[ { "id": "https://authors.library.caltech.edu/records/w9sxn-f7e77", "eprint_status": "archive", "datestamp": "2023-12-22 17:11:26", "lastmod": "2024-01-09 22:23:33", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Vasquez-Ayala-Adriana", "name": { "family": "Vasquez Ayala", "given": "Adriana" }, "orcid": "0000-0001-6917-3581" }, { "id": "Hsu-Chia-Yun", "name": { "family": "Hsu", "given": "Chia-Yun" }, "orcid": "0000-0002-5283-1020" }, { "id": "Oles-Renee-E", "name": { "family": "Oles", "given": "Renee E." }, "orcid": "0000-0001-5945-0215" }, { "id": "Matsuo-Kazuhiko", "name": { "family": "Matsuo", "given": "Kazuhiko" }, "orcid": "0000-0001-5782-5300" }, { "id": "Loomis-Luke-R", "name": { "family": "Loomis", "given": "Luke R." }, "orcid": "0009-0003-1131-7185" }, { "id": "Buzun-Ekaterina", "name": { "family": "Buzun", "given": "Ekaterina" }, "orcid": "0000-0002-1223-1290" }, { "id": "Carrillo-Terrazas-Marvic", "name": { "family": "Carrillo Terrazas", "given": "Marvic" }, "orcid": "0000-0002-8830-5161" }, { "id": "Gerner-Romana-R", "name": { "family": "Gerner", "given": "Romana R." }, "orcid": "0000-0003-2377-6509" }, { "id": "Lu-Hsueh-Han", "name": { "family": "Lu", "given": "Hsueh-Han" }, "orcid": "0000-0002-0832-9607" }, { "id": "Kim-Sohee", "name": { "family": "Kim", "given": "Sohee" }, "orcid": "0009-0003-0989-5584" }, { "id": "Zhang-Ziyue", "name": { "family": "Zhang", "given": "Ziyue" }, "orcid": "0009-0002-8996-6049" }, { "id": "Park-Jong-Hwee", "name": { "family": "Park", "given": "Jong Hwee" }, "orcid": "0009-0002-6522-7049" }, { "id": "Rivaud-Paul", "name": { "family": "Rivaud", "given": "Paul" }, "orcid": "0000-0001-8637-3331" }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" }, "orcid": "0000-0003-1021-1234" }, { "id": "Lu-Li-Fan", "name": { "family": "Lu", "given": "Li-Fan" }, "orcid": "0000-0002-9727-0036" }, { "id": "Min-Booki", "name": { "family": "Min", "given": "Booki" }, "orcid": "0000-0002-2151-9413" }, { "id": "Chu-Hiutung", "name": { "family": "Chu", "given": "Hiutung" }, "orcid": "0000-0001-7489-0446" } ] }, "title": "Commensal bacteria promote type I interferon signaling to maintain immune tolerance in mice", "ispublished": "pub", "full_text_status": "public", "keywords": "Immunology; Immunology and Allergy", "note": "
\u00a9 2023 Vasquez Ayala et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
\n\nWe thank members of the Chu lab for technical support and helpful discussions, and A. Khosravi and G. Sharon for critical reading of the manuscript. We thank Drs. Victor Nizet (University of California, San Diego, La Jolla, CA, USA) and Manuela Raffatellu (University of California, San Diego, La Jolla, CA, USA) for sharing bacterial strains and to the Flow Cytometry Core Facility at the La Jolla Institute and Cheryl Kim for their expertise and instrument support.
This work was supported by R00 DK110534 and P30 DK120515 from the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK), R01 A167860 from the National Institute of Allergy and Infectious Diseases (NIAID), and the Chiba University-UC San Diego Center for Mucosal Immunology, Allergy and Vaccines to H. Chu; and NIAID AI108651 and AI163813 to L-F. Lu and AI125247 to B. Min. Additional support was provided to H. Chu by the Canadian Institute for Advanced Research Humans and the Microbiome Program, The Hartwell Foundation, and Japan Agency for Medical Research and Development (JP233fa627003). M. Carrillo Terrazas was supported by T32 DK007202 (NIDDK), the National Academies of Sciences, Engineering and Medicine through the Predoctoral Fellowship of the Ford Foundation, and the Howard Hughes Medical Institute Graduate Fellowships grant (GT15123).
\n\nH. Chu conceived the project and designed the experiments. A. Vasquez Ayala, C-Y. Hsu, K. Matsuo, E. Buzun, M. Carrillo Terrazas, L.R. Loomis, H-H. Lu, R.R. Gerner, and H. Chu performed the experiments. J.H. Park and P. Rivaud performed the single-cell analysis experiments, R.E. Oles performed computational analyses, and A. Vasquez Ayala, K. Matsuo, C-Y. Hsu, H-H. Lu, and H. Chu analyzed the data. M. Thomson supported and supervised the single-cell RNA sequencing studies. Z. Zhang, S. Kim, L-F. Lu, and B. Min provided key resources and technical guidance. H. Chu supervised the project and wrote the manuscript with contributions from all authors.
\n\nThe data are available from the corresponding author upon reasonable request. The single-cell RNA sequencing data underlying Fig. 4 are openly available in the NCBI Gene Expression Omnibus (GEO) under accession number GSE248021.
", "abstract": "Type I interferons (IFNs) exert a broad range of biological effects important in coordinating immune responses, which have classically been studied in the context of pathogen clearance. Yet, whether immunomodulatory bacteria operate through IFN pathways to support intestinal immune tolerance remains elusive. Here, we reveal that the commensal bacterium, Bacteroides fragilis, utilizes canonical antiviral pathways to modulate intestinal dendritic cells (DCs) and regulatory T cell (Treg) responses. Specifically, IFN signaling is required for commensal-induced tolerance as IFNAR1-deficient DCs display blunted IL-10 and IL-27 production in response to B. fragilis. We further establish that IFN-driven IL-27 in DCs is critical in shaping the ensuing Foxp\u00b3\u207a Treg via IL-27R\u03b1 signaling. Consistent with these findings, single-cell RNA sequencing of gut Tregs demonstrated that colonization with B. fragilis promotes a distinct IFN gene signature in Foxp3+ Tregs during intestinal inflammation. Altogether, our findings demonstrate a critical role of commensal-mediated immune tolerance via tonic type I IFN signaling.
", "date": "2024-01-01", "date_type": "published", "publication": "Journal of Experimental Medicine", "volume": "221", "number": "1", "publisher": "Rockefeller University Press", "pagerange": "e20230063", "issn": "0022-1007", "official_url": "https://authors.library.caltech.edu/records/w9sxn-f7e77", "funders": { "items": [ { "grant_number": "R00 DK110534" }, { "grant_number": "P30 DK120515" }, { "grant_number": "R01 A167860" }, {}, {}, { "grant_number": "AI108651" }, { "grant_number": "AI163813" }, { "grant_number": "AI125247" }, {}, {}, { "grant_number": "JP233fa627003" }, { "grant_number": "T32 DK007202" }, {}, {}, { "grant_number": "GT15123" } ] }, "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" }, { "id": "Tianqiao-and-Chrissy-Chen-Institute-for-Neuroscience" } ] }, "doi": "10.1084/jem.20230063", "pmcid": "PMC10716256", "primary_object": { "basename": "JEM_20230063.pdf", "url": "https://authors.library.caltech.edu/records/w9sxn-f7e77/files/JEM_20230063.pdf" }, "resource_type": "article", "pub_year": "2024", "author_list": "Vasquez Ayala, Adriana; Hsu, Chia-Yun; et el." }, { "id": "https://authors.library.caltech.edu/records/e527q-6pq77", "eprint_status": "archive", "datestamp": "2023-09-12 21:11:18", "lastmod": "2024-01-09 22:19:20", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Pool-Allan-Hermann", "name": { "family": "Pool", "given": "Allan-Hermann" }, "orcid": "0000-0002-0811-9861" }, { "id": "Poldsam-Helen", "name": { "family": "Poldsam", "given": "Helen" }, "orcid": "0009-0008-0390-2620" }, { "name": { "family": "Chen", "given": "Sisi" } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" }, "orcid": "0000-0003-1021-1234" }, { "id": "Oka-Yuki", "name": { "family": "Oka", "given": "Yuki" }, "orcid": "0000-0003-2686-0677" } ] }, "title": "Recovery of missing single-cell RNA-sequencing data with optimized transcriptomic references", "ispublished": "pub", "full_text_status": "public", "keywords": "Cell Biology; Molecular Biology; Biochemistry; Biotechnology", "note": "\u00a9 2023. The Author(s), under exclusive licence to Springer Nature.
\n\nWe thank L. S. Pachter and members of the M.T. lab for helpful discussion and comments. We thank the Single-Cell Profiling Center (SPEC) in the Beckman Institute at Caltech for technical assistance with scRNA-seq. A.H.P. is supported by Eugene McDermott Scholar funds and by Startup funds from Peter O'Donnell Jr. Brain Institute at UT Southwestern. Y.O. is supported by Startup funds from the President and Provost of the California Institute of Technology and the Biology and Biological Engineering Division of California Institute of Technology, Searle Scholars Program, the Mallinckrodt Foundation, the McKnight Foundation, the Klingenstein\u2013Simons Foundation, the New York Stem Cell Foundation and the NIH (grant nos. R56MH113030 and R01NS109997).
\n\nA.-H.P. conceived and designed the project. A.-H.P. and H.P. devised and performed data analysis. A.-H.P. and S.C. generated the MnPO scRNA-seq dataset. S.C. and M.T. generated the human PBMC scRNA-seq dataset. S.C., M.T. and Y.O. provided conceptual advice on data analysis. All authors contributed to the manuscript as drafted by A.-H.P. and H.P. A.-H.P. and Y.O. supervised the overall project.
\n\nRaw and fully processed scRNA-seq data generated for this project (mouse MnPO and human PBMC) are available at the NCBI Gene Expression Omnibus (GEO, GSE198528). Additionally, previously published mouse and human datasets were analyzed including mouse 10x Genomics scRNA-seq datasets generated by the Tabula Muris consortium (bone marrow, SRR6835854; kidney, SRR6835849; lung, SRR6835860; tongue, SRR6835844), which can be accessed from the GEO repository GSE132042. Human brain scRNA-seq data generated from the prefrontal cortex (CS22_PFC) were acquired from the NEMO archive at https://assets.nemoarchive.org/dat-0rsydy7, which requires a custom data use agreement. Finally, human 10x Genomics scRNA-seq data (liver, TSP14_Liver_NA; lung, TSP14_Lung_Proximal; tongue, TSP14_Tongue_Anterior) generated by the Tabula Sapiens consortium can be accessed through the Tabula Sapiens AWS storage web service accessible from https://tabula-sapiens-portal.ds.czbiohub.org/ and requires a custom data use agreement. Baseline single-cell transcriptomic references for human (GRCh38) and mouse (mm10) datasets were downloaded from 10X Genomics (latest available version 2020-A): https://support.10xgenomics.com/single-cell-gene-expression/software/downloads/latest?. Latest optimized versions of the mouse and human reference transcriptomes and respective genome annotations are available for download at www.thepoollab.org/resources.
\n\nCustom scripts for analyzing data and generating figures are available at https://github.com/PoolLab/Generecovery. ReferenceEnhancer R package for optimizing genome annotations for scRNA-seq analysis is available at https://github.com/PoolLab/ReferenceEnhancer.
\n\nThe authors declare no competing interests.
", "abstract": "Single-cell RNA-sequencing (scRNA-seq) is an indispensable tool for characterizing cellular diversity and generating hypotheses throughout biology. Droplet-based scRNA-seq datasets often lack expression data for genes that can be detected with other methods. Here we show that the observed sensitivity deficits stem from three sources: (1) poor annotation of 3\u2032 gene ends; (2) issues with intronic read incorporation; and (3) gene overlap-derived read loss. We show that missing gene expression data can be recovered by optimizing the reference transcriptome for scRNA-seq through recovering false intergenic reads, implementing a hybrid pre-mRNA mapping strategy and resolving gene overlaps. We demonstrate, with a diverse collection of mouse and human tissue data, that reference optimization can substantially improve cellular profiling resolution and reveal missing cell types and marker genes. Our findings argue that transcriptomic references need to be optimized for scRNA-seq analysis and warrant a reanalysis of previously published datasets and cell atlases.
", "date": "2023-09-11", "date_type": "published", "publication": "Nature Methods", "publisher": "Nature Publishing Group", "issn": "1548-7091", "official_url": "https://authors.library.caltech.edu/records/e527q-6pq77", "funders": { "items": [ {}, {}, {}, {}, { "grant_number": "R56MH113030" }, { "grant_number": "R01NS109997" } ] }, "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1038/s41592-023-02003-w", "primary_object": { "basename": "41592_2023_2003_MOESM4_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/e527q-6pq77/files/41592_2023_2003_MOESM4_ESM.xlsx" }, "related_objects": [ { "basename": "41592_2023_2003_Fig6_ESM.jpg", "url": "https://authors.library.caltech.edu/records/e527q-6pq77/files/41592_2023_2003_Fig6_ESM.jpg" }, { "basename": "41592_2023_2003_Fig7_ESM.jpg", "url": "https://authors.library.caltech.edu/records/e527q-6pq77/files/41592_2023_2003_Fig7_ESM.jpg" }, { "basename": "41592_2023_2003_Fig8_ESM.jpg", "url": "https://authors.library.caltech.edu/records/e527q-6pq77/files/41592_2023_2003_Fig8_ESM.jpg" }, { "basename": "41592_2023_2003_Fig9_ESM.jpg", "url": "https://authors.library.caltech.edu/records/e527q-6pq77/files/41592_2023_2003_Fig9_ESM.jpg" }, { "basename": "41592_2023_2003_MOESM3_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/e527q-6pq77/files/41592_2023_2003_MOESM3_ESM.xlsx" } ], "resource_type": "article", "pub_year": "2023", "author_list": "Pool, Allan-Hermann; Poldsam, Helen; et el." }, { "id": "https://authors.library.caltech.edu/records/5bqk7-b1e47", "eprint_id": 121677, "eprint_status": "archive", "datestamp": "2023-08-22 21:31:10", "lastmod": "2023-12-22 23:31:01", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Bao-Min", "name": { "family": "Bao", "given": "Min" }, "orcid": "0000-0003-0992-9388" }, { "id": "Cornwall-Scoones-Jake", "name": { "family": "Cornwall-Scoones", "given": "Jake" }, "orcid": "0000-0002-7435-486X" }, { "id": "Sanchez-Vasquez-Estefania", "name": { "family": "Sanchez-Vasquez", "given": "Estefania" }, "orcid": "0000-0002-6585-8548" }, { "id": "Cox-Andy-L", "name": { "family": "Cox", "given": "Andy L." } }, { "id": "Chen-Dong-Yuan", "name": { "family": "Chen", "given": "Dong-Yuan" }, "orcid": "0000-0003-2179-2847" }, { "id": "De-Jonghe-Joachim", "name": { "family": "De Jonghe", "given": "Joachim" }, "orcid": "0000-0003-0584-8265" }, { "id": "Shadkhoo-Shahriar", "name": { "family": "Shadkhoo", "given": "Shahriar" }, "orcid": "0000-0003-3582-0634" }, { "id": "Hollfelder-Florian", "name": { "family": "Hollfelder", "given": "Florian" }, "orcid": "0000-0002-1367-6312" }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" }, "orcid": "0000-0003-1021-1234" }, { "id": "Glover-D-M", "name": { "family": "Glover", "given": "David M." }, "orcid": "0000-0003-0956-0103" }, { "id": "Zernicka-Goetz-M", "name": { "family": "Zernicka-Goetz", "given": "Magdalena" }, "orcid": "0000-0002-7004-2471" } ] }, "title": "Stem cell-derived synthetic embryos self-assemble by exploiting cadherin codes and cortical tension", "ispublished": "pub", "full_text_status": "public", "keywords": "Cell Biology", "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\nThis work was supported by the Wellcome Trust (207415/Z/17/Z), an European Research Council advanced grant (669198), a National Institutes of Health R01 (HD100456-01A1) grant, the National Institutes of Health Pioneer Award (DP1 HD104575-01), the Tianqiao and Chrissy Chen Institute for Neuroscience and Shurl and Kay Curci Foundation grants to M.Z.-G. E.S.-V. is supported by a Pew Latin America fellowship. M.B. is supported by a Caltech Postdoctoral Fellowship. We thank the Life Science Foundation, members of the M.Z.-G. laboratory and A. Winkel for invaluable comments and suggestions.\n\nPublished - 41556_2022_Article_984.pdf
Erratum - s41556-023-01157-1.pdf
", "abstract": "Mammalian embryos sequentially differentiate into trophectoderm and an inner cell mass, the latter of which differentiates into primitive endoderm and epiblast. Trophoblast stem (TS), extraembryonic endoderm (XEN) and embryonic stem (ES) cells derived from these three lineages can self-assemble into synthetic embryos, but the mechanisms remain unknown. Here, we show that a stem cell-specific cadherin code drives synthetic embryogenesis. The XEN cell cadherin code enables XEN cell sorting into a layer below ES cells, recapitulating the sorting of epiblast and primitive endoderm before implantation. The TS cell cadherin code enables TS cell sorting above ES cells, resembling extraembryonic ectoderm clustering above epiblast following implantation. Whereas differential cadherin expression drives initial cell sorting, cortical tension consolidates tissue organization. By optimizing cadherin code expression in different stem cell lines, we tripled the frequency of correctly formed synthetic embryos. Thus, by exploiting cadherin codes from different stages of development, lineage-specific stem cells bypass the preimplantation structure to directly assemble a postimplantation embryo.", "date": "2023-09", "date_type": "published", "publication": "Nature Cell Biology", "volume": "24", "number": "9", "publisher": "Nature Publishing Group", "pagerange": "1341-2349", "id_number": "CaltechAUTHORS:20230602-251540000.11", "issn": "1465-7392", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20230602-251540000.11", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Wellcome Trust", "grant_number": "207415/Z/17/Z" }, { "agency": "European Research Council (ERC)", "grant_number": "669198" }, { "agency": "NIH", "grant_number": "HD100456-01A1" }, { "agency": "NIH", "grant_number": "DP1 HD104575-01" }, { "agency": "Tianqiao and Chrissy Chen Institute for Neuroscience" }, { "agency": "Shurl and Kay Curci Foundation" }, { "agency": "Pew Latin American Fellows Program" }, { "agency": "Caltech Postdoctoral Fellowship" } ] }, "local_group": { "items": [ { "id": "Tianqiao-and-Chrissy-Chen-Institute-for-Neuroscience" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1038/s41556-022-00984-y", "pmcid": "PMC9481465", "primary_object": { "basename": "41556_2022_Article_984.pdf", "url": "https://authors.library.caltech.edu/records/5bqk7-b1e47/files/41556_2022_Article_984.pdf" }, "related_objects": [ { "basename": "s41556-023-01157-1.pdf", "url": "https://authors.library.caltech.edu/records/5bqk7-b1e47/files/s41556-023-01157-1.pdf" } ], "resource_type": "article", "pub_year": "2023", "author_list": "Bao, Min; Cornwall-Scoones, Jake; 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/n6ej8-0m894", "eprint_id": 122030, "eprint_status": "archive", "datestamp": "2023-08-20 16:50:40", "lastmod": "2023-12-22 23:39:47", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Lemma-Linnea-M", "name": { "family": "Lemma", "given": "Linnea M." }, "orcid": "0000-0001-8482-4573" }, { "id": "Varghese-Minu", "name": { "family": "Varghese", "given": "Minu" }, "orcid": "0000-0003-4410-0233" }, { "id": "Ross-Tyler-D", "name": { "family": "Ross", "given": "Tyler D." }, "orcid": "0000-0002-7872-3992" }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" }, "orcid": "0000-0003-1021-1234" }, { "id": "Baskaran-Aparna", "name": { "family": "Baskaran", "given": "Aparna" }, "orcid": "0000-0003-1899-9978" }, { "id": "Dogic-Zvonimir", "name": { "family": "Dogic", "given": "Zvonimir" }, "orcid": "0000-0003-0142-1838" } ] }, "title": "Spatio-temporal patterning of extensile active stresses in microtubule-based active fluids", "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\nWe acknowledge useful discussions with Seth Fraden. We thank Claire E. Walczak and Stephanie C. Ems-McClung for the gift of kinesin-14 protein. We thank Bezia Lemma for help with kinesin-14 experiments. \n\nThis work was primary supported by the Department of Energy (DOE) DE-SC0022291. Biochemical portion of this work was supported by the Brandeis Center for Bioinspired Soft Materials, an NSF MRSEC (DMR-2011846). We also acknowledge the use of a MRSEC optical and biosynthesis facility supported by NSF-MRSEC-2011846, the use of the NRI-MCDB Microscopy Facility at UCSB supported by NSF-MRI grant 1625770. \n\nAuthors' contribution. L.M.L. and Z.D. conceived the experiments; L.M.L. and T.D.R. conducted experiments; M.V. and A.B. created the hydrodynamic model; L.M.L. and M.V. performed data analysis; M.T., A.B. and Z.D supervised the project; all authors wrote and reviewed the manuscript. \n\nData availability. Data is available from https://doi.org/10.5061/dryad.83bk3j9vh.\n\nPublished - pgad130.pdf
Supplemental Material - pgad130_supplementary_data.zip
", "abstract": "Microtubule-based active fluids exhibit turbulent-like autonomous flows, which are driven by the molecular motor powered motion of filamentous constituents. Controlling active stresses in space and time is an essential prerequisite for controlling the intrinsically chaotic dynamics of extensile active fluids. We design single-headed kinesin molecular motors that exhibit optically enhanced clustering and thus enable precise and repeatable spatial and temporal control of extensile active stresses. Such motors enable rapid, reversible switching between flowing and quiescent states. In turn, spatio-temporal patterning of the active stress controls the evolution of the ubiquitous bend instability of extensile active fluids and determines its critical length dependence. Combining optically controlled clusters with conventional kinesin motors enables one-time switching from contractile to extensile active stresses. These results open a path towards real-time control of the autonomous flows generated by active fluids.", "date": "2023-05", "date_type": "published", "publication": "PNAS Nexus", "volume": "2", "number": "5", "publisher": "Oxford University Press", "pagerange": "Art. No. pgad130", "id_number": "CaltechAUTHORS:20230628-257194000.34", "issn": "2752-6542", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20230628-257194000.34", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Department of Energy", "grant_number": "DE-SC0022291" }, { "agency": "NSF", "grant_number": "DMR-2011846" }, { "agency": "NSF", "grant_number": "DBI-1625770" } ] }, "local_group": { "items": [ { "id": "Tianqiao-and-Chrissy-Chen-Institute-for-Neuroscience" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1093/pnasnexus/pgad130", "pmcid": "PMC10165807", "primary_object": { "basename": "pgad130.pdf", "url": "https://authors.library.caltech.edu/records/n6ej8-0m894/files/pgad130.pdf" }, "related_objects": [ { "basename": "pgad130_supplementary_data.zip", "url": "https://authors.library.caltech.edu/records/n6ej8-0m894/files/pgad130_supplementary_data.zip" } ], "resource_type": "article", "pub_year": "2023", "author_list": "Lemma, Linnea M.; Varghese, Minu; 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/694bn-4vx45", "eprint_id": 121366, "eprint_status": "archive", "datestamp": "2023-08-22 19:00:12", "lastmod": "2023-12-22 23:09:03", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Banks-Rachel-A", "name": { "family": "Banks", "given": "Rachel A." }, "orcid": "0000-0003-2028-2925" }, { "id": "Galstyan-Vahe", "name": { "family": "Galstyan", "given": "Vahe" }, "orcid": "0000-0001-7073-9175" }, { "id": "Lee-Heun-Jin", "name": { "family": "Lee", "given": "Heun Jin" } }, { "id": "Hirokawa-Soichi", "name": { "family": "Hirokawa", "given": "Soichi" }, "orcid": "0000-0001-5584-2676" }, { "id": "Ierokomos-Athena", "name": { "family": "Ierokomos", "given": "Athena" } }, { "id": "Ross-Tyler-D", "name": { "family": "Ross", "given": "Tyler D." }, "orcid": "0000-0002-7872-3992" }, { "id": "Bryant-Zev", "name": { "family": "Bryant", "given": "Zev" } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" }, "orcid": "0000-0003-1021-1234" }, { "id": "Phillips-R", "name": { "family": "Phillips", "given": "Rob" }, "orcid": "0000-0003-3082-2809" } ] }, "title": "Motor processivity and speed determine structure and dynamics of microtubule-motor assemblies", "ispublished": "pub", "full_text_status": "public", "keywords": "General Immunology and Microbiology; General Biochemistry, Genetics and Molecular Biology; General Medicine; General Neuroscience", "note": "\u00a9 2023, Banks 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\nWe are grateful to Dan Needleman, Madhav Mani, Peter Foster, and Ana Duarte for fruitful discussions. We acknowledge support from the NIH through grant 1R35 GM118043-01; the John Templeton Foundation as part of the Boundaries of Life Initiative through grants 51250 and 60973; the Foundational Questions Institute and Fetzer Franklin Fund through FQXi 1816. \n\nData availability. All data associated with this study are stored on the CaltechData archive at https://doi.org/10.22002/D1.2152.\n\nPublished - elife-79402.pdf
