Committee (IACUC). \n\nConsent for publication: Not applicable. \n\nCompeting interests: The contents of this article are the subject of a patent application filed by Caltech.\n\nPublished - document.pdf
Supplemental Material - 40168_2020_785_MOESM1_ESM.zip
", "abstract": "Background: The upper gastrointestinal tract plays a prominent role in human physiology as the primary site for enzymatic digestion and nutrient absorption, immune sampling, and drug uptake. Alterations to the small intestine microbiome have been implicated in various human diseases, such as non-alcoholic steatohepatitis and inflammatory bowel conditions. Yet, the physiological and functional roles of the small intestine microbiota in humans remain poorly characterized because of the complexities associated with its sampling. Rodent models are used extensively in microbiome research and enable the spatial, temporal, compositional, and functional interrogation of the gastrointestinal microbiota and its effects on the host physiology and disease phenotype. Classical, culture-based studies have documented that fecal microbial self-reinoculation (via coprophagy) affects the composition and abundance of microbes in the murine proximal gastrointestinal tract. This pervasive self-reinoculation behavior could be a particularly relevant study factor when investigating small intestine microbiota. Modern microbiome studies either do not take self-reinoculation into account, or assume that approaches such as single housing mice or housing on wire mesh floors eliminate it. These assumptions have not been rigorously tested with modern tools. Here, we used quantitative 16S rRNA gene amplicon sequencing, quantitative microbial functional gene content inference, and metabolomic analyses of bile acids to evaluate the effects of self-reinoculation on microbial loads, composition, and function in the murine upper gastrointestinal tract. \n\nResults: In coprophagic mice, continuous self-exposure to the fecal flora had substantial quantitative and qualitative effects on the upper gastrointestinal microbiome. These differences in microbial abundance and community composition were associated with an altered profile of the small intestine bile acid pool, and, importantly, could not be inferred from analyzing large intestine or stool samples. Overall, the patterns observed in the small intestine of non-coprophagic mice (reduced total microbial load, low abundance of anaerobic microbiota, and bile acids predominantly in the conjugated form) resemble those typically seen in the human small intestine. \n\nConclusions: Future studies need to take self-reinoculation into account when using mouse models to evaluate gastrointestinal microbial colonization and function in relation to xenobiotic transformation and pharmacokinetics or in the context of physiological states and diseases linked to small intestine microbiome and to small intestine dysbiosis.", "date": "2020-02-12", "date_type": "published", "publication": "Microbiome", "volume": "8", "publisher": "BioMed Central", "pagerange": "Art. No. 19", "id_number": "CaltechAUTHORS:20200212-152816065", "issn": "2049-2618", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200212-152816065", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Kenneth Rainin Foundation", "grant_number": "2018-1207" }, { "agency": "Army Research Office (ARO)", "grant_number": "W911NF-17-1-0402" }, { "agency": "Jacobs Institute for Molecular Engineering for Medicine" }, { "agency": "NSF", "grant_number": "EFMA-1137089" } ] }, "local_group": { "items": [ { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1186/s40168-020-0785-4", "pmcid": "PMC7017497", "primary_object": { "basename": "40168_2020_785_MOESM1_ESM.zip", "url": "https://authors.library.caltech.edu/records/ahsp6-e8a25/files/40168_2020_785_MOESM1_ESM.zip" }, "related_objects": [ { "basename": "document.pdf", "url": "https://authors.library.caltech.edu/records/ahsp6-e8a25/files/document.pdf" } ], "resource_type": "article", "pub_year": "2020", "author_list": "Bogatyrev, Said R.; Rolando, Justin C.; et el." }, { "id": "https://authors.library.caltech.edu/records/gjzvx-agj04", "eprint_id": 101169, "eprint_status": "archive", "datestamp": "2023-08-19 19:53:37", "lastmod": "2023-12-22 23:37:58", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Jue-Erik", "name": { "family": "Jue", "given": "Erik" }, "orcid": "0000-0001-7585-3794" }, { "id": "Witter-Dann", "name": { "family": "Witters", "given": "Daan" }, "orcid": "0000-0003-2179-5300" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Two-phase wash to solve the ubiquitous contaminant-carryover problem in commercial nucleic-acid extraction kits", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. \n\nReceived 24 October 2019. Accepted 2 January 2020. Published 6 February 2020. \n\nThis work was supported in part by the Defense Threat Reduction Agency (DTRA) award MCDC-18-01-01-007, an effort sponsored by the U.S. Government under Other Transaction number W15QKN-16-9-1002 between the MCDC, and the Government. The U.S. Government is authorized to reproduce and distribute reprints for Governmental purposes notwithstanding any copyright notation thereon. The views and conclusions contained herein are those of the authors and should not be interpreted as necessarily representing the official policies or endorsements, either expressed or implied, of the U.S. Government. This work was also supported by a Burroughs Wellcome Fund Innovation in Regulatory Science Award, a National Science Foundation Graduate Research Fellowship DGE-1144469 (to E.J.), an NIH National Research Service Award (NRSA) [5T32GM07616NSF] (to E.J.), a grant from the Rothenberg Innovation Initiative (RI2) and a grant from the Joseph J. Jacobs Institute for Molecular Engineering for Medicine. We thank Kevin Winzey for running the buffer-dilution experiments for Figure 2, Nathan Schoepp for optimized reaction conditions for LAMP, E. coli extractions and E. coli primers, Pedro Ojeda for running exploratory experiments with ethanol and octanol spiked into LAMP, Andrew Friedman for running exploratory experiments with octanol and 1-undecanol TPW extractions, and Natasha Shelby for contributions to writing and editing this manuscript. \n\nAuthor Contributions: E.J. Acquired funding. Planned and analyzed buffer dilution experiments for Figure 2. Planned, ran, and analyzed all remaining experiments. Generated all figures, and wrote the manuscript. D.W. Ran preliminary experiments evaluating the use of TPW to reduce buffer carryover. R.F.I. Supervised the project, acquired funding, helped to analyze the data, and reviewed and edited the manuscript. \n\nFull dataset available through CaltechDATA, https://doi.org/10.22002/D1.1298; https://data.caltech.edu/records/1298.\n\nCompeting interests: The content of this manuscript is the subject of a patent application filed by Caltech. R.F.I. has a financial interest in Talis Biomedical Corp.; all other authors have no conflict of interest.\n\nPublished - s41598-020-58586-3.pdf
Supplemental Material - 41598_2020_58586_MOESM1_ESM.pdf
", "abstract": "The success of fundamental and applied nucleic acid (NA) research depends on NA purity, but obtaining pure NAs from raw, unprocessed samples is challenging. Purification using solid-phase NA extractions utilizes sequential additions of lysis and wash buffers followed by elution. The resulting eluent contains NAs and carryover of extraction buffers. Typically, these inhibitory buffers are heavily diluted by the reaction mix (e.g., 10x dilution is 1\u2009\u00b5L eluent in 9\u2009\u00b5L reaction mix), but in applications requiring high sensitivity (e.g., single-cell sequencing, pathogen diagnostics) it is desirable to use low dilutions (e.g., 2x) to maximize NA concentration. Here, we demonstrate pervasive carryover of inhibitory buffers into eluent when several commercial sample-preparation kits are used following manufacturer protocols. At low eluent dilution (2\u20132.5x) we observed significant reaction inhibition of polymerase chain reaction (PCR), loop-mediated isothermal amplification (LAMP), and reverse transcription (RT). We developed a two-phase wash (TPW) method by adding a wash buffer with low water solubility prior to the elution step. The TPW reduces carryover of extraction buffers, phase-separates from the eluent, and does not reduce NA yield (measured by digital PCR). We validated the TPW for silica columns and magnetic beads by demonstrating significant improvements in performance and reproducibility of qPCR, LAMP, and RT reactions.", "date": "2020-02-06", "date_type": "published", "publication": "Scientific Reports", "volume": "10", "publisher": "Nature Publishing Group", "pagerange": "Art. No. 1940", "id_number": "CaltechAUTHORS:20200206-125057522", "issn": "2045-2322", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200206-125057522", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Defense Threat Reduction Agency (DTRA)", "grant_number": "MCDC-18-01-01-007" }, { "agency": "Defense Threat Reduction Agency (DTRA)", "grant_number": "W15QKN-16-9-1002" }, { "agency": "Burroughs Wellcome Fund" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "5T32GM07616NSF" }, { "agency": "Rothenberg Innovation Initiative (RI2)" }, { "agency": "NSF Graduate Research Fellowship", "grant_number": "DGE-1144469" }, { "agency": "Jacobs Institute for Molecular Engineering for Medicine" } ] }, "local_group": { "items": [ { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1038/s41598-020-58586-3", "pmcid": "PMC7004994", "primary_object": { "basename": "41598_2020_58586_MOESM1_ESM.pdf", "url": "https://authors.library.caltech.edu/records/gjzvx-agj04/files/41598_2020_58586_MOESM1_ESM.pdf" }, "related_objects": [ { "basename": "s41598-020-58586-3.pdf", "url": "https://authors.library.caltech.edu/records/gjzvx-agj04/files/s41598-020-58586-3.pdf" } ], "resource_type": "article", "pub_year": "2020", "author_list": "Jue, Erik; Witters, Daan; et el." }, { "id": "https://authors.library.caltech.edu/records/91xgk-csy72", "eprint_id": 98147, "eprint_status": "archive", "datestamp": "2023-08-19 18:13:38", "lastmod": "2023-10-18 17:05:33", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Zhukov-D-V", "name": { "family": "Zhukov", "given": "Dmitriy V." }, "orcid": "0000-0002-4834-3147" }, { "id": "Khorosheva-E-M", "name": { "family": "Khorosheva", "given": "Eugenia M." }, "orcid": "0000-0003-3620-4884" }, { "id": "Khazaei-Tahmineh", "name": { "family": "Khazaei", "given": "Tahmineh" }, "orcid": "0000-0002-4743-2383" }, { "id": "Du-Wenbin", "name": { "family": "Du", "given": "Wenbin" }, "orcid": "0000-0002-7401-1410" }, { "id": "Selck-D-A", "name": { "family": "Selck", "given": "David A." } }, { "id": "Shishkin-A-A", "name": { "family": "Shishkin", "given": "Alexander A." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Microfluidic SlipChip device for multistep multiplexed biochemistry on a nanoliter scale", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2019 The Royal Society of Chemistry. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. \n\nThe article was received on 06 Jun 2019, accepted on 29 Jul 2019 and first published on 23 Aug 2019. \n\nData availability: Any data not in the ESI will be made available upon request to the corresponding author. \n\nConflicts of interest: This paper is the subject of a patent application filed by Caltech. R. F. I. has a financial interest in Talis Biomedical Corp. \n\nThis research was supported in part by a seed grant from the Donna & Benjamin M. Rosen Bioengineering Center (Caltech), an NSF Graduate Research Fellowship [DGE-1144469] to D. V. Z., a Natural Sciences and Engineering Research Council of Canada (NSERC) fellowship [PGSD3-438474-2013] to T. K., an NIH Director's Pioneer Award [DP50D012190], an Achievement Rewards for College Scientists (ARCS) fellowship to D. A. S., and an NIH NRSA [5T32GM07616NSF] to D. A. S. We thank Andres Collazo at Caltech's Beckman Institute Biological Imaging Facility for imaging advice, and Igor Antoshechkin at Caltech's Millard and Muriel Jacobs Genetics and Genomics Laboratory for cDNA library sequencing. We also thank Mitchell Guttman for advice on total transcriptome sequencing, Mario Blanco and Jacob Barlow for helpful consultations on sequencing data processing, Erik B. Jue for helpful advice on 3D rendering of devices in CAD, and Natasha Shelby for contributions to writing and editing this manuscript.\n\nPublished - c9lc00541b.pdf
Supplemental Material - c9lc00541b2_si2.pdf
", "abstract": "We have developed a multistep microfluidic device that expands the current SlipChip capabilities by enabling multiple steps of droplet merging and multiplexing. Harnessing the interfacial energy between carrier and sample phases, this manually operated device accurately meters nanoliter volumes of reagents and transfers them into on-device reaction wells. Judiciously shaped microfeatures and surface-energy traps merge droplets in a parallel fashion. Wells can be tuned for different volumetric capacities and reagent types, including for pre-spotted reagents that allow for unique identification of original well contents even after their contents are pooled. We demonstrate the functionality of the multistep SlipChip by performing RNA transcript barcoding on-device for synthetic spiked-in standards and for biologically derived samples. This technology is a good candidate for a wide range of biological applications that require multiplexing of multistep reactions in nanoliter volumes, including single-cell analyses.", "date": "2019-10-07", "date_type": "published", "publication": "Lab on a Chip", "volume": "19", "number": "19", "publisher": "Royal Society of Chemistry", "pagerange": "3200-3211", "id_number": "CaltechAUTHORS:20190823-090755927", "issn": "1473-0197", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190823-090755927", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Donna and Benjamin M. Rosen Bioengineering Center" }, { "agency": "NSF Graduate Research Fellowship", "grant_number": "DGE-1144469" }, { "agency": "Natural Sciences and Engineering Research Council of Canada (NSERC)", "grant_number": "PGSD3-438474-2013" }, { "agency": "NIH", "grant_number": "DP50D012190" }, { "agency": "ARCS Foundation" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "5T32GM07616NSF" } ] }, "local_group": { "items": [ { "id": "Rosen-Bioengineering-Center" } ] }, "doi": "10.1039/c9lc00541b", "primary_object": { "basename": "c9lc00541b2_si2.pdf", "url": "https://authors.library.caltech.edu/records/91xgk-csy72/files/c9lc00541b2_si2.pdf" }, "related_objects": [ { "basename": "c9lc00541b.pdf", "url": "https://authors.library.caltech.edu/records/91xgk-csy72/files/c9lc00541b.pdf" } ], "resource_type": "article", "pub_year": "2019", "author_list": "Zhukov, Dmitriy V.; Khorosheva, Eugenia M.; et el." }, { "id": "https://authors.library.caltech.edu/records/j7xv9-9wj47", "eprint_id": 98146, "eprint_status": "archive", "datestamp": "2023-08-19 17:57:05", "lastmod": "2023-10-18 17:05:30", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Porter-M-K", "name": { "family": "Porter", "given": "Michael K." }, "orcid": "0000-0002-0777-7563" }, { "id": "Steinberg-A-P", "name": { "family": "Steinberg", "given": "Asher Preska" }, "orcid": "0000-0002-8694-7224" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Interplay of motility and polymer-driven depletion forces in the initial stages of bacterial aggregation", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2019 The Royal Society of Chemistry. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. \n\nThe article was received on 17 Apr 2019, accepted on 29 Jul 2019 and first published on 23 Aug 2019. \n\nConflicts of interest: The technology described in this publication is the subject of a patent application filed by Caltech. \n\nThis work was funded in part by the Army Research Office (ARO) Multidisciplinary University Research Initiative (MURI) contract #W911NF-17-1-0402, the Jacobs Institute for Molecular Engineering for Medicine, an NSF Graduate Research Fellowship DGE-144469 (to APS), and a Center for Environmental Microbial Interactions (CEMI) Caldwell Graduate Fellowship (to APS). We thank Andres Collazo and the Beckman Imaging Facility for help with imaging, and we thank Natasha Shelby for contributions to writing and editing this manuscript.\n\nPublished - c9sm00791a.pdf
Supplemental Material - c9sm00791a1_si.pdf
", "abstract": "Motile bacteria are often found in complex, polymer-rich environments in which microbes can aggregate via polymer-induced depletion forces. Bacterial aggregation has many biological implications; it can promote biofilm formation, upregulate virulence factors, and lead to quorum sensing. The steady state aggregation behavior of motile bacteria in polymer solutions has been well studied and shows that stronger depletion forces are required to aggregate motile bacteria as compared with their nonmotile analogs. However, no one has studied whether these same trends hold at the initial stages of aggregation. We use experiments and numerical calculations to investigate the polymer-induced depletion aggregation of motile Escherichia coli in polyethylene glycol solutions on short experimental timescales (\u223c10 min). Our work reveals that in the semi-dilute polymer concentration regime and at short timescales, in contrast to what is found at steady state, bacterial motility actually enhances aggregate formation by increasing the collision rate in viscous environments. These unexpected findings have implications for developing models of active matter, and for understanding bacterial aggregation in dynamic, biological environments, where the system may never reach steady state.", "date": "2019-09-21", "date_type": "published", "publication": "Soft Matter", "volume": "15", "number": "35", "publisher": "Royal Society of Chemistry", "pagerange": "7071-7079", "id_number": "CaltechAUTHORS:20190823-085722494", "issn": "1744-683X", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190823-085722494", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Army Research Office (ARO)", "grant_number": "W911NF-17-1-0402" }, { "agency": "Jacobs Institute for Molecular Engineering for Medicine" }, { "agency": "NSF Graduate Research Fellowship", "grant_number": "DGE-144469" }, { "agency": "Caltech Center for Environmental Microbial Interactions (CEMI)" } ] }, "local_group": { "items": [ { "id": "Caltech-Center-for-Environmental-Microbial-Interactions-(CEMI)" }, { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" } ] }, "doi": "10.1039/c9sm00791a", "primary_object": { "basename": "c9sm00791a1_si.pdf", "url": "https://authors.library.caltech.edu/records/j7xv9-9wj47/files/c9sm00791a1_si.pdf" }, "related_objects": [ { "basename": "c9sm00791a.pdf", "url": "https://authors.library.caltech.edu/records/j7xv9-9wj47/files/c9sm00791a.pdf" } ], "resource_type": "article", "pub_year": "2019", "author_list": "Porter, Michael K.; Steinberg, Asher Preska; et el." }, { "id": "https://authors.library.caltech.edu/records/bwz2h-8h679", "eprint_id": 95766, "eprint_status": "archive", "datestamp": "2023-08-19 16:47:38", "lastmod": "2023-10-20 20:32:59", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Yu-Mengchao", "name": { "family": "Yu", "given": "Mengchao" }, "orcid": "0000-0002-2535-429X" }, { "id": "Chen-Xiaoying", "name": { "family": "Chen", "given": "Xiaoying" } }, { "id": "Qu-Haijun", "name": { "family": "Qu", "given": "Haijun" } }, { "id": "Ma-Liang", "name": { "family": "Ma", "given": "Liang" } }, { "id": "Xu-Lei", "name": { "family": "Xu", "given": "Lei" } }, { "id": "Lv-Weiyuan", "name": { "family": "Lv", "given": "Weiyuan" } }, { "id": "Wang-Hua", "name": { "family": "Wang", "given": "Hua" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Li-Min", "name": { "family": "Li", "given": "Min" } }, { "id": "Shen-Feng", "name": { "family": "Shen", "given": "Feng" }, "orcid": "0000-0002-4709-330X" } ] }, "title": "Multistep SlipChip for the Generation of Serial Dilution Nanoliter Arrays and Hepatitis B Viral Load Quantification by Digital Loop Mediated Isothermal Amplification", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2019 American Chemical Society. \n\nReceived: March 11, 2019; Accepted: May 20, 2019. Publication Date: May 22, 2019. \n\nThis work is supported by the National Natural Science Foundation of China (Grant No. 21705109), the Innovation Research Plan supported by the Shanghai Municipal Education Commission (Grant No. ZXWF082101), and the Shanghai Jiao Tong University Fund (Grant No. WF220408214). \n\nThe authors declare no competing financial interest.\n\nSupplemental Material - ac9b01270_si_001.pdf
", "abstract": "Serial dilution is a commonly used technique that generates a low-concentration working sample from a high-concentration stock solution and is used to set up screening conditions over a large dynamic range for biological study, optimization of reaction conditions, drug screening, etc. Creating an array of serial dilutions usually requires cumbersome manual pipetting steps or a robotic liquid handling system. Moreover, it is very challenging to set up an array of serial dilutions in nanoliter volumes in miniaturized assays. Here, a multistep SlipChip microfluidic device is presented for generating serial dilution nanoliter arrays in high throughput with a series of simple sliding motions. The dilution ratio can be precisely predetermined by the volumes of mother microwells and daughter microwells, and this paper demonstrates devices designed to have dilution ratios of 1:1, 1:2, and 1:4. Furthermore, an eight-step serial dilution SlipChip with a dilution ratio of 1:4 is applied for digital loop-mediated isothermal amplification (LAMP) across a large dynamic range and tested for hepatitis B viral load quantification with clinical samples. With 64 wells of each dilution and fewer than 600 wells in total, the serial dilution SlipChip can achieve a theoretical quantification dynamic range of 7 orders of magnitude.", "date": "2019-07-16", "date_type": "published", "publication": "Analytical Chemistry", "volume": "91", "number": "14", "publisher": "American Chemical Society", "pagerange": "8751-8755", "id_number": "CaltechAUTHORS:20190523-142111730", "issn": "0003-2700", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190523-142111730", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "National Natural Science Foundation of China", "grant_number": "21705109" }, { "agency": "Shanghai Municipal Education Commission", "grant_number": "ZXWF082101" }, { "agency": "Shanghai Jiao Tong University", "grant_number": "WF220408214" } ] }, "doi": "10.1021/acs.analchem.9b01270", "primary_object": { "basename": "ac9b01270_si_001.pdf", "url": "https://authors.library.caltech.edu/records/bwz2h-8h679/files/ac9b01270_si_001.pdf" }, "resource_type": "article", "pub_year": "2019", "author_list": "Yu, Mengchao; Chen, Xiaoying; et el." }, { "id": "https://authors.library.caltech.edu/records/0hjjc-kj831", "eprint_id": 96519, "eprint_status": "archive", "datestamp": "2023-08-19 16:43:02", "lastmod": "2023-10-20 21:15:43", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Preska-Steinberg-A", "name": { "family": "Preska Steinberg", "given": "Asher" }, "orcid": "0000-0002-8694-7224" }, { "id": "Wang-Zhen-Gang", "name": { "family": "Wang", "given": "Zhen-Gang" }, "orcid": "0000-0002-3361-6114" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Food Polyelectrolytes Compress the Colonic Mucus Hydrogel by a Donnan Mechanism", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2019 American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. \n\nReceived: March 29, 2019; Revised: May 23, 2019; Published: June 19, 2019. \n\nThis work was supported in part by Army Research Office (ARO) Multidisciplinary University Research Initiative (MURI) contract no. W911NF-17-1-0402, the Jacobs Institute for Molecular Engineering for Medicine, the Center for Environmental Microbial Interactions (CEMI), an NSF Graduate Research Fellowship DGE-144469 (to A.P.S.), and a Caldwell CEMI Graduate Fellowship (to A.P.S.). We acknowledge Michael Porter for useful discussion and providing feedback on the manuscript; Andres Collazo and Caltech's Beckman Institute Biological Imaging Facility, the Caltech Office of Laboratory Animal Resources, and the Caltech veterinary technicians for technical support; Justin Rolando for providing microparticles; and Natasha Shelby for contributions to writing and editing this manuscript. \n\nAuthor Contributions: A.P.S. and R.F.I. designed the research; A.P.S. performed the research; A.P.S. analyzed the data. Z.-G.W. guided the theoretical analysis. All authors wrote the paper. \n\nThe authors declare the following competing financial interest(s): The technology described in this publication is the subject of a patent application filed by Caltech.\n\nPublished - acs.biomac.9b00442.pdf
Supplemental Material - bm9b00442_si_001.pdf
Supplemental Material - bm9b00442_si_002.zip
", "abstract": "Systems consisting of a polyelectrolyte solution in contact with a cross-linked polyelectrolyte network are ubiquitous (e.g., biofilms, drug-delivering hydrogels, and mammalian extracellular matrices), yet the underlying physics governing these interactions is not well understood. Here, we find that carboxymethyl cellulose, a polyelectrolyte commonly found in processed foods and associated with inflammation and obesity, compresses the colonic mucus hydrogel (a key regulator of host\u2013microbe interactions and a protective barrier) in mice. The extent of this polyelectrolyte-induced compression is enhanced by the degree of polymer negative charge. Through animal experiments and numerical calculations, we find that this phenomenon can be described by a Donnan mechanism. Further, the observed behavior can be quantitatively described by a simple, one-parameter model. This work suggests that polymer charge should be considered when developing food products because of its potential role in modulating the protective properties of colonic mucus.", "date": "2019-07-08", "date_type": "published", "publication": "Biomacromolecules", "volume": "20", "number": "7", "publisher": "American Chemical Society", "pagerange": "2675-2683", "id_number": "CaltechAUTHORS:20190619-091518942", "issn": "1525-7797", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190619-091518942", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Army Research Office (ARO)", "grant_number": "W911NF-17-1-0402" }, { "agency": "Jacobs Institute for Molecular Engineering for Medicine" }, { "agency": "Caltech Center for Environmental Microbial Interactions (CEMI)" }, { "agency": "NSF Graduate Research Fellowship", "grant_number": "DGE-144469" } ] }, "local_group": { "items": [ { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" }, { "id": "Caltech-Center-for-Environmental-Microbial-Interactions-(CEMI)" } ] }, "doi": "10.1021/acs.biomac.9b00442", "primary_object": { "basename": "bm9b00442_si_001.pdf", "url": "https://authors.library.caltech.edu/records/0hjjc-kj831/files/bm9b00442_si_001.pdf" }, "related_objects": [ { "basename": "bm9b00442_si_002.zip", "url": "https://authors.library.caltech.edu/records/0hjjc-kj831/files/bm9b00442_si_002.zip" }, { "basename": "acs.biomac.9b00442.pdf", "url": "https://authors.library.caltech.edu/records/0hjjc-kj831/files/acs.biomac.9b00442.pdf" } ], "resource_type": "article", "pub_year": "2019", "author_list": "Preska Steinberg, Asher; Wang, Zhen-Gang; et el." }, { "id": "https://authors.library.caltech.edu/records/xq49y-sfb72", "eprint_id": 100926, "eprint_status": "archive", "datestamp": "2023-08-19 16:39:49", "lastmod": "2023-10-19 22:15:14", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Savela-E", "name": { "family": "Savela", "given": "Emily" } }, { "id": "Schoepp-N-G", "name": { "family": "Schoepp", "given": "Nathan G." }, "orcid": "0000-0002-2406-3693" }, { "id": "Rolando-J-C", "name": { "family": "Rolando", "given": "Justin" }, "orcid": "0000-0001-8948-319X" }, { "id": "Soge-O", "name": { "family": "Soge", "given": "Olusegun" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem" }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Cell Envelope Damage of N. gonorrhoeae after 15-min Beta-Lactam Exposure Enables Rapid Antimicrobial Susceptibility Testing", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 2019 BMJ Publishing Group. \n\nDisclosure: No significant relationships.", "abstract": "Background: Designing diagnostic tools to perform phenotypic antimicrobial susceptibility testing (AST) at the point-of-care (POC) is a vital step in tackling the global threat of antimicrobial resistance. Gonorrhea infections with resistance to the first-line dual therapy have already emerged, highlighting the impending threat of untreatable gonorrhea. A rapid, phenotypic AST could enable evidence-based (instead of empirical) therapy and improve surveillance. The focus of this work is to develop innovative strategies to measure the phenotypic antimicrobial susceptibility of Neisseria gonorrhoeae clinical isolates after just 15\u201330 min of exposure with an antibiotic. We focused on the duration of the exposure step because it remains the bottleneck for phenotypic AST with fastidious and slow-growing microorganisms. \n\nMethods: We selected nucleic acid readout because our longterm goals include building fully integrated POC devices that determine the phenotypic response to antibiotic of a specific pathogen rapidly. We have been developing rapid phenotypic ASTs based on quantification of nucleic-acid concentrations in antibiotic-exposed samples. We describe a new phenotypic AST that does not depend on the speed of DNA replication and applies to beta-lactams penicillin, ceftriaxone, and cefixime acting on clinical isolates of N. gonorrhoeae very rapidly. \n\nResults: Our assay had 100% categorical agreement with the gold-standard agar dilution AST when N. gonorrhoeae isolates were incubated for 15-min with penicillin, and 100% categorical agreement when incubated for 30 min with ceftriaxone and cefixime, and steps can be performed within 35 min measured from contrived urine samples exposed to penicillin. \n\nConclusion: By designing techniques which allow us to rapidly determine the antibiotic phenotype, evidence-based prescription of antibiotics will become possible.", "date": "2019-07", "date_type": "published", "publication": "Sexually Transmitted Infections", "volume": "95", "number": "S1", "publisher": "BMJ Publishing Group", "pagerange": "A291", "id_number": "CaltechAUTHORS:20200127-080528197", "issn": "1368-4973", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200127-080528197", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1136/sextrans-2019-sti.729", "resource_type": "article", "pub_year": "2019", "author_list": "Savela, Emily; Schoepp, Nathan G.; et el." }, { "id": "https://authors.library.caltech.edu/records/k10ak-7tt92", "eprint_id": 97029, "eprint_status": "archive", "datestamp": "2023-08-22 01:56:43", "lastmod": "2023-10-20 21:51:13", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Poceviciute-R", "name": { "family": "Poceviciute", "given": "Roberta" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Human-gut-microbiome on a chip", "ispublished": "pub", "full_text_status": "restricted", "keywords": "Applied microbiology; Gastrointestinal models; Tissue engineering", "note": "\u00a9 2019 Springer Nature Publishing AG. \n\nPublished 05 July 2019.", "abstract": "A microfluidic chip incorporating oxygen gradients, a diverse human microbiota and patient-derived cells, mimics interactions between microorganisms and host tissue in the human gut.", "date": "2019-07", "date_type": "published", "publication": "Nature Biomedical Engineering", "volume": "3", "number": "7", "publisher": "Nature Publishing Group", "pagerange": "500-501", "id_number": "CaltechAUTHORS:20190710-125335706", "issn": "2157-846X", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190710-125335706", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1038/s41551-019-0425-0", "resource_type": "article", "pub_year": "2019", "author_list": "Poceviciute, Roberta and Ismagilov, Rustem F." }, { "id": "https://authors.library.caltech.edu/records/yvcat-rz898", "eprint_id": 91660, "eprint_status": "archive", "datestamp": "2023-08-19 13:58:30", "lastmod": "2023-10-20 22:06:02", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Preska-Steinberg-Asher", "name": { "family": "Preska Steinberg", "given": "Asher" }, "orcid": "0000-0002-8694-7224" }, { "id": "Datta-Sujit-S", "name": { "family": "Datta", "given": "Sujit S." }, "orcid": "0000-0003-2400-1561" }, { "id": "Naragon-Thomas-H", "name": { "family": "Naragon", "given": "Thomas" }, "orcid": "0000-0002-5373-4257" }, { "id": "Rolando-Justin-C", "name": { "family": "Rolando", "given": "Justin C." }, "orcid": "0000-0001-8948-319X" }, { "id": "Bogatyrev-Said-R", "name": { "family": "Bogatyrev", "given": "Said R." }, "orcid": "0000-0003-0486-9451" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "High-molecular-weight polymers from dietary fiber drive aggregation of particulates in the murine small intestine", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2019 Preska Steinberg et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. \n\nReceived: 24 July 2018; Accepted: 28 December 2018; Published: 22 January 2019. \n\nThis work was supported in part by DARPA Biological Robustness in Complex Settings (BRICS) contract HR0011-15-C-0093, Army Research Office (ARO) Multidisciplinary University Research Initiative (MURI) contract #W911NF-17-1-0402, the Jacobs Institute for Molecular Engineering for Medicine, and an NSF Graduate Research Fellowship DGE-144469 (to APS). We acknowledge Michael Porter, Joong Hwan Bahng, Jacob Barlow, Zhen-Gang Wang, Julia Kornfield, David Tirrell, Justin Bois, and Greg Donaldson for useful discussions; the Beckman Institute Biological Imaging Facility, the Broad Animal Facility, and the Church Animal Facility for experimental resources; Jennifer Costanza, Taren Thron, the Caltech Office of Laboratory Animal Resources, and the veterinary technicians at the California Institute of Technology for technical support; Joanne Lau for assistance with Western blot measurements; Emily Wyatt for assistance with zeta potential measurements; the Mazmanian laboratory for providing Rag1KO mice; the Eugene Chang Lab (University of Chicago) for providing the initial breeding pairs for the MUC2KO colony and Leonard H Augenlicht at the Department of Oncology of Albert Einstein Cancer Center for providing the original MUC2KO line to them; and Natasha Shelby for contributions to writing and editing this manuscript. \n\nThe funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. \n\nCompeting interests: Rustem F Ismagilov: The technology described in this publication is the subject of provisional patent application 62/696,743, filed by Caltech on 7/11/18. The other authors declare that no competing interests exist.\n\nAuthor contributions: \nAsher Preska Steinberg, Conceptualization, Resources, Data curation, Software, Formal analysis,\nFunding acquisition, Validation, Investigation, Visualization, Methodology, Writing\u2014original draft,\nWriting\u2014review and editing, Co-designed all experiments and co-analyzed all experimental results;\ndeveloped theoretical tools and performed all calculations; co-developed imaging analysis pipeline\nin ImageJ; developed computational tools for bootstrapping procedure; co-developed microscopy\nassay (Fig 1C-D;Co-performed, designed, and analyzed data from gavage experiments in Fig 1;per-\nformed, designed, and analyzed data from all ex vivo SI aggregation experiments in Figs 2, 3, 5-7;\nperformed, designed, and analyzed data from all GPC measurements in Figs 3, 5-7, and Tables 1-7;\nperformed, designed, and analyzed data from all in vitro PEG aggregation experiments in Fig 4D,\nFig 4 - supplements2-3, and with dietary fiber in Fig 7A; developed a computational approach forth-eoretical calculations in 4H and 4I and performed all calculations; performed, designed, and analyzed\ndata from Western blots in Figs 5E, 6E, Fig 6- supplements 1-2; helped supervise animal husbandry\nof MUC2KO colony; performed animal husbandry for WT mice on autoclaved diets in Fig 6; performed animal husbandry for mice on pectin and Fibersol-2 diets in Fig 7; performed, designed, and analyzed all zeta potential measurements in Table 8; performed pH measurements on luminal fluid in Fig\n4 - supplement 1; co-interpreted results.; Sujit S Datta, Conceptualization, Investigation, Methodology, Writing\u2014review and editing, Conceived and co-planned the project; initially observed the\naggregation phenomenon; co-designed and co-analyzed preliminary experiments; performed preliminary ex vivo and in vitro aggregation experiments; co-developed microscopy assay used in Fig 1C\nand 1D; developed exvivo/in vitro aggregation assay used in Figs 2-7; co-developed approach to\nextract liquid fraction of murine intestinal contents; co-developed NMR protocol; organized transfer\nand initial set up of MUC2KO colony; co-interpreted results.; Thomas Naragon, Data curation, Software, Formal analysis, Methodology, Writing\u2014original draft, Co-developed imaging analysis pipeline in ImageJ; co-analyzed ex vivo aggregation data in Fig 2; co-designed and co-analyzed\npreliminary ex vivo aggregation experiments with MUC2KO mice; provided useful advice on boot-strapping procedure; co-interpreted results.; Justin C Rolando, Data curation, Formal analysis, Investigation, Methodology, Writing\u2014original draft, Developed protocol for NMR measurements on\nPEG-coated particles, Performed synthesis of particles, Performed NMR measurements in Table 8;\nSaid R Bogatyrev, Investigation, Methodology, Writing\u2014review and editing, Co-performed preliminary experiments; developed fluorescent laser scanning approach appearing in Fig 1A and 1B;\nAdministered particles to mice in Fig 1; co-developed approach to extract liquid fraction of murine\nintestinal contents; co-organized transfer and initial set up of MUC2KO colony; setup genotyping of\nMUC2KO mice; helped supervise animal husbandry of MUC2KO colony; helped with interpretation of results.; Rustem F Ismagilov, Resources, Formal analysis, Supervision, Funding acquisition, Investigation, Methodology, Writing\u2014original draft, Project administration, Writing\u2014review and editing.\n\nEthics: Animal experimentation: All animal experiments were approved by the California Institute of Technology (Caltech) Institutional Animal Care and Use Committee (IACUC) under IACUC protocol #1691, and the U.S. Army's Animal Care and Use Review Office (ACURO) under ACURO protocols #DARPA-533.02 and #70905-LS-MUR.03. Mice were euthanized via CO2 inhalation as approved by the Caltech IACUC in accordance with the American Veterinary Medical Association Guidelines on Euthanasia.\n\nPublished - elife-40387-v1.pdf
Submitted - 490920.full.pdf
Supplemental Material - elife-40387-transrepform-v1.pdf
", "abstract": "The lumen of the small intestine (SI) is filled with particulates: microbes, therapeutic particles, and food granules. The structure of this particulate suspension could impact uptake of drugs and nutrients and the function of microorganisms; however, little is understood about how this suspension is re-structured as it transits the gut. Here, we demonstrate that particles spontaneously aggregate in SI luminal fluid ex vivo. We find that mucins and immunoglobulins are not required for aggregation. Instead, aggregation can be controlled using polymers from dietary fiber in a manner that is qualitatively consistent with polymer-induced depletion interactions, which do not require specific chemical interactions. Furthermore, we find that aggregation is tunable; by feeding mice dietary fibers of different molecular weights, we can control aggregation in SI luminal fluid. This work suggests that the molecular weight and concentration of dietary polymers play an underappreciated role in shaping the physicochemical environment of the gut.", "date": "2019-01-22", "date_type": "published", "publication": "eLife", "volume": "8", "publisher": "eLife Sciences Publications", "pagerange": "Art. No. e40387", "id_number": "CaltechAUTHORS:20181210-140412486", "issn": "2050-084X", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20181210-140412486", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Defense Advanced Research Projects Agency (DARPA)", "grant_number": "HR0011-15-C-0093" }, { "agency": "Army Research Office (ARO)", "grant_number": "W911NF-17-1-0402" }, { "agency": "Jacobs Institute for Molecular Engineering for Medicine" }, { "agency": "NSF Graduate Research Fellowship", "grant_number": "DGE-1144469" } ] }, "local_group": { "items": [ { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" } ] }, "doi": "10.7554/eLife.40387", "pmcid": "PMC6342521", "primary_object": { "basename": "490920.full.pdf", "url": "https://authors.library.caltech.edu/records/yvcat-rz898/files/490920.full.pdf" }, "related_objects": [ { "basename": "elife-40387-transrepform-v1.pdf", "url": "https://authors.library.caltech.edu/records/yvcat-rz898/files/elife-40387-transrepform-v1.pdf" }, { "basename": "elife-40387-v1.pdf", "url": "https://authors.library.caltech.edu/records/yvcat-rz898/files/elife-40387-v1.pdf" } ], "resource_type": "article", "pub_year": "2019", "author_list": "Preska Steinberg, Asher; Datta, Sujit S.; et el." }, { "id": "https://authors.library.caltech.edu/records/dk2yf-f8095", "eprint_id": 91953, "eprint_status": "archive", "datestamp": "2023-08-19 13:46:32", "lastmod": "2023-10-19 23:51:26", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Rolando-Justin-C", "name": { "family": "Rolando", "given": "Justin C." }, "orcid": "0000-0001-8948-319X" }, { "id": "Jue-Erik", "name": { "family": "Jue", "given": "Erik" }, "orcid": "0000-0001-7585-3794" }, { "id": "Schoepp-Nathan-G", "name": { "family": "Schoepp", "given": "Nathan G." }, "orcid": "0000-0002-2406-3693" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Real-Time, Digital LAMP with Commercial Microfluidic Chips Reveals the Interplay of Efficiency, Speed, and Background Amplification as a Function of Reaction Temperature and Time", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2018 American Chemical Society. ACS AuthorChoice - This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. \n\nReceived: September 21, 2018; Accepted: December 5, 2018; Published: December 19, 2018. \n\nThis research was supported in part by the Burroughs Wellcome Fund Innovation in Regulatory Science Award (to R.F.I.) and a grant from the Jacobs Institute for Molecular Engineering for Medicine. Research reported in this publication was also supported by the Department of Health and Human Services (HHS) Office of the Assistant Secretary for Preparedness and Response (ASPR) and the Wellcome Trust under the CARB-X program (federal award no. IDSEP160030-02); the content is solely the responsibility of the authors and does not necessarily represent the official views of the Department of HHS Office of the ASPR. This work is funded in part by CARB-X as a collaboration between Talis Biomedical Corporation and Caltech. This project benefited from the use of instrumentation at the Jim Hall Design and Prototyping Lab at the California Institute of Technology. We thank Travis Schlappi for performing the extractions of the archived clinical samples and Natasha Shelby for contributions to writing and editing this manuscript. \n\nAuthor Contributions: All authors have given approval to the final version of the manuscript. \n\nThe authors declare the following competing financial interest(s): The technology described in this publication is the subject of a patent application filed by Caltech. R.F.I. has a financial interest in Talis Biomedical Corporation.\n\nPublished - acs.analchem.8b04324.pdf
Supplemental Material - ac8b04324_si_001.pdf
", "abstract": "Real-time, isothermal, digital nucleic acid amplification is emerging as an attractive approach for a multitude of applications including diagnostics, mechanistic studies, and assay optimization. Unfortunately, there is no commercially available and affordable real-time, digital instrument validated for isothermal amplification; thus, most researchers have not been able to apply digital, real-time approaches to isothermal amplification. Here, we generate an approach to real-time digital loop-mediated isothermal amplification (LAMP) using commercially available microfluidic chips and reagents and open-source components. We demonstrate this approach by testing variables that influence LAMP reaction speed and the probability of detection. By analyzing the interplay of amplification efficiency, background, and speed of amplification, this real-time digital method enabled us to test enzymatic performance over a range of temperatures, generating high-precision kinetic and end-point measurements. We were able to identify the unique optimal temperature for two polymerase enzymes while accounting for amplification efficiency, nonspecific background, and time to threshold. We validated this digital LAMP assay and pipeline by performing a phenotypic antibiotic susceptibility test on 17 archived clinical urine samples from patients diagnosed with urinary tract infections. We provide all the necessary workflows to perform digital LAMP using standard laboratory equipment and commercially available materials. This real-time digital approach will be useful to others in the future to understand the fundamentals of isothermal chemistries, including which components determine amplification fate, reaction speed, and enzymatic performance. Researchers can also adapt this pipeline, which uses only standard equipment and commercial components, to quickly study and optimize assays using precise, real-time digital quantification, accelerating development of critically needed diagnostics.", "date": "2019-01-02", "date_type": "published", "publication": "Analytical Chemistry", "volume": "91", "number": "1", "publisher": "American Chemical Society", "pagerange": "1034-1042", "id_number": "CaltechAUTHORS:20181221-105356677", "issn": "0003-2700", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20181221-105356677", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Burroughs Wellcome Fund" }, { "agency": "Jacobs Institute for Molecular Engineering for Medicine" }, { "agency": "Department of Health and Human Services", "grant_number": "IDSEP160030-02" }, { "agency": "Wellcome Trust" }, { "agency": "Talis Biomedical Corporation" } ] }, "local_group": { "items": [ { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" } ] }, "doi": "10.1021/acs.analchem.8b04324", "pmcid": "PMC6322147", "primary_object": { "basename": "acs.analchem.8b04324.pdf", "url": "https://authors.library.caltech.edu/records/dk2yf-f8095/files/acs.analchem.8b04324.pdf" }, "related_objects": [ { "basename": "ac8b04324_si_001.pdf", "url": "https://authors.library.caltech.edu/records/dk2yf-f8095/files/ac8b04324_si_001.pdf" } ], "resource_type": "article", "pub_year": "2019", "author_list": "Rolando, Justin C.; Jue, Erik; et el." }, { "id": "https://authors.library.caltech.edu/records/jhqfe-dfs86", "eprint_id": 88495, "eprint_status": "archive", "datestamp": "2023-08-19 10:58:37", "lastmod": "2023-10-18 22:06:20", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Khazaei-Tahmineh", "name": { "family": "Khazaei", "given": "Tahmineh" }, "orcid": "0000-0002-4743-2383" }, { "id": "Barlow-J-T", "name": { "family": "Barlow", "given": "Jacob T." }, "orcid": "0000-0002-1842-4835" }, { "id": "Schoepp-N-G", "name": { "family": "Schoepp", "given": "Nathan G." }, "orcid": "0000-0002-2406-3693" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "RNA markers enable phenotypic test of antibiotic susceptibility in Neisseria gonorrhoeae after 10\u2009minutes of ciprofloxacin exposure", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2018 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. \n\nReceived 11 April 2018; Accepted 11 July 2018; Published 02 August 2018. \n\nData availability: Data on candidate markers for N. gonorrhoeae and sequences for the primers used in this study are provided in the Supplementary file available. The complete sequencing data generated during this study are available in the National Center for Biotechnology Information Sequence Read Archive repository under the study accession number SRP150785. \n\nThis work was supported in part by a Burroughs Wellcome Fund Innovation in Regulatory Science Award, a Natural Sciences and Engineering Research Council of Canada (NSERC) fellowship [PGSD3-438474-2013] (to T.K.), an NIH National Research Service Award (NRSA) [5T32GM07616NSF] (to N.G.S.), and a grant from the Joseph J. Jacobs Institute for Molecular Engineering for Medicine. Research reported in this publication was also supported by the Department of Health and Human Services (HHS) Office of the Assistant Secretary for Preparedness and Response (ASPR) and the Wellcome Trust under the CARB-X program (federal award number IDSEP160030-02); the content is solely the responsibility of the authors and does not necessarily represent the official views of the Department of HHS Office of the ASPR. This work is funded in part by CARB-X as a collaboration between Talis Biomedical and Caltech. This work was also supported by the Millard & Muriel Jacobs Genetics and Genomics Laboratory at the California Institute of Technology and we acknowledge lab director Igor Antoshechkin for his assistance. We thank Dr. Olusegun O. Soge at the UW Neisseria Reference Laboratory, and the Clinical Microbiology Laboratory at UCLA for providing N. gonorrhoeae isolates. We also thank Natasha Shelby for contributions to writing and editing this manuscript. \n\nAuthor Contributions: T.K., N.G.S., and R.F.I. designed the study; T.K., N.G.S, J.T.B., and R.F.I. developed the methodology and performed the research; T.K., J.T.B., and R.F.I analyzed and interpreted the data; T.K. wrote the text for the manuscript, and all authors contributed to the final preparation of the submission. \n\nCompeting Interests: The technology described in this publication is the subject of a patent application filed by Caltech. R.F.I. has a financial interest in Talis Biomedical.\n\nPublished - s41598-018-29707-w.pdf
Supplemental Material - 41598_2018_29707_MOESM1_ESM.pdf
", "abstract": "Antimicrobial-resistant Neisseria gonorrhoeae is an urgent public-health threat, with continued worldwide incidents of infection and rising resistance to antimicrobials. Traditional culture-based methods for antibiotic susceptibility testing are unacceptably slow (1\u20132 days), resulting in the use of broad-spectrum antibiotics and the further development and spread of resistance. Critically needed is a rapid antibiotic susceptibility test (AST) that can guide treatment at the point-of-care. Rapid phenotypic approaches using quantification of DNA have been demonstrated for fast-growing organisms (e.g. E. coli) but are challenging for slower-growing pathogens such as N. gonorrhoeae. Here, we investigate the potential of RNA signatures to provide phenotypic responses to antibiotics in N. gonorrhoeae that are faster and greater in magnitude compared with DNA. Using RNA sequencing, we identified antibiotic-responsive transcripts. Significant shifts (>4-fold change) in transcript levels occurred within 5\u2009min of antibiotic exposure. We designed assays for responsive transcripts with the highest abundances and fold changes, and validated gene expression using digital PCR. Using the top two markers (porB and rpmB) we correctly determined the antibiotic susceptibility and resistance of 49 clinical isolates after 10\u2009min exposure to ciprofloxacin. RNA signatures are therefore promising as an approach on which to build rapid AST devices for N. gonorrhoeae at the point-of-care, which is critical for disease management, surveillance, and antibiotic stewardship efforts.", "date": "2018-08-02", "date_type": "published", "publication": "Scientific Reports", "volume": "8", "publisher": "Nature Publishing Group", "pagerange": "Art. No. 11606", "id_number": "CaltechAUTHORS:20180802-093834589", "issn": "2045-2322", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20180802-093834589", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Burroughs Wellcome Fund" }, { "agency": "Natural Sciences and Engineering Research Council of Canada (NSERC)", "grant_number": "PGSD3-438474-2013" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "5T32GM07616NSF" }, { "agency": "Joseph J. Jacobs Institute for Molecular Engineering for Medicine" }, { "agency": "Department of Health and Human Services", "grant_number": "IDSEP160030-02" }, { "agency": "Wellcome Trust" }, { "agency": "Talis Biomedical" }, { "agency": "Millard and Muriel Jacobs Genetics and Genomics Laboratory" } ] }, "local_group": { "items": [ { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" }, { "id": "Millard-and-Muriel-Jacobs-Genetics-and-Genomics-Laboratory" } ] }, "doi": "10.1038/s41598-018-29707-w", "pmcid": "PMC6072703", "primary_object": { "basename": "41598_2018_29707_MOESM1_ESM.pdf", "url": "https://authors.library.caltech.edu/records/jhqfe-dfs86/files/41598_2018_29707_MOESM1_ESM.pdf" }, "related_objects": [ { "basename": "s41598-018-29707-w.pdf", "url": "https://authors.library.caltech.edu/records/jhqfe-dfs86/files/s41598-018-29707-w.pdf" } ], "resource_type": "article", "pub_year": "2018", "author_list": "Khazaei, Tahmineh; Barlow, Jacob T.; et el." }, { "id": "https://authors.library.caltech.edu/records/ye1wh-40d17", "eprint_id": 72778, "eprint_status": "archive", "datestamp": "2023-08-19 05:32:10", "lastmod": "2023-10-23 22:56:12", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Schoepp-Nathan-G", "name": { "family": "Schoepp", "given": "Nathan G." }, "orcid": "0000-0002-2406-3693" }, { "id": "Schlappi-Travis-S", "name": { "family": "Schlappi", "given": "Travis S." }, "orcid": "0000-0001-6132-6459" }, { "id": "Curtis-Matthew-S", "name": { "family": "Curtis", "given": "Matthew S." }, "orcid": "0000-0002-9662-3266" }, { "id": "Butkovich-Slava-S", "name": { "family": "Butkovich", "given": "Slava S." }, "orcid": "0000-0001-9468-595X" }, { "id": "Miller-Shelley", "name": { "family": "Miller", "given": "Shelley" } }, { "id": "Humphries-Romney-M", "name": { "family": "Humphries", "given": "Romney M." }, "orcid": "0000-0002-6568-156X" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Rapid pathogen-specific phenotypic antibiotic susceptibility testing using digital LAMP quantification in clinical samples", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. \n\nSubmitted 16 December 2016; Resubmitted 30 June 2017; Accepted 5 September 2017; Published 4 October 2017. \n\nWe thank N. Shelby for contributions to manuscript writing and editing, M. Lee at the Clinical Microbiology Laboratory at UCLA for assistance with clinical sample and data acquisition, SlipChip Corp. for providing injection-molded SlipChips for dLAMP quantification, and W. Liu and D. Capule of SlipChip Corp. for providing technical assistance and expertise. Funding: This research was supported by the Defense Advanced Research Projects Agency (DARPA) Cooperative Agreement HR0011-11-2-0006, NIH grant R01EB012946, a Burroughs Wellcome Fund Innovation in Regulatory Science award, an NIH National Research Service Award (NRSA) (5T32GM07616NSF) to N.G.S., and a grant from the Joseph J. Jacobs Institute for Molecular Engineering for Medicine. Author contributions: The order of co-first authors was determined by coin toss. T.S.S., N.G.S., and R.F.I. contributed to the design and/or interpretation of the reported experiments or results. T.S.S., N.G.S., M.S.C., S.S.B., and R.F.I. contributed to the acquisition and/or analysis of the data. T.S.S., N.G.S., R.M.H., and R.F.I. contributed to the drafting and/or revising of the manuscript. M.S.C. was primarily responsible for real-time imaging acquisition and analysis. S.M. and R.M.H. were primarily responsible for acquiring clinical samples and performing gold standard broth microdilution ASTs. R.F.I. and R.M.H. contributed administrative, technical, and supervisory support. Competing interests: R.F.I., T.S.S., M.S.C., and N.G.S. are inventors on a patent (PCT/US2015/059344) filed by Caltech and SlipChip Corp. and on provisional patent applications 62/399,196 and 62/460,625 filed by Caltech that cover devices and methods for rapid digital antibiotic susceptibility testing. R.F.I. has a financial interest in SlipChip Corp. and is a consultant for SlipChip Corp. Data and materials availability: Requests for additional information should be addressed to R.F.I. (rustem.admin@caltech.edu).\n\nAccepted Version - nihms-1051221.pdf
Supplemental Material - aal3693_SM.pdf
", "abstract": "Rapid antimicrobial susceptibility testing (AST) is urgently needed for informing treatment decisions and preventing the spread of antimicrobial resistance resulting from the misuse and overuse of antibiotics. To date, no phenotypic AST exists that can be performed within a single patient visit (30 min) directly from clinical samples. We show that AST results can be obtained by using digital nucleic acid quantification to measure the phenotypic response of Escherichia coli present within clinical urine samples exposed to an antibiotic for 15 min. We performed this rapid AST using our ultrafast (~7 min) digital real-time loop-mediated isothermal amplification (dLAMP) assay [area under the curve (AUC), 0.96] and compared the results to a commercial (~2 hours) digital polymerase chain reaction assay (AUC, 0.98). The rapid dLAMP assay can be used with SlipChip microfluidic devices to determine the phenotypic antibiotic susceptibility of E. coli directly from clinical urine samples in less than 30 min. With further development for additional pathogens, antibiotics, and sample types, rapid digital AST (dAST) could enable rapid clinical decision-making, improve management of infectious diseases, and facilitate antimicrobial stewardship.", "date": "2017-10-04", "date_type": "published", "publication": "Science Translational Medicine", "volume": "9", "number": "410", "publisher": "American Association for the Advancement of Science", "pagerange": "Art. No. eaal3693", "id_number": "CaltechAUTHORS:20161213-131157930", "issn": "1946-6234", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20161213-131157930", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Defense Advanced Research Projects Agency (DARPA)", "grant_number": "HR0011-11-2-0006" }, { "agency": "NIH", "grant_number": "R01EB012946" }, { "agency": "Burroughs Wellcome Fund" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "5T32GM07616NSF" }, { "agency": "Joseph J. Jacobs Institute for Molecular Engineering for Medicine" } ] }, "local_group": { "items": [ { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" } ] }, "doi": "10.1126/scitranslmed.aal3693", "pmcid": "PMC6765391", "primary_object": { "basename": "nihms-1051221.pdf", "url": "https://authors.library.caltech.edu/records/ye1wh-40d17/files/nihms-1051221.pdf" }, "related_objects": [ { "basename": "aal3693_SM.pdf", "url": "https://authors.library.caltech.edu/records/ye1wh-40d17/files/aal3693_SM.pdf" } ], "resource_type": "article", "pub_year": "2017", "author_list": "Schoepp, Nathan G.; Schlappi, Travis S.; et el." }, { "id": "https://authors.library.caltech.edu/records/dfvz5-b7x61", "eprint_id": 78633, "eprint_status": "archive", "datestamp": "2023-08-19 03:22:08", "lastmod": "2023-10-26 00:14:47", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Pompano-Rebecca-R", "name": { "family": "Pompano", "given": "Rebecca R." } }, { "id": "Chiang-Andrew-H", "name": { "family": "Chiang", "given": "Andrew H." } }, { "id": "Kastrup-Christian-J", "name": { "family": "Kastrup", "given": "Christian J." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Conceptual and Experimental Tools to Understand Spatial Effects and Transport Phenomena in Nonlinear Biochemical Networks Illustrated with Patchy Switching", "ispublished": "pub", "full_text_status": "restricted", "keywords": "state switching, signaling, flow, mass transfer, Damk\u00f6hler number, microfluidics", "note": "\u00a9 2017 Annual Reviews. \n\nThis work was supported in part by a National Institutes of Health Director's Pioneer Award (DP10D003584, R.F.I.), a Jacobs Institute for Molecular Engineering for Medicine Award (R.F.I.), a National Science Foundation Emerging Frontiers in Research and Innovation Award (1137089, R.F.I.), an Individual Biomedical Research Award from The Hartwell Foundation (R.R.P.), and a Canadian Institutes of Health Research Award (MSH-130166, C.J.K.). We thank Natasha Shelby for contributions to writing and editing this manuscript. \n\nThe authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.", "abstract": "Many biochemical systems are spatially heterogeneous and exhibit nonlinear behaviors, such as state switching in response to small changes in the local concentration of diffusible molecules. Systems as varied as blood clotting, intracellular calcium signaling, and tissue inflammation are all heavily influenced by the balance of rates of reaction and mass transport phenomena including flow and diffusion. Transport of signaling molecules is also affected by geometry and chemoselective confinement via matrix binding. In this review, we use a phenomenon referred to as patchy switching to illustrate the interplay of nonlinearities, transport phenomena, and spatial effects. Patchy switching describes a change in the state of a network when the local concentration of a diffusible molecule surpasses a critical threshold. Using patchy switching as an example, we describe conceptual tools from nonlinear dynamics and chemical engineering that make testable predictions and provide a unifying description of the myriad possible experimental observations. We describe experimental microfluidic and biochemical tools emerging to test conceptual predictions by controlling transport phenomena and spatial distribution of diffusible signals, and we highlight the unmet need for in vivo tools.", "date": "2017-06", "date_type": "published", "publication": "Annual Review of Biochemistry", "volume": "86", "publisher": "Annual Reviews", "pagerange": "333-356", "id_number": "CaltechAUTHORS:20170628-083437438", "issn": "0066-4154", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170628-083437438", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "DP10D003584" }, { "agency": "Jacobs Institute for Molecular Engineering for Medicine" }, { "agency": "NSF", "grant_number": "EFMA-1137089" }, { "agency": "Hartwell Foundation" }, { "agency": "Canadian Institutes of Health", "grant_number": "MSH-130166" } ] }, "local_group": { "items": [ { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" } ] }, "doi": "10.1146/annurev-biochem-060815-014207", "resource_type": "article", "pub_year": "2017", "author_list": "Pompano, Rebecca R.; Chiang, Andrew H.; et el." }, { "id": "https://authors.library.caltech.edu/records/g9ews-vzq36", "eprint_id": 71625, "eprint_status": "archive", "datestamp": "2023-08-20 14:03:06", "lastmod": "2023-10-23 15:15:46", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Selck-D-A", "name": { "family": "Selck", "given": "David A." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Instrument for Real-Time Digital Nucleic Acid Amplification on Custom Microfluidic Devices", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2016 Selck, Ismagilov. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. \n\nReceived: July 7, 2016; Accepted: September 1, 2016; Published: October 19, 2016. \n\nWe thank David H. Tracy for designing the optical system for the instrument and Natasha Shelby for contributions to writing and editing this manuscript. \n\nThis work was supported in part by DARPA Cooperative Agreement No. HR0011-11-2-0006, the National Institutes of Health grant No. R01EB012946, an NIH NRSA (5T32GM07616NSF) to D.A.S., and an Achievement Rewards for College Scientists (ARCS) fellowship to D.A.S. \n\nAuthor Contributions: \nConceptualization: DAS RFI.\nData curation: DAS.\nFormal analysis: DAS RFI.\nFunding acquisition: DAS RFI.\nInvestigation: DAS.\nMethodology: DAS RFI.\nProject administration: RFI.\nResources: DAS RFI.\nSoftware: DAS.\nSupervision: RFI.\nValidation: DAS.\nVisualization: DAS.\nWriting \u2013 original draft: DAS RFI.\nWriting \u2013 review & editing: DAS RFI. \n\nData Availability: Source code for the software described herein is located at dx.doi.org/10.6070/H4N29V0S. \n\nThe authors have declared that no competing interests exist.\n\nPublished - journal.pone.0163060.PDF
Supplemental Material - journal.pone.0163060.s001.PDF
Supplemental Material - journal.pone.0163060.s002.PDF
Supplemental Material - journal.pone.0163060.s003.XLSX
Supplemental Material - journal.pone.0163060.s004.PDF
Supplemental Material - journal.pone.0163060.s005.PDF
", "abstract": "Nucleic acid amplification tests that are coupled with a digital readout enable the absolute quantification of single molecules, even at ultralow concentrations. Digital methods are robust, versatile and compatible with many amplification chemistries including isothermal amplification, making them particularly invaluable to assays that require sensitive detection, such as the quantification of viral load in occult infections or detection of sparse amounts of DNA from forensic samples. A number of microfluidic platforms are being developed for carrying out digital amplification. However, the mechanistic investigation and optimization of digital assays has been limited by the lack of real-time kinetic information about which factors affect the digital efficiency and analytical sensitivity of a reaction. Commercially available instruments that are capable of tracking digital reactions in real-time are restricted to only a small number of device types and sample-preparation strategies. Thus, most researchers who wish to develop, study, or optimize digital assays rely on the rate of the amplification reaction when performed in a bulk experiment, which is now recognized as an unreliable predictor of digital efficiency. To expand our ability to study how digital reactions proceed in real-time and enable us to optimize both the digital efficiency and analytical sensitivity of digital assays, we built a custom large-format digital real-time amplification instrument that can accommodate a wide variety of devices, amplification chemistries and sample-handling conditions. Herein, we validate this instrument, we provide detailed schematics that will enable others to build their own custom instruments, and we include a complete custom software suite to collect and analyze the data retrieved from the instrument. We believe assay optimizations enabled by this instrument will improve the current limits of nucleic acid detection and quantification, improving our fundamental understanding of single-molecule reactions and providing advancements in practical applications such as medical diagnostics, forensics and environmental sampling.", "date": "2016-10", "date_type": "published", "publication": "PLOS ONE", "volume": "11", "number": "10", "publisher": "Public Library of Science", "pagerange": "Art. No. e0163060", "id_number": "CaltechAUTHORS:20161031-113924216", "issn": "1932-6203", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20161031-113924216", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Defense Advanced Research Projects Agency (DARPA)", "grant_number": "HR0011-11-2-0006" }, { "agency": "NIH", "grant_number": "R01EB012946" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "5T32GM07616NSF" }, { "agency": "Achievement Rewards for College Scientists (ARCS) Foundation" } ] }, "doi": "10.1371/journal.pone.0163060", "pmcid": "PMC5070811", "primary_object": { "basename": "journal.pone.0163060.PDF", "url": "https://authors.library.caltech.edu/records/g9ews-vzq36/files/journal.pone.0163060.PDF" }, "related_objects": [ { "basename": "journal.pone.0163060.s001.PDF", "url": "https://authors.library.caltech.edu/records/g9ews-vzq36/files/journal.pone.0163060.s001.PDF" }, { "basename": "journal.pone.0163060.s002.PDF", "url": "https://authors.library.caltech.edu/records/g9ews-vzq36/files/journal.pone.0163060.s002.PDF" }, { "basename": "journal.pone.0163060.s003.XLSX", "url": "https://authors.library.caltech.edu/records/g9ews-vzq36/files/journal.pone.0163060.s003.XLSX" }, { "basename": "journal.pone.0163060.s004.PDF", "url": "https://authors.library.caltech.edu/records/g9ews-vzq36/files/journal.pone.0163060.s004.PDF" }, { "basename": "journal.pone.0163060.s005.PDF", "url": "https://authors.library.caltech.edu/records/g9ews-vzq36/files/journal.pone.0163060.s005.PDF" } ], "resource_type": "article", "pub_year": "2016", "author_list": "Selck, David A. and Ismagilov, Rustem F." }, { "id": "https://authors.library.caltech.edu/records/kzer7-dy654", "eprint_id": 68822, "eprint_status": "archive", "datestamp": "2023-08-20 13:18:58", "lastmod": "2023-10-23 15:14:24", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Schoepp-Nathan-G", "name": { "family": "Schoepp", "given": "Nathan G." }, "orcid": "0000-0002-2406-3693" }, { "id": "Khorosheva-Eugenia-M", "name": { "family": "Khorosheva", "given": "Eugenia M." }, "orcid": "0000-0003-3620-4884" }, { "id": "Schlappi-Travis-S", "name": { "family": "Schlappi", "given": "Travis S." }, "orcid": "0000-0001-6132-6459" }, { "id": "Curtis-Matthew-S", "name": { "family": "Curtis", "given": "Matthew S." }, "orcid": "0000-0002-9662-3266" }, { "id": "Humphries-Romney-M", "name": { "family": "Humphries", "given": "Romney M." }, "orcid": "0000-0002-6568-156X" }, { "id": "Hindler-Janet-A", "name": { "family": "Hindler", "given": "Janet A." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Digital Quantification of DNA Replication and Chromosome Segregation Enables Determination of Antimicrobial Susceptibility after only 15 Minutes of Antibiotic Exposure", "ispublished": "pub", "full_text_status": "public", "keywords": "analytical methods \u00b7 antibiotics \u00b7 DNA replication \u00b7 polymerase chain reaction \u00b7 susceptibility", "note": "\u00a9 2016 WILEY-VCH Verlag GmbH & Co. \n\nReceived: March 29, 2016. Revised: May 5, 2016. Version of Record online: 30 Jun 2016. \n\nThis research was supported by DARPA Cooperative Agreement HR0011-11-2-0006, NIH Grant R01EB012946, and a grant from the Joseph J. Jacobs Institute for Molecular Engineering for Medicine. We thank Shelley Miller for advice and experimental assistance. We thank Natasha Shelby for contributions to writing and editing this manuscript.\n\nIn the \"Antibiotic exposure time course experiments\" section of the \"Experimental Section\" of the Supporting Information for this Communication, \"early logarithmic\" should read \"early stationary (OD600 3.1\u20136.9).\"\n\nAlso, the authors do not recommend the use of Epicentre QuickExtract RNA Extraction Solution for pathogens because they found that this solution does not reproducibly and completely lyse some clinical E. coli isolates, which could present a biohazard unless the extracts are handled at the appropriate biosafety level.\n\nAccepted Version - nihms832692.pdf
Supplemental Material - ange201602763-sup-0001-misc_information.pdf
", "abstract": "Rapid antimicrobial susceptibility testing (AST) would decrease misuse and overuse of antibiotics. The \"holy grail\" of AST is a phenotype-based test that can be performed within a doctor visit. Such a test requires the ability to determine a pathogen's susceptibility after only a short antibiotic exposure. Herein, digital PCR (dPCR) was employed to test whether measuring DNA replication of the target pathogen through digital single-molecule counting would shorten the required time of antibiotic exposure. Partitioning bacterial chromosomal DNA into many small volumes during dPCR enabled AST results after short exposure times by 1)\u2005precise quantification and 2)\u2005a measurement of how antibiotics affect the states of macromolecular assembly of bacterial chromosomes. This digital AST (dAST) determined susceptibility of clinical isolates from urinary tract infections (UTIs) after 15\u2005min of exposure for all four antibiotic classes relevant to UTIs. This work lays the foundation to develop a rapid, point-of-care AST and strengthen global antibiotic stewardship.", "date": "2016-08-08", "date_type": "published", "publication": "Angewandte Chemie International Edition in English", "volume": "55", "number": "33", "publisher": "Wiley", "pagerange": "9557-9561", "id_number": "CaltechAUTHORS:20160705-083001025", "issn": "0570-0833", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160705-083001025", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Defense Advanced Research Projects Agency (DARPA)", "grant_number": "HR0011-11-2-0006" }, { "agency": "NIH", "grant_number": "R01EB012946" }, { "agency": "Joseph J. Jacobs Institute for Molecular Engineering for Medicine" } ] }, "local_group": { "items": [ { "id": "Jacobs-Institute-for-Molecular-Engineering-for-Medicine" } ] }, "doi": "10.1002/ange.201602763", "pmcid": "PMC5215780", "primary_object": { "basename": "ange201602763-sup-0001-misc_information.pdf", "url": "https://authors.library.caltech.edu/records/kzer7-dy654/files/ange201602763-sup-0001-misc_information.pdf" }, "related_objects": [ { "basename": "nihms832692.pdf", "url": "https://authors.library.caltech.edu/records/kzer7-dy654/files/nihms832692.pdf" } ], "resource_type": "article", "pub_year": "2016", "author_list": "Schoepp, Nathan G.; Khorosheva, Eugenia M.; et el." }, { "id": "https://authors.library.caltech.edu/records/2xw3m-2dy26", "eprint_id": 69188, "eprint_status": "archive", "datestamp": "2023-08-20 13:16:19", "lastmod": "2023-10-20 16:38:25", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Schlappi-T-S", "name": { "family": "Schlappi", "given": "Travis S." }, "orcid": "0000-0001-6132-6459" }, { "id": "McCalla-S-E", "name": { "family": "McCalla", "given": "Stephanie E." } }, { "id": "Schoepp-N-G", "name": { "family": "Schoepp", "given": "Nathan G." }, "orcid": "0000-0002-2406-3693" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Flow-through Capture and in Situ Amplification Can Enable Rapid Detection of a Few Single Molecules of Nucleic Acids from Several Milliliters of Solution", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2016 American Chemical Society. \n\nReceived: April 15, 2016. Accepted: July 3, 2016. Publication Date (Web): July 18, 2016. \n\nThis work was supported by DARPA Cooperative Agreement HR0011-11-2-0006. The content of this article does not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred. We thank Justin Rolando for chemistry advice and chitosan purification and Natasha Shelby for contributions to writing and editing this manuscript. \n\nAuthor Contributions: T.S.S. and S.E.M. contributed equally. T.S.S., S.E.M., N.G.S., and R.F.I. designed the study and wrote the manuscript. T.S.S. and S.E.M. performed theoretical analysis. T.S.S., S.E.M., and N.G.S. performed experiments and data analysis. \n\nThe authors declare no competing financial interest.\n\nSupplemental Material - ac6b01485_si_001.pdf