", "abstract": "Active matter systems can generate highly ordered structures, avoiding equilibrium through the consumption of energy by individual constituents. How the microscopic parameters that characterize the active agents are translated to the observed mesoscopic properties of the assembly has remained an open question. These active systems are prevalent in living matter; for example, in cells, the cytoskeleton is organized into structures such as the mitotic spindle through the coordinated activity of many motor proteins walking along microtubules. Here, we investigate how the microscopic motor-microtubule interactions affect the coherent structures formed in a reconstituted motor-microtubule system. This question is of deeper evolutionary significance as we suspect motor and microtubule type contribute to the shape and size of resulting structures. We explore key parameters experimentally and theoretically, using a variety of motors with different speeds, processivities, and directionalities. We demonstrate that aster size depends on the motor used to create the aster, and develop a model for the distribution of motors and microtubules in steady-state asters that depends on parameters related to motor speed and processivity. Further, we show that network contraction rates scale linearly with the single-motor speed in quasi-one-dimensional contraction experiments. In all, this theoretical and experimental work helps elucidate how microscopic motor properties are translated to the much larger scale of collective motor-microtubule assemblies.", "date": "2023-02-08", "date_type": "published", "publication": "eLife", "volume": "12", "publisher": "eLife Sciences Publications", "pagerange": "Art. No. e79402", "id_number": "CaltechAUTHORS:20230510-982977000.2", "issn": "2050-084X", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20230510-982977000.2", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "1R35 GM118043-01" }, { "agency": "John Templeton Foundation", "grant_number": "51250" }, { "agency": "John Templeton Foundation", "grant_number": "60973" }, { "agency": "Foundational Questions Institute (FQXI)", "grant_number": "FQXi 1816" }, { "agency": "Fetzer Franklin Fund" } ] }, "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.7554/elife.79402", "pmcid": "PMC10014072", "primary_object": { "basename": "elife-79402.pdf", "url": "https://authors.library.caltech.edu/records/694bn-4vx45/files/elife-79402.pdf" }, "resource_type": "article", "pub_year": "2023", "author_list": "Banks, Rachel A.; Galstyan, Vahe; et el." }, { "id": "https://authors.library.caltech.edu/records/fy1nv-rgf30", "eprint_id": 120057, "eprint_status": "archive", "datestamp": "2023-08-22 18:58:53", "lastmod": "2023-12-22 23:29:52", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" }, "orcid": "0000-0003-1021-1234" } ] }, "title": "Spin glasses, error correcting codes, and synchronization of human stem cell organoids", "ispublished": "pub", "full_text_status": "public", "keywords": "General Biochemistry, Genetics and Molecular Biology", "note": "\u00a9 2023 Elsevier. \n\nThe author would like to acknowledge Angela Andersen for editorial assistance and Inna-Marie Strazhnik for assistance with the illustration. \n\nThe author declares no competing interests.", "abstract": "Magnetic spins, pendulum clocks, and fireflies all self-organize into coherent collectives when arranged into groups of spatially coupled and interacting individuals. Ramanathan and colleagues demonstrate that spatial coupling of human stem cell organoids induces coherent progression through developmental transitions, allowing the dissection of molecular circuits underlying human development.", "date": "2023-02-02", "date_type": "published", "publication": "Cell", "volume": "186", "number": "3", "publisher": "Cell Press", "pagerange": "461-463", "id_number": "CaltechAUTHORS:20230314-846690800.94", "issn": "0092-8674", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20230314-846690800.94", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1016/j.cell.2023.01.006", "resource_type": "article", "pub_year": "2023", "author_list": "Thomson, Matt" }, { "id": "https://authors.library.caltech.edu/records/ndk7v-fhz93", "eprint_id": 118212, "eprint_status": "archive", "datestamp": "2023-08-22 18:09:55", "lastmod": "2023-12-22 23:31:03", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Abdel-Haq-Reem", "name": { "family": "Abdel-Haq", "given": "Reem" }, "orcid": "0000-0002-7418-5736" }, { "id": "Schlachetzki-Johannes-C-M", "name": { "family": "Schlachetzki", "given": "Johannes C. M." }, "orcid": "0000-0002-7801-9743" }, { "id": "Boktor-Joseph-C", "name": { "family": "Boktor", "given": "Joseph C." }, "orcid": "0000-0003-2456-1913" }, { "id": "Cantu-Jungles-Thaisa-M", "name": { "family": "Cantu-Jungles", "given": "Thaisa M." }, "orcid": "0000-0001-8928-9717" }, { "id": "Thron-Taren-M", "name": { "family": "Thron", "given": "Taren" }, "orcid": "0000-0001-9577-2617" }, { "id": "Zhang-Mengying", "name": { "family": "Zhang", "given": "Mengying" } }, { "id": "Bostick-John-W", "name": { "family": "Bostick", "given": "John W." }, "orcid": "0000-0001-8925-2447" }, { "id": "Khazaei-Tahmineh", "name": { "family": "Khazaei", "given": "Tahmineh" }, "orcid": "0000-0002-4743-2383" }, { "id": "Chilakala-Sujatha", "name": { "family": "Chilakala", "given": "Sujatha" }, "orcid": "0000-0003-1581-3381" }, { "id": "Morais-Livia-H", "name": { "family": "Morais", "given": "Livia H." }, "orcid": "0000-0002-5738-2658" }, { "id": "Humphrey-Gregory", "name": { "family": "Humphrey", "given": "Greg" } }, { "id": "Keshavarzian-Ali", "name": { "family": "Keshavarzian", "given": "Ali" }, "orcid": "0000-0002-7969-3369" }, { "id": "Katz-Jonathan-E", "name": { "family": "Katz", "given": "Jonathan E." } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matthew" }, "orcid": "0000-0003-1021-1234" }, { "id": "Knight-Rob", "name": { "family": "Knight", "given": "Rob" }, "orcid": "0000-0002-0975-9019" }, { "id": "Gradinaru-V", "name": { "family": "Gradinaru", "given": "Viviana" }, "orcid": "0000-0001-5868-348X" }, { "id": "Hamaker-Bruce-R", "name": { "family": "Hamaker", "given": "Bruce R." }, "orcid": "0000-0001-6591-942X" }, { "id": "Glass-Christopher-K", "name": { "family": "Glass", "given": "Christopher K." }, "orcid": "0000-0003-4344-3592" }, { "id": "Mazmanian-S-K", "name": { "family": "Mazmanian", "given": "Sarkis K." }, "orcid": "0000-0003-2713-1513" } ] }, "title": "A prebiotic diet modulates microglial states and motor deficits in \u03b1-synuclein overexpressing mice", "ispublished": "pub", "full_text_status": "public", "keywords": "General Immunology and Microbiology; General Biochemistry, Genetics and Molecular Biology; General Medicine; General Neuroscience", "note": "We thank members of the Mazmanian laboratory and Dr. Catherine Oikonomou for critical review of this manuscript. We thank the Caltech Office of Laboratory Animal Research (OLAR) for animal husbandry, Dr. Wei-Li Wu for assistance with SCFA brain measurements, Dr. Sisi Chen and the Caltech Single-Cell Profiling and Engineering Center (SPEC) for technical assistance and support, the Caltech Flow Cytometry and Cell Sorting Facility for technical assistance, the Caltech Bioinformatics Center for data analysis support, and the Caltech Biological Imaging Facility (BIF) for training and use of confocal microscopes. We thank Prof. Chen-Chih Hsu's laboratory in the Department of Chemistry at National Taiwan University and BIOTOOLS Co, Ltd. for the feces and brain SCFA measurements. RA was supported by the U.S. Department of Defense, the Donna and Benjamin M Rosen Bioengineering Center, and the Biotechnology Leadership Program at Caltech. This study was funded by grants to SKM from the U.S. Department of Defense (PD160030), Heritage Medical Research Institute (HMRI-15-09-01), and by the joint efforts of the Michael J Fox Foundation for Parkinson's Research (MJFF) and the Aligning Science Across Parkinson's (ASAP) initiative. MJFF administers the grant (ASAP-000375) on behalf of ASAP and itself. \n\nThe funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. \n\nData availability. All datasets generated or analyzed in this study can be found through the Zenodo depository: https://doi.org/10.5281/zenodo.6377704. All experimental protocols can be found on protocols.io.", "abstract": "Parkinson's disease (PD) is a movement disorder characterized by neuroinflammation, \u03b1-synuclein pathology, and neurodegeneration. Most cases of PD are non-hereditary, suggesting a strong role for environmental factors, and it has been speculated that disease may originate in peripheral tissues such as the gastrointestinal (GI) tract before affecting the brain. The gut microbiome is altered in PD and may impact motor and GI symptoms as indicated by animal studies, although mechanisms of gut-brain interactions remain incompletely defined. Intestinal bacteria ferment dietary fibers into short-chain fatty acids, with fecal levels of these molecules differing between PD and healthy controls and in mouse models. Among other effects, dietary microbial metabolites can modulate activation of microglia, brain-resident immune cells implicated in PD. We therefore investigated whether a fiber-rich diet influences microglial function in \u03b1-synuclein overexpressing (ASO) mice, a preclinical model with PD-like symptoms and pathology. Feeding a prebiotic high-fiber diet attenuates motor deficits and reduces \u03b1-synuclein aggregation in the substantia nigra of mice. Concomitantly, the gut microbiome of ASO mice adopts a profile correlated with health upon prebiotic treatment, which also reduces microglial activation. Single-cell RNA-seq analysis of microglia from the substantia nigra and striatum uncovers increased pro-inflammatory signaling and reduced homeostatic responses in ASO mice compared to wild-type counterparts on standard diets. However, prebiotic feeding reverses pathogenic microglial states in ASO mice and promotes expansion of protective disease-associated macrophage (DAM) subsets of microglia. Notably, depletion of microglia using a CSF1R inhibitor eliminates the beneficial effects of prebiotics by restoring motor deficits to ASO mice despite feeding a prebiotic diet. These studies uncover a novel microglia-dependent interaction between diet and motor symptoms in mice, findings that may have implications for neuroinflammation and PD.", "date": "2022-11-08", "date_type": "published", "publication": "eLife", "volume": "11", "publisher": "eLife Sciences Publications", "pagerange": "Art. No. e81453", "id_number": "CaltechAUTHORS:20221202-906989500.8", "issn": "2050-084X", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20221202-906989500.8", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Department of Defense", "grant_number": "PD160030" }, { "agency": "Donna and Benjamin M. Rosen Bioengineering Center" }, { "agency": "Caltech Biotechnology Leadership Program" }, { "agency": "Heritage Medical Research Institute", "grant_number": "HMRI-15-09-01" }, { "agency": "Michael J Fox Foundation for Parkinson's Research" }, { "agency": "Aligning Science Across Parkinson's", "grant_number": "ASAP-000375" } ] }, "local_group": { "items": [ { "id": "Rosen-Bioengineering-Center" }, { "id": "Heritage-Medical-Research-Institute" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.7554/elife.81453", "pmcid": "PMC9668333", "resource_type": "article", "pub_year": "2022", "author_list": "Abdel-Haq, Reem; Schlachetzki, Johannes C. M.; et el." }, { "id": "https://authors.library.caltech.edu/records/am7bp-3g465", "eprint_id": 117071, "eprint_status": "archive", "datestamp": "2023-08-22 17:41:05", "lastmod": "2023-12-22 23:31:06", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Bao-Min", "name": { "family": "Bao", "given": "Min" }, "orcid": "0000-0003-0992-9388" }, { "id": "Cornwall-Scoones-Jake", "name": { "family": "Cornwall-Scoones", "given": "Jake" }, "orcid": "0000-0002-7435-486X" }, { "id": "Sanchez-Vasquez-Estefania", "name": { "family": "Sanchez-Vasquez", "given": "Estefania" }, "orcid": "0000-0002-6585-8548" }, { "id": "Cox-Andy-L", "name": { "family": "Cox", "given": "Andy L." } }, { "id": "Chen-Dong-Yuan", "name": { "family": "Chen", "given": "Dong-Yuan" }, "orcid": "0000-0003-2179-2847" }, { "id": "De-Jonghe-Joachim", "name": { "family": "De Jonghe", "given": "Joachim" }, "orcid": "0000-0003-0584-8265" }, { "id": "Shadkhoo-Shahriar", "name": { "family": "Shadkhoo", "given": "Shahriar" }, "orcid": "0000-0003-3582-0634" }, { "id": "Hollfelder-Florian", "name": { "family": "Hollfelder", "given": "Florian" }, "orcid": "0000-0002-1367-6312" }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" }, "orcid": "0000-0003-1021-1234" }, { "id": "Glover-D-M", "name": { "family": "Glover", "given": "David M." }, "orcid": "0000-0003-0956-0103" }, { "id": "Zernicka-Goetz-M", "name": { "family": "Zernicka-Goetz", "given": "Magdalena" }, "orcid": "0000-0002-7004-2471" } ] }, "title": "Stem cell-derived synthetic embryos self-assemble by exploiting cadherin codes and cortical tension", "ispublished": "pub", "full_text_status": "public", "keywords": "Cell Biology", "note": "\u00a9 The Author(s) 2022, corrected publication 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\nThis work was supported by the Wellcome Trust (207415/Z/17/Z), an European Research Council advanced grant (669198), a National Institutes of Health R01 (HD100456-01A1) grant, the National Institutes of Health Pioneer Award (DP1 HD104575-01), the Tianqiao and Chrissy Chen Institute for Neuroscience and Shurl and Kay Curci Foundation grants to M.Z.-G. E.S.-V. is supported by a Pew Latin America fellowship. M.B. is supported by a Caltech Postdoctoral Fellowship. We thank the Life Science Foundation, members of the M.Z.-G. laboratory and A. Winkel for invaluable comments and suggestions. \n\nContributions. M.B. and M.Z.-G. conceived of the idea. M.B. developed the methodology and performed the investigation. J.D.J., F.H. and M.B. performed the bioinformatics analyses. J.C.-S., S.S. and M.T. performed the modelling. E.S.-V. and M.B. performed the chimera experiments. A.L.C. contributed to experimental design, pilot experiments and schematics. D.-Y.C. and J.C.-S. provided experimental assistance. M.Z.-G. supervised the study. D.M.G. co-supervised the study. M.B., J.C.-S., D.M.G. and M.Z.-G. wrote the paper. \n\nData availability. Previously published scRNA-seq data that were re-analysed here are available under accession code GSE161947. All other data supporting the findings of this study are available from the corresponding author upon reasonable request. Source data are provided with this paper. \n\nCode availability. The source code used for the numerical simulations is available on GitHub at https://github.com/jakesorel/CPM_ETX_2022. \n\nCompeting interests. We would like to disclose that we have filed a patent for this study. The applicants and inventors for this Patent are Min Bao and Magdalena Zernicka-Goetz. The patent was filed on September 2, 2022 by Caltech. This patent pertains to and covers the \"Differential adhesion and tension guided formation of stem cell derived embryos\". The Patent was filed under the following number: 63/403685. The remaining authors declare no competing interests.\n\nIn the version of this article initially published, author Andy L. Cox (Division of Biology and\nBiological Engineering, California Institute of Technology, Pasadena, CA, USA) was mistakenly\nomitted from the author list. The error has been corrected in the HTML and PDF versions of\nthe article.\n\nPublished - s41556-022-00984-y.pdf
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", "abstract": "Mammalian embryos sequentially differentiate into trophectoderm and an inner cell mass, the latter of which differentiates into primitive endoderm and epiblast. Trophoblast stem (TS), extraembryonic endoderm (XEN) and embryonic stem (ES) cells derived from these three lineages can self-assemble into synthetic embryos, but the mechanisms remain unknown. Here, we show that a stem cell-specific cadherin code drives synthetic embryogenesis. The XEN cell cadherin code enables XEN cell sorting into a layer below ES cells, recapitulating the sorting of epiblast and primitive endoderm before implantation. The TS cell cadherin code enables TS cell sorting above ES cells, resembling extraembryonic ectoderm clustering above epiblast following implantation. Whereas differential cadherin expression drives initial cell sorting, cortical tension consolidates tissue organization. By optimizing cadherin code expression in different stem cell lines, we tripled the frequency of correctly formed synthetic embryos. Thus, by exploiting cadherin codes from different stages of development, lineage-specific stem cells bypass the preimplantation structure to directly assemble a postimplantation embryo.", "date": "2022-09-13", "date_type": "published", "publication": "Nature Cell Biology", "volume": "24", "number": "9", "publisher": "Nature Publishing Group", "pagerange": "1341-1349", "id_number": "CaltechAUTHORS:20220919-149101800", "issn": "1465-7392", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20220919-149101800", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Wellcome Trust", "grant_number": "207415/Z/17/Z" }, { "agency": "European Research Council (ERC)", "grant_number": "669198" }, { "agency": "NIH", "grant_number": "HD100456-01A1" }, { "agency": "NIH", "grant_number": "DP1 HD104575-01" }, { "agency": "Tianqiao and Chrissy Chen Institute for Neuroscience" }, { "agency": "Shurl and Kay Curci Foundation" }, { "agency": "Pew Latin American Fellows Program" }, { "agency": "Caltech Postdoctoral Fellowship" } ] }, "local_group": { "items": [ { "id": "Tianqiao-and-Chrissy-Chen-Institute-for-Neuroscience" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1038/s41556-022-00984-y", "pmcid": "PMC9481465", "primary_object": { "basename": "41556_2022_984_MOESM6_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/am7bp-3g465/files/41556_2022_984_MOESM6_ESM.xlsx" }, "related_objects": [ { "basename": "41556_2022_984_MOESM13_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/am7bp-3g465/files/41556_2022_984_MOESM13_ESM.xlsx" }, { "basename": "41556_2022_984_MOESM1_ESM.pdf", "url": "https://authors.library.caltech.edu/records/am7bp-3g465/files/41556_2022_984_MOESM1_ESM.pdf" }, { "basename": "41556_2022_984_MOESM4_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/am7bp-3g465/files/41556_2022_984_MOESM4_ESM.xlsx" }, { "basename": "41556_2022_984_MOESM15_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/am7bp-3g465/files/41556_2022_984_MOESM15_ESM.xlsx" }, { "basename": "41556_2022_984_MOESM5_ESM.mov", "url": "https://authors.library.caltech.edu/records/am7bp-3g465/files/41556_2022_984_MOESM5_ESM.mov" }, { "basename": "41556_2022_984_MOESM7_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/am7bp-3g465/files/41556_2022_984_MOESM7_ESM.xlsx" }, { "basename": "41556_2022_984_MOESM10_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/am7bp-3g465/files/41556_2022_984_MOESM10_ESM.xlsx" }, { "basename": "41556_2022_984_MOESM12_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/am7bp-3g465/files/41556_2022_984_MOESM12_ESM.xlsx" }, { "basename": "41556_2022_984_MOESM14_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/am7bp-3g465/files/41556_2022_984_MOESM14_ESM.xlsx" }, { "basename": "41556_2022_984_MOESM11_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/am7bp-3g465/files/41556_2022_984_MOESM11_ESM.xlsx" }, { "basename": "41556_2022_984_MOESM8_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/am7bp-3g465/files/41556_2022_984_MOESM8_ESM.xlsx" }, { "basename": "s41556-022-00984-y.pdf", "url": "https://authors.library.caltech.edu/records/am7bp-3g465/files/s41556-022-00984-y.pdf" }, { "basename": "41556_2022_984_MOESM9_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/am7bp-3g465/files/41556_2022_984_MOESM9_ESM.xlsx" } ], "resource_type": "article", "pub_year": "2022", "author_list": "Bao, Min; Cornwall-Scoones, Jake; et el." }, { "id": "https://authors.library.caltech.edu/records/4hyzx-m8z96", "eprint_id": 115708, "eprint_status": "archive", "datestamp": "2024-01-18 23:04:31", "lastmod": "2024-01-18 23:04:31", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Murrow-Lyndsay-M", "name": { "family": "Murrow", "given": "Lyndsay M." } }, { "id": "Weber-Robert-J", "name": { "family": "Weber", "given": "Robert J." } }, { "id": "Caruso-Joseph-A", "name": { "family": "Caruso", "given": "Joseph A." } }, { "id": "McGinnis-Christopher-S", "name": { "family": "McGinnis", "given": "Christopher S." } }, { "id": "Phong-Kiet", "name": { "family": "Phong", "given": "Kiet" } }, { "id": "Gascard-Philippe", "name": { "family": "Gascard", "given": "Philippe" } }, { "id": "Rabadam-Gabrielle", "name": { "family": "Rabadam", "given": "Gabrielle" } }, { "id": "Borowsky-Alexander-D", "name": { "family": "Borowsky", "given": "Alexander D." } }, { "id": "Desai-T-A", "name": { "family": "Desai", "given": "Tejal A." } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matthew" }, "orcid": "0000-0003-1021-1234" }, { "id": "Tlsty-Thea", "name": { "family": "Tlsty", "given": "Thea" } }, { "id": "Gartner-Zev-J", "name": { "family": "Gartner", "given": "Zev J." } } ] }, "title": "Mapping hormone-regulated cell-cell interaction networks in the human breast at single-cell resolution", "ispublished": "pub", "full_text_status": "public", "keywords": "scRNA-seq; cell-cell interactions; human breast; hormone signaling; single-cell genomics; sample heterogeneity; Cell Biology; Histology; Pathology and Forensic Medicine", "note": "\u00a9 2022 The Authors. Published by Elsevier Under a Creative Commons license - Attribution 4.0 International (CC BY 4.0). \n\nReceived 2 February 2021, Revised 2 March 2022, Accepted 22 June 2022, Available online 20 July 2022. \n\nWe thank Drs. Tom Norman and Jonathan Weissman for technical support and for generously providing access to equipment and computing resources. Sequencing was performed in the Center for Advanced Technology at UCSF. Tissue samples were provided by the Cooperative Human Tissue Network (CHTN), which is funded by the National Cancer Institute. Other investigators may have received specimens from the same subjects. Samples from the Susan G. KTB at the IU Simon Cancer Center were used in this study. We thank contributors, including Indiana University who collected samples used in this study, as well as donors and their families, whose help and participation made this work possible. This research was supported by grants from the Department of Defense Breast Cancer Research Program (W81XWH-10-1-1023 and W81XWH-13-1-0221), NIH (U01CA199315 and DP2 HD080351-01), the NSF (MCB-1330864), and the UCSF Center for Cellular Construction (DBI-1548297), an NSF Science and Technology Center, to Z.J.G. Z.J.G. is a Chan Zuckerberg BioHub Investigator. L.M.M. is a former Damon Runyon Fellow supported by the Damon Runyon Cancer Research Foundation (DRG-2239-15). \n\nAuthor contributions. L.M.M., R.J.W., and Z.J.G. conceived the project. L.M.M., J.A.C., R.J.W., C.S.M., and K.P. performed the sequencing experiments. C.S.M. generated aligned reads and barcode matrices. C.S.M. and L.M.M. performed sample demultiplexing. P.G. coordinated sample acquisition and provided critical guidance for sample selection. L.M.M. and J.A.C. performed fluorescent immunohistochemistry and RNA-FISH experiments. L.M.M. and J.A.C. performed flow cytometry experiments. L.M.M. and J.A.C. performed histopathology on tissue sections. A.D.B. performed histopathological tissue analysis. L.M.M. analyzed and visualized the data. L.M.M., C.S.M., and G.R. wrote and tested the code used in data analysis. M.T. provided guidance in data analyses and computational approaches. T.T. and A.D.B. provided guidance in human breast biology. T.T., M.T., and Z.J.G. provided critical resources. T.A.D., M.T., T.T., and Z.J.G. supervised the project. L.M.M. and Z.J.G. wrote the manuscript. All authors reviewed and edited the manuscript. \n\nDeclaration of interests. Z.J.G. and C.S.M. hold patents related to the MULTI-seq barcoding method. Z.J.G. is an equity holder in Scribe Biosciences and Provenance bio and a member of the scientific advisory board of Serotiny Bio. C.S.M. is a consultant for ImYoo. Since January 10, 2022, L.M.M. is an employee of Genentech, a member of the Roche group. \n\nInclusion and diversity. We worked to ensure ethnic or other types of diversity in the recruitment of human subjects. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper self-identifies as living with a disability.\n\nData and code availability:\n\nSingle-cell RNA-seq data (raw FASTQ files, processed gene expression and barcode count matrices, and de-identified patient metadata) have been deposited at the Gene Expression Omnibus (GEO: GSE198732) and are publicly available as of the date of publication. Accession numbers are listed in the key resources table. All original code has been deposited at Zenodo and Github and is publicly available as of the date of publication. DOIs are listed in the key resources table. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.", "abstract": "The rise and fall of estrogen and progesterone across menstrual cycles and during pregnancy regulates breast development and modifies cancer risk. How these hormones impact each cell type in the breast remains poorly understood because they act indirectly through paracrine networks. Using single-cell analysis of premenopausal breast tissue, we reveal a network of coordinated transcriptional programs representing the tissue-level response to changing hormone levels. Our computational approach, DECIPHER-seq, leverages person-to-person variability in breast composition and cell state to uncover programs that co-vary across individuals. We use differences in cell-type proportions to infer a subset of programs that arise from direct cell-cell interactions regulated by hormones. Further, we demonstrate that prior pregnancy and obesity modify hormone responsiveness through distinct mechanisms: obesity reduces the proportion of hormone-responsive cells, whereas pregnancy dampens the direct response of these cells to hormones. Together, these results provide a comprehensive map of the cycling human breast.", "date": "2022-08-17", "date_type": "published", "publication": "Cell Systems", "volume": "13", "number": "8", "publisher": "Cell Press", "pagerange": "644-664.e8", "id_number": "CaltechAUTHORS:20220720-918411000", "issn": "2405-4712", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20220720-918411000", "funders": { "items": [ { "agency": "National Cancer Institute" }, { "agency": "Department of Defense", "grant_number": "W81XWH-10-1-1023" }, { "agency": "Department of Defense", "grant_number": "W81XWH-13-1-0221" }, { "agency": "NIH", "grant_number": "U01CA199315" }, { "agency": "NIH", "grant_number": "DP2 HD080351-01" }, { "agency": "NSF", "grant_number": "MCB-1330864" }, { "agency": "NSF", "grant_number": "DBI-1548297" }, { "agency": "Chan-Zuckerberg Biohub" }, { "agency": "Damon Runyon Cancer Research Foundation", "grant_number": "DRG-2239-15" } ] }, "local_group": { "items": [ { "id": "Heritage-Medical-Research-Institute" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1016/j.cels.2022.06.005", "pmcid": "PMC9590200", "primary_object": { "basename": "1-s2.0-S2405471222002757-main.pdf", "url": "https://authors.library.caltech.edu/records/4hyzx-m8z96/files/1-s2.0-S2405471222002757-main.pdf" }, "related_objects": [ { "basename": "1-s2.0-S2405471222002757-mmc10.xlsx", "url": "https://authors.library.caltech.edu/records/4hyzx-m8z96/files/1-s2.0-S2405471222002757-mmc10.xlsx" }, { "basename": "1-s2.0-S2405471222002757-mmc11.xlsx", "url": "https://authors.library.caltech.edu/records/4hyzx-m8z96/files/1-s2.0-S2405471222002757-mmc11.xlsx" }, { "basename": "1-s2.0-S2405471222002757-mmc2.xlsx", "url": "https://authors.library.caltech.edu/records/4hyzx-m8z96/files/1-s2.0-S2405471222002757-mmc2.xlsx" }, { "basename": "1-s2.0-S2405471222002757-mmc5.xlsx", "url": "https://authors.library.caltech.edu/records/4hyzx-m8z96/files/1-s2.0-S2405471222002757-mmc5.xlsx" }, { "basename": "1-s2.0-S2405471222002757-mmc7.xlsx", "url": "https://authors.library.caltech.edu/records/4hyzx-m8z96/files/1-s2.0-S2405471222002757-mmc7.xlsx" }, { "basename": "1-s2.0-S2405471222002757-mmc1.pdf", "url": "https://authors.library.caltech.edu/records/4hyzx-m8z96/files/1-s2.0-S2405471222002757-mmc1.pdf" }, { "basename": "1-s2.0-S2405471222002757-mmc3.xlsx", "url": "https://authors.library.caltech.edu/records/4hyzx-m8z96/files/1-s2.0-S2405471222002757-mmc3.xlsx" }, { "basename": "1-s2.0-S2405471222002757-mmc6.xlsx", "url": "https://authors.library.caltech.edu/records/4hyzx-m8z96/files/1-s2.0-S2405471222002757-mmc6.xlsx" }, { "basename": "1-s2.0-S2405471222002757-mmc12.xlsx", "url": "https://authors.library.caltech.edu/records/4hyzx-m8z96/files/1-s2.0-S2405471222002757-mmc12.xlsx" }, { "basename": "1-s2.0-S2405471222002757-mmc4.xlsx", "url": "https://authors.library.caltech.edu/records/4hyzx-m8z96/files/1-s2.0-S2405471222002757-mmc4.xlsx" }, { "basename": "1-s2.0-S2405471222002757-mmc8.xlsx", "url": "https://authors.library.caltech.edu/records/4hyzx-m8z96/files/1-s2.0-S2405471222002757-mmc8.xlsx" }, { "basename": "1-s2.0-S2405471222002757-mmc9.xlsx", "url": "https://authors.library.caltech.edu/records/4hyzx-m8z96/files/1-s2.0-S2405471222002757-mmc9.xlsx" } ], "resource_type": "article", "pub_year": "2022", "author_list": "Murrow, Lyndsay M.; Weber, Robert J.; et el." }, { "id": "https://authors.library.caltech.edu/records/6my79-qzx21", "eprint_id": 115708, "eprint_status": "archive", "datestamp": "2023-09-29 21:38:21", "lastmod": "2024-01-09 22:21:38", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Murrow-Lyndsay-M", "name": { "family": "Murrow", "given": "Lyndsay M." } }, { "id": "Weber-Robert-J", "name": { "family": "Weber", "given": "Robert J." } }, { "id": "Caruso-Joseph-A", "name": { "family": "Caruso", "given": "Joseph A." } }, { "id": "McGinnis-Christopher-S", "name": { "family": "McGinnis", "given": "Christopher S." } }, { "id": "Phong-Kiet", "name": { "family": "Phong", "given": "Kiet" } }, { "id": "Gascard-Philippe", "name": { "family": "Gascard", "given": "Philippe" } }, { "id": "Rabadam-Gabrielle", "name": { "family": "Rabadam", "given": "Gabrielle" } }, { "id": "Borowsky-Alexander-D", "name": { "family": "Borowsky", "given": "Alexander D." } }, { "id": "Desai-T-A", "name": { "family": "Desai", "given": "Tejal A." } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matthew" }, "orcid": "0000-0003-1021-1234" }, { "id": "Tlsty-Thea", "name": { "family": "Tlsty", "given": "Thea" } }, { "id": "Gartner-Zev-J", "name": { "family": "Gartner", "given": "Zev J." } } ] }, "title": "Mapping hormone-regulated cell-cell interaction networks in the human breast at single-cell resolution", "ispublished": "pub", "full_text_status": "public", "keywords": "scRNA-seq; cell-cell interactions; human breast; hormone signaling; single-cell genomics; sample heterogeneity; Cell Biology; Histology; Pathology and Forensic Medicine", "note": "\u00a9 2022 The Authors. Published by Elsevier Under a Creative Commons license - Attribution 4.0 International (CC BY 4.0). \n\nReceived 2 February 2021, Revised 2 March 2022, Accepted 22 June 2022, Available online 20 July 2022. \n\nWe thank Drs. Tom Norman and Jonathan Weissman for technical support and for generously providing access to equipment and computing resources. Sequencing was performed in the Center for Advanced Technology at UCSF. Tissue samples were provided by the Cooperative Human Tissue Network (CHTN), which is funded by the National Cancer Institute. Other investigators may have received specimens from the same subjects. Samples from the Susan G. KTB at the IU Simon Cancer Center were used in this study. We thank contributors, including Indiana University who collected samples used in this study, as well as donors and their families, whose help and participation made this work possible. This research was supported by grants from the Department of Defense Breast Cancer Research Program (W81XWH-10-1-1023 and W81XWH-13-1-0221), NIH (U01CA199315 and DP2 HD080351-01), the NSF (MCB-1330864), and the UCSF Center for Cellular Construction (DBI-1548297), an NSF Science and Technology Center, to Z.J.G. Z.J.G. is a Chan Zuckerberg BioHub Investigator. L.M.M. is a former Damon Runyon Fellow supported by the Damon Runyon Cancer Research Foundation (DRG-2239-15). \n\nAuthor contributions. L.M.M., R.J.W., and Z.J.G. conceived the project. L.M.M., J.A.C., R.J.W., C.S.M., and K.P. performed the sequencing experiments. C.S.M. generated aligned reads and barcode matrices. C.S.M. and L.M.M. performed sample demultiplexing. P.G. coordinated sample acquisition and provided critical guidance for sample selection. L.M.M. and J.A.C. performed fluorescent immunohistochemistry and RNA-FISH experiments. L.M.M. and J.A.C. performed flow cytometry experiments. L.M.M. and J.A.C. performed histopathology on tissue sections. A.D.B. performed histopathological tissue analysis. L.M.M. analyzed and visualized the data. L.M.M., C.S.M., and G.R. wrote and tested the code used in data analysis. M.T. provided guidance in data analyses and computational approaches. T.T. and A.D.B. provided guidance in human breast biology. T.T., M.T., and Z.J.G. provided critical resources. T.A.D., M.T., T.T., and Z.J.G. supervised the project. L.M.M. and Z.J.G. wrote the manuscript. All authors reviewed and edited the manuscript. \n\nDeclaration of interests. Z.J.G. and C.S.M. hold patents related to the MULTI-seq barcoding method. Z.J.G. is an equity holder in Scribe Biosciences and Provenance bio and a member of the scientific advisory board of Serotiny Bio. C.S.M. is a consultant for ImYoo. Since January 10, 2022, L.M.M. is an employee of Genentech, a member of the Roche group. \n\nInclusion and diversity. We worked to ensure ethnic or other types of diversity in the recruitment of human subjects. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper self-identifies as living with a disability.\n\nData and code availability:\n\nSingle-cell RNA-seq data (raw FASTQ files, processed gene expression and barcode count matrices, and de-identified patient metadata) have been deposited at the Gene Expression Omnibus (GEO: GSE198732) and are publicly available as of the date of publication. Accession numbers are listed in the key resources table. All original code has been deposited at Zenodo and Github and is publicly available as of the date of publication. DOIs are listed in the key resources table. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.\n\nIn Press - 1-s2.0-S2405471222002757-main.pdf
Supplemental Material - 1-s2.0-S2405471222002757-mmc1.pdf
Supplemental Material - 1-s2.0-S2405471222002757-mmc10.xlsx
Supplemental Material - 1-s2.0-S2405471222002757-mmc11.xlsx
Supplemental Material - 1-s2.0-S2405471222002757-mmc12.xlsx
Supplemental Material - 1-s2.0-S2405471222002757-mmc2.xlsx
Supplemental Material - 1-s2.0-S2405471222002757-mmc3.xlsx
Supplemental Material - 1-s2.0-S2405471222002757-mmc4.xlsx
Supplemental Material - 1-s2.0-S2405471222002757-mmc5.xlsx
Supplemental Material - 1-s2.0-S2405471222002757-mmc6.xlsx
Supplemental Material - 1-s2.0-S2405471222002757-mmc7.xlsx
Supplemental Material - 1-s2.0-S2405471222002757-mmc8.xlsx
Supplemental Material - 1-s2.0-S2405471222002757-mmc9.xlsx
", "abstract": "The rise and fall of estrogen and progesterone across menstrual cycles and during pregnancy regulates breast development and modifies cancer risk. How these hormones impact each cell type in the breast remains poorly understood because they act indirectly through paracrine networks. Using single-cell analysis of premenopausal breast tissue, we reveal a network of coordinated transcriptional programs representing the tissue-level response to changing hormone levels. Our computational approach, DECIPHER-seq, leverages person-to-person variability in breast composition and cell state to uncover programs that co-vary across individuals. We use differences in cell-type proportions to infer a subset of programs that arise from direct cell-cell interactions regulated by hormones. Further, we demonstrate that prior pregnancy and obesity modify hormone responsiveness through distinct mechanisms: obesity reduces the proportion of hormone-responsive cells, whereas pregnancy dampens the direct response of these cells to hormones. Together, these results provide a comprehensive map of the cycling human breast.", "date": "2022-08-17", "date_type": "published", "publication": "Cell Systems", "volume": "13", "number": "8", "publisher": "Cell Press", "pagerange": "644-664.e8", "id_number": "CaltechAUTHORS:20220720-918411000", "issn": "2405-4712", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20220720-918411000", "funders": { "items": [ { "agency": "National Cancer Institute" }, { "agency": "Department of Defense", "grant_number": "W81XWH-10-1-1023" }, { "agency": "Department of Defense", "grant_number": "W81XWH-13-1-0221" }, { "agency": "NIH", "grant_number": "U01CA199315" }, { "agency": "NIH", "grant_number": "DP2 HD080351-01" }, { "agency": "NSF", "grant_number": "MCB-1330864" }, { "agency": "NSF", "grant_number": "DBI-1548297" }, { "agency": "Chan-Zuckerberg Biohub" }, { "agency": "Damon Runyon Cancer Research Foundation", "grant_number": "DRG-2239-15" } ] }, "local_group": { "items": [ { "id": "Heritage-Medical-Research-Institute" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1016/j.cels.2022.06.005", "pmcid": "PMC9590200", "primary_object": { "basename": "1-s2.0-S2405471222002757-main.pdf", "url": "https://authors.library.caltech.edu/records/6my79-qzx21/files/1-s2.0-S2405471222002757-main.pdf" }, "related_objects": [ { "basename": "1-s2.0-S2405471222002757-mmc1.pdf", "url": "https://authors.library.caltech.edu/records/6my79-qzx21/files/1-s2.0-S2405471222002757-mmc1.pdf" }, { "basename": "1-s2.0-S2405471222002757-mmc6.xlsx", "url": "https://authors.library.caltech.edu/records/6my79-qzx21/files/1-s2.0-S2405471222002757-mmc6.xlsx" }, { "basename": "1-s2.0-S2405471222002757-mmc7.xlsx", "url": "https://authors.library.caltech.edu/records/6my79-qzx21/files/1-s2.0-S2405471222002757-mmc7.xlsx" }, { "basename": "1-s2.0-S2405471222002757-mmc4.xlsx", "url": "https://authors.library.caltech.edu/records/6my79-qzx21/files/1-s2.0-S2405471222002757-mmc4.xlsx" }, { "basename": "1-s2.0-S2405471222002757-mmc5.xlsx", "url": "https://authors.library.caltech.edu/records/6my79-qzx21/files/1-s2.0-S2405471222002757-mmc5.xlsx" }, { "basename": "1-s2.0-S2405471222002757-mmc8.xlsx", "url": "https://authors.library.caltech.edu/records/6my79-qzx21/files/1-s2.0-S2405471222002757-mmc8.xlsx" }, { "basename": "1-s2.0-S2405471222002757-mmc11.xlsx", "url": "https://authors.library.caltech.edu/records/6my79-qzx21/files/1-s2.0-S2405471222002757-mmc11.xlsx" }, { "basename": "1-s2.0-S2405471222002757-mmc12.xlsx", "url": "https://authors.library.caltech.edu/records/6my79-qzx21/files/1-s2.0-S2405471222002757-mmc12.xlsx" }, { "basename": "1-s2.0-S2405471222002757-mmc2.xlsx", "url": "https://authors.library.caltech.edu/records/6my79-qzx21/files/1-s2.0-S2405471222002757-mmc2.xlsx" }, { "basename": "1-s2.0-S2405471222002757-mmc10.xlsx", "url": "https://authors.library.caltech.edu/records/6my79-qzx21/files/1-s2.0-S2405471222002757-mmc10.xlsx" }, { "basename": "1-s2.0-S2405471222002757-mmc3.xlsx", "url": "https://authors.library.caltech.edu/records/6my79-qzx21/files/1-s2.0-S2405471222002757-mmc3.xlsx" }, { "basename": "1-s2.0-S2405471222002757-mmc9.xlsx", "url": "https://authors.library.caltech.edu/records/6my79-qzx21/files/1-s2.0-S2405471222002757-mmc9.xlsx" } ], "resource_type": "article", "pub_year": "2022", "author_list": "Murrow, Lyndsay M.; Weber, Robert J.; et el." }, { "id": "https://authors.library.caltech.edu/records/77z9r-qkg14", "eprint_id": 109742, "eprint_status": "archive", "datestamp": "2023-08-22 16:55:11", "lastmod": "2023-12-22 23:34:38", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Wang-Zitong-Jerry", "name": { "family": "Wang", "given": "Zitong Jerry" }, "orcid": "0000-0001-8008-7318" }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" }, "orcid": "0000-0003-1021-1234" } ] }, "title": "Localization of signaling receptors maximizes cellular information acquisition in spatially structured natural environments", "ispublished": "pub", "full_text_status": "public", "keywords": "spatial organization; environmental statistics; cell migration; information theory; cell sensing; tissue microenvironment; synthetic circuit; haptotaxis; chemotaxis; search strategies", "note": "\u00a9 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). \n\nReceived 5 November 2021, Revised 8 February 2022, Accepted 12 May 2022, Available online 8 June 2022. \n\nWe thank Michael Elowitz, Erik Winfree, and David Sivak for scientific discussions; Dominik Schildknecht, Han Kim, Guruprasad Raghavan, Pranav Bhamidipati, Abdullah Farooq for feedback on the manuscript; Inna-Marie Strazhnik for illustrations; and Angela Anderson for editorial advice. We also would like to thank Eugenio Marco and Katarzyna Rejniak for technical advice with receptor feedback and tissue simulations, respectively. The authors would like to acknowledge the Heritage Medical Research Institute and Packard Foundation for funding and intellectual support. \n\nAuthor contributions: Conceptualization, Z.J.W. and M.T.; methodology, Z.J.W. and M.T.; manuscript writing, Z.J.W. and M.T.; supervision, M.T.; funding acquisition, M.T. \n\nDeclaration of interests: M.T. is a member of the advisory board of Cell Systems. \n\nData and code availability: All data have been deposited on the Caltech Research Data Repository and are publicly available as of the date of publication. DOIs are listed in the key resources table. \n\nAll original code has been deposited at Zenodo (10.5281/zenodo.6432083) and is publicly available as of the date of publication. DOIs are listed in the key resources table. \n\nAny additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.\n\nPublished - 1-s2.0-S2405471222002253-main.pdf
Submitted - 2021.07.01.450787v4.full.pdf
Supplemental Material - 1-s2.0-S2405471222002253-mmc1.pdf
Supplemental Material - 1-s2.0-S2405471222002253-mmc2.pdf
", "abstract": "Cells in natural environments, such as tissue or soil, sense and respond to extracellular ligands with intricately structured and non-monotonic spatial distributions, sculpted by processes such as fluid flow and substrate adhesion. In this work, we show that spatial sensing and navigation can be optimized by adapting the spatial organization of signaling pathways to the spatial structure of the environment. We develop an information-theoretic framework for computing the optimal spatial organization of a sensing system for a given signaling environment. We find that receptor localization previously observed in cells maximizes information acquisition in simulated natural contexts, including tissue and soil. Specifically, information acquisition is maximized when receptors form localized patches at regions of maximal ligand concentration. Receptor localization extends naturally to produce a dynamic protocol for continuously redistributing signaling receptors, which when implemented using simple feedback, boosts cell navigation efficiency by 30-fold.", "date": "2022-07-20", "date_type": "published", "publication": "Cell Systems", "volume": "13", "number": "7", "publisher": "Cell Press", "pagerange": "530-546", "id_number": "CaltechAUTHORS:20210707-155629727", "issn": "2405-4712", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210707-155629727", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Heritage Medical Research Institute" }, { "agency": "David and Lucile Packard Foundation" } ] }, "local_group": { "items": [ { "id": "Heritage-Medical-Research-Institute" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1016/j.cels.2022.05.004", "primary_object": { "basename": "1-s2.0-S2405471222002253-main.pdf", "url": "https://authors.library.caltech.edu/records/77z9r-qkg14/files/1-s2.0-S2405471222002253-main.pdf" }, "related_objects": [ { "basename": "1-s2.0-S2405471222002253-mmc1.pdf", "url": "https://authors.library.caltech.edu/records/77z9r-qkg14/files/1-s2.0-S2405471222002253-mmc1.pdf" }, { "basename": "1-s2.0-S2405471222002253-mmc2.pdf", "url": "https://authors.library.caltech.edu/records/77z9r-qkg14/files/1-s2.0-S2405471222002253-mmc2.pdf" }, { "basename": "2021.07.01.450787v4.full.pdf", "url": "https://authors.library.caltech.edu/records/77z9r-qkg14/files/2021.07.01.450787v4.full.pdf" } ], "resource_type": "article", "pub_year": "2022", "author_list": "Wang, Zitong Jerry and Thomson, Matt" }, { "id": "https://authors.library.caltech.edu/records/n9ncy-s9d66", "eprint_id": 115426, "eprint_status": "archive", "datestamp": "2023-08-22 16:05:12", "lastmod": "2023-12-22 23:32:13", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chen-Xiaoqiao", "name": { "family": "Chen", "given": "Xiaoqiao" }, "orcid": "0000-0003-4685-3466" }, { "id": "Chen-Sisi", "name": { "family": "Chen", "given": "Sisi" }, "orcid": "0000-0001-9448-9713" }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" }, "orcid": "0000-0003-1021-1234" } ] }, "title": "Minimal gene set discovery in single-cell mRNA-seq datasets with ActiveSVM", "ispublished": "pub", "full_text_status": "public", "keywords": "Computer Networks and Communications; Computer Science Applications; Computer Science (miscellaneous)", "note": "\u00a9 The Author(s) 2022, corrected publication 2022. 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 23 July 2021. Accepted 17 May 2022. \nPublished 27 June 2022. \n\nWe would like to thank I.-M. Strazhnik for expert assistance with preparation of illustrations and G. Riddihough of Life Science Editors for Editorial Assistance. We thank J. Jiang, Y. Yue, L. Cai, D. Sivak, D. Angeles and K. Zinn for discussion. The work was supported by the Heritage Medical Research Institute, the Beckman Institute Single-cell Profiling and Engineering Center (SPEC), NIH (R01HD100039), and the The Margaret E. Early Medical Research Trust. \n\nContributions. X.C. conceived the ActiveSVM algorithm. X.C. and M.T. refined the algorithm and developed the application to single-cell genomics. X.C., S.C. and M.T. performed numerical experiments, biological interpretation, and data analysis. S.C. analyzed the Tabula Muris and multiple myeloma datasets and established biological interpretation of ActiveSVM results. X.C., S.C. and M.T. wrote the paper. \n\nData availability\nAll of the data used in the paper have been previously published. The PBMC Single-cell RNA-seq data have been deposited in the Short Read Archive under accession no. SRP073767 by the authors of ref. 13. Data are also available at http://support.10xgenomics.com/single-cell/datasets. The original Tabula Muris dataset is available at https://figshare.com/projects/Tabula_Muris_Transcriptomic_characterization_of_20_organs_and_tissues_from_Mus_musculus_at_single_cell_resolution/27733. The original multiple myeloma PBMC data, which contain two healthy donors and four multiple myeloma donors, are available at https://figshare.com/articles/dataset/PopAlign_Data/11837097/3. The 10x Genomics Megacell dataset is available at http://support.10xgenomics.com/single-cell/datasets. The perturb-seq dataset17 is available at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM2396856 The spatial transcriptomics data18 are available at https://github.com/CaiGroup/seqFISH-PLUS. Source Data are provided with this paper.\n\nCode availability\nOur method is integrated as an installable Python package called ActiveSVC. The installation instructions and user guidance are shown at https://pypi.org/project/activeSVC. The source codes of activeSVC and some demo examples are publicly available on GitHub at https://github.com/xqchen/activeSVC and Zenodo56. We also created a Google colaboratory project demonstrating three examples: the PBMC demo is at https://colab.research.google.com/drive/16h8hsnJ3ukTWAPnCB581dwj-nN5oopyM?usp=sharing, the Tabula Muris demo is at https://colab.research.google.com/drive/1SLehIKIQqpjK6BzEKc9m0y3uJ_LBqRzA?usp=sharing, and the PBMC cross-validation57 demo is at https://colab.research.google.com/drive/1fhQ8GD3NyzB3w0vof9WimXK6BLqDNuDC?usp=sharing. \n\nThe authors declare no completing interests. \n\nPeer review. Nature Computational Science thanks the anonymous reviewers for their contribution to the peer review of this work. Handling editor: Ananya Rastogi, in collaboration with the Nature Computational Science team.\n\n04 July 2022In the version of this article initially published, edited Source Data captions for Fig. 6 and Extended Data Fig. 1 mistakenly referred to \"Extended Data\" figures rather than folders with \"ED\" prefixes in the data. The captions have been corrected in the HTML version of the article.\n\nPublished - s43588-022-00263-8.pdf
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", "abstract": "Sequencing costs currently prohibit the application of single-cell mRNA-seq to many biological and clinical analyses. Targeted single-cell mRNA-sequencing reduces sequencing costs by profiling reduced gene sets that capture biological information with a minimal number of genes. Here we introduce an active learning method that identifies minimal but highly informative gene sets that enable the identification of cell types, physiological states and genetic perturbations in single-cell data using a small number of genes. Our active feature selection procedure generates minimal gene sets from single-cell data by employing an active support vector machine (ActiveSVM) classifier. We demonstrate that ActiveSVM feature selection identifies gene sets that enable ~90% cell-type classification accuracy across, for example, cell atlas and disease-characterization datasets. The discovery of small but highly informative gene sets should enable reductions in the number of measurements necessary for application of single-cell mRNA-seq to clinical tests, therapeutic discovery and genetic screens.", "date": "2022-06", "date_type": "published", "publication": "Nature Computational Science", "volume": "2", "number": "6", "publisher": "Nature Publishing Group", "pagerange": "387-398", "id_number": "CaltechAUTHORS:20220707-978247000", "issn": "2662-8457", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20220707-978247000", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Heritage Medical Research Institute" }, { "agency": "Beckman Institute Single-cell Profiling and Engineering Center (SPEC)" }, { "agency": "NIH", "grant_number": "R01HD100039" }, { "agency": "Margaret E. Early Medical Research Trust" } ] }, "local_group": { "items": [ { "id": "Hydrodynamics-Laboratory" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1038/s43588-022-00263-8", "primary_object": { "basename": "s43588-022-00263-8.pdf", "url": "https://authors.library.caltech.edu/records/n9ncy-s9d66/files/s43588-022-00263-8.pdf" }, "related_objects": [ { "basename": "43588_2022_263_Fig7_ESM.jpg", "url": "https://authors.library.caltech.edu/records/n9ncy-s9d66/files/43588_2022_263_Fig7_ESM.jpg" }, { "basename": "43588_2022_263_MOESM1_ESM.pdf", "url": "https://authors.library.caltech.edu/records/n9ncy-s9d66/files/43588_2022_263_MOESM1_ESM.pdf" }, { "basename": "43588_2022_263_MOESM5_ESM.zip", "url": "https://authors.library.caltech.edu/records/n9ncy-s9d66/files/43588_2022_263_MOESM5_ESM.zip" }, { "basename": "43588_2022_263_MOESM6_ESM.zip", "url": "https://authors.library.caltech.edu/records/n9ncy-s9d66/files/43588_2022_263_MOESM6_ESM.zip" }, { "basename": "43588_2022_263_MOESM2_ESM.zip", "url": "https://authors.library.caltech.edu/records/n9ncy-s9d66/files/43588_2022_263_MOESM2_ESM.zip" }, { "basename": "43588_2022_263_MOESM3_ESM.zip", "url": "https://authors.library.caltech.edu/records/n9ncy-s9d66/files/43588_2022_263_MOESM3_ESM.zip" }, { "basename": "43588_2022_263_MOESM4_ESM.zip", "url": "https://authors.library.caltech.edu/records/n9ncy-s9d66/files/43588_2022_263_MOESM4_ESM.zip" }, { "basename": "43588_2022_263_MOESM7_ESM.zip", "url": "https://authors.library.caltech.edu/records/n9ncy-s9d66/files/43588_2022_263_MOESM7_ESM.zip" } ], "resource_type": "article", "pub_year": "2022", "author_list": "Chen, Xiaoqiao; Chen, Sisi; et el." }, { "id": "https://authors.library.caltech.edu/records/0fp8r-q9q88", "eprint_id": 114432, "eprint_status": "archive", "datestamp": "2023-08-22 13:57:52", "lastmod": "2023-12-22 23:09:05", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Duarte-Ana-I", "name": { "family": "Duarte", "given": "Ana I." } }, { "id": "Jin-Lee-Heun", "name": { "family": "Jin Lee", "given": "Heun" } }, { "id": "Banks-Rachel-A", "name": { "family": "Banks", "given": "Rachel A." }, "orcid": "0000-0003-2028-2925" }, { "id": "Hirokawa-Soichi", "name": { "family": "Hirokawa", "given": "Soichi" }, "orcid": "0000-0001-5584-2676" }, { "id": "Galstyan-Vahe", "name": { "family": "Galstyan", "given": "Vahe" }, "orcid": "0000-0001-7073-9175" }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" } }, { "id": "Phillips-R", "name": { "family": "Phillips", "given": "Rob" }, "orcid": "0000-0003-3082-2809" } ] }, "title": "Measuring energy consumption through space and time in an active matter system of cytoskeletal motors and filaments", "ispublished": "pub", "full_text_status": "restricted", "keywords": "Biophysics", "note": "\u00a9 2021 Biophysical Society. Published by Elsevier Inc. \n\nAvailable online 11 February 2022, Version of Record 11 February 2022.", "abstract": "Active matter systems consume energy from their environment to form organized, dynamical patterns and structures. These ordered states do not exist in the absence of an energy source. As such, a more general description of energy-driven behavior than is offered by near-equilibrium approaches is required to describe active matter. To gain insight into the energetic cost to form and maintain order, we investigate the assembly of an ordered aster from a disordered, homogeneous mixture of microtubules. This formation occurs due to optogenetically controllable cross-linking of the molecular motors that walk on the microtubules and hydrolyze ATP. Theoretical reaction-diffusion models predict a non-equilibrium ATP distribution resulting from a corresponding motor profile; we test these models via fluorescent readouts of ATP and motor concentrations in both space and time. Comparing the theoretical versus measured ATP profiles provides insight into the dynamics of structure formation and properties of the motors, such as if motors operate cooperatively. Our experiments revealed an ATP depletion gradient that is maximized at the aster core, where the concentration of the motors is highest. This work is a first step in understanding the role of energy consumption through space and time in the formation and maintenance of organization