", "abstract": "Detecting nucleic acids (NAs) at zeptomolar concentrations (few molecules per milliliter) currently requires expensive equipment and lengthy processing times to isolate and concentrate the NAs into a volume that is amenable to amplification processes, such as PCR or LAMP. Shortening the time required to concentrate NAs and integrating this procedure with amplification on-device would be invaluable to a number of analytical fields, including environmental monitoring and clinical diagnostics. Microfluidic point-of-care (POC) devices have been designed to address these needs, but they are not able to detect NAs present in zeptomolar concentrations in short time frames because they require slow flow rates and/or they are unable to handle milliliter-scale volumes. In this paper, we theoretically and experimentally investigate a flow-through capture membrane that solves this problem by capturing NAs with high sensitivity in a short time period, followed by direct detection via amplification. Theoretical predictions guided the choice of physical parameters for a chitosan-coated nylon membrane; these predictions can also be applied generally to other capture situations with different requirements. The membrane is also compatible with in situ amplification, which, by eliminating an elution step enables high sensitivity and will facilitate integration of this method into sample-to-answer detection devices. We tested a wide range of combinations of sample volumes and concentrations of DNA molecules using a capture membrane with a 2 mm radius. We show that for nucleic acid detection, this approach can concentrate and detect as few as \u223c10 molecules of DNA with flow rates as high as 1 mL/min, handling samples as large as 50 mL. In a specific example, this method reliably concentrated and detected \u223c25 molecules of DNA from 50 mL of sample.", "date": "2016-08-02", "date_type": "published", "publication": "Analytical Chemistry", "volume": "88", "number": "15", "publisher": "American Chemical Society", "pagerange": "7647-7653", "id_number": "CaltechAUTHORS:20160725-102649276", "issn": "0003-2700", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160725-102649276", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Defense Advanced Research Projects Agency (DARPA)", "grant_number": "HR0011-11-2-0006" } ] }, "doi": "10.1021/acs.analchem.6b01485", "primary_object": { "basename": "ac6b01485_si_001.pdf", "url": "https://authors.library.caltech.edu/records/2xw3m-2dy26/files/ac6b01485_si_001.pdf" }, "resource_type": "article", "pub_year": "2016", "author_list": "Schlappi, Travis S.; McCalla, Stephanie E.; et el." }, { "id": "https://authors.library.caltech.edu/records/x2xza-km768", "eprint_id": 67925, "eprint_status": "archive", "datestamp": "2023-08-22 18:09:22", "lastmod": "2023-10-19 22:05:23", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Datta-Sujit-S", "name": { "family": "Datta", "given": "Sujit S." }, "orcid": "0000-0003-2400-1561" }, { "id": "Preska-Steinberg-Asher", "name": { "family": "Preska Steinberg", "given": "Asher" }, "orcid": "0000-0002-8694-7224" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Polymers in the gut compress the colonic mucus hydrogel", "ispublished": "pub", "full_text_status": "public", "keywords": "hydrogel; biophysics; biomaterials; polymers; mucus", "note": "\u00a9 2016 National Academy of Sciences. Freely available online through the PNAS open access option. \n\nEdited by David A. Weitz, Harvard University, Cambridge, MA, and approved May 6, 2016 (received for review February 18, 2016) Published online before print June 14, 2016, doi: 10.1073/pnas.1602789113 \n\nWe thank Said Bogatyrev, Andres Collazo, Elaine Hsiao, Julia Kornfield, Octavio Mondragon-Palomino, Ahmad Omar, Alexandre Persat, David Tirrell, Zhen-Gang Wang, and David Weitz for useful discussions; the Beckman Institute Biological Imaging Facility, the Broad Animal Facility, and the Church Animal Facility for experimental resources; the veterinary technicians at the California Institute of Technology for experimental assistance; Jennifer R. Keeffe for assistance with dynamic light scattering measurements; Dorothy Pan for assistance with gel permeation chromatography measurements; and Natasha Shelby for contributions to writing and editing this manuscript. This work was supported in part by Defense Advanced Research Projects Agency Biological Robustness in Complex Settings Contract HR0011-15-C-0093, National Science Foundation (NSF) Emerging Frontiers in Research and Innovation Award Grant 1137089, and NSF Graduate Research Fellowship DGE\u20101144469 (to A.P.S.). \n\nAuthor contributions: S.S.D., A.P.S., and R.F.I. designed research; S.S.D. and A.P.S. performed research; S.S.D. and A.P.S. contributed new reagents/analytic tools; S.S.D. and A.P.S. analyzed data; and S.S.D., A.P.S., and R.F.I. wrote the paper. \n\nThe authors declare no conflict of interest. \n\nThis article is a PNAS Direct Submission. \n\nThis article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1602789113/-/DCSupplemental.\n\nPublished - PNAS-2016-Datta-7041-6.pdf
Supplemental Material - pnas.201602789SI.pdf
", "abstract": "Colonic mucus is a key biological hydrogel that protects the gut from infection and physical damage and mediates host\u2013microbe interactions and drug delivery. However, little is known about how its structure is influenced by materials it comes into contact with regularly. For example, the gut abounds in polymers such as dietary fibers or administered therapeutics, yet whether such polymers interact with the mucus hydrogel, and if so, how, remains unclear. Although several biological processes have been identified as potential regulators of mucus structure, the polymeric composition of the gut environment has been ignored. Here, we demonstrate that gut polymers do in fact regulate mucus hydrogel structure, and that polymer\u2013mucus interactions can be described using a thermodynamic model based on Flory\u2013Huggins solution theory. We found that both dietary and therapeutic polymers dramatically compressed murine colonic mucus ex vivo and in vivo. This behavior depended strongly on both polymer concentration and molecular weight, in agreement with the predictions of our thermodynamic model. Moreover, exposure to polymer-rich luminal fluid from germ-free mice strongly compressed the mucus hydrogel, whereas exposure to luminal fluid from specific-pathogen-free mice\u2014whose microbiota degrade gut polymers\u2014did not; this suggests that gut microbes modulate mucus structure by degrading polymers. These findings highlight the role of mucus as a responsive biomaterial, and reveal a mechanism of mucus restructuring that must be integrated into the design and interpretation of studies involving therapeutic polymers, dietary fibers, and fiber-degrading gut microbes.", "date": "2016-06-28", "date_type": "published", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "volume": "113", "number": "26", "publisher": "National Academy of Sciences", "pagerange": "7041-7046", "id_number": "CaltechAUTHORS:20160614-141541328", "issn": "0027-8424", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160614-141541328", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Defense Advanced Research Projects Agency (DARPA)", "grant_number": "HR0011-15-C-0093" }, { "agency": "NSF", "grant_number": "ENG-1137089" }, { "agency": "NSF Graduate Research Fellowship", "grant_number": "DGE\u20101144469" } ] }, "doi": "10.1073/pnas.1602789113", "pmcid": "PMC4932961", "primary_object": { "basename": "PNAS-2016-Datta-7041-6.pdf", "url": "https://authors.library.caltech.edu/records/x2xza-km768/files/PNAS-2016-Datta-7041-6.pdf" }, "related_objects": [ { "basename": "pnas.201602789SI.pdf", "url": "https://authors.library.caltech.edu/records/x2xza-km768/files/pnas.201602789SI.pdf" } ], "resource_type": "article", "pub_year": "2016", "author_list": "Datta, Sujit S.; Preska Steinberg, Asher; et el." }, { "id": "https://authors.library.caltech.edu/records/7jrba-0e405", "eprint_id": 66582, "eprint_status": "archive", "datestamp": "2023-08-20 11:42:18", "lastmod": "2023-10-18 18:36:11", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Jue-Erik", "name": { "family": "Jue", "given": "Erik" }, "orcid": "0000-0001-7585-3794" }, { "id": "Schoepp-N-G", "name": { "family": "Schoepp", "given": "Nathan G." }, "orcid": "0000-0002-2406-3693" }, { "id": "Witters-D", "name": { "family": "Witters", "given": "Daan" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Evaluating 3D printing to solve the sample-to-device interface for LRS and POC diagnostics: example of an interlock meter-mix device for metering and lysing clinical urine samples", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2016 The Royal Society of Chemistry. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. \n\nReceived 01 Mar 2016, Accepted 18 Apr 2016. First published online 28 Apr 2016. \n\nThis article is part of themed collection: 3D Printing and Open access articles from Lab on a Chip. \n\nThis research was supported by DARPA Cooperative Agreement HR0011-11-2-0006. The content of this article does not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred. This material is also based upon work supported by National Science Foundation Graduate Research Fellowships DGE-1144469 (to E. J.). R. F. I. holds an Innovation in Regulatory Science Award from BWF. We thank Natasha Shelby for contributions to writing and editing this manuscript.\n\nPublished - c6lc00292g.pdf
Supplemental Material - c6lc00292g1.mp4
", "abstract": "This paper evaluates the potential of 3D printing, a semi-automated additive prototyping technology, as a means to design and prototype a sample-to-device interface, amenable to diagnostics in limited-resource settings, where speed, accuracy and user-friendly design are critical components. As a test case, we built and validated an interlock meter-mix device for accurately metering and lysing human urine samples for use in downstream nucleic acid amplification. Two plungers and a multivalve generated and controlled fluid flow through the device and demonstrate the utility of 3D printing to create leak-free seals. Device operation consists of three simple steps that must be performed sequentially, eliminating manual pipetting and vortexing to provide rapid (5 to 10 s) and accurate metering and mixing. Bretherton's prediction was applied, using the bond number to guide a design that prevents potentially biohazardous samples from leaking from the device. We employed multi-material 3D printing technology, which allows composites with rigid and elastomeric properties to be printed as a single part. To validate the meter-mix device with a clinically relevant sample, we used urine spiked with inactivated Chlamydia trachomatis and Neisseria gonorrhoeae. A downstream nucleic acid amplification by quantitative PCR (qPCR) confirmed there was no statistically significant difference between samples metered and mixed using the standard protocol and those prepared with the meter-mix device, showing the 3D-printed device could accurately meter, mix and dispense a human urine sample without loss of nucleic acids. Although there are some limitations to 3D printing capabilities (e.g. dimension limitations related to support material used in the printing process), the advantages of customizability, modularity and rapid prototyping illustrate the utility of 3D printing for developing sample-to-device interfaces for diagnostics.", "date": "2016-05-21", "date_type": "published", "publication": "Lab on a Chip", "volume": "16", "number": "10", "publisher": "Royal Society of Chemistry", "pagerange": "1852-1860", "id_number": "CaltechAUTHORS:20160502-101837713", "issn": "1473-0197", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160502-101837713", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Defense Advanced Research Projects Agency (DARPA)", "grant_number": "HR0011-11-2-0006" }, { "agency": "NSF Graduate Research Fellowship", "grant_number": "DGE-1144469" }, { "agency": "Burroughs Wellcome Fund" } ] }, "doi": "10.1039/C6LC00292G", "primary_object": { "basename": "c6lc00292g.pdf", "url": "https://authors.library.caltech.edu/records/7jrba-0e405/files/c6lc00292g.pdf" }, "related_objects": [ { "basename": "c6lc00292g1.mp4", "url": "https://authors.library.caltech.edu/records/7jrba-0e405/files/c6lc00292g1.mp4" } ], "resource_type": "article", "pub_year": "2016", "author_list": "Jue, Erik; Schoepp, Nathan G.; et el." }, { "id": "https://authors.library.caltech.edu/records/taq1z-0hn65", "eprint_id": 64512, "eprint_status": "archive", "datestamp": "2023-08-20 11:03:05", "lastmod": "2023-10-17 21:27:42", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Jiang-Cheng-Ying", "name": { "family": "Jiang", "given": "Cheng-Ying" } }, { "id": "Dong-Libing", "name": { "family": "Dong", "given": "Libing" } }, { "id": "Zhao-Jian-Kang", "name": { "family": "Zhao", "given": "Jian-Kang" } }, { "id": "Hu-Xiaofang", "name": { "family": "Hu", "given": "Xiaofang" } }, { "id": "Shen-Chaohua", "name": { "family": "Shen", "given": "Chaohua" } }, { "id": "Qiao-Yuxin", "name": { "family": "Qiao", "given": "Yuxin" } }, { "id": "Zhang-Xinyue", "name": { "family": "Zhang", "given": "Xinyue" } }, { "id": "Wang-Yapei", "name": { "family": "Wang", "given": "Yapei" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Liu-Shuang-Jiang", "name": { "family": "Liu", "given": "Shuang-Jiang" } }, { "id": "Du-Wenbin", "name": { "family": "Du", "given": "Wenbin" }, "orcid": "0000-0002-7401-1410" } ] }, "title": "High throughput Single-cell Cultivation on Microfluidic Streak Plates", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2016 American Society for Microbiology. \n\nReceived 4 November 2015; Accepted 19 January 2016; Accepted manuscript posted online 5 February 2016. \n\nWe thank Natasha Shelby and Liang Ma for help in editing the manuscript. \n\nWe declare no conflict of interest.\n\nThis work is supported by the National Natural Science Foundation of\nChina (31230003, 21205134, 21377161, and 31470221), the program of China Ocean Mineral Resources R&D Association (DY125-15-R-02), the Strategic Priority Research Program of Chinese Academy of Sciences (XDB15040102), and the National High Technology Research and Development Program of China (2012AA092103).\n\nPublished - Appl._Environ._Microbiol.-2016-Jiang-2210-8.pdf
Supplemental Material - zam999117053so1.pdf
", "abstract": "This paper describes the microfluidic streak plate (MSP), a facile method for high-throughput microbial cell separation and cultivation in nanoliter sessile droplets. The MSP method builds upon the conventional streak plate technique by using microfluidic devices to generate nanoliter droplets that can be streaked manually or robotically onto petri dishes prefilled with carrier oil for cultivation of single cells. In addition, chemical gradients could be encoded in the droplet array for comprehensive dose-response analysis. The MSP method was validated by using single-cell isolation of Escherichia coli and antimicrobial susceptibility testing of Pseudomonas aeruginosa PAO1. The robustness of the MSP work flow was demonstrated by cultivating a soil community that degrades polycyclic aromatic hydrocarbons. Cultivation in droplets enabled detection of the richest species diversity with better coverage of rare species. Moreover, isolation and cultivation of bacterial strains by MSP led to the discovery of several species with high degradation efficiency, including four Mycobacterium isolates and a previously unknown fluoranthene-degrading Blastococcus species.", "date": "2016-04", "date_type": "published", "publication": "Applied and Environmental Microbiology", "volume": "82", "number": "7", "publisher": "American Society for Microbiology", "pagerange": "2210-2218", "id_number": "CaltechAUTHORS:20160216-130203405", "issn": "0099-2240", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160216-130203405", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "National Natural Science Foundation of China", "grant_number": "31230003" }, { "agency": "National Natural Science Foundation of China", "grant_number": "21205134" }, { "agency": "National Natural Science Foundation of China", "grant_number": "21377161" }, { "agency": "National Natural Science Foundation of China", "grant_number": "31470221" }, { "agency": "Program of China Ocean Mineral Resources R&D Association", "grant_number": "DY125-15-R-02" }, { "agency": "Chinese Academy of Sciences", "grant_number": "XDB15040102" }, { "agency": "National High Technology Research and Development Program of China", "grant_number": "2012AA092103" } ] }, "doi": "10.1128/AEM.03588-15", "pmcid": "PMC4807504", "primary_object": { "basename": "Appl._Environ._Microbiol.-2016-Jiang-2210-8.pdf", "url": "https://authors.library.caltech.edu/records/taq1z-0hn65/files/Appl._Environ._Microbiol.-2016-Jiang-2210-8.pdf" }, "related_objects": [ { "basename": "zam999117053so1.pdf", "url": "https://authors.library.caltech.edu/records/taq1z-0hn65/files/zam999117053so1.pdf" } ], "resource_type": "article", "pub_year": "2016", "author_list": "Jiang, Cheng-Ying; Dong, Libing; et el." }, { "id": "https://authors.library.caltech.edu/records/fycvn-0ez10", "eprint_id": 64682, "eprint_status": "archive", "datestamp": "2023-08-20 10:31:07", "lastmod": "2023-10-17 21:36:01", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Rodriguez-Manzano-Jesus", "name": { "family": "Rodriguez-Manzano", "given": "Jesus" }, "orcid": "0000-0002-2583-8366" }, { "id": "Karymov-Mikhail-A", "name": { "family": "Karymov", "given": "Mikhail A." } }, { "id": "Begolo-Stefano", "name": { "family": "Begolo", "given": "Stefano" } }, { "id": "Selck-David-A", "name": { "family": "Selck", "given": "David A." }, "orcid": "0000-0002-0591-4165" }, { "id": "Zhukov-Dmitriy-V", "name": { "family": "Zhukov", "given": "Dmitriy V." }, "orcid": "0000-0002-4834-3147" }, { "id": "Jue-Erik", "name": { "family": "Jue", "given": "Erik" }, "orcid": "0000-0001-7585-3794" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Reading Out Single-Molecule Digital RNA and DNA Isothermal Amplification in Nanoliter Volumes with Unmodified Camera Phones", "ispublished": "pub", "full_text_status": "public", "keywords": "nanoliter reactions, single-molecule counting, cell phone camera, digital, isothermal, microfluidics, ratiometric visual readout", "note": "\u00a9 2016 American Chemical Society. ACS AuthorChoice - This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. \n\nReceived: November 20, 2015. Accepted: February 3, 2016. Publication Date (Web): February 22, 2016. \n\nThis research was supported by DARPA Cooperative Agreement HR0011-11-2-0006. The content of this article does not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred. Multivolume SlipChip design and analysis were based on work supported by NIH Grant R01EB012946 administered by the National Institute of Biomedical Imaging and Bioengineering. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. R.F.I. holds an Innovation in Regulatory Science Award from BWF. This material is also based upon work supported by National Science Foundation Graduate Research Fellowships DGE-1144469 (to D.V.Z. and E.J). We thank T. Schlappi for multivolume device design calculations and N. Shelby for contributions to writing and editing this manuscript. R.F.I. has a financial interest in SlipChip Corp. \n\nJ.R.-M. and M.A.K. contributed equally to this work. \n\nThe authors declare the following competing financial interest(s): Rustem F. Ismagilov has a financial interest in SlipChip Corp.\n\nPublished - acsnano_2E5b07338.pdf
Supplemental Material - nn5b07338_si_001.pdf
", "abstract": "Digital single-molecule technologies are expanding diagnostic capabilities, enabling the ultrasensitive quantification of targets, such as viral load in HIV and hepatitis C infections, by directly counting single molecules. Replacing fluorescent readout with a robust visual readout that can be captured by any unmodified cell phone camera will facilitate the global distribution of diagnostic tests, including in limited-resource settings where the need is greatest. This paper describes a methodology for developing a visual readout system for digital single-molecule amplification of RNA and DNA by (i) selecting colorimetric amplification-indicator dyes that are compatible with the spectral sensitivity of standard mobile phones, and (ii) identifying an optimal ratiometric image-process for a selected dye to achieve a readout that is robust to lighting conditions and camera hardware and provides unambiguous quantitative results, even for colorblind users. We also include an analysis of the limitations of this methodology, and provide a microfluidic approach that can be applied to expand dynamic range and improve reaction performance, allowing ultrasensitive, quantitative measurements at volumes as low as 5 nL. We validate this methodology using SlipChip-based digital single-molecule isothermal amplification with \u03bbDNA as a model and hepatitis C viral RNA as a clinically relevant target. The innovative combination of isothermal amplification chemistry in the presence of a judiciously chosen indicator dye and ratiometric image processing with SlipChip technology allowed the sequence-specific visual readout of single nucleic acid molecules in nanoliter volumes with an unmodified cell phone camera. When paired with devices that integrate sample preparation and nucleic acid amplification, this hardware-agnostic approach will increase the affordability and the distribution of quantitative diagnostic and environmental tests.", "date": "2016-03", "date_type": "published", "publication": "ACS Nano", "volume": "10", "number": "3", "publisher": "American Chemical Society", "pagerange": "3102-3113", "id_number": "CaltechAUTHORS:20160223-132834891", "issn": "1936-0851", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160223-132834891", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Defense Advanced Research Projects Agency (DARPA)", "grant_number": "HR0011-11-2-0006" }, { "agency": "NIH", "grant_number": "R01EB012946" }, { "agency": "Burroughs Wellcome Fund" }, { "agency": "NSF Graduate Research Fellowship", "grant_number": "DGE-1144469" } ] }, "doi": "10.1021/acsnano.5b07338", "pmcid": "PMC4819493", "primary_object": { "basename": "acsnano_2E5b07338.pdf", "url": "https://authors.library.caltech.edu/records/fycvn-0ez10/files/acsnano_2E5b07338.pdf" }, "related_objects": [ { "basename": "nn5b07338_si_001.pdf", "url": "https://authors.library.caltech.edu/records/fycvn-0ez10/files/nn5b07338_si_001.pdf" } ], "resource_type": "article", "pub_year": "2016", "author_list": "Rodriguez-Manzano, Jesus; Karymov, Mikhail A.; et el." }, { "id": "https://authors.library.caltech.edu/records/563jp-mhk84", "eprint_id": 60339, "eprint_status": "archive", "datestamp": "2023-08-20 10:01:51", "lastmod": "2023-10-24 16:27:01", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Khorosheva-Eugenia-M", "name": { "family": "Khorosheva", "given": "Eugenia M." }, "orcid": "0000-0003-3620-4884" }, { "id": "Karymov-Mikhail-A", "name": { "family": "Karymov", "given": "Mikhail A." } }, { "id": "Selck-David-A", "name": { "family": "Selck", "given": "David A." }, "orcid": "0000-0002-0591-4165" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Lack of correlation between reaction speed and analytical sensitivity in isothermal amplification reveals the value of digital methods for optimization: validation using digital real-time RT-LAMP", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2015 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. \n\nReceived September 12, 2014. Revision received August 14, 2015. Accepted August 20, 2015. First published online: September 10, 2015. \n\nWe thank Dr Nathan Tanner for providing the New England Biolabs enzyme system RTx Bst 2.0 specially designed for performing RT-LAMP reactions in one step; Matthew S. Curtis for HCV LAMP amplicon secondary structure predictions; Jesus Rodriguez-Manzano for his advice and help with bioinformatics and for independent validation experiments; and Natasha Shelby for contributions to writing and editing this manuscript. \n\nFunding:DARPA Cooperative Agreement No. HR0011-11-2-0006, National Institutes of Health [R01EB012946]; NIH Director's Pioneer Award DP1OD003584; NIH NRSA [5T32GM07616NSF to D.A.S.]; Caltech Innovation Initiative CI2. The content of this article does not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred. Funding for open access charge: DARPA Cooperative Agreement No. HR0011-11-2-0006. \n\nConflict of interest statement. Rustem F. Ismagilov has a financial interest in SlipChip Corp.\n\nPublished - Nucl._Acids_Res.-2016-Khorosheva-e10.pdf
Supplemental Material - Isothermal_NAR_SI_revised_9.1.15.pdf
", "abstract": "In this paper, we asked if it is possible to identify the best primers and reaction conditions based on improvements in reaction speed when optimizing isothermal reactions. We used digital single-molecule, real-time analyses of both speed and efficiency of isothermal amplification reactions, which revealed that improvements in the speed of isothermal amplification reactions did not always correlate with improvements in digital efficiency (the fraction of molecules that amplify) or with analytical sensitivity. However, we observed that the speeds of amplification for single-molecule (in a digital device) and multi-molecule (e.g. in a PCR well plate) formats always correlated for the same conditions. Also, digital efficiency correlated with the analytical sensitivity of the same reaction performed in a multi-molecule format. Our finding was supported experimentally with examples of primer design, the use or exclusion of loop primers in different combinations, and the use of different enzyme mixtures in one-step reverse-transcription loop-mediated amplification (RT-LAMP). Our results show that measuring the digital efficiency of amplification of single-template molecules allows quick, reliable comparisons of the analytical sensitivity of reactions under any two tested conditions, independent of the speeds of the isothermal amplification reactions.", "date": "2016-01-29", "date_type": "published", "publication": "Nucleic Acids Research", "volume": "44", "number": "2", "publisher": "Oxford University Press", "pagerange": "Art. No. E10", "id_number": "CaltechAUTHORS:20150918-141812518", "issn": "0305-1048", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150918-141812518", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Defense Advanced Research Projects Agency (DARPA)", "grant_number": "HR0011-11-2-0006" }, { "agency": "NIH", "grant_number": "R01EB012946" }, { "agency": "NIH", "grant_number": "DP1OD003584" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "5T32GM07616NSF" }, { "agency": "Caltech Innovation Initiative (CI2)" } ] }, "doi": "10.1093/nar/gkv877", "pmcid": "PMC4737171", "primary_object": { "basename": "Isothermal_NAR_SI_revised_9.1.15.pdf", "url": "https://authors.library.caltech.edu/records/563jp-mhk84/files/Isothermal_NAR_SI_revised_9.1.15.pdf" }, "related_objects": [ { "basename": "Nucl._Acids_Res.-2016-Khorosheva-e10.pdf", "url": "https://authors.library.caltech.edu/records/563jp-mhk84/files/Nucl._Acids_Res.-2016-Khorosheva-e10.pdf" } ], "resource_type": "article", "pub_year": "2016", "author_list": "Khorosheva, Eugenia M.; Karymov, Mikhail A.; et el." }, { "id": "https://authors.library.caltech.edu/records/ycm4f-g2c72", "eprint_id": 58448, "eprint_status": "archive", "datestamp": "2023-08-20 06:03:59", "lastmod": "2023-10-23 19:21:39", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Yeon-Ju-Hun", "name": { "family": "Yeon", "given": "Ju Hun" } }, { "id": "Chan-Karen-Y-T", "name": { "family": "Chan", "given": "Karen Y. T." } }, { "id": "Wong-Ting-Chia", "name": { "family": "Wong", "given": "Ting-Chia" } }, { "id": "Chan-Kelvin", "name": { "family": "Chan", "given": "Kelvin" } }, { "id": "Sutherland-M-R", "name": { "family": "Sutherland", "given": "Michael R." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Pryzdial-E-L-G", "name": { "family": "Pryzdial", "given": "Edward L. G." } }, { "id": "Kastrup-C-J", "name": { "family": "Kastrup", "given": "Christian J." } } ] }, "title": "A biochemical network can control formation of a synthetic material by sensing numerous specific stimuli", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2015 Macmillan Publishers Limited. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/\n\nReceived 30 January 2015; Accepted 10 April 2015; Published 15 May 2015.\n\nThis work was funded by Canadian Institutes of Health Research (MOP-119426 and MSH-130166), the Canadian Foundation for Innovation (31928), and the BC Knowledge Development Fund. We thank S. Novakowski, J. Baylis, N. Mazinani, and B. Pentelute for helpful suggestions, and D. Horne from the UBC Bioimaging facility for help with SEM. \n\nAuthor Contributions: J.H.Y., K.Y.T.C., T.C.W., R.F.I., E.L.G.P., and C.J.K. conceived the hypotheses, methods, and applications; K.Y.T.C., J.H.Y., T.C.W., K.C., M.R.S., and C.J.K. performed experiments; K.Y.T.C., J.H.Y., T.C.W., K.C., and C.J.K. analyzed data; K.Y.T.C., J.H.Y., T.C.W., and C.J.K. wrote the manuscript; and all authors discussed results and commented on the manuscript. J.H.Y. and K.Y.T.C. contributed equally. \n\nCompeting financial interests: The authors declare no competing financial interests.\n\nPublished - srep10274.pdf
Supplemental Material - srep10274-s1.pdf
", "abstract": "Developing bio-compatible smart materials that assemble in response to environmental cues requires strategies that can discriminate multiple specific stimuli in a complex milieu. Synthetic materials have yet to achieve this level of sensitivity, which would emulate the highly evolved and tailored reaction networks of complex biological systems. Here we show that the output of a naturally occurring network can be replaced with a synthetic material. Exploiting the blood coagulation system as an exquisite biological sensor, the fibrin clot end-product was replaced with a synthetic material under the biological control of a precisely regulated cross-linking enzyme. The functions of the coagulation network remained intact when the material was incorporated. Clot-like polymerization was induced in indirect response to distinct small molecules, phospholipids, enzymes, cells, viruses, an inorganic solid, a polyphenol, a polysaccharide, and a membrane protein. This strategy demonstrates for the first time that an existing stimulus-responsive biological network can be used to control the formation of a synthetic material by diverse classes of physiological triggers.", "date": "2015-05", "date_type": "published", "publication": "Scientific Reports", "volume": "5", "number": "5", "publisher": "Nature Publishing Group", "pagerange": "Art. No. 10274", "id_number": "CaltechAUTHORS:20150623-114233631", "issn": "2045-2322", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150623-114233631", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Canadian Institutes of Health Research (CIHR)", "grant_number": "MOP-119426" }, { "agency": "Canadian Institutes of Health Research (CIHR)", "grant_number": "MSH-130166" }, { "agency": "Canadian Foundation for Innovation (CFI)", "grant_number": "31928" }, { "agency": "British Columbia Knowledge Development Fund" } ] }, "doi": "10.1038/srep10274", "pmcid": "PMC4432564", "primary_object": { "basename": "srep10274-s1.pdf", "url": "https://authors.library.caltech.edu/records/ycm4f-g2c72/files/srep10274-s1.pdf" }, "related_objects": [ { "basename": "srep10274.pdf", "url": "https://authors.library.caltech.edu/records/ycm4f-g2c72/files/srep10274.pdf" } ], "resource_type": "article", "pub_year": "2015", "author_list": "Yeon, Ju Hun; Chan, Karen Y. T.; et el." }, { "id": "https://authors.library.caltech.edu/records/1n749-wdv15", "eprint_id": 56514, "eprint_status": "archive", "datestamp": "2023-08-20 05:47:06", "lastmod": "2023-10-23 15:37:10", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Yano-Jessica-M", "name": { "family": "Yano", "given": "Jessica M." } }, { "id": "Yu-Kristie-B", "name": { "family": "Yu", "given": "Kristie" }, "orcid": "0000-0001-6735-3968" }, { "id": "Donaldson-Gregory-P", "name": { "family": "Donaldson", "given": "Gregory P." }, "orcid": "0000-0002-8551-374X" }, { "id": "Shastri-Gauri-G", "name": { "family": "Shastri", "given": "Gauri G." } }, { "id": "Ann-Phoebe", "name": { "family": "Ann", "given": "Phoebe" } }, { "id": "Ma-Liang", "name": { "family": "Ma", "given": "Liang" } }, { "id": "Nagler-Cathryn-R", "name": { "family": "Nagler", "given": "Cathryn R." }, "orcid": "0000-0001-7254-6617" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Mazmanian-S-K", "name": { "family": "Mazmanian", "given": "Sarkis K." }, "orcid": "0000-0003-2713-1513" }, { "id": "Hsiao-Elaine-Y-Bio", "name": { "family": "Hsiao", "given": "Elaine Y." }, "orcid": "0000-0002-1633-588X" } ] }, "title": "Indigenous Bacteria from the Gut Microbiota Regulate Host Serotonin Biosynthesis", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2015 Elsevier Inc. \n\nReceived: September 25, 2014; Revised: December 16, 2014; Accepted: February 18, 2015; Published: April 9, 2015. \n\nThe authors acknowledge the assistance of Andrew Stefka and Taylor Feehley (University of Chicago) for contributing pilot serum and fecal samples, Taren Thron, Sara McBride, and Alyssa Maskell for caring for the animals, Drs. Nathan Dalleska and Jesse Allen (Caltech) for conducting pilot LC/MS experiments, Said Bogatyrev (Caltech) for helpful advice, Natasha Shelby (Caltech) for editing the manuscript, and the late Dr. Paul H. Patterson for his valuable support. This work was supported by the NIH Director's Early Independence Award (5DP5OD017924 to E.Y.H.), Caltech Center for Environmental Microbial Interactions Award (to E.Y.H.), National Science Foundatio (NSF) Emerging Frontiers in Research and Innovation Award (EFRI-1137089 to R.F.I. and S.K.M.), National Human Genome Research Institute (NHGRI) grant (R01HG005826 to R.F.I.), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant (DK078938 to S.K.M.) and National Institute of Mental Health (NIMH) grant (MH100556 to S.K.M.), National Institute of Allergy and Infectious Diseases (NIAID) grant (AI106302 to C.R.N.), and Food Allergy Research and Education (FARE) and University of Chicago Digestive Diseases Center Core Grant (P30DK42086 to C.R.N.).\n\nIn Figure S5D of this article, the representative flow cytometry plot of forward versus side scatter for unstimulated platelets was incorrectly duplicated during the final formatting of the paper for SPF+PCPA and GF conditions. The figure has been corrected online, and the originally published descriptions of the results in the text and figure legend are accurate.\n\nIn Figure 3A, the \"GF+conv\" bar represents germ-free (GF) mice conventionalized with standard pathogen-free (SPF) microbiota on postnatal day 21 (P21). The published main text incorrectly referred to conventionalization on P42. Though we show in Figure 1B very similar levels of colonic serotonin after conventionalization on P21 versus P42, the \"GF+conv\" data in Figure 3A is specifically from GF mice conventionalized on P21. This error in the text has also been corrected online.\n\nOverall, these changes have no bearing on the experimental results or conclusions presented in the manuscript. We apologize for any inconvenience that these errors have caused.\n\nAccepted Version - nihms669675.pdf
Supplemental Material - table_s1.xls
", "abstract": "The gastrointestinal (GI) tract contains much of the body's serotonin (5-hydroxytryptamine, 5-HT), but mechanisms controlling the metabolism of gut-derived 5-HT remain unclear. Here, we demonstrate that the microbiota plays a critical role in regulating host 5-HT. Indigenous spore-forming bacteria (Sp) from the mouse and human microbiota promote 5-HT biosynthesis from colonic enterochromaffin cells (ECs), which supply 5-HT to the mucosa, lumen, and circulating platelets. Importantly, microbiota-dependent effects on gut 5-HT significantly impact host physiology, modulating GI motility and platelet function. We identify select fecal metabolites that are increased by Sp and that elevate 5-HT in chromaffin cell cultures, suggesting direct metabolic signaling of gut microbes to ECs. Furthermore, elevating luminal concentrations of particular microbial metabolites increases colonic and blood 5-HT in germ-free mice. Altogether, these findings demonstrate that Sp are important modulators of host 5-HT and further highlight a key role for host-microbiota interactions in regulating fundamental 5-HT-related biological processes.", "date": "2015-04-09", "date_type": "published", "publication": "Cell", "volume": "161", "number": "2", "publisher": "Cell Press", "pagerange": "264-276", "id_number": "CaltechAUTHORS:20150409-093248232", "issn": "0092-8674", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150409-093248232", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "5DP5OD017924" }, { "agency": "Caltech Center for Environmental Microbial Interactions (CEMI)" }, { "agency": "NSF", "grant_number": "EFRI-1137089" }, { "agency": "NIH", "grant_number": "R01HG005826" }, { "agency": "NIH", "grant_number": "DK078938" }, { "agency": "NIH", "grant_number": "MH100556" }, { "agency": "NIH", "grant_number": "AI106302" }, { "agency": "NIH", "grant_number": "P30DK42086" } ] }, "local_group": { "items": [ { "id": "Caltech-Center-for-Environmental-Microbial-Interactions-(CEMI)" } ] }, "doi": "10.1016/j.cell.2015.02.047", "pmcid": "PMC4393509", "primary_object": { "basename": "nihms669675.pdf", "url": "https://authors.library.caltech.edu/records/1n749-wdv15/files/nihms669675.pdf" }, "related_objects": [ { "basename": "table_s1.xls", "url": "https://authors.library.caltech.edu/records/1n749-wdv15/files/table_s1.xls" } ], "resource_type": "article", "pub_year": "2015", "author_list": "Yano, Jessica M.; Yu, Kristie; et el." }, { "id": "https://authors.library.caltech.edu/records/3kz0k-z7430", "eprint_id": 50021, "eprint_status": "archive", "datestamp": "2023-08-20 04:05:39", "lastmod": "2024-01-09 20:37:24", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Begolo-S", "name": { "family": "Begolo", "given": "Stefano" } }, { "id": "Zhukov-D-V", "name": { "family": "Zhukov", "given": "Dmitriy V." }, "orcid": "0000-0002-4834-3147" }, { "id": "Selck-D-A", "name": { "family": "Selck", "given": "David A." } }, { "id": "Li-Liang", "name": { "family": "Li", "given": "Liang" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "The pumping lid: investigating multi-material 3D printing for equipment-free, programmable generation of positive and negative pressures for microfluidic applications", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2014 Royal Society of Chemistry.\n\nReceived 5th August 2014; accepted 5th September 2014.\n\nFirst published online 18 Sep 2014.\n\nThis work was funded in part by DARPA Cooperative Agreement\nHR0011-11-2-0006 and National Institutes of Health\nNRSA training grant 5T32GM07616NSF (to D.A.S.). This material is also based upon work supported by a National Science Foundation Graduate Research Fellowship under grant no. DGE\u20101144469 (to D.V.Z.). This paper does not necessarily\nreflect the position or policy of the U.S. government or these agencies, and no official endorsement should be inferred. We wish to thank Mikhail Karymov for preliminary experiments, Roberta Poceviciute for help with the theoretical analysis, and Natasha Shelby for contributions to writing and editing this manuscript. We also wish to thank the 6 year-old volunteer for performing the demonstrations shown in Fig. 6. Disclosure: R.F.I. and L.L. have a financial interest in SlipChip Corp.\n\nPublished - c4lc00910j.pdf
Supplemental Material - c4lc00910j1.mp4
Supplemental Material - c4lc00910j2.pdf
", "abstract": "Equipment-free pumping is a challenging problem and an active area of research in microfluidics, with applications for both laboratory and limited-resource settings. This paper describes the pumping lid method, a strategy to achieve equipment-free pumping by controlled generation of pressure. Pressure was generated using portable, lightweight, and disposable parts that can be integrated with existing microfluidic devices to simplify workflow and eliminate the need for pumping equipment. The development of this method was enabled by multi-material 3D printing, which allows fast prototyping, including composite parts that combine materials with different mechanical properties (e.g. both rigid and elastic materials in the same part). The first type of pumping lid we describe was used to produce predictable positive or negative pressures via controlled compression or expansion of gases. A model was developed to describe the pressures and flow rates generated with this approach and it was validated experimentally. Pressures were pre-programmed by the geometry of the parts and could be tuned further even while the experiment was in progress. Using multiple lids or a composite lid with different inlets enabled several solutions to be pumped independently in a single device. The second type of pumping lid, which relied on vapor\u2013liquid equilibrium to generate pressure, was designed, modeled, and experimentally characterized. The pumping lid method was validated by controlling flow in different types of microfluidic applications, including the production of droplets, control of laminar flow profiles, and loading of SlipChip devices. We believe that applying the pumping lid methodology to existing microfluidic devices will enhance their use as portable diagnostic tools in limited resource settings as well as accelerate adoption of microfluidics in laboratories.", "date": "2014-12-21", "date_type": "published", "publication": "Lab on a Chip", "volume": "14", "number": "24", "publisher": "Royal Society of Chemistry", "pagerange": "4616-4628", "id_number": "CaltechAUTHORS:20140925-085504154", "issn": "1473-0197", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140925-085504154", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Defense Advanced Research Projects Agency (DARPA)", "grant_number": "HR0011-11-2-0006" }, { "agency": "NIH", "grant_number": "5T32GM07616NSF" }, { "agency": "NSF Graduate Research Fellowship", "grant_number": "DGE\u20101144469" } ] }, "doi": "10.1039/C4LC00910J", "pmcid": "PMC10773560", "primary_object": { "basename": "c4lc00910j1.mp4", "url": "https://authors.library.caltech.edu/records/3kz0k-z7430/files/c4lc00910j1.mp4" }, "related_objects": [ { "basename": "c4lc00910j2.pdf", "url": "https://authors.library.caltech.edu/records/3kz0k-z7430/files/c4lc00910j2.pdf" }, { "basename": "c4lc00910j.pdf", "url": "https://authors.library.caltech.edu/records/3kz0k-z7430/files/c4lc00910j.pdf" } ], "resource_type": "article", "pub_year": "2014", "author_list": "Begolo, Stefano; Zhukov, Dmitriy V.; et el." }, { "id": "https://authors.library.caltech.edu/records/n8jjf-1v846", "eprint_id": 52770, "eprint_status": "archive", "datestamp": "2023-08-20 03:47:46", "lastmod": "2023-10-18 21:04:04", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Kelley-S-O", "name": { "family": "Kelley", "given": "Shana O." }, "orcid": "0000-0003-3360-5359" }, { "id": "Mirkin-C-A", "name": { "family": "Mirkin", "given": "Chad A." }, "orcid": "0000-0002-6634-7627" }, { "id": "Walt-D-R", "name": { "family": "Walt", "given": "David R." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Toner-M", "name": { "family": "Toner", "given": "Mehmet" } }, { "id": "Sargent-E-H", "name": { "family": "Sargent", "given": "Edward H." }, "orcid": "0000-0003-0396-6495" } ] }, "title": "Advancing the speed, sensitivity and accuracy of biomolecular detection using multi-length-scale engineering", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2014 Macmillan Publishers Limited. All rights reserved\n\nReceived 9 March 2014; accepted 13 October 2014;\npublished online 3 December 2014\n\nS.O.K. and E.H.S. acknowledge Genome Canada, the Canadian Institute of Health Research, the Natural Sciences and Engineering Research Council, and the Ontario Research Fund for support of their work. M.T. acknowledges the National Institute of Health (NIH) P41 Resource Center, NIH National Institute of Biomedical Imaging and Bioengineering Quantum Grant. R.F.I acknowledges NIH grant R01EB012946 and the Defense Advanced Research Projects Agency (DARPA) Cooperative Agreement HR0011-11-2-0006 for support. D.R.W. acknowledges generous support from DARPA (HR0011-12-2,0001: SUB #5-55065) and a Department of Defense Innovator Award BC100510(W81XWH-11-1-0814). C.A.M. acknowledges support from the Center for Cancer Nanotechnology Excellence (CCNE) initiative of the National Institutes of Health (NIH), the Nanoscale Science and Engineering Centers (NSEC) initiative of the National Science Foundation, the Prostate Cancer Foundation, National Institute of Arthritis and Musculosketal and Skin Diseases/NIH, and DARPA. \n\nR.F.I. is a scientific founder, a Director, and has equity in SlipChip. D.R.W. is a scientific founder, a Director, and has equity in Quanterix. S.O.K. is a founder, a Director, and has equity in Xagenic. E.H.S. holds equity in Xagenic.\n\nAccepted Version - nihms699385.pdf
", "abstract": "Rapid progress in identifying disease biomarkers has increased the importance of creating high-performance detection technologies. Over the last decade, the design of many detection platforms has focused on either the nano or micro length scale. Here, we review recent strategies that combine nano- and microscale materials and devices to produce large improvements in detection sensitivity, speed and accuracy, allowing previously undetectable biomarkers to be identified in clinical samples. Microsensors that incorporate nanoscale features can now rapidly detect disease-related nucleic acids expressed in patient samples. New microdevices that separate large clinical samples into nanocompartments allow precise quantitation of analytes, and microfluidic systems that utilize nanoscale binding events can detect rare cancer cells in the bloodstream more accurately than before. These advances will lead to faster and more reliable clinical diagnostic devices.", "date": "2014-12", "date_type": "published", "publication": "Nature Nanotechnology", "volume": "9", "number": "12", "publisher": "Nature Publishing Group", "pagerange": "969-980", "id_number": "CaltechAUTHORS:20141212-133134775", "issn": "1748-3387", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20141212-133134775", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Genome Canada" }, { "agency": "Canadian Institutes of Health Research (CIHR)" }, { "agency": "Natural Sciences and Engineering Research Council of Canada (NSERC)" }, { "agency": "Ontario Research Fund" }, { "agency": "NIH", "grant_number": "R01EB012946" }, { "agency": "Defense Advanced Research Projects Agency (DARPA)", "grant_number": "HR0011-11-2-0006" }, { "agency": "Defense Advanced Research Projects Agency (DARPA)", "grant_number": "HR0011-12-2,0001: SUB #5-55065" }, { "agency": "Department of Defense Innovator Award", "grant_number": "BC100510(W81XWH-11-1-0814)" }, { "agency": "NSF" }, { "agency": "Prostate Cancer Foundation" } ] }, "doi": "10.1038/NNANO.2014.261", "pmcid": "PMC4472305", "primary_object": { "basename": "nihms699385.pdf", "url": "https://authors.library.caltech.edu/records/n8jjf-1v846/files/nihms699385.pdf" }, "resource_type": "article", "pub_year": "2014", "author_list": "Kelley, Shana O.; Mirkin, Chad A.; et el." }, { "id": "https://authors.library.caltech.edu/records/v0dw7-bhr74", "eprint_id": 49070, "eprint_status": "archive", "datestamp": "2023-08-20 03:27:14", "lastmod": "2023-10-17 21:07:09", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Pickard-J-M", "name": { "family": "Pickard", "given": "Joseph M." } }, { "id": "Maurice-C-F", "name": { "family": "Maurice", "given": "Corinne F." } }, { "id": "Kinnebrew-M-A", "name": { "family": "Kinnebrew", "given": "Melissa A." } }, { "id": "Abt-M-C", "name": { "family": "Abt", "given": "Michael C." } }, { "id": "Schenten-D", "name": { "family": "Schenten", "given": "Diminik" } }, { "id": "Golovkina-T-V", "name": { "family": "Golovkina", "given": "Tatyana V." } }, { "id": "Bogatyrev-S-R", "name": { "family": "Bogatyrev", "given": "Said R." }, "orcid": "0000-0003-0486-9451" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Pamer-E-G", "name": { "family": "Pamer", "given": "Eric G." } }, { "id": "Turnbaugh-P-J", "name": { "family": "Turnbaugh", "given": "Peter J." } }, { "id": "Chernovsky-A-V", "name": { "family": "Chrenovsky", "given": "Alexander V." } } ] }, "title": "Rapid fucosylation of intestinal epithelium sustains host\u2013commensal symbiosis in sickness", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2014 Macmillan Publishers Limited. \n\nReceived 16 December 2013; accepted 3 September 2014. Published online 1 October 2014. \n\nWe thank C. Reardon and C. Daly for sequencing support, H. Ye for help with metabolic cage analysis, N. F. Dalleska for assistance and use of GC\u2013MS instrumentation in the Environmental Analysis Center at the California Institute of Technology, and G. Nu\u00f1ez for luciferase-expressing C. rodentium. This work was supported by grants from the National Institutes of Health (P50 GM068763 to P.J.T., AI96706 and AI42135 to E.G.P., T32 AI065382 to J.M.P.), the Harvard Bauer Fellows Program, National Science Foundation grant EFRI-1137089 to R.F.I. and A.V.C., Digestive Disease Research Core Center grant DK42086 and a Kenneth Rainin Foundation grant to A.V.C. \n\nJ.M.P., M.A.K., M.C.A. and E.G.P. performed analysis of inducible fucosylation in mice, including mutant strains; J.M.P. and C.F.M. produced DNA and RNA sequencing data and P.J.T. analysed these data; D.S. produced Myd88fl/fl mice; T.V.G. produced GF BALB/c mice and performed cytokine ELISA analysis; S.R.B. and R.F.I. performed analysis of short-chain fatty acids; R.F.I., E.G.P. and P.J.T. contributed to writing of the manuscript; A.V.C. conceived the project, analysed the results and wrote the manuscript. All authors discussed the results and commented on the manuscript. \n\nCompeting financial interests: The authors declare no competing financial interests.\n\nAccepted Version - nihms-625847.pdf
Supplemental Material - nature13823-s1.pdf
", "abstract": "Systemic infection induces conserved physiological responses that include both resistance and 'tolerance of infection' mechanisms. Temporary anorexia associated with an infection is often beneficial, reallocating energy from food foraging towards resistance to infection or depriving pathogens of nutrients. However, it imposes a stress on intestinal commensals, as they also experience reduced substrate availability; this affects host fitness owing to the loss of caloric intake and colonization resistance (protection from additional infections). We hypothesized that the host might utilize internal resources to support the gut microbiota during the acute phase of the disease. Here we show that systemic exposure to Toll-like receptor (TLR) ligands causes rapid \u03b1(1,2)-fucosylation of small intestine epithelial cells (IECs) in mice, which requires the sensing of TLR agonists, as well as the production of interleukin (IL)-23 by dendritic cells, activation of innate lymphoid cells and expression of fucosyltransferase 2 (Fut2) by IL-22-stimulated IECs. Fucosylated proteins are shed into the lumen and fucose is liberated and metabolized by the gut microbiota, as shown by reporter bacteria and community-wide analysis of microbial gene expression. Fucose affects the expression of microbial metabolic pathways and reduces the expression of bacterial virulence genes. It also improves host tolerance of the mild pathogen Citrobacter rodentium. Thus, rapid IEC fucosylation appears to be a protective mechanism that utilizes the host's resources to maintain host\u2013microbial interactions during pathogen-induced stress.", "date": "2014-10-30", "date_type": "published", "publication": "Nature", "volume": "514", "number": "7524", "publisher": "Nature Publishing Group", "pagerange": "638-641", "id_number": "CaltechAUTHORS:20140829-120953993", "issn": "0028-0836", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140829-120953993", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "P50 GM068763" }, { "agency": "NIH", "grant_number": "AI96706" }, { "agency": "NIH", "grant_number": "AI42135" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "T32 AI065382" }, { "agency": "Harvard Bauer Fellows Program" }, { "agency": "NSF", "grant_number": "EFRI-1137089" }, { "agency": "NIH", "grant_number": "DK42086" }, { "agency": "Kenneth Rainin Foundation" } ] }, "doi": "10.1038/nature13823", "pmcid": "PMC4214913", "primary_object": { "basename": "nature13823-s1.pdf", "url": "https://authors.library.caltech.edu/records/v0dw7-bhr74/files/nature13823-s1.pdf" }, "related_objects": [ { "basename": "nihms-625847.pdf", "url": "https://authors.library.caltech.edu/records/v0dw7-bhr74/files/nihms-625847.pdf" } ], "resource_type": "article", "pub_year": "2014", "author_list": "Pickard, Joseph M.; Maurice, Corinne F.; et el." }, { "id": "https://authors.library.caltech.edu/records/fxrae-42803", "eprint_id": 50404, "eprint_status": "archive", "datestamp": "2023-08-20 03:24:09", "lastmod": "2023-10-17 23:26:16", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Ge-Shencheng", "name": { "family": "Ge", "given": "Shencheng" } }, { "id": "Liu-Weishan", "name": { "family": "Liu", "given": "Weishan" } }, { "id": "Schlappi-T-S", "name": { "family": "Schlappi", "given": "Travis" }, "orcid": "0000-0001-6132-6459" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Digital, Ultrasensitive, End-Point Protein Measurements with Large Dynamic Range via Brownian Trapping with Drift", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2014 American Chemical Society. ACS AuthorChoice - This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. \n\nReceived: July 31, 2014. Publication Date (Web): October 7, 2014. \n\nThis work was supported by DARPA Cooperative Agreement\nHR0011-11-2-0006. We thank Kevin Kan, Melissa Melendes,\nShawn Hsu, Songzi Kou, Alexander Tucker-Schwartz, Mikhail\nKarymov, Jason Kreutz and Stephanie McCalla for discussions\nand experimental help, and Natasha Shelby for contributions to\nwriting and editing this manuscript.\n\nPublished - ja507849b.pdf
Supplemental Material - ja507849b_si_001.pdf
", "abstract": "This communication shows that the concept of Brownian trapping with drift can be applied to improve quantitative molecular measurements. It has the potential to combine the robustness of end-point spatially resolved readouts, the ultrasensitivity of digital single-molecule measurements, and the large dynamic range of qPCR; furthermore, at low concentrations of analytes, it can provide a direct comparison of the signals arising from the analyte and from the background. It relies on the finding that molecules simultaneously diffusing, drifting (via slow flow), and binding to an array of nonsaturable surface traps have an exponentially decreasing probability of escaping the traps over time and therefore give rise to an exponentially decaying distribution of trapped molecules in space. This concept was tested with enzyme and protein measurements in a microfluidic device.", "date": "2014-10-22", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "136", "number": "42", "publisher": "American Chemical Society", "pagerange": "14662-14665", "id_number": "CaltechAUTHORS:20141015-105804358", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20141015-105804358", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Defense Advanced Research Projects Agency (DARPA)", "grant_number": "HR0011-11-2-0006" } ] }, "doi": "10.1021/ja507849b", "primary_object": { "basename": "ja507849b.pdf", "url": "https://authors.library.caltech.edu/records/fxrae-42803/files/ja507849b.pdf" }, "related_objects": [ { "basename": "ja507849b_si_001.pdf", "url": "https://authors.library.caltech.edu/records/fxrae-42803/files/ja507849b_si_001.pdf" } ], "resource_type": "article", "pub_year": "2014", "author_list": "Ge, Shencheng; Liu, Weishan; et el." }, { "id": "https://authors.library.caltech.edu/records/y9fxh-aht69", "eprint_id": 46116, "eprint_status": "archive", "datestamp": "2023-08-20 02:53:12", "lastmod": "2023-10-26 18:42:01", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Witters-D", "name": { "family": "Witters", "given": "Daan" } }, { "id": "Sun-Bing", "name": { "family": "Sun", "given": "Bing" } }, { "id": "Begolo-S", "name": { "family": "Begolo", "given": "Stefano" } }, { "id": "Rodriguez-Manzano-J", "name": { "family": "Rodriguez-Manzano", "given": "Jesus" } }, { "id": "Robles-W", "name": { "family": "Robles", "given": "Whitney" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Digital biology and chemistry", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2014 The Royal Society of Chemistry. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. \n\nReceived 27 Feb 2014, Accepted 19 May 2014,\nFirst published online 02 Jun 2014.\n\nWe would like to thank the five-year-old volunteer for\nperforming the demonstration in Video S1, the six-year-old\nvolunteer for performing the demonstration shown in Video S2,\nand Liang Li of SlipChip Corp. for providing the chip used\nin this experiment. Disclosure: R.F.I. has a financial interest\nin SlipChip Corp.\n\nPublished - c4lc00248b.pdf
Supplemental Material - VideoS1.mp4
Supplemental Material - VideoS2.mp4
", "abstract": "This account examines developments in \"digital\" biology and chemistry within the context of microfluidics, from a personal perspective. Using microfluidics as a frame of reference, we identify two areas of research within digital biology and chemistry that are of special interest: (i) the study of systems that switch between discrete states in response to changes in chemical concentration of signals, and (ii) the study of single biological entities such as molecules or cells. In particular, microfluidics accelerates analysis of switching systems (i.e., those that exhibit a sharp change in output over a narrow range of input) by enabling monitoring of multiple reactions in parallel over a range of concentrations of signals. Conversely, such switching systems can be used to create new kinds of microfluidic detection systems that provide \"analog-to-digital\" signal conversion and logic. Microfluidic compartmentalization technologies for studying and isolating single entities can be used to reconstruct and understand cellular processes, study interactions between single biological entities, and examine the intrinsic heterogeneity of populations of molecules, cells, or organisms. Furthermore, compartmentalization of single cells or molecules in \"digital\" microfluidic experiments can induce switching in a range of reaction systems to enable sensitive detection of cells or biomolecules, such as with digital ELISA or digital PCR. This \"digitizing\" offers advantages in terms of robustness, assay design, and simplicity because quantitative information can be obtained with qualitative measurements. While digital formats have been shown to improve the robustness of existing chemistries, we anticipate that in the future they will enable new chemistries to be used for quantitative measurements, and that digital biology and chemistry will continue to provide further opportunities for measuring biomolecules, understanding natural systems more deeply, and advancing molecular and cellular analysis. Microfluidics will impact digital biology and chemistry and will also benefit from them if it becomes massively distributed.", "date": "2014-09-07", "date_type": "published", "publication": "Lab on a Chip", "volume": "14", "number": "17", "publisher": "Royal Society of Chemistry", "pagerange": "3225-3232", "id_number": "CaltechAUTHORS:20140606-091339805", "issn": "1473-0197", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140606-091339805", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1039/c4lc00248b", "primary_object": { "basename": "VideoS1.mp4", "url": "https://authors.library.caltech.edu/records/y9fxh-aht69/files/VideoS1.mp4" }, "related_objects": [ { "basename": "VideoS2.mp4", "url": "https://authors.library.caltech.edu/records/y9fxh-aht69/files/VideoS2.mp4" }, { "basename": "c4lc00248b.pdf", "url": "https://authors.library.caltech.edu/records/y9fxh-aht69/files/c4lc00248b.pdf" } ], "resource_type": "article", "pub_year": "2014", "author_list": "Witters, Daan; Sun, Bing; et el." }, { "id": "https://authors.library.caltech.edu/records/72rme-7f619", "eprint_id": 46410, "eprint_status": "archive", "datestamp": "2023-08-20 02:03:34", "lastmod": "2023-10-26 19:43:42", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Ma-Liang", "name": { "family": "Ma", "given": "Liang" } }, { "id": "Datta-S-S", "name": { "family": "Datta", "given": "Sujit S." }, "orcid": "0000-0003-2400-1561" }, { "id": "Karymov-M-A", "name": { "family": "Karymov", "given": "Mikhail A." } }, { "id": "Pan-Qichao", "name": { "family": "Pan", "given": "Qichao" } }, { "id": "Begolo-S", "name": { "family": "Begolo", "given": "Stefano" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Individually addressable arrays of replica microbial cultures enabled by splitting SlipChips", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2014 The Royal Society of Chemistry. \n\nReceived 15th May 2014, Accepted 5th June 2014. \n\nFirst published online 23 Jun 2014.\n\nThis work was supported by the National Human Genome\nResearch Institute of the National Institutes of Health under\nAward Number R01HG005826. We thank Toan Huynh for\nwriting scripts for laser fabrication of through-holes on a\nSlipChip, Helmut Krebs and chemistry student shop at the\nUniversity of Chicago for fabricating the holder, Whitney\nRobles for contributions to writing and editing this manuscript,\nand Elena Davydova and George Sawicki for helpful discussions.\nWork with clinical samples is approved by the Institutional\nReview Boards at Caltech and the University of Chicago,\nand by the Institutional Biosafety Committee. We thank Dr\nEugene Chang, Dr Thomas Schmidt, Dongjuan Dai, and Kwi\nKim for providing archived de-identified clinical samples and\nfor helpful discussions and advice. Disclosure: R.F.I. has a\nfinancial interest in SlipChip Corporation.\n\nPublished - c4ib00109e.pdf
Supplemental Material - c4ib00109e1.pdf
", "abstract": "Isolating microbes carrying genes of interest from environmental samples is important for applications in biology and medicine. However, this involves the use of genetic assays that often require lysis of microbial cells, which is not compatible with the goal of obtaining live cells for isolation and culture. This paper describes the design, fabrication, biological validation, and underlying physics of a microfluidic SlipChip device that addresses this challenge. The device is composed of two conjoined plates containing 1000 microcompartments, each comprising two juxtaposed wells, one on each opposing plate. Single microbial cells are stochastically confined and subsequently cultured within the microcompartments. Then, we split each microcompartment into two replica droplets, both containing microbial culture, and then controllably separate the two plates while retaining each droplet within each well. We experimentally describe the droplet retention as a function of capillary pressure, viscous pressure, and viscosity of the aqueous phase. Within each pair of replicas, one can be used for genetic analysis, and the other preserves live cells for growth. This microfluidic approach provides a facile way to cultivate anaerobes from complex communities. We validate this method by targeting, isolating, and culturing Bacteroides vulgatus, a core gut anaerobe, from a clinical sample. To date, this methodology has enabled isolation of a novel microbial taxon, representing a new genus. This approach could also be extended to the study of other microorganisms and even mammalian systems, and may enable targeted retrieval of solutions in applications including digital PCR, sequencing, single cell analysis, and protein crystallization.", "date": "2014-08", "date_type": "published", "publication": "Integrative Biology", "volume": "6", "number": "8", "publisher": "Royal Society of Chemistry", "pagerange": "796-805", "id_number": "CaltechAUTHORS:20140620-180156638", "issn": "1757-9694", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140620-180156638", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01HG005826" } ] }, "doi": "10.1039/c4ib00109e", "pmcid": "PMC4131746", "primary_object": { "basename": "c4ib00109e.pdf", "url": "https://authors.library.caltech.edu/records/72rme-7f619/files/c4ib00109e.pdf" }, "related_objects": [ { "basename": "c4ib00109e1.pdf", "url": "https://authors.library.caltech.edu/records/72rme-7f619/files/c4ib00109e1.pdf" } ], "resource_type": "article", "pub_year": "2014", "author_list": "Ma, Liang; Datta, Sujit S.; et el." }, { "id": "https://authors.library.caltech.edu/records/zz27g-zjb70", "eprint_id": 46161, "eprint_status": "archive", "datestamp": "2023-08-22 13:15:52", "lastmod": "2023-10-26 18:43:53", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Sun-Bing", "name": { "family": "Sun", "given": "Bing" } }, { "id": "Rodriguez-Manzano-Jesus", "name": { "family": "Rodriguez-Manzano", "given": "Jesus" } }, { "id": "Selck-David-A", "name": { "family": "Selck", "given": "David A." } }, { "id": "Korosheva-Eugenia", "name": { "family": "Khorosheva", "given": "Eugenia" } }, { "id": "Karymov-Mikhail-A", "name": { "family": "Karymov", "given": "Mikhail A." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Measuring Fate and Rate of Single-Molecule Competition of Amplification and Restriction Digestion, and Its Use for Rapid Genotyping Tested with Hepatitis C Viral RNA", "ispublished": "pub", "full_text_status": "public", "keywords": "Analysemethoden; Einzelmolek\u00fclstudien; Genotypisierung; Globale Gesundheit; Hepatitis C", "note": "\u00a9 2014 Wiley-VCH Verlag GmbH & Co. Manuscript Received: 5 Mar 2014. Article first published online: 2 Jun 2014. Early View (Online Version of Record published before inclusion in an issue). This research was supported by NIH grants R01EB012946 and DP1OD003584, the Caltech Innovation Initiative, and NIH/NRSA training grant 5T32GM07616. We thank T. Schlappi for data analysis, A. Tucker-Schwartz for helpful discussions, and Whitney Robles for contributions to the preparation of this manuscript. R.F.I. has a financial interest in SlipChip Corp.\n\nAccepted Version - nihms-603001.pdf
", "abstract": "We experimentally monitored, at the single-molecule level, the competition among reverse transcription, exponential amplification (RT-LAMP), and linear degradation (restriction enzymes) starting with hepatitis C viral RNA molecules. We found significant heterogeneity in the rate of single-molecule amplification; introduction of the restriction enzymes affected both the rate and the \"fate\" (the binary outcome) of single-molecule amplification. While end-point digital measurements were primarily sensitive to changes in fate, the bulk real-time kinetic measurements were dominated by the rate of amplification of the earliest molecules, and were not sensitive to fate of the rest of the molecules. We show how this competition of reactions can be used for rapid HCV genotyping with either digital or bulk readout. This work advances our understanding of single-molecule dynamics in reaction networks and may help bring genotyping capabilities out of clinical labs and into limited-resource settings.", "date": "2014-07-28", "date_type": "published", "publication": "Angewandte Chemie International Edition", "volume": "53", "number": "31", "publisher": "Wiley", "pagerange": "8088-8092", "id_number": "CaltechAUTHORS:20140609-150635938", "issn": "1433-7851", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140609-150635938", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01EB012946" }, { "agency": "NIH", "grant_number": "DP1OD003584" }, { "agency": "Caltech Innovation Initiative" }, { "agency": "NIH/NRSA Institutional training grant", "grant_number": "5T32 GM07616" } ] }, "doi": "10.1002/ange.201403035", "pmcid": "PMC4116457", "primary_object": { "basename": "nihms-603001.pdf", "url": "https://authors.library.caltech.edu/records/zz27g-zjb70/files/nihms-603001.pdf" }, "resource_type": "article", "pub_year": "2014", "author_list": "Sun, Bing; Rodriguez-Manzano, Jesus; et el." }, { "id": "https://authors.library.caltech.edu/records/1t9mb-4k126", "eprint_id": 46397, "eprint_status": "archive", "datestamp": "2023-08-22 13:10:09", "lastmod": "2023-10-26 19:43:04", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Ma-Liang", "name": { "family": "Ma", "given": "Liang" } }, { "id": "Kim-Jungwoo", "name": { "family": "Kim", "given": "Jungwoo" }, "orcid": "0000-0002-5215-2044" }, { "id": "Hatzenpichler-R", "name": { "family": "Hatzenpichler", "given": "Roland" }, "orcid": "0000-0002-5489-3444" }, { "id": "Karymov-M-A", "name": { "family": "Karymov", "given": "Mikhail A." } }, { "id": "Hubert-N", "name": { "family": "Hubert", "given": "Nathaniel" } }, { "id": "Hanan-I-M", "name": { "family": "Hanan", "given": "Ira M." } }, { "id": "Chang-Eugene-B", "name": { "family": "Chang", "given": "Eugene B." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Gene-targeted microfluidic cultivation validated by isolation of a gut bacterium listed in Human Microbiome Project's Most Wanted taxa", "ispublished": "pub", "full_text_status": "public", "keywords": "microscale; anaerobe; aerobe; cultivate; metagenome", "note": "\u00a9 2014 National Academy of Sciences. Freely available online through the PNAS open access option. \n\nEdited by Robert Haselkorn, The University of Chicago, Chicago, IL, and approved May 19, 2014 (received for review March 20, 2014) \n\nWe thank Igor Antoshechkin and the Jacobs Genetics and Genomics Laboratory at California Institute of Technology for help with next-generation sequencing and assembly of the genome. We thank Alasdair McDowall from Prof. Grant Jensen's lab for assistance with electron microscopy, Whitney Robles for contributions to writing and editing this manuscript, Prof. Tom Schmidt for discussions of 16S rRNA heterogeneity and experimental techniques, and for suggesting the creation of the 100 \"Most Wanted\" list at the HMP meeting, Prof. Jared Leadbetter for discussion on nomenclature of the isolate, Prof. Victoria Orphan for access to lab facilities, and Dionysios A. Antonopoulos for providing the anaerobic chamber to process the clinical samples. We thank Robert Edgar, J. Gregory Caporaso, Justin Kuczynski, William A. Walters, Hiroyuki Imachi, George M. Garrity, and Ashlee M. Earl for helpful discussions. Research reported in this publication was supported by the National Human Genome Research Institute of the National Institutes of Health under Award R01HG005826. R.H. was supported via an Erwin Schr\u04e7dinger Postdoctoral Fellowship by the Austrian Science Fund (Fonds zur F\u00f6rderung der Wissenschaftlichen Forschung; J 3162-B20). \n\nAuthor contributions: L.M., J.K., R.H., E.B.C., and R.F.I. designed research; L.M., J.K., R.H., M.A.K., N.H., and I.M.H. performed research; L.M., J.K., and R.H. analyzed data; and L.M., R.H., and R.F.I. wrote the paper. \n\nConflict of interest statement: R.F.I. has a financial interest in SlipChip Corporation. \n\nThis article is a PNAS Direct Submission. \n\nData deposition: The genome sequences reported in this paper have been deposited in the Joint Genome Institute's Integrated Microbial Genomes database, https://img.jgi.doe.gov/cgi-bin/w/main.cgi (accession no. 2545555870). The 16S rRNA gene sequences of isolate microfluidicus 1 reported in this paper have been deposited in the GenBank database (accession nos. KJ875866 and KJ875867). \n\nThis article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1404753111/-/DCSupplemental.\n\nPublished - 9768.full.pdf
Supplemental Material - pnas.1404753111.sapp.pdf
", "abstract": "This paper describes a microfluidics-based workflow for genetically targeted isolation and cultivation of microorganisms from complex clinical samples. Data sets from high-throughput sequencing suggest the existence of previously unidentified bacterial taxa and functional genes with high biomedical importance. Obtaining isolates of these targets, preferably in pure cultures, is crucial for advancing understanding of microbial genetics and physiology and enabling physical access to microbes for further applications. However, the majority of microbes have not been cultured, due in part to the difficulties of both identifying proper growth conditions and characterizing and isolating each species. We describe a method that enables genetically targeted cultivation of microorganisms through a combination of microfluidics and on- and off-chip assays. This method involves (i) identification of cultivation conditions for microbes using growth substrates available only in small quantities as well as the correction of sampling bias using a \"chip wash\" technique; and (ii) performing on-chip genetic assays while also preserving live bacterial cells for subsequent scale-up cultivation of desired microbes, by applying recently developed technology to create arrays of individually addressable replica microbial cultures. We validated this targeted approach by cultivating a bacterium, here referred to as isolate microfluidicus 1, from a human cecal biopsy. Isolate microfluidicus 1 is, to our knowledge, the first successful example of targeted cultivation of a microorganism from the high-priority group of the Human Microbiome Project's \"Most Wanted\" list, and, to our knowledge, the first cultured representative of a previously unidentified genus of the Ruminococcaceae family.", "date": "2014-07-08", "date_type": "published", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "volume": "111", "number": "27", "publisher": "National Academy of Sciences", "pagerange": "9768-9773", "id_number": "CaltechAUTHORS:20140620-103511347", "issn": "0027-8424", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20140620-103511347", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01HG005826" }, { "agency": "FWF Der Wissenschaftsfonds", "grant_number": "J 3162-B20" }, { "agency": "National Human Genome Research Institute" } ] }, "doi": "10.1073/pnas.1404753111", "pmcid": "PMC4103313", "primary_object": { "basename": "9768.full.pdf", "url": "https://authors.library.caltech.edu/records/1t9mb-4k126/files/9768.full.pdf" }, "related_objects": [ { "basename": "pnas.1404753111.sapp.pdf", "url": "https://authors.library.caltech.edu/records/1t9mb-4k126/files/pnas.1404753111.sapp.pdf" } ], "resource_type": "article", "pub_year": "2014", "author_list": "Ma, Liang; Kim, Jungwoo; et el." }, { "id": "https://authors.library.caltech.edu/records/bhj62-sf283", "eprint_id": 42341, "eprint_status": "archive", "datestamp": "2023-08-19 22:12:53", "lastmod": "2023-10-25 15:51:11", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Selck-D-A", "name": { "family": "Selck", "given": "David A." } }, { "id": "Karymov-M-A", "name": { "family": "Karymov", "given": "Mikhail A." } }, { "id": "Sun-Bing", "name": { "family": "Sun", "given": "Bing" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Increased Robustness of Single-Molecule Counting with Microfluidics, Digital Isothermal Amplification, and a Mobile Phone versus Real-Time Kinetic Measurements", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2013 American Chemical Society.\nReceived: September 23, 2013;\nAccepted: October 17, 2013;\nPublished: November 7, 2013.\n\n\nThis work was supported in part by DARPA Cooperative Agreement No. HR0011-11-2-0006, \nNIH grant No. R01EB012946, and NIH grant No. 5DP1OD003584. We thank Whitney Robles \nfor contributions to writing and editing this manuscript. We also thank the five-year-old \nvolunteer for performing the demonstration shown in Video S1.\n\nAccepted Version - nihms539046.pdf
Supplemental Material - Single_Molecule_Counting_with_Mobile_Phone_supplementary_information_revised.pdf
Supplemental Material - Video_S1.mpg