in this active matter system. More broadly, our work provides a case study towards the larger effort of developing generalized theories of non-equilibrium systems.", "date": "2022-02-11", "date_type": "published", "publication": "Biophysical Journal", "volume": "121", "number": "3", "publisher": "Biophysical Society", "pagerange": "521a-522a", "id_number": "CaltechAUTHORS:20220422-296339700", "issn": "0006-3495", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20220422-296339700", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1016/j.bpj.2021.11.2745", "resource_type": "article", "pub_year": "2022", "author_list": "Duarte, Ana I.; Jin Lee, Heun; et el." }, { "id": "https://authors.library.caltech.edu/records/twv8k-e4262", "eprint_id": 114436, "eprint_status": "archive", "datestamp": "2023-08-22 13:58:35", "lastmod": "2023-12-22 23:09:07", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Larios-David-A", "name": { "family": "Larios", "given": "David A." } }, { "id": "Phillips-R", "name": { "family": "Phillips", "given": "Rob" }, "orcid": "0000-0003-3082-2809" }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" }, "orcid": "0000-0003-1021-1234" } ] }, "title": "Reconstituting the nonequilibrium biophysics of the LECA cytoskeleton in active matter", "ispublished": "pub", "full_text_status": "restricted", "keywords": "Biophysics", "note": "\u00a9 2021 Biophysical Society. Published by Elsevier Inc. \n\nAvailable online 11 February 2022, Version of Record 11 February 2022.", "abstract": "The eukaryotic cytoskeleton is a dense network of filaments and motor proteins that enables nearly all cellular force-generating behaviors, including movement, internal transport, and genome segregation through the mitotic spindle. Even though prokaryotes contain homologous force-generating filaments that drive processes like motion and cell division, no motor proteins have been found in bacterial and archaeal genomes. Current models suggest that eukaryotes emerged from the endosymbiosis and coevolution of two prokaryotic organisms; however, bioinformatic reconstructions reveal a LECA (Last Eukaryotic Common Ancestor) with multiple families of filaments and motor proteins. In this project, we aim to explore how the cytoskeleton underwent such a radical functional expansion during eukaryotic evolution, as well as to reconstruct a minimal active matter model of the LECA cytoskeleton. To do so, we built a computational-experimental platform to identify and synthesize cytoskeletal components in vitro and characterize their self-organizing properties with functional assays. As a proof of concept, we generated two synthetic protozoan motors, one of which produces a novel phase with ballistic microtubule motion. With this approach, our future work will expand our platform to a broader range of cytoskeletal components, including prokaryotic filaments. By exploring diverse eukaryotic and hybrid (eukaryote-prokaryote) cytoskeletal systems under multiple physiological conditions, we aim to provide insights into the evolution of eukaryotic active matter.", "date": "2022-02-11", "date_type": "published", "publication": "Biophysical Journal", "volume": "121", "number": "3", "publisher": "Biophysical Society", "pagerange": "521a", "id_number": "CaltechAUTHORS:20220422-225704323", "issn": "0006-3495", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20220422-225704323", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1016/j.bpj.2021.11.2744", "resource_type": "article", "pub_year": "2022", "author_list": "Larios, David A.; Phillips, Rob; et el." }, { "id": "https://authors.library.caltech.edu/records/jbnpr-kv294", "eprint_id": 112615, "eprint_status": "archive", "datestamp": "2023-08-22 13:26:57", "lastmod": "2023-12-22 23:34:36", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Schildknecht-Dominik", "name": { "family": "Schildknecht", "given": "Dominik" }, "orcid": "0000-0002-0678-0904" }, { "id": "Popova-Anastasia-N", "name": { "family": "Popova", "given": "Anastasia N." } }, { "id": "Stellwagen-Jack", "name": { "family": "Stellwagen", "given": "Jack" } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" }, "orcid": "0000-0003-1021-1234" } ] }, "title": "Reinforcement learning reveals fundamental limits on the mixing of active particles", "ispublished": "pub", "full_text_status": "public", "keywords": "Condensed Matter Physics; General Chemistry", "note": "\u00a9 The Royal Society of Chemistry 2022. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. \n\nSubmitted 29 Sep 2021; Accepted 11 Dec 2021; First published 13 Dec 2021. \n\nWe thank Arjuna Subramanian, Jerry Wang, Pranav Bhamidipati, Ivan Jimenez, Jeremy Bernstein, Dr Guannan Qu, Dr Christopher Miles, and Dr Shahriar Shadkhoo for scientific discussions and feedback on the manuscript. We thank Inna-Marie Strazhnik for help with the figures. We acknowledge funding through the Foundational Questions Institute and Fetzer Franklin Fund through FQXi 1816, the Packard Foundation (2019-69662), and the Heritage medical research institute. ANP acknowledges additional funding through the SFP SURF program. \n\nAuthor contributions. DS and MT conceived the project. DS, ANP, and JS wrote the simulation environment. DS performed the simulations and analyzed the results. DS and MT wrote the manuscript with input from all authors. \n\nThere are no conflicts to declare.\n\nPublished - d1sm01400e.pdf
Supplemental Material - d1sm01400e1.pdf
", "abstract": "The control of far-from-equilibrium physical systems, including active materials, requires advanced control strategies due to the non-linear dynamics and long-range interactions between particles, preventing explicit solutions to optimal control problems. In such situations, Reinforcement Learning (RL) has emerged as an approach to derive suitable control strategies. However, for active matter systems, it is an important open question how the mathematical structure and the physical properties determine the tractability of RL. In this paper, we demonstrate that RL can only find good mixing strategies for active matter systems that combine attractive and repulsive interactions. Using analytic results from dynamical systems theory, we show that combining both interaction types is indeed necessary for the existence of mixing-inducing hyperbolic dynamics and therefore the ability of RL to find homogeneous mixing strategies. In particular, we show that for drag-dominated translational-invariant particle systems, mixing relies on combined attractive and repulsive interactions. Therefore, our work demonstrates which experimental developments need to be made to make protein-based active matter applicable, and it provides some classification of microscopic interactions based on macroscopic behavior.", "date": "2022-01-21", "date_type": "published", "publication": "Soft Matter", "volume": "18", "number": "3", "publisher": "Royal Society of Chemistry", "pagerange": "617-625", "id_number": "CaltechAUTHORS:20211221-866382000", "issn": "1744-683X", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20211221-866382000", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Foundational Questions Institute (FQXI)", "grant_number": "1816" }, { "agency": "David and Lucile Packard Foundation", "grant_number": "2019-69662" }, { "agency": "Heritage Medical Research Institute" }, { "agency": "Caltech Summer Undergraduate Research Fellowship (SURF)" } ] }, "local_group": { "items": [ { "id": "Heritage-Medical-Research-Institute" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1039/d1sm01400e", "primary_object": { "basename": "d1sm01400e.pdf", "url": "https://authors.library.caltech.edu/records/jbnpr-kv294/files/d1sm01400e.pdf" }, "related_objects": [ { "basename": "d1sm01400e1.pdf", "url": "https://authors.library.caltech.edu/records/jbnpr-kv294/files/d1sm01400e1.pdf" } ], "resource_type": "article", "pub_year": "2022", "author_list": "Schildknecht, Dominik; Popova, Anastasia N.; et el." }, { "id": "https://authors.library.caltech.edu/records/zvjg3-dry41", "eprint_id": 109639, "eprint_status": "archive", "datestamp": "2023-08-20 05:40:32", "lastmod": "2023-12-22 23:30:57", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Brown-David", "name": { "family": "Brown", "given": "David" }, "orcid": "0000-0002-9757-1744" }, { "id": "Altermatt-Michael", "name": { "family": "Altermatt", "given": "Michael" }, "orcid": "0000-0003-2841-5374" }, { "id": "Dobreva-Tatyana", "name": { "family": "Dobreva", "given": "Tatyana" }, "orcid": "0000-0002-2625-8873" }, { "id": "Chen-Sisi", "name": { "family": "Chen", "given": "Sisi" }, "orcid": "0000-0001-9448-9713" }, { "id": "Wang-Alexander", "name": { "family": "Wang", "given": "Alexander" }, "orcid": "0000-0001-7375-5445" }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" } }, { "id": "Gradinaru-V", "name": { "family": "Gradinaru", "given": "Viviana" }, "orcid": "0000-0001-5868-348X" } ] }, "title": "Deep Parallel Characterization of AAV Tropism and AAV-Mediated Transcriptional Changes via Single-Cell RNA Sequencing", "ispublished": "pub", "full_text_status": "public", "keywords": "gene therapy, next generation sequencing, computational biology, molecular biology, neuroscience", "note": "\u00a9 2021 Brown, Altermatt, Dobreva, Chen, Wang, Thomson and Gradinaru. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. \n\nReceived: 25 June 2021; Accepted: 17 September 2021; Published: 21 October 2021. \n\nWe thank the Gradinaru and Thomson labs for helpful discussions, Allan-Hermann Pool for advice on the mouse brain tissue dissociation procedure, Jeff Park for advice on 10X Genomics Chromium single-cell library preparation, Min Jee Jang for help in designing probes and troubleshooting FISH-HCR, and Ben Deverman and Ken Chan for early discussions on strategy. We also thank the software packages employed for visualization. Figures 1, 2, and Supplemental Figures 1, 2, and 4 were partially created with Biorender.com. Bar graphs, scatter plots, and box plots were generated with the help of the Plotly Python graphing library. \n\nThis work was supported by the NIH Pioneer DP1OD025535, NIH BRAIN R01MH117069, Beckman Institute for CLARITY, Optogenetics and Vector Engineering Research (CLOVER) at Caltech, the Single-Cell Profiling and Engineering Center (SPEC) in the Beckman Institute at Caltech, the Curci Foundation, the CZI Neurodegeneration Challenge Network (VG), and the Vallee Foundation (VG). VG and MT are Heritage Principal Investigators supported by the Heritage Medical Research Institute. DB was supported by PHS Grant Number 5T32NS105595-02. \n\nData Availability Statement: All raw FASTQ files are available under the SRA BioProject PRJNA758711 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA758711/). Processed gene count matrices for droplets identified as cells, as well as the demultiplexed virus cargo counts, are available at CaltechData, doi: 22002/D1.2090 (http://dx.doi.org/10.22002/D1.2090). \n\nEthics Statement: Animal husbandry and all experimental procedures involving animals were performed in accordance with the California Institute of Technology Institutional Animal Care and Use Committee (IACUC) guidelines and reviewed and approved by the Office of Laboratory Animal Resources at the California Institute of Technology (animal protocol no. 1650). \n\nAuthor Contributions: DB, MA, TD, and VG conceived the project and designed the experiments. SC and MT provided critical single-cell RNA sequencing expertise. TD, MA, and DB prepared the DNA constructs and produced virus. MA performed the injections, tissue dissociation, histology, imaging and image quantification. DB and TD performed the single-cell library preparation and prepared samples for sequencing. DB and MA built the data processing pipeline. DB, MA, TD, and AW performed the analysis. All authors contributed to the MS as drafted by DB, MA, and VG. MT supervised single-cell RNA sequencing computational pipelines while VG supervised the overall project. All authors contributed to the article and approved the submitted version. \n\nConflict of Interest: VG is a Co-founder and BoD member for Capsida Biotherapeutics, a Fully Integrated AAV Engineering and Gene Therapy Company in Southern California. \n\nThe remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublished - fimmu-12-730825.pdf
Submitted - 2021.06.25.449955v2.full.pdf
Supplemental Material - 5672098.zip
", "abstract": "Engineered variants of recombinant adeno-associated viruses (rAAVs) are being developed rapidly to meet the need for gene-therapy delivery vehicles with particular cell-type and tissue tropisms. While high-throughput AAV engineering and selection methods have generated numerous variants, subsequent tropism and response characterization have remained low throughput and lack resolution across the many relevant cell and tissue types. To fully leverage the output of these large screening paradigms across multiple targets, we have developed an experimental and computational single-cell RNA sequencing (scRNA-seq) pipeline for in vivo characterization of barcoded rAAV pools at high resolution. Using this platform, we have both corroborated previously reported viral tropisms and discovered unidentified AAV capsid targeting biases. As expected, we observed that the tropism profile of AAV.CAP-B10 in mice was shifted toward neurons and away from astrocytes when compared with AAV-PHP.eB. Transcriptomic analysis revealed that this neuronal bias is due mainly to increased targeting efficiency for glutamatergic neurons, which we confirmed by RNA fluorescence in situ hybridization. We further uncovered cell subtype tropisms of AAV variants in vascular and glial cells, such as low transduction of pericytes and Myoc+ astrocytes. Additionally, we have observed cell-type-specific transitory responses to systemic AAV-PHP.eB administration, such as upregulation of genes involved in p53 signaling in endothelial cells three days post-injection, which return to control levels by day twenty-five. The presented experimental and computational approaches for parallel characterization of AAV tropism will facilitate the advancement of safe and precise gene delivery vehicles, and showcase the power of understanding responses to gene therapies at the single-cell level.", "date": "2021-10-21", "date_type": "published", "publication": "Frontiers in Immunology", "volume": "12", "publisher": "Frontiers Media", "pagerange": "Art. No. 730825", "id_number": "CaltechAUTHORS:20210629-153450418", "issn": "1664-3224", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210629-153450418", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "DP1OD025535" }, { "agency": "NIH", "grant_number": "R01MH117069" }, { "agency": "Caltech Beckman Institute" }, { "agency": "Shurl and Kay Curci Foundation" }, { "agency": "Chan Zuckerberg Initiative" }, { "agency": "Vallee Foundation" }, { "agency": "Heritage Medical Research Institute" }, { "agency": "NIH", "grant_number": "5T32NS105595-02" } ] }, "local_group": { "items": [ { "id": "Heritage-Medical-Research-Institute" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.3389/fimmu.2021.730825", "pmcid": "PMC8574206", "primary_object": { "basename": "2021.06.25.449955v2.full.pdf", "url": "https://authors.library.caltech.edu/records/zvjg3-dry41/files/2021.06.25.449955v2.full.pdf" }, "related_objects": [ { "basename": "5672098.zip", "url": "https://authors.library.caltech.edu/records/zvjg3-dry41/files/5672098.zip" }, { "basename": "fimmu-12-730825.pdf", "url": "https://authors.library.caltech.edu/records/zvjg3-dry41/files/fimmu-12-730825.pdf" } ], "resource_type": "article", "pub_year": "2021", "author_list": "Brown, David; Altermatt, Michael; et el." }, { "id": "https://authors.library.caltech.edu/records/ks7h3-tf644", "eprint_id": 106594, "eprint_status": "archive", "datestamp": "2023-08-22 10:56:38", "lastmod": "2023-12-22 23:33:01", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Qu-Zijie", "name": { "family": "Qu", "given": "Zijie" }, "orcid": "0000-0003-1500-3207" }, { "id": "Schildknecht-Dominik", "name": { "family": "Schildknecht", "given": "Dominik" }, "orcid": "0000-0002-0678-0904" }, { "id": "Shadkhoo-Shahriar", "name": { "family": "Shadkhoo", "given": "Shahriar" }, "orcid": "0000-0003-3582-0634" }, { "id": "Amaya-Enrique", "name": { "family": "Amaya", "given": "Enrique" } }, { "id": "Jiang-Jialong", "name": { "family": "Jiang", "given": "Jialong" } }, { "id": "Lee-Heun-Jin", "name": { "family": "Lee", "given": "Heun Jin" } }, { "id": "Larios-David", "name": { "family": "Larios", "given": "David" } }, { "id": "Yang-Fan", "name": { "family": "Yang", "given": "Fan" }, "orcid": "0000-0002-2248-2026" }, { "id": "Phillips-R", "name": { "family": "Phillips", "given": "Rob" }, "orcid": "0000-0003-3082-2809" }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" } } ] }, "title": "Persistent fluid flows defined by active matter boundaries", "ispublished": "pub", "full_text_status": "public", "keywords": "Biological physics; Fluid dynamics; Permeation and transport", "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 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 03 April 2021; Accepted 10 August 2021; Published 27 August 2021. \n\nWe acknowledge funding from the Donna and Benjamin M. Rosen Bioengineering Center, Foundational Questions Institute and Fetzer Franklin Fund (through FQXi 1816), The Moore Foundation, The Packard Foundation, and Heritage Medical Research Institute. We thank Inna-Marie Strazhnik for the preparation of figures and illustrations. We acknowledge Dr. Guy Riddihough for his editorial assistance with the paper. \n\nData availability: The data is openly available at https://doi.org/10.22002/D1.1858. \n\nCode availability: The code to reproduce our main findings can be found on the following Github repositories: The FEM code can be found on https://github.com/domischi/StokesFEM and the PIV analysis code is on https://github.com/ShaiShdk/ActiveFlow_PIV. \n\nAuthor Contributions: Z.Q., J.J., H.J.L., R.P., and M.T. conceived the project. Z.Q., H.J.L., D.L., and F.Y. performed the experiments. J.J. performed the initial investigations of the model. D.S. developed the theoretical framework and performed the finite-element simulations. S.S. performed the PIV analysis. E.A. performed the image segmentation analysis. Z.Q., D.S., and M.T. wrote the paper with input from all authors. \n\nThe authors declare no competing interests. \n\nPeer review information: Communications Physics thanks the anonymous reviewers for their contribution to the peer review of this work.\n\nPublished - s42005-021-00703-3.pdf
Submitted - 2010.08112.pdf
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", "abstract": "Biological systems control ambient fluids through the self-organization of active protein structures, including flagella, cilia, and cytoskeletal networks. Self-organization of protein components enables the control and modulation of fluid flow fields on micron scales, however, the physical principles underlying the organization and control of active-matter-driven fluid flows are poorly understood. Here, we use an optically-controlled active-matter system composed of microtubule filaments and light-switchable kinesin motor proteins to analyze the emergence of persistent flow fields. Using light, we form contractile microtubule networks of varying size and shape, and demonstrate that the geometry of microtubule flux at the corners of contracting microtubule networks predicts the architecture of fluid flow fields across network geometries through a simple point force model. Our work provides a foundation for programming microscopic fluid flows with controllable active matter and could enable the engineering of versatile and dynamic microfluidic devices.", "date": "2021-08-27", "date_type": "published", "publication": "Communications Physics", "volume": "4", "publisher": "Nature Publishing Group", "pagerange": "Art. No. 198", "id_number": "CaltechAUTHORS:20201110-143708446", "issn": "2399-3650", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20201110-143708446", "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": "Foundational Questions Institute (FQXI)", "grant_number": "FQXi 1816" }, { "agency": "Gordon and Betty Moore Foundation" }, { "agency": "David and Lucile Packard Foundation" }, { "agency": "Heritage Medical Research Institute" } ] }, "local_group": { "items": [ { "id": "Heritage-Medical-Research-Institute" }, { "id": "Rosen-Bioengineering-Center" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1038/s42005-021-00703-3", "primary_object": { "basename": "42005_2021_703_MOESM11_ESM.pdf", "url": "https://authors.library.caltech.edu/records/ks7h3-tf644/files/42005_2021_703_MOESM11_ESM.pdf" }, "related_objects": [ { "basename": "42005_2021_703_MOESM2_ESM.mov", "url": "https://authors.library.caltech.edu/records/ks7h3-tf644/files/42005_2021_703_MOESM2_ESM.mov" }, { "basename": "42005_2021_703_MOESM5_ESM.mov", "url": "https://authors.library.caltech.edu/records/ks7h3-tf644/files/42005_2021_703_MOESM5_ESM.mov" }, { "basename": "42005_2021_703_MOESM1_ESM.pdf", "url": "https://authors.library.caltech.edu/records/ks7h3-tf644/files/42005_2021_703_MOESM1_ESM.pdf" }, { "basename": "42005_2021_703_MOESM8_ESM.mov", "url": "https://authors.library.caltech.edu/records/ks7h3-tf644/files/42005_2021_703_MOESM8_ESM.mov" }, { "basename": "s42005-021-00703-3.pdf", "url": "https://authors.library.caltech.edu/records/ks7h3-tf644/files/s42005-021-00703-3.pdf" }, { "basename": "2010.08112.pdf", "url": "https://authors.library.caltech.edu/records/ks7h3-tf644/files/2010.08112.pdf" }, { "basename": "42005_2021_703_MOESM10_ESM.pdf", "url": "https://authors.library.caltech.edu/records/ks7h3-tf644/files/42005_2021_703_MOESM10_ESM.pdf" }, { "basename": "42005_2021_703_MOESM6_ESM.mov", "url": "https://authors.library.caltech.edu/records/ks7h3-tf644/files/42005_2021_703_MOESM6_ESM.mov" }, { "basename": "42005_2021_703_MOESM3_ESM.mov", "url": "https://authors.library.caltech.edu/records/ks7h3-tf644/files/42005_2021_703_MOESM3_ESM.mov" }, { "basename": "42005_2021_703_MOESM4_ESM.mov", "url": "https://authors.library.caltech.edu/records/ks7h3-tf644/files/42005_2021_703_MOESM4_ESM.mov" }, { "basename": "42005_2021_703_MOESM7_ESM.mov", "url": "https://authors.library.caltech.edu/records/ks7h3-tf644/files/42005_2021_703_MOESM7_ESM.mov" }, { "basename": "42005_2021_703_MOESM9_ESM.mov", "url": "https://authors.library.caltech.edu/records/ks7h3-tf644/files/42005_2021_703_MOESM9_ESM.mov" } ], "resource_type": "article", "pub_year": "2021", "author_list": "Qu, Zijie; Schildknecht, Dominik; et el." }, { "id": "https://authors.library.caltech.edu/records/j2jhj-wph98", "eprint_id": 110014, "eprint_status": "archive", "datestamp": "2023-08-20 04:45:12", "lastmod": "2023-12-22 23:22:19", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Desai-Ravi-V", "name": { "family": "Desai", "given": "Ravi V." }, "orcid": "0000-0002-0336-0883" }, { "id": "Chen-Xinyue", "name": { "family": "Chen", "given": "Xinyue" }, "orcid": "0000-0001-8288-7685" }, { "id": "Martin-Benjamin", "name": { "family": "Martin", "given": "Benjamin" }, "orcid": "0000-0002-9673-2008" }, { "id": "Chaturvedi-Sonali", "name": { "family": "Chaturvedi", "given": "Sonali" }, "orcid": "0000-0002-9175-8110" }, { "id": "Hwang-Dong-Woo", "name": { "family": "Hwang", "given": "Dong Woo" }, "orcid": "0000-0001-5806-067X" }, { "id": "Li-Weihan", "name": { "family": "Li", "given": "Weihan" }, "orcid": "0000-0003-4718-1884" }, { "id": "Yu-Chen", "name": { "family": "Yu", "given": "Chen" } }, { "id": "Ding-Sheng", "name": { "family": "Ding", "given": "Sheng" }, "orcid": "0000-0002-7525-2144" }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" }, "orcid": "0000-0003-1021-1234" }, { "id": "Singer-Robert-H", "name": { "family": "Singer", "given": "Robert H." } }, { "id": "Coleman-Robert-A", "name": { "family": "Coleman", "given": "Robert A." } }, { "id": "Hansen-Maike-M-K", "name": { "family": "Hansen", "given": "Maike M. K." }, "orcid": "0000-0001-7998-6631" }, { "id": "Weinberger-Leor-S", "name": { "family": "Weinberger", "given": "Leor S." }, "orcid": "0000-0002-9987-6357" } ] }, "title": "A DNA repair pathway can regulate transcriptional noise to promote cell fate transitions", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2021 American Association for the Advancement of Science. \nThis is an article distributed under the terms of the Science Journals Default License. \n\n31 May 2020; accepted 8 July 2021; Published online 22 July 2021. \n\nWe thank M. Simpson, B. Bruneau, J. Weissman, G. Balazsi, and members of the Weinberger laboratory for thoughtful discussions and suggestions; K. Claiborn for editing; G. Maki for graphics support; N. Raman in the Gladstone Institute Flow Cytometry Facility (NIH S10 RR028962, P30 AI027763, DARPA, and the James B. Pendleton Charitable Trust) for technical assistance; the Gladstone Assay Development and Drug Discovery Core for technical assistance with drug screening; K. Thorn and D. Larson in the UCSF Nikon Imaging Center (NIH S10 1S10OD017993-01A1) for technical assistance with imaging; M. Jost and J. Weissman for CRISPRi reagents; and the Gladstone Institute Genomics Core for technical assistance with single-cell RNA-sequencing. The dual-tagged Sox2 mESCs were a kind donation from B. Bruneau and E. Nora. The Oct4-GFP reprogrammable MEFs (harbor stably integrated OKSM factors) were a kind donation from S. Guo. \n\nR.V.D. is supported by an NIH/NICHD F30 fellowship (HD095614-03). R.A.C. acknowledges support from NIH award 1R01GM126045-05. R.H.S. acknowledges support from NIH awards NS083085 and 1R35GM136296. M.M.K.H. acknowledges support from a Dutch Research Council (NWO) ENW-XS award (OCENW.XS3.055). L.S.W. acknowledges support from a Bowes Distinguished Professorship, Alfred P. Sloan Research Fellowship, Pew Scholars in the Biomedical Sciences Program, NIH award R01AI109593, and the NIH Director's New Innovator Award (OD006677) and Pioneer Award (OD17181) programs. \n\nAuthor contributions: R.V.D., M.T., and L.S.W. conceived and designed the study. R.V.D., B.M., and M.T. analyzed the sequencing data. R.V.D., X.C., C.U., S.D., and L.S.W conceived and designed the cellular reprogramming experiments. X.C., D.W.H., W.L., R.H.S., R.A.C., and L.S.W conceived and designed the MS2 imaging experiments. R.V.D., X.C., S.C., D.W.H., W.L., and C.U. performed the experiments. R.V.D., X.C., B.M., M.T., R.A.C., M.M.K.H., and L.S.W. analyzed data. R.V.D., M.M.K.H., B.M., and L.S.W. constructed and analyzed the mathematical models. R.V.D., M.M.K.H., and L.S.W. wrote the manuscript. \n\nThe authors declare no competing interests. \n\nData and materials availability: The raw and processed sequencing data reported herein have been deposited onto the Gene Expression Omnibus under accession number GSE176044. Custom code for analysis of scRNA-seq data and mathematical modeling are available on GitHub at https://github.com/weinbergerlab-ucsf/Code_Desai_et_al and are archived on Zenodo (79). Reagents, including plasmids and cell lines, are available from the corresponding author upon request.\n\nAccepted Version - nihms-1762191.pdf
Supplemental Material - abc6506-Desai-SM-Reproducibility-Checklist.pdf
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", "abstract": "Stochastic fluctuations in gene expression (\"noise\") are often considered detrimental, but fluctuations can also be exploited for benefit (e.g., dither). We show here that DNA base excision repair amplifies transcriptional noise to facilitate cellular reprogramming. Specifically, the DNA repair protein Apex1, which recognizes both naturally occurring and unnatural base modifications, amplifies expression noise while homeostatically maintaining mean expression levels. This amplified expression noise originates from shorter-duration, higher-intensity transcriptional bursts generated by Apex1-mediated DNA supercoiling. The remodeling of DNA topology first impedes and then accelerates transcription to maintain mean levels. This mechanism, which we refer to as \"discordant transcription through repair\" (\"DiThR,\" which is pronounced \"dither\"), potentiates cellular reprogramming and differentiation. Our study reveals a potential functional role for transcriptional fluctuations mediated by DNA base modifications in embryonic development and disease.", "date": "2021-08-20", "date_type": "published", "publication": "Science", "volume": "373", "number": "6557", "publisher": "American Association for the Advancement of Science", "pagerange": "Art. No. eabc6506", "id_number": "CaltechAUTHORS:20210726-193944737", "issn": "0036-8075", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210726-193944737", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH Postdoctoral Fellowship", "grant_number": "F30HD095614-03" }, { "agency": "NIH", "grant_number": "1R01GM126045-05" }, { "agency": "NIH", "grant_number": "NS083085" }, { "agency": "NIH", "grant_number": "1R35GM136296" }, { "agency": "Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)", "grant_number": "OCENW.XS3.055" }, { "agency": "Bowes Distinguished Professorship" }, { "agency": "Alfred P. Sloan Foundation" }, { "agency": "Pew Charitable Trust" }, { "agency": "NIH", "grant_number": "R01AI109593" }, { "agency": "NIH", "grant_number": "OD006677" }, { "agency": "NIH", "grant_number": "OD17181" } ] }, "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1126/science.abc6506", "pmcid": "PMC8667278", "primary_object": { "basename": "abc6506-Desai-SM-Table-S6.xlsx", "url": "https://authors.library.caltech.edu/records/j2jhj-wph98/files/abc6506-Desai-SM-Table-S6.xlsx" }, "related_objects": [ { "basename": "abc6506-Desai-SM-Table-S8.xlsx", "url": "https://authors.library.caltech.edu/records/j2jhj-wph98/files/abc6506-Desai-SM-Table-S8.xlsx" }, { "basename": "abc6506-Desai-SM.pdf", "url": "https://authors.library.caltech.edu/records/j2jhj-wph98/files/abc6506-Desai-SM.pdf" }, { "basename": "abc6506-Desai-SM-Table-S1.xlsx", "url": "https://authors.library.caltech.edu/records/j2jhj-wph98/files/abc6506-Desai-SM-Table-S1.xlsx" }, { "basename": "abc6506-Desai-SM-Table-S2.xlsx", "url": "https://authors.library.caltech.edu/records/j2jhj-wph98/files/abc6506-Desai-SM-Table-S2.xlsx" }, { "basename": "abc6506-Desai-SM-Table-S3.xlsx", "url": "https://authors.library.caltech.edu/records/j2jhj-wph98/files/abc6506-Desai-SM-Table-S3.xlsx" }, { "basename": "abc6506-Desai-SM-Table-S4.xlsx", "url": "https://authors.library.caltech.edu/records/j2jhj-wph98/files/abc6506-Desai-SM-Table-S4.xlsx" }, { "basename": "abc6506-Desai-SM-Reproducibility-Checklist.pdf", "url": "https://authors.library.caltech.edu/records/j2jhj-wph98/files/abc6506-Desai-SM-Reproducibility-Checklist.pdf" }, { "basename": "abc6506-Desai-SM-Table-S5.xlsx", "url": "https://authors.library.caltech.edu/records/j2jhj-wph98/files/abc6506-Desai-SM-Table-S5.xlsx" }, { "basename": "abc6506-Desai-SM-Table-S7.xlsx", "url": "https://authors.library.caltech.edu/records/j2jhj-wph98/files/abc6506-Desai-SM-Table-S7.xlsx" }, { "basename": "nihms-1762191.pdf", "url": "https://authors.library.caltech.edu/records/j2jhj-wph98/files/nihms-1762191.pdf" } ], "resource_type": "article", "pub_year": "2021", "author_list": "Desai, Ravi V.; Chen, Xinyue; et el." }, { "id": "https://authors.library.caltech.edu/records/ztte2-h5j24", "eprint_id": 104902, "eprint_status": "archive", "datestamp": "2023-08-20 04:22:52", "lastmod": "2023-12-22 23:34:28", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Schildknecht-Dominik", "name": { "family": "Schildknecht", "given": "Dominik" }, "orcid": "0000-0002-0678-0904" }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" }, "orcid": "0000-0003-1021-1234" } ] }, "title": "Phenomenological model of motility by spatiotemporal modulation of active interactions", "ispublished": "pub", "full_text_status": "public", "keywords": "protein-based active matter, phenomenological description, molecular dynamics simulations", "note": "\u00a9 2021 The Author(s). Published by IOP Publishing Ltd on behalf of the Institute of Physics and Deutsche Physikalische Gesellschaft. Original content from this work may be used under the terms of the Creative Commons Attribution 4.0 licence. Any further distribution of this work must maintain attribution to the author(s) and the title of the work, journal citation and DOI. \n\nRECEIVED 16 April 2021. REVISED 24 June 2021. ACCEPTED FOR PUBLICATION 5 July 2021. PUBLISHED 30 July 2021. \n\nWe thank Jerry Wang, Arjuna Subramanian, Dr Zijie Qu, and Dr Shahriar Shadkhoo for scientific discussions and feedback on the manuscript. We thank Inna-Marie Strazhnik for help preparing some of the figures. Furthermore, we acknowledge funding through the Foundational Questions Institute and Fetzer Franklin Fund through FQXi 1816, the Packard Foundation (2019-69662), and the Heritage Medical Research Institute. \n\nData availability statement: The data that support the findings of this study are openly available at the following URL/DOI: http://dx.doi.org/10.22002/D1.1451.\n\nPublished - Schildknecht_2021_New_J._Phys._23_083001.pdf
Submitted - 2007.04461.pdf
", "abstract": "Transport at microscopic length scales is essential in biological systems and various technologies, including microfluidics. Recent experiments achieved self-organized transport phenomena in microtubule active matter using light to modulate motor-protein activity in time and space. Here, we introduce a novel phenomenological model to explain such experiments. Our model, based on spatially modulated particle interactions, reveals a possible mechanism for emergent transport phenomena in light-controlled active matter, including motility and contraction. In particular, the model's analytic treatment elucidates the conservation of the center of mass of activated particles as a fundamental mechanism of material transport and demonstrates the necessity of memory for sustained motility. Furthermore, we generalize the model to explain other phenomena, like microtubule aster\u2013aster interactions induced by more complicated activation geometries. Our results demonstrate that the model provides a possible foundation for the phenomenological understanding of light-controlled active matter, and it will enable the design and optimization of transport protocols for active matter devices.", "date": "2021-08", "date_type": "published", "publication": "New Journal of Physics", "volume": "23", "number": "8", "publisher": "IOP", "pagerange": "Art. No. 083001", "id_number": "CaltechAUTHORS:20200811-074939566", "issn": "1367-2630", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200811-074939566", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Foundational Questions Institute (FQXI)", "grant_number": "FQXi 1816" }, { "agency": "David and Lucile Packard Foundation", "grant_number": "2019-69662" }, { "agency": "Heritage Medical Research Institute" } ] }, "local_group": { "items": [ { "id": "Heritage-Medical-Research-Institute" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1088/1367-2630/ac1144", "primary_object": { "basename": "2007.04461.pdf", "url": "https://authors.library.caltech.edu/records/ztte2-h5j24/files/2007.04461.pdf" }, "related_objects": [ { "basename": "Schildknecht_2021_New_J._Phys._23_083001.pdf", "url": "https://authors.library.caltech.edu/records/ztte2-h5j24/files/Schildknecht_2021_New_J._Phys._23_083001.pdf" } ], "resource_type": "article", "pub_year": "2021", "author_list": "Schildknecht, Dominik and Thomson, Matt" }, { "id": "https://authors.library.caltech.edu/records/zngyj-6pw88", "eprint_id": 108922, "eprint_status": "archive", "datestamp": "2023-08-20 01:51:02", "lastmod": "2023-12-22 23:22:24", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Srivastava-Vasudha", "name": { "family": "Srivastava", "given": "Vasudha" } }, { "id": "Hu-Jennifer-L", "name": { "family": "Hu", "given": "Jennifer L." } }, { "id": "Garbe-James-C", "name": { "family": "Garbe", "given": "James C." } }, { "id": "Stampfer-Martha-R", "name": { "family": "Stampfer", "given": "Martha R." } }, { "id": "LaBarge-Mark-A", "name": { "family": "LaBarge", "given": "Mark A." } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matthew" } }, { "id": "Gartner-Zev-J", "name": { "family": "Gartner", "given": "Zev J." } } ] }, "title": "Identifying Enthalpic Barriers to Entropically-Driven Structural Disruption in Breast Cancers", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 2021 Biophysical Society. \n\nAvailable online 12 February 2021.", "abstract": "Tissues can span a large structural phase space, but only occupy a small set of configurations as interfacial tension-driven self-organization counters entropically-favored disorganization. Historical self-organization models often do not address structural variability and transitions commonly observed during morphogenesis and disease. In breast cancer, structural breakdown of the bilayered mammary epithelium, comprised of inner luminal (LEP) layer surrounded by an outer myoepithelial (MEP) layer, is directly linked increased patient risk upon invasion. Organotypic cultures of patient-derived human mammary epithelial cells self-organize in vitro, largely driven by differences in favorability of LEP and MEP interface with the extracellular matrix. The observed distribution of organoid structures closely aligns with Boltzmann statistics - a function of the underlying interfacial energies (enthalpy), geometric constraints (entropy), and mechanical fluctuations (activity) of the tissue. We predict that transformations which increase the probability of LEP occupancy in the basal compartment can destabilize tissue structure and promote invasion, consistent with observations in murine organoid models.To test these predictions experimentally, we examined the ability of 15 cancer-associated genetic changes to alter interfacial tensions of LEP and disrupt self-organization in reconstituted human mammary organoids. While most perturbations only minimally impacted self-organization, PIK3CA activation in LEP uniquely reduced their ECM interfacial energy and disrupted tissue structure. Modeling predicts that normalization of PIK3CA-LEP interfacial energy or decreasing overall tissue activity can correct tissue structure, which we confirm experimentally. Consistently, upregulation of basal adhesion (enthalpy) is observed during progression from in situ to invasive human cancers. Additionally changes in tissue composition (entropy) and remodeling (activity) are linked to changes in cancer risk post-pregnancy. Collectively, this statistical mechanical framework presents a new strategy for understanding and targeting cancer progression, emphasizing the importance of structural probability distributions rather than average structures.", "date": "2021-02-12", "date_type": "published", "publication": "Biophysical Journal", "volume": "120", "number": "3", "publisher": "Biophysical Society", "pagerange": "196A", "id_number": "CaltechAUTHORS:20210503-102948566", "issn": "0006-3495", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210503-102948566", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1016/j.bpj.2020.11.1347", "resource_type": "article", "pub_year": "2021", "author_list": "Srivastava, Vasudha; Hu, Jennifer L.; et el." }, { "id": "https://authors.library.caltech.edu/records/teegz-hk924", "eprint_id": 101233, "eprint_status": "archive", "datestamp": "2023-08-20 00:52:14", "lastmod": "2023-12-22 23:09:11", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Zhu-Meng", "name": { "family": "Zhu", "given": "Meng" }, "orcid": "0000-0001-6157-8840" }, { "id": "Cornwall-Scoones-Jake", "name": { "family": "Cornwall-Scoones", "given": "Jake" }, "orcid": "0000-0002-7435-486X" }, { "id": "Wang-Peizhe", "name": { "family": "Wang", "given": "Peizhe" } }, { "id": "Handford-Charlotte-E", "name": { "family": "Handford", "given": "Charlotte E." }, "orcid": "0000-0002-5245-8027" }, { "id": "Na-Jie", "name": { "family": "Na", "given": "Jie" }, "orcid": "0000-0003-1820-0548" }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" }, "orcid": "0000-0003-1021-1234" }, { "id": "Zernicka-Goetz-M", "name": { "family": "Zernicka-Goetz", "given": "Magdalena" }, "orcid": "0000-0002-7004-2471" } ] }, "title": "Developmental clock and mechanism of de novo polarization of the mouse embryo", "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 https://www.sciencemag.org/about/science-licenses-journal-article-reuse. This is an article distributed under the terms of the Science Journals Default License. \n\nReceived for publication June 10, 2020. Accepted for publication October 14, 2020. \n\nWe thank E. Munro, D. Glover, A. Andersen, and M. Shahbazi for helpful discussion; S. Shadkhoo for comments on the model; and S. Malas for the Gata3-GFP transgenic line. Some of the computations were conducted on the Caltech High Performance Cluster, supported by a Gordon and Betty Moore Foundation grant. \n\nThis work was supported by grants from the Wellcome Trust (098287/Z/12/Z), ERC (669198), Leverhulme Trust (RPG-2018-085), Open Philanthropy/Silicon Valley, Weston Havens Foundations and NIH R01 HD100456-01A1 to M.Z.-G; Packard Foundation, Heritage Medical Research Institute, NIH U01CA244109 to M.T.; and the National Key R&D Program of China grants 2017YFA0102802 and 2019YFA0110001 to J.N. \n\nAuthor contributions: Conceptualization: M.Z. and M.Z.-G. Investigation: M.Z., J.C.-S., P.W., and C.E.H. Writing: M.Z. and M.Z.-G. Supervision: M.Z.-G., M.T., and J.N. \n\nThe authors declare no competing interests. \n\nData and materials availability: All raw data are available upon request from the corresponding author. The RNA-seq data have been deposited in the Gene Expression Omnibus database (accession number GSE124755). The code for computation simulation has been deposited at https://jakesorel.github.io/Apical_Domain_2020/.\n\nAccepted Version - nihms-1714014.pdf
Submitted - 2020.02.10.942201v1.full.pdf
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", "abstract": "Embryo polarization is critical for mouse development; however, neither the regulatory clock nor the molecular trigger that it activates is known. Here, we show that the embryo polarization clock reflects the onset of zygotic genome activation, and we identify three factors required to trigger polarization. Advancing the timing of transcription factor AP-2 gamma (Tfap2c) and TEA domain transcription factor 4 (Tead4) expression in the presence of activated Ras homolog family member A (RhoA) induces precocious polarization as well as subsequent cell fate specification and morphogenesis. Tfap2c and Tead4 induce expression of actin regulators that control the recruitment of apical proteins on the membrane, whereas RhoA regulates their lateral mobility, allowing the emergence of the apical domain. Thus, Tfap2c, Tead4, and RhoA are regulators for the onset of polarization and cell fate segregation in the mouse.", "date": "2020-12-11", "date_type": "published", "publication": "Science", "volume": "370", "number": "6522", "publisher": "American Association for the Advancement of Science", "pagerange": "Art. No. eabd2703", "id_number": "CaltechAUTHORS:20200212-084819179", "issn": "0036-8075", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200212-084819179", "funders": { "items": [ { "agency": "Gordon and Betty Moore Foundation" }, { "agency": "Wellcome Trust", "grant_number": "098287/Z/12/Z" }, { "agency": "European Research Council (ERC)", "grant_number": "669198" }, { "agency": "Leverhulme Trust", "grant_number": "RPG-2018-085" }, { "agency": "Open Philanthropy" }, { "agency": "Weston Havens Foundation" }, { "agency": "NIH", "grant_number": "R01 HD100456-01A1" }, { "agency": "David and Lucile Packard Foundation" }, { "agency": "Heritage Medical Research Institute" }, { "agency": "NIH", "grant_number": "U01CA244109" }, { "agency": "National Key Research and Development Program of China", "grant_number": "2017YFA0102802" }, { "agency": "National Key Research and Development Program of China", "grant_number": "2019YFA0110001" } ] }, "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1126/science.abd2703", "pmcid": "PMC8210885", "primary_object": { "basename": "nihms-1714014.pdf", "url": "https://authors.library.caltech.edu/records/teegz-hk924/files/nihms-1714014.pdf" }, "related_objects": [ { "basename": "abd2703s1.mov", "url": "https://authors.library.caltech.edu/records/teegz-hk924/files/abd2703s1.mov" }, { "basename": "abd2703s12.mov", "url": "https://authors.library.caltech.edu/records/teegz-hk924/files/abd2703s12.mov" }, { "basename": "abd2703s5.mov", "url": "https://authors.library.caltech.edu/records/teegz-hk924/files/abd2703s5.mov" }, { "basename": "abd2703s9.mov", "url": "https://authors.library.caltech.edu/records/teegz-hk924/files/abd2703s9.mov" }, { "basename": "2020.02.10.942201v1.full.pdf", "url": "https://authors.library.caltech.edu/records/teegz-hk924/files/2020.02.10.942201v1.full.pdf" }, { "basename": "abd2703s14.mov", "url": "https://authors.library.caltech.edu/records/teegz-hk924/files/abd2703s14.mov" }, { "basename": "abd2703s3.mov", "url": "https://authors.library.caltech.edu/records/teegz-hk924/files/abd2703s3.mov" }, { "basename": "abd2703s4.mov", "url": "https://authors.library.caltech.edu/records/teegz-hk924/files/abd2703s4.mov" }, { "basename": "abd2703s6.mov", "url": "https://authors.library.caltech.edu/records/teegz-hk924/files/abd2703s6.mov" }, { "basename": "abd2703s8.mov", "url": "https://authors.library.caltech.edu/records/teegz-hk924/files/abd2703s8.mov" }, { "basename": "abd2703s11.mov", "url": "https://authors.library.caltech.edu/records/teegz-hk924/files/abd2703s11.mov" }, { "basename": "abd2703s10.mov", "url": "https://authors.library.caltech.edu/records/teegz-hk924/files/abd2703s10.mov" }, { "basename": "abd2703s13.mov", "url": "https://authors.library.caltech.edu/records/teegz-hk924/files/abd2703s13.mov" }, { "basename": "abd2703s15.mov", "url": "https://authors.library.caltech.edu/records/teegz-hk924/files/abd2703s15.mov" }, { "basename": "abd2703s2.mov", "url": "https://authors.library.caltech.edu/records/teegz-hk924/files/abd2703s2.mov" }, { "basename": "abd2703_Zhu_SM.pdf", "url": "https://authors.library.caltech.edu/records/teegz-hk924/files/abd2703_Zhu_SM.pdf" }, { "basename": "abd2703s7.mov", "url": "https://authors.library.caltech.edu/records/teegz-hk924/files/abd2703s7.mov" }, { "basename": "abd2703_MDAR_Reproducibility_Checklist.pdf", "url": "https://authors.library.caltech.edu/records/teegz-hk924/files/abd2703_MDAR_Reproducibility_Checklist.pdf" } ], "resource_type": "article", "pub_year": "2020", "author_list": "Zhu, Meng; Cornwall-Scoones, Jake; et el." }, { "id": "https://authors.library.caltech.edu/records/c03z0-nfg11", "eprint_id": 106842, "eprint_status": "archive", "datestamp": "2023-08-22 07:41:52", "lastmod": "2023-12-22 23:34:34", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Dobreva-Tatyana", "name": { "family": "Dobreva", "given": "Tatyana" }, "orcid": "0000-0002-2625-8873" }, { "id": "Brown-David", "name": { "family": "Brown", "given": "David" }, "orcid": "0000-0002-9757-1744" }, { "id": "Park-Jong-Hwee", "name": { "family": "Park", "given": "Jong Hwee" } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" } } ] }, "title": "Single cell profiling of capillary blood enables out of clinic human immunity studies", "ispublished": "pub", "full_text_status": "public", "keywords": "Gene expression analysis; Gene regulation in immune cells", "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 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/. \n\nReceived 23 July 2020; Accepted 30 October 2020; Published 25 November 2020. \n\nThe funding was provided by Shurl and Kay Curci Foundation, the Beckman Institute at Caltech, and Heritage Medical Research Institute. \n\nData availability: Gene expression matrix and relevant metadata are available on https://data.caltech.edu/records/1407. FASTQ files are not being released to protect the identity of the subjects. \n\nCode availability: Custom code made for diurnal and subject specific gene detection is available on https://github.com/thomsonlab/capblood-seq. \n\nAuthor Contributions: T.D., D.B. and M.T. designed the study. T.D., D.B. and J.P. performed blood extraction and single-cell experiments. T.D. and D.B. performed computational analysis. T.D., D.B. and M.T. wrote the manuscript. All authors reviewed the manuscript. \n\nThe authors declare no competing interests.\n\nPublished - s41598-020-77073-3.pdf
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", "abstract": "An individual's immune system is driven by both genetic and environmental factors that vary over time. To better understand the temporal and inter-individual variability of gene expression within distinct immune cell types, we developed a platform that leverages multiplexed single-cell sequencing and out-of-clinic capillary blood extraction to enable simplified, cost-effective profiling of the human immune system across people and time at single-cell resolution. Using the platform, we detect widespread differences in cell type-specific gene expression between subjects that are stable over multiple days.", "date": "2020-11-25", "date_type": "published", "publication": "Scientific Reports", "volume": "10", "publisher": "Nature Publishing Group", "pagerange": "Art. No. 20540", "id_number": "CaltechAUTHORS:20201130-100709314", "issn": "2045-2322", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20201130-100709314", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Shurl and Kay Curci Foundation" }, { "agency": "Caltech Beckman Institute" }, { "agency": "Heritage Medical Research Institute" } ] }, "local_group": { "items": [ { "id": "Heritage-Medical-Research-Institute" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1038/s41598-020-77073-3", "pmcid": "PMC7688970", "primary_object": { "basename": "41598_2020_77073_MOESM1_ESM.docx", "url": "https://authors.library.caltech.edu/records/c03z0-nfg11/files/41598_2020_77073_MOESM1_ESM.docx" }, "related_objects": [ { "basename": "41598_2020_77073_MOESM2_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/c03z0-nfg11/files/41598_2020_77073_MOESM2_ESM.xlsx" }, { "basename": "41598_2020_77073_MOESM3_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/c03z0-nfg11/files/41598_2020_77073_MOESM3_ESM.xlsx" }, { "basename": "s41598-020-77073-3.pdf", "url": "https://authors.library.caltech.edu/records/c03z0-nfg11/files/s41598-020-77073-3.pdf" } ], "resource_type": "article", "pub_year": "2020", "author_list": "Dobreva, Tatyana; Brown, David; et el." }, { "id": "https://authors.library.caltech.edu/records/0cqqx-m7s93", "eprint_id": 90008, "eprint_status": "archive", "datestamp": "2023-08-22 07:37:39", "lastmod": "2023-12-22 23:34:32", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Chen-Sisi", "name": { "family": "Chen", "given": "Sisi" }, "orcid": "0000-0001-9448-9713" }, { "id": "Rivaud-Paul", "name": { "family": "Rivaud", "given": "Paul" }, "orcid": "0000-0001-8637-3331" }, { "id": "Park-Jong-Hwee", "name": { "family": "Park", "given": "Jong H." } }, { "id": "Tsou-Tiffany", "name": { "family": "Tsou", "given": "Tiffany" }, "orcid": "0000-0002-5651-2879" }, { "id": "Charles-Emeric", "name": { "family": "Charles", "given": "Emeric" } }, { "id": "Haliburton-John-R", "name": { "family": "Haliburton", "given": "John R." } }, { "id": "Pichiorri-Flavia", "name": { "family": "Pichiorri", "given": "Flavia" }, "orcid": "0009-0006-8429-9397" }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" }, "orcid": "0000-0003-1021-1234" } ] }, "title": "Dissecting heterogeneous cell populations across drug and disease conditions with PopAlign", "ispublished": "pub", "full_text_status": "public", "keywords": "single-cell genomics; probabilistic models; single cell mRNA-seq", "note": "\u00a9 2020 National Academy of Sciences. Published under the PNAS license. \n\nEdited by Jonathan S. Weissman, University of California, San Francisco, CA, and approved September 25, 2020 (received for review March 31, 2020). PNAS first published October 30, 2020. \n\nWe thank Justin Bois, Eric Chow, Allan-Hermann Pool, Jase Gehring, Tami Khazaei, and members of the M.T. laboratory for helpful feedback and discussions; Chris McGinnis and David Patterson for experimental guidance; and Inna-Marie Strazhnik for figure editing and illustrations. This work was performed at the Beckman Institute Single-Cell Profiling and Engineering Center. M.T. was supported by the Shurl and Kay Curci Foundation and the Heritage Medical Research Institute. \n\nData Availability: Single-cell gene-expression data have been deposited in Figshare (https://doi.org/10.6084/m9.figshare.11837097) (48). The software package, implemented in Python 3, can be found at GitHub, https://github.com/thomsonlab/popalign. \n\nAuthor contributions: S.C., P.R., F.P., and M.T. designed research; S.C., P.R., J.H.P., T.T., E.C., J.R.H., and M.T. performed research; S.C., P.R., and M.T. contributed new reagents/analytic tools; S.C., P.R., and M.T. analyzed data; S.C. and M.T. wrote the paper; and F.P. provided clinical guidance and context for data interpretation. Competing interest statement: S.C., M.T., and P.R. have filed a US and Patent Cooperation Treaty patent for the PopAlign computational framework. \n\nThis article is a PNAS Direct Submission. This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2005990117/-/DCSupplemental.\n\nPublished - 28784.full.pdf