", "abstract": "Quantitative bioanalytical measurements are commonly performed in a kinetic format and are known to not be robust to perturbation that affects the kinetics itself or the measurement of kinetics. We hypothesized that the same measurements performed in a \"digital\" (single-molecule) format would show increased robustness to such perturbations. Here, we investigated the robustness of an amplification reaction (reverse-transcription loop-mediated amplification, RT-LAMP) in the context of fluctuations in temperature and time when this reaction is used for quantitative measurements of HIV-1 RNA molecules under limited-resource settings (LRS). The digital format that counts molecules using dRT-LAMP chemistry detected a 2-fold change in concentration of HIV-1 RNA despite a 6 \u00b0C temperature variation (p-value = 6.7 \u00d7 10^\u20137), whereas the traditional kinetic (real-time) format did not (p-value = 0.25). Digital analysis was also robust to a 20 min change in reaction time, to poor imaging conditions obtained with a consumer cell-phone camera, and to automated cloud-based processing of these images (R^2 = 0.9997 vs true counts over a 100-fold dynamic range). Fluorescent output of multiplexed PCR amplification could also be imaged with the cell phone camera using flash as the excitation source. Many nonlinear amplification schemes based on organic, inorganic, and biochemical reactions have been developed, but their robustness is not well understood. This work implies that these chemistries may be significantly more robust in the digital, rather than kinetic, format. It also calls for theoretical studies to predict robustness of these chemistries and, more generally, to design robust reaction architectures. The SlipChip that we used here and other digital microfluidic technologies already exist to enable testing of these predictions. Such work may lead to identification or creation of robust amplification chemistries that enable rapid and precise quantitative molecular measurements under LRS. Furthermore, it may provide more general principles describing robustness of chemical and biological networks in digital formats.", "date": "2013-11-07", "date_type": "published", "publication": "Analytical Chemistry", "volume": "85", "number": "22", "publisher": "American Chemical Society", "pagerange": "11129-11136", "id_number": "CaltechAUTHORS:20131108-122433726", "issn": "0003-2700", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20131108-122433726", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "DARPA Cooperative Agreement", "grant_number": "HR0011-11-2-0006" }, { "agency": "NIH", "grant_number": "R01EB012946" }, { "agency": "NIH Roadmap for Medical Research", "grant_number": "5DP1OD003584" } ] }, "doi": "10.1021/ac4030413", "pmcid": "PMC3924768", "primary_object": { "basename": "Single_Molecule_Counting_with_Mobile_Phone_supplementary_information_revised.pdf", "url": "https://authors.library.caltech.edu/records/bhj62-sf283/files/Single_Molecule_Counting_with_Mobile_Phone_supplementary_information_revised.pdf" }, "related_objects": [ { "basename": "Video_S1.mpg", "url": "https://authors.library.caltech.edu/records/bhj62-sf283/files/Video_S1.mpg" }, { "basename": "nihms539046.pdf", "url": "https://authors.library.caltech.edu/records/bhj62-sf283/files/nihms539046.pdf" } ], "resource_type": "article", "pub_year": "2013", "author_list": "Selck, David A.; Karymov, Mikhail A.; et el." }, { "id": "https://authors.library.caltech.edu/records/5pedx-y1p08", "eprint_id": 42058, "eprint_status": "archive", "datestamp": "2023-08-19 21:48:18", "lastmod": "2023-10-25 15:04:14", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Huynh-Toan", "name": { "family": "Huynh", "given": "Toan" } }, { "id": "Sun-Bing", "name": { "family": "Sun", "given": "Bing" } }, { "id": "Li-Liang", "name": { "family": "Li", "given": "Liang" } }, { "id": "Nichols-K-P", "name": { "family": "Nichols", "given": "Kevin P." } }, { "id": "Koyner-J-L", "name": { "family": "Koyner", "given": "Jay L." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Chemical Analog-to-Digital Signal Conversion Based on Robust Threshold Chemistry and Its Evaluation in the Context of Microfluidics-Based Quantitative Assays", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2013 American Chemical Society. \n\nPublished In Issue: October 02, 2013. Article ASAP: September 24, 2013. Received: June 24, 2013. \n\nThis work was supported in part by the NIH Director's Pioneer\nAward DP10D003584, NIH Career Development Award\nK23DK081616 (J.K.), DARPA Cooperative Agreement No.\nHR0011-11-2-0006, and ONR Grant No. N00014-08-1-0936.\nThe authors thank Jordany Maignan and Roman Manetsch for\nproviding pure syn-(S)-TZ2PIQ-A5 (AChE inhibitor), Elena K.\nDavydova and Jason E. Kreutz for aiding in selection of cystatin\nC, Liang Ma for the idea of depositing plugs, Weishan Liu for\nadvice about manipulation of magnetic beads, Andrew Chiang\nfor references about thresholds, Yu-Hsiang Hsu for suggestions\nfor the imaging of chips, Stefano Begolo for suggestions about\nimage processing, and Bridget Samuels and Whitney Robles for\ncontributions to the writing and editing of this manuscript.\n\nAccepted Version - nihms-527231.pdf
Supplemental Material - Analog_to_digital_conversion_with_threshold_chemistry_supporting_information_submitted.pdf
", "abstract": "In this article, we describe a nonlinear threshold chemistry based on enzymatic inhibition and demonstrate how it can be coupled with microfluidics to convert a chemical concentration (analog input) into patterns of ON or OFF reaction outcomes (chemical digital readout). Quantification of small changes in concentration is needed in a number of assays, such as that for cystatin C, where a 1.5-fold increase in concentration may indicate the presence of acute kidney injury or progression of chronic kidney disease. We developed an analog-to-digital chemical signal conversion that gives visual readout and applied it to an assay for cystatin C as a model target. The threshold chemistry is based on enzymatic inhibition and gives sharper responses with tighter inhibition. The chemistry described here uses acetylcholinesterase (AChE) and produces an unambiguous color change when the input is above a predetermined threshold concentration. An input gives a pattern of ON/OFF responses when subjected to a monotonic sequence of threshold concentrations, revealing the input concentration at the point of transition from OFF to ON outcomes. We demonstrated that this threshold chemistry can detect a 1.30-fold increase in concentration at 22 \u00b0C and that it is robust to experimental fluctuations: it provided the same output despite changes in temperature (22\u201334 \u00b0C) and readout time (10-fold range). We applied this threshold chemistry to diagnostics by coupling it with a traditional sandwich immunoassay for serum cystatin C. Because one quantitative measurement comprises several assays, each with its own threshold concentration, we used a microfluidic SlipChip device to process 12 assays in parallel, detecting a 1.5-fold increase (from 0.64 (49 nM) to 0.96 mg/L (74 nM)) of cystatin C in serum. We also demonstrated applicability to analysis of patient serum samples and the ability to image results using a cell phone camera. This work indicates that combining developments in nonlinear chemistries with microfluidics may lead to development of user-friendly diagnostic assays with simple readouts.", "date": "2013-10-02", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "135", "number": "39", "publisher": "American Chemical Society", "pagerange": "14775-14783", "id_number": "CaltechAUTHORS:20131024-155658108", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20131024-155658108", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "DP10D003584" }, { "agency": "NIH", "grant_number": "K23DK081616" }, { "agency": "Defense Advanced Research Projects Agency (DARPA)", "grant_number": "HR0011-11-2-0006" }, { "agency": "Office of Naval Research (ONR)", "grant_number": "N00014-08-1-0936" } ] }, "doi": "10.1021/ja4062882", "pmcid": "PMC3860884", "primary_object": { "basename": "nihms-527231.pdf", "url": "https://authors.library.caltech.edu/records/5pedx-y1p08/files/nihms-527231.pdf" }, "related_objects": [ { "basename": "Analog_to_digital_conversion_with_threshold_chemistry_supporting_information_submitted.pdf", "url": "https://authors.library.caltech.edu/records/5pedx-y1p08/files/Analog_to_digital_conversion_with_threshold_chemistry_supporting_information_submitted.pdf" } ], "resource_type": "article", "pub_year": "2013", "author_list": "Huynh, Toan; Sun, Bing; et el." }, { "id": "https://authors.library.caltech.edu/records/ynbt6-p8710", "eprint_id": 41614, "eprint_status": "archive", "datestamp": "2023-08-19 21:29:07", "lastmod": "2023-10-24 23:53:32", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Begolo-S", "name": { "family": "Begolo", "given": "Stefano" } }, { "id": "Shen-Feng", "name": { "family": "Shen", "given": "Feng" }, "orcid": "0000-0002-4709-330X" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "A microfluidic device for dry sample preservation in remote settings", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2013 The Royal Society of Chemistry.\nReceived 22 Jun 2013, Accepted 15 Aug 2013; First published online 17 Sep 2013.\n\nThis work was funded in part by DARPA Cooperative Agreement\nNo. HR0011-11-2-0006 (for plasma filtration and integration)\nand by NIH grant No. R01EB012946 administered by\nthe National Institute of Biomedical Imaging and Bioengineering\n(for initial concept development). This paper does not necessarily\nreflect the position or policy of the U.S. government\nor these agencies, and no official endorsement should be\ninferred. The authors would like to thank the Millard and\nMuriel Jacobs Genetics and Genomics Laboratory for access\nto its bioanalyzer, Liang Li for discussions about pumping\nand device fabrication, Qichao Pan for work on the bibliography,\ndiscussions about stabilization, and initial tests of\ndrying on a previous version of the device, Bing Sun and\nStephanie McCalla for their help in setting up RT-PCR\nquantification, Yu-Hsiang Hsu, Liang Ma and Alexander\nTucker-Schwartz for discussions about device design and\nproperties, Rolf Muller and Judy Muller-Cohn at Biomatrica\nInc. for useful discussions about sample preservation, and\nWhitney Robles for contributions to writing and editing\nthis manuscript. Disclosure: R.F.I. and F.S. have a financial\ninterest in SlipChip Corp.\n\nSupplemental Material - c3lc50747e.pdf
Supplemental Material - c3lc50747e.wmv
Supplemental Material - c3lc50747e_2.wmv
Supplemental Material - c3lc50747e_3.wmv
", "abstract": "This paper describes a microfluidic device for dry preservation of biological specimens at room temperature that\nincorporates chemical stabilization matrices. Long-term stabilization of samples is crucial for remote medical analysis,\nbiosurveillance, and archiving, but the current paradigm for transporting remotely obtained samples relies on\nthe costly \"cold chain\" to preserve analytes within biospecimens. We propose an alternative approach that involves\nthe use of microfluidics to preserve samples in the dry state with stabilization matrices, developed by others, that\nare based on self-preservation chemistries found in nature. We describe a SlipChip-based device that allows minimally\ntrained users to preserve samples with the three simple steps of placing a sample at an inlet, closing a lid,\nand slipping one layer of the device. The device fills automatically, and a pre-loaded desiccant dries the samples.\nLater, specimens can be rehydrated and recovered for analysis in a laboratory. This device is portable, compact,\nand self-contained, so it can be transported and operated by untrained users even in limited-resource settings. Features\nsuch as dead-end and sequential filling, combined with a \"pumping lid\" mechanism, enable precise quantification\nof the original sample's volume while avoiding overfilling. In addition, we demonstrated that the device can\nbe integrated with a plasma filtration module, and we validated device operations and capabilities by testing the\nstability of purified RNA solutions. These features and the modularity of this platform (which facilitates integration\nand simplifies operation) would be applicable to other microfluidic devices beyond this application. We envision\nthat as the field of stabilization matrices develops, microfluidic devices will be useful for cost-effectively facilitating\nremote analysis and biosurveillance while also opening new opportunities for diagnostics, drug development, and\nother medical fields.", "date": "2013-09-17", "date_type": "published", "publication": "Lab on a Chip", "volume": "13", "number": "22", "publisher": "Royal Society of Chemistry", "pagerange": "4331-4342", "id_number": "CaltechAUTHORS:20131002-113705785", "issn": "1473-0197", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20131002-113705785", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Defense Advanced Research Projects Agency (DARPA)", "grant_number": "HR0011-11-2-0006" }, { "agency": "NIH", "grant_number": "R01EB012946" } ] }, "doi": "10.1039/c3lc50747e", "pmcid": "PMC3851311", "primary_object": { "basename": "c3lc50747e_3.wmv", "url": "https://authors.library.caltech.edu/records/ynbt6-p8710/files/c3lc50747e_3.wmv" }, "related_objects": [ { "basename": "c3lc50747e.pdf", "url": "https://authors.library.caltech.edu/records/ynbt6-p8710/files/c3lc50747e.pdf" }, { "basename": "c3lc50747e.wmv", "url": "https://authors.library.caltech.edu/records/ynbt6-p8710/files/c3lc50747e.wmv" }, { "basename": "c3lc50747e_2.wmv", "url": "https://authors.library.caltech.edu/records/ynbt6-p8710/files/c3lc50747e_2.wmv" } ], "resource_type": "article", "pub_year": "2013", "author_list": "Begolo, Stefano; Shen, Feng; et el." }, { "id": "https://authors.library.caltech.edu/records/rdfze-ycn24", "eprint_id": 37763, "eprint_status": "archive", "datestamp": "2023-08-19 14:48:47", "lastmod": "2023-10-23 18:02:07", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Mahdavi-Alborz", "name": { "family": "Mahdavi", "given": "Alborz" }, "orcid": "0000-0002-8790-8112" }, { "id": "Segall-Shapiro-T-H", "name": { "family": "Segall-Shapiro", "given": "Thomas H." } }, { "id": "Kou-Songzi", "name": { "family": "Kou", "given": "Songzi" } }, { "id": "Jindal-G-A", "name": { "family": "Jindal", "given": "Granton A." } }, { "id": "Hoff-K-G", "name": { "family": "Hoff", "given": "Kevin G." } }, { "id": "Liu-Shirley", "name": { "family": "Liu", "given": "Shirley" } }, { "id": "Chitsaz-M", "name": { "family": "Chitsaz", "given": "Mohsen" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Silberg-J-J", "name": { "family": "Silberg", "given": "Jonathan J." } }, { "id": "Tirrell-D-A", "name": { "family": "Tirrell", "given": "David A." }, "orcid": "0000-0003-3175-4596" } ] }, "title": "A Genetically Encoded AND Gate for Cell-Targeted Metabolic Labeling of Proteins", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2013 American Chemical Society. \n\nReceived: January 15, 2013; Published: February 13, 2013. \n\nWe are grateful for financial support by National Institutes of Health grant NIH RO1 GM062523 and the Programmable Molecular Technology Initiative of the Gordon and Betty Moore Foundation (D.A.T.), the Institute for Collaborative Biotechnologies through grant W911NF-09-0001 from U.S. Army Research Office (D.A.T. and R.F.I.), the American Heart Association (J.J.S.), and the Robert A. Welch Foundation (J.J.S.). A.M. was supported by a scholarship from the National Science and Engineering Research Council of Canada and by a postgraduate scholarship from the Donna and Benjamin M. Rosen Center for Bioengineering at Caltech.\n\nPublished - ja400448f.pdf
Accepted Version - nihms449509.pdf
Supplemental Material - ja400448f_si_001.pdf
", "abstract": "We describe a genetic AND gate for cell-targeted metabolic labeling and proteomic analysis in complex cellular systems. The centerpiece of the AND gate is a bisected methionyl-tRNA synthetase (MetRS) that charges the Met surrogate azidonorleucine (Anl) to tRNAMet. Cellular protein labeling occurs only upon activation of two different promoters that drive expression of the N- and C-terminal fragments of the bisected MetRS. Anl-labeled proteins can be tagged with fluorescent dyes or affinity reagents via either copper-catalyzed or strain-promoted azide\u2013alkyne cycloaddition. Protein labeling is apparent within 5 min after addition of Anl to bacterial cells in which the AND gate has been activated. This method allows spatial and temporal control of proteomic labeling and identification of proteins made in specific cellular subpopulations. The approach is demonstrated by selective labeling of proteins in bacterial cells immobilized in the center of a laminar-flow microfluidic channel, where they are exposed to overlapping, opposed gradients of inducers of the N- and C-terminal MetRS fragments. The observed labeling profile is predicted accurately from the strengths of the individual input signals.", "date": "2013-02-27", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "135", "number": "8", "publisher": "American Chemical Society", "pagerange": "2979-2982", "id_number": "CaltechAUTHORS:20130404-103625840", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130404-103625840", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "RO1 GM062523" }, { "agency": "Gordon and Betty Moore Foundation" }, { "agency": "Army Research Office (ARO)", "grant_number": "W911NF-09-0001" }, { "agency": "American Heart Association" }, { "agency": "Robert A. Welch Foundation" }, { "agency": "Natural Sciences and Engineering Research Council of Canada (NSERC)" }, { "agency": "Donna and Benjamin M. Rosen Center for Bioengineering" } ] }, "doi": "10.1021/ja400448f", "pmcid": "PMC3620012", "primary_object": { "basename": "ja400448f.pdf", "url": "https://authors.library.caltech.edu/records/rdfze-ycn24/files/ja400448f.pdf" }, "related_objects": [ { "basename": "ja400448f_si_001.pdf", "url": "https://authors.library.caltech.edu/records/rdfze-ycn24/files/ja400448f_si_001.pdf" }, { "basename": "nihms449509.pdf", "url": "https://authors.library.caltech.edu/records/rdfze-ycn24/files/nihms449509.pdf" } ], "resource_type": "article", "pub_year": "2013", "author_list": "Mahdavi, Alborz; Segall-Shapiro, Thomas H.; et el." }, { "id": "https://authors.library.caltech.edu/records/ye8xy-tn052", "eprint_id": 37579, "eprint_status": "archive", "datestamp": "2023-08-19 14:37:55", "lastmod": "2023-10-23 17:48:51", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Sun-Bing", "name": { "family": "Sun", "given": "Bing" } }, { "id": "Shen-Feng", "name": { "family": "Shen", "given": "Feng" }, "orcid": "0000-0002-4709-330X" }, { "id": "McCalla-S-E", "name": { "family": "McCalla", "given": "Stephanie E." } }, { "id": "Kreutz-J-E", "name": { "family": "Kreutz", "given": "Jason E." } }, { "id": "Karymov-M-A", "name": { "family": "Karymov", "given": "Mikhail A." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Mechanistic Evaluation of the Pros and Cons of Digital RT-LAMP for HIV-1 Viral Load Quantification on a Microfluidic Device and Improved Efficiency via a Two-Step Digital Protocol", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2013 American Chemical Society. \n\nReceived: September 20, 2012; Accepted: December 27, 2012; Published: January 16, 2013. \n\nThis work was supported by NIH Grant R01EB012946 administered by the National Institute of Biomedical Imaging and Bioengineering and by the NIH Director's Pioneer Award program, part of the NIH Roadmap for Medical Research (5DP1OD003584). We thank Bridget Samuels for contributions to writing and editing this manuscript. We thank Dr. Loren Joseph and Dr. Reddy Poluru for providing RNA purified from patient samples.\n\nAccepted Version - nihms-436938.pdf
Supplemental Material - ac3037206_si_001.pdf
", "abstract": "Here we used a SlipChip microfluidic device to evaluate the performance of digital reverse transcription-loop-mediated isothermal amplification (dRT-LAMP) for quantification of HIV viral RNA. Tests are needed for monitoring HIV viral load to control the emergence of drug resistance and to diagnose acute HIV infections. In resource-limited settings, in vitro measurement of HIV viral load in a simple format is especially needed, and single-molecule counting using a digital format could provide a potential solution. We showed here that when one-step dRT-LAMP is used for quantification of HIV RNA, the digital count is lower than expected and is limited by the yield of desired cDNA. We were able to overcome the limitations by developing a microfluidic protocol to manipulate many single molecules in parallel through a two-step digital process. In the first step we compartmentalize the individual RNA molecules (based on Poisson statistics) and perform reverse transcription on each RNA molecule independently to produce DNA. In the second step, we perform the LAMP amplification on all individual DNA molecules in parallel. Using this new protocol, we increased the absolute efficiency (the ratio between the concentration calculated from the actual count and the expected concentration) of dRT-LAMP 10-fold, from 2% to 23%, by (i) using a more efficient reverse transcriptase, (ii) introducing RNase H to break up the DNA:RNA hybrid, and (iii) adding only the BIP primer during the RT step. We also used this two-step method to quantify HIV RNA purified from four patient samples and found that in some cases, the quantification results were highly sensitive to the sequence of the patient's HIV RNA. We learned the following three lessons from this work: (i) digital amplification technologies, including dLAMP and dPCR, may give adequate dilution curves and yet have low efficiency, thereby providing quantification values that underestimate the true concentration. Careful validation is essential before a method is considered to provide absolute quantification; (ii) the sensitivity of dLAMP to the sequence of the target nucleic acid necessitates additional validation with patient samples carrying the full spectrum of mutations; (iii) for multistep digital amplification chemistries, such as a combination of reverse transcription with amplification, microfluidic devices may be used to decouple these steps from one another and to perform them under different, individually optimized conditions for improved efficiency.", "date": "2013-02-05", "date_type": "published", "publication": "Analytical Chemistry", "volume": "85", "number": "3", "publisher": "American Chemical Society", "pagerange": "1540-1546", "id_number": "CaltechAUTHORS:20130320-140730972", "issn": "0003-2700", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130320-140730972", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01EB012946" }, { "agency": "NIH", "grant_number": "5DP1OD003584" } ] }, "doi": "10.1021/ac3037206", "pmcid": "PMC3578705", "primary_object": { "basename": "ac3037206_si_001.pdf", "url": "https://authors.library.caltech.edu/records/ye8xy-tn052/files/ac3037206_si_001.pdf" }, "related_objects": [ { "basename": "nihms-436938.pdf", "url": "https://authors.library.caltech.edu/records/ye8xy-tn052/files/nihms-436938.pdf" } ], "resource_type": "article", "pub_year": "2013", "author_list": "Sun, Bing; Shen, Feng; et el." }, { "id": "https://authors.library.caltech.edu/records/kjj6n-4nc93", "eprint_id": 29400, "eprint_status": "archive", "datestamp": "2023-08-19 09:40:00", "lastmod": "2023-10-24 22:09:43", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Pompano-R-R", "name": { "family": "Pompano", "given": "Rebecca R." } }, { "id": "Platt-C-E", "name": { "family": "Platt", "given": "Carol E." } }, { "id": "Karymov-M-A", "name": { "family": "Karymov", "given": "Mikhail A." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Control of Initiation, Rate, and Routing of Spontaneous Capillary-Driven Flow of Liquid Droplets through Microfluidic Channels on SlipChip", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2012 American Chemical Society. \n\nReceived: November 8, 2011. Revised: December 19, 2011. Publication Date (Web): January 10, 2012. T\n\nhis work was supported by DARPA Grant No. 11-39-DxODLRS-FP-016 and NIH Grant No. 1R01 EB012946 administered by the National Institute of Biomedical Imaging and Bioengineering. We thank Liang Li for discussions of chip design and oil rupture, Tom Witten for discussions of fluid instabilities, Stefano Begolo for discussions of pressures vs forces, and for considering the Cassie\u2212Wenzel transition and means to test it, and Toan Huynh for developing the FEP dipping protocol. We thank Heidi Park for contributions to writing and editing this manuscript. R.F.I. has a financial interest in SlipChip LLC.\n\nAccepted Version - nihms-349448.pdf
Supplemental Material - la204399m_si_001.pdf
Supplemental Material - la204399m_si_002.avi
Supplemental Material - la204399m_si_003.avi
Supplemental Material - la204399m_si_004.avi
", "abstract": "This Article describes the use of capillary pressure to initiate and control the rate of spontaneous liquid\u2013liquid flow through microfluidic channels. In contrast to flow driven by external pressure, flow driven by capillary pressure is dominated by interfacial phenomena and is exquisitely sensitive to the chemical composition and geometry of the fluids and channels. A stepwise change in capillary force was initiated on a hydrophobic SlipChip by slipping a shallow channel containing an aqueous droplet into contact with a slightly deeper channel filled with immiscible oil. This action induced spontaneous flow of the droplet into the deeper channel. A model predicting the rate of spontaneous flow was developed on the basis of the balance of net capillary force with viscous flow resistance, using as inputs the liquid\u2013liquid surface tension, the advancing and receding contact angles at the three-phase aqueous\u2013oil\u2013surface contact line, and the geometry of the devices. The impact of contact angle hysteresis, the presence or absence of a lubricating oil layer, and adsorption of surface-active compounds at liquid\u2013liquid or liquid\u2013solid interfaces were quantified. Two regimes of flow spanning a 104-fold range of flow rates were obtained and modeled quantitatively, with faster (mm/s) flow obtained when oil could escape through connected channels as it was displaced by flowing aqueous solution, and slower (micrometer/s) flow obtained when oil escape was mostly restricted to a micrometer-scale gap between the plates of the SlipChip (\"dead-end flow\"). Rupture of the lubricating oil layer (reminiscent of a Cassie\u2013Wenzel transition) was proposed as a cause of discrepancy between the model and the experiment. Both dilute salt solutions and complex biological solutions such as human blood plasma could be flowed using this approach. We anticipate that flow driven by capillary pressure will be useful for the design and operation of flow in microfluidic applications that do not require external power, valves, or pumps, including on SlipChip and other droplet- or plug-based microfluidic devices. In addition, this approach may be used as a sensitive method of evaluating interfacial tension, contact angles, and wetting phenomena on chip.", "date": "2012-01-24", "date_type": "published", "publication": "Langmuir", "volume": "28", "number": "3", "publisher": "American Chemical Society", "pagerange": "1931-1941", "id_number": "CaltechAUTHORS:20120222-071637506", "issn": "0743-7463", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120222-071637506", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Defense Advanced Research Projects Agency (DARPA)", "grant_number": "11-39-DxOD-LRS-FP-016" }, { "agency": "NIH", "grant_number": "1R01 EB012946" } ] }, "doi": "10.1021/la204399m", "pmcid": "PMC3271727", "primary_object": { "basename": "la204399m_si_003.avi", "url": "https://authors.library.caltech.edu/records/kjj6n-4nc93/files/la204399m_si_003.avi" }, "related_objects": [ { "basename": "la204399m_si_004.avi", "url": "https://authors.library.caltech.edu/records/kjj6n-4nc93/files/la204399m_si_004.avi" }, { "basename": "nihms-349448.pdf", "url": "https://authors.library.caltech.edu/records/kjj6n-4nc93/files/nihms-349448.pdf" }, { "basename": "la204399m_si_001.pdf", "url": "https://authors.library.caltech.edu/records/kjj6n-4nc93/files/la204399m_si_001.pdf" }, { "basename": "la204399m_si_002.avi", "url": "https://authors.library.caltech.edu/records/kjj6n-4nc93/files/la204399m_si_002.avi" } ], "resource_type": "article", "pub_year": "2012", "author_list": "Pompano, Rebecca R.; Platt, Carol E.; et el." }, { "id": "https://authors.library.caltech.edu/records/ytsqa-axv28", "eprint_id": 27798, "eprint_status": "archive", "datestamp": "2023-08-19 08:37:35", "lastmod": "2023-10-24 17:26:03", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Shen-Feng", "name": { "family": "Shen", "given": "Feng" }, "orcid": "0000-0002-4709-330X" }, { "id": "Sun-Bing", "name": { "family": "Sun", "given": "Bing" } }, { "id": "Kreutz-J-E", "name": { "family": "Kreutz", "given": "Jason E." } }, { "id": "Davydova-E-K", "name": { "family": "Davydova", "given": "Elena K." } }, { "id": "Du-Wenbin", "name": { "family": "Du", "given": "Wenbin" }, "orcid": "0000-0002-7401-1410" }, { "id": "Reddy-P-L", "name": { "family": "Reddy", "given": "Poluru L." } }, { "id": "Joseph-L-J", "name": { "family": "Joseph", "given": "Loren J." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Multiplexed Quantification of Nucleic Acids with Large Dynamic\n Range Using Multivolume Digital RT-PCR on a Rotational SlipChip Tested with HIV and Hepatitis C Viral Load", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2011 American Chemical Society. \n\nReceived: June 28, 2011. Publication Date (Web): October 13, 2011. \n\nThis work was supported by NIH Grant No. 1R01 EB012946 administered by the National Institute of Biomedical Imaging and Bioengineering and by the NIH Director's Pioneer Award program, part of the NIH Roadmap for Medical Research (1 DP1 OD003584). We thank Heidi Park for contributions to writing and editing this manuscript. Disclosure: F.S. and R.F.I. have a financial interest in SlipChip LLC.\n\nAccepted Version - nihms332187.pdf
Supplemental Material - ja2060116_si_001.pdf
", "abstract": "In this paper, we are working toward a problem of great importance to global health: determination of viral HIV and hepatitis C (HCV) loads under point-of-care and resource limited settings. While antiretroviral treatments are becoming widely available, viral load must be evaluated at regular intervals to prevent the spread of drug resistance and requires a quantitative measurement of RNA concentration over a wide dynamic range (from 50 up to 10^6 molecules/mL for HIV and up to 108 molecules/mL for HCV). \"Digital\" single molecule measurements are attractive for quantification, but the dynamic range of such systems is typically limited or requires excessive numbers of compartments. Here we designed and tested two microfluidic rotational SlipChips to perform multivolume digital RT-PCR (MV digital RT-PCR) experiments with large and tunable dynamic range. These designs were characterized using synthetic control RNA and validated with HIV viral RNA and HCV control viral RNA. The first design contained 160 wells of each of four volumes (125 nL, 25 nL, 5 nL, and 1 nL) to achieve a dynamic range of 5.2 \u00d7 10^2 to 4.0 \u00d7 10^6 molecules/mL at 3-fold resolution. The second design tested the flexibility of this approach, and further expanded it to allow for multiplexing while maintaining a large dynamic range by adding additional wells with volumes of 0.2 nL and 625 nL and dividing the SlipChip into five regions to analyze five samples each at a dynamic range of 1.8 \u00d7 10^3 to 1.2 \u00d7 10^7 molecules/mL at 3-fold resolution. No evidence of cross-contamination was observed. The multiplexed SlipChip can be used to analyze a single sample at a dynamic range of 1.7 \u00d7 10^2 to 2.0 \u00d7 10^7 molecules/mL at 3-fold resolution with limit of detection of 40 molecules/mL. HIV viral RNA purified from clinical samples were tested on the SlipChip, and viral load results were self-consistent and in good agreement with results determined using the Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 Test. With further validation, this SlipChip should become useful to precisely quantify viral HIV and HCV RNA for high-performance diagnostics in resource-limited settings. These microfluidic designs should also be valuable for other diagnostic and research applications, including detecting rare cells and rare mutations, prenatal diagnostics, monitoring residual disease, and quantifying copy number variation and gene expression patterns. The theory for the design and analysis of multivolume digital PCR experiments is presented in other work by Kreutz et al.", "date": "2011-11-09", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "133", "number": "44", "publisher": "American Chemical Society", "pagerange": "17705-17712", "id_number": "CaltechAUTHORS:20111116-090435392", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20111116-090435392", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "1R01 EB012946" }, { "agency": "NIH", "grant_number": "1 DPOD003584" } ] }, "doi": "10.1021/ja2060116", "pmcid": "PMC3216675", "primary_object": { "basename": "nihms332187.pdf", "url": "https://authors.library.caltech.edu/records/ytsqa-axv28/files/nihms332187.pdf" }, "related_objects": [ { "basename": "ja2060116_si_001.pdf", "url": "https://authors.library.caltech.edu/records/ytsqa-axv28/files/ja2060116_si_001.pdf" } ], "resource_type": "article", "pub_year": "2011", "author_list": "Shen, Feng; Sun, Bing; et el." }, { "id": "https://authors.library.caltech.edu/records/d3cnh-s9x12", "eprint_id": 28457, "eprint_status": "archive", "datestamp": "2023-08-19 08:35:02", "lastmod": "2023-10-24 17:54:51", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Kreutz-J-E", "name": { "family": "Kreutz", "given": "Jason E." } }, { "id": "Munson-T", "name": { "family": "Munson", "given": "Todd" } }, { "id": "Huynh-Toan", "name": { "family": "Huynh", "given": "Toan" } }, { "id": "Shen-Feng", "name": { "family": "Shen", "given": "Feng" }, "orcid": "0000-0002-4709-330X" }, { "id": "Du-Wenbin", "name": { "family": "Du", "given": "Wenbin" }, "orcid": "0000-0002-7401-1410" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Theoretical Design and Analysis of Multivolume Digital Assays with Wide Dynamic Range Validated Experimentally with Microfluidic Digital PCR", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2011 American Chemical Society. \n\nReceived: June 30, 2011; Accepted: September 22, 2011. Publication Date (Web): October 7, 2011. \n\nThis work was supported by the NIH Director's Pioneer Award program, part of the NIH Roadmap for Medical Research (1 DP1 OD003584) and NIH Grant No. 1R01 EB012946 administered by the National Institute of Biomedical Imaging and Bioengineering and the Office of Advanced Scientific Computing Research, Office of Science, U.S. Department of Energy, under Contract DE-AC02-06CH11357. We thank Mary-Sara McPeek, Margaret Loudermilk, and Ian Foster for helpful discussion of the statistical analysis. Disclosure: F.S. and R.F.I. have a financial interest in SlipChip LLC.\n\nAccepted Version - nihms330518.pdf
Supplemental Material - ac201658s_si_001.pdf
Supplemental Material - ac201658s_si_002.zip
", "abstract": "This paper presents a protocol using theoretical methods and free software to design and analyze multivolume digital PCR (MV digital PCR) devices; the theory and software are also applicable to design and analysis of dilution series in digital PCR. MV digital PCR minimizes the total number of wells required for \"digital\" (single molecule) measurements while maintaining high dynamic range and high resolution. In some examples, multivolume designs with fewer than 200 total wells are predicted to provide dynamic range with 5-fold resolution similar to that of single-volume designs requiring 12\u2009000 wells. Mathematical techniques were utilized and expanded to maximize the information obtained from each experiment and to quantify performance of devices and were experimentally validated using the SlipChip platform. MV digital PCR was demonstrated to perform reliably, and results from wells of different volumes agreed with one another. No artifacts due to different surface-to-volume ratios were observed, and single molecule amplification in volumes ranging from 1 to 125 nL was self-consistent. The device presented here was designed to meet the testing requirements for measuring clinically relevant levels of HIV viral load at the point-of-care (in plasma, <500 molecules/mL to >1\u2009000\u2009000 molecules/mL), and the predicted resolution and dynamic range was experimentally validated using a control sequence of DNA. This approach simplifies digital PCR experiments, saves space, and thus enables multiplexing using separate areas for each sample on one chip, and facilitates the development of new high-performance diagnostic tools for resource-limited applications. The theory and software presented here are general and are applicable to designing and analyzing other digital analytical platforms including digital immunoassays and digital bacterial analysis. It is not limited to SlipChip and could also be useful for the design of systems on platforms including valve-based and droplet-based platforms. In a separate publication by Shen et al. (J. Am. Chem. Soc., 2011, DOI: 10.1021/ja2060116), this approach is used to design and test digital RT-PCR devices for quantifying RNA.", "date": "2011-11-01", "date_type": "published", "publication": "Analytical Chemistry", "volume": "83", "number": "21", "publisher": "American Chemical Society", "pagerange": "8158-8168", "id_number": "CaltechAUTHORS:20111213-144640436", "issn": "0003-2700", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20111213-144640436", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "1 DPOD003584" }, { "agency": "NIH", "grant_number": "1R01 EB012946" }, { "agency": "Department of Energy (DOE)", "grant_number": "DE-AC02-06CH11357" } ] }, "doi": "10.1021/ac201658s", "pmcid": "PMC3216679", "primary_object": { "basename": "ac201658s_si_001.pdf", "url": "https://authors.library.caltech.edu/records/d3cnh-s9x12/files/ac201658s_si_001.pdf" }, "related_objects": [ { "basename": "ac201658s_si_002.zip", "url": "https://authors.library.caltech.edu/records/d3cnh-s9x12/files/ac201658s_si_002.zip" }, { "basename": "nihms330518.pdf", "url": "https://authors.library.caltech.edu/records/d3cnh-s9x12/files/nihms330518.pdf" } ], "resource_type": "article", "pub_year": "2011", "author_list": "Kreutz, Jason E.; Munson, Todd; et el." }, { "id": "https://authors.library.caltech.edu/records/2ng39-t2e84", "eprint_id": 40852, "eprint_status": "archive", "datestamp": "2023-08-19 08:19:02", "lastmod": "2023-10-24 22:30:35", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Nichols-K-P", "name": { "family": "Nichols", "given": "Kevin P." } }, { "id": "Pompano-R-R", "name": { "family": "Pompano", "given": "Rebecca R." } }, { "id": "Li-Liang", "name": { "family": "Li", "given": "Liang" } }, { "id": "Gelis-A-V", "name": { "family": "Gelis", "given": "Artem V." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Toward Mechanistic Understanding of Nuclear Reprocessing Chemistries by Quantifying Lanthanide Solvent Extraction Kinetics via Microfluidics with Constant Interfacial Area and Rapid Mixing", "ispublished": "pub", "full_text_status": "public", "note": "Copyright \u00a9 2011 American Chemical Society. \n\nPublished In Issue: October 05, 2011. Article ASAP: September 02, 2011. Received: June 28, 2011. \n\nThis work was supported by the U.S. Department of Energy, Office of Nuclear Energy, Fuel Cycle Research and Development Project under Contract DE-AC02-06CH11357. We thank Heidi Park for contributions to writing and editing this manuscript.\n\nSupplemental Material - Ismagilov_JACS_2011_TALSPEAK_Extractor_KN_RP_LL_supp_info.pdf
", "abstract": "The closing of the nuclear fuel cycle is an unsolved problem of great importance. Separating radionuclides produced in a nuclear reactor is useful both for the storage of nuclear waste and for recycling of nuclear fuel. These separations can be performed by designing appropriate chelation chemistries and liquid-liquid extraction schemes, such as in the TALSPEAK process (Trivalent Actinide-Lanthanide Separation by Phosphorus reagent Extraction from Aqueous Komplexes). However, there are no approved methods for the industrial scale reprocessing of civilian nuclear fuel in the United States. One bottleneck in the design of next-generation solvent extraction-based nuclear fuel reprocessing schemes is a lack of interfacial mass transfer rate constants obtained under well-controlled conditions for lanthanide and actinide ligand complexes; such rate constants are a prerequisite for mechanistic understanding of the extraction chemistries involved and are of great assistance in the design of new chemistries. In addition, rate constants obtained under conditions of known interfacial area have immediate, practical utility in models required for the scaling-up of laboratory-scale demonstrations to industrial-scale solutions. Existing experimental techniques for determining these rate constants suffer from two key drawbacks: either slow mixing or unknown interfacial area. The volume of waste produced by traditional methods is an additional, practical concern in experiments involving radioactive elements, both from disposal cost and experimenter safety standpoints. In this paper, we test a plug-based microfluidic system that uses flowing plugs (droplets) in microfluidic channels to determine absolute interfacial mass transfer rate constants under conditions of both rapid mixing and controlled interfacial area. We utilize this system to determine, for the first time, the rate constants for interfacial transfer of all lanthanides, minus promethium, plus yttrium, under TALSPEAK process conditions, as a first step toward testing the molecular mechanism of this separation process.", "date": "2011-10-05", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "133", "number": "39", "publisher": "American Chemical Society", "pagerange": "15721-9", "id_number": "CaltechAUTHORS:20130821-160728693", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160728693", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Department of Energy (DOE)", "grant_number": "DE-AC02-06CH11357" } ] }, "doi": "10.1021/ja206020u", "primary_object": { "basename": "Ismagilov_JACS_2011_TALSPEAK_Extractor_KN_RP_LL_supp_info.pdf", "url": "https://authors.library.caltech.edu/records/2ng39-t2e84/files/Ismagilov_JACS_2011_TALSPEAK_Extractor_KN_RP_LL_supp_info.pdf" }, "resource_type": "article", "pub_year": "2011", "author_list": "Nichols, Kevin P.; Pompano, Rebecca R.; et el." }, { "id": "https://authors.library.caltech.edu/records/fgpqe-ff172", "eprint_id": 40777, "eprint_status": "archive", "datestamp": "2023-08-19 07:11:27", "lastmod": "2023-10-24 17:23:26", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Bodnarchuk-M-I", "name": { "family": "Bodnarchuk", "given": "Maryna I." } }, { "id": "Li-Liang", "name": { "family": "Li", "given": "Liang" } }, { "id": "Fok-Alice", "name": { "family": "Fok", "given": "Alice" } }, { "id": "Nachtergaele-S", "name": { "family": "Nachtergaele", "given": "Sigrid" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Talapin-D-V", "name": { "family": "Talapin", "given": "Dmitri V." } } ] }, "title": "Three-Dimensional Nanocrystal Superlattices Grown in Nanoliter Microfluidic Plugs", "ispublished": "pub", "full_text_status": "public", "keywords": "binary nanoparticle superlattices ferrite core/shell nanocrystals protein crystallization structural-analysis colloidal crystals system membrane droplets size optimization", "note": "Copyright \u00a9 2011 American Chemical Society.\n\nPublished In Issue: June 15, 2011. Article ASAP: May 17, 2011. Just Accepted Manuscript: April 21, 2011. Received: February 05, 2011. \n\nWe thank M. V. Kovalenko and S. Rupich for stimulating discussions and samples of CdSe and PbS NCs. This work was partially supported by the Office of Naval Research under Award N00014-10-1-0190. The collaborative work used the Chicago MRSEC Microfluidic Facility and was supported in part by the Chicago MRSEC funded by the NSF under Award DMR-0213745. D.V.T. thanks the David and Lucile Packard Foundation. R.F.I. and D.V.T. also acknowledge support from the Camille Dreyfus Teacher-Scholar Program.\n\nSupporting Information\nAdditional experimental details, SEM and optical images, and a video clip (AVI). This material is available free of charge via the Internet at http://pubs.acs.org.\n\nSupplemental Material - Ismagilov_JACS_2011_3D_Nanocrystals_LL_AF_SN_v133_8956-8960_SI.pdf
Supplemental Material - ja201129n_si_002.avi
", "abstract": "We studied the self-assembly of inorganic nanocrystals (NCs) confined inside nanoliter droplets (plugs) into long-range ordered superlattices. We showed that a capillary microfluidic platform can be used for the optimization of growth conditions for NC superlattices and can provide insights into the kinetics of the NC assembly process. The utility of our approach was demonstrated by growing large (up to 200 \u03bcm) three-dimensional (3D) superlattices of various NCs, including Au, PbS, CdSe, and CoFe(2)O(4). We also showed that it is possible to grow 3D binary nanoparticle superlattices in the microfluidic plugs.", "date": "2011-06-15", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "133", "number": "23", "publisher": "American Chemical Society", "pagerange": "8956-8960", "id_number": "CaltechAUTHORS:20130821-160716001", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160716001", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Office of Naval Research (ONR)", "grant_number": "N00014-10-1-0190" }, { "agency": "NSF", "grant_number": "DMR-0213745" }, { "agency": "David and Lucile Packard Foundation" }, { "agency": "Henry and Camille Dreyfus Foundation" } ] }, "doi": "10.1021/ja201129n", "primary_object": { "basename": "Ismagilov_JACS_2011_3D_Nanocrystals_LL_AF_SN_v133_8956-8960_SI.pdf", "url": "https://authors.library.caltech.edu/records/fgpqe-ff172/files/Ismagilov_JACS_2011_3D_Nanocrystals_LL_AF_SN_v133_8956-8960_SI.pdf" }, "related_objects": [ { "basename": "ja201129n_si_002.avi", "url": "https://authors.library.caltech.edu/records/fgpqe-ff172/files/ja201129n_si_002.avi" } ], "resource_type": "article", "pub_year": "2011", "author_list": "Bodnarchuk, Maryna I.; Li, Liang; et el." }, { "id": "https://authors.library.caltech.edu/records/caam1-ak276", "eprint_id": 40863, "eprint_status": "archive", "datestamp": "2023-08-19 06:27:55", "lastmod": "2023-10-24 22:31:27", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Shen-Feng", "name": { "family": "Shen", "given": "Feng" }, "orcid": "0000-0002-4709-330X" }, { "id": "Davydova-E-K", "name": { "family": "Davydova", "given": "Elena K." } }, { "id": "Du-Wenbin", "name": { "family": "Du", "given": "Wenbin" }, "orcid": "0000-0002-7401-1410" }, { "id": "Kreutz-J-E", "name": { "family": "Kreutz", "given": "Jason E." } }, { "id": "Piepenburg-O", "name": { "family": "Piepenburg", "given": "Olaf" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Digital Isothermal Quantification of Nucleic Acids via Simultaneous Chemical Initiation of Recombinase Polymerase Amplification Reactions on SlipChip", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2011 American Chemical Society. \n\nPublished In Issue: May 01, 2011. Article ASAP: April 08, 2011. Received: January 28, 2011. Accepted: March 25, 2011. \n\nThis work was supported by the NIH Director's Pioneer Award program, part of the NIH Roadmap for Medical Research (1 DP1 OD003584), NIH Grant No. 1R01 EB012946 administered by the National Institute of Biomedical Imaging and Bioengineering, and by the W. M. Keck Foundation. Part of this work was performed at the Materials Research Science and Engineering Centers microfluidics facility (funded by the National Science Foundation). We thank Kevin P. Nichols for assisting with fabrication of the SlipChip. We thank Heidi Park for contributions to writing and editing this manuscript.\n\nSupporting Information\nChemicals and materials, detailed experimental procedures, and additional figures. This material is available free of charge via the Internet at http://pubs.acs.org.\n\nAccepted Version - nihms287957.pdf
Supplemental Material - Ismagilov_Anal_Chem_2011_digital_RPA_FS_ED_WD_JEK_SI.pdf
", "abstract": "In this paper, digital quantitative detection of nucleic acids was achieved at the single-molecule level by chemical initiation of over one thousand sequence-specific, nanoliter isothermal amplification reactions in parallel. Digital polymerase chain reaction (digital PCR), a method used for quantification of nucleic acids, counts the presence or absence of amplification of individual molecules. However, it still requires temperature cycling, which is undesirable under resource-limited conditions. This makes isothermal methods for nucleic acid amplification, such as recombinase polymerase amplification (RPA), more attractive. A microfluidic digital RPA SlipChip is described here for simultaneous initiation of over one thousand nL-scale RPA reactions by adding a chemical initiator to each reaction compartment with a simple slipping step after instrument-free pipet loading. Two designs of the SlipChip, two-step slipping and one-step slipping, were validated using digital RPA. By using the digital RPA SlipChip, false-positive results from preinitiation of the RPA amplification reaction before incubation were eliminated. End point fluorescence readout was used for \"yes or no\" digital quantification. The performance of digital RPA in a SlipChip was validated by amplifying and counting single molecules of the target nucleic acid, methicillin-resistant Staphylococcus aureus (MRSA) genomic DNA. The digital RPA on SlipChip was also tolerant to fluctuations of the incubation temperature (37\u221242 \u00b0C), and its performance was comparable to digital PCR on the same SlipChip design. The digital RPA SlipChip provides a simple method to quantify nucleic acids without requiring thermal cycling or kinetic measurements, with potential applications in diagnostics and environmental monitoring under resource-limited settings. The ability to initiate thousands of chemical reactions in parallel on the nanoliter scale using solvent-resistant glass devices is likely to be useful for a broader range of applications.", "date": "2011-05-01", "date_type": "published", "publication": "Analytical Chemistry", "volume": "83", "number": "9", "publisher": "American Chemical Society", "pagerange": "3533-3540", "id_number": "CaltechAUTHORS:20130821-160730642", "issn": "0003-2700", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160730642", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "1DP1 OD003584" }, { "agency": "NIH", "grant_number": "1R01 EB012946" }, { "agency": "W. M. Keck Foundation" }, { "agency": "NSF" } ] }, "doi": "10.1021/ac200247e", "pmcid": "PMC3101872", "primary_object": { "basename": "nihms287957.pdf", "url": "https://authors.library.caltech.edu/records/caam1-ak276/files/nihms287957.pdf" }, "related_objects": [ { "basename": "Ismagilov_Anal_Chem_2011_digital_RPA_FS_ED_WD_JEK_SI.pdf", "url": "https://authors.library.caltech.edu/records/caam1-ak276/files/Ismagilov_Anal_Chem_2011_digital_RPA_FS_ED_WD_JEK_SI.pdf" } ], "resource_type": "article", "pub_year": "2011", "author_list": "Shen, Feng; Davydova, Elena K.; et el." }, { "id": "https://authors.library.caltech.edu/records/1dn94-4mv61", "eprint_id": 40814, "eprint_status": "archive", "datestamp": "2023-08-19 05:25:52", "lastmod": "2023-10-24 22:01:17", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Kim-Hyun-Jung", "name": { "family": "Kim", "given": "Hyun Jung" } }, { "id": "Du-Wenbin", "name": { "family": "Du", "given": "Wenbin" }, "orcid": "0000-0002-7401-1410" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Complex Function by Design Using Spatially Pre-Structured Synthetic Microbial Communities: Degradation of Pentachlorophenol in the Presence of Hg(II)", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 The Royal Society of Chemistry 2011. \n\nReceived 24th March 2010, Accepted 10th July 2010. First published on the web 17th August 2010. \n\nPublished as part of a themed issue on Synthetic Biology: Guest Editor Professor John McCarthy.\n\nThis work was supported by the NSF CRC Grant CHE-0526693 and the NIH Director's Pioneer Award (1DP1 OD003584). Part of this work was performed at the microfluidics facility at the Chicago Materials Science and Research Center (Chicago MRSEC). HJK is a recipient of the Leo P. Kadanoff and Stuart A. Rice Fellowship from the Chicago MRSEC. Mercury analysis was performed by the STAT Analysis Corporation. We thank Chuan He for invaluable discussions and for the use of equipment, Songzi Kou for experimental assistance with the design and implementation of the experiment shown in Fig. 2d and e, and Elizabeth B. Haney and Heidi Park for contributions to writing and editing this manuscript.\n\nPublished - Ismagilov_Integr_Biol_2011_3_126_133_core_shell_HJK_WD.pdf
Accepted Version - nihms222075.pdf
Supplemental Material - Ismagilov_Integr_Biol_2010_core_shell_HJK_WD_supp_info.pdf
", "abstract": "Naturally occurring microbes perform a variety of useful functions, with more complex processes requiring multiple functions performed by communities of multiple microbes. Synthetic biology via genetic engineering may be used to achieve desired multiple functions, e.g. multistep chemical and biological transformations, by adding genes to a single organism, but this is sometimes not possible due to incompatible metabolic requirements or not desirable in certain applications, especially in medical or environmental applications. Achieving multiple functions by mixing microbes that have not evolved to function together may not work due to competition of microbes, or lack of interactions among microbes. In nature, microbial communities are commonly spatially structured. Here, we tested whether spatial structure can be used to create a community of microbes that can perform a function they do not perform individually or when simply mixed. We constructed a core\u2013shell fiber with Sphingobium chlorophenolicum, a pentachlorophenol (PCP) degrader, in the core layer and Ralstonia metallidurans, a mercuric ion (Hg(II)) reducer, in the shell layer as a structured community using microfluidic laminar flow techniques. We applied a mixture of PCP and Hg(II) to either a simple well-mixed culture broth (i.e. the unstructured community) or the spatially structured core\u2013shell fibers. We found that without spatial structure, the community was unable to degrade PCP in the presence of Hg(II) because S. chlorophenolicum is sensitive to Hg(II). In contrast, with spatial structure in a core\u2013shell fiber system, S. chlorophenolicum in a core layer was protected by R. metallidurans deposited in a shell layer, and the community was able to completely remove both PCP and Hg(II) from a mixture. The appropriate size of the core\u2013shell fiber was determined by the Damk\u00f6hler number\u2014the timescale of removal of Hg(II) was on the same order of the timescale of diffusion of Hg(II) through the outer layer when the shell layer was on the order of B200 mm. Ultimately, with the ease of a child putting together 'Legos' to build a complex structure, using this approach one may be able to put together microorganisms to build communities that perform functions in vitro or even in vivo, e.g. as in a ''microbiome on a pill''.", "date": "2011-02", "date_type": "published", "publication": "Integrative Biology", "volume": "3", "number": "2", "publisher": "Royal Society of Chemistry", "pagerange": "126-133", "id_number": "CaltechAUTHORS:20130821-160722342", "issn": "1757-9694", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160722342", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF", "grant_number": "CHE-0526693" }, { "agency": "NIH", "grant_number": "1DP1 OD003584" }, { "agency": "Leo P. Kadanoff and Stuart A. Rice Fellowship" } ] }, "doi": "10.1039/C0IB00019A", "pmcid": "PMC3005148", "primary_object": { "basename": "Ismagilov_Integr_Biol_2010_core_shell_HJK_WD_supp_info.pdf", "url": "https://authors.library.caltech.edu/records/1dn94-4mv61/files/Ismagilov_Integr_Biol_2010_core_shell_HJK_WD_supp_info.pdf" }, "related_objects": [ { "basename": "Ismagilov_Integr_Biol_2011_3_126_133_core_shell_HJK_WD.pdf", "url": "https://authors.library.caltech.edu/records/1dn94-4mv61/files/Ismagilov_Integr_Biol_2011_3_126_133_core_shell_HJK_WD.pdf" }, { "basename": "nihms222075.pdf", "url": "https://authors.library.caltech.edu/records/1dn94-4mv61/files/nihms222075.pdf" } ], "resource_type": "article", "pub_year": "2011", "author_list": "Kim, Hyun Jung; Du, Wenbin; et el." }, { "id": "https://authors.library.caltech.edu/records/5s1fc-m2h24", "eprint_id": 40855, "eprint_status": "archive", "datestamp": "2023-08-19 04:58:56", "lastmod": "2023-10-24 22:30:50", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Pompano-R-R", "name": { "family": "Pompano", "given": "Rebecca R." } }, { "id": "Liu-Weishan", "name": { "family": "Liu", "given": "Weishan" } }, { "id": "Du-Wenbin", "name": { "family": "Du", "given": "Wenbin" }, "orcid": "0000-0002-7401-1410" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Microfluidics Using Spatially Defined Arrays of Droplets in One, Two, and Three Dimensions", "ispublished": "pub", "full_text_status": "restricted", "note": "Copyright 2011 by Annual Reviews. \n\nFirst published online as a Review in Advance on March 1, 2011. \n\nDISCLOSURE STATEMENT: The authors are listed as coinventors on University of Chicago patents or patent applications for\nsome methods presented in this review. All authors may receive royalties from licensing University\nof Chicago patents or patent applications for some methods presented in this review. R.F.I. has\nan equity stake in SlipChip, LLC. \n\nACKNOWLEDGMENTS: The authors' work in this area was supported by the National Institutes of Health (grants U54\nGM074961 and 1DP1 OD003584) and the Office of Naval Research (grant N00014-08-1-0936).\nWe thank Heidi Park for contributions to the writing and editing of this manuscript. We thank\nLiang Ma, Jason Kreutz, and Liang Li for suggestions of literature to include and Megan E.\nVincent for help with Table 1.", "abstract": "Spatially defined arrays of droplets differ from bulk emulsions in that droplets in arrays can be indexed on the basis of one or more spatial variables to enable identification, monitoring, and addressability of individual droplets. Spatial indexing is critical in experiments with hundreds to millions of unique compartmentalized microscale processes\u2014for example, in applications such as digital measurements of rare events in a large sample, high-throughput time-lapse studies of the contents of individual droplets, and controlled droplet-droplet interactions. This review describes approaches for spatially organizing and manipulating droplets in one-, two-, and three-dimensional structured arrays, including aspiration, laminar flow, droplet traps, the SlipChip, self-assembly, and optical or electrical fields. This review also presents techniques to analyze droplets in arrays and applications of spatially defined arrays, including time-lapse studies of chemical, enzymatic, and cellular processes, as well as further opportunities in chemical, biological, and engineering sciences, including perturbation/response experiments and personal and point-of-care diagnostics.", "date": "2011", "date_type": "published", "publication": "Annual Review of Analytical Chemistry", "volume": "4", "publisher": "Annual Reviews", "pagerange": "59-81", "id_number": "CaltechAUTHORS:20130821-160729192", "issn": "1936-1327", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160729192", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "U54 GM074961" }, { "agency": "NIH", "grant_number": "1DP1 OD003584)" }, { "agency": "ONR", "grant_number": "N00014-08-1-0936" } ] }, "doi": "10.1146/annurev.anchem.012809.102303", "resource_type": "article", "pub_year": "2011", "author_list": "Pompano, Rebecca R.; Liu, Weishan; et el." }, { "id": "https://authors.library.caltech.edu/records/43mad-3yr47", "eprint_id": 40865, "eprint_status": "archive", "datestamp": "2023-08-19 04:09:38", "lastmod": "2023-10-24 22:31:39", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Shen-Feng", "name": { "family": "Shen", "given": "Feng" }, "orcid": "0000-0002-4709-330X" }, { "id": "Du-Wenbin", "name": { "family": "Du", "given": "Wenbin" }, "orcid": "0000-0002-7401-1410" }, { "id": "Kreutz-J-E", "name": { "family": "Kreutz", "given": "Jason E." } }, { "id": "Fok-Alice", "name": { "family": "Fok", "given": "Alice" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Digital PCR on a SlipChip", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 Royal Society of Chemistry 2010. \n\nReceived 22nd March 2010, Accepted 9th June 2010. First published on the web 1st July 2010. \n\nThis work was supported by ONR grant No. N00014-08-1-0936, the Camille Dreyfus Teacher-Scholar Awards program, the Chicago Center for Systems Biology (funded by the National Institute of General Medical Sciences at the NIH), and by the NIH Director's Pioneer Award program, part of the NIH Roadmap for Medical Research (1 DP1 OD003584). Part of this work was performed at the Materials Research Science and Engineering Centers microfluidics facility (funded by the National Science Foundation). We thank Elena M. Lucchetta for additional experimental validation and Elena K. Davydova for helpful suggestions in experimental design. We thank Heidi Park for contributions to writing and editing this manuscript.\n\nPublished - Ismagilov_LOC_2010_digital_PCR_FS_JEK_10_2666_2672.pdf
Accepted Version - nihms216770.pdf
Supplemental Material - Ismagilov_LOC_2010_digital_PCR_FS_JEK_10_2666_2672_supp_info.pdf
Cover Image - Ismagilov_LOC_2010_digital_PCR_FS_JEK_inside_front_cover.pdf
", "abstract": "This paper describes a SlipChip to perform digital PCR in a very simple and inexpensive format. The fluidic path for introducing the sample combined with the PCR mixture was formed using elongated wells in the two plates of the SlipChip designed to overlap during sample loading. This fluidic path was broken up by simple slipping of the two plates that removed the overlap among wells and brought each well in contact with a reservoir preloaded with oil to generate 1280 reaction compartments (2.6 nL each) simultaneously. After thermal cycling, end-point fluorescence intensity was used to detect the presence of nucleic acid. Digital PCR on the SlipChip was tested quantitatively by using Staphylococcus aureus genomic DNA. As the concentration of the template DNA in the reaction mixture was diluted, the fraction of positive wells decreased as expected from the statistical analysis. No cross-contamination was observed during the experiments. At the extremes of the dynamic range of digital PCR the standard confidence interval determined using a normal approximation of the binomial distribution is not satisfactory. Therefore, statistical analysis based on the score method was used to establish these confidence intervals. The SlipChip provides a simple strategy to count nucleic acids by using PCR. It may find applications in research applications such as single cell analysis, prenatal diagnostics, and point-of-care diagnostics. SlipChip would become valuable for diagnostics, including applications in resource-limited areas after integration with isothermal nucleic acid amplification technologies and visual readout.", "date": "2010-10-21", "date_type": "published", "publication": "Lab on a Chip", "volume": "10", "number": "20", "publisher": "Royal Society of Chemistry", "pagerange": "2666-2672", "id_number": "CaltechAUTHORS:20130821-160730931", "issn": "1473-0197", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160730931", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Office of Naval Research (ONR)", "grant_number": "N00014-08-1-0936" }, { "agency": "Camille and Henry Dreyfus Foundation" }, { "agency": "National Institute of General Medical Sciences" }, { "agency": "NIH", "grant_number": "1DP1 OD003584" }, { "agency": "NSF" } ] }, "doi": "10.1039/c004521g", "pmcid": "PMC2948063", "primary_object": { "basename": "Ismagilov_LOC_2010_digital_PCR_FS_JEK_10_2666_2672.pdf", "url": "https://authors.library.caltech.edu/records/43mad-3yr47/files/Ismagilov_LOC_2010_digital_PCR_FS_JEK_10_2666_2672.pdf" }, "related_objects": [ { "basename": "Ismagilov_LOC_2010_digital_PCR_FS_JEK_10_2666_2672_supp_info.pdf", "url": "https://authors.library.caltech.edu/records/43mad-3yr47/files/Ismagilov_LOC_2010_digital_PCR_FS_JEK_10_2666_2672_supp_info.pdf" }, { "basename": "Ismagilov_LOC_2010_digital_PCR_FS_JEK_inside_front_cover.pdf", "url": "https://authors.library.caltech.edu/records/43mad-3yr47/files/Ismagilov_LOC_2010_digital_PCR_FS_JEK_inside_front_cover.pdf" }, { "basename": "nihms216770.pdf", "url": "https://authors.library.caltech.edu/records/43mad-3yr47/files/nihms216770.pdf" } ], "resource_type": "article", "pub_year": "2010", "author_list": "Shen, Feng; Du, Wenbin; et el." }, { "id": "https://authors.library.caltech.edu/records/05ksv-g7s05", "eprint_id": 40837, "eprint_status": "archive", "datestamp": "2023-08-19 03:35:12", "lastmod": "2023-10-24 22:29:24", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Meier-M-M-M", "name": { "family": "Meier", "given": "Matthias" }, "orcid": "0000-0002-7179-4173" }, { "id": "Lucchetta-E-M", "name": { "family": "Lucchetta", "given": "Elena M." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Chemical Stimulation of the Arabidopsis thaliana Root using Multi-Laminar Flow on a Microfluidic Chip", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 Royal Society of Chemistry 2010. \n\nReceived 24th March 2010, Accepted 25th May 2010. First published on the web 11th June 2010. \n\nThis work was supported in part by Grant 1R01GM0773301 from the NIH and by the NIH Director's Pioneer Award program (1DP1OD003584). M.M. was supported by the Alexander v. Humboldt Society. E.M.L. was supported by the Yen Postdoctoral Fellowship. We thank Prof. Jocelyn Malamy at the University of Chicago for DR5::GFP Arabidopsis thaliana seeds and scientific comments.\n\nPublished - Ismagilov_LOC_2010_Arabidopsis_stimulation_multilaminar_flow_MM_EML_10_2147_2153_1_.pdf
Accepted Version - nihms-215129.pdf
", "abstract": "In this article, we developed a \"plant on a chip\" microfluidic platform that can control the local chemical environment around live roots of Arabidopsis thaliana with high spatial resolution using multi-laminar flow. We characterized the flow profile around the Arabidopsis root, and verified that the shear forces within the device ([similar]10 dyne cm^\u22122) did not impede growth of the roots. Our platform was able to deliver stimuli to the root at a spatial resolution of 10\u2013800 \u00b5m. Further, the platform was validated by exposing desired regions of the root with a synthetic auxin derivative, 2,4-dichlorophenoxyacetic acid (2,4-D), and its inhibitor N-1-naphthylphthalamic acid (NPA). The response to the stimuli was observed using a DR5::GFP Arabidopsis line, where GFP expression is coupled to the auxin response regulator DR5. GFP expression in the root matched the position of the flow-focused stream containing 2,4-D. When the regions around the 2,4-D stimulus were exposed to the auxin transport inhibitor NPA, the active and passive transport mechanisms of auxin could be differentiated, as NPA blocks active cell-to-cell transport of auxin. Finally, we demonstrated that local 2,4-D stimulation in a [similar]10 \u00b5m root segment enhanced morphological changes such as epidermal hair growth. These experiments were proof-of-concept and agreed with the results expected based on known root biology, demonstrating that this \"root on a chip\" platform can be used to test how root development is affected by any chemical component of interest, including nitrogen, phosphate, salts, and other plant hormones.", "date": "2010-08-21", "date_type": "published", "publication": "Lab on a Chip", "volume": "10", "number": "16", "publisher": "Royal Society of Chemistry", "pagerange": "2147-2153", "id_number": "CaltechAUTHORS:20130821-160725940", "issn": "1473-0197", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160725940", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "1R01GM0773301" }, { "agency": "NIH", "grant_number": "1DP1 OD003584" }, { "agency": "Alexander von Humboldt Foundation" }, { "agency": "Yen Postdoctoral Fellowship" } ] }, "doi": "10.1039/c004629a", "pmcid": "PMC2912432", "primary_object": { "basename": "Ismagilov_LOC_2010_Arabidopsis_stimulation_multilaminar_flow_MM_EML_10_2147_2153_1_.pdf", "url": "https://authors.library.caltech.edu/records/05ksv-g7s05/files/Ismagilov_LOC_2010_Arabidopsis_stimulation_multilaminar_flow_MM_EML_10_2147_2153_1_.pdf" }, "related_objects": [ { "basename": "nihms-215129.pdf", "url": "https://authors.library.caltech.edu/records/05ksv-g7s05/files/nihms-215129.pdf" } ], "resource_type": "article", "pub_year": "2010", "author_list": "Meier, Matthias; Lucchetta, Elena M.; et el." }, { "id": "https://authors.library.caltech.edu/records/2shp1-1p995", "eprint_id": 40824, "eprint_status": "archive", "datestamp": "2023-08-19 03:15:04", "lastmod": "2023-10-24 22:02:07", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Li-Liang", "name": { "family": "Li", "given": "Liang" } }, { "id": "Karymov-M-A", "name": { "family": "Karymov", "given": "Mikhail A." } }, { "id": "Nichols-K-P", "name": { "family": "Nichols", "given": "Kevin P." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Dead-end filling of SlipChip evaluated theoretically and experimentally as a function of the surface chemistry and the gap size between the plates for lubricated and dry SlipChips", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2010 American Chemical Society. \n\nPublished In Issue: July 20, 2010. Article ASAP: June 24, 2010. Received: April 13, 2010. Revised: June 10, 2010. \n\nThis work was supported by the NIH Protein Structure Initiative Specialized Centers Grant GM074961 (ATCG3D) and the NIH Director's Pioneer Award Program, part of the NIH Roadmap for Medical Research (1 DP1 OD003584). Part of this work was performed at the Materials Research Science and Engineering Centers microfluidic facility (funded by the National Science Foundation). We thank Heidi Park for contributions to writing and editing this manuscript.\n\nAccepted Version - nihms217098.pdf
Supplemental Material - Ismagilov_Langmuir_2010_deadend_filling_SlipChip_LL_MK_KN_supp_info.pdf
Supplemental Material - la101460z_si_002.mpg
", "abstract": "In this paper, we describe a method to load a microfluidic device, the SlipChip, via dead-end filling. In dead-end filling, the lubricating fluid that fills the SlipChip after assembly is dissipated through the gap between the two plates of the SlipChip instead of flowing through an outlet at the end of the fluidic path. We describe a theoretical model and associated predictions of dead-end filling that takes into consideration the interfacial properties and the gap size between plates of SlipChips. In this method, filling is controlled by the balance of pressures: for filling to occur without leaking, the inlet pressure must be greater than the capillary pressure but less than the maximum sealing pressure. We evaluated our prediction with experiments, and our empirical results agreed well with theory. Internal reservoirs were designed to prevent evaporation during loading of multiple solutions. Solutions were first loaded one at a time into inlet reservoirs; by applying a single pressure source to the device, we were able to fill multiple fluidic paths simultaneously. We used this method to fill both lubricated and dry SlipChips. Dry-loaded SlipChips were fabricated from fluorinated ethylene propylene (FEP) by using hot embossing techniques, and were successfully filled and slipped to perform a simple chemical reaction. The SlipChip design was also modified to enable ease of filling by using multiple access holes to the inlet reservoir.", "date": "2010-07-20", "date_type": "published", "publication": "Langmuir", "volume": "26", "number": "14", "publisher": "American Chemical Society", "pagerange": "12465-12471", "id_number": "CaltechAUTHORS:20130821-160723920", "issn": "0743-7463", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160723920", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM074961" }, { "agency": "NIH", "grant_number": "1DP1 OD003584" }, { "agency": "NSF" } ] }, "doi": "10.1021/la101460z", "pmcid": "PMC2923639", "primary_object": { "basename": "Ismagilov_Langmuir_2010_deadend_filling_SlipChip_LL_MK_KN_supp_info.pdf", "url": "https://authors.library.caltech.edu/records/2shp1-1p995/files/Ismagilov_Langmuir_2010_deadend_filling_SlipChip_LL_MK_KN_supp_info.pdf" }, "related_objects": [ { "basename": "la101460z_si_002.mpg", "url": "https://authors.library.caltech.edu/records/2shp1-1p995/files/la101460z_si_002.mpg" }, { "basename": "nihms217098.pdf", "url": "https://authors.library.caltech.edu/records/2shp1-1p995/files/nihms217098.pdf" } ], "resource_type": "article", "pub_year": "2010", "author_list": "Li, Liang; Karymov, Mikhail A.; et el." }, { "id": "https://authors.library.caltech.edu/records/3m594-9ee16", "eprint_id": 40795, "eprint_status": "archive", "datestamp": "2023-08-22 00:19:36", "lastmod": "2023-10-24 21:59:56", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Hom-R-A", "name": { "family": "Hom", "given": "Robert A." } }, { "id": "Chang-Pei-Yun", "name": { "family": "Chang", "given": "Pei-Yun" } }, { "id": "Roy-Siddhartha", "name": { "family": "Roy", "given": "Siddhartha" } }, { "id": "Musselman-C-A", "name": { "family": "Musselman", "given": "Catherine A." } }, { "id": "Glass-K-C", "name": { "family": "Glass", "given": "Karen C." } }, { "id": "Selezneva-A-I", "name": { "family": "Selezneva", "given": "Anna I." } }, { "id": "Gozani-O", "name": { "family": "Gozani", "given": "Or" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Cleary-M-L", "name": { "family": "Cleary", "given": "Michael L." } }, { "id": "Kutateladze-T-G", "name": { "family": "Kutateladze", "given": "Tatiana G." } } ] }, "title": "Molecular mechanism of MLL PHD3 and RNA recognition by the Cyp33 RRM domain", "ispublished": "pub", "full_text_status": "public", "keywords": "Amino Acid Sequence; Animals; Binding Sites; Crystallography, X-Ray; Cyclophilins/*chemistry/genetics/metabolism; Drosophila Proteins/*chemistry/genetics/metabolism Drosophila melanogaster Gene Expression Regulation Humans Models, Molecular Molecular Sequence Data Mutagenesis, Site-Directed Myeloid-Lymphoid Leukemia Protein/*chemistry/genetics/*metabolism Nuclear Magnetic Resonance, Biomolecular Protein Binding *Protein Structure, Secondary *Protein Structure, Tertiary *RNA/chemistry/metabolism Sequence Alignment Transcription, Genetic", "note": "\u00a9 2010 Elsevier. \n\nReceived 1 April 2010. Revised 30 April 2010. Accepted 30 April 2010. Available online 10 May 2010. Edited by M. F. Summers. \n\nWe thank Liang Li, Sigrid Nachtergaele, and Jennifer Schlegel for discussions and help with the experiments, A.I.S. and R.F.I. for the identification of crystallization conditions and providing the crystals of RRM, Jay Nix at beam line 4.2.2 of the ALS in Berkeley for help with data collection, and Tara Davis for providing the initial constructs of the RRM and catalytic domains of Cyp33. This research was supported by National Institutes of Health grants GM074961 and GM075827 (R.F.I.), CA55029 and CA116606 (M.L.C.), and CA113472 and GM071424 (T.G.K.).\n\nS.R., C.A.M., and K.C.G. contributed equally to this work.\n\nAccepted Version - nihms206208.pdf