Submitted - 421354v9.full.pdf
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Supplemental Material - pnas.2005990117.sapp.pdf
", "abstract": "Single-cell measurement techniques can now probe gene expression in heterogeneous cell populations from the human body across a range of environmental and physiological conditions. However, new mathematical and computational methods are required to represent and analyze gene expression changes that occur in complex mixtures of single cells as they respond to signals, drugs, or disease states. Here, we introduce a mathematical modeling platform, PopAlign, that automatically identifies subpopulations of cells within a heterogeneous mixture, and tracks gene expression and cell abundance changes across subpopulations by constructing and comparing probabilistic models. We apply PopAlign to analyze the impact of 42 different immunomodulatory compounds on a heterogeneous population of donor-derived human immune cells as well as patient-specific disease signatures in multiple myeloma. PopAlign scales to comparisons involving tens to hundreds of samples, enabling large-scale studies of natural and engineered cell populations as they respond to drugs, signals or physiological change.", "date": "2020-11-17", "date_type": "published", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "volume": "117", "number": "46", "publisher": "National Academy of Sciences", "pagerange": "28784-28794", "id_number": "CaltechAUTHORS:20180927-114224716", "issn": "0027-8424", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20180927-114224716", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Shurl and Kay Curci Foundation", "grant_number": "12540322" }, { "agency": "Heritage Medical Research Institute", "grant_number": "HMRI-15-09-01" } ] }, "local_group": { "items": [ { "id": "Heritage-Medical-Research-Institute" }, { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1073/pnas.2005990117", "pmcid": "PMC7682438", "primary_object": { "basename": "421354v9.full.pdf", "url": "https://authors.library.caltech.edu/records/0cqqx-m7s93/files/421354v9.full.pdf" }, "related_objects": [ { "basename": "pnas.2005990117.sapp.pdf", "url": "https://authors.library.caltech.edu/records/0cqqx-m7s93/files/pnas.2005990117.sapp.pdf" }, { "basename": "28784.full.pdf", "url": "https://authors.library.caltech.edu/records/0cqqx-m7s93/files/28784.full.pdf" }, { "basename": "421354-1.pdf", "url": "https://authors.library.caltech.edu/records/0cqqx-m7s93/files/421354-1.pdf" } ], "resource_type": "article", "pub_year": "2020", "author_list": "Chen, Sisi; Rivaud, Paul; et el." }, { "id": "https://authors.library.caltech.edu/records/wrtcf-y5749", "eprint_id": 105631, "eprint_status": "archive", "datestamp": "2023-08-19 23:28:01", "lastmod": "2023-12-22 23:09:20", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Gandhi-Shashank", "name": { "family": "Gandhi", "given": "Shashank" }, "orcid": "0000-0002-4081-4338" }, { "id": "Hutchins-Erica-J", "name": { "family": "Hutchins", "given": "Erica J." }, "orcid": "0000-0002-4316-0333" }, { "id": "Maruszko-Krystyna", "name": { "family": "Maruszko", "given": "Krystyna" } }, { "id": "Park-Jong-H", "name": { "family": "Park", "given": "Jong H." } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matthew" } }, { "id": "Bronner-M-E", "name": { "family": "Bronner", "given": "Marianne E." }, "orcid": "0000-0003-4274-1862" } ] }, "title": "Bimodal function of chromatin remodeler Hmga1 in neural crest induction and Wnt-dependent emigration", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2020, Gandhi 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 April 2020; Accepted: 23 September 2020; Published: 23 September 2020. \n\nFor technical assistance, we thank Fan Gao with the Caltech Bioinformatics Resource Center of the Beckman Institute, Giada Spigolon and Andres Collazo with the Caltech Biological Imaging facility of the Beckman Institute, and Sisi Chen and Paul Rivaud with the Single Cell Profiling and Engineering Center (SPEC) of the Beckman Institute. We thank members of the Bronner lab for helpful discussions. \n\nFunding: National Institutes of Health (R01DE027568) Marianne E Bronner; National Institutes of Health (R01HL14058) Marianne E Bronner; National Institutes of Health (R01DE027538) Marianne E Bronner; American Heart Association (18PRE34050063) Shashank Gandhi; National Institutes of Health (K99DE028592) Erica J Hutchins. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. \n\nAuthor contributions: Shashank Gandhi, Conceptualization, Resources, Software, Formal analysis, Supervision, Validation, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing; Erica J Hutchins, Resources, Validation, Investigation, Visualization, Writing - review and editing; Krystyna Maruszko, Investigation, Visualization, Writing - original draft; Jong H Park, Matthew Thomson, Resources, Methodology; Marianne E Bronner, Conceptualization, Supervision, Funding acquisition, Writing - review and editing. \n\nCompeting interests: Marianne E Bronner: Senior editor, eLife. The other authors declare that no competing interests\nexist. \n\nData availability: Sequencing data files have been deposited on NCBI under the accession number PRJNA624258.\n\nPublished - elife-57779-v2.pdf
Accepted Version - elife-57779-v1.pdf
Supplemental Material - elife-57779-supp-v1.zip
Supplemental Material - elife-57779-transrepform-v2.docx
", "abstract": "During gastrulation, neural crest cells are specified at the neural plate border, as characterized by Pax7 expression. Using single-cell RNA sequencing coupled with high resolution in situ hybridization to identify novel transcriptional regulators, we show that chromatin remodeler Hmga1 is highly expressed prior to specification and maintained in migrating chick neural crest cells. Temporally-controlled CRISPR-Cas9-mediated knockouts uncovered two distinct functions of Hmga1 in neural crest development. At the neural plate border, Hmga1 regulates Pax7-dependent neural crest lineage specification. At premigratory stages, a second role manifests where Hmga1 loss reduces cranial crest emigration from the dorsal neural tube independent of Pax7. Interestingly, this is rescued by stabilized \u00df-catenin, thus implicating Hmga1 as a canonical Wnt activator. Together, our results show that Hmga1 functions in a bimodal manner during neural crest development to regulate specification at the neural plate border, and subsequent emigration from the neural tube via canonical Wnt signaling.", "date": "2020-09-23", "date_type": "published", "publication": "eLife", "volume": "2020", "number": "9", "publisher": "eLife Sciences Publications", "pagerange": "Art. No. e57779", "id_number": "CaltechAUTHORS:20200929-102516984", "issn": "2050-084X", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200929-102516984", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01DE027568" }, { "agency": "NIH", "grant_number": "R01HL14058" }, { "agency": "NIH", "grant_number": "R01DE027538" }, { "agency": "American Heart Association", "grant_number": "18PRE34050063" }, { "agency": "NIH", "grant_number": "K99DE028592" } ] }, "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.7554/elife.57779", "pmcid": "PMC7591248", "primary_object": { "basename": "elife-57779-supp-v1.zip", "url": "https://authors.library.caltech.edu/records/wrtcf-y5749/files/elife-57779-supp-v1.zip" }, "related_objects": [ { "basename": "elife-57779-transrepform-v2.docx", "url": "https://authors.library.caltech.edu/records/wrtcf-y5749/files/elife-57779-transrepform-v2.docx" }, { "basename": "elife-57779-v1.pdf", "url": "https://authors.library.caltech.edu/records/wrtcf-y5749/files/elife-57779-v1.pdf" }, { "basename": "elife-57779-v2.pdf", "url": "https://authors.library.caltech.edu/records/wrtcf-y5749/files/elife-57779-v2.pdf" } ], "resource_type": "article", "pub_year": "2020", "author_list": "Gandhi, Shashank; Hutchins, Erica J.; et el." }, { "id": "https://authors.library.caltech.edu/records/zk45d-25a12", "eprint_id": 103692, "eprint_status": "archive", "datestamp": "2023-08-19 21:06:01", "lastmod": "2023-12-22 23:09:16", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Brown-D", "name": { "family": "Brown", "given": "David" } }, { "id": "Altermatt-M", "name": { "family": "Altermatt", "given": "Michael" } }, { "id": "Dobreva-T", "name": { "family": "Dobreva", "given": "Tatyana" }, "orcid": "0000-0002-2625-8873" }, { "id": "Park-Jong-H", "name": { "family": "Park", "given": "Jong H." } }, { "id": "Ravindra-Kumar-S", "name": { "family": "Ravindra-Kumar", "given": "Sripriya" }, "orcid": "0000-0001-6033-7631" }, { "id": "Chen-Xinhong", "name": { "family": "Chen", "given": "Xinhong" }, "orcid": "0000-0003-0408-0813" }, { "id": "Coughlin-G-M", "name": { "family": "Coughlin", "given": "Gerard M." } }, { "id": "Pool-A-H", "name": { "family": "Pool", "given": "Allan-Hermann" }, "orcid": "0000-0002-0811-9861" }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" } }, { "id": "Gradinaru-V", "name": { "family": "Gradinaru", "given": "Viviana" }, "orcid": "0000-0001-5868-348X" } ] }, "title": "A Computational and Experimental Platform for Detecting Full Transcriptome Cell Type Tropism of Lowly Expressed Barcoded and Pooled AAV Variants via Single-Cell RNA Sequencing", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 2020 American Society of Gene & Cell Therapy. \n\nAvailable online 28 April 2020.", "abstract": "Despite being one of the primary gene therapy delivery vehicles, adeno-associated viruses (AAVs) are limited in their specificity towards certain cell types implicated in disease. Recombinant AAVs (rAAVs) are addressing these limitations through both capsid engineering and gene regulatory approaches that alter viral tropism or viral expression patterns. Current rAAV targeting, selection, screening, and characterization methods are typically based on single- or few-molecule read-outs, such as promoter and enhancer-driven constructs, mouse lines expressing Cre recombinase under a cell type-specific promoter, or cell type-specific antibodies for imaging. Such methods harbor challenges for parallelizing rAAV characterization, or extending characterization and engineering to complex or previously unknown cell types. The recent advent of single-cell RNA sequencing (scRNAseq) has revealed a rich diversity of cell types and states, many of which are not associated with canonical cell type markers, and can even be defined by multi-gene programs. To aid in the engineering of rAAVs aimed at such complex cell states and aid in the discovery of novel tropisms, we have developed a scRNA-seq AAV screening method, whereby we inspect full transcriptomes of cells transduced with pools of AAV vectors in a single animal. To generate pools of variants that can be differentiated in sequencing, we package variants with either unique transgenes, or the same transgene with unique barcodes incorporated in the polyA region. We then co-inject mice with these pools of variants, wait for expression, and harvest tissue slices for downstream cell dissociation and single-cell sequencing using the Chromium 10X Single Cell Kit. In order to accommodate the low expression rates of virally delivered cargo and the loss of the region of mRNA upstream of the polyA capture site that identifies the capsid variant, we amplify the viral transcripts from the full cDNA library with primers near the differentiating region of the cargo. To characterize variants, we developed a customized computational pipeline that addresses the unique challenges of these datasets: (1) to discern the variant that delivered each transgene read, we demultiplex the amplified viral transgene reads based on their differentiating sequences; (2) to reduce the effects of PCR amplification noise, we convert variant transgene reads into probabilistic estimates of the number of transcripts per cell; and (3) to calculate cell type biases, we automatically identify a cell type hierarchy and compare the distribution of viral transcripts by cell type to a null model of empty droplets. Thus far, our platform has corroborated several expected virus tropism findings from imaging (e.g. for brain vasculature or neuronal preference). To apply this barcoding strategy to even larger pools without individually cloning and producing each variant, and link arbitrary mutations in the capsid genome to the barcode, we have further developed a plasmid that contains both the expressed transgene and the capsid gene, but inverted in orientation, with their 3' ends adjacent. With these barcoding strategies and computational methods, we enable fast identification and characterization of rAAV variant pools with precise disease-relevant tropisms, with the ultimate goal of aiding the gene therapy field in developing precision delivery vehicles.", "date": "2020-04-28", "date_type": "published", "publication": "Molecular Therapy", "volume": "28", "number": "4", "publisher": "American Society of Gene & Cell Therapy", "pagerange": "80-81", "id_number": "CaltechAUTHORS:20200604-102237108", "issn": "1525-0016", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200604-102237108", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1016/j.ymthe.2020.04.019", "resource_type": "article", "pub_year": "2020", "author_list": "Brown, David; Altermatt, Michael; et el." }, { "id": "https://authors.library.caltech.edu/records/rrtwx-57q24", "eprint_id": 103688, "eprint_status": "archive", "datestamp": "2023-08-19 21:05:38", "lastmod": "2023-12-22 23:09:18", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Altermatt-M", "name": { "family": "Altermatt", "given": "Michael" } }, { "id": "Brown-D", "name": { "family": "Brown", "given": "David" } }, { "id": "Dobreva-T", "name": { "family": "Dobreva", "given": "Tatyana" }, "orcid": "0000-0002-2625-8873" }, { "id": "Jang-Min-Jee", "name": { "family": "Jang", "given": "Min Jee" }, "orcid": "0000-0002-1536-7177" }, { "id": "Coughlin-G-M", "name": { "family": "Coughlin", "given": "Gerard M." } }, { "id": "Pool-A-H", "name": { "family": "Pool", "given": "Allan-Hermann" }, "orcid": "0000-0002-0811-9861" }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" } }, { "id": "Gradinaru-V", "name": { "family": "Gradinaru", "given": "Viviana" }, "orcid": "0000-0001-5868-348X" } ] }, "title": "In-Depth Parallel Profiling of Tissue and Cell-Type Tropism of AAV Variants by Single-Cell RNA Sequencing", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 2020 American Society of Gene & Cell Therapy. \n\nAvailable online 28 April 2020.", "abstract": "Adeno-associated viruses (AAVs) are popular gene delivery vehicles and there is a continuing high demand for AAV variants with improved transduction efficiency and specificity. Directed evolution and/or rational design have been used extensively to engineer the capsid of naturally occurring AAVs in order to better customize their properties for research and clinical work. While these engineering approaches are scalable and have generated useful variants, the subsequent transduction profiling of these variants remains either low throughput or lacks resolution across the many relevant cell and tissue types. Single-cell RNA sequencing (scRNA-seq) via droplet-based methods allows in-depth profiling of gene expression of several thousand individual cells. We established a tissue processing and data analysis pipeline that leverages the capabilities of scRNA-seq to achieve simultaneous characterization of AAV variants across multiplexed tissue cell types. To verify our approach, we retro-orbitally co-injected C57Bl/6 mice with PHP.eB (Chan et al., Nat. Neurosci., 2017) and a neuron-biased PHP.eB-evolved variant (Flytzanis*, Goeden* et al., ASGCT, 2019), each packaging a construct expressing different fluorophores. \n\nAfter two weeks of expression we harvested the brain and used one hemisphere for characterization by traditional immunohistochemistry and one hemisphere for characterization by scRNA-seq. Single-cell libraries were prepared with the Chromium Single Cell Kit by 10x Genomics and analyzed with multiplexed Illumina sequencing. As a proof of concept, we compared the two characterization methods by analyzing the infection rate of neurons (NeuN), astrocytes (S100b) or oligodendrocytes (Olig2). For immunohistochemistry, a cell was classified as infected based on expression of fluorophores while in scRNA-seq transduced cells were identified based on the presence of defining viral transcripts. Louvain community detection method (Blondel et al., J. Stat. Mech., 2008) followed by analysis of significantly differentially expressed genes was used to identify cell types in the scRNA-seq data set. Given the differences in RNA and protein abundance and detection thresholds between imaging and sequencing, the two characterization methods detect different absolute numbers of infection rates; however, the cell type transduction biases are consistent among the three different cell types we tested. After verifying our method, we further explored the data set beyond major cell types and discovered previously unnoticed sub-cell type enrichments in, for example, cortical inhibitory neurons. These findings are being confirmed by mapping mRNA expression using in situ hybridization chain reaction. Besides sub-cell type tropism characterization, we are analyzing the transcriptome of infected and non-infected cells in search of mechanistic insights into AAV transduction that could facilitate rational design of recombinant AAVs with disease-relevant cell-type specificity. Our approach will aid the gene therapy field to both characterize more thoroughly existing recombinant AAVs and guide engineering of novel AAV variants.", "date": "2020-04-28", "date_type": "published", "publication": "Molecular Therapy", "volume": "28", "number": "4", "publisher": "American Society of Gene & Cell Therapy", "pagerange": "399-400", "id_number": "CaltechAUTHORS:20200604-075354300", "issn": "1525-0016", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200604-075354300", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1016/j.ymthe.2020.04.019", "resource_type": "article", "pub_year": "2020", "author_list": "Altermatt, Michael; Brown, David; et el." }, { "id": "https://authors.library.caltech.edu/records/s9b9v-5r123", "eprint_id": 101201, "eprint_status": "archive", "datestamp": "2023-08-19 19:55:10", "lastmod": "2023-12-22 23:09:08", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Banks-R-A", "name": { "family": "Banks", "given": "Rachel" } }, { "id": "Lee-Heun-Jin", "name": { "family": "Lee", "given": "Heun Jin" } }, { "id": "Ross-T-D", "name": { "family": "Ross", "given": "Tyler" }, "orcid": "0000-0002-7872-3992" }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" } }, { "id": "Phillips-R", "name": { "family": "Phillips", "given": "Rob" }, "orcid": "0000-0003-3082-2809" } ] }, "title": "Bridging Kinesin Properties with System-scale Characteristics of Microtubule-Motor Assemblies", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 2020 Biophysical Society. \n\nAvailable online 7 February 2020.", "abstract": "In a dividing cell, multiple subfamilies of kinesin and dynein motors work together to form the mitotic spindle out of microtubule filaments. This complex structure has incited much study into how it is formed and regulated. Knockdown experiments in cells yielded a number of insights, however, the complex environment of the cell prevents a detailed quantitative picture connecting biophysical motor properties to the resulting mesoscopic phenomena. However, in vitro, reconstituted systems of few purified components strip away the other reactions occuring within the cell, creating the opportunity to work from the bottom up. We use an optogenetic system wherein motor interactions are controlled by light to form microtubule structures such as asters. We connect length and speed scales of microtubule structures to motor properties such as speed and processivity by performing experiments with various kinesin motors. With this approach, we develop and test a model explaining how contraction speed varies with network size and motor speed. We also observe how the motors are distributed within microtubule structures and how that varies depending on the motor used. Further, we arrange competition between kinesins that walk towards opposite ends of the microtubules and demonstrate how this competition yields unique structures with properties that depend on both motors. This work is a step towards bridging microscopic motor properties to mesoscopic system-scale characteristics and answering the question of how cooperation between various kinesins can result in the generation of cellular structures.", "date": "2020-02-07", "date_type": "published", "publication": "Biophysical Journal", "volume": "118", "number": "3", "publisher": "Biophysical Society", "pagerange": "176a-177a", "id_number": "CaltechAUTHORS:20200210-111806006", "issn": "0006-3495", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200210-111806006", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "local_group": { "items": [ { "id": "Division-of-Biology-and-Biological-Engineering" } ] }, "doi": "10.1016/j.bpj.2019.11.1081", "resource_type": "article", "pub_year": "2020", "author_list": "Banks, Rachel; Lee, Heun Jin; et el." }, { "id": "https://authors.library.caltech.edu/records/m07dw-3jq86", "eprint_id": 90524, "eprint_status": "archive", "datestamp": "2023-08-22 03:23:36", "lastmod": "2023-10-23 16:59:58", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Gehring-J", "name": { "family": "Gehring", "given": "Jase" }, "orcid": "0000-0002-3894-9495" }, { "id": "Park-Jong-Hwee", "name": { "family": "Park", "given": "Jong Hwee" } }, { "id": "Chen-Sisi", "name": { "family": "Chen", "given": "Sisi" }, "orcid": "0000-0001-9448-9713" }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matthew" } }, { "id": "Pachter-L", "name": { "family": "Pachter", "given": "Lior" }, "orcid": "0000-0002-9164-6231" } ] }, "title": "Highly multiplexed single-cell RNA-seq by DNA oligonucleotide tagging of cellular proteins", "ispublished": "pub", "full_text_status": "public", "keywords": "DNA; Molecular biology; Sequencing", "note": "\u00a9 2019 Nature Publishing Group. \n\nReceived 07 August 2018; Accepted 27 November 2019; Published 23 December 2019. \n\nWe thank Z. Gartner and C. McGinnis for helpful feedback regarding the ClickTag protocol and V. Svensson for suggestions regarding analysis of multiplexed datasets. Thanks to P. Melsted and S. Booeshaghi for developing the 'kallisto | bustools' functions used in the preprocessing workflow and to P. Rivaud for assistance with 10x data processing. Additional support was provided by the the Caltech Bioinformatics Resource Center and the Single Cell Profiling and Engineering Center (SPEC) in the Beckman Institute at Caltech. \n\nData availability: Sequencing data from these experiments can be obtained from CaltechDATA at https://doi.org/10.22002/D1.1311. \n\nCode availability: Code and tutorials for the kITE demultiplexing workflow can be found at https://www.kallistobus.tools/kite_tutorial.html. Python notebooks used to process data and generate figures are available on GitHub at https://github.com/pachterlab/GPCTP_2019. The same GitHub repository also contains a fully reproducible reanalysis using 'kallisto | bustools' transcript alignments and a Google Colab notebook. \n\nAuthor Contributions: J.G. conceived and developed the ClickTag multiplexing strategy. J.G., J.H.P. and S.C. designed the scRNA-seq experiments and J.G. and J.H.P. performed the experiments. J.H.P. performed all tissue culture operations and J.G. developed the kITE demultiplexing workflow and analyzed the scRNA-seq data. J.G., J.H.P., S.C, M.T. and L.P. contributed to the interpretation of the results and writing of the manuscript. \n\nCompeting interests: J.G., L.P., S.C. and J.H.P. are listed as co-inventors on a patent application related to this work (US patent application 16/296,075).\n\nSubmitted - 315333.full.pdf
Supplemental Material - 41587_2019_372_MOESM1_ESM.pdf
Supplemental Material - 41587_2019_372_MOESM2_ESM.pdf
Supplemental Material - 41587_2019_372_MOESM3_ESM.xlsx
Supplemental Material - 41587_2019_372_MOESM4_ESM.xlsx