", "abstract": "The nuclear protein cyclophilin 33 (Cyp33) is a peptidyl-prolyl cis-trans isomerase that catalyzes cis-trans isomerization of the peptide bond preceding a proline and promotes folding and conformational changes in folded and unfolded proteins. The N-terminal RNA-recognition motif (RRM) domain of Cyp33 has been found to associate with the third plant homeodomain (PHD3) finger of the mixed lineage leukemia (MLL) proto-oncoprotein and a poly(A) RNA sequence. Here, we report a 1.9 A resolution crystal structure of the RRM domain of Cyp33 and describe the molecular mechanism of PHD3 and RNA recognition. The Cyp33 RRM domain folds into a five-stranded antiparallel beta-sheet and two alpha-helices. The RRM domain, but not the catalytic module of Cyp33, binds strongly to PHD3, exhibiting a 2 muM affinity as measured by isothermal titration calorimetry. NMR chemical shift perturbation (CSP) analysis and dynamics data reveal that the beta strands and the beta2-beta3 loop of the RRM domain are involved in the interaction with PHD3. Mutations in the PHD3-binding site or deletions in the beta2-beta3 loop lead to a significantly reduced affinity or abrogation of the interaction. The RNA-binding pocket of the Cyp33 RRM domain, mapped on the basis of NMR CSP and mutagenesis, partially overlaps with the PHD3-binding site, and RNA association is abolished in the presence of MLL PHD3. Full-length Cyp33 acts as a negative regulator of MLL-induced transcription and reduces the expression levels of MLL target genes MEIS1 and HOXA9. Together, these in vitro and in vivo data provide insight into the multiple functions of Cyp33 RRM and suggest a Cyp33-dependent mechanism for regulating the transcriptional activity of MLL.", "date": "2010-07-09", "date_type": "published", "publication": "Journal of Molecular Biology", "volume": "400", "number": "2", "publisher": "Elsevier", "pagerange": "145-154", "id_number": "CaltechAUTHORS:20130821-160719024", "issn": "0022-2836", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160719024", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM074961" }, { "agency": "NIH", "grant_number": "GM075827" }, { "agency": "NIH", "grant_number": "CA55029" }, { "agency": "NIH", "grant_number": "CA116606" }, { "agency": "NIH", "grant_number": "CA113472" }, { "agency": "NIH", "grant_number": "GM071424" } ] }, "doi": "10.1016/j.jmb.2010.04.067", "pmcid": "PMC3204800", "primary_object": { "basename": "nihms206208.pdf", "url": "https://authors.library.caltech.edu/records/3m594-9ee16/files/nihms206208.pdf" }, "resource_type": "article", "pub_year": "2010", "author_list": "Hom, Robert A.; Chang, Pei-Yun; et el." }, { "id": "https://authors.library.caltech.edu/records/4rsj5-qn162", "eprint_id": 40864, "eprint_status": "archive", "datestamp": "2023-08-19 02:46:32", "lastmod": "2023-10-24 22:31:32", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Shen-Feng", "name": { "family": "Shen", "given": "Feng" }, "orcid": "0000-0002-4709-330X" }, { "id": "Du-Wenbin", "name": { "family": "Du", "given": "Wenbin" }, "orcid": "0000-0002-7401-1410" }, { "id": "Davydova-E-K", "name": { "family": "Davydova", "given": "Elena K." } }, { "id": "Karymov-M-A", "name": { "family": "Karymov", "given": "Mikhail A." } }, { "id": "Pandey-J", "name": { "family": "Pandey", "given": "Janmajay" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Nanoliter Multiplex PCR Arrays on a SlipChip", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2010 American Chemical Society. \n\nPublished In Issue: June 01, 2010. Article ASAP: May 06, 2010. Received: March 19, 2010. Accepted: April 14, 2010. \n\nThis work was supported by the NIH Director's Pioneer Award program, part of the NIH Roadmap for Medical Research (1 DP1 OD003584). Part of this work was performed at the Materials Research Science and Engineering Centers microfluidic facility (funded by the National Science Foundation). We thank Heidi Park for contributions to writing and editing this manuscript.\n\nAccepted Version - nihms203006.pdf
Supplemental Material - Ismagilov_Anal_Chem_2010_multiplex_PCR_slipchip_FS_WD_ED_MK_JP_supp_info.pdf
", "abstract": "The SlipChip platform was tested to perform highthroughput nanoliter multiplex PCR. The advantages of\nusing the SlipChip platform for multiplex PCR include the\nability to preload arrays of dry primers, instrument-free\nsample manipulation, small sample volume, and highthroughput capacity. The SlipChip was designed to preload one primer pair per reaction compartment and to\nscreen up to 384 different primer pairs with less than 30\nnanoliters of sample per reaction compartment. Both a\n40-well and a 384-well design of the SlipChip were tested\nfor multiplex PCR. In the geometries used here, the\nsample fluid was spontaneously compartmentalized into\ndiscrete volumes even before slipping of the two plates of\nthe SlipChip, but slipping introduced additional capabilities that made devices more robust and versatile. The\nwells of this SlipChip were designed to overcome potential\nproblems associated with thermal expansion. By using\ncircular wells filled with oil and overlapping them with\nsquare wells filled with the aqueous PCR mixture, a\ndroplet of aqueous PCR mixture was always surrounded\nby the lubricating fluid. In this design, during heating and\nthermal expansion, only oil was expelled from the compartment and leaking of the aqueous solution was prevented. Both 40-well and 384-well devices were found to\nbe free from cross-contamination, and end point fluorescence detection provided reliable readout. Multiple samples\ncould also be screened on the same SlipChip simultaneously. Multiplex PCR was validated on the 384-well\nSlipChip with 20 different primer pairs to identify 16\nbacterial and fungal species commonly presented in blood\ninfections. The SlipChip correctly identified five different\nbacterial or fungal species in separate experiments. In\naddition, the presence of the resistance gene mecA in\nmethicillin resistant Staphylococcus aureus (MRSA) was\nidentified. The SlipChip will be useful for applications\ninvolving PCR arrays and lays the foundation for new\nstrategies for diagnostics, point-of-care devices, and immobilization-based arrays.", "date": "2010-06-01", "date_type": "published", "publication": "Analytical Chemistry", "volume": "82", "number": "11", "publisher": "American Chemical Society", "pagerange": "4606-4612", "id_number": "CaltechAUTHORS:20130821-160730786", "issn": "0003-2700", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160730786", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "1DP1 OD003584" }, { "agency": "NSF" } ] }, "doi": "10.1021/ac1007249", "pmcid": "PMC2916686", "primary_object": { "basename": "nihms203006.pdf", "url": "https://authors.library.caltech.edu/records/4rsj5-qn162/files/nihms203006.pdf" }, "related_objects": [ { "basename": "Ismagilov_Anal_Chem_2010_multiplex_PCR_slipchip_FS_WD_ED_MK_JP_supp_info.pdf", "url": "https://authors.library.caltech.edu/records/4rsj5-qn162/files/Ismagilov_Anal_Chem_2010_multiplex_PCR_slipchip_FS_WD_ED_MK_JP_supp_info.pdf" } ], "resource_type": "article", "pub_year": "2010", "author_list": "Shen, Feng; Du, Wenbin; et el." }, { "id": "https://authors.library.caltech.edu/records/a1k69-5n905", "eprint_id": 40822, "eprint_status": "archive", "datestamp": "2023-08-22 00:02:03", "lastmod": "2023-10-24 22:01:56", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Li-Liang", "name": { "family": "Li", "given": "Liang" } }, { "id": "Fu-Qiang", "name": { "family": "Fu", "given": "Qiang" } }, { "id": "Kors-C-A", "name": { "family": "Kors", "given": "Christopher A." } }, { "id": "Stewart-L", "name": { "family": "Stewart", "given": "Lance" } }, { "id": "Nollert-P", "name": { "family": "Nollert", "given": "Peter" } }, { "id": "Laible-P-D", "name": { "family": "Laible", "given": "Philip D." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "A Plug-Based Microfluidic System for Dispensing Lipidic Cubic Phase (LCP) Material Validated by Crystallizing Membrane Proteins in Lipidic Mesophases", "ispublished": "pub", "full_text_status": "public", "keywords": "Droplet; Plugs; Lipidic cubic phase; Membrane protein; Protein crystallization", "note": "\u00a9 Springer 2010. \n\nReceived: 5 August 2009. Accepted: 22 September 2009. Published online: 14 October 2009. \n\nThis work was supported through Accelerated Technologies Center for Gene to 3D Structure (ATCG3D) funded by the National Institute of General Medical Sciences (NIGMS), National Center for Research Resources under the PSI-2 Specialized Center program (U54 GM074961); the National Institutes of Health Roadmap for Medical Research (R01 GM075827 and P01 GM75913), and University of Chicago/Argonne National Laboratory (ANL) Collaborative Seed Funding. We thank Nina Ponomarenko and James R. Norris at the University of Chicago for samples of Reaction Center from B. viridis. We thank Ray C. Stevens and Peter Kuhn for helpful discussion and Elizabeth B. Haney for contributions in writing and editing this manuscript. Use of the ANL General Medicine and Cancer Institute Collaborative Access Team (GM/CA CAT) beamlines at the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under Contract No. DE-AC02-06CH11357. GM/CA CAT has been funded in whole or in part with Federal funds from the National Cancer Institute (Y1-CO-1020) and the NIGMS (Y1-GM-1104).\n\nAccepted Version - nihms153329.pdf
Supplemental Material - Ismagilov_Microfluid_nanofluid_2009_online_first_LCP_plugs_LL_Supp_Mat.pdf
", "abstract": "This article presents a plug-based microfluidic system to dispense nanoliter-volume plugs of lipidic cubic phase (LCP) material and subsequently merge the LCP plugs with aqueous plugs. This system was validated by crystallizing membrane proteins in lipidic mesophases, including LCP. This system allows for accurate dispensing of LCP material in nanoliter volumes, prevents inadvertent phase transitions that may occur due to dehydration by enclosing LCP in plugs, and is compatible with the traditional method of forming LCP material using a membrane protein sample, as shown by the successful crystallization of bacteriorhodopsin from Halobacterium salinarum. Conditions for the formation of LCP plugs were characterized and presented in a phase diagram. This system was also implemented using two different methods of introducing the membrane protein: (1) the traditional method of generating the LCP material using a membrane protein sample and (2) post LCP-formation incorporation (PLI), which involves making LCP material without protein, adding the membrane protein sample externally to the LCP material, and allowing the protein to diffuse into the LCP material or into other lipidic mesophases that may result from phase transitions. Crystals of bacterial photosynthetic reaction centers from Rhodobacter sphaeroides and Blastochloris viridis were obtained using PLI. The plug-based, LCP-assisted microfluidic system, combined with the PLI method for introducing membrane protein into LCP, should be useful for minimizing consumption of samples and broadening the screening of parameter space in membrane protein crystallization.", "date": "2010-06", "date_type": "published", "publication": "Microfluidics and Nanofluidics", "volume": "8", "number": "6", "publisher": "Springer", "pagerange": "789-798", "id_number": "CaltechAUTHORS:20130821-160723624", "issn": "1613-4982", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160723624", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "National Institute of General Medical Sciences" }, { "agency": "NIH", "grant_number": "U54 GM074961" }, { "agency": "NIH", "grant_number": "R01 GM075827" }, { "agency": "NIH", "grant_number": "P01 GM75913" }, { "agency": "University of Chicago/Argonne National Laboratory (ANL) Collaborative Seed Funding" }, { "agency": "Department of Energy (DOE)", "grant_number": "DE-AC02-06CH11357" }, { "agency": "NIH", "grant_number": "Y1-CO-1020" }, { "agency": "NIH", "grant_number": "Y1-GM-1104" }, { "agency": "National Cancer Institute" } ] }, "doi": "10.1007/s10404-009-0512-8", "pmcid": "PMC2868346", "primary_object": { "basename": "Ismagilov_Microfluid_nanofluid_2009_online_first_LCP_plugs_LL_Supp_Mat.pdf", "url": "https://authors.library.caltech.edu/records/a1k69-5n905/files/Ismagilov_Microfluid_nanofluid_2009_online_first_LCP_plugs_LL_Supp_Mat.pdf" }, "related_objects": [ { "basename": "nihms153329.pdf", "url": "https://authors.library.caltech.edu/records/a1k69-5n905/files/nihms153329.pdf" } ], "resource_type": "article", "pub_year": "2010", "author_list": "Li, Liang; Fu, Qiang; et el." }, { "id": "https://authors.library.caltech.edu/records/966s2-k1w20", "eprint_id": 40827, "eprint_status": "archive", "datestamp": "2023-08-19 02:15:19", "lastmod": "2023-10-24 22:28:53", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Liu-Weishan", "name": { "family": "Liu", "given": "Weishan" } }, { "id": "Chen-Delai-L", "name": { "family": "Chen", "given": "Delai L." } }, { "id": "Du-Wenbin", "name": { "family": "Du", "given": "Wenbin" }, "orcid": "0000-0002-7401-1410" }, { "id": "Nichols-K-P", "name": { "family": "Nichols", "given": "Kevin P." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "SlipChip for immunoassays in nanoliter volumes", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2010 American Chemical Society. \n\nPublished In Issue: April 15, 2010. Article ASAP: March 24, 2010. Received: January 7, 2010. Accepted: March 5, 2010. \n\nThis work was supported by the NSF CRC Grant CHE-0526693 and the NIH Director's Pioneer Award program, part of the NIH Roadmap for Medical Research (Grant 1 DP1 OD003584). We thank Heidi Park for contributions to writing and editing this manuscript.\n\nAccepted Version - nihms191229.pdf
Supplemental Material - Ismagilov_Anal_Chem_2010_SlipChip_Immunoassays_WL_DC_WD_KP_supp_info.pdf
", "abstract": "This article describes a SlipChip-based approach to\nperform bead-based heterogeneous immunoassays with\nmultiple nanoliter-volume samples. As a potential device\nto analyze the output of the chemistrode, the performance\nof this platform was tested using low concentrations of\nbiomolecules. Two strategies to perform the immunoassay\nin the SlipChip were tested: (1) a unidirectional slipping\nmethod to combine the well containing a sample with a\nseries of wells preloaded with reagents and (2) a back-and-forth slipping method to introduce a series of reagents\nto a well containing the sample by reloading and slipping\nthe well containing the reagent. The SlipChips were\nfabricated with hydrophilic surfaces on the interior of the\nwells and with hydrophobic surfaces on the face of the\nSlipChip to enhance filling, transferring, and maintaining\naqueous solutions in shallow wells. Nanopatterning was\nused to increase the hydrophobic nature of the SlipChip\nsurface. Magnetic beads containing the capture antibody\nwere efficiently transferred between wells and washed by\nserial dilution. An insulin immunoenzymatic assay showed\na detection of limit of \u223c13 pM. A total of 48 droplets of\nnanoliter volume were analyzed in parallel, including an\non-chip calibration. The design of the SlipChip is flexible\nto accommodate other types of immunoassays, both\nheterogeneous and homogeneous. This work establishes\nthe possibility of using SlipChip-based immunoassays in\nsmall volumes for a range of possible applications, including analysis of plugs from a chemistrode, detection of\nmolecules from single cells, and diagnostic monitoring.", "date": "2010-04-15", "date_type": "published", "publication": "Analytical Chemistry", "volume": "82", "number": "8", "publisher": "American Chemical Society", "pagerange": "3276-3282", "id_number": "CaltechAUTHORS:20130821-160724379", "issn": "0003-2700", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160724379", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF", "grant_number": "CHE-0526693" }, { "agency": "NIH", "grant_number": "1DP1 OD003584" } ] }, "doi": "10.1021/ac100044c", "pmcid": "PMC2885842", "primary_object": { "basename": "nihms191229.pdf", "url": "https://authors.library.caltech.edu/records/966s2-k1w20/files/nihms191229.pdf" }, "related_objects": [ { "basename": "Ismagilov_Anal_Chem_2010_SlipChip_Immunoassays_WL_DC_WD_KP_supp_info.pdf", "url": "https://authors.library.caltech.edu/records/966s2-k1w20/files/Ismagilov_Anal_Chem_2010_SlipChip_Immunoassays_WL_DC_WD_KP_supp_info.pdf" } ], "resource_type": "article", "pub_year": "2010", "author_list": "Liu, Weishan; Chen, Delai L.; et el." }, { "id": "https://authors.library.caltech.edu/records/nxcrk-vg436", "eprint_id": 40818, "eprint_status": "archive", "datestamp": "2023-08-19 01:57:11", "lastmod": "2023-10-24 22:01:32", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Kreutz-J-E", "name": { "family": "Kreutz", "given": "Jason E." } }, { "id": "Shukhaev-A", "name": { "family": "Shukhaev", "given": "Anton" } }, { "id": "Du-Wenbin", "name": { "family": "Du", "given": "Wenbin" }, "orcid": "0000-0002-7401-1410" }, { "id": "Druskin-S", "name": { "family": "Druskin", "given": "Sasha" } }, { "id": "Daugulis-O", "name": { "family": "Daugulis", "given": "Olafs" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Evolution of catalysts directed by genetic algorithms in a plug-based microfluidic device tested with oxidation of methane by oxygen", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2010 American Chemical Society. \n\nPublished In Issue: March 10, 2010. Article ASAP: February 11, 2010. Received: November 20, 2009. \n\nThis work was supported by NIH T32 GM008720 (J.E.K.), the NSF CRC CHE-0526693, and the Camille Dreyfus Teacher-Scholar Awards Program (S.D.). O.D. is grateful to the Welch Foundation (Grant No. E-1571), A.P. Sloan Foundation, and Camille and Henry Dreyfus foundation for supporting this research. We thank Elizabeth B. Haney and Heidi Park for contributions to writing and editing this manuscript.\n\nAccepted Version - nihms178778.pdf
Supplemental Material - Ismagilov_JACS_2010_catalysis_GA_132_3128_3132_JEK_supp_info.pdf
Supplemental Material - ja909853x_si_002.mpg
", "abstract": "This paper uses microfluidics to implement genetic algorithms (GA) to discover new homogeneous catalysts using the oxidation of methane by molecular oxygen as a model system. The parameters of the GA were the catalyst, a cocatalyst capable of using molecular oxygen as the terminal oxidant, and ligands that could tune the catalytic system. The GA required running hundreds of reactions to discover and optimize catalyst systems of high fitness, and microfluidics enabled these numerous reactions to be run in parallel. The small scale and volumes of microfluidics offer significant safety benefits. The microfluidic system included methods to form diverse arrays of plugs containing catalysts, introduce gaseous reagents at high pressure, run reactions in parallel, and detect catalyst activity using an in situ indicator system. Platinum(II) was identified as an active catalyst, and iron(II) and the polyoxometalate H5PMo10V2O40 (POM-V2) were identified as active cocatalysts. The Pt/Fe system was further optimized and characterized using NMR experiments. After optimization, turnover numbers of approximately 50 were achieved with approximately equal production of methanol and formic acid. The Pt/Fe system demonstrated the compatibility of iron with the entire catalytic cycle. This approach of GA-guided evolution has the potential to accelerate discovery in catalysis and other areas where exploration of chemical space is essential, including optimization of materials for hydrogen storage and CO2 capture and modifications.", "date": "2010-03-10", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "132", "number": "9", "publisher": "American Chemical Society", "pagerange": "3128-3132", "id_number": "CaltechAUTHORS:20130821-160722961", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160722961", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH Predoctoral Fellowship", "grant_number": "T32 GM008720" }, { "agency": "NSF", "grant_number": "CHE-0526693" }, { "agency": "Camille and Henry Dreyfus Foundation" }, { "agency": "Welch Foundation", "grant_number": "E-1571" }, { "agency": "Alfred P. Sloan Foundation" } ] }, "doi": "10.1021/ja909853x", "pmcid": "PMC2861856", "primary_object": { "basename": "Ismagilov_JACS_2010_catalysis_GA_132_3128_3132_JEK_supp_info.pdf", "url": "https://authors.library.caltech.edu/records/nxcrk-vg436/files/Ismagilov_JACS_2010_catalysis_GA_132_3128_3132_JEK_supp_info.pdf" }, "related_objects": [ { "basename": "ja909853x_si_002.mpg", "url": "https://authors.library.caltech.edu/records/nxcrk-vg436/files/ja909853x_si_002.mpg" }, { "basename": "nihms178778.pdf", "url": "https://authors.library.caltech.edu/records/nxcrk-vg436/files/nihms178778.pdf" } ], "resource_type": "article", "pub_year": "2010", "author_list": "Kreutz, Jason E.; Shukhaev, Anton; et el." }, { "id": "https://authors.library.caltech.edu/records/ybsrf-bq611", "eprint_id": 40888, "eprint_status": "archive", "datestamp": "2023-08-19 01:51:01", "lastmod": "2023-10-24 22:33:20", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Vincent-M-E", "name": { "family": "Vincent", "given": "Meghan E." } }, { "id": "Liu-Weishan", "name": { "family": "Liu", "given": "Weishan" } }, { "id": "Haney-E-B", "name": { "family": "Haney", "given": "Elizabeth B." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Microfluidic stochastic confinement enhances analysis of rare cells by isolating cells and creating high density environments for control of diffusible signals", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 Royal Society of Chemistry 2010. \n\nReceived 1st September 2009. First published on the web 12th January 2010. \n\nThis work was supported by ONR Grant N000140610630, NSF CRC Grant No. 0526693 and NIH Director's Pioneer Award DP1 OD003584 to R.F.I. We thank Rebecca Pompano, James Boedicker, and Elena Lucchetta for helpful discussion and Heidi Park for contributions to writing and editing this manuscript. \n\nPart of the themed issue: From microfluidic application to nanofluidic phenomena.\n\nPublished - Ismagilov_CSR_2010_stoch_confine_rev_39_974_984_MV_WL.pdf
Accepted Version - nihms169974.pdf
", "abstract": "Rare cells can be difficult to analyze because they either occur in low numbers or coexist with a more abundant cell type, yet their detection is crucial for diagnosing disease and maintaining human health. In this tutorial review, we introduce the concept of microfluidic stochastic confinement for use in detection and analysis of rare cells. Stochastic confinement provides two advantages: (1) it separates rare single cells from the bulk mixture and (2) it allows signals to locally accumulate to a higher concentration around a single cell than in the bulk mixture. Microfluidics is an attractive method for implementing stochastic confinement because it provides simple handling of small volumes. We present technologies for microfluidic stochastic confinement that utilize both wells and droplets for the detection and analysis of single cells. We address how these microfluidic technologies have been used to observe new behavior, increase speed of detection, and enhance cultivation of rare cells. We discuss potential applications of microfluidic stochastic confinement to fields such as human diagnostics and environmental testing.", "date": "2010-03", "date_type": "published", "publication": "Chemical Society Reviews", "volume": "39", "number": "3", "publisher": "Royal Society of Chemistry", "pagerange": "974-984", "id_number": "CaltechAUTHORS:20130821-160734997", "issn": "0306-0012", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160734997", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Office of Naval Research (ONR)", "grant_number": "N000140610630" }, { "agency": "NSF", "grant_number": "CHE-0526693" }, { "agency": "NIH", "grant_number": "1DP1 OD003584" } ] }, "collection": "CaltechAUTHORS", "doi": "10.1039/B917851A", "pmcid": "PMC2829723", "primary_object": { "basename": "Ismagilov_CSR_2010_stoch_confine_rev_39_974_984_MV_WL.pdf", "url": "https://authors.library.caltech.edu/records/ybsrf-bq611/files/Ismagilov_CSR_2010_stoch_confine_rev_39_974_984_MV_WL.pdf" }, "related_objects": [ { "basename": "nihms169974.pdf", "url": "https://authors.library.caltech.edu/records/ybsrf-bq611/files/nihms169974.pdf" } ], "resource_type": "article", "pub_year": "2010", "author_list": "Vincent, Meghan E.; Liu, Weishan; et el." }, { "id": "https://authors.library.caltech.edu/records/crmb2-zjj74", "eprint_id": 40820, "eprint_status": "archive", "datestamp": "2023-08-19 01:26:03", "lastmod": "2023-10-24 22:01:44", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Li-Liang", "name": { "family": "Li", "given": "Liang" } }, { "id": "Du-Wenbin", "name": { "family": "Du", "given": "Wenbin" }, "orcid": "0000-0002-7401-1410" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Multiparameter Screening on SlipChip Used for Nanoliter Protein Crystallization Combining Free Interface Diffusion and Microbatch Methods", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2009 American Chemical Society. \n\nPublished In Issue: January 13, 2010. Article ASAP: December 14, 2009. Received: October 07, 2009. \n\nThis work was supported in part by NIH Roadmap for Medical Research R01 GM075827, by the NIH Protein Structure Initiative Specialized Centers Grant U54 GM074961 (ATCG3D), and by the NIH Director's Pioneer Award (1DP1OD003584). Use of the Argonne National Laboratory GM/CA beamlines at the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under Contract No. DE-AC02-06CH11357. GM/CA CAT has been funded in whole or in part with Federal funds from the National Cancer Institute (Y1-CO-1020) and the National Institute of General Medical Science (Y1-GM-1104). We thank James Norris of the University of Chicago for the generous gift of RC and SSGCID for the samples of glutaryl-CoA dehydrogenase. SSGCID is supported by Federal Contract No. HHSN272200700057C from NIAID to the Seattle Biomedical Research Institute and its collaborating subcontractors. We thank Bart Staker and Thomas Edwards for checking the structure of dihydrofolate reductase/thymidylate synthase and for helpful discussions. We thank Rebecca Pompano for helpful discussions and Heidi Park for contributions to writing and editing this manuscript.\n\nAccepted Version - nihms-159792.pdf
Supplemental Material - Ismagilov_JACS_2010_FID_mB_SlipChip_132_112_119_LL_WD_supp_info.pdf
Supplemental Material - ja908558m_si_003.mpg
", "abstract": "This paper describes two SlipChip-based approaches to protein crystallization: a SlipChip-based free interface diffusion (FID) method and a SlipChip-based composite method that simultaneously performs microbatch and FID crystallization methods in a single device. The FID SlipChip was designed to screen multiple reagents, each at multiple diffusion equilibration times, and was validated by screening conditions for crystallization of two proteins, enoyl-CoA hydratase from Mycobacterium tuberculosis and dihydrofolate reductase/thymidylate synthase from Babesia bovis, against 48 different reagents at five different equilibration times each, consuming 12 \u00b5L of each protein for a total of 480 experiments using three SlipChips. The composite SlipChip was designed to screen multiple reagents, each at multiple mixing ratios and multiple equilibration times, and was validated by screening conditions for crystallization of two proteins, enoylCoA hydratase from Mycobacterium tuberculosis and dihydrofolate reductase/thymidylate synthase from Babesia bovis. To prevent cross-contamination while keeping the solution in the neck channels for FID stable, the plates of the SlipChip were etched with a pattern of nanowells. This nanopattern was used to increase the contact angle of aqueous solutions on the surface of the silanized glass. The composite SlipChip increased the number of successful crystallization conditions and identified more conditions for crystallization than separate FID and microbatch screenings. Crystallization experiments were scaled up in well plates using conditions identified during the SlipChip screenings, and X-ray diffraction data were obtained to yield the protein structure of dihydrofolate reductase/thymidylate synthase at 1.95 \u00c5 resolution. This free-interface diffusion approach provides a convenient and high-throughput method of setting up gradients in microfluidic devices and may find additional applications in cell-based assays.", "date": "2010-01-13", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "132", "number": "1", "publisher": "American Chemical Society", "pagerange": "112-119", "id_number": "CaltechAUTHORS:20130821-160723281", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160723281", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01 GM075827" }, { "agency": "NIH", "grant_number": "U54 GM074961" }, { "agency": "NIH", "grant_number": "1DP1 OD003584" }, { "agency": "Department of Energy (DOE)", "grant_number": "DE-AC02-06CH11357" }, { "agency": "NIH", "grant_number": "Y1-CO-1020" }, { "agency": "NIH", "grant_number": "Y1-GM-1104" }, { "agency": "NIH", "grant_number": "HHSN272200700057C" }, { "agency": "National Cancer Institute" }, { "agency": "National Institute of General Medical Sciences" }, { "agency": "National Institute of Allergy and Infectious Diseases" } ] }, "doi": "10.1021/ja908558m", "pmcid": "PMC2805062", "primary_object": { "basename": "Ismagilov_JACS_2010_FID_mB_SlipChip_132_112_119_LL_WD_supp_info.pdf", "url": "https://authors.library.caltech.edu/records/crmb2-zjj74/files/Ismagilov_JACS_2010_FID_mB_SlipChip_132_112_119_LL_WD_supp_info.pdf" }, "related_objects": [ { "basename": "ja908558m_si_003.mpg", "url": "https://authors.library.caltech.edu/records/crmb2-zjj74/files/ja908558m_si_003.mpg" }, { "basename": "nihms-159792.pdf", "url": "https://authors.library.caltech.edu/records/crmb2-zjj74/files/nihms-159792.pdf" } ], "resource_type": "article", "pub_year": "2010", "author_list": "Li, Liang; Du, Wenbin; et el." }, { "id": "https://authors.library.caltech.edu/records/x27g9-9tf08", "eprint_id": 40821, "eprint_status": "archive", "datestamp": "2023-08-19 01:26:18", "lastmod": "2023-10-24 22:01:50", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Li-Liang", "name": { "family": "Li", "given": "Liang" } }, { "id": "Du-Wenbin", "name": { "family": "Du", "given": "Wenbin" }, "orcid": "0000-0002-7401-1410" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem" }, "orcid": "0000-0002-3680-4399" } ] }, "title": "User-Loaded SlipChip for Equipment-Free Multiplexed Nanoliter-Scale Experiments", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2009 American Chemical Society. \n\nPublished In Issue: January 13, 2010. Article ASAP: December 14, 2009. Received: October 07, 2009. \n\nThis work was supported in part by NIH Roadmap for Medical Research R01 GM075827, by the NIH Protein Structure Initiative Specialized Centers Grant U54 GM074961 (ATCG3D), and by the NIH Director's Pioneer Award (1DP1OD003584). Use of the Argonne National Laboratory GM/CA beamlines at the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under Contract No. DE-AC02-06CH11357. GM/CA CAT has been funded in whole or in part with Federal funds from the National Cancer Institute (Y1-CO-1020) and the National Institute of General Medical Science (Y1-GM-1104). We thank Kevin Nichols for providing the movie S1, frames of which were used to create Figure 1; James Norris of the University of Chicago for the generous gift of RC; and SSGCID for the samples of glutaryl-CoA dehydrogenase. SSGCID is supported by Federal Contract No. HHSN272200700057C from NIAID to the Seattle Biomedical Research Institute and its collaborating subcontractors. We thank Elizabeth B. Haney and Heidi Park for contributions to writing and editing this manuscript. We thank Bart Staker for checking the structure of glutaryl-CoA dehydrogenase for PDB deposition.\n\nSupporting Information\nChemicals and materials, detailed experimental procedures, additional figures and tables, and two supporting movies. This material is available free of charge via the Internet at http://pubs.acs.org.\n\nAccepted Version - nihms-159791.pdf
Supplemental Material - Ismagilov_JACS_2010_user_loaded_SlipChip_132_106_111_LL_WD_supp_info.pdf
Supplemental Material - ja908555n_si_002.mpg
Supplemental Material - ja908555n_si_003.avi
", "abstract": "This paper describes a microfluidic approach to perform multiplexed nanoliter-scale experiments\nby combining a sample with multiple different reagents, each at multiple mixing ratios. This approach employs\na user-loaded, equipment-free SlipChip. The mixing ratios, characterized by diluting a fluorescent dye,\ncould be controlled by the volume of each of the combined wells. The SlipChip design was validated on an\n\u223c12 nL scale by screening the conditions for crystallization of glutaryl-CoA dehydrogenase from Burkholderia\npseudomallei against 48 different reagents; each reagent was tested at 11 different mixing ratios, for a\ntotal of 528 crystallization trials. The total consumption of the protein sample was \u223c10 \u00b5L. Conditions for\ncrystallization were successfully identified. The crystallization experiments were successfully scaled up in\nwell plates using the conditions identified in the SlipChip. Crystals were characterized by X-ray diffraction\nand provided a protein structure in a different space group and at a higher resolution than the structure\nobtained by conventional methods. In this work, this user-loaded SlipChip has been shown to reliably handle\nfluids of diverse physicochemical properties, such as viscosities and surface tensions. Quantitative\nmeasurements of fluorescent intensities and high-resolution imaging were straighforward to perform in\nthese glass SlipChips. Surface chemistry was controlled using fluorinated lubricating fluid, analogous to\nthe fluorinated carrier fluid used in plug-based crystallization. Thus, we expect this approach to be valuable\nin a number of areas beyond protein crystallization, especially those areas where droplet-based microfluidic\nsystems have demonstrated successes, including measurements of enzyme kinetics and blood coagulation,\ncell-based assays, and chemical reactions.", "date": "2010-01-13", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "132", "number": "1", "publisher": "American Chemical Society", "pagerange": "106-111", "id_number": "CaltechAUTHORS:20130821-160723429", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160723429", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01 GM075827" }, { "agency": "NIH", "grant_number": "U54 GM074961" }, { "agency": "NIH", "grant_number": "1DP1 OD003584" }, { "agency": "Department of Energy (DOE)", "grant_number": "DE-AC02-06CH11357" }, { "agency": "NIH", "grant_number": "Y1-CO-1020" }, { "agency": "NIH", "grant_number": "Y1-GM-1104" }, { "agency": "NIH", "grant_number": "HHSN272200700057C" } ] }, "doi": "10.1021/ja908555n", "pmcid": "PMC2802657", "primary_object": { "basename": "Ismagilov_JACS_2010_user_loaded_SlipChip_132_106_111_LL_WD_supp_info.pdf", "url": "https://authors.library.caltech.edu/records/x27g9-9tf08/files/Ismagilov_JACS_2010_user_loaded_SlipChip_132_106_111_LL_WD_supp_info.pdf" }, "related_objects": [ { "basename": "ja908555n_si_002.mpg", "url": "https://authors.library.caltech.edu/records/x27g9-9tf08/files/ja908555n_si_002.mpg" }, { "basename": "ja908555n_si_003.avi", "url": "https://authors.library.caltech.edu/records/x27g9-9tf08/files/ja908555n_si_003.avi" }, { "basename": "nihms-159791.pdf", "url": "https://authors.library.caltech.edu/records/x27g9-9tf08/files/nihms-159791.pdf" } ], "resource_type": "article", "pub_year": "2010", "author_list": "Li, Liang; Du, Wenbin; et el." }, { "id": "https://authors.library.caltech.edu/records/daxyw-2tt16", "eprint_id": 40823, "eprint_status": "archive", "datestamp": "2023-08-19 01:09:17", "lastmod": "2023-10-24 22:02:02", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Li-Liang", "name": { "family": "Li", "given": "Liang" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Protein Crystallization using Microfluidic Technologies Based on Valves, Droplets, and SlipChip", "ispublished": "pub", "full_text_status": "restricted", "keywords": "free interface diffusion, high throughput, screening, phase diagram, in\nsitu diffraction", "note": "Copyright \ufffdc 2010 by Annual Reviews. \n\nFirst published online as a Review in Advance on February 1, 2010. \n\nDISCLOSURE STATEMENT: The authors are listed as coinventors on University of Chicago patents or patent applications\nfor some methods presented in this article. Rustem F. Ismagilov was a consultant to deCODE\nBiostructures.\n\nACKNOWLEDGMENTS: Authors work in this area was supported by the Department of Energy under section H.35 of Department of Energy Contract No. DE-AC02\u201306CH11357 to UChicago Argonne, LLC, to manage Argonne National Laboratory, NIH Protein Structure Initiative Specialized Centers Grant\nGM074961 (ATCG3D), and the National Institutes of Health through the NIH Roadmap for\nMedical Research, Grant 5 R01 GM075827. Information on Membrane Protein Production and\nStructure Determination can be found at http://nihroadmap.nih.gov/structuralbiology/. We\nthank Elizabeth B. Haney and Heidi Park for their contributions to writing and editing this\nmanuscript.", "abstract": "To obtain protein crystals, researchers must search for conditions in multidimensional chemical space. Empirically, thousands of crystallization experiments are carried out to screen various precipitants at multiple concentrations. Microfluidics can manipulate fluids on a nanoliter scale, and it affects crystallization twofold. First, it miniaturizes the experiments that can currently be done on a larger scale and enables crystallization of proteins that are available only in small amounts. Second, it offers unique experimental approaches that are difficult or impossible to implement on a larger scale. Ongoing development of microfluidic techniques and their integration with protein production, characterization, and in situ diffraction promises to accelerate the progress of structural biology.", "date": "2010", "date_type": "published", "publication": "Annual Review of Biophysics", "volume": "39", "publisher": "Annual Reviews", "pagerange": "139-158", "id_number": "CaltechAUTHORS:20130821-160723789", "issn": "1936-122X", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160723789", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Department of Energy (DOE)", "grant_number": "DE-AC02\u201306CH11357" }, { "agency": "NIH", "grant_number": "GM074961" }, { "agency": "NIH Roadmap for Medical Research", "grant_number": "5 R01 GM075827" } ] }, "doi": "10.1146/annurev.biophys.050708.133630", "resource_type": "article", "pub_year": "2010", "author_list": "Li, Liang and Ismagilov, Rustem F." }, { "id": "https://authors.library.caltech.edu/records/n51hm-56854", "eprint_id": 40830, "eprint_status": "archive", "datestamp": "2023-08-19 00:24:22", "lastmod": "2023-10-24 22:29:04", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Lucchetta-E-M", "name": { "family": "Lucchetta", "given": "Elena M." } }, { "id": "Carthew-R-W", "name": { "family": "Carthew", "given": "Richard W." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "The Endo-siRNA Pathway Is Essential for Robust Development of the Drosophila Embryo", "ispublished": "pub", "full_text_status": "public", "note": "Copyright: \u00a9 2009 Lucchetta et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. \n\nReceived: February 27, 2009; Accepted: August 3, 2009; Published: October 23, 2009. \n\nThis work was supported by the NIH (1R01GM077331 to R.F.I. and 5R01GM068743-05 to R.W.C.), by the Yen Postdoctoral Fellowship (E.M.L) and was performed in part at the Chicago MRSEC microfluidic facility funded by the NSF. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\nPublished - Ismagilov_PLoS_ONE_2009_Endo_siRNA_EL_e7576.pdf
Supplemental Material - Ismagilov_PLoS_ONE_2009_Endo_siRNA_EL_e7576_supplemental.pdf
", "abstract": "Background: Robustness to natural temperature fluctuations is critical to proper development in embryos and to cellular\nfunctions in adult organisms. However, mechanisms and pathways which govern temperature compensation remain largely\nunknown beyond circadian rhythms. Pathways which ensure robustness against temperature fluctuations may appear to be\nnonessential under favorable, uniform environmental conditions used in conventional laboratory experiments where there\nis little variation for which to compensate. The endo-siRNA pathway, which produces small double-stranded RNAs in\nDrosophila, appears to be nonessential for robust development of the embryo under ambient uniform temperature and to\nbe necessary only for viral defense. Embryos lacking a functional endo-siRNA pathway develop into phenotypically normal\nadults. However, we hypothesized that small RNAs may regulate the embryo's response to temperature, as a\nribonucleoprotein complex has been previously shown to mediate mammalian cell response to heat shock.\nPrincipal Findings: Here, we show that the genes DICER-2 and ARGONAUTE2, which code for integral protein components\nof the endo-siRNA pathway, are essential for robust development and temperature compensation in the Drosophila embryo\nwhen exposed to temperature perturbations. The regulatory functions of DICER-2 and ARGONAUTE2 were uncovered by\nusing microfluidics to expose developing Drosophila embryos to a temperature step, in which each half of the embryo\ndevelops at a different temperature through developmental cycle 14. Under this temperature perturbation, dicer-2 or\nargonaute2 embryos displayed abnormal segmentation. The abnormalities in segmentation are presumably due to the\ninability of the embryo to compensate for temperature-induced differences in rate of development and to coordinate\ndevelopmental timing in the anterior and posterior halves. A deregulation of the length of nuclear division cycles 10\u201314 is\nalso observed in dicer-2 embryos at high temperatures.\nConclusions: Results presented herein uncover a novel function of the endo-siRNA pathway in temperature compensation\nand cell cycle regulation, and we hypothesize that the endo-siRNA pathway may regulate the degradation of maternal cell\ncycle regulators. Endo-siRNAs may have a more general role buffering against environmental perturbations in other\norganisms.", "date": "2009-10-23", "date_type": "published", "publication": "PLoS ONE", "volume": "4", "number": "10", "publisher": "Public Library of Science", "pagerange": "e7576", "id_number": "CaltechAUTHORS:20130821-160724842", "issn": "1932-6203", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160724842", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "1R01GM077331" }, { "agency": "NIH", "grant_number": "5R01GM068743-05" }, { "agency": "NSF" } ] }, "doi": "10.1371/journal.pone.0007576", "pmcid": "PMC2761733", "primary_object": { "basename": "Ismagilov_PLoS_ONE_2009_Endo_siRNA_EL_e7576_supplemental.pdf", "url": "https://authors.library.caltech.edu/records/n51hm-56854/files/Ismagilov_PLoS_ONE_2009_Endo_siRNA_EL_e7576_supplemental.pdf" }, "related_objects": [ { "basename": "Ismagilov_PLoS_ONE_2009_Endo_siRNA_EL_e7576.pdf", "url": "https://authors.library.caltech.edu/records/n51hm-56854/files/Ismagilov_PLoS_ONE_2009_Endo_siRNA_EL_e7576.pdf" } ], "resource_type": "article", "pub_year": "2009", "author_list": "Lucchetta, Elena M.; Carthew, Richard W.; et el." }, { "id": "https://authors.library.caltech.edu/records/5j8at-mxj77", "eprint_id": 40867, "eprint_status": "archive", "datestamp": "2023-08-19 00:22:54", "lastmod": "2023-10-24 22:31:42", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Shen-Feng", "name": { "family": "Shen", "given": "Feng" }, "orcid": "0000-0002-4709-330X" }, { "id": "Pompano-Rebecca-R", "name": { "family": "Pompano", "given": "Rebecca R." } }, { "id": "Kastrup-Christian-J", "name": { "family": "Kastrup", "given": "Christian J." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Confinement Regulates Complex Biochemical Networks: Initiation of Blood Clotting by \"Diffusion Acting\"", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2009 Biophysical Society. \n\nReceived 11 February 2009. Accepted 3 August 2009. Available online 19 October 2009.\n\nPublished - main.pdf
", "abstract": "This study shows that environmental confinement strongly affects the activation of nonlinear reaction networks, such as blood coagulation (clotting), by small quantities of activators. Blood coagulation is sensitive to the local concentration of soluble activators, initiating only when the activators surpass a threshold concentration, and therefore is regulated by mass transport phenomena such as flow and diffusion. Here, diffusion was limited by decreasing the size of microfluidic chambers, and it was found that microparticles carrying either the classical stimulus, tissue factor, or a bacterial stimulus, Bacillus cereus, initiated coagulation of human platelet-poor plasma only when confined. A simple analytical argument and numerical model were used to describe the mechanism for this phenomenon: confinement causes diffusible activators to accumulate locally and surpass the threshold concentration. To interpret the results, a dimensionless confinement number, Cn, was used to describe whether a stimulus was confined, and a Damkohler number, Da_(2), was used to describe whether a subthreshold stimulus could initiate coagulation. In the context of initiation of coagulation by bacteria, this mechanism can be thought of as \"diffusion acting\", which is distinct from \"diffusion sensing\". The ability of confinement and diffusion acting to change the outcome of coagulation suggests that confinement should also regulate other biological \"on\" and \"off\" processes that are controlled by thresholds.", "date": "2009-10-21", "date_type": "published", "publication": "Biophysical Journal", "volume": "97", "number": "8", "publisher": "Biophysical Society", "pagerange": "2137-2145", "id_number": "CaltechAUTHORS:20130821-160731264", "issn": "0006-3495", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160731264", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1016/j.bpj.2009.08.004", "pmcid": "PMC2764071", "primary_object": { "basename": "main.pdf", "url": "https://authors.library.caltech.edu/records/5j8at-mxj77/files/main.pdf" }, "resource_type": "article", "pub_year": "2009", "author_list": "Shen, Feng; Pompano, Rebecca R.; et el." }, { "id": "https://authors.library.caltech.edu/records/9xtqf-e0m16", "eprint_id": 40857, "eprint_status": "archive", "datestamp": "2023-08-21 22:15:55", "lastmod": "2023-10-24 22:30:55", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Ponomarenko-Nina-S", "name": { "family": "Ponomarenko", "given": "Nina S." } }, { "id": "Li-Liang", "name": { "family": "Li", "given": "Liang" } }, { "id": "Marino-Antony-R", "name": { "family": "Marino", "given": "Antony R." } }, { "id": "Tereshko-Valentina", "name": { "family": "Tereshko", "given": "Valentina" } }, { "id": "Ostafin-Agnes", "name": { "family": "Ostafin", "given": "Agnes" } }, { "id": "Popova-Julia-A", "name": { "family": "Popova", "given": "Julia A." } }, { "id": "Bylina-Edward-J", "name": { "family": "Bylina", "given": "Edward J." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Norris-James-R-Jr", "name": { "family": "Norris", "given": "James R., Jr." } } ] }, "title": "Structural and spectropotentiometric analysis of Blastochloris viridis heterodimer mutant reaction center", "ispublished": "pub", "full_text_status": "public", "keywords": "Blastochloris viridis; Heterodimer mutant; Reaction center structure; Primary donor redox potential; Photosynthetic reaction center; Microfluidic", "note": "\u00a9 2009 Elsevier. Open Access article.\n\nReceived 30 January 2009. Revised 6 May 2009. Accepted 3 June 2009. Available online 17 June 2009. \n\nWe gratefully acknowledge support from the US Department of Energy, Office of Basic Energy Sciences, and Division of Chemical Sciences Contract DEFG02-96ER14675. This work was supported in part through the NIH Roadmap for Medical Research (R01 GM075827-01). We thank Elizabeth B. Haney for contributions to editing this manuscript. L.L and R.F.I. are responsible for the microfluidic crystallization.\n\nPublished - Ismagilov_Biophys_Biochem_Acta_2009_RC_mutant_1788_1822_1831_LL.pdf
Accepted Version - nihms-139590.pdf
", "abstract": "Heterodimer mutant reaction centers (RCs) of Blastochloris viridis were crystallized using microfluidic\ntechnology. In this mutant, a leucine residue replaced the histidine residue which had acted as a fifth ligand\nto the bacteriochlorophyll (BChl) of the primary electron donor dimer M site (HisM200). With the loss of the\nhistidine-coordinated Mg, one bacteriochlorophyll of the special pair was converted into a bacteriopheophytin (BPhe), and the primary donor became a heterodimer supermolecule. The crystals had dimensions\n400 \u00d7 100 \u00d7100 \u03bcm, belonged to space group P43212, and were isomorphous to the ones reported earlier for\nthe wild type (WT) strain. The structure was solved to a 2.5 \u00c5 resolution limit. Electron-density maps\nconfirmed the replacement of the histidine residue and the absence of Mg. Structural changes in the\nheterodimer mutant RC relative to the WT included the absence of the water molecule that is typically\npositioned between the M side of the primary donor and the accessory BChl, a slight shift in the position of\namino acids surrounding the site of the mutation, and the rotation of the M194 phenylalanine. The\ncytochrome subunit was anchored similarly as in the WT and had no detectable changes in its overall\nposition. The highly conserved tyrosine L162, located between the primary donor and the highest potential\nheme C380, revealed only a minor deviation of its hydroxyl group. Concomitantly to modification of the BChl\nmolecule, the redox potential of the heterodimer primary donor increased relative to that of the WT\norganism (772 mV vs. 517 mV). The availability of this heterodimer mutant and its crystal structure provides\nopportunities for investigating changes in light-induced electron transfer that reflect differences in redox\ncascades.", "date": "2009-09", "date_type": "published", "publication": "Biochimica et Biophysica Acta - Biomembranes", "volume": "1788", "publisher": "Elsevier", "pagerange": "1822-1831", "id_number": "CaltechAUTHORS:20130821-160729461", "issn": "0005-2736", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160729461", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Department of Energy (DOE)", "grant_number": "DEFG02-96ER14675" }, { "agency": "NIH", "grant_number": "R01 GM075827-01" } ] }, "doi": "10.1016/j.bbamem.2009.06.006", "pmcid": "PMC2752317", "primary_object": { "basename": "Ismagilov_Biophys_Biochem_Acta_2009_RC_mutant_1788_1822_1831_LL.pdf", "url": "https://authors.library.caltech.edu/records/9xtqf-e0m16/files/Ismagilov_Biophys_Biochem_Acta_2009_RC_mutant_1788_1822_1831_LL.pdf" }, "related_objects": [ { "basename": "nihms-139590.pdf", "url": "https://authors.library.caltech.edu/records/9xtqf-e0m16/files/nihms-139590.pdf" } ], "resource_type": "article", "pub_year": "2009", "author_list": "Ponomarenko, Nina S.; Li, Liang; et el." }, { "id": "https://authors.library.caltech.edu/records/488kj-c6409", "eprint_id": 40789, "eprint_status": "archive", "datestamp": "2023-08-20 02:38:54", "lastmod": "2023-10-24 21:59:32", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Du-Wenbin", "name": { "family": "Du", "given": "Wenbin" }, "orcid": "0000-0002-7401-1410" }, { "id": "Li-Liang", "name": { "family": "Li", "given": "Liang" } }, { "id": "Nichols-Kevin-P", "name": { "family": "Nichols", "given": "Kevin P." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "SlipChip", "ispublished": "pub", "full_text_status": "public", "note": "This journal is \u00a9 The Royal Society of Chemistry 2009. \n\nReceived 6th May 2009, Accepted 12th May 2009. First published on the web 15th May 2009. \n\nThis work was supported in part by the NIH Director's Pioneer Award (1DP1OD003584), NIH Roadmap for Medical Research R01 GM075827 and by the NIH Protein Structure Initiative Specialized Centers Grant U54 GM074961 (ATCG3D). We thank James Norris of the University of Chicago for the generous gift of RC and Elizabeth B. Haney for contributions in editing and writing this manuscript.\n\nElectronic supplementary information (ESI) available: materials and experimental details, supporting table and figures, and a cartoon movie of using a preloaded SlipChip. See DOI: 10.1039/b908978k\n\nPublished - Ismagilov_LOC_2009_SlipChip_9_2286_2292_WD.pdf
Accepted Version - nihms125088.pdf
Supplemental Material - Ismagilov_LOC_2009_SlipChip_9_2286_2292_WD_supp_info.pdf
Supplemental Material - movie_b908978k.mov
", "abstract": "The SlipChip is a microfluidic device designed to perform multiplexed microfluidic reactions without\npumps or valves. The device has two plates in close contact. The bottom plate contains wells preloaded\nwith many reagents; in this paper plates with 48 reagents were used. These wells are covered by the top\nplate that acts as a lid for the wells with reagents. The device also has a fluidic path, composed of ducts\nin the bottom plate and wells in the top plate, which is connected only when the top and bottom plate\nare aligned in a specific configuration. Sample can be added into the fluidic path, filling both wells and\nducts. Then, the top plate is ''slipped'', or moved, relative to the bottom plate so the complementary\npatterns of wells in both plates overlap, exposing the sample-containing wells of the top plate to the\nreagent-containing wells of the bottom plate, and enabling diffusion and reactions. Between the two\nplates, a lubricating layer of fluorocarbon was used to facilitate relative motion of the plates. This paper\nimplements this approach on a nanoliter scale using devices fabricated in glass. Stability of preloaded\nsolutions, control of loading, and lack of cross-contamination were tested using fluorescent dyes.\nFunctionality of the device was illustrated via crystallization of a model membrane protein. Fabrication\nof this device is simple and does not require a bonding step. This device requires no pumps or valves and\nis applicable to resource-poor settings. Overall, this device should be valuable for multiplexed\napplications that require exposing one sample to many reagents in small volumes. One may think of the\nSlipChip as an easy-to-use analogue of a preloaded multi-well plate, or a preloaded liquid-phase\nmicroarray.", "date": "2009-08-21", "date_type": "published", "publication": "Lab on a Chip", "volume": "9", "number": "16", "publisher": "Royal Society of Chemistry", "pagerange": "2286-2292", "id_number": "CaltechAUTHORS:20130821-160718040", "issn": "1473-0197", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160718040", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "1DP1 OD003584" }, { "agency": "NIH", "grant_number": "R01 GM075827" }, { "agency": "NIH", "grant_number": "U54 GM074961" } ] }, "doi": "10.1039/B908978K", "pmcid": "PMC2719824", "primary_object": { "basename": "movie_b908978k.mov", "url": "https://authors.library.caltech.edu/records/488kj-c6409/files/movie_b908978k.mov" }, "related_objects": [ { "basename": "nihms125088.pdf", "url": "https://authors.library.caltech.edu/records/488kj-c6409/files/nihms125088.pdf" }, { "basename": "Ismagilov_LOC_2009_SlipChip_9_2286_2292_WD.pdf", "url": "https://authors.library.caltech.edu/records/488kj-c6409/files/Ismagilov_LOC_2009_SlipChip_9_2286_2292_WD.pdf" }, { "basename": "Ismagilov_LOC_2009_SlipChip_9_2286_2292_WD_supp_info.pdf", "url": "https://authors.library.caltech.edu/records/488kj-c6409/files/Ismagilov_LOC_2009_SlipChip_9_2286_2292_WD_supp_info.pdf" } ], "resource_type": "article", "pub_year": "2009", "author_list": "Du, Wenbin; Li, Liang; et el." }, { "id": "https://authors.library.caltech.edu/records/xz0jq-jkp15", "eprint_id": 40828, "eprint_status": "archive", "datestamp": "2023-08-20 02:32:02", "lastmod": "2023-10-24 22:28:56", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Liu-Weishan", "name": { "family": "Liu", "given": "Weishan" } }, { "id": "Kim-Hyun-Jung", "name": { "family": "Kim", "given": "Hyun Jung" } }, { "id": "Lucchetta-Elena-M", "name": { "family": "Lucchetta", "given": "Elena M." } }, { "id": "Du-Wenbin", "name": { "family": "Du", "given": "Wenbin" }, "orcid": "0000-0002-7401-1410" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Isolation, incubation, and parallel functional testing and identification by FISH of rare microbial single-copy cells from multi-species mixtures using the combination of chemistrode and stochastic confinement", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 Royal Society of Chemistry 2009. \n\nReceived 11th March 2009, Accepted 1st May 2009. First published on the web 14th May 2009. \n\nThis work was supported by the National Institutes of Health Director's Pioneer Award 1DP1OD003584. We thank Mitchell L. Sogin for helpful discussions, Jessica Mark Welch and Gary Borisy for advice on FISH, Delai Chen for advice on the chemistrode, and Elizabeth B. Haney for contributions to writing and editing this manuscript.\n\nPublished - Ismagilov_LOC_2009_Isolating_Splitting_9_2153_2162_WL.pdf
Accepted Version - nihms125087.pdf
Supplemental Material - Ismagilov_LOC_2009_Isolating_Splitting_9_2153_2162_WL_supp_info.pdf
", "abstract": "This paper illustrates a plug-based microfluidic approach combining the technique of the chemistrode and the principle of stochastic confinement, which can be used to i) starting from a mixture of cells, stochastically isolate single cells into plugs, ii) incubate the plugs to grow clones of the individual cells without competition among different clones, iii) split the plugs into arrays of identical daughter plugs, where each plug contained clones of the original cell, and iv) analyze each array by an independent technique, including cellulase assays, cultivation, cryo-preservation, Gram staining, and Fluorescence In Situ Hybridization (FISH). Functionally, this approach is equivalent to simultaneously assaying the clonal daughter cells by multiple killing and non-killing methods. A new protocol for single-cell FISH, a killing method, was developed to identify isolated cells of Paenibacillus curdlanolyticus in one array of daughter plugs using a 16S rRNA probe, Pc196. At the same time, live copies of P. curdlanolyticus in another array were obtained for cultivation. Among technical advances, this paper reports a chemistrode that enables sampling of nanoliter volumes directly from environmental specimens, such as soil slurries. In addition, a method for analyzing plugs is described: an array of droplets is deposited on the surface, and individual plugs are injected into the droplets of the surface array to induce a reaction and enable microscopy without distortions associated with curvature of plugs. The overall approach is attractive for identifying rare, slow growing microorganisms and would complement current methods to cultivate unculturable microbes from environmental samples.", "date": "2009-08-07", "date_type": "published", "publication": "Lab on a Chip", "volume": "9", "number": "15", "publisher": "Royal Society of Chemistry", "pagerange": "2153-2162", "id_number": "CaltechAUTHORS:20130821-160724539", "issn": "1473-0197", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160724539", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "1DP1 OD003584" } ] }, "doi": "10.1039/b904958d", "pmcid": "PMC2719823", "primary_object": { "basename": "Ismagilov_LOC_2009_Isolating_Splitting_9_2153_2162_WL.pdf", "url": "https://authors.library.caltech.edu/records/xz0jq-jkp15/files/Ismagilov_LOC_2009_Isolating_Splitting_9_2153_2162_WL.pdf" }, "related_objects": [ { "basename": "Ismagilov_LOC_2009_Isolating_Splitting_9_2153_2162_WL_supp_info.pdf", "url": "https://authors.library.caltech.edu/records/xz0jq-jkp15/files/Ismagilov_LOC_2009_Isolating_Splitting_9_2153_2162_WL_supp_info.pdf" }, { "basename": "nihms125087.pdf", "url": "https://authors.library.caltech.edu/records/xz0jq-jkp15/files/nihms125087.pdf" } ], "resource_type": "article", "pub_year": "2009", "author_list": "Liu, Weishan; Kim, Hyun Jung; et el." }, { "id": "https://authors.library.caltech.edu/records/89xab-bww64", "eprint_id": 40782, "eprint_status": "archive", "datestamp": "2023-08-21 21:44:47", "lastmod": "2023-10-24 21:59:04", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chen-Delai-L", "name": { "family": "Chen", "given": "Delai" } }, { "id": "Du-Wenbin", "name": { "family": "Du", "given": "Wenbin" }, "orcid": "0000-0002-7401-1410" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Using TIRF microscopy to quantify and confirm efficient mass transfer at the substrate surface of the chemistrode", "ispublished": "pub", "full_text_status": "public", "keywords": "Fluid dynamics; Electronics and devices; Surfaces, interfaces and thin films; Nanoscale science and low-D systems; Chemical physics and physical chemistry", "note": "\u00a9 IOP Publishing Ltd and Deutsche Physikalische Gesellschaft. \n\nReceived 20 January 2009. Published 31 July 2009. \n\nhis research was supported by the NIH Director's Pioneer Award 1DP1OD003584 and the NSF CRC CHE-0526693. RFI is a Cottrell Scholar of Research Corporation and a Camille Dreyfus Teacher-Scholar. A part of this work was performed at the MRSEC microfluidic facility funded by the NSF. We thank Elizabeth B Haney for contributions in English corrections and editing this manuscript.\n\nPublished - Ismagilov_NJP_TIRFM_in_chemistrode_Ms_DC.pdf
Accepted Version - nihms-136237.pdf
Supplemental Material - movie_S1.mov
Supplemental Material - movie_S2.mov
", "abstract": "This paper describes experiments for characterizing mass transfer\nat the hydrophilic surface of the substrate in a chemistrode. The chemistrode\nuses microfluidic plugs to deliver pulses of chemicals to a substrate with\nhigh temporal resolution, which requires efficient mass transfer between the\nwetting layer and the hydrophilic surface of the substrate. Here, total internal\nreflection fluorescence microscopy (TIRFM) was used to image the hydrophilic\nsurface of the substrate as plugs were made to flow over it. The surface of\nthe substrate was rapidly saturated with a fluorescent dye as the fluroesecent\nplugs passed over the substrate, confirming effective mass transfer between the\nwetting layer and the surface of the substrate. The dynamics of saturation are\nconsistent from cycle to cycle, indicating that the chemistrode can stimulate\nsurfaces with high reproducibility. The number of plugs required to reach\n90% saturation of the hydrophilic surface of the substrate, \u03c6(90%), only\nweakly depended on experimental conditions (the P\u00e9clet number or the capillary\nnumber). Furthermore, over a wide range of operating conditions, \u03c6(90%) was\nless than 4. These results are useful for improving the chemistrode and for\nunderstanding other phenomena that involve diffusional transfer in multiphase\nor recirculating flows near surfaces.", "date": "2009-07", "date_type": "published", "publication": "New Journal of Physics", "volume": "11", "number": "7", "publisher": "IOP", "pagerange": "Art. No. 075017", "id_number": "CaltechAUTHORS:20130821-160716895", "issn": "1367-2630", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160716895", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "1DP1 OD003584" }, { "agency": "NSF", "grant_number": "CHE-0526693" }, { "agency": "Cottrell Scholar of Research Corporation" }, { "agency": "Camille and Henry Dreyfus Foundation" } ] }, "doi": "10.1088/1367-2630/11/7/075017", "pmcid": "PMC2757094", "primary_object": { "basename": "Ismagilov_NJP_TIRFM_in_chemistrode_Ms_DC.pdf", "url": "https://authors.library.caltech.edu/records/89xab-bww64/files/Ismagilov_NJP_TIRFM_in_chemistrode_Ms_DC.pdf" }, "related_objects": [ { "basename": "movie_S1.mov", "url": "https://authors.library.caltech.edu/records/89xab-bww64/files/movie_S1.mov" }, { "basename": "movie_S2.mov", "url": "https://authors.library.caltech.edu/records/89xab-bww64/files/movie_S2.mov" }, { "basename": "nihms-136237.pdf", "url": "https://authors.library.caltech.edu/records/89xab-bww64/files/nihms-136237.pdf" } ], "resource_type": "article", "pub_year": "2009", "author_list": "Chen, Delai; Du, Wenbin; et el." }, { "id": "https://authors.library.caltech.edu/records/m8f63-s1c02", "eprint_id": 40816, "eprint_status": "archive", "datestamp": "2023-08-20 01:40:04", "lastmod": "2023-10-24 22:01:26", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Kreutz-Jason-E", "name": { "family": "Kreutz", "given": "Jason E." } }, { "id": "Li-Liang", "name": { "family": "Li", "given": "Liang" } }, { "id": "Roach-L-Spencer", "name": { "family": "Roach", "given": "L. Spencer" } }, { "id": "Hatakeyama-Takuji", "name": { "family": "Hatakeyama", "given": "Takuji" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Laterally Mobile, Functionalized Self-Assembled Monolayers at the Fluorous-Aqueous Interface in a Plug-Based Microfluidic System: Characterization and Testing with Membrane Protein Crystallization", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2009 American Chemical Society. \n\nPublished In Issue: May 06, 2009. Article ASAP: April 08, 2009. Received: November 08, 2008. Revised: March 26, 2009. \n\nThis work was funded in part by ATCG3D U54 GM074961 and by the NIH T32 GM008720 (J.E.K.). We thank Phil Laible of Argonne National Laboratory for the generous gift of hRC, Vytas Bindokas Matthias Meier and Mikhail Karymov for help with FRAP experiments and data processing, and Elizabeth B. Haney for contributions in editing and writing this manuscript.\n\nSupporting Information\nDetailed procedure for synthesis and experiments and additional figures. This material is available free of charge via the Internet at http://pubs.acs.org.\n\nAccepted Version - nihms125086.pdf
Supplemental Material - Ismagilov_JACS_2009_Mobile_Functional_SAMs_JEK_Supp_Info.pdf
", "abstract": "This paper describes a method to generate functionalizable, mobile self-assembled monolayers (SAMs) in plug-based microfluidics. Control of interfaces is advancing studies of biological interfaces, heterogeneous reactions, and nanotechnology. SAMs have been useful for such studies, but they are not laterally mobile. Lipid-based methods, though mobile, are not easily amenable to setting up the hundreds of experiments necessary for crystallization screening. Here we demonstrate a method, complementary to current SAM and lipid methods, for rapidly generating mobile, functionalized SAMs. This method relies on plugs, droplets surrounded by a fluorous carrier fluid, to rapidly explore chemical space. Specifically, we implemented his-tag binding chemistry to design a new fluorinated amphiphile, RfNTA, using an improved one-step synthesis of RfOEG under Mitsunobu conditions. RfNTA introduces specific binding of protein at the fluorous\u2212aqueous interface, which concentrates and orients proteins at the interface, even in the presence of other surfactants. We then applied this approach to the crystallization of a his-tagged membrane protein, Reaction Center from Rhodobacter sphaeroides, performed 2400 crystallization trials, and showed that this approach can increase the range of crystal-producing conditions, the success rate at a given condition, the rate of nucleation, and the quality of the crystal formed.", "date": "2009-05-06", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "131", "number": "17", "publisher": "American Chemical Society", "pagerange": "6042-6043", "id_number": "CaltechAUTHORS:20130821-160722626", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160722626", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "U54 GM074961" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "T32 GM008720" } ] }, "doi": "10.1021/ja808697e", "pmcid": "PMC2741014", "primary_object": { "basename": "Ismagilov_JACS_2009_Mobile_Functional_SAMs_JEK_Supp_Info.pdf", "url": "https://authors.library.caltech.edu/records/m8f63-s1c02/files/Ismagilov_JACS_2009_Mobile_Functional_SAMs_JEK_Supp_Info.pdf" }, "related_objects": [ { "basename": "nihms125086.pdf", "url": "https://authors.library.caltech.edu/records/m8f63-s1c02/files/nihms125086.pdf" } ], "resource_type": "article", "pub_year": "2009", "author_list": "Kreutz, Jason E.; Li, Liang; et el." }, { "id": "https://authors.library.caltech.edu/records/2nvy5-vw809", "eprint_id": 40829, "eprint_status": "archive", "datestamp": "2023-08-20 01:07:16", "lastmod": "2023-10-24 22:28:59", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Liu-Ying", "name": { "family": "Liu", "given": "Ying" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Dynamics of Coalescence of Plugs with a Hydrophilic Wetting Layer Induced by Flow in a Microfluidic Chemistrode", "ispublished": "pub", "full_text_status": "restricted", "note": "Copyright \u00a9 2009 American Chemical Society. \n\nPublished In Issue: March 03, 2009. Article ASAP: February 09, 2009. Received: October 22, 2008. Revised: December 09, 2008. \n\nThis work was supported by NSF Materials Research Science and Engineering Center Grant 0213745. R.F.I. is a Cottrell Scholar of Research Corporation and a Camille Dreyfus Teacher-Scholar. Part of this work was performed at the Chicago MRSEC. We thank Sidney R. Nagel and Wendy Zhang for helpful discussion, Jason E. Kreutz for synthesizing RfOEG, Wenbin Du for help with the chemistrode fabrication, and Elizabeth W. Boyd for contributions to editing this manuscript.", "abstract": "This manuscript analyzes the dynamics of coalescence of an incoming aqueous plug with a wetting layer above a hydrophilic surface in the chemistrode. The chemistrode is a recently described (Chen, D.; Du, W.; Liu, Y.; Liu, W.; Kuznetsov, A.; Mendez, F. E.; Philipson, L. H.; Ismagilov, R. F. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 16843-16848) microfluidic analogue of an electrode, but operating at the chemical rather than electrical level, developed with the aim of capturing local stimulus-response processes in chemistry and biology. The chemistrode consists of open-ended V-shaped microfluidic channels that can be brought into contact with a chemical or biological hydrophilic substrate. The chemistrode relies on multiphase aqueous/fluorous flow and uses plugs to achieve high temporal resolution of stimulation and sampling. Coalescence of the incoming plugs, containing the stimuli, with the liquid in the wetting layer is required for chemical exchange to take place in the chemistrode. Here, we investigate the system with triethyleneglycol mono1H, 1H-perfluorooctyl ether RfOEG as the surfactant. This surfactant was necessary to prevent nonspecific absorption of proteins to the aqueous fluorous interface and to ensure biocompatibility of the system, but too much surfactant increased the barrier for coalescence. In this system, coalescence was controlled by the capillary number. At a higher value of the capillary number, coalescence took more time, and deformation of the interface of the incoming plug and the wetting layer was more significant. Above a critical capillary number, coalescence did not occur between the incoming plug and the wetting layer. The critical capillary number was an increasing function of surface tension but was independent of viscosity ratio. Coalescence was surprisingly reproducible, presumably because film rupture during coalescence was reliably initiated at the hydrophilic substrate. These results are useful in rational operation of the chemistrode and also provide an experimental description of deformation, film drainage, and coalescence of surfactant-coated droplets in an external flow field.", "date": "2009-03-03", "date_type": "published", "publication": "Langmuir", "volume": "25", "number": "5", "publisher": "American Chemical Society", "pagerange": "2854-2859", "id_number": "CaltechAUTHORS:20130821-160724691", "issn": "0743-7463", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160724691", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF", "grant_number": "0213745" }, { "agency": "Cottrell Scholar of Research Corporation" }, { "agency": "Camille and Henry Dreyfus Foundation" } ] }, "doi": "10.1021/la803518b", "resource_type": "article", "pub_year": "2009", "author_list": "Liu, Ying and Ismagilov, Rustem F." }, { "id": "https://authors.library.caltech.edu/records/rhnsn-z3k82", "eprint_id": 40836, "eprint_status": "archive", "datestamp": "2023-08-20 00:53:03", "lastmod": "2023-10-24 22:29:22", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Meier-Matthias-M-M", "name": { "family": "Meier", "given": "Matthias" }, "orcid": "0000-0002-7179-4173" }, { "id": "Kennedy-Darling-J", "name": { "family": "Kennedy-Darling", "given": "Julia" } }, { "id": "Choi-Se-Hoon", "name": { "family": "Choi", "given": "Se Hoon" } }, { "id": "Norstrom-Eric-M", "name": { "family": "Norstrom", "given": "Eric M." } }, { "id": "Sisodia-Sangram-S", "name": { "family": "Sisodia", "given": "Sangram S." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Plug-Based Microfluidics with Defined Surface Chemistry to Miniaturize and Control Aggregation of Amyloidogenic Peptides", "ispublished": "pub", "full_text_status": "public", "note": "Copyright \u00a9 2009 WILEY-VCH. \n\nIssue published online: 30 JAN 2009. Article first published online: 16 JAN 2009. Manuscript Received: 25 OCT 2008. \n\nThis research was supported by the National Institutes of Health NIBIB EB000557 and the NIH Director's Pioneer Award DP1 OD003584 to R.F.I. and by Cure Alzheimer's Fund and NIH AG027854 to S.S.S. R.F.I. is a Camille Dreyfus Teacher-Scholar. M.M. was supported by the Alexander von Humboldt Society and J.K.-D. by the NIH Roadmap training program T90 DK070076. We thank Dr. A.\u2005M. Seddon and Dr. E. Chan for preliminary experiments and E.\u2005W. Haney for editing this manuscript.\n\nAccepted Version - nihms101444.pdf
Supplemental Material - Ismagilov_Angew_Chem_2009_aggregation_48_1487_1489_MM_JKD_supp_info.pdf
", "abstract": "Small with control: For miniaturization of protein aggregation experiments the interfacial chemistry must be controlled to avoid protein aggregation caused by interfacial adsorption. Plug-based microfluidics with defined surface chemistry (see schematic picture) can then be used to perform hundreds of aggregation experiments with volume-limited samples, such as cerebrospinal fluid from mice.", "date": "2009-02-09", "date_type": "published", "publication": "Angewandte Chemie International Edition", "volume": "48", "number": "8", "publisher": "Wiley", "pagerange": "1487-1489", "id_number": "CaltechAUTHORS:20130821-160725760", "issn": "1433-7851", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160725760", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "EB000557" }, { "agency": "NIH", "grant_number": "1DP1 OD003584" }, { "agency": "Cure Alzheimer's Fund" }, { "agency": "NIH", "grant_number": "AG027854" }, { "agency": "Camille and Henry Dreyfus Foundation" }, { "agency": "Alexander von Humboldt Foundation" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "T90 DK070076" } ] }, "doi": "10.1002/anie.200805225", "pmcid": "PMC2675571", "primary_object": { "basename": "nihms101444.pdf", "url": "https://authors.library.caltech.edu/records/rhnsn-z3k82/files/nihms101444.pdf" }, "related_objects": [ { "basename": "Ismagilov_Angew_Chem_2009_aggregation_48_1487_1489_MM_JKD_supp_info.pdf", "url": "https://authors.library.caltech.edu/records/rhnsn-z3k82/files/Ismagilov_Angew_Chem_2009_aggregation_48_1487_1489_MM_JKD_supp_info.pdf" } ], "resource_type": "article", "pub_year": "2009", "author_list": "Meier, Matthias; Kennedy-Darling, Julia; et el." }, { "id": "https://authors.library.caltech.edu/records/6c334-gzw38", "eprint_id": 40779, "eprint_status": "archive", "datestamp": "2023-08-20 00:26:37", "lastmod": "2023-10-24 21:58:57", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Boedicker-James-Q", "name": { "family": "Boedicker", "given": "James Q." }, "orcid": "0000-0003-4107-3719" }, { "id": "Vincent-Meghan-E", "name": { "family": "Vincent", "given": "Meghan E." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Microfluidic confinement of single cells of bacteria in small volumes initiates high density behavior of quorum sensing and growth and reveals its variability", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2009 WILEY-VCH.\n\nIssue published online: 22 JUL 2009. Article first published online: 29 JUN 2009. Manuscript Received: 21 MAR 2009. \n\nThis research was supported by the NIH Director's Pioneer Award DP1 OD003584 to R.F.I. We thank S. Molin for generously providing the reporter strain, J. Shapiro and O. Zaborina for helpful discussion, and E.\u2005B. Haney for contributions to writing this manuscript.\n\nAccepted Version - nihms132881.pdf
Supplemental Material - Ismagilov_Angew_Chem_2009_QS_48_5908_5911_JQB_MB_Supp_Info.pdf
", "abstract": "One is a quorum: As few as one to three cells of Pseudomonas aeruginosa bacteria are confined in small volumes by the use of microfluidics. These small numbers of cells are able to activate quorum sensing (QS) pathways and achieve QS-dependent growth. The results also show that at low numbers of cells, initiation of QS is highly variable within a clonal population.", "date": "2009", "date_type": "published", "publication": "Angewandte Chemie International Edition", "volume": "48", "number": "32", "publisher": "Wiley", "pagerange": "5908-5911", "id_number": "CaltechAUTHORS:20130821-160716355", "issn": "1433-7851", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160716355", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "1DP1 OD003584" } ] }, "doi": "10.1002/anie.200901550", "pmcid": "PMC2748941", "primary_object": { "basename": "Ismagilov_Angew_Chem_2009_QS_48_5908_5911_JQB_MB_Supp_Info.pdf", "url": "https://authors.library.caltech.edu/records/6c334-gzw38/files/Ismagilov_Angew_Chem_2009_QS_48_5908_5911_JQB_MB_Supp_Info.pdf" }, "related_objects": [ { "basename": "nihms132881.pdf", "url": "https://authors.library.caltech.edu/records/6c334-gzw38/files/nihms132881.pdf" } ], "resource_type": "article", "pub_year": "2009", "author_list": "Boedicker, James Q.; Vincent, Meghan E.; et el." }, { "id": "https://authors.library.caltech.edu/records/c8zsy-h1051", "eprint_id": 40805, "eprint_status": "archive", "datestamp": "2023-08-20 00:05:52", "lastmod": "2023-10-24 22:00:43", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Kastrup-Christian-J", "name": { "family": "Kastrup", "given": "Christian J." } }, { "id": "Boedicker-James-Q", "name": { "family": "Boedicker", "given": "James Q." }, "orcid": "0000-0003-4107-3719" }, { "id": "Pomerantsev-Andrei-P", "name": { "family": "Pomerantsev", "given": "Andrei P." } }, { "id": "Moayeri-Mahtab", "name": { "family": "Moayeri", "given": "Mahtab" } }, { "id": "Bian-Yao", "name": { "family": "Bian", "given": "Yao" } }, { "id": "Pompano-Rebecca-R", "name": { "family": "Pompano", "given": "Rebecca R." } }, { "id": "Kline-Timothy-R", "name": { "family": "Kline", "given": "Timothy R." } }, { "id": "Sylvestre-Patricia", "name": { "family": "Sylvestre", "given": "Patricia" } }, { "id": "Shen-Feng", "name": { "family": "Shen", "given": "Feng" }, "orcid": "0000-0002-4709-330X" }, { "id": "Leppia-Stephen-H", "name": { "family": "Leppla", "given": "Stephen H." } }, { "id": "Tang-Wei-Jen", "name": { "family": "Tang", "given": "Wei-Jen" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Spatial localization of bacteria controls coagulation of human blood by 'quorum acting'", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2008 Nature Publishing Group. \n\nReceived 7 May 2008; Accepted 8 October 2008; Published online 2 November 2008.\n\nThis work was supported in part by the US National Institutes of Health (NIH) Director's Pioneer Award (grant number DP1OD003584), the US National Science Foundation CAREER Award (grant number CHE-0349034), the US Office of Naval Research (grant number N000140610630), the Camille Dreyfus Teacher-Scholar Awards Program and the Cottrell Scholar of Research Corporation Awards Program to R.F.I., by NIH grants (GM 62548 and GM 81539) to W.-J.T., and by the Intramural Research Program of the NIAID. We thank J. Alverdy, B. Bishop, S. Crosson, C. Esmon, M. Mock, M. Runyon, J. Shapiro, U. Spitz, T. Van Ha, D. Wiebel and O. Zaborina for helpful discussions; O. Zaborina (The University of Chicago) for the gift of the EGPF plasmid for E. coli and for assisting in the transformation procedure; M. Mock (Institut Pasteur) for the gift of the mouse anti-InhA1 serum; L. Cheng and D. Crown for assisting in the animal studies; H. Herwald (Lund University) for the gift of the E. coli Ymel-1 strain; J. Handelsman (University of Wisconsin) for the gift of the B. cereus GFP strain; M. Blaser (New York University) for the gift of the B. anthracis DeltaluxS strain; and J. Price for contributions in writing and editing this manuscript. We thank C. Tallant (Institut de Biologia Molecular de Barcelona) for assistance in construction of the protease gene knockout strains.\n\nAuthor Contributions: C.J.K., J.Q.B., M.M., Y.B., R.R.P., T.R.K. and F.S. performed experiments; C.J.K., J.Q.B., M.M., Y.B., R.R.P., T.R.K., F.S., S.H.L., W.-J.T. and R.F.I. designed experiments and analyzed data; C.J.K., W.-J.T. and R.F.I. wrote the paper; A.P.P. and P.S. provided reagents.\n\nAccepted Version - nihms-91170.pdf
", "abstract": "Blood coagulation often accompanies bacterial infections and sepsis and is generally accepted as a consequence of immune\nresponses. Though many bacterial species can directly activate individual coagulation factors, they have not been shown to\ndirectly initiate the coagulation cascade that precedes clot formation. Here we demonstrated, using microfluidics and surface\npatterning, that the spatial localization of bacteria substantially affects coagulation of human and mouse blood and plasma.\nBacillus cereus and Bacillus anthracis, the anthrax-causing pathogen, directly initiated coagulation of blood in minutes when\nbacterial cells were clustered. Coagulation of human blood by B. anthracis required secreted zinc metalloprotease InhA1, which\nactivated prothrombin and factor X directly (not via factor XII or tissue factor pathways). We refer to this mechanism as 'quorum\nacting' to distinguish it from quorum sensing\u2014it does not require a change in gene expression, it can be rapid and it can be\nindependent of bacterium-to-bacterium communication.", "date": "2008-12", "date_type": "published", "publication": "Nature Chemical Biology", "volume": "4", "number": "12", "publisher": "Nature Publishing Group", "pagerange": "742-750", "id_number": "CaltechAUTHORS:20130821-160720712", "issn": "1552-4450", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160720712", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "1DP1 OD003584" }, { "agency": "NSF", "grant_number": "CHE-0349034" }, { "agency": "Office of Naval Research (ONR)", "grant_number": "N000140610630" }, { "agency": "Camille and Henry Dreyfus Foundation" }, { "agency": "Cottrell Scholar of Research Corporation" }, { "agency": "NIH", "grant_number": "GM 62548" }, { "agency": "NIH", "grant_number": "GM 81539" } ] }, "doi": "10.1038/nchembio.124", "pmcid": "PMC2651025", "primary_object": { "basename": "nihms-91170.pdf", "url": "https://authors.library.caltech.edu/records/c8zsy-h1051/files/nihms-91170.pdf" }, "resource_type": "article", "pub_year": "2008", "author_list": "Kastrup, Christian J.; Boedicker, James Q.; et el." }, { "id": "https://authors.library.caltech.edu/records/aps6x-9gh14", "eprint_id": 40813, "eprint_status": "archive", "datestamp": "2023-08-19 23:59:39", "lastmod": "2023-10-24 22:01:14", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Kim-Hyun-Jung", "name": { "family": "Kim", "given": "Hyun Jung" } }, { "id": "Boedicker-J-Q", "name": { "family": "Boedicker", "given": "James Q." }, "orcid": "0000-0003-4107-3719" }, { "id": "Choi-Jang-Wook", "name": { "family": "Choi", "given": "Jang Wook" }, "orcid": "0000-0001-8783-0901" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Defined spatial structure stabilizes a synthetic multispecies bacterial community", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2008 National Academy of Sciences. \n\nH.J.K. and J.Q.B. contributed equally to this work. (received for review September 9, 2008). Published online before print November 14, 2008. \n\nWe thank Elizabeth W. Boyd and Jessica M. Price for assistance with writing and editing this paper. This work was supported by the National Institutes of Health Director's Pioneer Award 1DP1OD003584 to R.F.I., the Leo P. Kadanoff and Stuart A. Rice Fellowship from the Chicago Materials Research Science and Engineering Center (Chicago MRSEC) to H.J.K., and the Yen Fellowship to J.W.C. Some of this work was performed at the Chicago MRSEC microfluidic facility (funded by the National Science Foundation). \n\nAuthor contributions: H.J.K., J.Q.B., and R.F.I. designed research; H.J.K., J.Q.B., and J.W.C. performed research; H.J.K., J.Q.B., and R.F.I. contributed new reagents/analytic tools; H.J.K. and J.Q.B. analyzed data; and H.J.K., J.Q.B., and R.F.I. wrote the paper.\n\nThe authors declare no conflict of interest.\n\nThis article is a PNAS Direct Submission.\n\nPublished - Ismagilov_Bacterial_community_PNAS_2008_105_18188_HJK.pdf
Supplemental Material - Ismagilov_PNAS_2008_bacteria_communuities_HJK_JB_Supp_Info.pdf
", "abstract": "This paper shows that for microbial communities, ''fences make\ngood neighbors.'' Communities of soil microorganisms perform\ncritical functions: controlling climate, enhancing crop production,\nand remediation of environmental contamination. Microbial communities in the oral cavity and the gut are of high biomedical\ninterest. Understanding and harnessing the function of these\ncommunities is difficult: artificial microbial communities in the\nlaboratory become unstable because of ''winner-takes-all'' competition among species. We constructed a community of three\ndifferent species of wild-type soil bacteria with syntrophic interactions using a microfluidic device to control spatial structure and\nchemical communication. We found that defined microscale spatial\nstructure is both necessary and sufficient for the stable coexistence\nof interacting bacterial species in the synthetic community. A\nmathematical model describes how spatial structure can balance\nthe competition and positive interactions within the community,\neven when the rates of production and consumption of nutrients\nby species are mismatched, by exploiting nonlinearities of these\nprocesses. These findings provide experimental and modeling\nevidence for a class of communities that require microscale spatial\nstructure for stability, and these results predict that controlling\nspatial structure may enable harnessing the function of natural and\nsynthetic multispecies communities in the laboratory.", "date": "2008-11-25", "date_type": "published", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "volume": "105", "number": "47", "publisher": "National Academy of Sciences", "pagerange": "18188-18193", "id_number": "CaltechAUTHORS:20130821-160722189", "issn": "0027-8424", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160722189", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "1DP1 OD003584" }, { "agency": "Leo P. Kadanoff and Stuart A. Rice Fellowship" }, { "agency": "Yen Postdoctoral Fellowship" }, { "agency": "NSF" } ] }, "doi": "10.1073/pnas.0807935105", "pmcid": "PMC2587551", "primary_object": { "basename": "Ismagilov_Bacterial_community_PNAS_2008_105_18188_HJK.pdf", "url": "https://authors.library.caltech.edu/records/aps6x-9gh14/files/Ismagilov_Bacterial_community_PNAS_2008_105_18188_HJK.pdf" }, "related_objects": [ { "basename": "Ismagilov_PNAS_2008_bacteria_communuities_HJK_JB_Supp_Info.pdf", "url": "https://authors.library.caltech.edu/records/aps6x-9gh14/files/Ismagilov_PNAS_2008_bacteria_communuities_HJK_JB_Supp_Info.pdf" } ], "resource_type": "article", "pub_year": "2008", "author_list": "Kim, Hyun Jung; Boedicker, James Q.; et el." }, { "id": "https://authors.library.caltech.edu/records/c89dv-f6h57", "eprint_id": 40833, "eprint_status": "archive", "datestamp": "2023-08-19 23:54:27", "lastmod": "2023-10-24 22:29:16", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Lucchetta-E-M", "name": { "family": "Lucchetta", "given": "Elena M." } }, { "id": "Vincent-M-E", "name": { "family": "Vincent", "given": "Meghan E." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "A Precise Bicoid Gradient Is Nonessential during Cycles 11\u201313 for Precise Patterning in the Drosophila Blastoderm", "ispublished": "pub", "full_text_status": "public", "note": "Copyright: \u00a9 2008 Lucchetta et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. \n\nWe thank Eric F. Wieschaus for providing the Bcd-eGFP stock, Gerold Schubiger for providing the His2AvD-GFP stock, Nipam H. Patel and Manfred Frasch for providing antibodies, Nipam H. Patel and Kevin P. White for helpful discussions, and Elizabeth W. Boyd for contributions to writing and editing this manuscript. We thank referees for helpful suggestions.\n\nAuthor Contributions: Conceived and designed the experiments: EML RFI. Performed the experiments: EML MEV. Analyzed the data: EML. Contributed reagents/materials/analysis tools: RFI. Wrote the paper: EML RFI. \n\nFunding: This work was funded by NIH Grant No. R01 GM077331 and the Yen Postdoctoral Fellowship (E.M.L.).\n\nCompeting interests: The authors have declared that no competing interests exist.\n\nPublished - Ismagilov_PLoSONE_2008_3_e3651_bcd_elena.pdf
Supplemental Material - Ismagilov_Bcd_PLoS_ONE_EML_SI_v1.pdf
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", "abstract": "Background: During development, embryos decode maternal morphogen inputs into highly precise zygotic gene\nexpression. The discovery of the morphogen Bicoid and its profound effect on developmental programming in the\nDrosophila embryo has been a cornerstone in understanding the decoding of maternal inputs. Bicoid has been described as\na classical morphogen that forms a concentration gradient along the antero-posterior axis of the embryo by diffusion and\ninitiates expression of target genes in a concentration-dependent manner in the syncytial blastoderm. Recent work has\nemphasized the stability of the Bicoid gradient as a function of egg length and the role of nuclear dynamics in maintaining\nthe Bicoid gradient. Bicoid and nuclear dynamics were observed but not modulated under the ideal conditions used\npreviously. Therefore, it has not been tested explicitly whether a temporally stable Bicoid gradient prior to cellularization is\nrequired for precise patterning.\nPrincipal Findings: Here, we modulate both nuclear dynamics and the Bicoid gradient using laminar flows of different\ntemperature in a microfluidic device to determine if stability of the Bicoid gradient prior to cellularization is essential for\nprecise patterning. Dramatic motion of both cytoplasm and nuclei was observed prior to cellularization, and the Bicoid\ngradient was disrupted by nuclear motion and was highly abnormal as a function of egg length. Despite an abnormal Bicoid\ngradient during cycles 11\u201313, Even-skipped patterning in these embryos remained precise.\nConclusions: These results indicate that the stability of the Bicoid gradient as a function of egg length is nonessential\nduring syncytial blastoderm stages. Further, presumably no gradient formed by simple diffusion on the scale of egg length\ncould be responsible for the robust antero-posterior patterning observed, as severe cytoplasmic and nuclear motion would\ndisrupt such a gradient. Additional mechanisms for how the embryo could sense its dimensions and interpret the Bicoid\ngradient are discussed.", "date": "2008-11-07", "date_type": "published", "publication": "PLoS ONE", "volume": "3", "number": "11", "publisher": "Public Library of Science", "pagerange": "e3651", "id_number": "CaltechAUTHORS:20130821-160725343", "issn": "1932-6203", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160725343", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01 GM077331" }, { "agency": "Yen Postdoctoral Fellowship" } ] }, "doi": "10.1371/journal.pone.0003651", "pmcid": "PMC2578877", "primary_object": { "basename": "journal.pone.0003651.s017.avi", "url": "https://authors.library.caltech.edu/records/c89dv-f6h57/files/journal.pone.0003651.s017.avi" }, "related_objects": [ { "basename": "Ismagilov_Bcd_PLoS_ONE_EML_SI_v1.pdf", "url": "https://authors.library.caltech.edu/records/c89dv-f6h57/files/Ismagilov_Bcd_PLoS_ONE_EML_SI_v1.pdf" }, { "basename": "Ismagilov_PLoSONE_2008_3_e3651_bcd_elena.pdf", "url": "https://authors.library.caltech.edu/records/c89dv-f6h57/files/Ismagilov_PLoSONE_2008_3_e3651_bcd_elena.pdf" }, { "basename": "journal.pone.0003651.s012.avi", "url": "https://authors.library.caltech.edu/records/c89dv-f6h57/files/journal.pone.0003651.s012.avi" }, { "basename": "journal.pone.0003651.s013.avi", "url": "https://authors.library.caltech.edu/records/c89dv-f6h57/files/journal.pone.0003651.s013.avi" }, { "basename": "journal.pone.0003651.s014.avi", "url": "https://authors.library.caltech.edu/records/c89dv-f6h57/files/journal.pone.0003651.s014.avi" }, { "basename": "journal.pone.0003651.s015.avi", "url": "https://authors.library.caltech.edu/records/c89dv-f6h57/files/journal.pone.0003651.s015.avi" }, { "basename": "journal.pone.0003651.s016.avi", "url": "https://authors.library.caltech.edu/records/c89dv-f6h57/files/journal.pone.0003651.s016.avi" } ], "resource_type": "article", "pub_year": "2008", "author_list": "Lucchetta, Elena M.; Vincent, Meghan E.; et el." }, { "id": "https://authors.library.caltech.edu/records/5mws5-zjr82", "eprint_id": 40783, "eprint_status": "archive", "datestamp": "2023-08-19 23:53:43", "lastmod": "2023-10-24 21:59:07", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chen-Delai-L", "name": { "family": "Chen", "given": "Delai" } }, { "id": "Du-Wenbin", "name": { "family": "Du", "given": "Wenbin" }, "orcid": "0000-0002-7401-1410" }, { "id": "Liu-Ying", "name": { "family": "Liu", "given": "Ying" } }, { "id": "Liu-Weishan", "name": { "family": "Liu", "given": "Weishan" } }, { "id": "Kuznetsov-A", "name": { "family": "Kuznetsov", "given": "Andrey" } }, { "id": "Mendez-F-E", "name": { "family": "Mendez", "given": "Felipe E." } }, { "id": "Philipson-L-H", "name": { "family": "Philipson", "given": "Louis H." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "The chemistrode: A droplet-based microfluidic device for stimulation and recording with high temporal, spatial, and chemical resolution", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2008 by The National Academy of Sciences of the USA. \n\nPublished online before print October 30, 2008. \n\nWe thank Vytas Bindokas for help with confocal microscopy and Jessica M. Price for contributions in writing and editing this manuscript. This work was supported by National Institutes of Health (NIH) Director's Pioneer Award 1DP1OD003584 and National Science Foundation (NSF) Collaborative Research in Chemistry Grant CHE-0526693 (to R.F.I.), NIH Grants DK48494, DK63493, and DK20595 (to L.H.P.) and the Blum\u2013Kovler Foundation (L.H.P.). R.F.I. is a Cottrell Scholar of Research Corporation and a Camille Dreyfus Teacher\u2013Scholar. A part of this work was performed at the Materials Research Science and Engineering Center microfluidic facility funded by the NSF. \n\nAuthor contributions: D.C., W.D., Y.L., W.L., A.K., L.H.P., and R.F.I. designed research; D.C., W.D., Y.L., W.L., and F.E.M. performed research; D.C., W.D., Y.L., W.L., A.K., L.H.P., and R.F.I. analyzed data; and D.C., W.D., Y.L., W.L., and R.F.I. wrote the paper.\n\nThe authors declare no conflict of interest.\n\nThis article is a PNAS Direct Submission.\n\nThis article contains supporting information online at www.pnas.org/cgi/content/full/0807916105/DCSupplemental.\n\nPublished - Ismagilov_PNAS_2008_105_16843_Chemistrode.pdf
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", "abstract": "Microelectrodes enable localized electrical stimulation and recording, and they have revolutionized our understanding of the spatiotemporal dynamics of systems that generate or respond to\nelectrical signals. However, such comprehensive understanding of\nsystems that rely on molecular signals\u2014e.g., chemical communication in multicellular neural, developmental, or immune systems\u2014remains elusive because of the inability to deliver, capture,\nand interpret complex chemical information. To overcome this\nchallenge, we developed the ''chemistrode,'' a plug-based microfluidic device that enables stimulation, recording, and analysis\nof molecular signals with high spatial and temporal resolution.\nStimulation with and recording of pulses as short as 50 ms was\ndemonstrated. A pair of chemistrodes fabricated by multilayer soft\nlithography recorded independent signals from 2 locations separated by 15 \u03bcm. Like an electrode, the chemistrode does not need\nto be built into an experimental system\u2014it is simply brought into\ncontact with a chemical or biological substrate, and, instead of\nelectrical signals, molecular signals are exchanged. Recorded molecular signals can be injected with additional reagents and analyzed off-line by multiple, independent techniques in parallel (e.g.,\nfluorescence correlation spectroscopy, MALDI-MS, and fluorescence microscopy). When recombined, these analyses provide a\ntime-resolved chemical record of a system's response to stimulation. Insulin secretion from a single murine islet of Langerhans was\nmeasured at a frequency of 0.67 Hz by using the chemistrode. This\narticle characterizes and tests the physical principles that govern\nthe operation of the chemistrode to enable its application to\nprobing local dynamics of chemically responsive matter in chemistry and biology.", "date": "2008-11-04", "date_type": "published", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "volume": "105", "number": "44", "publisher": "National Academy of Sciences", "pagerange": "16843-16848", "id_number": "CaltechAUTHORS:20130821-160717046", "issn": "0027-8424", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160717046", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "1DP1 OD003584" }, { "agency": "NSF", "grant_number": "CHE-0526693" }, { "agency": "NIH", "grant_number": "DK48494" }, { "agency": "NIH", "grant_number": "DK63493" }, { "agency": "NIH", "grant_number": "DK20595" }, { "agency": "Blum\u2013Kovler Foundation" }, { "agency": "Cottrell Scholar of Research Corporation" }, { "agency": "Camille and Henry Dreyfus Foundation" } ] }, "doi": "10.1073/pnas.0807916105", "pmcid": "PMC2579341", "primary_object": { "basename": "Ismagilov_PNAS_2008_105_16843_Chemistrode_SI.pdf", "url": "https://authors.library.caltech.edu/records/5mws5-zjr82/files/Ismagilov_PNAS_2008_105_16843_Chemistrode_SI.pdf" }, "related_objects": [ { "basename": "SM1.mov", "url": "https://authors.library.caltech.edu/records/5mws5-zjr82/files/SM1.mov" }, { "basename": "SM2.mov", "url": "https://authors.library.caltech.edu/records/5mws5-zjr82/files/SM2.mov" }, { "basename": "SM3.mov", "url": "https://authors.library.caltech.edu/records/5mws5-zjr82/files/SM3.mov" }, { "basename": "SM4.mov", "url": "https://authors.library.caltech.edu/records/5mws5-zjr82/files/SM4.mov" }, { "basename": "Ismagilov_PNAS_2008_105_16843_Chemistrode.pdf", "url": "https://authors.library.caltech.edu/records/5mws5-zjr82/files/Ismagilov_PNAS_2008_105_16843_Chemistrode.pdf" } ], "resource_type": "article", "pub_year": "2008", "author_list": "Chen, Delai; Du, Wenbin; et el." }, { "id": "https://authors.library.caltech.edu/records/b2j8v-gx577", "eprint_id": 40866, "eprint_status": "archive", "datestamp": "2023-08-19 23:51:52", "lastmod": "2023-10-20 22:55:56", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Shen-Feng", "name": { "family": "Shen", "given": "Feng" }, "orcid": "0000-0002-4709-330X" }, { "id": "Kastrup-C-J", "name": { "family": "Kastrup", "given": "Christian J." } }, { "id": "Liu-Ying", "name": { "family": "Liu", "given": "Ying" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Threshold Response of Initiation of Blood Coagulation by Tissue Factor in Patterned Microfluidic Capillaries Is Controlled by Shear Rate", "ispublished": "pub", "full_text_status": "restricted", "note": "Copyright \u00a9 2008 by American Heart Association. \n\nOriginal received May 13, 2008; final version accepted August 5, 2008. Published online before print August 14, 2008. \n\nWe thank Matthew Runyon, Howard Stone, and Thuong Van Ha for helpful discussions, Pamela Haltek and Sharice Davis for collecting blood samples, and Jessica M. Price for contributions in writing and editing this manuscript.\n\nSources of Funding: This work was supported in part by NSF CAREER Award No. CHE-0349034 and ONR grant No. N000140610630. R.F.I. is a Cottrell Scholar of Research Corporation and an A.P. Sloan Research Fellow. Some of this work was performed at the Materials Research Science and Engineering Center microfluidic facility funded by the NSF.", "abstract": "Objective\u2014Blood flow is considered one of the important parameters that contribute to venous thrombosis. We quantitatively\ntest the relationship between initiation of coagulation and shear rate and suggest a biophysical mechanism to understand\nthis relationship.\nMethods and Results\u2014Flowing human blood and plasma were exposed to cylindrical surfaces patterned with patches of\ntissue factor (TF) by using microfluidics. Initiation of coagulation of normal pooled plasma depended on shear rate, not\nvolumetric flow rate or flow velocity, and coagulation initiated only at shear rates below a critical value. Initiation of\ncoagulation of platelet-rich plasma and whole blood showed similar behavior. At constant shear rate, coagulation of\nplasma also showed a threshold response to the size of a patch of TF, consistent with our previous work in the absence\nof flow.\nConclusion\u2014Initiation of coagulation of flowing blood displays a threshold response to shear rate and to the size of a\nsurface patch of TF. Combined with the results of others, these results set the range of shear rates that limit initiation\nof coagulation by small surface areas of TF and by shear activation of platelets. This range fits the relatively narrow\nrange of physiological shear rates described by Murray's law. (Arterioscler Thromb Vasc Biol. 2008;28:2035-2041)", "date": "2008-11", "date_type": "published", "publication": "Arteriosclerosis, Thrombosis, and Vascular Biology", "volume": "28", "number": "11", "publisher": "American Heart Association", "pagerange": "2035-2041", "id_number": "CaltechAUTHORS:20130821-160731095", "issn": "1079-5642", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160731095", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF", "grant_number": "CHE-0349034" }, { "agency": "ONR", "grant_number": "N000140610630" }, { "agency": "Cottrell Scholar of Research Corporation" }, { "agency": "Alfred P. Sloan Foundation" } ] }, "doi": "10.1161/ATVBAHA.108.173930", "resource_type": "article", "pub_year": "2008", "author_list": "Shen, Feng; Kastrup, Christian J.; et el." }, { "id": "https://authors.library.caltech.edu/records/ayns4-hc719", "eprint_id": 40826, "eprint_status": "archive", "datestamp": "2023-08-19 23:49:08", "lastmod": "2023-10-24 22:28:48", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Li-Liang", "name": { "family": "Li", "given": "Liang" } }, { "id": "Nachtergaele-Sigrid", "name": { "family": "Nachtergaele", "given": "Sigrid" } }, { "id": "Seddon-Annela-M", "name": { "family": "Seddon", "given": "Annela M." } }, { "id": "Tereshko-Valentina", "name": { "family": "Tereshko", "given": "Valentina" } }, { "id": "Ponomarenko-Nina-S", "name": { "family": "Ponomarenko", "given": "Nina" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Simple Host-Guest Chemistry To Modulate the Process of Concentration and Crystallization of Membrane Proteins by Detergent Capture in a Microfluidic Device", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2008 American Chemical Society. \n\nPublished In Issue: October 29, 2008. Article ASAP: October 03, 2008. Received: July 10, 2008. \n\nThis work was supported in part through the NIH Roadmap for Medical Research (R01 GM075827-01) and UC/ANL Collaborative Seed Funding. We thank ATCG3D funded by the NIGMS and NCRR under the PSI-2 Specialized Center program (U54 GM074961) for providing some of the equipment used in this work. V.T. was supported by ATCG3D. A.M.S. was supported by an EPSRC LSI Postdoctoral Fellowship. S.N. was supported by the NIH Roadmap Physical and Chemical Biology undergraduate training program at UC. We would like to thank Eva Chi for discussion about DLS experiments and Elizabeth W. Boyd for contributions in writing and editing this manuscript. Use of the Argonne National Laboratory LS-CAT beamlines, BioCARS beamlines, and GM/CA beamlines at the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under Contract No. DE-AC02-06CH11357. GM/CA CAT has been funded in whole or in part with Federal funds from the National Cancer Institute (Y1-CO-1020) and the National Institute of General Medical Science (Y1-GM-1104). Use of the BioCARS Sector 14 was supported by the National Institutes of Health, National Center for Research Resources, under Grant Number RR07707. Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor for the support of this research program (Grant 085P1000817).\n\nSupporting Information: Details of chemicals and equipment used, experimental details for the preparation of samples for DLS and TLC, the details of the Labview program used to control the microfluidic crystallization method, and results obtained for control experiments and the construction of calibration curves. This material is available free of charge via the Internet at http://pubs.acs.org/.\n\nAccepted Version - nihms-79622.pdf
Supplemental Material - ismagilov_detergent_capture_JACS_130_2008_14324_LL_SI.pdf
", "abstract": "This paper utilizes cyclodextrin-based host-guest chemistry in a microfluidic device to modulate the crystallization of membrane proteins and the process of concentration of membrane protein samples. Methyl-beta-cyclodextrin (MBCD) can efficiently capture a wide variety of detergents commonly used for the stabilization of membrane proteins by sequestering detergent monomers. Reaction Center (RC) from Blastochloris viridis was used here as a model system. In the process of concentrating membrane protein samples, MBCD was shown to break up free detergent micelles and prevent them from being concentrated. The addition of an optimal amount of MBCD to the RC sample captured loosely bound detergent from the protein-detergent complex and improved sample homogeneity, as characterized by dynamic light scattering. Using plug-based microfluidics, RC crystals were grown in the presence of MBCD, giving a different morphology and space group than crystals grown without MBCD. The crystal structure of RC crystallized in the presence of MBCD was consistent with the changes in packing and crystal contacts hypothesized for removal of loosely bound detergent. The incorporation of MBCD into a plug-based microfluidic crystallization method allows efficient use of limited membrane protein sample by reducing the amount of protein required and combining sparse matrix screening and optimization in one experiment. The use of MBCD for detergent capture can be expanded to develop cyclodextrin-derived molecules for fine-tuned detergent capture and thus modulate membrane protein crystallization in an even more controllable way.", "date": "2008-10-29", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "130", "number": "43", "publisher": "American Chemical Society", "pagerange": "14324-14328", "id_number": "CaltechAUTHORS:20130821-160724242", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160724242", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01 GM075827-01" }, { "agency": "University of Chicago" }, { "agency": "NIH", "grant_number": "U54 GM074961" }, { "agency": "Engineering and Physical Sciences Research Council (EPSRC)" }, { "agency": "Department of Energy (DOE)", "grant_number": "DE-AC02-06CH11357" }, { "agency": "NIH", "grant_number": "Y1-CO-1020" }, { "agency": "NIH", "grant_number": "Y1-GM-1104" }, { "agency": "NIH", "grant_number": "RR07707" }, { "agency": "Michigan Economic Development Corporation" }, { "agency": "Michigan Technology Tri-Corridor", "grant_number": "085P1000817" }, { "agency": "Argonne National Laboratory" } ] }, "doi": "10.1021/ja805361j", "pmcid": "PMC2596067", "primary_object": { "basename": "ismagilov_detergent_capture_JACS_130_2008_14324_LL_SI.pdf", "url": "https://authors.library.caltech.edu/records/ayns4-hc719/files/ismagilov_detergent_capture_JACS_130_2008_14324_LL_SI.pdf" }, "related_objects": [ { "basename": "nihms-79622.pdf", "url": "https://authors.library.caltech.edu/records/ayns4-hc719/files/nihms-79622.pdf" } ], "resource_type": "article", "pub_year": "2008", "author_list": "Li, Liang; Nachtergaele, Sigrid; et el." }, { "id": "https://authors.library.caltech.edu/records/20tpx-g8t89", "eprint_id": 40815, "eprint_status": "archive", "datestamp": "2023-08-19 23:29:04", "lastmod": "2023-10-24 22:01:20", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Kline-Timothy-R", "name": { "family": "Kline", "given": "Timothy R." } }, { "id": "Runyon-Matthew-K", "name": { "family": "Runyon", "given": "Matthew K." } }, { "id": "Pothiwala-Mohammad", "name": { "family": "Pothiawala", "given": "Mohammad" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "ABO, D Blood Typing and Subtyping Using Plug-Based Microfluidics", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2008 American Chemical Society. \n\nPublished In Issue: August 15, 2008. Article ASAP: July 23, 2008. Received: March 07, 2008. Accepted: April 24, 2008. \n\nThis work was supported in part by the NIH and the NIBIB (Grant R01 EB001903) the Camille Dreyfus Teacher-Scholar Award. M.K.R. was supported in part by Burroughs Wellcome Fund Interfaces I.D. 1001447. R.F.I. is a Cottrell Scholar of the Research Corporation and an A. P. Sloan Research Fellow. Some of this work was performed at the MRSEC microfluidics facility (funded by the NSF). We thank Rebecca R. Pompano for helpful discussions and Jessica M. Price for assistance in writing and editing the manuscript.\n\nAccepted Version - nihms-79620.pdf
", "abstract": "A plug-based microfluidic approach was used to perform\nmultiple agglutination assays in parallel without crosscontamination and using only microliter volumes of blood.\nTo perform agglutination assays on-chip, a microfluidic\ndevice was designed to combine aqueous streams of\nantibody, buffer, and red blood cells (RBCs) to form\ndroplets 30-40 nL in volume surrounded by a fluorinated\ncarrier fluid. Using this approach, proof-of-concept ABO\nand D (Rh) blood typing and group A subtyping were\nsuccessfully performed by screening against multiple\nantigens without cross-contamination. On-chip subtyping\ndistinguished common A1 and A2\nRBCs by using a lectinbased dilution assay. This flexible platform was extended\nto differentiate rare, weakly agglutinating RBCs of A\nsubtypes by analyzing agglutination avidity as a function\nof shear rate. Quantitative analysis of changes in contrast\nwithin plugs revealed subtleties in agglutination kinetics\nand enabled characterization of agglutination of rare blood\nsubtypes. Finally, this platform was used to detect bacteria, demonstrating the potential usefulness of this assay\nin detecting sepsis and the potential for applications in\nagglutination-based viral detection. The speed, control,\nand minimal sample consumption provided by this technology present an advance for point of care applications,\nblood typing of newborns, and general blood assays in\nsmall model organisms.", "date": "2008-08-15", "date_type": "published", "publication": "Analytical Chemistry", "volume": "80", "number": "16", "publisher": "American Chemical Society", "pagerange": "6190-6197", "id_number": "CaltechAUTHORS:20130821-160722469", "issn": "0003-2700", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160722469", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01 EB001903" }, { "agency": "Camille and Henry Dreyfus Foundation" }, { "agency": "Burroughs Wellcome Fund Interfaces", "grant_number": "1001447" }, { "agency": "Cottrell Scholar of Research Corporation" }, { "agency": "Alfred P. Sloan Foundation" }, { "agency": "NSF" } ] }, "doi": "10.1021/ac800485q", "pmcid": "PMC2592685", "primary_object": { "basename": "nihms-79620.pdf", "url": "https://authors.library.caltech.edu/records/20tpx-g8t89/files/nihms-79620.pdf" }, "resource_type": "article", "pub_year": "2008", "author_list": "Kline, Timothy R.; Runyon, Matthew K.; et el." }, { "id": "https://authors.library.caltech.edu/records/e9mf6-5tr54", "eprint_id": 40854, "eprint_status": "archive", "datestamp": "2023-08-19 23:25:47", "lastmod": "2023-10-24 22:30:47", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Pompano-Rebecca-R", "name": { "family": "Pompano", "given": "Rebecca R." } }, { "id": "Li-Hung-Wing", "name": { "family": "Li", "given": "Hung-Wing" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Rate of mixing controls rate and outcome of autocatalytic processes\u2014theory and microfluidic experiments with chemical reactions and blood coagulation", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2008 The Biophysical Society. \n\nReceived 15 January 2008. Accepted 1 April 2008. Available online 24 November 2008. \n\nThis work was supported in part by ONR under Grant No. N00014-03-10482, the NIBIB under Grant No. ROI EB001903-04, and by the Camille Dreyfus Teacher-Scholar Awards Program. R.F.I. is a Cottrell Scholar of Research Corporation and an A. P. Sloan Research Fellow. Some of this work was performed at the MRSEC microfluidic facility (funded by the NSF). We thank Jessica M. Price for contributions in writing and editing this manuscript.\n\nSupplementary material\nTo view all of the supplemental files associated with this article, visit www.biophysj.org.\n\nPublished - BiophysJ_2008_95_1531_1543_mixing_rrp.pdf
Supplemental Material - BiophysJ_2008_95_1531_1543_mixing_rrp_SI.pdf
Supplemental Material - mmc2.mpg
Supplemental Material - mmc3.mpg
Supplemental Material - mmc4.mpg
Supplemental Material - mmc5.mpg
Supplemental Material - mmc6.mpg
Supplemental Material - mmc7.mpg
", "abstract": "This article demonstrates that the rate of mixing can regulate the rate and outcome of both biological and\nnonbiological autocatalytic reaction systems that display a threshold response to the concentration of an activator. Plug-based\nmicrofluidics was used to control the timing of reactions, the rate of mixing, and surface chemistry in blood clotting and its\nchemical model. Initiation of clotting of human blood plasma required addition of a critical concentration of thrombin. Clotting\ncould be prevented by rapid mixing when thrombin was added near the critical concentration, and mixing also affected the rate\nof clotting when thrombin was added at concentrations far above the critical concentration in two clinical clotting assays for\nhuman plasma. This phenomenon was modeled by a simple mechanism\u2014local and global competition between the clotting\nreaction, which autocatalytically produces an activator, and mixing, which removes the activator. Numerical simulations showed\nthat the Damk\u00f6hler number, which describes this competition, predicts the effects of mixing. Many biological systems are controlled by thresholds, and these results shed light on the dynamics of these systems in the presence of spatial heterogeneities\nand provide simple guidelines for designing and interpreting experiments with such systems.", "date": "2008-08-01", "date_type": "published", "publication": "Biophysical Journal", "volume": "95", "number": "3", "publisher": "Biophysical Society", "pagerange": "1531-1543", "id_number": "CaltechAUTHORS:20130821-160729017", "issn": "0006-3495", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160729017", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Office of Naval Research (ONR)", "grant_number": "N00014-03-10482" }, { "agency": "NIH", "grant_number": "ROI EB001903-04" }, { "agency": "Camille and Henry Dreyfus Foundation" }, { "agency": "Cottrell Scholar of Research Corporation" }, { "agency": "Alfred P. Sloan Foundation" }, { "agency": "NSF" } ] }, "doi": "10.1529/biophysj.108.129486", "pmcid": "PMC2479617", "primary_object": { "basename": "mmc2.mpg", "url": "https://authors.library.caltech.edu/records/e9mf6-5tr54/files/mmc2.mpg" }, "related_objects": [ { "basename": "mmc3.mpg", "url": "https://authors.library.caltech.edu/records/e9mf6-5tr54/files/mmc3.mpg" }, { "basename": "mmc4.mpg", "url": "https://authors.library.caltech.edu/records/e9mf6-5tr54/files/mmc4.mpg" }, { "basename": "mmc5.mpg", "url": "https://authors.library.caltech.edu/records/e9mf6-5tr54/files/mmc5.mpg" }, { "basename": "mmc6.mpg", "url": "https://authors.library.caltech.edu/records/e9mf6-5tr54/files/mmc6.mpg" }, { "basename": "mmc7.mpg", "url": "https://authors.library.caltech.edu/records/e9mf6-5tr54/files/mmc7.mpg" }, { "basename": "BiophysJ_2008_95_1531_1543_mixing_rrp.pdf", "url": "https://authors.library.caltech.edu/records/e9mf6-5tr54/files/BiophysJ_2008_95_1531_1543_mixing_rrp.pdf" }, { "basename": "BiophysJ_2008_95_1531_1543_mixing_rrp_SI.pdf", "url": "https://authors.library.caltech.edu/records/e9mf6-5tr54/files/BiophysJ_2008_95_1531_1543_mixing_rrp_SI.pdf" } ], "resource_type": "article", "pub_year": "2008", "author_list": "Pompano, Rebecca R.; Li, Hung-Wing; et el." }, { "id": "https://authors.library.caltech.edu/records/rqc6r-mj822", "eprint_id": 40807, "eprint_status": "archive", "datestamp": "2023-08-19 22:31:38", "lastmod": "2023-10-24 22:00:53", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Kastrup-Christian-J", "name": { "family": "Kastrup", "given": "Christian J." } }, { "id": "Runyon-Matthew-K", "name": { "family": "Runyon", "given": "Matthew K." } }, { "id": "Lucchetta-Elena-M", "name": { "family": "Lucchetta", "given": "Elena M." } }, { "id": "Price-Jessica-M", "name": { "family": "Price", "given": "Jessica M." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Using chemistry and microfluidics to understand the spatial dynamics of complex biological networks", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2008 American Chemical Society. \n\nPublished In Issue: April 15, 2008. Article ASAP: January 25, 2008. Received: July 26, 2007. \n\nThis work was supported in part by NSF CAREER Award CHE-0349034, ONR Grant N00014-03-10482, NIH Grant R01 GM077331, and the Dreyfus Teacher-Scholar Award. R.F.I. is a Cottrell Scholar of Research Corporation and an A. P. Sloan Research Fellow. Some of this work was performed at the MRSEC microfluidic facility funded by the NSF.\n\nAccepted Version - nihms79316.pdf
", "abstract": "Understanding the spatial dynamics of biochemical networks is both fundamentally important for understanding life at the systems level and also has practical implications for medicine, engineering, biology, and chemistry. Studies at the level of individual reactions provide essential information about the function, interactions, and localization of individual molecular species and reactions in a network. However, analyzing the spatial dynamics of complex biochemical networks at this level is difficult. Biochemical networks are non-equilibrium systems containing dozens to hundreds of reactions with nonlinear and time-dependent interactions, and these interactions are influenced by diffusion, flow, and the relative values of state-dependent kinetic parameters. To achieve an overall understanding of the spatial dynamics of a network and the global mechanisms that drive its function, networks must be analyzed as a whole, where all of the components and influential parameters of a network are simultaneously considered. Here, we describe chemical concepts and microfluidic tools developed for network-level investigations of the spatial dynamics of these networks. Modular approaches can be used to simplify these networks by separating them into modules, and simple experimental or computational models can be created by replacing each module with a single reaction. Microfluidics can be used to implement these models as well as to analyze and perturb the complex network itself with spatial control on the micrometer scale. We also describe the application of these network-level approaches to elucidate the mechanisms governing the spatial dynamics of two networks-hemostasis (blood clotting) and early patterning of the Drosophila embryo. To investigate the dynamics of the complex network of hemostasis, we simplified the network by using a modular mechanism and created a chemical model based on this mechanism by using microfluidics. Then, we used the mechanism and the model to predict the dynamics of initiation and propagation of blood clotting and tested these predictions with human blood plasma by using microfluidics. We discovered that both initiation and propagation of clotting are regulated by a threshold response to the concentration of activators of clotting, and that clotting is sensitive to the spatial localization of stimuli. To understand the dynamics of patterning of the Drosophila embryo, we used microfluidics to perturb the environment around a developing embryo and observe the effects of this perturbation on the expression of Hunchback, a protein whose localization is essential to proper development. We found that the mechanism that is responsible for Hunchback positioning is asymmetric, time-dependent, and more complex than previously proposed by studies of individual reactions. Overall, these approaches provide strategies for simplifying, modeling, and probing complex networks without sacrificing the functionality of the network. Such network-level strategies may be most useful for understanding systems with non-linear interactions where spatial dynamics is essential for function. In addition, microfluidics provides an opportunity to investigate the mechanisms responsible for robust functioning of complex networks. By creating nonideal, stressful, and perturbed environments, microfluidic experiments could reveal the function of pathways thought to be nonessential under ideal conditions.", "date": "2008-04-15", "date_type": "published", "publication": "Accounts of Chemical Research", "volume": "41", "number": "4", "publisher": "American Chemical Society", "pagerange": "549-558", "id_number": "CaltechAUTHORS:20130821-160721104", "issn": "0001-4842", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160721104", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF", "grant_number": "CHE-0349034" }, { "agency": "Office of Naval Research (ONR)", "grant_number": "N00014-03-10482" }, { "agency": "NIH", "grant_number": "R01 GM077331" }, { "agency": "Camille and Henry Dreyfus Foundation" }, { "agency": "Cottrell Scholar of Research Corporation" }, { "agency": "Alfred P. Sloan Foundation" } ] }, "doi": "10.1021/ar700174g", "pmcid": "PMC2593841", "primary_object": { "basename": "nihms79316.pdf", "url": "https://authors.library.caltech.edu/records/rqc6r-mj822/files/nihms79316.pdf" }, "resource_type": "article", "pub_year": "2008", "author_list": "Kastrup, Christian J.; Runyon, Matthew K.; et el." }, { "id": "https://authors.library.caltech.edu/records/hz44t-esr26", "eprint_id": 40861, "eprint_status": "archive", "datestamp": "2023-08-19 22:24:17", "lastmod": "2023-10-24 22:31:15", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Runyon-M-K", "name": { "family": "Runyon", "given": "Matthew K." } }, { "id": "Kastrup-C-J", "name": { "family": "Kastrup", "given": "Christian J." } }, { "id": "Johnson-Kerner-B-L", "name": { "family": "Johnson-Kerner", "given": "Bethany L." } }, { "id": "Van-Ha-Thuong-G", "name": { "family": "Van Ha", "given": "Thuong G." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Effects of shear rate on propagation of blood clotting determined using microfluidics and numerical simulations", "ispublished": "pub", "full_text_status": "public", "note": "Copyright \u00a9 2008 American Chemical Society. \n\nPublished In Issue: March 19, 2008. Received August 21, 2007. \n\nThis work was funded by the ONR (Grant N000140610630), the NSF CAREER Award (CHE-0349034), and the Camille Dreyfus Teacher-Scholar Awards Program. M.K.R. was supported in part by Burroughs Wellcome Fund Interfaces I.D. 1001774. R.F.I. is a Cottrell Scholar of Research Corporation and an A. P. Sloan Research Fellow. Some of this work was performed at the MRSEC microfluidic facility (funded by the NSF). We thank Jessica M. Price for contributions in writing and editing this manuscript.\n\nSupporting Information Available: Detailed procedure for the experiments and numerical simulations. This material is available free of charge via the Internet at http://pubs.acs.org.\n\nSupplemental Material - JACS_2008_130_3458_3464_Ismagilov_Effects_of_Shear_on_Propagation_SI.pdf
", "abstract": "This paper describes microfluidic experiments with human blood plasma and numerical simulations to determine the role of fluid flow in the regulation of propagation of blood clotting. We demonstrate that propagation of clotting can be regulated by different mechanisms depending on the volume-to-surface ratio of a channel. In small channels, propagation of clotting can be prevented by surface-bound inhibitors of clotting present on vessel walls. In large channels, where surface-bound inhibitors are ineffective, propagation of clotting can be prevented by a shear rate above a threshold value, in agreement with predictions of a simple reaction-diffusion mechanism. We also demonstrate that propagation of clotting in a channel with a large volume-to-surface ratio and a shear rate below a threshold shear rate can be slowed by decreasing the production of thrombin, an activator of clotting. These in vitro results make two predictions, which should be experimentally tested in vivo. First, propagation of clotting from superficial veins to deep veins may be regulated by shear rate, which might explain the correlation between superficial thrombosis and the development of deep vein thrombosis (DVT). Second, nontoxic thrombin inhibitors with high binding affinities could be locally administered to prevent recurrent thrombosis after a clot has been removed. In addition, these results demonstrate the utility of simplified mechanisms and microfluidics for generating and testing predictions about the dynamics of complex biochemical networks.", "date": "2008-03-19", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "130", "number": "11", "publisher": "American Chemical Society", "pagerange": "3458-3464", "id_number": "CaltechAUTHORS:20130821-160730150", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160730150", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "ONR", "grant_number": "N000140610630" }, { "agency": "NSF", "grant_number": "CHE-0349034" }, { "agency": "Camille and Henry Dreyfus Foundation" }, { "agency": "Burroughs Wellcome Fund Interfaces", "grant_number": "1001774" }, { "agency": "Cottrell Scholar of Research Corporation" }, { "agency": "Alfred P. Sloan Foundation" } ] }, "doi": "10.1021/ja076301r", "primary_object": { "basename": "JACS_2008_130_3458_3464_Ismagilov_Effects_of_Shear_on_Propagation_SI.pdf", "url": "https://authors.library.caltech.edu/records/hz44t-esr26/files/JACS_2008_130_3458_3464_Ismagilov_Effects_of_Shear_on_Propagation_SI.pdf" }, "resource_type": "article", "pub_year": "2008", "author_list": "Runyon, Matthew K.; Kastrup, Christian J.; et el." }, { "id": "https://authors.library.caltech.edu/records/8eteb-x0k54", "eprint_id": 40778, "eprint_status": "archive", "datestamp": "2023-08-19 21:50:24", "lastmod": "2023-10-24 17:23:31", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Boedicker-James-Q", "name": { "family": "Boedicker", "given": "James Q." }, "orcid": "0000-0003-4107-3719" }, { "id": "Li-Liang", "name": { "family": "Li", "given": "Liang" } }, { "id": "Kline-Timothy-R", "name": { "family": "Kline", "given": "Timothy R." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Detecting bacteria and determining their susceptibility to antibiotics by stochastic confinement in nanoliter droplets using plug-based microfluidics", "ispublished": "pub", "full_text_status": "public", "note": "This journal is \u00a9 The Royal Society of Chemistry 2008. \n\nReceived 26th March 2008, Accepted 21st May 2008. First published on the web 4th July 2008. \n\nThis work was supported in part by the NSF CRC (Grant No. 0526693) and by the NIH. We would like to thank Christian Kastrup, Helen Song, Urs Spitz, and Lukas Wick for helpful comments and Jessica M. Price for contributions in writing and editing this manuscript. R. F. I. is a Cottrell Scholar of Research Corporation and an A. P. Sloan Research Fellow. Some of this work was performed at the Materials Research Science and Engineering Centers microfluidic facility funded by the NSF.\n\nPublished - ismagilov_detecting_bacteria_LOC_JB.pdf
Supplemental Material - Ismagilov_LOC_2008_8_1265_1272_Detecting_Bacteria_jqb_SI.pdf
", "abstract": "This article describes plug-based microfluidic technology that enables rapid detection and drug\nsusceptibility screening of bacteria in samples, including complex biological matrices, without preincubation. Unlike conventional bacterial culture and detection methods, which rely on incubation\nof a sample to increase the concentration of bacteria to detectable levels, this method confines individual bacteria into droplets nanoliters in volume. When single cells are confined into plugs of small\nvolume such that the loading is less than one bacterium per plug, the detection time is proportional\nto plug volume. Confinement increases cell density and allows released molecules to accumulate\naround the cell, eliminating the pre-incubation step and reducing the time required to detect\nthe bacteria. We refer to this approach as 'stochastic confinement'. Using the microfluidic hybrid\nmethod, this technology was used to determine the antibiogram \u2013 or chart of antibiotic sensitivity\n\u2013 of methicillin-resistant Staphylococcus aureus (MRSA) to many antibiotics in a single experiment\nand to measure the minimal inhibitory concentration (MIC) of the drug cefoxitin (CFX) against\nthis strain. In addition, this technology was used to distinguish between sensitive and resistant\nstrains of S. aureus in samples of human blood plasma. High-throughput microfluidic techniques\ncombined with single-cell measurements also enable multiple tests to be performed simultaneously\non a single sample containing bacteria. This technology may provide a method of rapid\nand effective patient-specific treatment of bacterial infections and could be extended to a variety\nof applications that require multiple functional tests of bacterial samples on reduced timescales.", "date": "2008", "date_type": "published", "publication": "Lab on a Chip", "volume": "8", "number": "8", "publisher": "Royal Society of Chemistry", "pagerange": "1265-1272", "id_number": "CaltechAUTHORS:20130821-160716197", "issn": "1473-0197", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160716197", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF", "grant_number": "0526693" }, { "agency": "NIH" }, { "agency": "Cottrell Scholar of Research Corporation" }, { "agency": "Alfred P. Sloan Foundation" } ] }, "doi": "10.1039/B804911D", "pmcid": "PMC2612531", "primary_object": { "basename": "Ismagilov_LOC_2008_8_1265_1272_Detecting_Bacteria_jqb_SI.pdf", "url": "https://authors.library.caltech.edu/records/8eteb-x0k54/files/Ismagilov_LOC_2008_8_1265_1272_Detecting_Bacteria_jqb_SI.pdf" }, "related_objects": [ { "basename": "ismagilov_detecting_bacteria_LOC_JB.pdf", "url": "https://authors.library.caltech.edu/records/8eteb-x0k54/files/ismagilov_detecting_bacteria_LOC_JB.pdf" } ], "resource_type": "article", "pub_year": "2008", "author_list": "Boedicker, James Q.; Li, Liang; et el." }, { "id": "https://authors.library.caltech.edu/records/v0v0z-cm610", "eprint_id": 52734, "eprint_status": "archive", "datestamp": "2023-08-22 10:50:02", "lastmod": "2023-10-18 21:03:31", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Shen-Feng", "name": { "family": "Shen", "given": "Feng" }, "orcid": "0000-0002-4709-330X" }, { "id": "Kastrup-C-J", "name": { "family": "Kastrup", "given": "Christian J." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Using microfluidics to understand the effect of spatial distribution of tissue factor on blood coagulation", "ispublished": "pub", "full_text_status": "restricted", "keywords": "Clotting; Spatiotemporal dynamics; Hemostasis; Networks; Deep vein thrombosis", "note": "Copyright \u00a9 2008 Elsevier Ltd.\n\nPapers of the 4th Symposium on Hemostasis with Special Focus on Factor VIIa and Tissue Factor-Understanding the Molecular Mechanism.\n\nThis work was supported in part by NSF CAREER\nAward CHE-0349034, ONR Grant N00014-03-10482,\nand by the Dreyfus Teacher-Scholar Award.\nR.F.I. is a Cottrell Scholar of Research Corporation,\nand an A.P. Sloan Research Fellow. Some of this\nwork was performed at the MRSEC microfluidic\nfacility funded by the NSF. We thank Jessica M.\nPrice for assistance in writing and editing this\nmanuscript.", "abstract": "Initiation of blood coagulation by tissue factor (TF) is a robust, highly regulated process. Both the spatial distribution of TF and the geometry of the vasculature may play important roles in regulating coagulation. As this review describes, microfluidic systems provide a unique opportunity for investigating the spatiotemporal dynamics of blood coagulation in vitro. Microfluidic systems with surfaces of phospholipid bilayers patterned with TF have been used to demonstrate experimentally the threshold responses of initiation of coagulation to the size and shape of surfaces presenting TF. These systems have also been used to demonstrate experimentally that propagation of coagulation is regulated by the shear rate of blood flow in microcapillaries and microchannels. By understanding these and other aspects of the spatial dynamics that regulate blood coagulation, many new methods for treating clotting disorders, such as venous thromboembolism (VTE) and sepsis, could arise.", "date": "2008", "date_type": "published", "publication": "Thrombosis Research", "volume": "122", "number": "Suppl. 1", "publisher": "Elsevier", "pagerange": "S27-S30", "id_number": "CaltechAUTHORS:20141212-131800389", "issn": "0049-3848", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20141212-131800389", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF Career Award", "grant_number": "CHE-0349034" }, { "agency": "ONR", "grant_number": "N00014-03-10482" }, { "agency": "Dreyfus Teacher-Scholar Award" }, { "agency": "Cottrell Scholar of Research Corporation" }, { "agency": "A.P. Sloan Research Fellowship" } ] }, "doi": "10.1016/S0049-3848(08)70015-X", "resource_type": "article", "pub_year": "2008", "author_list": "Shen, Feng; Kastrup, Christian J.; et el." }, { "id": "https://authors.library.caltech.edu/records/63m5d-r9p84", "eprint_id": 40799, "eprint_status": "archive", "datestamp": "2023-08-19 21:34:00", "lastmod": "2023-10-24 22:00:17", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Maharbiz-Michel-M", "name": { "family": "Maharbiz", "given": "Michel M." } } ] }, "title": "Can we build synthetic, multicellular systems by controlling developmental signaling in space and time?", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2007 Elsevier. \n\nAvailable online 19 November 2007. \n\nThe work described in this review has been supported by National Science Foundation, the National Institutes of Health and the Keck Foundation. We thank our colleagues who have contributed to some of the work described here. We thank Tushar Bansal, Emory Chan, William Holtz, and Elena Lucchetta for helpful discussion. We thank Jessica M Price for contributions in editing and writing this manuscript.\n\nAccepted Version - nihms-35925.pdf
", "abstract": "Using biological machinery to make new, functional molecules\nis an exciting area in chemical biology. Complex molecules\ncontaining both 'natural' and 'unnatural' components are made\nby processes ranging from enzymatic catalysis to the\ncombination of molecular biology with chemical tools. Here, we\ndiscuss applying this approach to the next level of biological\ncomplexity \u2014 building synthetic, functional biotic systems by\nmanipulating biological machinery responsible for\ndevelopment of multicellular organisms. We describe recent\nadvances enabling this approach, including first, recent\ndevelopmental biology progress unraveling the pathways and\nmolecules involved in development and pattern formation;\nsecond, emergence of microfluidic tools for delivering stimuli to\na developing organism with exceptional control in space and\ntime; third, the development of molecular and synthetic biology\ntoolsets for redesigning or de novo engineering of signaling\nnetworks; and fourth, biological systems that are especially\namendable to this approach.", "date": "2007-12", "date_type": "published", "publication": "Current Opinion in Chemical Biology", "volume": "11", "number": "6", "publisher": "Elsevier", "pagerange": "604-611", "id_number": "CaltechAUTHORS:20130821-160719738", "issn": "1367-5931", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160719738", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF" }, { "agency": "NIH" }, { "agency": "W. M. Keck Foundation" } ] }, "doi": "10.1016/j.cbpa.2007.10.003", "pmcid": "PMC2203304", "primary_object": { "basename": "nihms-35925.pdf", "url": "https://authors.library.caltech.edu/records/63m5d-r9p84/files/nihms-35925.pdf" }, "resource_type": "article", "pub_year": "2007", "author_list": "Ismagilov, Rustem F. and Maharbiz, Michel M." }, { "id": "https://authors.library.caltech.edu/records/xbvf0-pth52", "eprint_id": 40810, "eprint_status": "archive", "datestamp": "2023-08-19 21:07:59", "lastmod": "2023-10-24 22:01:04", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Kastrup-Christian-J", "name": { "family": "Kastrup", "given": "Christian J." } }, { "id": "Shen-Feng", "name": { "family": "Shen", "given": "Feng" }, "orcid": "0000-0002-4709-330X" }, { "id": "Runyon-Matthew-K", "name": { "family": "Runyon", "given": "Matthew K." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Characterization of the Threshold Response of Initiation of Blood Clotting to Stimulus Patch Size", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2007 The Biophysical Society. \n\nReceived 29 March 2007. Accepted 12 June 2007. Available online 7 January 2009. \n\nWe thank Thuong Van Ha for helpful discussions, Pamela Haltek and Sharice Davis for collecting blood samples, and Jessica M. Price for contributions in editing and writing this article.\n\nThis work was supported in part by National Science Foundation CAREER Award No. CHE-0349034 and Office of Naval Research grant No. N000140610630. R.F.I. is a Cottrell Scholar of Research Corporation and an A.P. Sloan Research Fellow. Some of this work was performed at the Materials Research Science and Engineering Center microfluidic facility (funded by the National Science Foundation).\n\nPublished - Biophys_J_2007_93_2969_Ismagilov_Threshold_Response_in_Hemostasis.pdf
", "abstract": "This article demonstrates that the threshold response of initiation of blood clotting to the size of a patch of stimulus is a robust phenomenon under a wide range of conditions and follows a simple scaling relationship based on the Damkohler number. Human blood and plasma were exposed to surfaces patterned with patches presenting clotting stimuli using microfluidics. Perturbations of the complex network of hemostasis, including temperature, variations in the concentration of stimulus (tissue factor), and the absence or inhibition of individual components of the network (factor IIa, factor V, factor VIII, and thrombomodulin), did not affect the existence of this response. A scaling relationship between the threshold patch size and the timescale of reaction for clotting was supported in numerical simulations, a simple chemical model system, and experiments with human blood plasma. These results may be useful for understanding the spatiotemporal dynamics of other autocatalytic systems and emphasize the relevance of clustering of proteins and lipids in the regulation of signaling processes.", "date": "2007-10-15", "date_type": "published", "publication": "Biophysical Journal", "volume": "93", "number": "8", "publisher": "Biophysical Society", "pagerange": "2969-2977", "id_number": "CaltechAUTHORS:20130821-160721703", "issn": "0006-3495", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160721703", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF", "grant_number": "CHE-0349034" }, { "agency": "Office of Naval Research (ONR)", "grant_number": "N000140610630" }, { "agency": "Cottrell Scholar of Research Corporation" }, { "agency": "Alfred P. Sloan Foundation" } ] }, "doi": "10.1529/biophysj.107.109009", "pmcid": "PMC1989713", "primary_object": { "basename": "Biophys_J_2007_93_2969_Ismagilov_Threshold_Response_in_Hemostasis.pdf", "url": "https://authors.library.caltech.edu/records/xbvf0-pth52/files/Biophys_J_2007_93_2969_Ismagilov_Threshold_Response_in_Hemostasis.pdf" }, "resource_type": "article", "pub_year": "2007", "author_list": "Kastrup, Christian J.; Shen, Feng; et el." }, { "id": "https://authors.library.caltech.edu/records/e4xjv-wpy69", "eprint_id": 40806, "eprint_status": "archive", "datestamp": "2023-08-22 10:09:00", "lastmod": "2023-10-24 22:00:45", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Kastrup-C-J", "name": { "family": "Kastrup", "given": "Christian J." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "A physical organic mechanistic approach to understanding the complex reaction network of hemostasis (blood clotting)", "ispublished": "pub", "full_text_status": "restricted", "keywords": "coagulation; microfluidics; spatiotemporal dynamics; complexity; nonlinear; enzyme models; networks; modules", "note": "Copyright \u00a9 2007 John Wiley & Sons. \n\nReceived 17 April 2007; revised 14 June 2007; accepted 18 June 2007. \n\nThis work was supported in part by NSF CAREER Award\nCHE-0349034, ONR Grant N00014-03-10482, and by\nthe Dreyfus Teacher-Scholar Award. R.F.I. is a Cottrell\nScholar of Research Corporation, and an A. P. Sloan\nResearch Fellow. Some of this work was performed at\nthe MRSEC microfluidic facility funded by the NSF.\nWe thank Matthew Runyon for helpful discussions and\nJessica M. Price for assistance in editing and writing this\nmanuscript.", "abstract": "This review focuses on how the mechanistic approach of physical organic chemistry can be used to elucidate the mechanisms behind complex biochemical networks. The dynamics of biochemical reaction networks is difficult to describe by considering their individual reactions, just as the dynamics of organic reactions is difficult to describe by considering individual electrons and atomic nuclei. Physical organic chemists have developed a useful set of tools to predict the outcome of organic reactions by separating the interacting molecules into modules (functional groups), and defining general rules for how these modules interact (mechanisms). This review shows how these tools of physical organic chemistry may be used to describe reaction networks. In addition, it describes the application of these tools to develop a mechanistic understanding of the dynamics of the complex network of hemostasis, which regulates blood clotting.", "date": "2007-10", "date_type": "published", "publication": "Journal of Physical Organic Chemistry", "volume": "20", "number": "10", "publisher": "Wiley", "pagerange": "711-715", "id_number": "CaltechAUTHORS:20130821-160720940", "issn": "0894-3230", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160720940", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF", "grant_number": "CHE-0349034" }, { "agency": "ONR", "grant_number": "N00014-03-10482" }, { "agency": "Camille and Henry Dreyfus Foundation" }, { "agency": "Cottrell Scholar of Research Corporation" }, { "agency": "Alfred P. Sloan Foundation" } ] }, "doi": "10.1002/poc.1242", "resource_type": "article", "pub_year": "2007", "author_list": "Kastrup, Christian J. and Ismagilov, Rustem F." }, { "id": "https://authors.library.caltech.edu/records/c32j4-xft93", "eprint_id": 40853, "eprint_status": "archive", "datestamp": "2023-08-22 09:33:59", "lastmod": "2023-10-24 22:30:43", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Petty-Rafe-T", "name": { "family": "Petty", "given": "Rafe T." } }, { "id": "Li-Hung-Wing", "name": { "family": "Li", "given": "Hung-Wing" } }, { "id": "Maduram-Jane-H", "name": { "family": "Maduram", "given": "Jane H." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem" }, "orcid": "0000-0002-3680-4399" }, { "id": "Mrksich-Milan", "name": { "family": "Mrksich", "given": "Milan" }, "orcid": "0000-0002-4964-796X" } ] }, "title": "Attachment of cells to islands presenting gradients of adhesion ligands", "ispublished": "pub", "full_text_status": "public", "keywords": "self-assembled monolayers; fibronectin; chemotaxis; migration; surfaces", "note": "\u00a9 2007 American Chemical Society. \n\nPublished In Issue: July 25, 2007. Received May 18, 2007. \n\nThis work was supported by NSF-MRSEC and NIH. R.T.P. was supported by the NIH Chemistry & Biology Interface Pre-Doctoral Training Program (Grant T32 GM008720).\n\nSupporting Information Available\nDetails for fabrication of \u03bcFNs, preparation of SAMs, cell culture, mass spectrometric analysis, fluorescent images of the gradient, and data analysis. This material is available free of charge via the Internet at http://pubs.acs.org.\n\nAccepted Version - nihms63755.pdf
Supplemental Material - Ismagilov_cell_adhesion_Hung_Wing_JACS_129_29_8966_SI.pdf
", "abstract": "This paper reports a strategy that uses microfluidic networks to pattern self-assembled monolayers with gradient microislands for the attachment of individual cells. A microfluidic network is first used to pattern a monolayer into square regions that present maleimide groups and then used to flow a solution having a gradient of the cell adhesion peptide Arg-Gly-Asp over the substrate. In this way, the surface is patterned with microislands approximately 33 x 33 micrometers in size and each having a defined gradient of immobilized cell adhesion ligand. B16F10 cells were allowed to attach to the patterned islands and were found to display a nonuniform distribution of cytoskeletal structures in response to the gradient of adhesion ligand. This work is significant because it permits studies of the influence of a nonuniform microenvironment on the polarization, differentiation, and signaling of adherent cells.", "date": "2007-07-25", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "129", "number": "29", "publisher": "American Chemical Society", "pagerange": "8966-8967", "id_number": "CaltechAUTHORS:20130821-160728859", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160728859", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "T32 GM008720" } ] }, "doi": "10.1021/ja0735709", "pmcid": "PMC2543034", "primary_object": { "basename": "Ismagilov_cell_adhesion_Hung_Wing_JACS_129_29_8966_SI.pdf", "url": "https://authors.library.caltech.edu/records/c32j4-xft93/files/Ismagilov_cell_adhesion_Hung_Wing_JACS_129_29_8966_SI.pdf" }, "related_objects": [ { "basename": "nihms63755.pdf", "url": "https://authors.library.caltech.edu/records/c32j4-xft93/files/nihms63755.pdf" } ], "resource_type": "article", "pub_year": "2007", "author_list": "Petty, Rafe T.; Li, Hung-Wing; et el." }, { "id": "https://authors.library.caltech.edu/records/sjn7h-bv729", "eprint_id": 40860, "eprint_status": "archive", "datestamp": "2023-08-22 09:17:20", "lastmod": "2023-10-24 22:31:12", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Runyon-M-K", "name": { "family": "Runyon", "given": "Matthew K." } }, { "id": "Johnson-Kerner-B-L", "name": { "family": "Johnson-Kerner", "given": "Bethany L." } }, { "id": "Kastrup-C-J", "name": { "family": "Kastrup", "given": "Christian J." } }, { "id": "Van-Ha-Thuong-G", "name": { "family": "Van Ha", "given": "Thuong G." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Propagation of blood clotting in the complex biochemical network of hemostasis is described by a simple mechanism", "ispublished": "pub", "full_text_status": "public", "keywords": "tissue factor; thrombus formation; coagulation; model; flow", "note": "Copyright \u00a9 2007 American Chemical Society. \n\nPublished In Issue: June 06, 2007. Received April 13, 2007. \n\nThis work was funded by the ONR (Grant N000140610630), the Camille Dreyfus Teacher-Scholar Awards Program, and the NSF CAREER Award (CHE-0349034). M.K.R. was supported in part by Burroughs Wellcome Fund Interfaces I.D. 1001774. R.F.I. is a Cottrell Scholar of Research Corporation and an A. P. Sloan Research Fellow. Some of this work was performed at the MRSEC microfluidic facility (funded by the NSF). We thank Jessica M. Price for contributions in editing and writing this manuscript.\n\nSupporting Information Available\nDetailed procedure for experiments and movie comparing the recirculation in the \"valve\" at high and low shear rates. This material is available free of charge via the Internet at http://pubs.acs.org.\n\nSupplemental Material - Ismagilov_JACS_2007_propagation_SI_movie_MR.avi
Supplemental Material - Ismagilov_JACS_2007_propagation_SI_text_MR.pdf
", "abstract": "Hemostasis is the complex biochemical network that controls blood clotting. We previously described a chemical model that mimicked the dynamics of hemostasis based on a simple regulatory mechanisma threshold response due to the competition between production and removal of activators. Here, we used human blood plasma in phospholipid-coated microfluidic channels to test predictions based on this mechanism. We demonstrated that, for a given geometry of channels, clot propagation from an obstructed channel into a channel with flowing blood plasma is dependent on the shear rate in the channel with flowing blood plasma. If confirmed in vivo, these results may explain clot propagation from a small vessel to a larger, clinically relevant vessel. In addition, these results would further validate the use of modular mechanisms, simplified chemical models, and microfluidics to study complex biochemical networks.", "date": "2007-06-06", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "129", "number": "22", "publisher": "American Chemical Society", "pagerange": "7014-7015", "id_number": "CaltechAUTHORS:20130821-160729975", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160729975", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "ONR", "grant_number": "N000140610630" }, { "agency": "Camille and Henry Dreyfus Foundation" }, { "agency": "NSF", "grant_number": "CHE-0349034" }, { "agency": "Burroughs Wellcome Fund Interfaces", "grant_number": "1001774" }, { "agency": "Cottrell Scholar of Research Corporation" }, { "agency": "Alfred P. Sloan Foundation" } ] }, "doi": "10.1021/ja072602p", "primary_object": { "basename": "Ismagilov_JACS_2007_propagation_SI_movie_MR.avi", "url": "https://authors.library.caltech.edu/records/sjn7h-bv729/files/Ismagilov_JACS_2007_propagation_SI_movie_MR.avi" }, "related_objects": [ { "basename": "Ismagilov_JACS_2007_propagation_SI_text_MR.pdf", "url": "https://authors.library.caltech.edu/records/sjn7h-bv729/files/Ismagilov_JACS_2007_propagation_SI_text_MR.pdf" } ], "resource_type": "article", "pub_year": "2007", "author_list": "Runyon, Matthew K.; Johnson-Kerner, Bethany L.; et el." }, { "id": "https://authors.library.caltech.edu/records/9fv09-b9f68", "eprint_id": 40809, "eprint_status": "archive", "datestamp": "2023-08-22 09:03:47", "lastmod": "2023-10-24 22:00:58", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Kastrup-C-J", "name": { "family": "Kastrup", "given": "Christian J." } }, { "id": "Shen-Feng", "name": { "family": "Shen", "given": "Feng" }, "orcid": "0000-0002-4709-330X" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Response to shape emerges in a complex biochemical network and its simple chemical analogue", "ispublished": "pub", "full_text_status": "restricted", "keywords": "biophysics; coagulation; emergence; enzyme models; microfluidics blood-coagulation; pattern-formation; tissue factor; initiation; systems; hemostasis; oxidation; model; waves", "note": "Copyright \u00a9 2007 WILEY-VCH. \n\nReceived: December 11, 2006. Published online: April 3, 2007. \n\nThis work was supported in part by NSF CAREER Award CHE-0349034 and ONR Grant N000140610630. R.F.I. is a Cottrell Scholar of Research Corporation and an A.\u2005P. Sloan Research Fellow. Some of this work was performed at the MRSEC Microfluidic Facility (funded by the NSF). We thank Professors Michael Brenner, Irving Epstein, Yannis Kevrekidis, Matthew Runyon, Kenneth Showalter, and Thuong Van Ha for helpful discussions, and Jessica Price for her assistance in preparing this manuscript.", "abstract": "n/a", "date": "2007-05-11", "date_type": "published", "publication": "Angewandte Chemie International Edition", "volume": "46", "number": "20", "publisher": "Wiley", "pagerange": "3660-3662", "id_number": "CaltechAUTHORS:20130821-160721515", "issn": "1433-7851", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160721515", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF", "grant_number": "CHE-0349034" }, { "agency": "ONR", "grant_number": "N000140610630" }, { "agency": "Cottrell Scholar of Research Corporation" }, { "agency": "Alfred P. Sloan Foundation" } ] }, "doi": "10.1002/anie.200604995", "resource_type": "article", "pub_year": "2007", "author_list": "Kastrup, Christian J.; Shen, Feng; et el." }, { "id": "https://authors.library.caltech.edu/records/46gj7-60s97", "eprint_id": 40819, "eprint_status": "archive", "datestamp": "2023-08-19 19:59:55", "lastmod": "2023-10-24 22:01:38", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Li-Liang", "name": { "family": "Li", "given": "Liang" } }, { "id": "Boedicker-James-Q", "name": { "family": "Boedicker", "given": "James Q." }, "orcid": "0000-0003-4107-3719" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Using a Multijunction Microfluidic Device To Inject Substrate into an Array of Preformed Plugs without Cross-Contamination: Comparing Theory and Experiments", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2007 American Chemical Society. \n\nPublished In Issue: April 01, 2007. Received for review November 17, 2006. Accepted January 24, 2007. \n\nThis work was supported in part by the NIH Roadmap for Medical Research under Grant No. R01 GM075827-02, the NIBIB under Grant No. R01 EB001903-04, and the UC/ANL Collaborative Seed Funding. We thank Helen Song for helpful discussions and Jessica Price for assistance in writing and editing this manuscript.\n\nSupporting Information Available\nThree additional figures. This material is available free of charge via the Internet at http://pubs.acs.org.\n\nAccepted Version - nihms-29427.pdf