", "abstract": "We describe a universal sample multiplexing method for single-cell RNA sequencing in which fixed cells are chemically labeled by attaching identifying DNA oligonucleotides to cellular proteins. Analysis of a 96-plex perturbation experiment revealed changes in cell population structure and transcriptional states that cannot be discerned from bulk measurements, establishing an efficient method for surveying cell populations from large experiments or clinical samples with the depth and resolution of single-cell RNA sequencing.", "date": "2020-01", "date_type": "published", "publication": "Nature Biotechnology", "volume": "38", "number": "1", "publisher": "Nature Publishing Group", "pagerange": "35-38", "id_number": "CaltechAUTHORS:20181030-145533155", "issn": "1087-0156", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20181030-145533155", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Caltech Beckman Institute" } ] }, "doi": "10.1038/s41587-019-0372-z", "primary_object": { "basename": "315333.full.pdf", "url": "https://authors.library.caltech.edu/records/m07dw-3jq86/files/315333.full.pdf" }, "related_objects": [ { "basename": "41587_2019_372_MOESM1_ESM.pdf", "url": "https://authors.library.caltech.edu/records/m07dw-3jq86/files/41587_2019_372_MOESM1_ESM.pdf" }, { "basename": "41587_2019_372_MOESM2_ESM.pdf", "url": "https://authors.library.caltech.edu/records/m07dw-3jq86/files/41587_2019_372_MOESM2_ESM.pdf" }, { "basename": "41587_2019_372_MOESM3_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/m07dw-3jq86/files/41587_2019_372_MOESM3_ESM.xlsx" }, { "basename": "41587_2019_372_MOESM4_ESM.xlsx", "url": "https://authors.library.caltech.edu/records/m07dw-3jq86/files/41587_2019_372_MOESM4_ESM.xlsx" } ], "resource_type": "article", "pub_year": "2020", "author_list": "Gehring, Jase; Park, Jong Hwee; et el." }, { "id": "https://authors.library.caltech.edu/records/kp5yc-avm39", "eprint_id": 91968, "eprint_status": "archive", "datestamp": "2023-08-19 17:16:24", "lastmod": "2023-10-20 22:02:13", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Ross-Tyler-D", "name": { "family": "Ross", "given": "Tyler D." }, "orcid": "0000-0002-7872-3992" }, { "id": "Lee-Heun-Jin", "name": { "family": "Lee", "given": "Heun Jin" } }, { "id": "Qu-Zijie", "name": { "family": "Qu", "given": "Zijie" }, "orcid": "0000-0003-1500-3207" }, { "id": "Banks-Rachel-A", "name": { "family": "Banks", "given": "Rachel A." }, "orcid": "0000-0003-2028-2925" }, { "id": "Phillips-R", "name": { "family": "Phillips", "given": "Rob" }, "orcid": "0000-0003-3082-2809" }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" }, "orcid": "0000-0003-1021-1234" } ] }, "title": "Controlling Organization and Forces in Active Matter Through Optically-Defined Boundaries", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2019 Springer Nature Publishing AG. \n\nReceived 11 January 2019; Accepted 05 June 2019; Published 07 August 2019. \n\nData availability: The data that support the findings of this study are available from the Caltech Research Data Repository at https://data.caltech.edu/records/1160. All plasmids used in this study are available at https://www.addgene.org. All of the other reagents and the source code used for this study are available from the corresponding authors upon reasonable request. \n\nWe thank M. Anjur-Dietrich, J. Brady, J. Bruck, V. Galstyan, S. Hirokawa, C. Hueschen, Y. Lazebnik, W. Lim, W. Marshall, D. Mullins, D. Needleman, P. Rothemund and E. Winfree for scientific discussions. We thank L. Bugaj, Z. Dogic, A. Frost, W. Huynh, R. Ismagilov, L. Metcalf, H. Nguyen and R. Vale for advice and assistance during the development of the experimental system; K. van den Dries for assistance with three-dimensional visualization of asters; P. Sternberg for use of a microscopy system for initial light-activation experiments. We are grateful to N. Orme for assistance with figures and illustrations. We acknowledge support from the NIH through grants 1R35 GM118043-01 (R.P.) and NIH DP5 OD012194 (M.T.); the NSF through NSF 1330864 (M.T.); the John Templeton Foundation as part of the Boundaries of Life Initiative through grants 51250 & 60973 (R.P.); the Foundational Questions Institute and Fetzer Franklin Fund through FQXi 1816 (R.P., M.T.); and the UCSF Center for Systems and Synthetic Biology NIGMS P50 GM081879 (M.T.). M.T. acknowledges support from the Heritage Medical Research Institute. \n\nAuthor Contributions: T.D.R., H.J.L., R.P. and M.T. conceived the experiments and interpreted the results. T.D.R., H.J.L., R.A.B., Z.Q. and M.T. wrote the manuscript. T.D.R. designed and cloned iLID motor fusion constructs. T.D.R., H.J.L. and R.A.B. performed protein purification. T.D.R. and H.J.L. designed, performed and analysed the active-matter experiments. Z.Q. analysed and modelled flow data and tracked trajectories of moving asters. R.A.B. performed and analysed gliding assays. All authors discussed the results and commented on the manuscript. \n\nThe authors declare no competing interests.\n\nAccepted Version - nihms-1531196.pdf
Submitted - 1812.09418.pdf
Submitted - 504456.full.pdf
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", "abstract": "Living systems are capable of locomotion, reconfiguration and replication. To perform these tasks, cells spatiotemporally coordinate the interactions of force-generating, 'active' molecules that create and manipulate non-equilibrium structures and force fields of up to millimetre length scales. Experimental active-matter systems of biological or synthetic molecules are capable of spontaneously organizing into structures and generating global flows. However, these experimental systems lack the spatiotemporal control found in cells, limiting their utility for studying non-equilibrium phenomena and bioinspired engineering. Here we uncover non-equilibrium phenomena and principles of boundary-mediated control by optically modulating structures and fluid flow in an engineered system of active biomolecules. Our system consists of purified microtubules and light-activatable motor proteins that crosslink and organize the microtubules into distinct structures upon illumination. We develop basic operations\u2014defined as sets of light patterns\u2014to create, move and merge the microtubule structures. By combining these operations, we create microtubule networks that span several hundred micrometres in length and contract at speeds up to an order of magnitude higher than the speed of an individual motor protein. We manipulate these contractile networks to generate and sculpt persistent fluid flows. The principles of boundary-mediated control that we uncover may be used to study emergent cellular structures and forces and to develop programmable active-matter devices.", "date": "2019-08-08", "date_type": "published", "publication": "Nature", "volume": "572", "number": "7768", "publisher": "Nature Publishing Group", "pagerange": "224-229", "id_number": "CaltechAUTHORS:20190102-092232993", "issn": "0028-0836", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190102-092232993", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "1R35 GM118043-01" }, { "agency": "NIH", "grant_number": "DP5 OD012194" }, { "agency": "NSF", "grant_number": "MCB-1330864" }, { "agency": "John Templeton Foundation", "grant_number": "51250" }, { "agency": "John Templeton Foundation", "grant_number": "60973" }, { "agency": "Foundational Questions Institute (FQXI)", "grant_number": "FQXi-RFP-1816" }, { "agency": "NIH", "grant_number": "P50 GM081879" }, { "agency": "Heritage Medical Research Institute" } ] }, "local_group": { "items": [ { "id": "Heritage-Medical-Research-Institute" } ] }, "doi": "10.1038/s41586-019-1447-1", "pmcid": "PMC6719720", "primary_object": { "basename": "41586_2019_1447_MOESM12_ESM.m4v", "url": "https://authors.library.caltech.edu/records/kp5yc-avm39/files/41586_2019_1447_MOESM12_ESM.m4v" }, "related_objects": [ { "basename": "41586_2019_1447_MOESM15_ESM.mov", "url": "https://authors.library.caltech.edu/records/kp5yc-avm39/files/41586_2019_1447_MOESM15_ESM.mov" }, { "basename": "1812.09418.pdf", "url": "https://authors.library.caltech.edu/records/kp5yc-avm39/files/1812.09418.pdf" }, { "basename": "41586_2019_1447_MOESM1_ESM.pdf", "url": "https://authors.library.caltech.edu/records/kp5yc-avm39/files/41586_2019_1447_MOESM1_ESM.pdf" }, { "basename": "41586_2019_1447_MOESM5_ESM.m4v", "url": "https://authors.library.caltech.edu/records/kp5yc-avm39/files/41586_2019_1447_MOESM5_ESM.m4v" }, { "basename": "41586_2019_1447_MOESM7_ESM.m4v", "url": "https://authors.library.caltech.edu/records/kp5yc-avm39/files/41586_2019_1447_MOESM7_ESM.m4v" }, { "basename": "504456.full.pdf", "url": "https://authors.library.caltech.edu/records/kp5yc-avm39/files/504456.full.pdf" }, { "basename": "41586_2019_1447_MOESM13_ESM.m4v", "url": "https://authors.library.caltech.edu/records/kp5yc-avm39/files/41586_2019_1447_MOESM13_ESM.m4v" }, { "basename": "41586_2019_1447_MOESM2_ESM.avi", "url": "https://authors.library.caltech.edu/records/kp5yc-avm39/files/41586_2019_1447_MOESM2_ESM.avi" }, { "basename": "41586_2019_1447_MOESM3_ESM.avi", "url": "https://authors.library.caltech.edu/records/kp5yc-avm39/files/41586_2019_1447_MOESM3_ESM.avi" }, { "basename": "41586_2019_1447_MOESM4_ESM.avi", "url": "https://authors.library.caltech.edu/records/kp5yc-avm39/files/41586_2019_1447_MOESM4_ESM.avi" }, { "basename": "41586_2019_1447_MOESM6_ESM.avi", "url": "https://authors.library.caltech.edu/records/kp5yc-avm39/files/41586_2019_1447_MOESM6_ESM.avi" }, { "basename": "41586_2019_1447_MOESM8_ESM.m4v", "url": "https://authors.library.caltech.edu/records/kp5yc-avm39/files/41586_2019_1447_MOESM8_ESM.m4v" }, { "basename": "41586_2019_1447_MOESM10_ESM.mp4", "url": "https://authors.library.caltech.edu/records/kp5yc-avm39/files/41586_2019_1447_MOESM10_ESM.mp4" }, { "basename": "41586_2019_1447_MOESM11_ESM.m4v", "url": "https://authors.library.caltech.edu/records/kp5yc-avm39/files/41586_2019_1447_MOESM11_ESM.m4v" }, { "basename": "41586_2019_1447_MOESM14_ESM.m4v", "url": "https://authors.library.caltech.edu/records/kp5yc-avm39/files/41586_2019_1447_MOESM14_ESM.m4v" }, { "basename": "41586_2019_1447_MOESM9_ESM.m4v", "url": "https://authors.library.caltech.edu/records/kp5yc-avm39/files/41586_2019_1447_MOESM9_ESM.m4v" }, { "basename": "nihms-1531196.pdf", "url": "https://authors.library.caltech.edu/records/kp5yc-avm39/files/nihms-1531196.pdf" } ], "resource_type": "article", "pub_year": "2019", "author_list": "Ross, Tyler D.; Lee, Heun Jin; et el." }, { "id": "https://authors.library.caltech.edu/records/j2fzf-ybw74", "eprint_id": 89477, "eprint_status": "archive", "datestamp": "2023-08-19 12:39:06", "lastmod": "2023-10-18 22:46:42", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Xu-Alexander-M", "name": { "family": "Xu", "given": "Alexander M." }, "orcid": "0000-0003-4877-4358" }, { "id": "Liu-Qianhe", "name": { "family": "Liu", "given": "Qianhe" }, "orcid": "0000-0002-7517-4772" }, { "id": "Takata-Kaitlyn-L", "name": { "family": "Takata", "given": "Kaitlyn L." }, "orcid": "0000-0003-4864-9741" }, { "id": "Jeoung-Sarah", "name": { "family": "Jeoung", "given": "Sarah" } }, { "id": "Su-Yapeng", "name": { "family": "Su", "given": "Yapeng" }, "orcid": "0000-0002-6305-8467" }, { "id": "Antoshechkin-I-A", "name": { "family": "Antoshechkin", "given": "Igor" }, "orcid": "0000-0002-9934-3040" }, { "id": "Chen-Sisi", "name": { "family": "Chen", "given": "Sisi" }, "orcid": "0000-0001-9448-9713" }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matthew" } }, { "id": "Heath-J-R", "name": { "family": "Heath", "given": "James R." }, "orcid": "0000-0001-5356-4385" } ] }, "title": "Integrated measurement of intracellular proteins and transcripts in single cells", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2018 The Royal Society of Chemistry. \n\nReceived 22nd June 2018, Accepted 24th August 2018. First published on 27th August 2018. \n\nThis study was assisted by the facilities of the Center for High Throughput Single Cell Monitoring and Engineering, the Millard and Muriel Jacobs Genetics and Genomics Laboratory, and the Institute for Systems Biology Sequencing Core. Paul Rivaud, Devdoot Majumdar, Sylvia Plevritis, and Lior Pachter contributed helpful discussions. Q. L., K. L. T., and S. J. were participants of the Caltech Summer Undergraduate Research Fellowship program. Q. L. was supported by the Donald S. Clark SURF Fellowship. The research was funded by U54 NSBCC grant 1U54 CA199090-01, the Jean Perkins Foundation, and the Ben and Catherine Ivy Foundation. M. T. acknowledges support from the Beckman Institute at Caltech and the NIH Office of the Director (OD) NIH DP5 OD012194. A. M. X. is supported by a Ruth L. Kirschstein F32 Postdoctoral Fellowship F32CA213966. \n\nAccession numbers: Transcriptome data was deposited in the Sequence Read Archive under Bioproject PRJNA472815. \n\nAuthor contributions: A. M. X., Q. L., K. L. T., S. J., and Y. S. performed experiments. A. M. X., I. A., and J. R. H. designed experiments. A. M. X. and Y. S. analyzed data. A. M. X., S. C., and M. T. developed software. A. M. X. and J. R. H. wrote the manuscript. \n\nConflicts of interest: JRH is a founder and board member of Isoplexis, a company that is seeking to commercialize certain aspects of the SCBC platform.\n\nAccepted Version - nihms-1049039.pdf
Supplemental Material - c8lc00639c1.zip
", "abstract": "Biological function arises from the interplay of proteins, transcripts, and metabolites. An ongoing revolution in miniaturization technologies has created tools to analyze any one of these species in single cells, thus resolving the heterogeneity of tissues previously invisible to bulk measurements. An emerging frontier is single cell multi-omics, which is the measurement of multiple classes of analytes from single cells. Here, we combine bead-based transcriptomics with microchip-based proteomics to measure intracellular proteins and transcripts from single cells and defined small numbers of cells. The transcripts and proteins are independently measured by sequencing and fluorescent immunoassays respectively, to preserve their optimal measurement modes, and linked by encoding the physical address locations of the cells into digital sequencing space using spatially patterned DNA barcodes. We resolve cell-type-specific protein and transcript signatures and present a path forward to scaling the platform to high-throughput.", "date": "2018-11-07", "date_type": "published", "publication": "Lab on a Chip", "volume": "18", "number": "21", "publisher": "Royal Society of Chemistry", "pagerange": "3251-3262", "id_number": "CaltechAUTHORS:20180910-090801725", "issn": "1473-0197", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20180910-090801725", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Caltech Summer Undergraduate Research Fellowship (SURF)" }, { "agency": "NIH", "grant_number": "1U54 CA199090-01" }, { "agency": "Jean Perkins Foundation" }, { "agency": "Ben and Catherine Ivy Foundation" }, { "agency": "Caltech Beckman Institute" }, { "agency": "NIH", "grant_number": "DP5 OD012194" }, { "agency": "NIH Postdoctoral Fellowship", "grant_number": "F32CA213966" } ] }, "doi": "10.1039/c8lc00639c", "pmcid": "PMC6752714", "primary_object": { "basename": "c8lc00639c1.zip", "url": "https://authors.library.caltech.edu/records/j2fzf-ybw74/files/c8lc00639c1.zip" }, "related_objects": [ { "basename": "nihms-1049039.pdf", "url": "https://authors.library.caltech.edu/records/j2fzf-ybw74/files/nihms-1049039.pdf" } ], "resource_type": "article", "pub_year": "2018", "author_list": "Xu, Alexander M.; Liu, Qianhe; et el." }, { "id": "https://authors.library.caltech.edu/records/2xggp-q6k41", "eprint_id": 84779, "eprint_status": "archive", "datestamp": "2023-08-19 07:45:34", "lastmod": "2023-10-20 21:50:29", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Hendel-Nathan-L", "name": { "family": "Hendel", "given": "Nathan L." } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matthew" } }, { "id": "Marshall-Wallace-F", "name": { "family": "Marshall", "given": "Wallace F." } } ] }, "title": "Diffusion as a Ruler: Modeling Kinesin Diffusion as a Length Sensor for Intraflagellar Transport", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2017 Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). \n\nSubmitted June 29, 2017, and accepted for publication November 29, 2017. \n\nWe thank Greyson Lewis for help with the math and derivations and Ahmet Yildiz for sharing results ahead of publication. \n\nThis work was supported by National Institutes of Health (NIH) grant GM097017. \n\nAuthor Contributions: N.L.H. wrote the simulations. N.L.H., M.T., and W.F.M. developed ideas and worked out math. N.L.H. and W.F.M. wrote the manuscript.\n\nPublished - 1-s2.0-S0006349517350464-main.pdf
Submitted - 156760.full.pdf
Supplemental Material - mmc1.pdf
", "abstract": "An important question in cell biology is whether cells are able to measure size, either whole cell size or organelle size. Perhaps cells have an internal chemical representation of size that can be used to precisely regulate growth, or perhaps size is just an accident that emerges due to constraint of nutrients. The eukaryotic flagellum is an ideal model for studying size sensing and control because its linear geometry makes it essentially one-dimensional, greatly simplifying mathematical modeling. The assembly of flagella is regulated by intraflagellar transport (IFT), in which kinesin motors carry cargo adaptors for flagellar proteins along the flagellum and then deposit them at the tip, lengthening the flagellum. The rate at which IFT motors are recruited to begin transport into the flagellum is anticorrelated with the flagellar length, implying some kind of communication between the base and the tip and possibly indicating that cells contain some mechanism for measuring flagellar length. Although it is possible to imagine many complex scenarios in which additional signaling molecules sense length and carry feedback signals to the cell body to control IFT, might the already-known components of the IFT system be sufficient to allow length dependence of IFT? Here we investigate a model in which the anterograde kinesin motors unbind after cargo delivery, diffuse back to the base, and are subsequently reused to power entry of new IFT trains into the flagellum. By mathematically modeling and simulating such a system, we are able to show that the diffusion time of the motors can in principle be sufficient to serve as a proxy for length measurement. We found that the diffusion model can not only achieve a stable steady-state length without the addition of any other signaling molecules or pathways, but also is able to produce the anticorrelation between length and IFT recruitment rate that has been observed in quantitative imaging studies.", "date": "2018-02-06", "date_type": "published", "publication": "Biophysical Journal", "volume": "114", "number": "3", "publisher": "Biophysical Society", "pagerange": "663-674", "id_number": "CaltechAUTHORS:20180212-080247041", "issn": "0006-3495", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20180212-080247041", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "GM097017" } ] }, "doi": "10.1016/j.bpj.2017.11.3784", "pmcid": "PMC5985012", "primary_object": { "basename": "mmc1.pdf", "url": "https://authors.library.caltech.edu/records/2xggp-q6k41/files/mmc1.pdf" }, "related_objects": [ { "basename": "1-s2.0-S0006349517350464-main.pdf", "url": "https://authors.library.caltech.edu/records/2xggp-q6k41/files/1-s2.0-S0006349517350464-main.pdf" }, { "basename": "156760.full.pdf", "url": "https://authors.library.caltech.edu/records/2xggp-q6k41/files/156760.full.pdf" } ], "resource_type": "article", "pub_year": "2018", "author_list": "Hendel, Nathan L.; Thomson, Matthew; et el." }, { "id": "https://authors.library.caltech.edu/records/pzdeb-r9f71", "eprint_id": 86576, "eprint_status": "archive", "datestamp": "2023-08-19 07:44:08", "lastmod": "2023-10-18 19:44:27", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Hendel-N-L", "name": { "family": "Hendel", "given": "Nathan L." } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" } }, { "id": "Marshall-W-F", "name": { "family": "Marshall", "given": "Wallace F." } } ] }, "title": "Diffusion as a Ruler: Modeling Kinesin Diffusion as a Lenth Sensor for Intraflagellar Transport", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 2018 Biophysical Society. \n\nAvailable online 6 February 2018.", "abstract": "An important question in cell biology is how cells know how big to make their organelles. The eukaryotic flagellum is an ideal model for studying size control because its linear geometry makes it essentially one-dimensional, greatly simplifying mathematical modeling. The assembly of flagella is regulated by intraflagellar transport (IFT), in which trains of kinesin motors walk to the tip of the flagellum and deposit the cargo necessary for the flagellum to grow. The competing length control factor is a length-independent decay of the flagellum. In Chlamydomonas reinhardtii flagella, this process results in initial rapid growth followed by convergence to a steady-state length. Curiously, the rate at which motors are recruited to begin transport is indirectly proportional to the length, implying some kind of communication between the base and the tip. We propose a model in which motors unbind after cargo delivery and diffuse back to the base, and are reused in IFT. In this model, the diffusion time of the motors serves as a proxy for length measurement. To explore the viability of this diffusion-based length control, we computationally built this model in three different ways. First, we built an agent-based model in which we used object-oriented programming to explicitly model flagella and motors, including time dynamics. Second, we modeled the number density along the flagellum as a vector, and built a stochastic matrix to simulate time dynamics and determine a steady-state. Third, we used differential equations to directly solve for the steady-state length. In all three, we found that the diffusion model can achieve steady-state length and an inverse relationship between length and recruitment rate. This is remarkable because this is perhaps the simplest explanation of length control, giving it credence in light of evolution.", "date": "2018-02-02", "date_type": "published", "publication": "Biophysical Journal", "volume": "114", "number": "3", "publisher": "Biophysical Society", "pagerange": "335A-336A", "id_number": "CaltechAUTHORS:20180523-145718338", "issn": "0006-3495", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20180523-145718338", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1016/j.bpj.2017.11.1877", "resource_type": "article", "pub_year": "2018", "author_list": "Hendel, Nathan L.; Thomson, Matt; et el." }, { "id": "https://authors.library.caltech.edu/records/7efyr-ajm67", "eprint_id": 84649, "eprint_status": "archive", "datestamp": "2023-08-21 22:44:31", "lastmod": "2023-10-18 16:25:38", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Obernier-Kirsten", "name": { "family": "Obernier", "given": "Kirsten" } }, { "id": "Cebrian-Silla-Arantxa", "name": { "family": "Cebrian-Silla", "given": "Arantxa" } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matthew" } }, { "id": "Parraguez-Jos\u00e9-Ignacio", "name": { "family": "Parraguez", "given": "Jos\u00e9 Ignacio" } }, { "id": "Anderson-Rio", "name": { "family": "Anderson", "given": "Rio" } }, { "id": "Guinto-Cristina", "name": { "family": "Guinto", "given": "Cristina" } }, { "id": "Rodriguez-Jos\u00e9-Rodas", "name": { "family": "Rodriguez", "given": "Jos\u00e9 Rodas" } }, { "id": "Garcia-Verdugo-J-M", "name": { "family": "Garcia-Verdugo", "given": "Jos\u00e9-Manuel" }, "orcid": "0000-0001-9872-6499" }, { "id": "Alvarez-Buylla-A", "name": { "family": "Alvarez-Buylla", "given": "Arturo" }, "orcid": "0000-0003-4426-8925" } ] }, "title": "Adult Neurogenesis Is Sustained by Symmetric Self-Renewal and Differentiation", "ispublished": "pub", "full_text_status": "public", "keywords": "neural stem cells; B1 cells; ventricular-subventricular zone; self-renewal; neurogenesis; symmetric division; division mode; lineage tracing; time-lapse imaging; aging", "note": "\u00a9 2018 Elsevier Inc. \n\nReceived 17 January 2017, Revised 16 October 2017, Accepted 2 January 2018, Available online 1 February 2018. \n\nAuthor Contributions: Conceptualization, K.O. and A.A.-B; Methodology, K.O., A.C.-S., and M.T.; Formal Analysis, K.O., A.C.-S., and M.T.; Investigation, K.O., A.C.-S., J.I.P., R.A., C.G., and J.R.R; Software, M.T.; Resources, J.-M.G.-V. and A.A.-B.; Writing \u2013 Original Draft, K.O., A.C.-S., M.T., and A.A.-B.; Visualization, K.O., A.C.-S., and M.T.; Supervision, J.-M.G.-V. and A.A.-B.; Funding Acquisition, K.O. and A.A.-B. \n\nDeclaration of Interests: A.A.-B. is co-founder and on the Scientific Advisory Board of Neurona Therapeutics. \n\nWe would like to thank Daniel Lim, Luis Fuentealba, and members of the Alvarez-Buylla lab for helpful discussions. K.O. was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation). A.C.-S. and J.-M.G.-V. were supported by Generalitat Valenciana (PROMETEOII/2014/075). M.T. received support from the NIH Office of the Director (OD), the National Cancer Institute, and the National Institute of Dental and Craniofacial Research (NIDCR)NIH DP5 OD012194, as well as the UCSF Center for Systems and Synthetic Biology (NIGMS) P50 GM081879. J.I.P. was supported by the Chilean government (Becas Chile). Work in the Alvarez-Buylla laboratory was supported by NIH grants NS028478 and HD032116 and a generous gift from the John G. Bowes Research Fund. A.A.-B. is the Heather and Melanie Muss Endowed Chair and Professor of Neurological Surgery at UCSF.\n\nAccepted Version - nihms932927.pdf
Supplemental Material - mmc1.pdf
Supplemental Material - mmc2.mp4
Supplemental Material - mmc3.mp4
", "abstract": "Somatic stem cells have been identified in multiple adult tissues. Whether self-renewal occurs symmetrically or asymmetrically is key to understanding long-term stem cell maintenance and generation of progeny for cell replacement. In the adult mouse brain, neural stem cells (NSCs) (B1 cells) are retained in the walls of the lateral ventricles (ventricular-subventricular zone [V-SVZ]). The mechanism of B1 cell retention into adulthood for lifelong neurogenesis is unknown. Using multiple clonal labeling techniques, we show that the vast majority of B1 cells divide symmetrically. Whereas 20%\u201330% symmetrically self-renew and can remain in the niche for several months before generating neurons, 70%\u201380% undergo consuming divisions generating progeny, resulting in the depletion of B1 cells over time. This cellular mechanism decouples self-renewal from the generation of progeny. Limited rounds of symmetric self-renewal and consuming symmetric differentiation divisions can explain the levels of neurogenesis observed throughout life.", "date": "2018-02-01", "date_type": "published", "publication": "Cell Stem Cell", "volume": "22", "number": "2", "publisher": "Cell Press", "pagerange": "221-234", "id_number": "CaltechAUTHORS:20180202-090924087", "issn": "1934-5909", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20180202-090924087", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Deutsche Forschungsgemeinschaft (DFG)" }, { "agency": "Generalitat Valenciana", "grant_number": "PROMETEOII/2014/075" }, { "agency": "National Cancer Institute" }, { "agency": "National Institute of Dental and Craniofacial Research (NIDCR)" }, { "agency": "NIH", "grant_number": "DP5 OD012194" }, { "agency": "NIH", "grant_number": "P50 GM081879" }, { "agency": "Government of Chile" }, { "agency": "NIH", "grant_number": "NS028478" }, { "agency": "NIH", "grant_number": "HD032116" }, { "agency": "John G. Bowes Research Fund" } ] }, "doi": "10.1016/j.stem.2018.01.003", "pmcid": "PMC5802882", "primary_object": { "basename": "mmc1.pdf", "url": "https://authors.library.caltech.edu/records/7efyr-ajm67/files/mmc1.pdf" }, "related_objects": [ { "basename": "mmc2.mp4", "url": "https://authors.library.caltech.edu/records/7efyr-ajm67/files/mmc2.mp4" }, { "basename": "mmc3.mp4", "url": "https://authors.library.caltech.edu/records/7efyr-ajm67/files/mmc3.mp4" }, { "basename": "nihms932927.pdf", "url": "https://authors.library.caltech.edu/records/7efyr-ajm67/files/nihms932927.pdf" } ], "resource_type": "article", "pub_year": "2018", "author_list": "Obernier, Kirsten; Cebrian-Silla, Arantxa; et el." }, { "id": "https://authors.library.caltech.edu/records/11k8x-brh50", "eprint_id": 85405, "eprint_status": "archive", "datestamp": "2023-08-19 06:54:46", "lastmod": "2023-10-18 18:11:35", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Hendel-Nathan-L", "name": { "family": "Hendel", "given": "N. L." } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "M." } }, { "id": "Marshall-Wallace-F", "name": { "family": "Marshall", "given": "W. F." } } ] }, "title": "Diffusion as a ruler: Modeling kinesin diffusion as a length sensor for intraflagellar transport", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2017 American Society for Cell Biology. Free via Creative Commons 2 months after publication.\n\nPublished - Hendel_2017pM196.pdf