Supplemental Material - Ismagilov_merging_liang_anal_chem_2007_79_2756_SI.pdf
", "abstract": "Abstract: In this paper we describe a multijunction microfluidic device for the injection of a substrate into an array of preformed plugs carried by an immiscible fluid in a microchannel. The device uses multiple junctions to inject substrate into preformed plugs without synchronization of the flow of substrate and the array of preformed plugs of reagent, which reduces cross-contamination of the plugs, eliminates formation of small droplets of substrate, and allows a greater range of injection ratios compared to that of a single T-junction. The device was based on a previously developed physical model for transport that was here adapted to describe injection and experimentally verified. After characterization, the device was applied to two biochemical assays, including evaluation of the enzymatic activity of thrombin and determination of the coagulation time of human blood plasma, which both provided reliable results. The reduction of cross-contamination and greater range of injection ratios achieved by this device may improve the processes that involve addition and titration of reagents into plugs, such as high-throughput screening of protein crystallization conditions.", "date": "2007-04-01", "date_type": "published", "publication": "Analytical Chemistry", "volume": "79", "number": "7", "publisher": "American Chemical Society", "pagerange": "2756-2761", "id_number": "CaltechAUTHORS:20130821-160723117", "issn": "0003-2700", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160723117", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01 GM075827-02" }, { "agency": "NIH", "grant_number": "R01 EB001903-04" }, { "agency": "University of Chicago" }, { "agency": "Argonne National Laboratory" } ] }, "doi": "10.1021/ac062179n", "pmcid": "PMC2080796", "primary_object": { "basename": "Ismagilov_merging_liang_anal_chem_2007_79_2756_SI.pdf", "url": "https://authors.library.caltech.edu/records/46gj7-60s97/files/Ismagilov_merging_liang_anal_chem_2007_79_2756_SI.pdf" }, "related_objects": [ { "basename": "nihms-29427.pdf", "url": "https://authors.library.caltech.edu/records/46gj7-60s97/files/nihms-29427.pdf" } ], "resource_type": "article", "pub_year": "2007", "author_list": "Li, Liang; Boedicker, James Q.; et el." }, { "id": "https://authors.library.caltech.edu/records/wpdey-73g81", "eprint_id": 40786, "eprint_status": "archive", "datestamp": "2023-08-22 08:31:51", "lastmod": "2023-10-24 21:59:20", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chen-Delai-L", "name": { "family": "Chen", "given": "Delai L." } }, { "id": "Li-Liang", "name": { "family": "Li", "given": "Liang" } }, { "id": "Reyes-Sebastian", "name": { "family": "Reyes", "given": "Sebastian" } }, { "id": "Adamson-David-N", "name": { "family": "Adamson", "given": "David N." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Using three-phase flow of immiscible liquids to prevent coalescence of droplets in microfluidic channels: Criteria to identify the third liquid and validation with protein crystallization", "ispublished": "pub", "full_text_status": "public", "keywords": "tyrosyl-dna phosphodiesterase; monodisperse double emulsions; nanoliter plugs; segmented flow; devices; system; surfactants; capillary; particles; scale", "note": "\u00a9 2007 American Chemical Society. \n\nPublished In Issue: February 13, 2007. Received July 21, 2006. Revised November 6, 2006. \n\nThis work was supported in part by ATCG3D, which is funded by the National Institute of General Medical Sciences and National Center for Research Resources under the PSI-2 Specialized Center program (U54 GM074961), and by the NSF MRSEC Program under DMR-0213745. Experiments were performed in part at the MRSEC microfluidic facility funded by NSF. S.R. was supported by the Chicago-Chile Materials Collaboration Program. We thank Thomas A. Witten at University of Chicago for suggestions and comments on the manuscript, and thank Doug Davies, Li Zhang, and Alex Burgin at deCODE biostructures for supplying the purified Tdp1 protein and for advice on crystallization experiments.\n\nAccepted Version - nihms-29425.pdf
", "abstract": "This manuscript describes the effect of interfacial tensions on three-phase liquid-liquid-liquid flow in microfluidic channels and the use of this flow to prevent microfluidic plugs from coalescing. One problem in using microfluidic plugs as microreactors is the coalescence of adjacent plugs caused by the relative motion of plugs during flow. Here, coalescence of reagent plugs was eliminated by using plugs of a third immiscible liquid as spacers to separate adjacent reagent plugs. This work tested the requirements of interfacial tensions for plugs of a third liquid to be effective spacers. Two candidates satisfying the requirements were identified, and one of these liquids was used in the crystallization of protein human Tdp1 to demonstrate its compatibility with protein crystallization in plugs. This method for identifying immiscible liquids for use as a spacer will also be useful for applications involving manipulation of large arrays of droplets in microfluidic channels.", "date": "2007-02-13", "date_type": "published", "publication": "Langmuir", "volume": "23", "number": "4", "publisher": "American Chemical Society", "pagerange": "2255-2260", "id_number": "CaltechAUTHORS:20130821-160717523", "issn": "0743-7463", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160717523", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "U54 GM074961" }, { "agency": "NSF", "grant_number": "DMR-0213745" }, { "agency": "Chicago-Chile Materials Collaboration Program" } ] }, "doi": "10.1021/la062152z", "pmcid": "PMC1986632", "primary_object": { "basename": "nihms-29425.pdf", "url": "https://authors.library.caltech.edu/records/wpdey-73g81/files/nihms-29425.pdf" }, "resource_type": "article", "pub_year": "2007", "author_list": "Chen, Delai L.; Li, Liang; et el." }, { "id": "https://authors.library.caltech.edu/records/d06ze-1dq58", "eprint_id": 40825, "eprint_status": "archive", "datestamp": "2023-08-19 19:06:26", "lastmod": "2023-10-24 22:28:43", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Li-Liang", "name": { "family": "Li", "given": "Liang" } }, { "id": "Mustafi-D", "name": { "family": "Mustafi", "given": "Debarshi" } }, { "id": "Fu-Qiang", "name": { "family": "Fu", "given": "Qiang" } }, { "id": "Tereshko-V", "name": { "family": "Tereshko", "given": "Valentina" } }, { "id": "Chen-Delai-L", "name": { "family": "Chen", "given": "Delai L." } }, { "id": "Tice-J-D", "name": { "family": "Tice", "given": "Joshua D." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Nanoliter microfluidic hybrid method for simultaneous screening and optimization validated with crystallization of membrane proteins", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2006 by The National Academy of Sciences of the USA. \n\nEdited by Robert M. Stroud, University of California, San Francisco, CA, and approved October 27, 2006 (received for review August 29, 2006). \n\nWe thank Nina Ponomarenko and James R. Norris [University of Chicago (UC)] for samples of RC from R. viridis, the Philip D. Laible group at Argonne National Laboratory (ANL), UC/ANL Collaborative Seed Funding for samples of Porin R. capsulatus, Cory J. Gerdts for the image in Fig. 2 c and for helpful discussions, and Jessica Price for contributions in editing and writing this manuscript. Use of the ANL Structural Biology Center beamlines, BioCARS beamlines, and the National Institute for General Medical Sciences (GM) and National Cancer Institute (CA) GM/CA beamlines at the Advanced Photon Source was supported by Department of Energy Grant W-31-109-Eng-38. GM/CA-Collaborative Access Team (CAT) has been funded in whole or in part by National Cancer Institute Grant Y1-CO-1020 and National Institute of General Medical Sciences (NIGMS) Grant Y1-GM-1104. Use of the BioCARS Sector 14 was supported by National Institutes of Health (NIH) National Center for Research Resources (NCRR) Grant RR07707. We thank ATCG3D funded by the NIGMS and NCRR under the PSI-2 Specialized Center program (U54 GM074961) for partial support of V.T. and deCode Biostructures for providing the custom screening kit for membrane protein crystallization. Undergraduate research was supported by the NIH Roadmap Physical and Chemical Biology training program at UC (D.M.). This work was supported in part by NIH Roadmap for Medical Research Grant R01 GM075827-01). \n\nAuthor contributions: L.L., D.M., Q.F., D.L.C., J.D.T., and R.F.I. designed research; L.L., D.M., Q.F., D.L.C., and J.D.T. performed research; L.L., D.M., Q.F., D.L.C., and J.D.T. contributed new reagents/analytic tools; L.L., D.M., Q.F., V.T., D.L.C., J.D.T., and R.F.I. analyzed data; and L.L., D.M., Q.F., V.T., and R.F.I. wrote the paper.\n\nThe authors declare no conflict of interest.\n\nThis article is a PNAS direct submission.\n\nData deposition: The coordinates and structure factors have been deposited in the Protein Data Bank, www.pdb.org (PDB ID code 2I5N).\n\nPublished - ismagilov_hybrid_membrane_protein_PNAS_103_19243_LL.pdf
Supplemental Material - Ismagilov_SI_PNAS_2006_103_19243_Hybrid_liang.pdf
", "abstract": "High-throughput screening and optimization experiments are critical to a number of fields, including chemistry and structural and molecular biology. The separation of these two steps may introduce false negatives and a time delay between initial screening and subsequent optimization. Although a hybrid method combining both steps may address these problems, miniaturization is required to minimize sample consumption. This article reports a \"hybrid\" droplet-based microfluidic approach that combines the steps of screening and optimization into one simple experiment and uses nanoliter-sized plugs to minimize sample consumption. Many distinct reagents were sequentially introduced as approx. 140-nl plugs into a microfluidic device and combined with a substrate and a diluting buffer. Tests were conducted in approx. 10-nl plugs containing different concentrations of a reagent. Methods were developed to form plugs of controlled concentrations, index concentrations, and incubate thousands of plugs inexpensively and without evaporation. To validate the hybrid method and demonstrate its applicability to challenging problems, crystallization of model membrane proteins and handling of solutions of detergents and viscous precipitants were demonstrated. By using 10 \u03bcl of protein solution, approx. 1,300 crystallization trials were set up within 20 min by one researcher. This method was compatible with growth, manipulation, and extraction of high-quality crystals of membrane proteins, demonstrated by obtaining high-resolution diffraction images and solving a crystal structure. This robust method requires inexpensive equipment and supplies, should be especially suitable for use in individual laboratories, and could find applications in a number of areas that require chemical, biochemical, and biological screening and optimization.", "date": "2006-12-19", "date_type": "published", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "volume": "103", "number": "51", "publisher": "National Academy of Sciences", "pagerange": "19243-19248", "id_number": "CaltechAUTHORS:20130821-160724073", "issn": "0027-8424", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160724073", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Department of Energy (DOE)", "grant_number": "W-31-109-ENG-38" }, { "agency": "NIH", "grant_number": "Y1-CO-1020" }, { "agency": "NIH", "grant_number": "Y1-GM-1104" }, { "agency": "NIH", "grant_number": "RR07707" }, { "agency": "NIH", "grant_number": "U54 GM074961" }, { "agency": "NIH", "grant_number": "R01 GM075827-01" }, { "agency": "National Cancer Institute" }, { "agency": "National Institute of General Medical Sciences" } ] }, "doi": "10.1073/pnas.0607502103", "pmcid": "PMC1748211", "primary_object": { "basename": "ismagilov_hybrid_membrane_protein_PNAS_103_19243_LL.pdf", "url": "https://authors.library.caltech.edu/records/d06ze-1dq58/files/ismagilov_hybrid_membrane_protein_PNAS_103_19243_LL.pdf" }, "related_objects": [ { "basename": "Ismagilov_SI_PNAS_2006_103_19243_Hybrid_liang.pdf", "url": "https://authors.library.caltech.edu/records/d06ze-1dq58/files/Ismagilov_SI_PNAS_2006_103_19243_Hybrid_liang.pdf" } ], "resource_type": "article", "pub_year": "2006", "author_list": "Li, Liang; Mustafi, Debarshi; et el." }, { "id": "https://authors.library.caltech.edu/records/5ft01-pwm48", "eprint_id": 40791, "eprint_status": "archive", "datestamp": "2023-08-19 19:04:15", "lastmod": "2023-10-24 21:59:40", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Gerdts-Cory-J", "name": { "family": "Gerdts", "given": "Cory J." } }, { "id": "Tereshko-Valentina", "name": { "family": "Tereshko", "given": "Valentina" } }, { "id": "Yadav-Maneesh-K", "name": { "family": "Yadav", "given": "Maneesh K." } }, { "id": "Dementieva-Irina", "name": { "family": "Dementieva", "given": "Irina" } }, { "id": "Collart-Frank", "name": { "family": "Collart", "given": "Frank" } }, { "id": "Joachimiak-Andrzej", "name": { "family": "Joachimiak", "given": "Andrzej" } }, { "id": "Stevens-Raymond-C", "name": { "family": "Stevens", "given": "Raymond C." }, "orcid": "0000-0002-4522-8725" }, { "id": "Kuhn-Peter", "name": { "family": "Kuhn", "given": "Peter" } }, { "id": "Kossiakoff-Anthony-A", "name": { "family": "Kossiakoff", "given": "Anthony" }, "orcid": "0000-0003-3174-9359" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Time-Controlled Microfluidic Seeding in nL-Volume Droplets To Separate Nucleation and Growth Stages of Protein Crystallization", "ispublished": "pub", "full_text_status": "public", "keywords": "crystal growth, microfluidics, nucleation, protein structures", "note": "Copyright \u00a9 2006 WILEY-VCH. \n\nIssue published online: 4 DEC 2006. Article first published online: 13 NOV 2006. Manuscript Revised: 12 SEP 2006. Manuscript Received: 22 JUL 2006. \n\nThis work was supported by NIH Protein Structure Initiative Specialized Centers Grant GM074961 (ATCG3D) and the NIH (R01 EB001903). Use of the Advanced Photon Source was supported by the US Department of Energy (contract no. W-31\u2013109-Eng-38). Use of the BioCARS Sector 14 was supported by the NIH National Center for Research Resources (grant number RR07707). GM/CA-CAT has been funded in whole or in part by the National Cancer Institute (Y1-CO-1020) and the National Institute of General Medical Sciences (Y1-GM-1104). Funding for functional and structural proteomics of SARS CoV-related proteins is provided through NIH-NIAID contract HHSN266200400058C. We thank Ruslan Sanishvili (GM/CA Cat station 23ID-D staff support) for technical assistance; Scott Lovell and Lance Stewart (deCODE Biostructures) for helpful assistance and discussions; Shu Moy (Midwest Center for Structural Genomics) for cloning work on Oligoendopeptidase F; Vanitha Subramanian (The Scripps Research Institute) for cloning, expression, and purification of SARS nucleocapsid N-terminal domain; and L. Spencer Roach (University of Chicago) for help with thaumatin X-ray diffraction comparisons.\n\nAccepted Version - nihms14613.pdf
", "abstract": "This paper describes a method of time-controlled seeding to separate the stages of nucleation and growth in protein crystallization using a microfluidic device.", "date": "2006-12-11", "date_type": "published", "publication": "Angewandte Chemie International Edition", "volume": "45", "number": "48", "publisher": "Wiley", "pagerange": "8156-8160", "id_number": "CaltechAUTHORS:20130821-160718311", "issn": "1433-7851", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160718311", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM074961" }, { "agency": "NIBIB", "grant_number": "R01 EB001903" }, { "agency": "Department of Energy (DOE)", "grant_number": "W-31\u2013109-Eng-38" }, { "agency": "National Center for Research Resources", "grant_number": "RR07707" }, { "agency": "National Cancer Institute", "grant_number": "Y1-CO-1020" }, { "agency": "National Institute of General Medical Sciences", "grant_number": "Y1-GM-1104" }, { "agency": "NIH-NIAID", "grant_number": "HHSN266200400058C" } ] }, "doi": "10.1002/anie.200602946", "pmcid": "PMC1766323", "primary_object": { "basename": "nihms14613.pdf", "url": "https://authors.library.caltech.edu/records/5ft01-pwm48/files/nihms14613.pdf" }, "resource_type": "article", "pub_year": "2006", "author_list": "Gerdts, Cory J.; Tereshko, Valentina; et el." }, { "id": "https://authors.library.caltech.edu/records/p9d6v-w7z37", "eprint_id": 40871, "eprint_status": "archive", "datestamp": "2023-08-22 07:13:45", "lastmod": "2023-10-24 22:31:54", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Song-Helen", "name": { "family": "Song", "given": "Helen" } }, { "id": "Chen-Delai-L", "name": { "family": "Chen", "given": "Delai L." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Reactions in droplets in microfluidic channels", "ispublished": "pub", "full_text_status": "public", "keywords": "analytical systems; interfaces; microfluidics; microreactors; plugs flow-injection analysis; electrowetting-based actuation; polymerase-chain-reaction; gas-liquid flow; on-a-chip; protein crystallization conditions; monodisperse double emulsions; microfluidic device; segmented-flow; microchannel emulsification", "note": "\u00a9 2006 WILEY-VCH. \n\nReceived: April 19, 2006. Revised: July 4, 2006. \n\nThe research in our laboratory has been supported by the NIH\n(National Institute for Biomedical Imaging and Bioengineering R01 EB001903 and the National Institute of General\nMedical Sciences R01 GM075827), the Beckman Young\nInvestigator Program, and by the DuPont Young Professor\nAward. We thank Joshua D. Tice for the images in Figure 9 and\nall members of our research group for their work described\nherein. We thank our colleagues in the field of droplet-based\nmicrofluidics for providing figures and for valuable suggestions.\n\nAccepted Version - nihms14617.pdf
", "abstract": "Fundamental and applied research in chemistry and biology benefits\nfrom opportunities provided by droplet-based microfluidic systems.\nThese systems enable the miniaturization of reactions by compartmentalizing reactions in droplets of femoliter to microliter volumes.\nCompartmentalization in droplets provides rapid mixing of reagents,\ncontrol of the timing of reactions on timescales from milliseconds to\nmonths, control of interfacial properties, and the ability to synthesize\nand transport solid reagents and products. Droplet-based microfluidics can help to enhance and accelerate chemical and biochemical\nscreening, protein crystallization, enzymatic kinetics, and assays.\nMoreover, the control provided by droplets in microfluidic devices can\nlead to new scientific methods and insights.", "date": "2006-11-13", "date_type": "published", "publication": "Angewandte Chemie International Edition", "volume": "45", "number": "44", "publisher": "Wiley", "pagerange": "7336-7356", "id_number": "CaltechAUTHORS:20130821-160732141", "issn": "1433-7851", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160732141", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01 EB001903" }, { "agency": "NIH", "grant_number": "R01 GM075827" }, { "agency": "Arnold and Mabel Beckman Foundation" }, { "agency": "E. I. DuPont de Nemours and Company, Inc." } ] }, "doi": "10.1002/anie.200601554", "pmcid": "PMC1766322", "primary_object": { "basename": "nihms14617.pdf", "url": "https://authors.library.caltech.edu/records/p9d6v-w7z37/files/nihms14617.pdf" }, "resource_type": "article", "pub_year": "2006", "author_list": "Song, Helen; Chen, Delai L.; et el." }, { "id": "https://authors.library.caltech.edu/records/xwgv0-s3q82", "eprint_id": 40808, "eprint_status": "archive", "datestamp": "2023-08-19 18:45:55", "lastmod": "2023-10-24 22:00:56", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Kastrup-C-J", "name": { "family": "Kastrup", "given": "Christian J." } }, { "id": "Runyon-M-K", "name": { "family": "Runyon", "given": "Matthew K." } }, { "id": "Shen-Feng", "name": { "family": "Shen", "given": "Feng" }, "orcid": "0000-0002-4709-330X" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Modular chemical mechanism predicts spatiotemporal dynamics of initiation in the complex network of hemostasis", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2006 by The National Academy of Sciences of the USA. \n\nEdited by George M. Whitesides, Harvard University, Cambridge, MA, and approved August 30, 2006 (received for review July 3, 2006). \n\nWe thank Shaun R. Coughlin, Jay T. Groves, Satish Kumar, Yannis Kevrekidis, Daniel Koshland, Ka Yee Lee, Jonathan L. Miller, Atul Parikh, Thuong Van Ha, and Ding-Djung Yang for discussions and advice. This work was supported in part by National Science Foundation CAREER Award CHE-0349034 and Office of Naval Research Grant N00014-03-10482. M.K.R. was supported by Burroughs Wellcome Fund Interfaces ID 1001774. R.F.I. is a Cottrell Scholar of Research Corporation and an A. P. Sloan Research Fellow. Some of this work was performed at the Materials Research Science and Engineering Centers microfluidic facility (funded by the National Science Foundation). \n\nAuthor contributions: C.J.K., M.K.R., and R.F.I. designed research; C.J.K., M.K.R., and F.S. performed research; C.J.K. and M.K.R. contributed new reagents/analytic tools; C.J.K., M.K.R., F.S., and R.F.I. analyzed data; and C.J.K., M.K.R., and R.F.I. wrote the paper.\n\nThe authors declare no conflict of interest.\n\nThis article is a PNAS direct submission.\n\nPublished - Ismagilov_Chem_model_for_clot_initiation_CK_PNAS_2006_103_43_15747.pdf
Supplemental Material - Ismagilov_SI_PNAS_2006_103_15747_chemical_model_Christian.pdf
", "abstract": "This article demonstrates that a simple chemical model system, built by using a modular approach, may be used to predict the spatiotemporal dynamics of initiation of blood clotting in the complex network of hemostasis. Microfluidics was used to create in vitro environments that expose both the complex network and the model system to surfaces patterned with patches presenting clotting stimuli. Both systems displayed a threshold response, with clotting initiating only on isolated patches larger than a threshold size. The magnitude of the threshold patch size for both systems was described by the Damkohler number, measuring competition of reaction and diffusion. Reaction produces activators at the patch, and diffusion removes activators from the patch. The chemical model made additional predictions that were validated experimentally with human blood plasma. These experiments show that blood can be exposed to significant amounts of clot-inducing stimuli, such as tissue factor, without initiating clotting. Overall, these results demonstrate that such chemical model systems, implemented with microfluidics, may be used to predict spatiotemporal dynamics of complex biochemical networks.", "date": "2006-10-24", "date_type": "published", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "volume": "103", "number": "43", "publisher": "National Academy of Sciences", "pagerange": "15747-15752", "id_number": "CaltechAUTHORS:20130821-160721372", "issn": "0027-8424", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160721372", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF", "grant_number": "CHE-0349034" }, { "agency": "Office of Naval Research (ONR)", "grant_number": "N00014-03-10482" }, { "agency": "Burroughs Wellcome Fund", "grant_number": "1001774" }, { "agency": "Cottrell Scholar of Research Corporation" }, { "agency": "Alfred P. Sloan Foundation" } ] }, "doi": "10.1073/pnas.0605560103", "pmcid": "PMC1635074", "primary_object": { "basename": "Ismagilov_Chem_model_for_clot_initiation_CK_PNAS_2006_103_43_15747.pdf", "url": "https://authors.library.caltech.edu/records/xwgv0-s3q82/files/Ismagilov_Chem_model_for_clot_initiation_CK_PNAS_2006_103_43_15747.pdf" }, "related_objects": [ { "basename": "Ismagilov_SI_PNAS_2006_103_15747_chemical_model_Christian.pdf", "url": "https://authors.library.caltech.edu/records/xwgv0-s3q82/files/Ismagilov_SI_PNAS_2006_103_15747_chemical_model_Christian.pdf" } ], "resource_type": "article", "pub_year": "2006", "author_list": "Kastrup, Christian J.; Runyon, Matthew K.; et el." }, { "id": "https://authors.library.caltech.edu/records/w9zwk-d1t14", "eprint_id": 40873, "eprint_status": "archive", "datestamp": "2023-08-22 06:05:33", "lastmod": "2023-10-24 22:32:06", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Song-Helen", "name": { "family": "Song", "given": "Helen" } }, { "id": "Li-Hung-Wing", "name": { "family": "Li", "given": "Hung-Wing" } }, { "id": "Munson-Matthew-S", "name": { "family": "Munson", "given": "Matthew S." } }, { "id": "Van-Ha-Thuong-G", "name": { "family": "Van Ha", "given": "Thuong G." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "On-chip titration of an anticoagulant argatroban and determination of the clotting time within whole blood or plasma using a plug-based microfluidic system", "ispublished": "pub", "full_text_status": "public", "keywords": "flow-injection analysis; electrowetting-based actuation; protein crystallization conditions; heparin-induced thrombocytopenia; polymerase-chain-reaction; gas-liquid flow; of-care poc; a-chip; platelet-function; clinical diagnostics", "note": "\u00a9 2006 American Chemical Society. \n\nPublished In Issue: July 15, 2006. Received for review January 25, 2006. Accepted April 21, 2006. \n\nThis work was supported by NIH (R01 EB001903) and performed in part in the MRSEC microfluidic facility funded by NSF. We thank Jeffrey Gist, Krzysztof Mikrut, and Charlot Webb from the Coagulation Lab at the University of Chicago Hospital for measurement of the APTT with the commercial STA Coagulation instrument. We thank Matthew Runyon and Christian Kastrup for invaluable suggestions and assistance. We thank Bethany Johnson-Kerner for preliminary results. We thank Dr. Jonathan Miller and Dr. Rocky Shiu-ki Hui for helpful discussions. We thank Liang Li for surface tension and viscosity measurements for the carrier fluid.\n\nSupporting Information Available: Additional information as noted in the text:\u2009 a movie of the merging junction with the hydrophilic glass capillary, where CaCl2 solution is injected into a plug containing whole blood; a movie of a single plug being followed through a microchannel as a fibrin clot formed within the plug; and characterization of the size of the aqueous plug and the carrier fluid spacing between plugs for various water fractions. This material is available free of charge via the Internet at http://pubs.acs.org.\n\nAccepted Version - nihms14612.pdf
Supplemental Material - Ismagilov_SI_Anal_chem_2006_78_4839_on_chip_titration_helen.pdf
", "abstract": "This paper describes extending plug-based microfluidics to handling complex biological fluids such as blood, solving the problem of injecting additional reagents into plugs, and applying this system to measuring of clotting time in small volumes of whole blood and plasma. Plugs are droplets transported through microchannels by fluorocarbon fluids. A plug-based microfluidic system was developed to titrate an anticoagulant (argatroban) into blood samples and to measure the clotting time using the activated partial thromboplastin time (APTT) test. To carry out these experiments, the following techniques were developed for a plug-based system: (i) using Teflon AF coating on the microchannel wall to enable formation of plugs containing blood and transport of the solid fibrin clots within plugs, (ii) using a hydrophilic glass capillary to enable reliable merging of a reagent from an aqueous stream into plugs, (iii) using bright-field microscopy to detect the formation of a fibrin clot within plugs and using fluorescent microscopy to detect the production of thrombin using a fluorogenic substrate, and (iv) titration of argatroban (0-1.5 mu g/mL) into plugs and measurement of the resulting APTTs at room temperature (23 degrees C) and physiological temperature (37 degrees C). APTT measurements were conducted with normal pooled plasma (platelet-poor plasma) and with donor's blood samples ( both whole blood and platelet-rich plasma). APTT values and APTT ratios measured by the plug-based microfluidic device were compared to the results from a clinical laboratory at 37 degrees C. APTT obtained from the on-chip assay were about double those from the clinical laboratory but the APTT ratios from these two methods agreed well with each other.", "date": "2006-07-15", "date_type": "published", "publication": "Analytical Chemistry", "volume": "78", "number": "14", "publisher": "American Chemical Society", "pagerange": "4839-4849", "id_number": "CaltechAUTHORS:20130821-160732540", "issn": "0003-2700", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160732540", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01 EB001903" }, { "agency": "NSF" } ] }, "doi": "10.1021/ac0601718", "pmcid": "PMC1851927", "primary_object": { "basename": "Ismagilov_SI_Anal_chem_2006_78_4839_on_chip_titration_helen.pdf", "url": "https://authors.library.caltech.edu/records/w9zwk-d1t14/files/Ismagilov_SI_Anal_chem_2006_78_4839_on_chip_titration_helen.pdf" }, "related_objects": [ { "basename": "nihms14612.pdf", "url": "https://authors.library.caltech.edu/records/w9zwk-d1t14/files/nihms14612.pdf" } ], "resource_type": "article", "pub_year": "2006", "author_list": "Song, Helen; Li, Hung-Wing; et el." }, { "id": "https://authors.library.caltech.edu/records/ss744-gq430", "eprint_id": 40785, "eprint_status": "archive", "datestamp": "2023-08-22 05:49:06", "lastmod": "2023-10-24 21:59:18", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chen-Delai-L", "name": { "family": "Chen", "given": "Delai L." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Microfluidic cartridges preloaded with nanoliter plugs of reagents: an alternative to 96-well plates for screening", "ispublished": "pub", "full_text_status": "public", "keywords": "protein crystallization conditions; multistep synthesis; system; droplets; microarray; volumes; assays; scale; time; flow", "note": "\u00a9 2006 Elsevier. \n\nAvailable online 3 May 2006. \n\nThe work described in this review has been supported by the National Institute for Biomedical Imaging and Bioengineering (R01 EB001903), by the National Institute of General Medical Sciences (R01 GM075827), by the Beckman Young Investigator Program and by the DuPont Young Professor Award. We thank our colleagues in the Ismagilov laboratory who have contributed to the work described here.\n\nAccepted Version - nihms14615.pdf
", "abstract": "In traditional screening with 96-well plates, microliters of substrates are consumed for each reaction. Further miniaturization is limited by the special equipment and techniques required to dispense nanoliter volumes of fluid. Plug-based microfluidics confines reagents in nanoliter plugs (droplets surrounded by fluorinated carrier fluid), and uses simple pumps to control the flow of plugs. By using cartridges pre-loaded with nanoliter plugs of reagents, only two pumps and a merging junction are needed to set up a screen. Screening with preloaded cartridges uses only nanoliters of substrate per reaction, and requires no microfabrication. The low cost and simplicity of this method has the potential of replacing 96-well and other multi-well plates, and has been applied to enzymatic assays, protein crystallization and optimization of organic reactions.", "date": "2006-06", "date_type": "published", "publication": "Current Opinion in Chemical Biology", "volume": "10", "number": "3", "publisher": "Elsevier", "pagerange": "226-231", "id_number": "CaltechAUTHORS:20130821-160717350", "issn": "1367-5931", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160717350", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01 EB001903" }, { "agency": "NIH", "grant_number": "R01 GM075827" }, { "agency": "Arnold and Mabel Beckman Foundation" }, { "agency": "E. I. DuPont de Nemours and Company, Inc." } ] }, "doi": "10.1016/j.cbpa.2006.04.004", "pmcid": "PMC1764868", "primary_object": { "basename": "nihms14615.pdf", "url": "https://authors.library.caltech.edu/records/ss744-gq430/files/nihms14615.pdf" }, "resource_type": "article", "pub_year": "2006", "author_list": "Chen, Delai L. and Ismagilov, Rustem F." }, { "id": "https://authors.library.caltech.edu/records/sw90n-wh349", "eprint_id": 40792, "eprint_status": "archive", "datestamp": "2023-08-22 05:19:30", "lastmod": "2023-10-24 21:59:48", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Hatakeyama-Takuji", "name": { "family": "Hatakeyama", "given": "Takuji" } }, { "id": "Chen-Delai-L", "name": { "family": "Chen", "given": "Delai L." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Microgram-scale testing of reaction conditions in solution using nanoliter plugs in microfluidics with detection by MALDI-MS", "ispublished": "pub", "full_text_status": "public", "keywords": "mass-spectrometry; system; flow; polymerization; glycosylation; neurons; device; time", "note": "\u00a9 2006 American Chemical Society. \n\nPublished In Issue: March 01, 2006. Received November 13, 2005. \n\nThis work was supported by the NIH (R01 EB001903), NSF CRC CHE-0526693, and DuPont Young Professor Award. R.F.I. is an Alfred P. Sloan Research fellow. T.H. is a research fellow of the Japan Society for the Promotion of Science.\n\nAccepted Version - nihms14616.pdf
Supplemental Material - Ismagilov_SI_JACS_2006_128_2518_rxn_screen_takuji.pdf
", "abstract": "This paper describes a microfluidic system to screen and optimize organic reaction conditions on a submicrogram scale. The system uses discrete droplets (plugs) as microreactors separated and transported by a continuous phase of a fluorinated carrier fluid. Previously, we demonstrated the use of a microfabricated PDMS plug-based microfluidic system to perform assays and crystallization experiments in aqueous solutions with optical detection. Here, we developed an approach that does not require microfabrication of microfluidic devices, is applicable to synthetic reactions in organic solvents, and uses detection by MALDI-MS. As a demonstration, conditions for selective deacetylation of ouabain hexaacetate were tested, and the optimum conditions for mono-, bis-, or trisdeacetylation have been identified. These conditions were validated by scale-up reactions and isolating these potentially neurotoxic products. Mono- and bisdeacetylated products are unstable intermediates in the deacetylation and were isolated for the first time. This system enables no-loss handling of submicroliter volumes containing a few micrograms of a compound of interest. It could become valuable for investigating or optimizing reactions of precious substrates (e.g., products of long synthetic sequences and natural products that can be isolated only in small quantities).", "date": "2006-03-01", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "128", "number": "8", "publisher": "American Chemical Society", "pagerange": "2518-2519", "id_number": "CaltechAUTHORS:20130821-160718478", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160718478", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01 EB001903" }, { "agency": "NSF", "grant_number": "CHE-0526693" }, { "agency": "E. I. DuPont de Nemours and Company, Inc." }, { "agency": "Alfred P. Sloan Foundation" }, { "agency": "Japan Society for the Promotion of Science (JSPS)" } ] }, "doi": "10.1021/ja057720w", "pmcid": "PMC1851926", "primary_object": { "basename": "Ismagilov_SI_JACS_2006_128_2518_rxn_screen_takuji.pdf", "url": "https://authors.library.caltech.edu/records/sw90n-wh349/files/Ismagilov_SI_JACS_2006_128_2518_rxn_screen_takuji.pdf" }, "related_objects": [ { "basename": "nihms14616.pdf", "url": "https://authors.library.caltech.edu/records/sw90n-wh349/files/nihms14616.pdf" } ], "resource_type": "article", "pub_year": "2006", "author_list": "Hatakeyama, Takuji; Chen, Delai L.; et el." }, { "id": "https://authors.library.caltech.edu/records/ykjg2-md758", "eprint_id": 40832, "eprint_status": "archive", "datestamp": "2023-08-22 04:49:06", "lastmod": "2023-10-24 22:29:13", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Lucchetta-E-M", "name": { "family": "Lucchetta", "given": "Elena M." } }, { "id": "Munson-M-S", "name": { "family": "Munson", "given": "Matthew S." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Characterization of the local temperature in space and time around a developing Drosophila embryo in a microfluidic device", "ispublished": "pub", "full_text_status": "public", "keywords": "laminar; network; neurons; flows; gene", "note": "\u00a9 Royal Society of Chemistry 2006. \n\nReceived 14th November 2005, Accepted 16th December 2005. First published on the web 12th January 2006. \n\nWe thank Nipam H. Patel (Department of Integrative Biology, Molecular and Cell Biology, and Howard Hughes Medical Institute, University of California\u2013Berkeley, Berkeley, CA 94720-3140, USA) for helpful discussions and for providing DP311 antibody. This work was supported by the Searle Scholars Program, the NSF MRSEC Program under DMR-0213745, and the MRSEC microfluidic facility funded by the NSF.\n\nPublished - b516119c.pdf
Supplemental Material - Ismagilov_loc_Lucchetta_2006_6_185_embryo_local_temperature_characterization.pdf
", "abstract": "This paper characterizes a microfluidic platform that differentially controls the temperature of each half of a living Drosophila melanogaster fruitfly embryo in space and time (E. M. Lucchetta, J. H. Lee, L. A. Fu, N. H. Patel and R. F. Ismagilov, Nature, 2005, 434, 1134-1138). This platform relies on laminar flow of two streams of liquid with different temperature, and on rapid prototyping in polydimethylsiloxane (PDMS). Here, we characterized fluid flow and heat transport in this platform both experimentally and by numerical simulation, and estimated the temperature distribution around and within the embryo by numerical simulation, to identify the conditions for creating a sharper temperature difference (temperature step) over the embryo. Embryos were removed from the device and immunostained histochemically for detection of Paired protein. Biochemical processes are sensitive to small differences in environmental temperature. The microfluidic platform characterized here could prove useful in understanding dynamics of biochemical networks as they respond to changes in temperature.", "date": "2006", "date_type": "published", "publication": "Lab on a Chip", "volume": "6", "number": "2", "publisher": "Royal Society of Chemistry", "pagerange": "185-190", "id_number": "CaltechAUTHORS:20130821-160725195", "issn": "1473-0197", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160725195", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Searle Scholars Program" }, { "agency": "NSF", "grant_number": "DMR-0213745" } ] }, "doi": "10.1039/B516119C", "primary_object": { "basename": "Ismagilov_loc_Lucchetta_2006_6_185_embryo_local_temperature_characterization.pdf", "url": "https://authors.library.caltech.edu/records/ykjg2-md758/files/Ismagilov_loc_Lucchetta_2006_6_185_embryo_local_temperature_characterization.pdf" }, "related_objects": [ { "basename": "b516119c.pdf", "url": "https://authors.library.caltech.edu/records/ykjg2-md758/files/b516119c.pdf" } ], "resource_type": "article", "pub_year": "2006", "author_list": "Lucchetta, Elena M.; Munson, Matthew S.; et el." }, { "id": "https://authors.library.caltech.edu/records/9wybq-h6d37", "eprint_id": 40776, "eprint_status": "archive", "datestamp": "2023-08-22 04:48:58", "lastmod": "2023-10-24 17:23:24", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Adamson-David-N", "name": { "family": "Adamson", "given": "David N." } }, { "id": "Mustafi-Debarshi", "name": { "family": "Mustafi", "given": "Debarshi" } }, { "id": "Zhang-John-X-J", "name": { "family": "Zhang", "given": "John X. J." } }, { "id": "Zheng-Bo", "name": { "family": "Zheng", "given": "Bo" }, "orcid": "0000-0001-8344-3445" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Production of arrays of chemically distinct nanolitre plugs via repeated splitting in microfluidic devices", "ispublished": "pub", "full_text_status": "public", "keywords": "gas-liquid flow; circular tubes; surfactants; droplets; drops; poly(dimethylsiloxane); capillary; system; motion; valves", "note": "This journal is \u00a9 The Royal Society of Chemistry 2006. \n\nReceived 6th April 2006, Accepted 20th June 2006. First published on the web 27th July 2006. \n\nThis work was partially supported by the NIH (RO1 GM075827). We acknowledge ATCG3D, funded by the National Institute of General Medical Sciences and National Center for Research Resources under the PSI-2 Specialized Center program (U54 GM074961), for providing equipment. Undergraduate research was supported by Dreyfus Teacher-Scholar award to R. F. I. (D. A.) and by the NIH Roadmap Physical and Chemical Biology training program at the University of Chicago (D. M.). We thank the Haselkorn group at the University of Chicago and Peter Kuhn and Ray Stevens groups at the Scripps Research Institute for protein samples. Fluorescent measurements were performed at the Chicago MRSEC microfluidic facility funded by NSF. We thank Qiang Fu, Helen Song and Liang Li for helpful discussions.\n\nPublished - Ismagilov_group_loc_2006_6_1178_splitting_david.pdf
", "abstract": "This paper reports a method for the production of arrays of nanolitre plugs with distinct chemical compositions. One of the primary constraints on the use of plug-based microfluidics for large scale biological screening is the difficulty of fabricating arrays of chemically distinct plugs on the nanolitre scale. Here, using microfluidic devices with several T-junctions linked in series, a single input array of large (similar to 320 nL) plugs was split to produce 16 output arrays of smaller (similar to 20 nL) plugs; the composition and configuration of these arrays were identical to that of the input. This paper shows how the passive break-up of plugs in T-junction microchannel geometries can be used to produce a set of smaller-volume output arrays useful for chemical screening from a single large-volume array. A simple theoretical description is presented to describe splitting as a function of the Capillary number, the capillary pressure, the total pressure difference across the channel, and the geometric fluidic resistance. By accounting for these considerations, plug coalescence and plug -plug contamination can be eliminated from the splitting process and the symmetry of splitting can be preserved. Furthermore, single-outlet splitting devices were implemented with both valve-and volume-based methods for coordinating the release of output arrays. Arrays of plugs containing commercial sparse matrix screens were obtained from the presented splitting method and these arrays were used in protein crystallization trials. The techniques presented in this paper may facilitate the implementation of high-throughput chemical and biological screening.", "date": "2006", "date_type": "published", "publication": "Lab on a Chip", "volume": "6", "number": "9", "publisher": "Royal Society of Chemistry", "pagerange": "1178-1186", "id_number": "CaltechAUTHORS:20130821-160715778", "issn": "1473-0197", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160715778", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "U54 GM074961" }, { "agency": "Camille and Henry Dreyfus Foundation" }, { "agency": "NSF" } ] }, "doi": "10.1039/b604993a", "pmcid": "PMC1851925", "primary_object": { "basename": "Ismagilov_group_loc_2006_6_1178_splitting_david.pdf", "url": "https://authors.library.caltech.edu/records/9wybq-h6d37/files/Ismagilov_group_loc_2006_6_1178_splitting_david.pdf" }, "resource_type": "article", "pub_year": "2006", "author_list": "Adamson, David N.; Mustafi, Debarshi; et el." }, { "id": "https://authors.library.caltech.edu/records/dgg5g-bk766", "eprint_id": 40890, "eprint_status": "archive", "datestamp": "2023-08-22 04:31:26", "lastmod": "2023-10-24 22:33:26", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Yadav-Maneesh-K", "name": { "family": "Yadav", "given": "Maneesh K." } }, { "id": "Gerdts-Cory-J", "name": { "family": "Gerdts", "given": "Cory J." } }, { "id": "Sanishvili-Ruslan", "name": { "family": "Sanishvili", "given": "Ruslan" } }, { "id": "Smith-Ward-W", "name": { "family": "Smith", "given": "Ward W." } }, { "id": "Roach-L-Spencer", "name": { "family": "Roach", "given": "L. Spencer" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Kuhn-Peter", "name": { "family": "Kuhn", "given": "Peter" } }, { "id": "Stevens-Raymond-C", "name": { "family": "Stevens", "given": "Raymond C." }, "orcid": "0000-0002-4522-8725" } ] }, "title": "In situ data collection and structure refinement from microcapillary protein crystallization", "ispublished": "pub", "full_text_status": "public", "keywords": "x-ray-diffraction; microfluidic system; radiation-damage; crystallography; crystals; microbatch; resolution; diffusion; droplets; beam", "note": "\u00a9 2005 International Union of Crystallography. \n\nReceived 1 June 2005. Accepted 18 August 2005. \n\nWe are grateful to Drs Janet Smith and Robert Fischetti for the access to the GM/CA-CAT beamline at the APS during its commissioning time. GM/CA-CAT has been funded in whole or in part with Federal funds from the National Cancer Institute (Y1-CO-1020) and the National Institute of General Medical Sciences (Y1-GM-1104). Use of the APS was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract #W-31-109-Eng-38. This study was supported by NIH/NIAID Contract #HHSN 266200400058C, `Functional and Structural Proteomics of the SARS-CoV' (to PK), NIH Roadmap Award GM073197, `Joint Center for Innovative Membrane Protein Technology' (to RCS), NIH Protein Structure Initiative Specialized Centers Grant GM074961 (to PK, RCS and RFI), and NIH award EB001903 (to RFI). We greatly appreciate the careful reading of and comments on the manuscript by Dr Elspeth Garman.\n\nPublished - Ismagilov_JApplCryst_2005_38_900_in_situ_protein_structure.pdf
Accepted Version - nihms14610.pdf
", "abstract": "In situ X-ray data collection has the potential to eliminate the challenging task of mounting and cryocooling often fragile protein crystals, reducing a major bottleneck in the structure determination process. An apparatus used to grow protein crystals in capillaries and to compare the background X-ray scattering of the components, including thin-walled glass capillaries against Teflon, and various fluorocarbon oils against each other, is described. Using thaumatin as a test case at 1.8 angstrom resolution, this study demonstrates that high-resolution electron density maps and refined models can be obtained from in situ diffraction of crystals grown in microcapillaries.", "date": "2005-12", "date_type": "published", "publication": "Journal of Applied Crystallography", "volume": "38", "number": "6", "publisher": "International Union of Crystallography", "pagerange": "900-905", "id_number": "CaltechAUTHORS:20130821-160735377", "issn": "0021-8898", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160735377", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "Y1-CO-1020" }, { "agency": "NIH", "grant_number": "Y1-GM-1104" }, { "agency": "Department of Energy (DOE)", "grant_number": "W-31-109-ENG-38" }, { "agency": "NIH", "grant_number": "266200400058C" }, { "agency": "NIH", "grant_number": "GM073197" }, { "agency": "NIH", "grant_number": "GM074961" }, { "agency": "NIH", "grant_number": "EB001903" } ] }, "doi": "10.1107/S002188980502649X", "pmcid": "PMC1858637", "primary_object": { "basename": "Ismagilov_JApplCryst_2005_38_900_in_situ_protein_structure.pdf", "url": "https://authors.library.caltech.edu/records/dgg5g-bk766/files/Ismagilov_JApplCryst_2005_38_900_in_situ_protein_structure.pdf" }, "related_objects": [ { "basename": "nihms14610.pdf", "url": "https://authors.library.caltech.edu/records/dgg5g-bk766/files/nihms14610.pdf" } ], "resource_type": "article", "pub_year": "2005", "author_list": "Yadav, Maneesh K.; Gerdts, Cory J.; et el." }, { "id": "https://authors.library.caltech.edu/records/2yhp4-m8e50", "eprint_id": 40848, "eprint_status": "archive", "datestamp": "2023-08-22 04:25:43", "lastmod": "2023-10-24 22:30:14", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Nelsen-S-F", "name": { "family": "Nelsen", "given": "Stephen F." } }, { "id": "Konradsson-A-E", "name": { "family": "Konradsson", "given": "Asgeir E." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Guzei-I-A", "name": { "family": "Guzei", "given": "Ilia A." } } ] }, "title": "Crystallographic characterization of the geometry changes upon electron loss from 2-tert-butyl-3-aryl-2,3-diazabicyclo 2.2.2 octanes", "ispublished": "pub", "full_text_status": "public", "keywords": "pair dihedral angles; photoelectron-spectra; intervalence compounds; radical cations; transfer rates; hydrazines; state", "note": "Copyright \u00a9 2005 American Chemical Society. \n\nPublished In Issue: November 02, 2005. Received April 14, 2005. Revised Manuscript Received May 12, 2005. \n\nWe thank the National Science Foundation for partial financial support under CHE-9988727 and CHE-0240197 (S.F.N.) and CHE-9310428 for the purchase of X-ray instrument and computers. We thank Douglas R. Powell and Randy K. Hayashi for the determination of X-ray structures.\n\nNote Added after ASAP Publication: An earlier version of this paper posted ASAP on the web on July 14, 2005, contained two errors in the compound names on lines 15 and 16 of the abstract. The names have been corrected in this new version posted September 30, 2005.\n\nSupporting Information Available: Summary of the data used to give the ranges in Table 5. Crystal structural data for HyDU^+NO_3^-, Hy^1NA^+SbF_6^-, Hy^2NA^+SbF_6^-, Hy_2^(15)NA^(2+)(Ph_4B^-)_2, and Hy_2^(27)NA^(2+)(SbF_6^-)_2\u00b7CH_3CN. This material is available free of charge via the Internet at http://pubs.acs.org.\n\nSupplemental Material - cg050154wsi20050414_041204.pdf
", "abstract": "Crystal structures of 2-tert-butyl-3-(2,3,5,6-tetramethylphenyl)-2,3-diazabicyclo[2.2.2]-octane radical cation nitrate (HyDU+NO_3-) [Hy = (2-tert-butyl-2,3-diazabicyclo[2.2.2]oct-3-yl]; 2-tert-butyl-3-(1-naphthyl)-2,3-diazabicyclo[2.2.2]octane radical cation hexafluoroantiminate (Hy^1NA+SbF_6-); 2-tert-butyl-3-(2-naphthyl)-2,3-diazabicyclo-[2.2.2]octane radical cation hexafluoroantiminate (Hy^2NA+SbF_6-); 1,5-bis(2-tert-butyl-2,3-diazabicyclo[2.2.2]oct-3-yl)naphthalene dication bis(tetraphenylborate) (Hy_2^(15)NA^(2+)(Ph_4B^-)_2); and 2,7-bis(2-tert-butyl-2,3-diazabicyclo[2.2.2]oct-3-yl)naphthalene dication bis(hexafluoroantiminate) (Hy_2^(27)NA^(2+)(SbF_6^-)_2\u00b7CH_3CN) are reported, and the geometries about the oxidized Hy units compared with literature data for neutral Hy-substituted analogues and the geometry changes upon electron loss for these compounds, which have a lone pair, lone pair twist angle in the neutral form (\u03b8(0)) in the range 122\u2212130\u00b0, are compared with those for tetraalkylhydrazines that have \u03b8(0) values near 180, 90, and 0\u00b0.", "date": "2005-11-02", "date_type": "published", "publication": "Crystal Growth and Design", "volume": "5", "number": "6", "publisher": "American Chemical Society", "pagerange": "2344-2347", "id_number": "CaltechAUTHORS:20130821-160727982", "issn": "1528-7483", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160727982", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF", "grant_number": "CHE-9988727" }, { "agency": "NSF", "grant_number": "CHE-0240197" }, { "agency": "NSF", "grant_number": "CHE-9310428" } ] }, "doi": "10.1021/cg050154w", "primary_object": { "basename": "cg050154wsi20050414_041204.pdf", "url": "https://authors.library.caltech.edu/records/2yhp4-m8e50/files/cg050154wsi20050414_041204.pdf" }, "resource_type": "article", "pub_year": "2005", "author_list": "Nelsen, Stephen F.; Konradsson, Asgeir E.; et el." }, { "id": "https://authors.library.caltech.edu/records/emdmv-e3886", "eprint_id": 40891, "eprint_status": "archive", "datestamp": "2023-08-22 04:14:16", "lastmod": "2023-10-24 22:33:29", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Zheng-Bo", "name": { "family": "Zheng", "given": "Bo" }, "orcid": "0000-0001-8344-3445" }, { "id": "Gerdts-Cory-J", "name": { "family": "Gerdts", "given": "Cory J." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Using nanoliter plugs in microfluidics to facilitate and understand protein crystallization", "ispublished": "pub", "full_text_status": "public", "keywords": "x-ray crystallography; monodisperse double emulsions; structural genomics; crystal-structure; macromolecular crystallization; system; time; droplets; growth; nucleation", "note": "\u00a9 2005 Elsevier. \n\nAvailable online 8 September 2005. \n\nThe work described in this review has been supported by the National Institute for Biomedical Imaging and Bioengineering (R01 EB001903), by the National Institute of General Medical Sciences and National Center for Research Resources under the PSI-2 Specialized Center program (U54 GM074961), by the Beckman Young Investigator Program and by the DuPont Young Professor Award. We thank Keith Moffat, Chuan He and Phoebe Rice for their help in advancing the work described in this review. We thank our colleagues in the Ismagilov laboratory who have contributed to the work described here, and Peter Kuhn, Ray Stevens and Lance Stewart for helpful discussions.\n\nAccepted Version - nihms14607.pdf
", "abstract": "Protein crystallization is important for determining protein structures by X-ray diffraction. Nanoliter-sized plugs aqueous droplets surrounded by a fluorinated carrier fluid have been applied to the screening of protein crystallization conditions. Preformed arrays of plugs in capillary cartridges enable sparse matrix screening. Crystals grown in plugs inside a microcapillary may be analyzed by in situ X-ray diffraction. Screening using plugs, which are easily formed in PDMS microfluidic channels, is simple and economical, and minimizes consumption of the protein. This approach also has the potential to improve our understanding of the fundamentals of protein crystallization, such as the effect of mixing on the nucleation of crystals.", "date": "2005-10", "date_type": "published", "publication": "Current Opinion in Structural Biology", "volume": "15", "number": "5", "publisher": "Elsevier", "pagerange": "548-555", "id_number": "CaltechAUTHORS:20130821-160735572", "issn": "0959-440X", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160735572", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01 EB001903" }, { "agency": "NIH", "grant_number": "U54 GM074961" }, { "agency": "Arnold and Mabel Beckman Foundation" }, { "agency": "E. I. DuPont de Nemours and Company, Inc." } ] }, "doi": "10.1016/j.sbi.2005.08.009", "pmcid": "PMC1764865", "primary_object": { "basename": "nihms14607.pdf", "url": "https://authors.library.caltech.edu/records/emdmv-e3886/files/nihms14607.pdf" }, "resource_type": "article", "pub_year": "2005", "author_list": "Zheng, Bo; Gerdts, Cory J.; et el." }, { "id": "https://authors.library.caltech.edu/records/2025f-b6f45", "eprint_id": 40784, "eprint_status": "archive", "datestamp": "2023-08-22 03:55:10", "lastmod": "2023-10-24 21:59:13", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chen-Delai-L", "name": { "family": "Chen", "given": "Delai L." } }, { "id": "Gerdts-Cory-J", "name": { "family": "Gerdts", "given": "Cory J." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Using microfluidics to observe the effect of mixing on nucleation of protein crystals", "ispublished": "pub", "full_text_status": "public", "keywords": "crystallization conditions; droplets; time; system; diffusion; kinetics; growth", "note": "\u00a9 2005 American Chemical Society. \n\nPublished In Issue: July 13, 2005. Received April 8, 2005. \n\nThis work was supported by the NIH (R01EB001903), ONR Young Investigator Award (N00014-03-10482), the Beckman Young Investigator program, and the MRSEC microfluidic facility funded by NSF. We thank Dr. Brenda Schulman for providing the ubiquitination protein and L. Spencer Roach for preliminary experiments.\n\nSupporting Information Available\nExperimental details and additional data (PDF). This material is available free of charge via the Internet at http://pubs.acs.org.\n\nAccepted Version - nihms14609.pdf
Supplemental Material - Ismagilov_SI_JACS_2005_127_9672_mixing_effect_delai.pdf
", "abstract": "This paper analyzes the effect of mixing on nucleation of protein crystals. The mixing of protein and precipitant was controlled by changing the flow rate in a plug-based microfluidic system. The nucleation rate inversely depended on the flow rate, and flow rate could be used to control nucleation. For example, at higher supersaturations, precipitation happened at low flow rates while large crystals grew at high flow rates. Mixing at low flow velocities in a winding channel induces nucleation more effectively than mixing in straight channels. A qualitative scaling argument that relies on a number of assumptions is presented to understand the experimental results. In addition to helping fundamental understanding, this result may be used to control nucleation, using rapid chaotic mixing to eliminate formation of precipitates at high supersaturation and using slow chaotic mixing to induce nucleation at lower supersaturation.", "date": "2005-07-13", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "127", "number": "27", "publisher": "American Chemical Society", "pagerange": "9672-9673", "id_number": "CaltechAUTHORS:20130821-160717199", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160717199", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01EB001903" }, { "agency": "Office of Naval Research (ONR)", "grant_number": "N00014-03-10482" }, { "agency": "Arnold and Mabel Beckman Foundation" }, { "agency": "NSF" } ] }, "doi": "10.1021/ja052279v", "pmcid": "PMC1766325", "primary_object": { "basename": "nihms14609.pdf", "url": "https://authors.library.caltech.edu/records/2025f-b6f45/files/nihms14609.pdf" }, "related_objects": [ { "basename": "Ismagilov_SI_JACS_2005_127_9672_mixing_effect_delai.pdf", "url": "https://authors.library.caltech.edu/records/2025f-b6f45/files/Ismagilov_SI_JACS_2005_127_9672_mixing_effect_delai.pdf" } ], "resource_type": "article", "pub_year": "2005", "author_list": "Chen, Delai L.; Gerdts, Cory J.; et el." }, { "id": "https://authors.library.caltech.edu/records/zdc3e-x1y89", "eprint_id": 40877, "eprint_status": "archive", "datestamp": "2023-08-22 03:41:03", "lastmod": "2023-10-24 22:32:27", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Su-Jing", "name": { "family": "Su", "given": "Jing" } }, { "id": "Bringer-M-R", "name": { "family": "Bringer", "given": "Michelle R." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Mrksich-M", "name": { "family": "Mrksich", "given": "Milan" } } ] }, "title": "Combining microfluidic networks and peptide arrays for multi-enzyme assays", "ispublished": "pub", "full_text_status": "public", "keywords": "self-assembled monolayers; mass-spectrometry; selective inhibitor; tyrosine kinase; chip; poly(dimethylsiloxane); immunoassay; fabrication; devices; systems", "note": "Copyright \u00a9 2005 American Chemical Society. \n\nPublished In Issue: May 25, 2005. Received March 3, 2005. \n\nThis work was supported by the NSF-MRSEC and used the microfluidics and protein expression facilities.\n\nSupporting Information Available: Details for fabrication of \u03bcFNs, preparation of SAMs, enzyme assays, mass spectrometric analysis, and cell extract preparation. This material is available free of charge via the Internet at http://pubs.acs.org.\n\nSupplemental Material - ja051371osi20050417_102001.pdf
", "abstract": "This paper reports the use of microfluidic networks (\u03bcFNs) to both prepare peptide microarrays and carry out label-free enzyme assays on self-assembled monolayers (SAMs) of alkanethiolates on gold. A poly(dimethylsiloxane) (PDMS) stamp fabricated with microchannels is used to immobilize a linear array of cysteine-terminated peptides onto SAMs presenting maleimide groups. The stamp is then reapplied to the SAM in a perpendicular direction to introduce enzyme solutions so that each solution can interact with an identical linear array of immobilized peptides. The \u03bcFNs enable multiple enzyme\u2212substrate interactions to be simultaneously evaluated at a submicroliter scale, while the use of SAMs enables the use of MALDI mass spectrometry (MS) to analyze the enzyme activities. This paper demonstrates applications of this system for assaying multiple kinases and for profiling the activities of kinases and phosphatases in human K562 cell extracts. The combination of \u03bcFN, SAMs, and MS detection provides a flexible platform for assaying enzyme activities in biological samples.", "date": "2005-05-25", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "127", "number": "20", "publisher": "American Chemical Society", "pagerange": "7280-7281", "id_number": "CaltechAUTHORS:20130821-160733236", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160733236", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF" } ] }, "doi": "10.1021/ja051371o", "primary_object": { "basename": "ja051371osi20050417_102001.pdf", "url": "https://authors.library.caltech.edu/records/zdc3e-x1y89/files/ja051371osi20050417_102001.pdf" }, "resource_type": "article", "pub_year": "2005", "author_list": "Su, Jing; Bringer, Michelle R.; et el." }, { "id": "https://authors.library.caltech.edu/records/m1yr2-aqc46", "eprint_id": 40831, "eprint_status": "archive", "datestamp": "2023-08-22 03:32:10", "lastmod": "2023-10-24 22:29:10", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Lucchetta-Elena-M", "name": { "family": "Lucchetta", "given": "Elena M." } }, { "id": "Lee-Ji-Hwan", "name": { "family": "Lee", "given": "Ji Hwan" } }, { "id": "Fu-Lydia-A", "name": { "family": "Fu", "given": "Lydia A." } }, { "id": "Patel-Nipam-H", "name": { "family": "Patel", "given": "Nipam H." }, "orcid": "0000-0003-4328-654X" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Dynamics of Drosophila embryonic patterning network perturbed in space and time using microfluidics", "ispublished": "pub", "full_text_status": "public", "keywords": "expression patterns; poly(dimethylsiloxane); protein; devices", "note": "\u00a9 2005 Nature Publishing Group. \n\nReceived 11 November 2004; Accepted 23 February 2005. \n\nThis work was supported by the Searle Scholars Program and was performed at the Chicago MRSEC microfluidic facility funded by the NSF. N.H.P. is an Investigator of the Howard Hughes Medical Institute. We thank J. B. Brokaw, C. A. Macrander and M. Giorgianni for preliminary experiments. We thank D. Bilder and I. Hariharan for discussions and comments on the manuscript.\n\nCompeting interests statement: The authors declare no competing financial interests.\n\nAccepted Version - nihms94333.pdf
Supplemental Material - Ismagilov_nature03509-s1_pdf.pdf
", "abstract": "Biochemical networks are perturbed both by fluctuations in environmental conditions and genetic variation. These perturbations must be compensated for, especially when they occur during embryonic pattern formation. Complex chemical reaction networks displaying spatiotemporal dynamics have been controlled and understood by perturbing their environment in space and time. Here, we apply this approach using microfluidics to investigate the robust network in Drosophila melanogaster that compensates for variation in the Bicoid morphogen gradient. We show that the compensation system can counteract the effects of extremely unnatural environmental conditions-a temperature step-in which the anterior and posterior halves of the embryo are developing at different temperatures and thus at different rates. Embryonic patterning was normal under this condition, suggesting that a simple reciprocal gradient system is not the mechanism of compensation. Time-specific reversals of the temperature step narrowed down the critical period for compensation to between 65 and 100 min after onset of embryonic development. The microfluidic technology used here may prove useful to future studies, as it allows spatial and temporal regulation of embryonic development.", "date": "2005-04-28", "date_type": "published", "publication": "Nature", "volume": "434", "number": "7037", "publisher": "Nature Publishing Group", "pagerange": "1134-1138", "id_number": "CaltechAUTHORS:20130821-160725036", "issn": "0028-0836", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160725036", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Searle Scholars Program" }, { "agency": "NSF" }, { "agency": "Howard Hughes Medical Institute (HHMI)" } ] }, "doi": "10.1038/nature03509", "pmcid": "PMC2656922", "primary_object": { "basename": "Ismagilov_nature03509-s1_pdf.pdf", "url": "https://authors.library.caltech.edu/records/m1yr2-aqc46/files/Ismagilov_nature03509-s1_pdf.pdf" }, "related_objects": [ { "basename": "nihms94333.pdf", "url": "https://authors.library.caltech.edu/records/m1yr2-aqc46/files/nihms94333.pdf" } ], "resource_type": "article", "pub_year": "2005", "author_list": "Lucchetta, Elena M.; Lee, Ji Hwan; et el." }, { "id": "https://authors.library.caltech.edu/records/ebrxv-jyt12", "eprint_id": 40892, "eprint_status": "archive", "datestamp": "2023-08-22 03:31:50", "lastmod": "2023-10-24 22:33:38", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Zheng-Bo", "name": { "family": "Zheng", "given": "Bo" }, "orcid": "0000-0001-8344-3445" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "A Microfluidic Approach for Screening Submicroliter Volumes against Multiple Reagents by Using Preformed Arrays of Nanoliter Plugs in a Three-Phase Liquid/Liquid/Gas Flow", "ispublished": "pub", "full_text_status": "public", "keywords": "crystal growth; enzymatic arrays; microreactors; screening methods; three-phase system protein crystallization conditions; chip; system; droplets; device; chemistry; diffusion; transport", "note": "\u00a9 2005 WILEY-VCH. \n\nIssue published online: 21 APR 2005. Article first published online: 22 MAR 2005. Manuscript Received: 9 DEC 2004. \n\nThis work was supported by the National Institutes of Health (grant no. R01\u2009EB001903) and by the Beckman Young Investigator Program and was performed at the MRSEC microfluidic facility funded by the National Science Foundation. We thank David Adamson for invaluable experimental assistance.\n\nAccepted Version - nihms14606.pdf
", "abstract": "Plugging a gap in screening: Arrays of nanoliter-sized plugs of different compositions can be preformed in a three-phase liquid/liquid/gas flow. The arrays can be transported into a microfluidic channel to test against a target (see schematic representation), as demonstrated in protein crystallization and an enzymatic assay.", "date": "2005-04-22", "date_type": "published", "publication": "Angewandte Chemie International Edition", "volume": "44", "number": "17", "publisher": "Wiley", "pagerange": "2520-2523", "id_number": "CaltechAUTHORS:20130821-160735736", "issn": "1433-7851", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160735736", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01\u2009EB001903" }, { "agency": "Arnold and Mabel Beckman Foundation" }, { "agency": "NSF" } ] }, "doi": "10.1002/anie.200462857", "pmcid": "PMC1766320", "primary_object": { "basename": "nihms14606.pdf", "url": "https://authors.library.caltech.edu/records/ebrxv-jyt12/files/nihms14606.pdf" }, "resource_type": "article", "pub_year": "2005", "author_list": "Zheng, Bo and Ismagilov, Rustem F." }, { "id": "https://authors.library.caltech.edu/records/5ck26-hyq79", "eprint_id": 40858, "eprint_status": "archive", "datestamp": "2023-08-22 03:10:12", "lastmod": "2023-10-24 22:31:01", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Roach-L-Spencer", "name": { "family": "Roach", "given": "L. Spencer" } }, { "id": "Song-Helen", "name": { "family": "Song", "given": "Helen" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Controlling nonspecific protein adsorption in a plug-based microfluidic system by controlling interfacial chemistry using fluorous-phase surfactants", "ispublished": "pub", "full_text_status": "public", "keywords": "self-assembled monolayers; water-soluble surfactants; bovine serum-albumin; droplet formation; fibrinogen adsorption; poly(ethylene glycol); tension measurements; air/water interface; liquid interfaces; microchannel emulsification", "note": "\u00a9 2005 American Chemical Society. \n\nPublished In Issue: February 01, 2005. Received for review June 27, 2004. Accepted October 29, 2004. \n\nThis work was supported by the NIH (R01 EB001903), Dupont Young Professor Award (R.F.I.), the Burroughs Wellcome Fund Interfaces Fellowship No. 1001774 (L.S.R.) and the Predoctoral Training Grant (H.S.) of the NIH (GM 08720). At the University of Chicago, work was performed at the MRSEC microfluidic facility funded by the NSF. We thank Yelena Koldobskaya for help with numerical simulations.\n\nSupporting Information Available: Additional information as noted in text:\u2009 details of R_f\u2009-OEG extraction; drop tensiometry measurements for alkaline phosphatase at interfaces that presented each one of the three following surfactants:\u2009 R_f\u2009-COOH, R_f\u2009-CH_2CH_2OH, or R_f\u2009-OEG; tensiometry data for variable concentrations of fibrinogen at an interface that presents the R_f\u2009-COOH surfactant; tensiometry data for the adsorption of concentrated fibrinogen to a pure fluorocarbon interface, and also Selwyn's plots for alkaline phosphatase kinetics measured within a microfluidic device for plugs formed with each one of the following three surfactants:\u2009 R_f\u2009-COOH, R_f\u2009-CH_2CH_2OH, or R_f\u2009-OEG. This material is available free of charge via the Internet at http://pubs.acs.org.\n\nAccepted Version - nihms14608.pdf
Supplemental Material - Ismagilov_SI_Anal_Chem_2005_77_785_surface_adsorption_spencer.pdf
", "abstract": "Control of surface chemistry and protein adsorption is important for using microfluidic devices for biochemical analysis and high-throughput screening assays. This paper describes the control of protein adsorption at the liquid-liquid interface in a plug-based microfluidic system. The microfluidic system uses multiphase flows of immiscible fluorous and aqueous fluids to form plugs, which are aqueous droplets that are completely surrounded by fluorocarbon oil and do not come into direct contact with the hydrophobic surface of the microchannel. Protein adsorption at the aqueous-fluorous interface was controlled by using surfactants; that were soluble in fluorocarbon oil but insoluble in aqueous solutions. Three perfluorinated alkane surfactants capped with different functional groups were used: a carboxylic acid, an alcohol, and a triethylene glycol group that was synthesized from commercially available materials. Using complementary methods of analysis, adsorption was characterized for several proteins (bovine serum albumin (BSA) and fibrinogen), including enzymes (ribonuclease A (RNase A) and alkaline phosphatase). These complementary methods involved characterizing adsorption in microliter-sized droplets by drop tensiometry and in nanoliter plugs by fluorescence microscopy and kinetic measurements of enzyme catalysis. The oligoethylene glycol-capped surfactant prevented protein adsorption in all cases. Adsorption of proteins to the carboxylic acid-capped surfactant in nanoliter plugs could be described by using the Langmuir model and tensiometry results for microliter drops. The microfluidic system was fabricated using rapid prototyping in poly(dimethylsiloxane) (PDMS). Black PDMS microfluidic devices, fabricated by curing a suspension of charcoal in PDMS, were used to measure the changes in fluorescence intensity more sensitively. This system will be useful for microfluidic bioassays, enzymatic kinetics, and protein crystallization, because it does not require surface modification during fabrication to control surface chemistry and protein adsorption.", "date": "2005-02-01", "date_type": "published", "publication": "Analytical Chemistry", "volume": "77", "number": "3", "publisher": "American Chemical Society", "pagerange": "785-796", "id_number": "CaltechAUTHORS:20130821-160729676", "issn": "0003-2700", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160729676", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01 EB001903" }, { "agency": "E. I. DuPont de Nemours and Company, Inc." }, { "agency": "Burroughs Wellcome Fund", "grant_number": "1001774" }, { "agency": "NIH", "grant_number": "GM 08720" }, { "agency": "NSF" } ] }, "doi": "10.1021/ac049061w", "pmcid": "PMC1941690", "primary_object": { "basename": "Ismagilov_SI_Anal_Chem_2005_77_785_surface_adsorption_spencer.pdf", "url": "https://authors.library.caltech.edu/records/5ck26-hyq79/files/Ismagilov_SI_Anal_Chem_2005_77_785_surface_adsorption_spencer.pdf" }, "related_objects": [ { "basename": "nihms14608.pdf", "url": "https://authors.library.caltech.edu/records/5ck26-hyq79/files/nihms14608.pdf" } ], "resource_type": "article", "pub_year": "2005", "author_list": "Roach, L. Spencer; Song, Helen; et el." }, { "id": "https://authors.library.caltech.edu/records/rqf8w-39r07", "eprint_id": 40894, "eprint_status": "archive", "datestamp": "2023-08-22 02:17:04", "lastmod": "2023-10-24 22:33:48", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Zheng-Bo", "name": { "family": "Zheng", "given": "Bo" }, "orcid": "0000-0001-8344-3445" }, { "id": "Tice-Joshua-D", "name": { "family": "Tice", "given": "Joshua D." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Formation of arrayed droplets of soft lithography and two-phase fluid flow, and application in protein crystallization", "ispublished": "pub", "full_text_status": "public", "keywords": "microfluidic devices; reduction photolithography; laminar-flow; poly(dimethylsiloxane); microchannels; fabrication; generation; diffusion; capillaries; systems", "note": "\u00a9 2004 WILEY-VCH. \n\nIssue published online: 25 AUG 2004. Article first published online: 25 AUG 2004. \n\nThis work was supported in part by the NIH (R01 EB001903) and the Beckman Young Investigator Program, and was performed at the MRSEC microfluidic facility funded by the NSF.\n\nAccepted Version - nihms14603.pdf
", "abstract": "This paper presents an overview of our recent work on the use of soft lithography and two-phase fluid flow to form arrays of droplets. The crucial issues in the formation of stable arrays of droplets and alternating droplets of two sets of aqueous solutions include the geometry of the microchannels, the capillary number, and the water fraction of the system. Glass capillaries could be coupled to the PDMS microchannels and droplets could be transferred into glass capillaries for long-term storage. The arrays of droplets have been applied to screen the conditions for protein crystallization with microbatch and vapor diffusion techniques.", "date": "2004-08-03", "date_type": "published", "publication": "Advanced Materials", "volume": "16", "number": "15", "publisher": "Wiley", "pagerange": "1365-1368", "id_number": "CaltechAUTHORS:20130821-160736036", "issn": "0935-9648", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160736036", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01 EB001903" }, { "agency": "Arnold and Mabel Beckman Foundation" }, { "agency": "NSF" } ] }, "doi": "10.1002/adma.200400590", "pmcid": "PMC1858636", "primary_object": { "basename": "nihms14603.pdf", "url": "https://authors.library.caltech.edu/records/rqf8w-39r07/files/nihms14603.pdf" }, "resource_type": "article", "pub_year": "2004", "author_list": "Zheng, Bo; Tice, Joshua D.; et el." }, { "id": "https://authors.library.caltech.edu/records/750pr-xej70", "eprint_id": 40790, "eprint_status": "archive", "datestamp": "2023-08-19 13:37:29", "lastmod": "2023-10-24 21:59:37", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Gerdts-C-J", "name": { "family": "Gerdts", "given": "Cory J." } }, { "id": "Sharoyan-D-E", "name": { "family": "Sharoyan", "given": "David E." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "A Synthetic Reaction Network: Chemical Amplification Using Nonequilibrium Autocatalytic Reactions Coupled in Time", "ispublished": "pub", "full_text_status": "restricted", "note": "Copyright \u00a9 2004 American Chemical Society. \n\nPublished In Issue: May 26, 2004. Received December 12, 2003. \n\nThis work was supported by Office of Naval Research Young Investigator Award (N00014-03-10482). At The University of Chicago, work was performed at the MRSEC microfluidic facility funded by NSF. Photolithography was performed at MAL of UIC. We thank Yelena Koldobskaya for insightful comments.", "abstract": "This article reports a functional chemical reaction network synthesized in a microfluidic device.\nThis chemical network performs chemical 5000-fold amplification and shows a threshold response. It\noperates in a feedforward manner in two stages: the output of the first stage becomes the input of the\nsecond stage. Each stage of amplification is performed by a reaction autocatalytic in Co^(2+). The microfluidic\nnetwork is used to maintain the two chemical reactions away from equilibrium and control the interactions\nbetween them in time. Time control is achieved as described previously (Angew. Chem., Int. Ed. 2003, 42,\n768) by compartmentalizing the reaction mixture inside plugs which are aqueous droplets carried through\na microchannel by an immiscible fluorinated fluid. Autocatalytic reaction displayed sensitivity to mixing;\nmore rapid mixing corresponded to slower reaction rates. Synthetic chemical reaction networks may help\nunderstand the function of biochemical reaction networks, the goal of systems biology. They may also find\npractical applications. For example, the system described here may be used to detect visually, in a simple\nformat, picoliter volumes of nanomolar concentrations of Co^(2+), an environmental pollutant.", "date": "2004-05-26", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "126", "number": "20", "publisher": "American Chemical Society", "pagerange": "6327-6331", "id_number": "CaltechAUTHORS:20130821-160718167", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160718167", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "ONR", "grant_number": "N00014-03-10482" }, { "agency": "NSF" } ] }, "doi": "10.1021/ja031689l", "resource_type": "article", "pub_year": "2004", "author_list": "Gerdts, Cory J.; Sharoyan, David E.; et el." }, { "id": "https://authors.library.caltech.edu/records/rsr0p-kcs98", "eprint_id": 40780, "eprint_status": "archive", "datestamp": "2023-08-22 01:57:22", "lastmod": "2023-10-24 21:59:02", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Bringer-Michelle-R", "name": { "family": "Bringer", "given": "Michelle R." } }, { "id": "Gerdts-Cory-J", "name": { "family": "Gerdts", "given": "Cory J." } }, { "id": "Song-Helen", "name": { "family": "Song", "given": "Helen" } }, { "id": "Tice-Joshua-D", "name": { "family": "Tice", "given": "Joshua D." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Microfluidic Systems for Chemical Kinetics that Rely on Chaotic Mixing in Droplets", "ispublished": "pub", "full_text_status": "public", "keywords": "microfluidics; mixing; chaotic advection; droplet; kinetics; multiphase flow", "note": "\u00a9 The Royal Society 2004. \n\nPublished online 18 March 2004. \n\nThis work was supported by the NIH (R01 EB001903), ONR Young Investigator Award (N00014-03-10482), the Beckman foundation, the Camille and Henry Dreyfus New Faculty Award, the Research Innovation Award from Research Corporation and the Chicago MRSEC funded by the NSF. At The University of Chicago work was performed at the microfluidic facility of the Chicago MRSEC and at the Cancer Center DLMF. Photolithography was performed at MAL of the UIC by H.S.\n\nAccepted Version - nihms14620.pdf
", "abstract": "This paper reviews work on a microfluidic system that relies on chaotic advection\nto rapidly mix multiple reagents isolated in droplets (plugs). Using a combination\nof turns and straight sections, winding microfluidic channels create unsteady fluid\nflows that rapidly mix the multiple reagents contained within plugs. The scaling\nof mixing for a range of channel widths, flow velocities and diffusion coefficients\nhas been investigated. Due to rapid mixing, low sample consumption and transport\nof reagents with no dispersion, the system is particularly appropriate for chemical\nkinetics and biochemical assays. The mixing occurs by chaotic advection and is rapid\n(sub-millisecond), allowing for an accurate description of fast reaction kinetics. In\naddition, mixing has been characterized and explicitly incorporated into the kinetic\nmodel.", "date": "2004-05-15", "date_type": "published", "publication": "Philosophical Transactions A: Mathematical, Physical and Engineering Sciences", "volume": "362", "number": "1818", "publisher": "Royal Society of London", "pagerange": "1087-1104", "id_number": "CaltechAUTHORS:20130821-160716511", "issn": "1364-503X", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160716511", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01 EB001903" }, { "agency": "Office of Naval Research (ONR)", "grant_number": "N00014-03-10482" }, { "agency": "Arnold and Mabel Beckman Foundation" }, { "agency": "Camille and Henry Dreyfus Foundation" }, { "agency": "Research Corporation" }, { "agency": "NSF" } ] }, "doi": "10.1098/rsta.2003.1364", "pmcid": "PMC1769314", "primary_object": { "basename": "nihms14620.pdf", "url": "https://authors.library.caltech.edu/records/rsr0p-kcs98/files/nihms14620.pdf" }, "resource_type": "article", "pub_year": "2004", "author_list": "Bringer, Michelle R.; Gerdts, Cory J.; et el." }, { "id": "https://authors.library.caltech.edu/records/bhw79-ptr61", "eprint_id": 40896, "eprint_status": "archive", "datestamp": "2023-08-22 01:55:33", "lastmod": "2023-10-24 22:33:59", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Zheng-Bo", "name": { "family": "Zheng", "given": "Bo" }, "orcid": "0000-0001-8344-3445" }, { "id": "Tice-Joshua-D", "name": { "family": "Tice", "given": "Joshua D." } }, { "id": "Roach-L-Spencer", "name": { "family": "Roach", "given": "L. Spencer" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "A Droplet-Based, Composite PDMS/Glass Capillary Microfluidic System for Evaluating Protein Crystallization Conditions by Microbatch and Vapor-Diffusion Methods with On-Chip X-Ray Diffraction", "ispublished": "pub", "full_text_status": "public", "keywords": "crystal growth; microfluidics; microreactors; proteins; X-ray diffraction", "note": "\u00a9 2004 WILEY-VCH. \n\nIssue published online: 28 APR 2004. Article first published online: 13 APR 2004. Manuscript Received: 9 FEB 2004. \n\nThis work was supported by the NIH (R01 EB001903), and by Beckman Young Investigator Program, and was performed at the MRSEC microfluidic facility funded by NSF. L.S.R. is supported by the Burroughs Wellcome Fund Cross-Disciplinary Training Program in Biophysical Dynamics. We thank Adam Lyon for preliminary experiments. We thank Phoebe Rice, Keith Moffatt, Andrzej Joachimiak, Chuan He, and Erica Duguid for valuable discussions and help with protein crystallography. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under Contract No. W-31-109-Eng-38. Use of the BioCARS Sector 14 was supported by the National Institutes of Health, National Center for Research Resources, under grant number RR07707.\n\nAccepted Version - nihms14605.pdf
", "abstract": "On-chip protein crystallization and diffraction: Proteins can be crystallized in nanoliter volumes by using both microbatch and vapor-diffusion techniques inside composite PDMS/glass microfluidic devices (PDMS=polydimethylsiloxane). The quality of crystals can be assessed directly by on-chip X-ray diffraction.", "date": "2004-05-03", "date_type": "published", "publication": "Angewandte Chemie International Edition", "volume": "43", "number": "19", "publisher": "Wiley", "pagerange": "2508-2511", "id_number": "CaltechAUTHORS:20130821-160736358", "issn": "1433-7851", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160736358", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01 EB001903" }, { "agency": "Arnold and Mabel Beckman Foundation" }, { "agency": "Burroughs Wellcome Fund" }, { "agency": "Department of Energy (DOE)", "grant_number": "W-31-109-ENG-38" }, { "agency": "NIH", "grant_number": "RR07707" } ] }, "doi": "10.1002/anie.200453974", "pmcid": "PMC1766324", "primary_object": { "basename": "nihms14605.pdf", "url": "https://authors.library.caltech.edu/records/bhw79-ptr61/files/nihms14605.pdf" }, "resource_type": "article", "pub_year": "2004", "author_list": "Zheng, Bo; Tice, Joshua D.; et el." }, { "id": "https://authors.library.caltech.edu/records/qvpvf-4wf12", "eprint_id": 40881, "eprint_status": "archive", "datestamp": "2023-08-22 01:48:19", "lastmod": "2023-10-24 22:32:42", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Tice-J-D", "name": { "family": "Tice", "given": "J. D." } }, { "id": "Lyon-A-D", "name": { "family": "Lyon", "given": "A. D." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "R. F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Effects of viscosity on droplet formation and mixing in microfluidic channels", "ispublished": "pub", "full_text_status": "restricted", "keywords": "viscosity, microfluidic, mixing, multiphase, droplet, plug total analysis systems; capillary tubes; surface-tension; image-analysis; bubbles; pendant; motion; device", "note": "Copyright \u00a9 2003 Elsevier. \n\nReceived 4 August 2003. Revised 22 October 2003. Accepted 7 November 2003. Available online 8 January 2004. \n\nThis work was supported by the Camille and Henry Dreyfus New Faculty Award, Chicago MRSEC funded by NSF, the ONR Young Investigator Award N00014-03-10482, the NIH (R01 EB001903), and by the Beckman Foundation. The work was performed at the Chicago MRSEC microfluidic facility. We thank H. Song and C.J. Gerdts for performing photolithography at MAL of UIC and for advice. We thank M.R. Bringer for helpful discussions.", "abstract": "This paper characterizes the conditions required to form nanoliter-sized droplets (plugs) of viscous aqueous reagents in flows of inuniscible carrier fluid within microfluidic channels. For both non-viscous (viscosity of 2.0 mPa s) and viscous (viscosity of 18 mPa s) aqueous solutions, plugs formed reliably in a flow of water-immiscible carrier fluid for Capillary number less than 0.01, although plugs were able to form at higher Capillary numbers at lower ratios of the aqueous phase flow rate to the flow rate of the carrier fluid (in all the experiments performed, the Reynolds number was less than 1). The paper also shows that combining viscous and non-viscous reagents can enhance mixing in droplets moving through straight microchannels by providing a nearly ideal initial distribution of reagents within each droplet. The study should facilitate the use of this droplet-based microfluidic platform for investigation of protein crystallization, kinetics, and assays.", "date": "2004-04-01", "date_type": "published", "publication": "Analytica Chimica Acta", "volume": "507", "number": "1", "publisher": "Elsevier", "pagerange": "73-77", "id_number": "CaltechAUTHORS:20130821-160733899", "issn": "0003-2670", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160733899", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Camille and Henry Dreyfus Foundation" }, { "agency": "NSF" }, { "agency": "ONR", "grant_number": "N00014-03-10482" }, { "agency": "NIBIB", "grant_number": "R01 EB001903" }, { "agency": "Arnold and Mabel Beckman Foundation" } ] }, "doi": "10.1016/j.aca.2003.11.024", "resource_type": "article", "pub_year": "2004", "author_list": "Tice, J. D.; Lyon, A. D.; et el." }, { "id": "https://authors.library.caltech.edu/records/gw0cd-hyp12", "eprint_id": 40859, "eprint_status": "archive", "datestamp": "2023-08-22 01:42:00", "lastmod": "2023-10-24 22:31:06", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Runyon-M-K", "name": { "family": "Runyon", "given": "Matthew K." } }, { "id": "Johnson-Kerner-B-L", "name": { "family": "Johnson-Kerner", "given": "Bethany L." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Minimal Functional Model of Hemostasis in a Biomimetic Microfluidic System", "ispublished": "pub", "full_text_status": "restricted", "keywords": "autocatalysis; biomimetic synthesis; hemostasis; microfluidic systems; self-repairing systems", "note": "Copyright \u00a9 2004 WILEY-VCH. \n\nIssue published online: 9 MAR 2004. Article first published online: 24 FEB 2004. Manuscript Received: 28 NOV 2003. \n\nThis work was supported by NSF CAREER Award, Office of Naval Research Young Investigator Award (N00014-03-10482), Searle Scholars Program, and by Dreyfus New Faculty Award. We thank Professors G. M. Whitesides, C. Chen, C. Hall, T. Van Ha, V. Turitto, and M. LaBarbera for invaluable suggestions.", "abstract": "The proof of the model is in the function: A minimal model of hemostasis (a complex biochemical network responsible for blood coagulation) may be implemented with only three chemical reactions, which creates a biomimetic functional microfluidic system that is capable of repairing itself (as modeled in the figure). This simple system shows threshold response and sensitivity to flow similar to that observed in hemostasis.", "date": "2004-03-12", "date_type": "published", "publication": "Angewandte Chemie International Edition", "volume": "43", "number": "12", "publisher": "Wiley", "pagerange": "1531-1536", "id_number": "CaltechAUTHORS:20130821-160729811", "issn": "1433-7851", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160729811", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF CAREER" }, { "agency": "ONR", "grant_number": "N00014-03-10482" }, { "agency": "Searle Scholars Program" }, { "agency": "Camille and Henry Dreyfus Foundation" } ] }, "doi": "10.1002/anie.200353428", "resource_type": "article", "pub_year": "2004", "author_list": "Runyon, Matthew K.; Johnson-Kerner, Bethany L.; et el." }, { "id": "https://authors.library.caltech.edu/records/t0afb-m2818", "eprint_id": 40895, "eprint_status": "archive", "datestamp": "2023-08-22 01:19:36", "lastmod": "2023-10-24 22:33:51", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Zheng-Bo", "name": { "family": "Zheng", "given": "Bo" }, "orcid": "0000-0001-8344-3445" }, { "id": "Tice-Joshua-D", "name": { "family": "Tice", "given": "Joshua D." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Formation of droplets of alternating composition in microfluidic channels and applications to indexing of concentrations in droplet-based assays", "ispublished": "pub", "full_text_status": "public", "keywords": "protein crystallization conditions; linear flow; coalescence; systems; poly(dimethylsiloxane); compatibilizer; microchannels; deformation; generation; kinetics", "note": "\u00a9 2004 American Chemical Society. \n\nPublished In Issue: September 01, 2004. Received for review March 18, 2004. Accepted June 9, 2004. \n\nThis work was supported by the NIH (R01 EB001903) and was performed at the MRSEC microfluidic facility funded by NSF. J.D.T. is a Beckman Fellow. We thank Wendy Zhang for helpful discussions.\n\nAccepted Version - nihms14604.pdf
", "abstract": "For screening the conditions for a reaction by using droplets (or plugs) as microreactors, the composition of the droplets must be indexed. Indexing here refers to measuring the concentration of a solute by addition of a marker, either internal or external. Indexing may be performed by forming droplet pairs, where in each pair the first droplet is used to conduct the reaction, and the second droplet is used to index the composition of the first droplet. This paper characterizes a method for creating droplet pairs by generating alternating droplets, of two sets of aqueous solutions in a flow of immiscible carrier fluid within PDMS and glass microfluidic channels. The paper also demonstrates that the technique can be used to index the composition of the droplets, and this application is illustrated by screening conditions of protein crystallization. The fluid properties required to form the steady flow of the alternating droplets in a microchannel were characterized as a function of the capillary number Ca and water fraction. Four regimes were observed. At the lowest values of Ca, the droplets of the two streams coalesced; at intermediate values of Ca the alternating droplets formed reliably. At even higher values of Ca, shear forces dominated and caused formation of droplets that were smaller than the cross-sectional dimension of the channel; at the highest values of Ca, coflowing laminar streams of the two immiscible fluids formed. In addition to screening of protein crystallization conditions, understanding of the fluid flow in this system may extend this indexing approach to other chemical and biological assays performed on a microfluidic chip.", "date": "2004", "date_type": "published", "publication": "Analytical Chemistry", "volume": "76", "number": "17", "publisher": "American Chemical Society", "pagerange": "4977-4982", "id_number": "CaltechAUTHORS:20130821-160736217", "issn": "0003-2700", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160736217", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01 EB001903" }, { "agency": "NSF" }, { "agency": "Arnold and Mabel Beckman Foundation" } ] }, "doi": "10.1021/ac0495743", "pmcid": "PMC1766978", "primary_object": { "basename": "nihms14604.pdf", "url": "https://authors.library.caltech.edu/records/t0afb-m2818/files/nihms14604.pdf" }, "resource_type": "article", "pub_year": "2004", "author_list": "Zheng, Bo; Tice, Joshua D.; et el." }, { "id": "https://authors.library.caltech.edu/records/jwp5s-20346", "eprint_id": 40869, "eprint_status": "archive", "datestamp": "2023-08-19 12:45:54", "lastmod": "2023-10-24 22:31:48", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Shestopalov-I", "name": { "family": "Shestopalov", "given": "Ilya" } }, { "id": "Tice-J-D", "name": { "family": "Tice", "given": "Joshua D." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Multi-step synthesis of nanoparticles performed on millisecond time scale in a microfluidic droplet-based system", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 Royal Society of Chemistry 2004. \n\nReceived 4th March 2004, Accepted 12th May 2004. First published on the web 5th July 2004. \n\nThis work was supported by the Beckman Young Investigator Program and Chicago MRSEC funded by NSF. At The University of Chicago, work was performed at the MRSEC microfluidic facility. JDT is a Beckman Scholar. We thank David Sharoyan and Bo Zheng for helpful discussions and preliminary experiments. We thank Cory J. Gerdts and Helen Song for performing photolithography at MAL of the UIC. \n\nLab on a Chip special issue: The Science and Application of Droplets in Microfluidic Devices\n\nPublished - Ismagilov_LOC_2004_4_316_Shestopalov_Mulitstep_synthesis_nanoparticles_ms_timescale_ufl_droplet_system.pdf
", "abstract": "This paper reports a plug-based, microfluidic method for performing multi-step chemical reactions with millisecond\ntime-control. It builds upon a previously reported method where aqueous reagents were injected into a flow of\nimmiscible fluid (fluorocarbons) (H. Song et al., Angew. Chem. Int. Ed., 2003, 42, 768). The aqueous reagents formed\nplugs \u2013 droplets surrounded and transported by the immiscible fluid. Winding channels rapidly mixed the reagents in\ndroplets. This paper shows that further stages of the reaction could be initiated by flowing additional reagent streams\ndirectly into the droplets of initial reaction mixture. The conditions necessary for an aqueous stream to merge with\naqueous droplets were characterized. The Capillary number could be used to predict the behavior of the two-phase flow\nat the merging junction. By transporting solid reaction products in droplets, the products were kept from aggregating on\nthe walls of the microchannels. To demonstrate the utility of this microfluidic method it was used to synthesize colloidal\nCdS and CdS/CdSe core-shell nanoparticles.", "date": "2004", "date_type": "published", "publication": "Lab on a Chip", "volume": "4", "number": "4", "publisher": "Royal Society of Chemistry", "pagerange": "316-321", "id_number": "CaltechAUTHORS:20130821-160731532", "issn": "1473-0197", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160731532", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Beckman Young Investigator award" }, { "agency": "NSF" } ] }, "doi": "10.1039/B403378G", "primary_object": { "basename": "Ismagilov_LOC_2004_4_316_Shestopalov_Mulitstep_synthesis_nanoparticles_ms_timescale_ufl_droplet_system.pdf", "url": "https://authors.library.caltech.edu/records/jwp5s-20346/files/Ismagilov_LOC_2004_4_316_Shestopalov_Mulitstep_synthesis_nanoparticles_ms_timescale_ufl_droplet_system.pdf" }, "resource_type": "article", "pub_year": "2004", "author_list": "Shestopalov, Ilya; Tice, Joshua D.; et el." }, { "id": "https://authors.library.caltech.edu/records/exqg6-0r797", "eprint_id": 40872, "eprint_status": "archive", "datestamp": "2023-08-22 01:08:51", "lastmod": "2023-10-24 22:32:00", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Song-Helen", "name": { "family": "Song", "given": "Helen" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Millisecond kinetics on a microfluidic chip using nanoliters of reagents", "ispublished": "pub", "full_text_status": "public", "keywords": "x-ray-scattering; ribonuclease-a; time; flow; microreactor; substrate; enzyme; assay; base; step", "note": "\u00a9 2003 American Chemical Society. \n\nPublished In Issue: November 26, 2003. Received April 4, 2003. \n\nThis work was supported by the NIH (R01 EB001903), the Beckman Young Investigator program, Searle Scholars Program, the Predoctoral Training Grant (H.S.) of the NIH (GM 08720), and the Camille and Henry Dreyfus New Faculty Award. At The University of Chicago, work was performed at the MRSEC microfluidic facility funded by the NSF and at the Cancer Center DLMF. Photolithography was performed at MAL of the UIC. We thank A.V. Korennykh and Prof. J. A. Piccirilli for helpful suggestions and for providing samples of RNase A, Prof. T. R. Sosnick and Prof. T. Pan for helpful discussions, and J.D. Tice for the image shown in Figure 1 and for invaluable experimental assistance.\n\nAccepted Version - nihms14600.pdf
", "abstract": "This paper describes a microfluidic chip for performing kinetic measurements with better than millisecond resolution. Rapid kinetic measurements in microfluidic systems are complicated by two problems: mixing is slow and dispersion is large. These problems also complicate biochemical assays performed in microfluidic chips. We have recently shown (Song, H.; Tice, J. D.; Ismagilov, R. F. Angew. Chem., Int. Ed. 2003, 42, 768-772) how multiphase fluid flow in microchannels can be used to address both problems by transporting the reagents inside aqueous droplets (plugs) surrounded by an immiscible fluid. Here, this droplet-based microfluidic system was used to extract kinetic parameters of an enzymatic reaction. Rapid single-turnover kinetics of ribonuclease A (RNase A) was measured with better than millisecond resolution using sub-microliter volumes of solutions. To obtain the single-turnover rate constant (k = 1100 +/- 250 s(-1)), four new features for this microfluidics platform were demonstrated: (i) rapid on-chip dilution, (ii) multiple time range access, (iii) biocompatibility with RNase A, and (iv) explicit treatment of mixing for improving time resolution of the system. These features are discussed using kinetics of RNase A. From fluorescent images integrated for 2-4 s, each kinetic profile can be obtained using less than 150 nL of solutions of reagents because this system relies on chaotic advection inside moving droplets rather than on turbulence to achieve rapid mixing. Fabrication of these devices in PDMS is straightforward and no specialized equipment, except for a standard microscope with a CCD camera, is needed to run the experiments. This microfluidic platform could serve as an inexpensive and economical complement to stopped-flow methods for a broad range of time-resolved experiments and assays in chemistry and biochemistry.", "date": "2003-11-26", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "125", "number": "47", "publisher": "American Chemical Society", "pagerange": "14613-14619", "id_number": "CaltechAUTHORS:20130821-160732315", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160732315", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01 EB001903" }, { "agency": "Arnold and Mabel Beckman Foundation" }, { "agency": "Searle Scholars Program" }, { "agency": "NIH", "grant_number": "GM 08720" }, { "agency": "Camille and Henry Dreyfus Foundation" }, { "agency": "NSF" } ] }, "doi": "10.1021/ja0354566", "pmcid": "PMC1769313", "primary_object": { "basename": "nihms14600.pdf", "url": "https://authors.library.caltech.edu/records/exqg6-0r797/files/nihms14600.pdf" }, "resource_type": "article", "pub_year": "2003", "author_list": "Song, Helen and Ismagilov, Rustem F." }, { "id": "https://authors.library.caltech.edu/records/012af-kmz12", "eprint_id": 40882, "eprint_status": "archive", "datestamp": "2023-08-22 01:02:04", "lastmod": "2023-10-24 22:32:48", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Tice-J-D", "name": { "family": "Tice", "given": "Joshua D." } }, { "id": "Song-Helen", "name": { "family": "Song", "given": "Helen" } }, { "id": "Lyon-A-D", "name": { "family": "Lyon", "given": "Adam D." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Formation of droplets and mixing in multiphase microfluidics at low values of the Reynolds and the capillary numbers", "ispublished": "pub", "full_text_status": "restricted", "keywords": "total analysis systems; surface-tension; image-analysis; scaling laws; flow; microchannels; poly(dimethylsiloxane); device; proteomics; technology", "note": "Copyright \u00a9 2003 American Chemical Society. \n\nPublished In Issue: October 28, 2003. Received March 4, 2003. Revised June 11, 2003. \n\nThis work was supported by the Camille and Henry Dreyfus New Faculty Award, the Research Innovation Award from Research Corporation, by Chicago MRSEC funded by NSF, and by the Predoctoral Training Grant (H.S.) of the NIH (GM 08720). This work has been performed at the Chicago MRSEC microfluidics facility. Photolithography was performed at MAL of UIC. We thank Professors Sidney R. Nagel and Thomas A. Witten for helpful discussions on the subjects of the Capillary number and the mechanisms of eddy formation.", "abstract": "This paper reports an experimental characterization of a simple method for rapid formation of droplets, or plugs, of multiple aqueous reagents without bringing reagents into contact prior to mixing. Droplet-based microfluidics offers a simple method of achieving rapid mixing and transport with no dispersion. In addition, this paper shows that organic dyes at high concentrations should not be used for the visualization of flow patterns and mixing of aqueous plugs in multiphase flows in this system (fluorinated carrier fluid and PDMS microchannels). It reports an inorganic dye that can be used instead. This work focuses on mixing in plugs moving through straight channels. It demonstrates that, when traveling through straight microchannels, mixing within plugs by steady recirculating flow is highly sensitive to the initial distribution of the aqueous reagents established by the eddy flow at the tip of the forming plug (twirling). The results also show how plugs with proper distribution of the aqueous reagents could be formed in order to achieve optimal mixing of the reagents in this system.", "date": "2003-10-28", "date_type": "published", "publication": "Langmuir", "volume": "19", "number": "22", "publisher": "American Chemical Society", "pagerange": "9127-9133", "id_number": "CaltechAUTHORS:20130821-160734086", "issn": "0743-7463", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160734086", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Camille and Henry Dreyfus Foundation" }, { "agency": "Research Innovation Award from Research Corporation" }, { "agency": "NSF" }, { "agency": "NIH", "grant_number": "GM 08720" } ] }, "doi": "10.1021/la030090w", "resource_type": "article", "pub_year": "2003", "author_list": "Tice, Joshua D.; Song, Helen; et el." }, { "id": "https://authors.library.caltech.edu/records/vt9r8-5sp43", "eprint_id": 40893, "eprint_status": "archive", "datestamp": "2023-08-22 00:56:52", "lastmod": "2023-10-24 22:33:43", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Zheng-Bo", "name": { "family": "Zheng", "given": "Bo" }, "orcid": "0000-0001-8344-3445" }, { "id": "Roach-L-S", "name": { "family": "Roach", "given": "L. Spencer" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Screening of protein crystallization conditions on a microfluidic chip using nanoliter-size droplets", "ispublished": "pub", "full_text_status": "restricted", "keywords": "macromolecular crystallization; structural genomics; growth", "note": "Copyright \u00a9 2003 American Chemical Society. \n\nPublished In Issue: September 17, 2003. Received July 9, 2003. \n\nThis work was supported by the Searle Scholars Program and by the Beckman Young Investigator Program, and was performed at the MRSEC microfluidic facility funded by NSF. We thank Professors Keith Moffat, Phoebe Rice, and Chuan He for valuable suggestions, and we thank H. Song and J. Tice for experimental advice.", "abstract": "Protein crystallization is a major bottleneck in determining tertiary protein structures from genomic sequence data. This paper describes a microfluidic system for screening hundreds of protein crystallization conditions using less than 4 nL of protein solution for each crystallization droplet. The droplets are formed by mixing protein, precipitant, and additive stock solutions in variable ratios in a flow of water-immiscible fluids inside microchannels. Each droplet represents a discrete trial testing different conditions. The system has been validated by crystallization of several water-soluble proteins.", "date": "2003-09-17", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "125", "number": "37", "publisher": "American Chemical Society", "pagerange": "11170-11171", "id_number": "CaltechAUTHORS:20130821-160735877", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160735877", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Searle Scholars Program" }, { "agency": "Beckman Young Investigator award" }, { "agency": "NSF" } ] }, "doi": "10.1021/ja037166v", "resource_type": "article", "pub_year": "2003", "author_list": "Zheng, Bo; Roach, L. Spencer; et el." }, { "id": "https://authors.library.caltech.edu/records/g73kc-wpk51", "eprint_id": 40798, "eprint_status": "archive", "datestamp": "2023-08-19 12:01:00", "lastmod": "2023-10-24 22:00:12", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Integrated microfluidic systems", "ispublished": "pub", "full_text_status": "restricted", "keywords": "analytical methods, enzymes, microfluidics, microreactors, protein structures", "note": "Copyright \u00a9 2003 WILEY-VCH. \n\nOriginal figures were generously provided by Prof. Richard Crooks and by Prof. Stephen Quake. Support by ONR is gratefully acknowledged.", "abstract": "Microchips: Multistep reactions may be catalyzed by enzymes immobilized on microbeads trapped inside microfluidic channels. Large integrated microfluidic circuits can be created by using multilayer soft lithography in poly(dimethylsiloxane). These circuits (see schematic representation) can be used to perform hundreds of different reactions simultaneously, and can be applied to a range of problems, from enzymatic assays to crystallization of proteins.", "date": "2003-09-15", "date_type": "published", "publication": "Angewandte Chemie International Edition", "volume": "42", "number": "35", "publisher": "Wiley", "pagerange": "4130-4132", "id_number": "CaltechAUTHORS:20130821-160719583", "issn": "1433-7851", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160719583", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "ONR" } ] }, "doi": "10.1002/anie.200301660", "resource_type": "article", "pub_year": "2003", "author_list": "Ismagilov, Rustem F." }, { "id": "https://authors.library.caltech.edu/records/6gnkw-hmq18", "eprint_id": 40875, "eprint_status": "archive", "datestamp": "2023-08-22 00:30:06", "lastmod": "2023-10-24 22:32:18", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Stroock-A-D", "name": { "family": "Stroock", "given": "Abraham D." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Stone-H-A", "name": { "family": "Stone", "given": "Howard A." } }, { "id": "Whitesides-G-M", "name": { "family": "Whitesides", "given": "George M." }, "orcid": "0000-0001-9451-2442" } ] }, "title": "Fluidic Ratchet Based on Marangoni\u2212B\u00e9nard Convection", "ispublished": "pub", "full_text_status": "restricted", "keywords": "instability; equilibrium; competition", "note": "Copyright \u00a9 2003 American Chemical Society. \n\nPublished In Issue: May 13, 2003. Received August 12, 2002. Revised February 24, 2003. \n\nThe work in the laboratory of G.M.W. was supported by the Department of Energy (DE-FG02-OOER45852). The work of both G.M.W. and H.A.S. was supported by NSF MRSEC DMR-9809363 and DARPA.", "abstract": "A mean flow is observed experimentally in a layer of fluid undergoing Marangoni-Benard convection over a heated substrate that presents a pattern of asymmetrical grooves. The direction of the mean flow is a function of the temperature difference across the layer and of the thickness of the layer; the direction can be controlled by changing these parameters. This system acts as a fluidic ratchet: the local structure of the thermally driven convection interacts with the asymmetry of the local topographical pattern and causes a net, global flow in the fluid. This fluidic ratchet may be useful in handling fluids on macroscopic and microscopic scales.", "date": "2003-05-13", "date_type": "published", "publication": "Langmuir", "volume": "19", "number": "10", "publisher": "American Chemical Society", "pagerange": "4358-4362", "id_number": "CaltechAUTHORS:20130821-160732896", "issn": "0743-7463", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160732896", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Department of Energy (DOE)", "grant_number": "DE-FG02-OOER45852" }, { "agency": "NSF", "grant_number": "DMR-9809363" }, { "agency": "DARPA" } ] }, "doi": "10.1021/la026400c", "resource_type": "article", "pub_year": "2003", "author_list": "Stroock, Abraham D.; Ismagilov, Rustem F.; et el." }, { "id": "https://authors.library.caltech.edu/records/b1nsr-ck282", "eprint_id": 40874, "eprint_status": "archive", "datestamp": "2023-08-22 00:14:16", "lastmod": "2023-10-24 22:32:15", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Song-Helen", "name": { "family": "Song", "given": "Helen" } }, { "id": "Tice-J-D", "name": { "family": "Tice", "given": "Joshua D." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "A Microfluidic System for Controlling Reaction Networks in Time", "ispublished": "pub", "full_text_status": "restricted", "keywords": "analytical methods; kinetics; microfluidics; microreactors; reaction networks cavity flows; scaling laws; microchannels; device; operations; pressure", "note": "\u00a9 2002 WILEY-VCH. \n\nIssue published online: 17 FEB 2003. Article first published online: 17 FEB 2003. Manuscript Received: 6 SEP 2002. \n\nThis work was supported by the Camille and Henry Dreyfus New Faculty Award Program, the Searle Scholars Program, an award from Research Corporation, the Chicago MRSEC funded by the NSF. H.S. was supported by a Predoctoral Training Grant of the NIH (GM\u200908720). We thank our colleagues at the University of Chicago for invaluable discussions and suggestions. We thank Prof. Sidney Nagel, in addition, for an equipment loan and Ian Hawkins for measuring surface tensions. Photolithography was performed by H.S. at MAL of the University of Illinois at Chicago. Microscopy was conducted at the University of Chicago Cancer Center Digital Light Microscopy Facility.", "abstract": "Millisecond mixing and transport with no dispersion are achieved by unsteady flows induced in droplets of about 60 pL that travel through winding microfluidic channels (top). Fluorescence can be used to monitor mixing (bottom) or measure reaction rates. In principle, arbitrarily complex reaction networks can be created by combining and splitting streams of such droplets.", "date": "2003-02-17", "date_type": "published", "publication": "Angewandte Chemie International Edition", "volume": "42", "number": "7", "publisher": "Wiley", "pagerange": "768-772", "id_number": "CaltechAUTHORS:20130821-160732735", "issn": "1433-7851", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160732735", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Camille and Henry Dreyfus Foundation" }, { "agency": "Searle Scholars Program" }, { "agency": "Research Corporation" }, { "agency": "NSF" }, { "agency": "NIH", "grant_number": "GM\u200908720" } ] }, "doi": "10.1002/anie.200390203", "resource_type": "article", "pub_year": "2003", "author_list": "Song, Helen; Tice, Joshua D.; et el." }, { "id": "https://authors.library.caltech.edu/records/7m9bq-gfk14", "eprint_id": 40870, "eprint_status": "archive", "datestamp": "2023-08-22 00:00:32", "lastmod": "2023-10-24 22:31:51", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Song-Helen", "name": { "family": "Song", "given": "Helen" } }, { "id": "Bringer-Michelle-R", "name": { "family": "Bringer", "given": "Michelle R." } }, { "id": "Tice-Joshua-D", "name": { "family": "Tice", "given": "Joshua D." } }, { "id": "Gerdts-Cory-J", "name": { "family": "Gerdts", "given": "Cory J." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Experimental test of scaling of mixing by chaotic advection in droplets moving through microfluidic channels", "ispublished": "pub", "full_text_status": "public", "keywords": "microchannels; flows; mixing, diffusion, chaos, scaling phenomena, microfluidics, channel flow, drops", "note": "\u00a9 2003 American Institute of Physics. \n\nReceived 11 July 2003; accepted 6 October 2003. \n\nThis work was supported by ONR Young Investigator Award (N00014-03-10482), the Camille and Henry Dreyfus New Faculty Award, the Research Innovation Award from Research Corporation, the NIH (R01 EB001903), Chicago MRSEC funded by NSF, and Predoctoral Training Grant (H.S.) of the NIH (GM 08720). This work was performed at the Chicago MRSEC Microfluidic Facility. Photolithography was performed (by H.S.) at MAL of UIC. We thank Prof. H. A. Stone, Prof. A. D. Stroock, and Prof. J. M. Ottino for helpful discussions.\n\nPublished - Ismagilov_APL_2003_83_4664_Song_Experimental_Test_Scaling_Chaotic_Mixing_Droplets.pdf
Accepted Version - nihms14599.pdf
", "abstract": "This letter describes an experimental test of a simple argument that predicts the scaling of chaotic mixing in a droplet moving through a winding microfluidic channel. Previously, scaling arguments for chaotic mixing have been described for a flow that reduces striation length by stretching, folding, and reorienting the fluid in a manner similar to that of the baker's transformation. The experimentally observed flow patterns within droplets (or plugs) resembled the baker's transformation. Therefore, the ideas described in the literature could be applied to mixing in droplets to obtain the scaling argument for the dependence of the mixing time, t \u223c (aw/U)log(Pe), where w [m] is the cross-sectional dimension of the microchannel, a is the dimensionless length of the plug measured relative to w, U [m\u200as^\u22121] is the flow velocity, Pe is the P\u00e9clet number (Pe = wU/D), and D [m^2\u200as^\u22121] is the diffusion coefficient of the reagent being mixed. Experiments were performed to confirm the scaling argument by varying the parameters w, U, and D. Under favorable conditions, submillisecond mixing has been demonstrated in this system.", "date": "2003", "date_type": "published", "publication": "Applied Physics Letters", "volume": "83", "number": "22", "publisher": "American Institute of Physics", "pagerange": "4664-4666", "id_number": "CaltechAUTHORS:20130821-160731877", "issn": "0003-6951", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160731877", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Office of Naval Research (ONR)", "grant_number": "N00014-03-10482" }, { "agency": "Camille and Henry Dreyfus Foundation" }, { "agency": "Research Corporation" }, { "agency": "NIH", "grant_number": "R01 EB001903" }, { "agency": "NSF" }, { "agency": "NIH", "grant_number": "GM 08720" } ] }, "doi": "10.1063/1.1630378", "pmcid": "PMC2025702", "primary_object": { "basename": "Ismagilov_APL_2003_83_4664_Song_Experimental_Test_Scaling_Chaotic_Mixing_Droplets.pdf", "url": "https://authors.library.caltech.edu/records/7m9bq-gfk14/files/Ismagilov_APL_2003_83_4664_Song_Experimental_Test_Scaling_Chaotic_Mixing_Droplets.pdf" }, "related_objects": [ { "basename": "nihms14599.pdf", "url": "https://authors.library.caltech.edu/records/7m9bq-gfk14/files/nihms14599.pdf" } ], "resource_type": "article", "pub_year": "2003", "author_list": "Song, Helen; Bringer, Michelle R.; et el." }, { "id": "https://authors.library.caltech.edu/records/hpe9w-e2462", "eprint_id": 40803, "eprint_status": "archive", "datestamp": "2023-08-21 23:03:22", "lastmod": "2023-10-24 22:00:32", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Schwartz-A", "name": { "family": "Schwartz", "given": "Alexander" } }, { "id": "Bowden-N", "name": { "family": "Bowden", "given": "Ned" } }, { "id": "Whitesides-G-M", "name": { "family": "Whitesides", "given": "George M." }, "orcid": "0000-0001-9451-2442" } ] }, "title": "Autonomous movement and self-assembly", "ispublished": "pub", "full_text_status": "restricted", "keywords": "microfluidic systems; molecular motors; polymer gels; motion; complexity; patterns; water; atp", "note": "\u00a9 2002 WILEY-VCH. \n\nIssue published online: 14 FEB 2002. Article first published online: 14 FEB 2002. Manuscript Received: 22 NOV 2001 .\n\nThis work was supported by DoE under grant 00ER45852. The salary of R.F.I. was provided by the DARPA and NSF under grant NSF ECS-9729405; the salary of A.S. was provided by the NSF under grant NSF CHE-9901358.", "abstract": "The artificial millimeter-scale \"autonomous movers\" glide across the surface of a liquid without an external power source. This system is based on a combination of two processes: Motion of individual objects powered by the catalytic decomposition of hydrogen peroxide, and relative motion (self-assembly) caused by capillary interactions at the fluid/air interface. The picture shows the rotational/translational motion of a single object; the motion of a pair of these object depends on their chirality.", "date": "2002-02-15", "date_type": "published", "publication": "Angewandte Chemie International Edition", "volume": "41", "number": "4", "publisher": "Wiley", "pagerange": "652-654", "id_number": "CaltechAUTHORS:20130821-160720419", "issn": "1433-7851", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160720419", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Department of Energy (DOE)", "grant_number": "00ER45852" }, { "agency": "DARPA" }, { "agency": "NSF", "grant_number": "ECS-9729405" }, { "agency": "NSF", "grant_number": "CHE-9901358" } ] }, "doi": "10.1002/1521-3773(20020215)41:4<652::AID-ANIE652>3.0.CO;2-U", "resource_type": "article", "pub_year": "2002", "author_list": "Ismagilov, Rustem F.; Schwartz, Alexander; et el." }, { "id": "https://authors.library.caltech.edu/records/fmpcf-bej39", "eprint_id": 40800, "eprint_status": "archive", "datestamp": "2023-08-21 22:42:08", "lastmod": "2023-10-24 22:00:19", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Ng-Jessamine-M-K", "name": { "family": "Ng", "given": "Jessamine M. K." } }, { "id": "Kenis-P-J-A", "name": { "family": "Kenis", "given": "Paul J. A." } }, { "id": "Whitesides-G-M", "name": { "family": "Whitesides", "given": "George M." }, "orcid": "0000-0001-9451-2442" } ] }, "title": "Microfluidic arrays of fluid-fluid diffusional contacts as detection elements and combinatorial tools", "ispublished": "pub", "full_text_status": "restricted", "keywords": "western blots; proteins; systems; fabrication; cells; flows; pdms", "note": "Copyright \u00a9 2001 American Chemical Society. \n\nPublished In Issue: November 01, 2001. Received for review May 2, 2001. Accepted July 24, 2001.\n\nThis work was supported by DARPA and NSF (ECS-0004030). We thank Steve Metallo (Harvard University) for helpful discussions.", "abstract": "This paper describes microfluidic systems that can be used to investigate multiple chemical or biochemical interactions in a parallel format. These three-dimensional systems are generated by crossing two sets of microfluidic channels, fabricated in two different layers, at tight angles. Solutions of the reagents are placed in the channels; in different modes of operation, these solutions can be either flowing or stationary- the latter is important when one set of channels is filled with viscous gels with immobilized reagents. At every crossing, the channels are separated either by a single membrane or by a composite separator comprising a membrane, a microwell, and a second membrane. These components allow diffusive mass transport and minimize convective transport through the crossing. Polycarbonate membranes with 0.1-1-mum vertical pores were used to fabricate the devices. Each crossing of parallel channels serves as an element in which chemical or biochemical interactions can take place; interactions can be detected by monitoring changes in fluorescence and absorbance. These all- organic systems are straightforward to fabricate and to operate and may find applications as portable microanalytical systems and as tools in combinatorial research.", "date": "2001-11-01", "date_type": "published", "publication": "Analytical Chemistry", "volume": "73", "number": "21", "publisher": "American Chemical Society", "pagerange": "5207-5213", "id_number": "CaltechAUTHORS:20130821-160719890", "issn": "0003-2700", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160719890", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "DARPA" }, { "agency": "NSF", "grant_number": "ECS-0004030" } ] }, "doi": "10.1021/ac010502a", "resource_type": "article", "pub_year": "2001", "author_list": "Ismagilov, Rustem F.; Ng, Jessamine M. K.; et el." }, { "id": "https://authors.library.caltech.edu/records/warvr-y6x22", "eprint_id": 40802, "eprint_status": "archive", "datestamp": "2023-08-21 22:36:54", "lastmod": "2023-10-24 22:00:30", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Rosmarin-D", "name": { "family": "Rosmarin", "given": "David" } }, { "id": "Kenis-P-J-A", "name": { "family": "Kenis", "given": "Paul J. A." } }, { "id": "Chiu-Daniel-T", "name": { "family": "Chiu", "given": "Daniel T." } }, { "id": "Zhang-Wendy", "name": { "family": "Zhang", "given": "Wendy" } }, { "id": "Stone-H-A", "name": { "family": "Stone", "given": "Howard A." } }, { "id": "Whitesides-G-M", "name": { "family": "Whitesides", "given": "George M." }, "orcid": "0000-0001-9451-2442" } ] }, "title": "Pressure-driven laminar flow in tangential microchannels: an elastomeric microfluidic switch", "ispublished": "pub", "full_text_status": "restricted", "keywords": "systems; fabrication; poly(dimethylsiloxane); networks; pdms", "note": "Copyright \u00a9 2001 American Chemical Society. \n\nPublished In Issue: October 01, 2001. Received for review April 2, 2001. Accepted July 8, 2001. \n\nThis work was supported by DARPA and NSF ECS-0004030 and ECS-9729405. We thank Jacqueline Ashmore (Harvard) for helpful discussions.", "abstract": "This paper describes laminar fluid flow through a three- dimensional elastomeric microstructure formed by two microfluidic channels, fabricated in layers that contact one another face-to-face (typically at a 90 degrees angle), with the fluid flows in tangential contact. There are two ways to control fluid flow through these tangentially connected microchannels. First, the flow profiles through the crossings are sensitive to the aspect ratio of the channels; the flow can be controlled by applying external pressure and changing this aspect ratio. Second, the flow direction of an individual laminar stream in multiphase laminar flow depends on the lateral position of the stream within the channel; this position can be controlled by injecting additional streams of fluid into the channel. We describe two microfluidic switches based on these two ways for controlling fluid flow through tangential microchannels and present theoretical arguments that explain the observed dependence of the flow profiles on the aspect ratio of the channels.", "date": "2001-10-01", "date_type": "published", "publication": "Analytical Chemistry", "volume": "73", "number": "19", "publisher": "American Chemical Society", "pagerange": "4682-4687", "id_number": "CaltechAUTHORS:20130821-160720235", "issn": "0003-2700", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160720235", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "DARPA" }, { "agency": "NSF", "grant_number": "ECS-0004030" }, { "agency": "NSF", "grant_number": "ECS-9729405" } ] }, "doi": "10.1021/ac010374q", "resource_type": "article", "pub_year": "2001", "author_list": "Ismagilov, Rustem F.; Rosmarin, David; et el." }, { "id": "https://authors.library.caltech.edu/records/2vtmg-1y153", "eprint_id": 40801, "eprint_status": "archive", "datestamp": "2023-08-21 22:26:41", "lastmod": "2023-10-24 22:00:24", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Rosmarin-D", "name": { "family": "Rosmarin", "given": "David" } }, { "id": "Gracias-D-H", "name": { "family": "Gracias", "given": "David H." } }, { "id": "Stroock-A-D", "name": { "family": "Stroock", "given": "Abraham D." } }, { "id": "Whitesides-G-M", "name": { "family": "Whitesides", "given": "George M." }, "orcid": "0000-0001-9451-2442" } ] }, "title": "Competition of intrinsic and topographically imposed patterns in Benard-Marangoni convection", "ispublished": "pub", "full_text_status": "public", "keywords": "commensurate; equilibrium; systems; layers; Benard convection, flow visualisation, infrared imaging, periodic structures", "note": "\u00a9 2001 American Institute of Physics. \n\n(Received 15 March 2001; accepted 18 May 2001) \n\nThis work was supported by DoE under Grant No. 00ER45852. The authors thank Howard Stone (Harvard) for many valuable discussions, and Allen Frechette and Kellie Reardon (FLIR Systems), and John Boucher (Harvard University) for technical assistance with IR imaging and for providing the IR camera used in this work.\n\nPublished - ApplPhysLett_79_439.pdf
", "abstract": "The structure of Benard-Marangoni convection cells can be controlled by periodic topographic patterns on the heated surface that generates the convection. When the periodicity of the topographic pattern matches the intrinsic periodicity of the convection cells, a convective pattern is formed that is 1:1 commensurate with the topographic pattern. Arrays of hexagonal, square, and triangular convection cells were generated over the appropriately designed topographic patterns, and visualized by infrared imaging. For imposed patterns with periodicity in two dimensions, as the ratio of the intrinsic and perturbing length scales changes, the pattern of the convection cells shows sharp transitions between different patterns commensurate with the imposed pattern. For imposed patterns with periodicity in one dimension (i.e., lines) the convection cells use the unconstrained dimension to adapt continuously to the external perturbation. Topographically controlled convection cells can be used to assemble microscopic particles into externally switchable regular lattices. (C) 2001 American Institute of Physics.", "date": "2001-07-16", "date_type": "published", "publication": "Applied Physics Letters", "volume": "79", "number": "3", "publisher": "American Institute of Physics", "pagerange": "439-441", "id_number": "CaltechAUTHORS:20130821-160720076", "issn": "0003-6951", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160720076", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Department of Energy (DOE)", "grant_number": "00ER45852" } ] }, "doi": "10.1063/1.1384473", "primary_object": { "basename": "ApplPhysLett_79_439.pdf", "url": "https://authors.library.caltech.edu/records/2vtmg-1y153/files/ApplPhysLett_79_439.pdf" }, "resource_type": "article", "pub_year": "2001", "author_list": "Ismagilov, Rustem F.; Rosmarin, David; et el." }, { "id": "https://authors.library.caltech.edu/records/pp34s-cre17", "eprint_id": 40851, "eprint_status": "archive", "datestamp": "2023-08-21 22:21:03", "lastmod": "2023-10-24 22:30:32", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Nelsen-S-F", "name": { "family": "Nelsen", "given": "Stephen F." } }, { "id": "Trieber-D-A-II", "name": { "family": "Trieber", "given": "Dwight A., II" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Teki-Y", "name": { "family": "Teki", "given": "Yoshio" } } ] }, "title": "Solvent effects on charge transfer bands of nitrogen-centered intervalence compounds", "ispublished": "pub", "full_text_status": "public", "keywords": "electron-transfer-reactions; ruthenium ammine complexes; coupling matrix-elements; transfer rate constants; reorganization energy; radical cations; mulliken-hush; polar liquids; exchange; temperature", "note": "Copyright \u00a9 2001 American Chemical Society. \n\nPublished In Issue: June 20, 2001. Received September 19, 2000. Revised Manuscript Received February 6, 2001. \n\nWe thank the National Science Foundation (Grants CHE-9417946 and CHE-9988727) and the Research Corporation (Grant RA0269) for partial financial support of this research.\n\nSupporting Information Available: Tables of solvent parameters employed, cyclic voltammetric data, and variable temperature optical data. This material is available free of charge via the Internet at http://pubs.acs.org.\n\nSupplemental Material - ja003436n_s.pdf
", "abstract": "Electron transfer parameters are extracted from the optical spectra of intervalence bis(hydrazine) radical cations. Compounds with 2-tert-butyl-3-phenyl-2,3-diazabicyclo[2.2.2]octyl-containing charge-bearing units that are doubly linked by 4-\u03c3-bond and by 6-\u03c3-bond saturated bridges are compared with ones having tert-butylisopropyl- and diphenyl-substituted charge bearing units and others having the aromatic units functioning as the bridge. Solvent effect studies show that the optical transition energy (E_(op)) does not behave as dielectric continuum theory predicts but that solvent reorganization energy may be usefully separated from the vibrational reorganization energy by including linear terms in both the Pekar factor (\u03b3) and the Gutmann donor number (DN) in correlating the solvent effect. Solvation of the bridge for these compounds is too large to ignore, which makes dielectric continuum theory fail to properly predict solvent effects on either E_(op) or the free energy for comproportionation.", "date": "2001-06-20", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "123", "number": "24", "publisher": "American Chemical Society", "pagerange": "5684-5694", "id_number": "CaltechAUTHORS:20130821-160728530", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160728530", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF", "grant_number": "CHE-9417946" }, { "agency": "NSF", "grant_number": "CHE-9988727" }, { "agency": "Research Corporation", "grant_number": "RA0269" } ] }, "doi": "10.1021/ja003436n", "primary_object": { "basename": "ja003436n_s.pdf", "url": "https://authors.library.caltech.edu/records/pp34s-cre17/files/ja003436n_s.pdf" }, "resource_type": "article", "pub_year": "2001", "author_list": "Nelsen, Stephen F.; Trieber, Dwight A., II; et el." }, { "id": "https://authors.library.caltech.edu/records/b1ede-7p147", "eprint_id": 40794, "eprint_status": "archive", "datestamp": "2023-08-21 22:20:44", "lastmod": "2023-10-24 21:59:53", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Holmlin-R-E", "name": { "family": "Holmlin", "given": "R. Erik" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Haag-R", "name": { "family": "Haag", "given": "Rainer" } }, { "id": "Mujica-V", "name": { "family": "Mujica", "given": "Vladimiro" } }, { "id": "Ratner-M-A", "name": { "family": "Ratner", "given": "Mark A." } }, { "id": "Rampi-M-A", "name": { "family": "Rampi", "given": "Maria Anita" } }, { "id": "Whitesides-G-M", "name": { "family": "Whitesides", "given": "George M." }, "orcid": "0000-0001-9451-2442" } ] }, "title": "Correlating electron transport and molecular structure in organic thin films", "ispublished": "pub", "full_text_status": "restricted", "keywords": "electron transfer; monolayers; self assembly; thin films self-assembled monolayers; alkanethiol monolayers; gold; conductance; spectra; bond", "note": "\u00a9 2001 WILEY-VCH. \n\nArticle first published online: 13 JUN 2001.\n\nThis work was supported by the Office of Naval Research, the Defense Advanced Research Project Agency, and the National Science Foundation ECS-97294053. R.E.H. thanks the National Institutes of Health for a postdoctoral fellowship, and R.H. thanks the Deutsche Forschungsgemeinschaft and the BASF fellowship program for financial support. We thank Andreas Terfort for the synthesis of aromatic thiols. Collaboration between Caracas and Evanston is supported by NSF Conicit.", "abstract": "A convenient experimental system is described, with which electron transport through structurally well-defined, 2\u20135 nm-thick, organic films can be examined. Two types of junction J have been studied in which self-assembled monolayers (SAMs, for example, SAM(1) formed on Ag from aliphatic and aromatic thiols, and SAM(2), formed on Hg from hexadecanethiol) are in contact through either van der Waals interactions (see picture) or through covalent, hydrogen, or ionic bonds.", "date": "2001-06-18", "date_type": "published", "publication": "Angewandte Chemie International Edition", "volume": "40", "number": "12", "publisher": "Wiley", "pagerange": "2316-2320", "id_number": "CaltechAUTHORS:20130821-160718857", "issn": "1433-7851", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160718857", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Office of Naval Research (ONR)" }, { "agency": "Defense Advanced Research Projects Agency (DARPA)" }, { "agency": "NSF", "grant_number": "ECS-97294053" }, { "agency": "NIH" }, { "agency": "Deutsche Forschungsgemeinschaft (DFG)" }, { "agency": "BASF" }, { "agency": "NSF Conicit" } ] }, "doi": "10.1002/1521-3773(20010618)40:12<2316::AID-ANIE2316>3.0.CO;2-#", "resource_type": "article", "pub_year": "2001", "author_list": "Holmlin, R. Erik; Ismagilov, Rustem F.; et el." }, { "id": "https://authors.library.caltech.edu/records/wwktg-f5w34", "eprint_id": 40793, "eprint_status": "archive", "datestamp": "2023-08-21 22:16:26", "lastmod": "2023-10-23 15:51:39", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Holmlin-R-E", "name": { "family": "Holmlin", "given": "R. Erik" } }, { "id": "Haag-R", "name": { "family": "Haag", "given": "Rainer" } }, { "id": "Chabinyc-M-L", "name": { "family": "Chabinyc", "given": "Michael L." }, "orcid": "0000-0003-4641-3508" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Cohen-A-E", "name": { "family": "Cohen", "given": "Adam E." } }, { "id": "Terfort-A", "name": { "family": "Terfort", "given": "Andreas" } }, { "id": "Rampi-M-A", "name": { "family": "Rampi", "given": "Maria Anita" } }, { "id": "Whitesides-G-M", "name": { "family": "Whitesides", "given": "George M." }, "orcid": "0000-0001-9451-2442" } ] }, "title": "Electron transport through thin organic films in metal- insulator-metal junctions based on self-assembled monolayers", "ispublished": "pub", "full_text_status": "public", "keywords": "molecular wires; alkanethiol monolayers; biological molecules; distance dependence; free-energy; rhodobacter-sphaeroides; charge-transport; reaction centers; pathway analysis; transfer rates", "note": "Copyright \u00a9 2001 American Chemical Society.\n\nPublished In Issue: May 30, 2001. Received November 22, 2000.\n\nThis work was supported by the ONR, DARPA, and the NSF (ECS-9729405). R.E.H. and M.L.C. thank the National Institutes of Health for postdoctoral fellowships and R.H. thanks the Deutsche Forschungsgemeinschaft and the BASF-fellowship program for financial support.\n\nSupporting Information Available\nExperimental details of control experiments, plots of current\u2212voltage data, and a detailed discussion of the statistical analysis of the data (PDF). This material is available free of charge via the Internet at http://pubs.acs.org.\n\nThe affiliation listed for Dr. Andreas Terfort should have been the following:\u2009 Institute for Inorganic and Applied Chemistry, University of Hamburg, 20146, Hamburg, Germany. The compounds supplied by Dr. Terfort and used in this paper were synthesized at Hamburg. 06/21/2002\n\nSupplemental Material - ja004055c_s.pdf
", "abstract": "This paper describes an experimentally simple system for measuring rates of electron transport across organic thin films having a range of molecular structures. The system uses a metal\u2212insulator\u2212metal junction based on self-assembled monolayers (SAMs); it is particularly easy to assemble. The junction consists of a SAM supported on a silver film (Ag-SAM(1)) in contact with a second SAM supported on the surface of a drop of mercury (Hg-SAM(2))that is, a Ag-SAM(1)SAM(2)-Hg junction. SAM(1) and SAM(2) can be derived from the same or different thiols. The current that flowed across junctions with SAMs of aliphatic thiols or aromatic thiols on Ag and a SAM of hexadecane thiol on Hg depended both on the molecular structure and on the thickness of the SAM on Ag:\u2009 the current density at a bias of 0.5 V ranged from 2 \u00d7 10^-10 A/cm^2 for HS(CH_2)_15CH_3 on Ag to 1 \u00d7 10^-6 A/cm^2 for HS(CH_2)_7CH_3 on Ag, and from 3 \u00d7 10^-6 A/cm^2 for HS(Ph)_3H (Ph = 1,4-C_6H4_) on Ag to 7 \u00d7 10^-4 A/cm^2 for HSPhH on Ag. The current density increased roughly linearly with the area of contact between SAM(1) and SAM(2), and it was not different between Ag films that were 100 or 200 nm thick. The current\u2212voltage curves were symmetrical around V = 0. The current density decreased with increasing distance between the electrodes according to the relation I = I0e-\u03b2dAg,Hg, where dAg,Hg is the distance between the electrodes, and \u03b2 is the structure-dependent attenuation factor for the molecules making up SAM(1). At an applied potential of 0.5 V, \u03b2 was 0.87 \u00b1 0.1 \u00c5-1 for alkanethiols, 0.61 \u00b1 0.1 \u00c5-1 for oligophenylene thiols, and 0.67 \u00b1 0.1 \u00c5-1 for benzylic derivatives of oligophenylene thiols. The values of \u03b2 did not depend significantly on applied potential over the range of 0.1 to 1 V. These junctions provide a test bed with which to screen the intrinsic electrical properties of SAMs made up of molecules with different structures; information obtained using these junctions will be useful in correlating molecular structure and rates of electron transport.", "date": "2001-05-30", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "123", "number": "21", "publisher": "American Chemical Society", "pagerange": "5075-5085", "id_number": "CaltechAUTHORS:20130821-160718693", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160718693", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Office of Naval Research (ONR)" }, { "agency": "Defense Advanced Research Projects Agency (DARPA)" }, { "agency": "NSF", "grant_number": "ECS-9729405" }, { "agency": "NIH" }, { "agency": "Deutsche Forschungsgemeinschaft (DFG)" }, { "agency": "BASF" } ] }, "doi": "10.1021/ja004055c", "primary_object": { "basename": "ja004055c_s.pdf", "url": "https://authors.library.caltech.edu/records/wwktg-f5w34/files/ja004055c_s.pdf" }, "resource_type": "article", "pub_year": "2001", "author_list": "Holmlin, R. Erik; Haag, Rainer; et el." }, { "id": "https://authors.library.caltech.edu/records/vkf5k-mvj68", "eprint_id": 40811, "eprint_status": "archive", "datestamp": "2023-08-21 21:47:18", "lastmod": "2023-10-24 22:01:09", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Kenis-P-J-A", "name": { "family": "Kenis", "given": "Paul J. A." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Takayama-Shuichi", "name": { "family": "Takayama", "given": "Shuichi" } }, { "id": "Whitesides-G-M", "name": { "family": "Whitesides", "given": "George M." }, "orcid": "0000-0001-9451-2442" }, { "id": "Li-Shulong", "name": { "family": "Li", "given": "Shulong" } }, { "id": "White-H-S", "name": { "family": "White", "given": "Henry S." } } ] }, "title": "Fabrication inside microchannels using fluid flow", "ispublished": "pub", "full_text_status": "restricted", "keywords": "capillary-electrophoresis; fractionation; networks; fiber; cells", "note": "Copyright \u00a9 2000 American Chemical Society. \n\nPublished In Issue: December 19, 2000. Received April 18, 2000. \n\nThe work at Harvard was supported financially by DARPA through NSF Grant ECS-97294505, and MRSEC-shared facilities supported by the NSF under Grant NSF DMR-9809363 were used. Work at the University of Utah was supported by the Office of Naval Research. P.J.A.K. acknowledges the Netherlands Organization for Scientific Research (NWO) for a postdoctoral fellowship. S.T. thanks the Leukemia and Lymphoma Society for a postdoctoral fellowship.", "abstract": "This Account summarizes techniques for carrying out microfabrication of structures with dimensions down to 10 mum in microchannels that are 0.02-2 mm wide. These methods are largely based on the exploitation of laminar flow at low Reynolds number (Re) to control the spatial delivery of reagents. These methods are illustrated by fabrication of fibers, microelectrode arrays, arrays of crystals, and patterns of proteins and cells.", "date": "2000-12-19", "date_type": "published", "publication": "Accounts of Chemical Research", "volume": "33", "number": "12", "publisher": "American Chemical Society", "pagerange": "841-847", "id_number": "CaltechAUTHORS:20130821-160721858", "issn": "0001-4842", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160721858", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "DARPA" }, { "agency": "NSF", "grant_number": "ECS-97294505" }, { "agency": "NSF", "grant_number": "DMR-9809363" }, { "agency": "Office of Naval Research" }, { "agency": "Netherlands Organization for Scientific Research (NWO)" }, { "agency": "Leukemia and Lymphoma Society" } ] }, "doi": "10.1021/ar000062u", "resource_type": "article", "pub_year": "2000", "author_list": "Kenis, Paul J. A.; Ismagilov, Rustem F.; et el." }, { "id": "https://authors.library.caltech.edu/records/ydewe-tsv40", "eprint_id": 40796, "eprint_status": "archive", "datestamp": "2023-08-21 21:12:32", "lastmod": "2023-10-24 22:00:00", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Hong-Sun-Hee", "name": { "family": "Hong", "given": "Sun Hee" } }, { "id": "Evans-D-H", "name": { "family": "Evans", "given": "Dennis H." } }, { "id": "Nelsen-S-F", "name": { "family": "Nelsen", "given": "Stephen F." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Evidence for a two-step electron-transfer process in the electrode reactions of tetraisopropylhydrazine, tetracyclohexylhydrazine and their radical cation salts", "ispublished": "pub", "full_text_status": "restricted", "keywords": "electron-transfer process; tetraisopropylhydrazine; tetracyclohexylhydrazine cyclic voltammetry; hydrazines; tetraalkylhydrazines; oxidation", "note": "Copyright \u00a9 2000 Elsevier. \n\nThis work was supported by the National Science Foundation, Grant CHE-9704211 (DHE) and in part by Grant CHE-9417546 (SFN).", "abstract": "The heterogeneous electron-transfer kinetics of tetraisopropylhydrazine (4), tetraisopropylhydrazine radical cation hexafluoroantimonate (4+radical dot SbF_6^\u2212), tetracyclohexylhydrazine (5) and tetracyclohexylhydrazine radical cation hexafluoroantimonate (5+radical dot SbF_6^\u2212) have been studied by cyclic voltammetry at a gold working electrode in acetonitrile containing 0.10 M tetrabutylammonium hexafluorophosphate. Results were obtained at eight scan rates between 0.2 and 40 V s^\u22121 and six temperatures ranging from \u221215 to 50\u00b0C. The results were analyzed according to two models: (1) A direct, one-step electron transfer in which structural change and electron transfer are concerted. (2) A two-step process in which structural change is considered as a separate chemical reaction that precedes or follows the electron-transfer event. Specifically, a square scheme is proposed in which the favored untwisted radical cation can convert to a twisted version, which then receives an electron to form the favored twisted neutral hydrazine. Also, the favored twisted neutral can convert to an untwisted version, which can give up an electron to form the favored untwisted radical cation, thus completing the square. It was found that the one-step model was unable to account for the voltammetric data. On the other hand, analysis by the two-step mechanism produced substantially better agreement between simulation and experiment, particularly for 4 and 4+radical dot SbF_6^\u2212. The present experiments provide the first evidence that two-step electron transfer reactions occur with acyclic tetraalkylhydrazines.", "date": "2000-05-22", "date_type": "published", "publication": "Journal of Electroanalytical Chemistry", "volume": "486", "number": "1", "publisher": "Elsevier", "pagerange": "75-84", "id_number": "CaltechAUTHORS:20130821-160719216", "issn": "0022-0728", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160719216", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF", "grant_number": "CHE-9704211" }, { "agency": "NSF", "grant_number": "CHE-9417546" } ] }, "doi": "10.1016/S0022-0728(00)00137-6", "resource_type": "article", "pub_year": "2000", "author_list": "Hong, Sun Hee; Evans, Dennis H.; et el." }, { "id": "https://authors.library.caltech.edu/records/w6fvd-m9p56", "eprint_id": 40876, "eprint_status": "archive", "datestamp": "2023-08-21 21:05:10", "lastmod": "2023-10-23 15:49:40", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Stroock-A-D", "name": { "family": "Stroock", "given": "Abraham D." } }, { "id": "Weck-M", "name": { "family": "Weck", "given": "Marcus" } }, { "id": "Chiu-Daniel-T", "name": { "family": "Chiu", "given": "Daniel T." } }, { "id": "Huck-W-T-S", "name": { "family": "Huck", "given": "Wilhelm T. S." } }, { "id": "Kenis-P-J-A", "name": { "family": "Kenis", "given": "Paul J. A." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Whitesides-G-M", "name": { "family": "Whitesides", "given": "George M." }, "orcid": "0000-0001-9451-2442" } ] }, "title": "Patterning electro-osmotic flow with patterned surface charge", "ispublished": "pub", "full_text_status": "public", "keywords": "elctroosmosis; particles", "note": "\u00a9 2000 The American Physical Society. \n\nReceived 2 November 1999; published in the issue dated 10 April 2000. \n\nWe are grateful to Professor A. Ajdari (Ecole Sup\u00e9rieure\nde Physique et Chimie Industrielles de Paris) and Professor H. Stone (DEAS, Harvard University) for helpful\ndiscussions. This work was supported by DARPA: NSF\nECS-9729405, NIH: GM51559, and NSF: DMR-9809363\nMRSEC. A. D. S. was supported by NIH Molecular Biophysics Training Grant No. 5T32GM08313-10. M. W. was\nsupported by the German Academic Exchange Service\n(DAAD). P. J. A. K. was supported by Netherlands Organization for Scientific Research (NWO).\n\nPublished - PhysRevLett.84.3314.pdf
Erratum - PhysRevLett.86.6050.pdf
", "abstract": "This Letter reports the measurement of electro-osmotic flows (EOF) in microchannels with surface charge patterned on the 200 mu m scale. We have investigated two classes of patterns: (1) Those in which the surface charge varies along a direction perpendicular to the electric field used to drive the EOF; this type of pattern generates multidirectional flow along the direction of the field. (2) Those in which the surface charge pattern varies parallel to the field; this pattern generates recirculating cellular flew, and thus causes motion both parallel and perpendicular to the external field. Measurements of both of these flours agree well with theory in the Limit of thin double layers and low surface potential.", "date": "2000-04-10", "date_type": "published", "publication": "Physical Review Letters", "volume": "84", "number": "15", "publisher": "American Physical Society", "pagerange": "3314-3317", "id_number": "CaltechAUTHORS:20130821-160733045", "issn": "0031-9007", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160733045", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "DARPA" }, { "agency": "NSF", "grant_number": "ECS-9729405" }, { "agency": "NIH", "grant_number": "GM51559" }, { "agency": "NSF", "grant_number": "DMR-9809363" }, { "agency": "NIH", "grant_number": "5T32GM08313-10" }, { "agency": "German Academic Exchange Service (DAAD)" }, { "agency": "Netherlands Organization for Scientific Research (NWO)" } ] }, "doi": "10.1103/PhysRevLett.84.3314", "primary_object": { "basename": "PhysRevLett.84.3314.pdf", "url": "https://authors.library.caltech.edu/records/w6fvd-m9p56/files/PhysRevLett.84.3314.pdf" }, "related_objects": [ { "basename": "PhysRevLett.86.6050.pdf", "url": "https://authors.library.caltech.edu/records/w6fvd-m9p56/files/PhysRevLett.86.6050.pdf" } ], "resource_type": "article", "pub_year": "2000", "author_list": "Stroock, Abraham D.; Weck, Marcus; et el." }, { "id": "https://authors.library.caltech.edu/records/z555n-g6v03", "eprint_id": 40788, "eprint_status": "archive", "datestamp": "2023-08-21 20:55:56", "lastmod": "2023-10-24 21:59:30", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Deng-Tao", "name": { "family": "Deng", "given": "Tao" } }, { "id": "Arias-F", "name": { "family": "Arias", "given": "Francisco" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Kenis-P-J-A", "name": { "family": "Kenis", "given": "Paul J. A." } }, { "id": "Whitesides-G-M", "name": { "family": "Whitesides", "given": "George M." }, "orcid": "0000-0001-9451-2442" } ] }, "title": "Fabrication of metallic microstructures using exposed, developed silver halide-based photographic film", "ispublished": "pub", "full_text_status": "restricted", "keywords": "replication; complex", "note": "Copyright \u00a9 2000 American Chemical Society.\n\nPublished In Issue: February 15, 2000. Received for review September 1, 1999. Accepted December 3, 1999.\n\nThis work was supported by DARPA and the NSF (Grant ECS-9729405). P.J.A.K. acknowledges The Netherlands Organization for Scientific Research (NWO) for a postdoctoral fellowship. We thank Scott T. Brittain for helpful discussions. This work used MRSEC shared facilities supported by the NSF (Grants DMR-9400396 and DMR-9809363).", "abstract": "This paper demonstrates that the pattern of silver particles embedded in the gelatin matrix of exposed and developed silver halide-based photographic film can serve as a template in a broadly applicable method for the microfabrication of metallic microstructures. In this method, a CAD file is reproduced in the photographic film by exposure and developing. The resulting pattern of discontinuous silver grains is augmented and made electrically continuous by electroless deposition of silver, and the electrically continuous structure is then used as the cathode for electrochemical deposition of an additional layer of the same or different metal. The overall process can be completed within 2 h, starting from a CAD file, and can generate electrically continuous structures with the smallest dimension in the plane of the film of 30 \u03bcm. Structures with aspect ratio of up to 5 can also be obtained by using the metallic structures as photomasks in photolithography using SU-8 photoresist on the top of the electroplated pattern and exposed from the bottom, followed by development and electroplating through the patterned photoresist. This method of fabrication uses readily available equipment and makes it possible to develop prototypes of a wide variety of metallic structures and devices. The resulting structures either supported on the film backing or freed from it are appropriate for use as passive, structural materials such as wire frames or meshes and can also be used in microfluidic, microanalytical, and microelectromechanical systems.", "date": "2000-02-15", "date_type": "published", "publication": "Analytical Chemistry", "volume": "72", "number": "4", "publisher": "American Chemical Society", "pagerange": "645-651", "id_number": "CaltechAUTHORS:20130821-160717870", "issn": "0003-2700", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160717870", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "DARPA" }, { "agency": "NSF", "grant_number": "ECS-9729405" }, { "agency": "Netherlands Organization for Scientific Research (NWO)" }, { "agency": "NSF", "grant_number": "DMR-9400396" }, { "agency": "NSF", "grant_number": "DMR-9809363" } ] }, "doi": "10.1021/ac991010p", "resource_type": "article", "pub_year": "2000", "author_list": "Deng, Tao; Arias, Francisco; et el." }, { "id": "https://authors.library.caltech.edu/records/0c10a-0z069", "eprint_id": 40804, "eprint_status": "archive", "datestamp": "2023-08-19 05:04:44", "lastmod": "2023-10-24 22:00:37", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Stroock-A-D", "name": { "family": "Stroock", "given": "Abraham D." } }, { "id": "Kenis-P-J-A", "name": { "family": "Kenis", "given": "Paul J. A." } }, { "id": "Whitesides-G-M", "name": { "family": "Whitesides", "given": "George" }, "orcid": "0000-0001-9451-2442" }, { "id": "Stone-H-A", "name": { "family": "Stone", "given": "Howard A." } } ] }, "title": "Experimental and theoretical scaling laws for transverse diffusive broadening in two-phase laminar flows in microchannels", "ispublished": "pub", "full_text_status": "public", "keywords": "mass-transfer, two-phase flow, chemically reactive flow, laminar flow, channel flow, flow visualisation, fluorescence, optical microscopy, scaling phenomena, chemical interdiffusion, reaction-diffusion systems", "note": "\u00a9 2000 American Institute of Physics.\n\n(Received 29 October 1999; accepted 24 February 2000)\n\nThis work was supported by DARPA, NSF ECS-9729405 [for one of the authors (G.M.W.)]; by DARPA Army Research Office DAAG55-97-1-0114 [for one of the authors (H.A.S.)], and by the NSF MRSEC DMR-9809363 [for two of the authors (G.M.W. and H.A.S.)]. One of the authors (A.D.S.) was supported by NIH Molecular Biophysical Training Grant No. 5T32GM08313-10. The authors acknowledge Shuichi Takayama for helpful suggestions.\n\nPublished - ApplPhysLett_76_2376.pdf
", "abstract": "This letter quantifies both experimentally and theoretically the diffusion of low-molecular-weight species across the interface between two aqueous solutions in pressure-driven laminar flow in microchannels at high Peclet numbers. Confocal fluorescent microscopy was used to visualize a fluorescent product formed by reaction between chemical species carried separately by the two solutions. At steady state, the width of the reaction-diffusion zone at the interface adjacent to the wall of the channel and transverse to the direction of flow scales as the one-third power of both the axial distance down the channel (from the point where the two streams join) and the average velocity of the flow, instead of the more familiar one- half power scaling which was measured in the middle of the channel. A quantitative description of reaction-diffusion processes near the walls of the channel, such as described in this letter, is required for the rational use of laminar flows for performing spatially resolved surface chemistry and biology inside microchannels and for understanding three-dimensional features of mass transport in shearing flows near surfaces.", "date": "2000", "date_type": "published", "publication": "Applied Physics Letters", "volume": "76", "number": "17", "publisher": "American Institute of Physics", "pagerange": "2376-2378", "id_number": "CaltechAUTHORS:20130821-160720579", "issn": "0003-6951", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160720579", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "DARPA" }, { "agency": "NSF", "grant_number": "ECS-9729405" }, { "agency": "Army Research Office", "grant_number": "DAAG55-97-1-0114" }, { "agency": "NSF", "grant_number": "DMR-9809363" }, { "agency": "NIH", "grant_number": "5T32GM08313-10" } ] }, "doi": "10.1063/1.126351", "primary_object": { "basename": "ApplPhysLett_76_2376.pdf", "url": "https://authors.library.caltech.edu/records/0c10a-0z069/files/ApplPhysLett_76_2376.pdf" }, "resource_type": "article", "pub_year": "2000", "author_list": "Ismagilov, Rustem F.; Stroock, Abraham D.; et el." }, { "id": "https://authors.library.caltech.edu/records/bakgz-9e982", "eprint_id": 40841, "eprint_status": "archive", "datestamp": "2023-08-22 13:56:54", "lastmod": "2023-10-24 22:29:40", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Nelsen-S-F", "name": { "family": "Nelsen", "given": "Stephen F." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Gentile-K-E", "name": { "family": "Gentile", "given": "Kevin E." } }, { "id": "Powell-D-R", "name": { "family": "Powell", "given": "Douglas R." } } ] }, "title": "Temperature effects on electron transfer within intervalence bis(hydrazine) radical cations", "ispublished": "pub", "full_text_status": "public", "keywords": "transfer rates; energy relationships; distance dependence; polar liquids; diporphyrins; complexes; systems; units", "note": "Copyright \u00a9 1999 American Chemical Society. \n\nPublished In Issue: August 04, 1999. Received November 23, 1998. Revised Manuscript Received May 24, 1999. \n\nWe thank the National Science Foundation for support of this work under grant CHE-9417946, the NSF major instrument program and the University of Wisconsin for funds used in purchase of the diffractometers, spectrometers, and computer equipment used, and the Dow Chemical Company for a fellowship for R.F.I.. We thank Dmitry Matyushov for discussion of temperature coefficients using his solvent theory.\n\nSupporting Information Available: Crystallographic data for 5^0, 5^(2+)(SbF_6^-)_2\u00b7CH_3CN, 8^+(SbF_6^-)\u00b7^(1/2)Et_2O, and 9^+(SbF_6^-), numbered thermal ellipsoid drawings, heavy atom positions, and experimental for preparation of 4, 5, 6, 8, 9, 10, and their radical cations. This material is available free of charge via the Internet at http://pubs.acs.org.\n\nSupplemental Material - ja984047k_s.pdf
", "abstract": "Analyses of the shape of intervalence charge-transfer bands at various temperatures (255\u2212325 K in most cases) in acetonitrile are reported for the radical cations of bis(2-tert-butyl-2,3-diazabicyclo[2.2.2]oct-3-yl) hydrazines that are bridged by 2,5-xylene-1,4-diyl (2^+), durene-1,4-diyl (3^+), naphthalene-1,4-diyl (4^+), biphenyl-4,4'-diyl (5^+), and 9,9-dimethylfluorene-2,7-diyl (6^+) aromatic rings. Electron-transfer (ET) rate constants measured by ESR as a function of temperature are reported for 4^+\u22126^+. Despite the fact that the ET barriers for these compounds are dominated by vibrational reorganization, explicit inclusion of vibronic coupling effects is not necessary for the prediction of their ET rate constants from the optical spectra. Rate constants in excellent agreement with the measured ones are predicted by a classical analysis of charge-transfer band shape, if the diabatic surfaces are changed from the usual assumption that they are parabolas to ones that fit the shape of the charge-transfer bands.", "date": "1999-08-04", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "121", "number": "30", "publisher": "American Chemical Society", "pagerange": "7108-7114", "id_number": "CaltechAUTHORS:20130821-160726623", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160726623", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF", "grant_number": "CHE-9417946" }, { "agency": "University of Wisconsin" }, { "agency": "Dow Chemical Company" } ] }, "doi": "10.1021/ja984047k", "primary_object": { "basename": "ja984047k_s.pdf", "url": "https://authors.library.caltech.edu/records/bakgz-9e982/files/ja984047k_s.pdf" }, "resource_type": "article", "pub_year": "1999", "author_list": "Nelsen, Stephen F.; Ismagilov, Rustem F.; et el." }, { "id": "https://authors.library.caltech.edu/records/8ztzk-xej66", "eprint_id": 40838, "eprint_status": "archive", "datestamp": "2023-08-22 13:53:22", "lastmod": "2023-10-24 22:29:29", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Nelsen-S-F", "name": { "family": "Nelsen", "given": "Stephen F." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Ion pairing effects on bis(hydrazine) intervalence radical cations", "ispublished": "pub", "full_text_status": "restricted", "keywords": "intramolecular electron-transfer; metal-complexes; charge- transfer; transition; dependence; strength; units", "note": "Copyright \u00a9 1999 American Chemical Society. \n\nPublished In Issue: July 08, 1999. Received April 20, 1999. Revised April 28, 1999. \n\nWe thank the National Science Foundation for support of parts of this work under grant CHE-9417946, the NSF major instrument program and the University of Wisconsin for funds used in purchase of the spectrometers and computer equipment used, and the Dow Chemical Company for a fellowship for R.F.I. We thank Jeff Curtis (University San Francisco) for valuable discussions.", "abstract": "Three bis(2-tert-butyl-2,3-diazabicyclo[2.2.2]oct-3-yl) radical cation salts, bridged by 2,3,5,6-tetramethylbenzene-1,4-diyl (1^+PF_6^-), biphenylene-4,4'-diyl (2^+PF_6^-), and 9,9-dimethyl-fluorene-2,7-diyl (3^+NO_3^-) groups, have been studied in methylene chloride. The transition energy at band maximum (E_(op)) increases as concentration increases and when ^nBu_4+BF_6^- is added, indicating that ion pairing increases E_(op). The E_(op) data fit a simple ion pairing equilibrium, giving ion pairing equilibrium constants at 293 K of 3100, 3100, and 6100 M^(-1), respectively. Electron-transfer rate constants measured by ESR are reported for 0.19 mM 2^+PF_6^- and for 1 mM 2^+PF_6^- and 3^+NO_3^- in the presence of 20 mM ^nBu_4+BF_6^- in methylene chloride. Prediction of k_(ET) from the optical spectrum of 2^+PF_6^- containing excess ^nBu_4^+BF_6^- was made both assuming the optical ET is endoenthalpic by an amount calculated from the increase in E_(op), and that \u0394G\u00b0 = 0 (that is, that the ion pairing effect may be lumped into the electron transfer coordinate along with the vertical and solvent reorganization effects). The predicted rate constant for the latter is only a factor of 2.5 times larger the former, so both agree rather well with the ESR-derived rate constant.", "date": "1999-07-08", "date_type": "published", "publication": "Journal of Physical Chemistry A", "volume": "103", "number": "27", "publisher": "American Chemical Society", "pagerange": "5373-5378", "id_number": "CaltechAUTHORS:20130821-160726092", "issn": "1089-5639", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160726092", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF", "grant_number": "CHE-9417946" }, { "agency": "University of Wisconsin" }, { "agency": "Dow Chemical Company" } ] }, "doi": "10.1021/jp991294h", "resource_type": "article", "pub_year": "1999", "author_list": "Nelsen, Stephen F. and Ismagilov, Rustem F." }, { "id": "https://authors.library.caltech.edu/records/xg3ce-ad362", "eprint_id": 40812, "eprint_status": "archive", "datestamp": "2023-08-22 13:53:05", "lastmod": "2023-10-24 22:01:11", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Kenis-P-J-A", "name": { "family": "Kenis", "given": "Paul J. A." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Whitesides-G-M", "name": { "family": "Whitesides", "given": "George M." }, "orcid": "0000-0001-9451-2442" } ] }, "title": "Microfabrication inside capillaries using multiphase laminar flow patterning", "ispublished": "pub", "full_text_status": "public", "keywords": "calcium-phosphate; microemulsions", "note": "\u00a9 1999 American Association for the Advancement of Science.\n\nReceived for publication 9 February 1999. Accepted for publication 15 April 1999. \n\nThis work was financially supported by the Defense Advanced Research Projects Agency and NSF grant ECS-9729405. Materials Research Science and Engineering Center\u2013shared facilities supported by the NSF under grant DMR-9400396 were used. P.J.A.K. acknowledges the Netherlands Organization for Scientific Research (NWO) for a postdoctoral fellowship. We acknowledge W. Huck and Y. Lu for their help with the atomic force microscopy and scanning electron microscopy experiments.\n\nPublished - Science-1999-Kenis-83-5.pdf
", "abstract": "The reaction of species in solutions flowing laminarly (without turbulent mixing) inside capillaries was used as the basis for a broadly applicable method of microfabrication. In this method, patterning occurs as a result of transport of reactive species to interfaces within the capillary by laminar flow. A wide range of chemistries can be used to generate structures with feature sizes of less than 5 micrometers and with spatial localization to within 5 micrometers. The method is applicable to the patterning of metals, organic polymers, inorganic crystals, and ceramics on the inner walls of preformed capillaries, using both additive and subtractive processes.", "date": "1999-07-02", "date_type": "published", "publication": "Science", "volume": "285", "number": "5424", "publisher": "American Association for the Advancement of Science", "pagerange": "83-85", "id_number": "CaltechAUTHORS:20130821-160722004", "issn": "0036-8075", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160722004", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Defense Advanced Research Projects Agency (DARPA)" }, { "agency": "NSF", "grant_number": "ECS-9729405" }, { "agency": "NSF", "grant_number": "DMR-9400396" }, { "agency": "Netherlands Organization for Scientific Research (NWO)" } ] }, "doi": "10.1126/science.285.5424.83", "primary_object": { "basename": "Science-1999-Kenis-83-5.pdf", "url": "https://authors.library.caltech.edu/records/xg3ce-ad362/files/Science-1999-Kenis-83-5.pdf" }, "resource_type": "article", "pub_year": "1999", "author_list": "Kenis, Paul J. A.; Ismagilov, Rustem F.; et el." }, { "id": "https://authors.library.caltech.edu/records/5bzbc-s3b95", "eprint_id": 40879, "eprint_status": "archive", "datestamp": "2023-08-22 13:46:54", "lastmod": "2023-10-24 22:32:31", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Takayama-Shuichi", "name": { "family": "Takayama", "given": "Shuichi" } }, { "id": "McDonald-J-Cooper", "name": { "family": "McDonald", "given": "J. Cooper" } }, { "id": "Ostuni-E", "name": { "family": "Ostuni", "given": "Emanuele" } }, { "id": "Liang-Michael-N", "name": { "family": "Liang", "given": "Michael N." } }, { "id": "Kenis-P-J-A", "name": { "family": "Kenis", "given": "Paul J. A." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Whitesides-G-M", "name": { "family": "Whitesides", "given": "George M." }, "orcid": "0000-0001-9451-2442" } ] }, "title": "Patterning cells and their environments using multiple laminar fluid flows in capillary networks", "ispublished": "pub", "full_text_status": "public", "keywords": "fibronectin; proteins; surfaces; growth; matrix; shape", "note": "\u00a9 1999, The National Academy of Sciences. \n\nAccepted March 17, 1999. \n\nSupported by the Defense Advanced Research Planning Agency (DARPA)/Space and Naval Warfare Systems Command, DARPA/Office of Naval Research, the National Science Foundation (NSF ECS-9729405), and the National Institutes of Health (NIH GM30367). We thank Prof. D. E. Ingber (Harvard Medical School) for use of his facilities and Dr. S. Warren (Massachusetts General Hospital) for the gift of E. coli (RB 128). S. T. is a Leukemia Society of America Fellow and thanks the society for a postdoctoral fellowship. J. C. M. thanks the National Science Foundation for a predoctoral fellowship. P. J. A. K. thanks the Netherlands Organization for Scientific Research (NWO) for a postdoctoral fellowship.\n\nPublished - PNAS-1999-Takayama-5545-8.pdf
Accepted Version - pq005545.pdf
", "abstract": "This paper describes the use of laminar flow of liquids in capillary systems to pattern the cell culture substrate, to perform patterned cell deposition, and to pattern the cell culture media. We demonstrate the patterning of the cell culture substrate with different proteins, the patterning of different types of cells adjacent to each other, the patterned delivery of chemicals to adhered cells, and performing enzymatic reactions over select cells or over a portion of a cell. This method offers a way to simultaneously control the characteristics of the surface to which cells are attached, the type of cells that are in their vicinity, and the kind of media that cells or part of a cell are exposed to. The method is experimentally simple, highly adaptable, and requires no special equipment except for an elastomeric relief that can be readily prepared by rapid prototyping.", "date": "1999-05-11", "date_type": "published", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "volume": "96", "number": "10", "publisher": "National Academy of Sciences", "pagerange": "5545-5548", "id_number": "CaltechAUTHORS:20130821-160733567", "issn": "0027-8424", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160733567", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Defense Advanced Research Planning Agency (DARPA)" }, { "agency": "Office of Naval Research (ONR)" }, { "agency": "NSF", "grant_number": "ECS-9729405" }, { "agency": "NIH", "grant_number": "GM30367" }, { "agency": "Leukemia Society of America" }, { "agency": "Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)" } ] }, "doi": "10.1073/pnas.96.10.5545", "pmcid": "PMC21896", "primary_object": { "basename": "PNAS-1999-Takayama-5545-8.pdf", "url": "https://authors.library.caltech.edu/records/5bzbc-s3b95/files/PNAS-1999-Takayama-5545-8.pdf" }, "related_objects": [ { "basename": "pq005545.pdf", "url": "https://authors.library.caltech.edu/records/5bzbc-s3b95/files/pq005545.pdf" } ], "resource_type": "article", "pub_year": "1999", "author_list": "Takayama, Shuichi; McDonald, J. Cooper; et el." }, { "id": "https://authors.library.caltech.edu/records/ekp2c-92x14", "eprint_id": 40889, "eprint_status": "archive", "datestamp": "2023-08-22 13:42:42", "lastmod": "2023-10-24 22:33:23", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Whitesides-G-M", "name": { "family": "Whitesides", "given": "George M." }, "orcid": "0000-0001-9451-2442" }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Complexity in chemistry", "ispublished": "pub", "full_text_status": "public", "keywords": "oscillatory kinetics; molecules; dynamics; shape", "note": "\u00a9 1999 American Association for the Advancement of Science. \n\nThis work was supported by the Defense Advanced Research Projects Agency and by NIH grant GM30367. We acknowledge F. Frankel for providing Fig. 2.\n\nPublished - Complexity.pdf
", "abstract": "\"Complexity\" is a subject that is beginning to be important in chemistry. Historically, chemistry has emphasized the approximation of complex nonlinear processes by simpler Linear ones. Complexity is becoming a profitable approach to a wide range of problems, especially the understanding of Life.", "date": "1999-04-02", "date_type": "published", "publication": "Science", "volume": "284", "number": "5411", "publisher": "American Association for the Advancement of Science", "pagerange": "89-92", "id_number": "CaltechAUTHORS:20130821-160735218", "issn": "0036-8075", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160735218", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Defense Advanced Research Projects Agency (DARPA)" }, { "agency": "NIH", "grant_number": "GM30367" } ] }, "doi": "10.1126/science.284.5411.89", "primary_object": { "basename": "Complexity.pdf", "url": "https://authors.library.caltech.edu/records/ekp2c-92x14/files/Complexity.pdf" }, "resource_type": "article", "pub_year": "1999", "author_list": "Whitesides, George M. and Ismagilov, Rustem F." }, { "id": "https://authors.library.caltech.edu/records/4a5jf-4h871", "eprint_id": 40880, "eprint_status": "archive", "datestamp": "2023-08-22 13:23:49", "lastmod": "2023-10-24 22:32:34", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Teki-Y", "name": { "family": "Teki", "given": "Yoshio" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Nelsen-S-F", "name": { "family": "Nelsen", "given": "Stephen F." } } ] }, "title": "Intra- and inter-molecular exchange on symmetrical hydrazine diradical dications and comparison of the magnetic exchange with ET parameters derived from their optical spectra", "ispublished": "pub", "full_text_status": "restricted", "keywords": "stable dication diradical; intramolecular exchange; electron transfer; spin alignment ground-state; spin; crystals", "note": "\u00a9 1999 Taylor & Francis. \n\nThis work was financially supported by a Grant-in-Aid for a General Scientific\nResearch (No. 07454191) from the Ministry of Education, Science, Sports, and\nCulture, Japan and Precursory Research for Embryonic Science and Technology\n(PEST) from Japan Science and Technology Corporation.", "abstract": "The spin alignment in a charged molecular field is important research issue in the molecular magnetism. In order to clarify the interrelation between spin alignment and the charged molecular field, we have investigated intra- and inter-molecular exchanges on some Hydrazine diradical dictations 1\u20133 shown in Scheme 1 (see texts) by ESR and magnetic susceptibility measurement. The magnetic behavior of the dication salt 1 has been well analyzed using the alternating linear chain models with J_(intra)/k_B = \u2212106 K, J_(inter_/k_B = \u221249 K and an alternating parameter \u03b1=0.46. The magnetic property of 3 has been also fitted to the alternating chain model with J/k_B = \u2212106 K J_(inter)/k_B = \u221242 K (\u03b1=0.40). On the other hand, 2 gives a robust triplet ground state with larger energy separation from other spin states. The energy separation has been estimated to be larger than 300 cm\u22121 (J_(intra)/k_B > \u00b1190 K) from the temperature dependence of the ESR signal intensity. These findings indicate that the sign of the intramolecular exchange depends on the linking position (m- or p-) of the hydrazine cation group, i.e. the topology of the \u03c0 orbital network even in the cationic molecular field. The magneto-optical correlation is also discussed based on the intramolecular electron transfer (ET) parameters.", "date": "1999", "date_type": "published", "publication": "Molecular Crystals and Liquid Crystals Science and Technology. Section A. Molecular Crystals and Liquid Crystals", "volume": "334", "number": "1", "publisher": "Taylor & Francis", "pagerange": "313-322", "id_number": "CaltechAUTHORS:20130821-160733739", "issn": "1542-1406", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160733739", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Ministry of Education, Science, Sports, and Culture, Japan", "grant_number": "07454191)" }, { "agency": "Japan Science and Technology Corporation" } ] }, "doi": "10.1080/10587259908023329", "resource_type": "article", "pub_year": "1999", "author_list": "Teki, Yoshio; Ismagilov, Rustem F.; et el." }, { "id": "https://authors.library.caltech.edu/records/tp393-cqa46", "eprint_id": 40840, "eprint_status": "archive", "datestamp": "2023-08-22 13:04:13", "lastmod": "2023-10-24 22:29:36", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Nelsen-S-F", "name": { "family": "Nelsen", "given": "Stephen F." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Gentile-K-E", "name": { "family": "Gentile", "given": "Kevin E." } }, { "id": "Nagy-M-A", "name": { "family": "Nagy", "given": "Mark A." } }, { "id": "Tran-Hieu-Q", "name": { "family": "Tran", "given": "Hieu Q." } }, { "id": "Qu-Qinling", "name": { "family": "Qu", "given": "Qinling" } }, { "id": "Halfen-D-T", "name": { "family": "Halfen", "given": "DeWayne T." } }, { "id": "Odegard-A-L", "name": { "family": "Odegard", "given": "Amy L." } }, { "id": "Pladziewicz-J-R", "name": { "family": "Pladziewicz", "given": "Jack R." } } ] }, "title": "Indirect determination of self-exchange electron transfer rate constants", "ispublished": "pub", "full_text_status": "restricted", "keywords": "radical cations; hydrazines; superconductors; conformations; chemistry; progress", "note": "Copyright \u00a9 1998 American Chemical Society. \n\nPublished In Issue: August 19, 1998. Received March 31, 1998. \n\nWe thank the National Science Foundation for partial financial support of this work under Grants CHE-9504133 (J.R.P.) and CHE-9417946 (S.F.N.). Acknowledgment is also make to the donors of the Petroleum Research Fund, administered by the American Chemical Society, for partial support of the research under Grant ACS-PRF 29982-B4 (J.R.P.).", "abstract": "Second-order rate constants kij(obsd) measured at 25 \u00b0C in acetonitrile by stopped-flow spectrophotometry for forty-four electron transfer (ET) reactions among fourteen 0/+1 couples [three aromatic compounds (tetrathiafulvalene, tetramethyltetraselenafulvalene, and 9,10-dimethyl-9,10-dihydrophenazine), four 2,3-disubstituted 2,3-diazabicyclo[2.2.2]octane derivatives, six acyclic hydrazines, and the bridgehead diamine 1,5-diazabicyclo[3.3.3]undecane] and seventeen compounds and forty-seven reactions from a previous study (J. Am. Chem. Soc. 1997, 119, 5900) [three p-phenylenediamine derivatives, four ferrocene derivatives, and ten tetraalkylhydrazines] are discussed. When all 91 kij(obsd) values are simultaneously fitted to Marcus's adiabatic cross rate formula kij(calcd) = (kiikjjKijfij)1/2, ln fij = (ln Kij)2/4 ln(kiikjj/Z2), best-fit self-exchange rate constants, kii(fit), are obtained that allow remarkably accurate calculation of kij(obsd); kij(obsd)/kij(calcd) is in the range 0.5\u22122.0 for all 91 reactions. The average difference without regard to sign, |\u0394\u0394Gij|, between observed cross reaction activation free energy and that calculated using the kii(fit) values and equilibrium constants is 0.13 kcal/mol. The \u0394Gii(fit) values obtained range from 2.3 kcal/mol for tetramethyltetraselenafulvalene0/+ to 21.8 kcal/mol for tetra-n-propylhydrazine0/+, corresponding to a factor of 2 \u00d7 1014 in kii(fit). The principal factor affecting kii(fit) for our data appears to be the internal vertical reorganization energy (\u03bbv), but kii(fit) values also incorportate the effects of changes in the electronic matrix coupling element (V). Significantly smaller V values for ferrocenes and for hydrazines with alkyl groups larger than methyl than for aromatics and tetramethylhydrazine are implied by the observed \u0394Gii(fit) values.", "date": "1998-08-19", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "120", "number": "32", "publisher": "American Chemical Society", "pagerange": "8230-8240", "id_number": "CaltechAUTHORS:20130821-160726422", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160726422", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF", "grant_number": "CHE-9504133" }, { "agency": "NSF", "grant_number": "CHE-9417946" }, { "agency": "Petroleum Research Fund", "grant_number": "ACS-PRF 29982-B4" } ] }, "doi": "10.1021/ja9810890", "resource_type": "article", "pub_year": "1998", "author_list": "Nelsen, Stephen F.; Ismagilov, Rustem F.; et el." }, { "id": "https://authors.library.caltech.edu/records/ap9t0-9h954", "eprint_id": 40844, "eprint_status": "archive", "datestamp": "2023-08-19 03:06:13", "lastmod": "2023-10-24 22:29:59", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Nelsen-S-F", "name": { "family": "Nelsen", "given": "Stephen F." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Powell-D-R", "name": { "family": "Powell", "given": "Douglas R." } } ] }, "title": "Effects of bridge redox state levels on the electron transfer and optical properties of intervalence compounds with hydrazine charge-bearing units", "ispublished": "pub", "full_text_status": "public", "note": "Copyright \u00a9 1996 American Chemical Society. \n\nPublished In Issue: July 03, 1996. Received February 16, 1996. \n\nWe thank the National Science Foundation for partial financial support of this work under Grant CHE-9417946, as well as the NSF, NIH, and University of Wisconsin for equipment grants used for purchasing the spectrometers and computers employed in this work.\n\nSupporting Information Available: Preparations and crystallographic data for 2, 2^+BPh_4^-, and 3^+NO_3^-; numbered thermal ellipsoid drawings, tables including heavy atom positions, bond lengths and angles, and anisotropic displacement parameters (20 pages).\n\nSupplemental Material - ja1924.cif
Supplemental Material - ja1924.pdf
", "abstract": "n/a", "date": "1998-07-03", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "120", "number": "8", "publisher": "American Chemical Society", "pagerange": "1924-1925", "id_number": "CaltechAUTHORS:20130821-160727245", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160727245", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF", "grant_number": "CHE-9417946" }, { "agency": "NIH" }, { "agency": "University of Wisconsin" } ] }, "doi": "10.1021/ja960500l", "primary_object": { "basename": "ja1924.cif", "url": "https://authors.library.caltech.edu/records/ap9t0-9h954/files/ja1924.cif" }, "related_objects": [ { "basename": "ja1924.pdf", "url": "https://authors.library.caltech.edu/records/ap9t0-9h954/files/ja1924.pdf" } ], "resource_type": "article", "pub_year": "1998", "author_list": "Nelsen, Stephen F.; Ismagilov, Rustem F.; et el." }, { "id": "https://authors.library.caltech.edu/records/mgkx8-3bn18", "eprint_id": 40797, "eprint_status": "archive", "datestamp": "2023-08-19 02:54:58", "lastmod": "2023-10-24 22:00:08", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" } ] }, "title": "Mathematical description of kinetic resolution with an enantiomerically impure catalyst and nonracemic substrate", "ispublished": "pub", "full_text_status": "restricted", "keywords": "asymmetric catalysis", "note": "Copyright \u00a9 1998 American Chemical Society. \n\nPublished In Issue: May 29, 1998. Received December 22, 1997. \n\nI thank Olafs Daugulis, Dr. Igor Alabugin, Prof. Edwin Vedejs, and Prof. Stephen Nelsen for helpful discussions and encouragement. A fellowship from Dow Chemical is gratefully acknowledged.", "abstract": "Kinetic resolution is an important method in organic chemistry; catalytic kinetic resolution is especially attractive because a smaller amount of the optically active material is required. In principle, a naturally occurring catalyst (enzyme) or a synthetic catalyst can be employed. Possible disadvantages of an enzymatic catalyst include limited scope of reactions and substrates; therefore, there is an increasing effort targeted at the design of chemical catalysts for kinetic resolution. The most useful parameter in comparing different catalysts is the selectivity factor S, which is the ratio of the rate constants for the reaction of the catalyst with the two enantiomers of the substrate (S = (k_1/k_2), see below). Mathematical treatment of kinetic resolution should provide a way to calculate S from experimental observables, and for enantiomerically pure catalysts the equations are well-known from the work of Kagan and others.", "date": "1998-05-29", "date_type": "published", "publication": "Journal of Organic Chemistry", "volume": "63", "number": "11", "publisher": "American Chemical Society", "pagerange": "3772-3774", "id_number": "CaltechAUTHORS:20130821-160719423", "issn": "0022-3263", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160719423", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Dow Chemical Company" } ] }, "doi": "10.1021/jo972299i", "resource_type": "article", "pub_year": "1998", "author_list": "Ismagilov, Rustem F." }, { "id": "https://authors.library.caltech.edu/records/w22j8-dze88", "eprint_id": 40850, "eprint_status": "archive", "datestamp": "2023-08-22 12:46:28", "lastmod": "2023-10-24 22:30:26", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Nelsen-S-F", "name": { "family": "Nelsen", "given": "Stephen F." } }, { "id": "Tran-Hieu-Q", "name": { "family": "Tran", "given": "Hieu Q." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Ramm-M-T", "name": { "family": "Ramm", "given": "Michael T." } }, { "id": "Chen-Ling-Jen", "name": { "family": "Chen", "given": "Ling-Jen" } }, { "id": "Powell-D-R", "name": { "family": "Powell", "given": "Douglas R." } } ] }, "title": "Structural information from hydrazine radical cation optical absorption spectra", "ispublished": "pub", "full_text_status": "public", "keywords": "sesquibicyclic hydrazines; lone pairs; x-ray; tetraalkylhydrazine; splittings; dication; nitrogen; syn", "note": "Copyright \u00a9 1998 American Chemical Society. \n\nPublished In Issue: April 17, 1998. Received October 3, 1997. \n\nWe thank the National Science Foundation for partial financial support of this work through Grant No. CHE-9417546 and the National Science Foundation, National Institutes of Health, and the University of Wisconsin for funds used in purchasing the spectrometers and computers used in this work. We are obviously indebted to Timothy Clark, who developed the NCG method and provided us with the software used. We thank Jack Pladziewicz for asking what 31+ showing two absorption maxima means.\n\nSupporting Information Available: Crystal data for 2+NO3- (21/22+), 15(AdN)2), 15+TsO-, and 31+Ar4B- (cHx2N)2+), thermal ellipsoid drawings, and crystal coordinates (11 pages).\n\nSupplemental Material - jo2536.pdf
", "abstract": "Transition energies (Eop) of the nitrogen-centered \u03c0,\u03c0* absorption of tetraalkylhydrazine radical cations are quite sensitive to twist at the NN bond, nitrogen pyramidality, and mixing of the \u03c3 orbitals with the \u03c0 system. Thirty-one examples for which Eop varies from 63 to 107.5 kcal/mol are discussed with the aid of calculated values (Ecalc) for the 0,0 transition energy using simple (no configuration interaction) neutral-in-cation-geometry calculations on AM1\u2212UHF geometry-optimized radical-cation structures. Significant changes in the difference between Eop and Ecalc are observed for bis-N,N'-bicyclic systems, which are syn pyramidalized at nitrogen (twist angles near 0\u00b0; Eop about 23 kcal/mol larger than Ecalc) and for bis-N,N-bicyclic ones, which are anti pyramidalized (twist angles of 180\u00b0; difference about 7 kcal/mol when calculations of 180\u00b0 structures are employed). Within these classes, changes in Eop caused by changes in pyramidality and \u03c3,\u03c0 interaction are predicted well by the calculations. The tetraisopropylhydrazine radical cation has \u03bbmax = 282 nm, but its tetracyclohexyl analogue shows two transitions, at 276 and 386 nm. This surprising difference is attributed to tetracyclohexylhydrazine radical cation having both untwisted and significantly twisted (estimated twist angle \u2248 44\u00b0) forms occupied in solution, although the isopropyl compound only has the untwisted form significantly occupied.", "date": "1998-04-17", "date_type": "published", "publication": "Journal of Organic Chemistry", "volume": "63", "number": "8", "publisher": "American Chemical Society", "pagerange": "2536-2543", "id_number": "CaltechAUTHORS:20130821-160728363", "issn": "0022-3263", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160728363", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF", "grant_number": "CHE-9417546" }, { "agency": "NSF" }, { "agency": "University of Wisconsin" } ] }, "doi": "10.1021/jo9718307", "primary_object": { "basename": "jo2536.pdf", "url": "https://authors.library.caltech.edu/records/w22j8-dze88/files/jo2536.pdf" }, "resource_type": "article", "pub_year": "1998", "author_list": "Nelsen, Stephen F.; Tran, Hieu Q.; et el." }, { "id": "https://authors.library.caltech.edu/records/p0nt0-a3k69", "eprint_id": 40862, "eprint_status": "archive", "datestamp": "2023-08-22 12:44:16", "lastmod": "2023-10-24 22:31:21", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Samoshin-V-V", "name": { "family": "Samoshin", "given": "Vyacheslav V." } }, { "id": "Troyansky-E-I", "name": { "family": "Troyansky", "given": "Emmanuil I." } }, { "id": "Demchuk-D-V", "name": { "family": "Demchuk", "given": "Dmitry V." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Chertkov-V-A", "name": { "family": "Chertkov", "given": "Vyacheslav A." } }, { "id": "Lindeman-S-V", "name": { "family": "Lindeman", "given": "Sergei V." } }, { "id": "Khrustalyov-V-N", "name": { "family": "Khrustalyov", "given": "Victor N." } }, { "id": "Struchkov-Y-T", "name": { "family": "Struchkov", "given": "Yury T." } } ] }, "title": "Conformational analysis of a 12-membered crown dithioether in the solid state and in solution", "ispublished": "pub", "full_text_status": "restricted", "keywords": "crown dithioether; conformational analysis; multicomponent equilibrium thioether macrocyclic chemistry; resolution nmr-spectra; coupling-constants; thiocrown ethers; molecular-structure; automated-analysis; crystal-structure; polythioethers; distance; design", "note": "Copyright \u00a9 1998 John Wiley & Sons. \n\nIssue published online: 4 DEC 1998. Article first published online: 4 DEC 1998. Manuscript Accepted: 29 SEP 1997. Manuscript Revised: 20 AUG 1997. Manuscript Received: 22 MAY 1997. \n\nNTAS. Grant Number: 94-1914\nRussian Foundation for Basic Research. Grant Number: 94-03-09296", "abstract": "The solid-state molecular structure and the conformational behaviour in solution of the 12-membered crown dithioether 8- methyl-1,4-dioxa-7,10-dithiacyclododecane-5,12-dione were studied by x-ray crystallography, H-1 and C-13 NMR spectroscopy and molecular mechanics. The conformational rigidity of some constituent structural fragments allowed a detailed analysis of the structure and distribution of the conformers. A protocol for studies of multiconformational equilibrium was developed by means of the combined use of structure calculations and dynamic NMR measurements. (C) 1998 John Wiley & Sons, Ltd.", "date": "1998-04", "date_type": "published", "publication": "Journal of Physical Organic Chemistry", "volume": "11", "number": "4", "publisher": "Wiley", "pagerange": "241-253", "id_number": "CaltechAUTHORS:20130821-160730344", "issn": "0894-3230", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160730344", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NTAS", "grant_number": "94-1914" }, { "agency": "Russian Foundation for Basic Research", "grant_number": "94-03-09296" } ] }, "doi": "10.1002/(SICI)1099-1395(199804)11:4<241::AID-POC999>3.0.CO;2-X", "resource_type": "article", "pub_year": "1998", "author_list": "Samoshin, Vyacheslav V.; Troyansky, Emmanuil I.; et el." }, { "id": "https://authors.library.caltech.edu/records/k3953-8sv75", "eprint_id": 40845, "eprint_status": "archive", "datestamp": "2023-08-22 12:41:36", "lastmod": "2023-10-24 22:30:01", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Nelsen-S-F", "name": { "family": "Nelsen", "given": "Stephen F." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Teki-Y", "name": { "family": "Teki", "given": "Yoshio" } } ] }, "title": "Comparison of the singlet, triplet energy gap of a symmetrical diradical dication with ET parameters derived from its optical spectrum", "ispublished": "pub", "full_text_status": "restricted", "keywords": "ion-pair formation; electron-transfer", "note": "Copyright \u00a9 1998 American Chemical Society. \n\nPublished In Issue: March 11, 1998. Received March 3, 1997. \n\nWe thank the National Science Foundation (CHE-9417946, S.F.N.) and the Ministry of Education, Science Sports, and Culture of Japan (GSR-07454191, Y.T.) for financial support of this work and the Japan Society for the Promotion of Chemistry for a fellowship (S.F.N.) which made this collaboration possible. We also thank the Instrument Center, Institute for Molecular Science, for the use of the magnetic susceptibility measurement facilities. We thank Prof. K. Itoh (Osaka City University) for helpful discussions and the use of his ESR apparatus, as well as J. R. Miller (Argonne) and M. Wasielewski (Argonne and Northwestern University) for fruitful discussions. We particularly thank a referee for straightening us out on analysis of the optical parameters.", "abstract": "n/a", "date": "1998-03-11", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "120", "number": "9", "publisher": "American Chemical Society", "pagerange": "2200-2201", "id_number": "CaltechAUTHORS:20130821-160727396", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160727396", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF", "grant_number": "CHE-9417946" }, { "agency": "Ministry of Education, Science Sports, and Culture of Japan", "grant_number": "GSR-07454191" }, { "agency": "Japan Society for the Promotion of Chemistry" } ] }, "doi": "10.1021/ja9706615", "resource_type": "article", "pub_year": "1998", "author_list": "Nelsen, Stephen F.; Ismagilov, Rustem F.; et el." }, { "id": "https://authors.library.caltech.edu/records/6jtfg-dvc59", "eprint_id": 40846, "eprint_status": "archive", "datestamp": "2023-08-22 11:58:42", "lastmod": "2023-10-24 22:30:06", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Nelsen-S-F", "name": { "family": "Nelsen", "given": "Stephen F." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Trieber-D-A-II", "name": { "family": "Trieber", "given": "Dwight A., II" } } ] }, "title": "Adiabatic electron transfer: Comparison of modified theory with experiment", "ispublished": "pub", "full_text_status": "public", "keywords": "charge recombination; distance dependence; solvent dependence; acceptor compounds; radical-cation; bis(hydrazine); separation; molecules; complexes; bridges", "note": "\u00a9 1997 American Association for the Advancement of Science. \n\nReceived for publication 16 July 1997. Accepted for publication 16 July 1997. \n\nWe thank the National Science Foundation for partial financial support of this work through grant CHE-9417946 and R. Young, for extended discussions.\n\nPublished - Science-1997-Nelsen-846-9.pdf
", "abstract": "The radical cations of properly designed bishydrazines allow comparison of observed and calculated electron transfer rate constants. These compounds have rate constants small enough to be measured by dynamic electron spin resonance spectroscopy and show charge transfer bands corresponding to vertical excitation from the energy well for the charge occurring upon one hydrazine unit to that for the electron-transferred species. Analysis of the data for all six compounds studied indicates that the shape of the adiabatic surface on which electron transfer occurs can be obtained from the charge transfer band accurately enough to successfully predict the electron transfer rate constant and that explicit tunneling corrections are not required for these compounds.", "date": "1997-10-31", "date_type": "published", "publication": "Science", "volume": "278", "number": "5339", "publisher": "American Association for the Advancement of Science", "pagerange": "846-849", "id_number": "CaltechAUTHORS:20130821-160727624", "issn": "0036-8075", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160727624", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF", "grant_number": "CHE-9417946" } ] }, "doi": "10.1126/science.278.5339.846", "primary_object": { "basename": "Science-1997-Nelsen-846-9.pdf", "url": "https://authors.library.caltech.edu/records/6jtfg-dvc59/files/Science-1997-Nelsen-846-9.pdf" }, "resource_type": "article", "pub_year": "1997", "author_list": "Nelsen, Stephen F.; Ismagilov, Rustem F.; et el." }, { "id": "https://authors.library.caltech.edu/records/y9edv-x4885", "eprint_id": 40843, "eprint_status": "archive", "datestamp": "2023-08-22 11:58:25", "lastmod": "2023-10-24 22:29:52", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Nelsen-S-F", "name": { "family": "Nelsen", "given": "Stephen F." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Powell-D-R", "name": { "family": "Powell", "given": "Douglas R." } } ] }, "title": "Charge-localized p-phenylenedihydrazine radical cations: ESR and optical studies of intramolecular electron transfer rates", "ispublished": "pub", "full_text_status": "public", "keywords": "splittings; complexes; ligand", "note": "Copyright \u00a9 1997 American Chemical Society. \n\nPublished In Issue: October 22, 1997. Received June 19, 1997. \n\nWe thank the National Science Foundation for support of this work under Grant CHE-9417946 and the major instrument program for funds used in purchase of the diffractometers, spectrometers, and computer equipment used.\n\nSupporting Information Available: Crystallographic data for 5^+(B(C_2H)_4^-, 3^(2+)BPh_4^-, 4^+BPh_4^-, and 4^(2+)(BPh_4^-_)2, numbered thermal ellipsoid drawings, and heavy atom positions (15 pages).\n\nSupplemental Material - ja10213.cif
Supplemental Material - ja10213.pdf
", "abstract": "1,4-Bis(2-tert-butyl-2,3-diazabicyclo[2.2.2]oct-3-yl)benzene-1,4-diyl (2) its 2,5-dimethyl and 2,3,5,6-tetramethyl derivatives (3 and 4), their radical cations, and bis-radical dications are studied. Crystal structures including those of 2^+BPh_4^-, 3^(2+)(BPh_4^-)_2, 4^+BPh_4^-, and 4^(2+)(BPh_4^-)_2 establish that ring methylation causes more N-lone pair, aryl \u03c0 twist without changing the NAr,NAr distance significantly and that both 2^+ and 4^+ have the charge localized in one hydrazine unit. NMR measurements show that 3^+ has about 6% of its spin at the four aryl CH and CMe carbons, while 4^+ has about 1.5% of its spin at the four CMe carbons. The average distance between the unpaired electrons of 3^(2+) and 4^(2+) was obtained from the dipolar splittings of their thermally excited triplet states and, as expected, is significantly smaller for 3^(2+) (5.25 \u00c5) than for 4^(2+) (5.63 \u00c5). Rate constants for electron transfer between the hydrazine units of 3^+ and 4^+ in CH_2Cl_2 and CH_3CN were determined by dynamic ESR. The intervalence radical cations show charge transfer bands corresponding to vertical electron transfer between the ground state and the highly vibrationally excited electron-shifted state, allowing calculation of the parameters controlling electron transfer. Electron transfer parameters obtained from the CT bands using adiabatic energy surfaces which approximate the CT band shapes observed produce rate constants within experimental error of those extrapolated to room temperature from the ESR data for both 3^+ and 4^+ in both solvents, without using tunneling corrections. The effects of mixing of the electronic wave functions of the reduced and oxidized hydrazine units of 2^+ on d_(NN), the C(t-Bu)N,NA(Ar) twist angle, and the aryl nitrogen lone pair, aryl \u03c0 twist angle which are observed by X-ray are close to those predicted from the position of the minima on the ET coordinate X of the adiabatic energy surface calculated from the CT band.", "date": "1997-10-22", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "119", "number": "42", "publisher": "American Chemical Society", "pagerange": "10213-10222", "id_number": "CaltechAUTHORS:20130821-160727091", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160727091", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF", "grant_number": "CHE-9417946" } ] }, "doi": "10.1021/ja9720321", "primary_object": { "basename": "ja10213.pdf", "url": "https://authors.library.caltech.edu/records/y9edv-x4885/files/ja10213.pdf" }, "related_objects": [ { "basename": "ja10213.cif", "url": "https://authors.library.caltech.edu/records/y9edv-x4885/files/ja10213.cif" } ], "resource_type": "article", "pub_year": "1997", "author_list": "Nelsen, Stephen F.; Ismagilov, Rustem F.; et el." }, { "id": "https://authors.library.caltech.edu/records/sv9a6-acy48", "eprint_id": 40847, "eprint_status": "archive", "datestamp": "2023-08-22 11:54:47", "lastmod": "2023-10-24 22:30:11", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Nelsen-S-F", "name": { "family": "Nelsen", "given": "Stephen F." } }, { "id": "Klein-S-J", "name": { "family": "Klein", "given": "Susan J." } }, { "id": "Trieber-D-A-II", "name": { "family": "Trieber", "given": "Dwight A., II" } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Powell-D-R", "name": { "family": "Powell", "given": "Douglas R." } } ] }, "title": "\u03c3,\u03c0 Interaction in Halogen-Substituted Biadamantylidene Radical Cations", "ispublished": "pub", "full_text_status": "public", "keywords": "oxy-cope rearrangement; face selectivity; 5-substituted adamantanones; nucleophilic-addition; cyclic voltammetry; chemical-shifts; ab-initio; adamantylideneadamantane; oxygenation; reduction", "note": "Copyright \u00a9 1997 American Chemical Society. \n\nPublished In Issue: September 19, 1997. Received February 11, 1997. \n\nWe thank the National Science Foundation for partial financial support of this work under grants CHE-9105485 and 9417946, as well as the Department of Education for a fellowship for S.J.K.\n\nSupporting Information Available: ^1H NMR spectra of 4(F), 4(Br), 8, and 9\u03b2/9\u03b1 mixture and ^(13)C NMR spectra of 8, 9\u03b1, and 9\u03b2 (7 pages).\n\nSupplemental Material - jo6539.pdf
", "abstract": "The order of E\u00b0' and vIP for 4-eq-halogenated-biadamantylidene is F > Cl Br, and the 5-F-substituted compound is harder to ozidize than the 4-eq-F-substituted one. The former result is most consistent with a detectable resonance contribution through the \u03c3-framework, and the latter with \u03c3-hyperconjugative destablilization proceeding through two pathways being more than double the same effect through one pathway (the Whiffen effect). AM1 calculations predict these results. The facial selectivity for epoxidation and diazetidine formation from 4-eq-halogenated 3 (4(X)) is in the order Cl > F > Br, and the 5-fluoro compound (8) is less selective than 4(F) for both reactions. Steric as well as electronic factors might well contribute to these results, neither of which was expected from consideration of \u03c3,\u03c0 interaction. Cation radical catalyzed chain dioxetane formation from 4(F) and 3(Cl) is significantly more face selective than epoxidation or diazetidine formation, as expected on electronic grounds; \u03c3,\u03c0 interaction should be larger in the radical cation.", "date": "1997-09-19", "date_type": "published", "publication": "Journal of Organic Chemistry", "volume": "62", "number": "19", "publisher": "American Chemical Society", "pagerange": "6539-6546", "id_number": "CaltechAUTHORS:20130821-160727814", "issn": "0022-3263", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160727814", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF", "grant_number": "CHE-9105485" }, { "agency": "NSF", "grant_number": "CHE-9417946" }, { "agency": "Department of Education" } ] }, "doi": "10.1021/jo970252r", "primary_object": { "basename": "jo6539.pdf", "url": "https://authors.library.caltech.edu/records/sv9a6-acy48/files/jo6539.pdf" }, "resource_type": "article", "pub_year": "1997", "author_list": "Nelsen, Stephen F.; Klein, Susan J.; et el." }, { "id": "https://authors.library.caltech.edu/records/ae9h4-dtp61", "eprint_id": 40849, "eprint_status": "archive", "datestamp": "2023-08-22 11:46:29", "lastmod": "2023-10-24 22:30:19", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Nelsen-S-F", "name": { "family": "Nelsen", "given": "Stephen F." } }, { "id": "Ramm-M-T", "name": { "family": "Ramm", "given": "Michael T." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Nagy-M-A", "name": { "family": "Nagy", "given": "Mark A." } }, { "id": "Trieber-D-A-II", "name": { "family": "Trieber", "given": "Dwight A., II" } }, { "id": "Powell-D-R", "name": { "family": "Powell", "given": "Douglas R." } }, { "id": "Chen-Xi-Wisconsin-Eau-Claire", "name": { "family": "Chen", "given": "Xi" } }, { "id": "Gengler-J-J", "name": { "family": "Gengler", "given": "Jamie J." } }, { "id": "Qu-Qinling", "name": { "family": "Qu", "given": "Qinling" } }, { "id": "Brandt-J-L", "name": { "family": "Brandt", "given": "Jennifer L." } }, { "id": "Pladziewicz-J-R", "name": { "family": "Pladziewicz", "given": "Jack R." } } ] }, "title": "Estimation of self-exchange electron transfer rate constants for organic compounds from stopped-flow studies", "ispublished": "pub", "full_text_status": "public", "keywords": "substituted para-phenylenediamines; activation parameters; radical cations; metal-complexes; marcus theory; kinetics; acetonitrile; quinonediimines; validity; systems", "note": "Copyright \u00a9 1997 American Chemical Society. \n\nPublished In Issue: June 25, 1997. Received January 30, 1997. \n\nWe thank the National Science Foundation for partial financial support of this work under Grants CHE-9504133 (J.R.P.) and \u22129417946 (S.F.N.). Acknowledgement is also made to the donors of the Petroleum Research Fund, administered by the ACS for partial support of the research under grant ACS-PRF 29982-B4 (JRP). We thank Fred King for assistance with Fortran programming.\n\nSupporting Information Available: Experimental for determination of ET rate constants for iPr2N)20/+ by 2H and 1H NMR, and crystal data for iPr2N)2, cHx2N)2, k33)2PD+PF6-, and k33N)2 (5 pages).\n\nSupplemental Material - ja5900.pdf
", "abstract": "Second-order rate constants k12(obsd) measured at 25 \u00b0C in acetonitrile by stopped-flow for 47 electron transfer (ET) reactions among ten tetraalkylhydrazines, four ferrocene derivatives, and three p-phenylenediamine derivatives are discussed. Marcus's adiabatic cross rate formula k12(calcd) = (k11 k22 k12 f12)1/2, ln f12 = (ln K12)2/4 ln(k11k22/Z2) works well to correlate these data. When all k12(obsd) values are simultaneously fitted to this relationship, best-fit self-exchange rate constants, kii(fit), are obtained that allow remarkably accurate calculation of k12(obsd); k12(obsd)/k12'(calcd) is in the range of 0.55\u22121.94 for all 47 reactions. The average \u0394\u0394Gij between observed activation free energy and that calculated using kii(fit) is 0.13 kcal/mol. Simulations using Jortner vibronic coupling theory to calculate k12 using parameters which produce the wide range of kii values observed predict that Marcus's formula should be followed even when V is as low as 0.1 kcal/mol, in the weakly nonadiabatic region. Tetracyclohexylhydrazine has a higher kii than tetraisopropylhydrazine by a factor of ca. 10. Replacing the dimethylamino groups of tetramethyl-p-phenylenediamine by 9-azabicyclo[3.3.1]nonyl groups has little effect on kii, demonstrating that conformations which have high intermolecular aromatic ring overlap are not necessary for large ET rate constants. Replacing a \u03b3 CH2 group of a 9-azabicyclo[3.3.1]nonyl group by a carbonyl group lowers kii by a factor of 17 for the doubly substituted hydrazine and by considerably less for the doubly substituted p-phenylenediamine.", "date": "1997-06-25", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "119", "number": "25", "publisher": "American Chemical Society", "pagerange": "5900-5907", "id_number": "CaltechAUTHORS:20130821-160728161", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160728161", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF", "grant_number": "CHE-9504133" }, { "agency": "NSF", "grant_number": "CHE-9417946" }, { "agency": "Petroleum Research Fund", "grant_number": "ACS-PRF 29982-B4" } ] }, "doi": "10.1021/ja970321j", "primary_object": { "basename": "ja5900.pdf", "url": "https://authors.library.caltech.edu/records/ae9h4-dtp61/files/ja5900.pdf" }, "resource_type": "article", "pub_year": "1997", "author_list": "Nelsen, Stephen F.; Ramm, Michael T.; et el." }, { "id": "https://authors.library.caltech.edu/records/pva1b-de575", "eprint_id": 40885, "eprint_status": "archive", "datestamp": "2023-08-19 00:44:17", "lastmod": "2023-10-24 22:33:08", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Troyansky-E-I", "name": { "family": "Troyansky", "given": "Emmanuil I." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Samoshin-V-V", "name": { "family": "Samoshin", "given": "Vyacheslav V." } } ] }, "title": "Homolytic cycloaddition of dithiols to alkynes leading to sulfur-containing heterocycles and crown thioethers: new comments to the mechanism", "ispublished": "pub", "full_text_status": "restricted", "abstract": "Multicenter three-electron (3e-2c) S-S bond formation can be employed to explain the cyclization in the homolytic addn. of \u03b1,\u03c9-thiols to alkynes.", "date": "1997", "date_type": "published", "publication": "Sulfur Letters", "volume": "20", "number": "5", "publisher": "Harwood", "pagerange": "219-224", "id_number": "CaltechAUTHORS:20130821-160734554", "issn": "0278-6117", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160734554", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "resource_type": "article", "pub_year": "1997", "author_list": "Troyansky, Emmanuil I.; Ismagilov, Rustem F.; et el." }, { "id": "https://authors.library.caltech.edu/records/rem7e-rcw77", "eprint_id": 40842, "eprint_status": "archive", "datestamp": "2023-08-22 11:08:08", "lastmod": "2023-10-24 22:29:46", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Nelsen-S-F", "name": { "family": "Nelsen", "given": "Stephen F." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Powell-D-R", "name": { "family": "Powell", "given": "Douglas R." } } ] }, "title": "Charge localization in a dihydrazine analogue of tetramethyl-p-phenylenediamine radical cation", "ispublished": "pub", "full_text_status": "public", "keywords": "electron-transfer reactions; substituted para- phenylenediamines; mixed-valence complexes; marcus theory; quinonediimines; dependence; validity", "note": "Copyright \u00a9 1996 American Chemical Society. \n\nPublished In Issue: July 03, 1996. Received February 16, 1996. \n\nWe thank the National Science Foundation for partial financial support of this work under Grant CHE-9417946, as well as the NSF, NIH, and University of Wisconsin for equipment grants used for purchasing the spectrometers and computers employed in this work.\n\nSupporting Information Available: Preparations and crystallographic data for 2, 2^+BPh_4^-, and 3^+NO_3^-; numbered thermal ellipsoid drawings, tables including heavy atom positions, bond lengths and angles, and anisotropic displacement parameters (20 pages).\n\nSupplemental Material - ja6313.cif
Supplemental Material - ja6313.html
Supplemental Material - ja6313.pdf
", "abstract": "n/a", "date": "1996-07-03", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "118", "number": "26", "publisher": "American Chemical Society", "pagerange": "6313-6314", "id_number": "CaltechAUTHORS:20130821-160726929", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160726929", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF", "grant_number": "CHE-9417946" }, { "agency": "NIH" }, { "agency": "University of Wisconsin" } ] }, "doi": "10.1021/ja960500l", "primary_object": { "basename": "ja6313.cif", "url": "https://authors.library.caltech.edu/records/rem7e-rcw77/files/ja6313.cif" }, "related_objects": [ { "basename": "ja6313.html", "url": "https://authors.library.caltech.edu/records/rem7e-rcw77/files/ja6313.html" }, { "basename": "ja6313.pdf", "url": "https://authors.library.caltech.edu/records/rem7e-rcw77/files/ja6313.pdf" } ], "resource_type": "article", "pub_year": "1996", "author_list": "Nelsen, Stephen F.; Ismagilov, Rustem F.; et el." }, { "id": "https://authors.library.caltech.edu/records/tx32h-adc58", "eprint_id": 40839, "eprint_status": "archive", "datestamp": "2023-08-22 10:52:13", "lastmod": "2023-10-24 22:29:33", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Nelsen-S-F", "name": { "family": "Nelsen", "given": "Stephen F." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Chen-Ling-Jen", "name": { "family": "Chen", "given": "Ling-Jen" } }, { "id": "Brandt-J-L", "name": { "family": "Brandt", "given": "Jennifer L." } }, { "id": "Chen-Xi-Wisconsin-Eau-Claire", "name": { "family": "Chen", "given": "Xi" } }, { "id": "Pladziewicz-J-R", "name": { "family": "Pladziewicz", "given": "Jack R." } } ] }, "title": "Slow electron transfer reactions involving tetraisopropylhydrazine", "ispublished": "pub", "full_text_status": "restricted", "keywords": "substituted para-phenylenediamines; organic-chemistry; sesquibicyclic hydrazine; activation parameters; transfer rates; marcus theory; outer-sphere; quinonediimines; validity; exchange", "note": "Copyright \u00a9 1996 American Chemical Society. \n\nPublished In Issue: February 14, 1996. Received November 3, 1995. \n\nWe thank the National Science Foundation for partial financial support of this work under Grants CHE-9504133 (J.R.P.) and -9105485 and -9417946 (S.F.N.). Acknowledgement is also made to the donors of the Petroleum Research Fund, administered by the American Chemical Society, for partial support of the research under Grant ACS-PRF 29982-B4 (J.R.P.).", "abstract": "n/a", "date": "1996-02-14", "date_type": "published", "publication": "Journal of the American Chemical Society", "volume": "118", "number": "6", "publisher": "American Chemical Society", "pagerange": "1555-1556", "id_number": "CaltechAUTHORS:20130821-160726256", "issn": "0002-7863", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160726256", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NSF", "grant_number": "CHE-9504133" }, { "agency": "NSF", "grant_number": "CHE-9105485" }, { "agency": "NSF", "grant_number": "CHE-9417946" }, { "agency": "Petroleum Research Fund", "grant_number": "ACS-PRF 29982-B4" } ] }, "doi": "10.1021/ja9537080", "resource_type": "article", "pub_year": "1996", "author_list": "Nelsen, Stephen F.; Ismagilov, Rustem F.; et el." }, { "id": "https://authors.library.caltech.edu/records/3nc7s-fm496", "eprint_id": 40886, "eprint_status": "archive", "datestamp": "2023-08-22 10:38:37", "lastmod": "2023-10-24 22:33:11", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Troyansky-E-I", "name": { "family": "Troyansky", "given": "Emmanuil I." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Samoshin-V-V", "name": { "family": "Samoshin", "given": "Vyacheslav V." } }, { "id": "Strelenko-Y-A", "name": { "family": "Strelenko", "given": "Yury A." } }, { "id": "Demchuk-D-V", "name": { "family": "Demchuk", "given": "Dmitry V." } }, { "id": "Nikishin-G-I", "name": { "family": "Nikishin", "given": "Gennady I." } }, { "id": "Lindeman-S-V", "name": { "family": "Lindeman", "given": "Sergey V." } }, { "id": "Khrustalyov-V-N", "name": { "family": "Khrustalyov", "given": "Viktor N." } }, { "id": "Struchkov-Y-T", "name": { "family": "Struchkov", "given": "Yury T." } } ] }, "title": "Stereoselective Free-Radical Cycloaddition-Macrocyclization in Facile Synthesis of Trans-Cyclohexano-Fused 12-Membered Crown Thioethers", "ispublished": "pub", "full_text_status": "public", "keywords": "ring-system; stereochemistry; cyclization; alkynes; construction; conformation; strategy; ethers; route", "note": "Copyright \u00a9 1995 Published by Elsevier. \n\n(Received in UK 27 June 1995; revsed 25 August 1995; accepted 1 September 1995) \n\nWe are grateful to Mr R Fleming (The University of Nottingham, U.K ) for recording several NMR (400 MHz) spectra We thank the InternatIonal Science Foundation (Soros Foundation) (Grant MPL 000) and Russian Foundation of Fundamental Studies (Projects 93-03-18110 and 94-03-09296) for generous financial support E.I.T. also indebtedly thanks the Royal Society for the Kapitza Fellowship and Professor Gerald Pattenden for very helpful discussion on macrocyclization. \n\nDedicated to Professor Nikolay S. Zefirnv on the occasion of his 60th birthday.", "abstract": "Homolytic cycloaddition of dithiols 1,2 derived from trans- and eis-1,2-cyclohexanediols to alkynes, induced by Pr3B-O2, offers an extremely simple approach to trans- and cis-cyclohexano-fused 12-membered crown thialactones 4a-c-7a-c. The reaction of trans-1 proceeds with pronounced remote 1,6-asymmetric induction to give predominantly (IS *, 6R *, 12S *)-4a\u2013c, while cis-2 reacts nonstereoselectively. Basing on molecular mechanics calculations the stereoselectivity is rationalized as a result of entropy favored pathway of macrocyclization.", "date": "1995-10-16", "date_type": "published", "publication": "Tetrahedron", "volume": "51", "number": "42", "publisher": "Elsevier", "pagerange": "11431-11444", "id_number": "CaltechAUTHORS:20130821-160734712", "issn": "0040-4020", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160734712", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "International Science Foundation", "grant_number": "MPL000" }, { "agency": "Russian Foundation for Fundamental Studies", "grant_number": "93-03-18110" }, { "agency": "Russian Foundation for Fundamental Studies", "grant_number": "94-03-09296" }, { "agency": "Royal Society" } ] }, "doi": "10.1016/0040-4020(95)00707-F", "resource_type": "article", "pub_year": "1995", "author_list": "Troyansky, Emmanuil I.; Ismagilov, Rustem F.; et el." }, { "id": "https://authors.library.caltech.edu/records/t6b6k-s7795", "eprint_id": 40887, "eprint_status": "archive", "datestamp": "2023-08-22 10:22:39", "lastmod": "2023-10-24 22:33:17", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Troyansky-E-I", "name": { "family": "Troyansky", "given": "Emmanuil I." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Strelenko-Y-A", "name": { "family": "Strelenko", "given": "Yury A." } }, { "id": "Samoshin-V-V", "name": { "family": "Samoshin", "given": "Vyacheslav V." } }, { "id": "Demchuk-D-V", "name": { "family": "Demchuk", "given": "Dmitry V." } }, { "id": "Nikishin-G-I", "name": { "family": "Nikishin", "given": "Gennady I." } }, { "id": "Lindeman-S-V", "name": { "family": "Lindeman", "given": "Sergey V." } }, { "id": "Khrustalyov-V-N", "name": { "family": "Khrustalyov", "given": "Viktor N." } }, { "id": "Struchkov-Y-T", "name": { "family": "Struchkov", "given": "Yury T." } } ] }, "title": "Remote Asymmetric Induction in Free-Radical Cycloaddition Leading to Trans-Cyclohexano-Fused 12-Membered Crown Thioethers", "ispublished": "pub", "full_text_status": "restricted", "keywords": "macrocyclization; construction; alkynes; route", "note": "Copyright \u00a9 1995 Elsevier. \n\nReceived 1 November 1994. Accepted 3 February 1995. Available online 14 June 2000. \n\nWe are grateful to Mr. R. Fleming (The University of Nottingham, U.K.) for recording several NMR spectra. We also thank the Russian Foundation of Fundamental Studies (Projects 93-03-18110 and 94-03-09296) and Intemational Science Foundation (Soros Foundation) (Grant MPL 000) for generous financial support.", "abstract": "Homolytic cycloaddition of dithiol 1, derived from trans-1,2-cyclohexanediol, to alkynes induced by Pr3B\ue5f8O2 occurs with 1,6-asymmetric induction to afford predominantly (1S\u2217, 6R\u2217, 12S\u2217)-trans-cyclohexano-fused 12-membered crown thialactones 4a-c. No pronounced diasteroselectivity was found in the corresponding reactions of dithiol 2, derived from cis-1,2-cyclohexanediol.", "date": "1995-03-27", "date_type": "published", "publication": "Tetrahedron Letters", "volume": "36", "number": "13", "publisher": "Elsevier", "pagerange": "2293-2294", "id_number": "CaltechAUTHORS:20130821-160734870", "issn": "0040-4039", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160734870", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Russian Foundation for Fundamental Studies", "grant_number": "93-03-18110" }, { "agency": "Russian Foundation for Fundamental Studies", "grant_number": "94-03-09296" }, { "agency": "International Science Foundation", "grant_number": "MPL000" } ] }, "doi": "10.1016/0040-4039(95)00287-5", "resource_type": "article", "pub_year": "1995", "author_list": "Troyansky, Emmanuil I.; Ismagilov, Rustem F.; et el." }, { "id": "https://authors.library.caltech.edu/records/0qkn1-h1484", "eprint_id": 40787, "eprint_status": "archive", "datestamp": "2023-08-22 10:20:45", "lastmod": "2023-10-24 21:59:25", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Demchuk-D-V", "name": { "family": "Demchuk", "given": "Dmitry V." } }, { "id": "Lazareva-M-I", "name": { "family": "Lazareva", "given": "Margarita I." } }, { "id": "Lindeman-S-V", "name": { "family": "Lindeman", "given": "Sergey V." } }, { "id": "Khrustalyov-V-N", "name": { "family": "Khrustalyov", "given": "Viktor N." } }, { "id": "Struchkov-Y-T", "name": { "family": "Struchkov", "given": "Yurii T." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Troyansky-E-I", "name": { "family": "Troyansky", "given": "Emmanuil I." } }, { "id": "Nikishin-G-I", "name": { "family": "Nikishin", "given": "Gennady I." } } ] }, "title": "Synthesis of 12-Membered and 13-Membered Sulfur-Containing Lactones by Homolytic Macrocyclization of Mercaptoacetic Esters with Alkynes", "ispublished": "pub", "full_text_status": "public", "keywords": "thiacrown lactones; homolytic macrocyclization; tripropylborane crown-ethers; route", "note": "\u00a9 Georg Thieme Verlag, R\u00fcdigerstr.\n\nReceived 11 August 1994.\n\nThe authors are grateful to the Russian Foundation of Fundamental Studies for financial support (Project 93-03-18110).\n\nPublished - s-1995-3891.pdf_update=003dtrue
Published - s-1995-3891.pdf_update=true
", "abstract": "Starting from mercaptoacetic acid esters of 1,2- or 1,3-diols and substituted acetylenes 12- and 13-membered sulfur-containing lactones as 1:1 adducts were synthesized in yields up to 48%. The mechanism of this homolytic reaction, which is initiated by the tripropylborane/oxygen system, includes generation of thiyl radicals and their addition to the triple bond of alkynes.", "date": "1995-03", "date_type": "published", "publication": "Synthesis-Stuttgart", "volume": "1995", "number": "3", "publisher": "Georg Thieme Verlag", "pagerange": "307-311", "id_number": "CaltechAUTHORS:20130821-160717675", "issn": "0039-7881", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160717675", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Russian Foundation for Fundamental Studies", "grant_number": "93-03-18110" } ] }, "doi": "10.1055/s-1995-3891", "primary_object": { "basename": "s-1995-3891.pdf_update=003dtrue", "url": "https://authors.library.caltech.edu/records/0qkn1-h1484/files/s-1995-3891.pdf_update=003dtrue" }, "resource_type": "article", "pub_year": "1995", "author_list": "Demchuk, Dmitry V.; Lazareva, Margarita I.; et el." }, { "id": "https://authors.library.caltech.edu/records/ypz31-m0t46", "eprint_id": 40883, "eprint_status": "archive", "datestamp": "2023-08-22 10:11:38", "lastmod": "2023-10-24 22:32:54", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Troyansky-E-I", "name": { "family": "Troyansky", "given": "Emmanuil I." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Korneeva-E-N", "name": { "family": "Korneeva", "given": "Ekaterina N." } }, { "id": "Pogosyan-M-S", "name": { "family": "Pogosyan", "given": "Mariam S." } }, { "id": "Nikishin-G-I", "name": { "family": "Nikishin", "given": "Gennady I." } } ] }, "title": "An Approach to 8-Membered, 16-Membered and 24-Membered Sulfur- Containing Heterocycles Via Homolytic Cycloaddition of Alkynes with Butane-1,4-Dithiol", "ispublished": "pub", "full_text_status": "restricted", "keywords": "crown thioethers; macrocyclization; construction; route", "note": "Copyright \u00a9 1995 jointly by The Russian Academy of Sciences and The Royal Society of Chemistry (Turpion Ltd). \n\nReceived 15 November 1994. Available online 11 March 2008. \n\nThe authors are indebted for financial support to the Russian Foundation for Fundamental Research (project no. 93-03-18110) and the International Science Foundation (grant no. MPL000).", "abstract": "Homolytic cycloaddition of butane-1,4-dithiol with alkynes offers a facile one-pot route to 8-membered 1,4-dithiocanes and 16-and 24-membered crown thioethers, 1,4,9,12-tetrathiacyclohexadecanes and 1,4,9,12,17,20-hexathiacyclotetracosanes.", "date": "1995", "date_type": "published", "publication": "Mendeleev Communications", "volume": "5", "number": "1", "publisher": "Elsevier", "pagerange": "18-20", "id_number": "CaltechAUTHORS:20130821-160734243", "issn": "0959-9436", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160734243", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Russian Foundation for Fundamental Studies", "grant_number": "93-03-18110" }, { "agency": "International Science Foundation", "grant_number": "MPL000" } ] }, "doi": "10.1070/MC1995v005n01ABEH000441", "resource_type": "article", "pub_year": "1995", "author_list": "Troyansky, Emmanuil I.; Ismagilov, Rustem F.; et el." }, { "id": "https://authors.library.caltech.edu/records/xwgef-ghj91", "eprint_id": 40884, "eprint_status": "archive", "datestamp": "2023-08-20 02:03:28", "lastmod": "2023-10-24 22:33:00", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Troyansky-E-I", "name": { "family": "Troyansky", "given": "Emmanuil I." } }, { "id": "Demchuk-D-V", "name": { "family": "Demchuk", "given": "Dmitry V." } }, { "id": "Ismagilov-R-F", "name": { "family": "Ismagilov", "given": "Rustem F." }, "orcid": "0000-0002-3680-4399" }, { "id": "Lazareva-M-I", "name": { "family": "Lazareva", "given": "Margarita I." } }, { "id": "Strelenko-Y-A", "name": { "family": "Strelenko", "given": "Yurii A." } }, { "id": "Nikishin-G-I", "name": { "family": "Nikishin", "given": "Gennady I." } } ] }, "title": "Homolytic Macrocyclization of Alkynes with Propane-1,3-Dithiol as a Route to 14-Membered and 21-Membered Crown Thioethers", "ispublished": "pub", "full_text_status": "restricted", "note": "Copyright \u00a9 1993 jointly by The Russian Academy of Sciences and The Royal Society of Chemistry (Turpion Ltd). \n\nReceived 8 January 1993.", "abstract": "Crown thioethers, 1,4,8,11-tetrathiacyclotetradecanes and 1,4,8,11,15,18-hexathiaheneicosanes, have been synthesized as 2:2 and 3:3 cycloadducts in a 'one-pot' homolytic macrocyclization of alkynes with propane-1,3-dithiol.", "date": "1993", "date_type": "published", "publication": "Mendeleev Communications", "volume": "3", "number": "3", "publisher": "Elsevier", "pagerange": "112-114", "id_number": "CaltechAUTHORS:20130821-160734409", "issn": "0959-9436", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130821-160734409", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1070/MC1993v003n03ABEH000248", "resource_type": "article", "pub_year": "1993", "author_list": "Troyansky, Emmanuil I.; Demchuk, Dmitry V.; et el." } ]