", "abstract": "An important question in cell biology is whether cells are able to measure size, either whole cell size or organelle size. Perhaps cells have an internal chemical representation of size that can be used to precisely regulate growth, or perhaps size is just an accident that emerges due to constraint of nutrients. The eukaryotic flagellum is an ideal model for studying size sensing and control because its linear geometry makes it essentially one\u2010dimensional, greatly simplifying mathematical modeling. The\nassembly of flagella is regulated by intraflagellar transport (IFT), in which kinesin motors carry cargo\nadaptors for flagellar proteins along the flagellum and then deposit them at the tip, lengthening the flagellum. The rate at which IFT motors are recruited to begin transport into the flagellum is anticorrelated with the flagellar length, implying some kind of communication between the base and the tip and possibly indicating that cells contain some mechanism for measuring flagellar length. Although it is possible to imagine many complex scenarios in which additional signaling molecules sense length and carry feedback signals to the cell body to control IFT, might the already\u2010known components of the IFT\nsystem be sufficient to allow length dependence of IFT? Here, we investigate a model in which the anterograde kinesin motors unbind after cargo delivery, diffuse back to the base, and are subsequently reused to power entry of new IFT trains into the flagellum. By modeling such a system at three different levels of abstraction we are able to show that the diffusion time of the motors can in principle be\nsufficient to serve as a proxy for length measurement. In all three implementations, we found that the diffusion model can not only achieve a stable steady\u2010state length without the addition of any other signaling molecules or pathways, but also is able to produce the anticorrelation between length and IFT recruitment rate that has been observed in quantitative imaging studies.", "date": "2017-12-15", "date_type": "published", "publication": "Molecular Biology of the Cell", "volume": "28", "number": "26", "publisher": "American Society for Cell Biology", "pagerange": "Art. No. M196", "id_number": "CaltechAUTHORS:20180321-144810107", "issn": "1059-1524", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20180321-144810107", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1091/mbc.E17-10-0618", "primary_object": { "basename": "Hendel_2017pM196.pdf", "url": "https://authors.library.caltech.edu/records/11k8x-brh50/files/Hendel_2017pM196.pdf" }, "resource_type": "article", "pub_year": "2017", "author_list": "Hendel, N. L.; Thomson, M.; et el." }, { "id": "https://authors.library.caltech.edu/records/3p2m6-a5p97", "eprint_id": 78088, "eprint_status": "archive", "datestamp": "2023-08-19 03:35:58", "lastmod": "2023-10-25 23:44:38", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Aull-K-H", "name": { "family": "Aull", "given": "Katherine H." } }, { "id": "Tanner-E-J", "name": { "family": "Tanner", "given": "Elizabeth J." } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matthew" } }, { "id": "Weinberger-L-S", "name": { "family": "Weinberger", "given": "Leor S." } } ] }, "title": "Transient Thresholding: A Mechanism Enabling Noncooperative Transcriptional Circuitry to Form a Switch", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2017 Biophysical Society. \n\nReceived 9 December 2016, Accepted 1 May 2017, Available online 11 June 2017. \n\nWe thank Brandon Razooky for key initial observations and reagents, and Marielle Cavrois of the Gladstone Institutes Flow Cytometry Core and Kurt Thorn of the University of California San Francisco Nikon Imaging Center for technical help and advice. \n\nThe Gladstone Institutes Flow Cytometry Core is supported by National Institutes of Health (NIH) grant Nos. P30 AI027763 and S10 RR028962. K.H.A. was supported by a National Science Foundation (NSF) Graduate Research Fellowship. M.T. acknowledges support from the National Institutes of Health (NIH) Office of the Director, the National Cancer Institute, and the National Institute of Dental and Craniofacial Research under NIH grant No. DP5 OD012194. L.S.W. acknowledges support from the NIH Director's New Innovator Award Program, grant No. OD006677, and NIH grant No. R01 AI109593.\n\nSubmitted - 134858.full.pdf
Supplemental Material - mmc1.pdf
", "abstract": "Threshold generation in fate-selection circuits is often achieved through deterministic bistability, which requires cooperativity (i.e., nonlinear activation) and associated hysteresis. However, the Tat positive-feedback loop that controls HIV's fate decision between replication and proviral latency lacks self-cooperativity and deterministic bistability. Absent cooperativity, it is unclear how HIV can temporarily remain in an off-state long enough for the kinetically slower epigenetic silencing mechanisms to act\u2014expression fluctuations should rapidly trigger active positive feedback and replication, precluding establishment of latency. Here, using flow cytometry and single-cell imaging, we find that the Tat circuit exhibits a transient activation threshold. This threshold largely disappears after \u223c40 h\u2014accounting for the lack of deterministic bistability\u2014and promoter activation shortens the lifetime of this transient threshold. Continuous differential equation models do not recapitulate this phenomenon. However, chemical reaction (master equation) models where the transcriptional transactivator and promoter toggle between inactive and active states can recapitulate the phenomenon because they intrinsically create a single-molecule threshold transiently requiring excess molecules in the inactive state to achieve at least one molecule (rather than a continuous fractional value) in the active state. Given the widespread nature of promoter toggling and transcription factor modifications, transient thresholds may be a general feature of inducible promoters.", "date": "2017-06-06", "date_type": "published", "publication": "Biophysical Journal", "volume": "112", "number": "11", "publisher": "Biophysical Society", "pagerange": "2428-2438", "id_number": "CaltechAUTHORS:20170612-083933304", "issn": "0006-3495", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170612-083933304", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "P30 AI027763" }, { "agency": "NIH", "grant_number": "S10 RR028962" }, { "agency": "NSF Graduate Research Fellowship" }, { "agency": "National Cancer Institute" }, { "agency": "National Institute of Dental and Craniofacial Research" }, { "agency": "NIH", "grant_number": "DP5 OD012194" }, { "agency": "NIH", "grant_number": "OD006677" }, { "agency": "NIH", "grant_number": "R01 AI109593" } ] }, "doi": "10.1016/j.bpj.2017.05.002", "pmcid": "PMC5474885", "primary_object": { "basename": "mmc1.pdf", "url": "https://authors.library.caltech.edu/records/3p2m6-a5p97/files/mmc1.pdf" }, "related_objects": [ { "basename": "134858.full.pdf", "url": "https://authors.library.caltech.edu/records/3p2m6-a5p97/files/134858.full.pdf" } ], "resource_type": "article", "pub_year": "2017", "author_list": "Aull, Katherine H.; Tanner, Elizabeth J.; et el." }, { "id": "https://authors.library.caltech.edu/records/73et7-25x08", "eprint_id": 72187, "eprint_status": "archive", "datestamp": "2023-08-18 23:59:30", "lastmod": "2023-10-23 18:01:32", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matthew" } } ] }, "title": "Signaling Boundary Conditions Drive Self-Organization of Human \"Gastruloids\"", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 2016 Elsevier Inc. \n\nAvailable online 7 November 2016.", "abstract": "Morphogenesis requires tissues to sense and respond to their geometry. In this issue of Developmental Cell, Etoc et al. (2016) show that a confined colony of human embryonic stem cells can spontaneously sense its boundary, generating a self-organized TGF-\u03b2 signaling gradient that patterns it into a tissue resembling a gastrulating embryo.", "date": "2016-11-07", "date_type": "published", "publication": "Developmental Cell", "volume": "39", "number": "3", "publisher": "Cell Press", "pagerange": "279-280", "id_number": "CaltechAUTHORS:20161121-084221387", "issn": "1534-5807", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20161121-084221387", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1016/j.devcel.2016.10.016", "resource_type": "article", "pub_year": "2016", "author_list": "Thomson, Matthew" }, { "id": "https://authors.library.caltech.edu/records/kb19k-wzt94", "eprint_id": 74044, "eprint_status": "archive", "datestamp": "2023-08-20 11:22:58", "lastmod": "2023-10-24 22:02:12", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Heimberg-G", "name": { "family": "Heimberg", "given": "Graham" } }, { "id": "Bhatnagar-R", "name": { "family": "Bhatnagar", "given": "Rajat" } }, { "id": "El-Samad-H", "name": { "family": "El-Samad", "given": "Hana" }, "orcid": "0000-0001-6239-9916" }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" } } ] }, "title": "Low Dimensionality in Gene Expression Data Enables the Accurate Extraction of Transcriptional Programs from Shallow Sequencing", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2016 The Authors. Under a Creative Commons license. \n\nReceived: November 30, 2015. Revised: March 8, 2016. Accepted: April 4, 2016. Published: April 27, 2016. \n\nThe authors would like to thank Jason Kreisberg, Alex Fields, David Sivak, Patrick Cahan, Jonathan Weissman, Chun Ye, Michael Chevalier, Satwik Rajaram, and Steve Altschuler for careful reading of the manuscript; Eric Chow,John Haliburton, Sisi Chen, and Emeric Charles for their experimental insights; and Paul Rivaud for website design assistance. This work was supported by the UCSF Center for Systems and Synthetic Biology (NIGMS P50 GM081879). H.E.S. acknowledges support from the Paul G. Allen Family Foundation. M.T. acknowledges support from the NIH Office of the Director, the National Cancer Institute, and the National Institute of Dental and Craniofacial Research (NIH DP5 OD012194).\n\nPublished - PIIS2405471216301090.pdf
Supplemental Material - mmc1.pdf
", "abstract": "A tradeoff between precision and throughput constrains all biological measurements, including sequencing-based technologies. Here, we develop a mathematical framework that defines this tradeoff between mRNA-sequencing depth and error in the extraction of biological information. We find that transcriptional programs can be reproducibly identified at 1% of conventional read depths. We demonstrate that this resilience to noise of \"shallow\" sequencing derives from a natural property, low dimensionality, which is a fundamental feature of gene expression data. Accordingly, our conclusions hold for \u223c350 single-cell and bulk gene expression datasets across yeast, mouse, and human. In total, our approach provides quantitative guidelines for the choice of sequencing depth necessary to achieve a desired level of analytical resolution. We codify these guidelines in an open-source read depth calculator. This work demonstrates that the structure inherent in biological networks can be productively exploited to increase measurement throughput, an idea that is now common in many branches of science, such as image processing.", "date": "2016-04-27", "date_type": "published", "publication": "Cell Systems", "volume": "2", "number": "4", "publisher": "Elsevier", "pagerange": "239-250", "id_number": "CaltechAUTHORS:20170203-145417665", "issn": "2405-4712", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170203-145417665", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "P50 GM081879" }, { "agency": "Paul G. Allen Family Foundation" }, { "agency": "NIH", "grant_number": "DP5 OD012194" } ] }, "doi": "10.1016/j.cels.2016.04.001", "pmcid": "PMC4856162", "primary_object": { "basename": "PIIS2405471216301090.pdf", "url": "https://authors.library.caltech.edu/records/kb19k-wzt94/files/PIIS2405471216301090.pdf" }, "related_objects": [ { "basename": "mmc1.pdf", "url": "https://authors.library.caltech.edu/records/kb19k-wzt94/files/mmc1.pdf" } ], "resource_type": "article", "pub_year": "2016", "author_list": "Heimberg, Graham; Bhatnagar, Rajat; et el." }, { "id": "https://authors.library.caltech.edu/records/8n4r3-btc28", "eprint_id": 74409, "eprint_status": "archive", "datestamp": "2023-08-20 10:50:31", "lastmod": "2023-10-24 22:36:34", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Myers-S-A", "name": { "family": "Myers", "given": "Samuel A." } }, { "id": "Peddada-S", "name": { "family": "Peddada", "given": "Sailaja" } }, { "id": "Chatterjee-N", "name": { "family": "Chatterjee", "given": "Nilanjana" } }, { "id": "Friedrich-T", "name": { "family": "Friedrich", "given": "Tara" } }, { "id": "Tomoda-Kiichrio", "name": { "family": "Tomoda", "given": "Kiichrio" } }, { "id": "Krings-G", "name": { "family": "Krings", "given": "Gregor" } }, { "id": "Thomas-S", "name": { "family": "Thomas", "given": "Sean" } }, { "id": "Maynard-J", "name": { "family": "Maynard", "given": "Jason" } }, { "id": "Broeker-M", "name": { "family": "Broeker", "given": "Michael" } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matthew" } }, { "id": "Pollard-K", "name": { "family": "Pollard", "given": "Katherine" } }, { "id": "Yamanaka-Shinya", "name": { "family": "Yamanaka", "given": "Shinya" } }, { "id": "Burlingame-A-L", "name": { "family": "Burlingame", "given": "Alma L." } }, { "id": "Panning-B", "name": { "family": "Panning", "given": "Barbara" }, "orcid": "0000-0002-8301-1172" } ] }, "title": "SOX2O-GlcNAcylation alters its protein-protein interactions and genomic occupancy to modulate gene expression in pluripotent cells", "ispublished": "pub", "full_text_status": "public", "note": "Copyright Myers 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: 08 August 2015. Accepted: 05 March 2016. Published: 07 March 2016. \n\nWe greatly appreciate the generous gifts from Tom Fazzio for the fMBD3 mESCs, Tim Townes for the KI SOX2 mESCs, Suzanne Walker for the His-OGT plasmid, Sy Redding, and David Bauer for Avi-tagged human Bio-SOX2. We thank Anne Claude Gingras, Joe Kleigman, Michael Lopez, Katie Worringer, and Anthony Shiver for technical assistance. Thank you to Kathyrn Lovero and Jonathan Fistorino for useful discussion, and Emily Myers and Lucas Sullivan for critical assessment of this manuscript. We also thank the Arraystar and the Gladstone Bioinformatics core for assistance analyzing the microarray and ChIP-seq data, respectively. This work was supported by the Biomedical Technology Research Centers program of the NIH National Institute of General Medical Sciences, NIH NIGMS P41GM103481, 1S10RR019934, Howard Hughes Medical Institute (purchase of ETD mass spectrometer) and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (ALB), NIH R01GM085186, CIRM RB4-05990, and University of California San Francisco Program for Breakthrough Biomedical Research (BP). SAM is supported by a National Institutes of Health National Institute of General Medical Sciences T32 training grant, the Genentech Predoctoral Fellowship Program and the QBC Fellowship for Interdisciplinary Research. The Cornell Stem Cell Core is supported by the Empire State Stem Cell fund through NYSDOH Contract # C024174, and opinions expressed here are solely those of the author and do not necessarily reflect those of the Empire State Stem Cell Fund, the NYSDOH, or the State of NY.\n\nPublished - e10647-download.pdf
Supplemental Material - elife-10647-supp1-v3-download.xlsx
", "abstract": "The transcription factor SOX2 is central in establishing and maintaining pluripotency. The processes that modulate SOX2 activity to promote pluripotency are not well understood. Here, we show SOX2 is O-GlcNAc modified in its transactivation domain during reprogramming and in mouse embryonic stem cells (mESCs). Upon induction of differentiation SOX2 O-GlcNAcylation at serine 248 is decreased. Replacing wild type with an O-GlcNAc-deficient SOX2 (S248A) increases reprogramming efficiency. ESCs with O-GlcNAc-deficient SOX2 exhibit alterations in gene expression. This change correlates with altered protein-protein interactions and genomic occupancy of the O-GlcNAc-deficient SOX2 compared to wild type. In addition, SOX2 O-GlcNAcylation impairs the SOX2-PARP1 interaction, which has been shown to regulate ESC self-renewal. These findings show that SOX2 activity is modulated by O-GlcNAc, and provide a novel regulatory mechanism for this crucial pluripotency transcription factor.", "date": "2016-03-07", "date_type": "published", "publication": "eLife", "volume": "5", "publisher": "eLife Sciences Publications", "pagerange": "Art. No. e10647", "id_number": "CaltechAUTHORS:20170217-152208931", "issn": "2050-084X", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170217-152208931", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "P41GM103481" }, { "agency": "Howard Hughes Medical Institute (HHMI)" }, { "agency": "California Institute for Regenerative Medicine (CIRM)", "grant_number": "RB4-05990" }, { "agency": "Dr. Miriam and Sheldon G. Adelson Medical Research Foundation" }, { "agency": "University of California, San Francisco (UCSF)" }, { "agency": "NIH", "grant_number": "1S10RR019934" }, { "agency": "NIH", "grant_number": "R01GM085186" }, { "agency": "Genentech Predoctoral Fellowship Program" }, { "agency": "QBC Fellowship for Interdisciplinary Research" }, { "agency": "Empire State Stem Cell fund", "grant_number": "C024174" } ] }, "doi": "10.7554/eLife.10647", "pmcid": "PMC4841768", "primary_object": { "basename": "e10647-download.pdf", "url": "https://authors.library.caltech.edu/records/8n4r3-btc28/files/e10647-download.pdf" }, "related_objects": [ { "basename": "elife-10647-supp1-v3-download.xlsx", "url": "https://authors.library.caltech.edu/records/8n4r3-btc28/files/elife-10647-supp1-v3-download.xlsx" } ], "resource_type": "article", "pub_year": "2016", "author_list": "Myers, Samuel A.; Peddada, Sailaja; et el." }, { "id": "https://authors.library.caltech.edu/records/2z7q3-72409", "eprint_id": 74412, "eprint_status": "archive", "datestamp": "2023-08-20 10:16:36", "lastmod": "2023-10-24 22:36:44", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Morsut-L", "name": { "family": "Morsut", "given": "Leonardo" } }, { "id": "Roybal-K-T", "name": { "family": "Roybal", "given": "Kole T." } }, { "id": "Xiong-Xin", "name": { "family": "Xiong", "given": "Xin" } }, { "id": "Gordley-R-M", "name": { "family": "Gordley", "given": "Russell M." } }, { "id": "Coyle-S-M", "name": { "family": "Coyle", "given": "Scott M." } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matthew" } }, { "id": "Lim-W-A", "name": { "family": "Lim", "given": "Wendell A." } } ] }, "title": "Engineering Customized Cell Sensing and Response Behaviors Using Synthetic Notch Receptors", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2016 Elsevier Inc. \n\nReceived: November 27, 2015. Revised: January 4, 2016. Accepted: January 8, 2016. Published: January 28, 2016. \n\nWe would like to thank members of the Lim lab for helpful discussions and comments on the manuscript. We thank K. McNally and Joan Garbarino for technical assistance and R. Nicoll for neurons. This work was supported by a Jane Coffin Childs Memorial Fund Postdoctoral Fellowship A121505 (K.T.R.), a Human Frontiers of Science Program (HFSP), a European Molecular Biology Organization (EMBO) Postdoctoral Fellowship (L.M.), NIH grants K99 1K99EB021030 (L.M.), PN2 EY016546, P50GM081879, R01 GM055040, and R01 CA196277, and the Howard Hughes Medical Institute (W.A.L.).\n\nAccepted Version - nihms751441.pdf
Supplemental Material - mmc1.xlsx
Supplemental Material - mmc2.mp4
", "abstract": "The Notch protein is one of the most mechanistically direct transmembrane receptors\u2014the intracellular domain contains a transcriptional regulator that is released from the membrane when engagement of the cognate extracellular ligand induces intramembrane proteolysis. We find that chimeric forms of Notch, in which both the extracellular sensor module and the intracellular transcriptional module are replaced with heterologous protein domains, can serve as a general platform for generating novel cell-cell contact signaling pathways. Synthetic Notch (synNotch) pathways can drive user-defined functional responses in diverse mammalian cell types. Because individual synNotch pathways do not share common signaling intermediates, the pathways are functionally orthogonal. Thus, multiple synNotch receptors can be used in the same cell to achieve combinatorial integration of environmental cues, including Boolean response programs, multi-cellular signaling cascades, and self-organized cellular patterns. SynNotch receptors provide extraordinary flexibility in engineering cells with customized sensing/response behaviors to user-specified extracellular cues.", "date": "2016-02-11", "date_type": "published", "publication": "Cell", "volume": "164", "number": "4", "publisher": "Elsevier", "pagerange": "780-791", "id_number": "CaltechAUTHORS:20170217-155108197", "issn": "0092-8674", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170217-155108197", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Jane Coffin Childs Memorial Fund", "grant_number": "A121505" }, { "agency": "Human Frontiers Science Program" }, { "agency": "European Molecular Biology Organization (EMBO)" }, { "agency": "NIH", "grant_number": "K99 1K99EB021030" }, { "agency": "NIH", "grant_number": "PN2 EY016546" }, { "agency": "NIH", "grant_number": "P50GM081879" }, { "agency": "NIH", "grant_number": "R01 GM055040" }, { "agency": "NIH", "grant_number": "R01 CA196277" }, { "agency": "Howard Hughes Medical Institute (HHMI)" } ] }, "doi": "10.1016/j.cell.2016.01.012", "pmcid": "PMC4752866", "primary_object": { "basename": "nihms751441.pdf", "url": "https://authors.library.caltech.edu/records/2z7q3-72409/files/nihms751441.pdf" }, "related_objects": [ { "basename": "mmc1.xlsx", "url": "https://authors.library.caltech.edu/records/2z7q3-72409/files/mmc1.xlsx" }, { "basename": "mmc2.mp4", "url": "https://authors.library.caltech.edu/records/2z7q3-72409/files/mmc2.mp4" } ], "resource_type": "article", "pub_year": "2016", "author_list": "Morsut, Leonardo; Roybal, Kole T.; et el." }, { "id": "https://authors.library.caltech.edu/records/j8q2p-50k32", "eprint_id": 74082, "eprint_status": "archive", "datestamp": "2023-08-20 07:53:54", "lastmod": "2023-10-24 22:04:29", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Sokolik-C", "name": { "family": "Sokolik", "given": "Cameron" } }, { "id": "Liu-Yanxia", "name": { "family": "Liu", "given": "Yanxia" } }, { "id": "Bauer-D", "name": { "family": "Bauer", "given": "David" } }, { "id": "McPherson-J", "name": { "family": "McPherson", "given": "Jade" } }, { "id": "Broeker-M", "name": { "family": "Broeker", "given": "Michael" } }, { "id": "Heimberg-G", "name": { "family": "Heimberg", "given": "Graham" } }, { "id": "Qi-Lei-S", "name": { "family": "Qi", "given": "Lei S." } }, { "id": "Sivak-D-A", "name": { "family": "Sivak", "given": "David A." } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" } } ] }, "title": "Transcription Factor Competition Allows Embryonic Stem Cells to Distinguish Authentic Signals from Noise", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2015 Elsevier Inc. \n\nReceived: January 7, 2015. Revised: May 18, 2015. Accepted: August 3, 2015. Published: August 26, 2015. \n\nThe authors thank Eric Siggia, Leor Weinberger, Saul Villeda, Long Cai, Carl Pabo, Angela Andersen, David Schaffer, Belinda Waltman, and Benoit Bruneau for scientific discussions and careful reading of the manuscript; Wendell Lim, Ron Vale, and Leo Morsut for scientific discussions. We thank Kurt Thorn, Eric Chow, Mekhala Maiti, DNA 2.0, and Pickersgill and Andersen for advice and technical assistance. This work was supported by the UCSF Center for Systems and Synthetic Biology NIGMS P50 GM081879 (L.S.Q., D.A.S., M.T.). M.T. acknowledges support from the NIH Office of the Director (OD), the National Cancer Institute, and the National Institute of Dental & Craniofacial Research (NIDCR) NIH DP5 OD012194. L.S.Q. acknowledges support from the UCSF Center for Systems and Synthetic Biology, NIH Office of the Director (OD), and National Institute of Dental and Craniofacial Research (NIDCR) NIH DP5 OD017887 (Y.L. and L.S.Q.).\n\nAccepted Version - nihms714076.pdf
Supplemental Material - mmc1.pdf
Supplemental Material - mmc2.mp4
Supplemental Material - mmc3.mp4
Supplemental Material - mmc4.mp4
Supplemental Material - mmc5.mp4
", "abstract": "Stem cells occupy variable environments where they must distinguish stochastic fluctuations from developmental cues. Here, we use optogenetics to investigate how the pluripotency network in embryonic stem cells (ESCs) achieves a robust response to differentiation cues but not to gene expression fluctuations. We engineered mouse ESCs to allow quantitative control over the endogenous mechanism of neural differentiation through a light-inducible Brn2 transgene and monitored differentiation status through a genome-integrated Nanog-GFP reporter. By exposing cells to pulses of Brn2, we find that the pluripotency network rejects Brn2 inputs that are below specific magnitude or duration thresholds, but allows rapid differentiation when both thresholds are satisfied. The filtering properties of the network arise through its positive feedback architecture and the intrinsic half-life of Nanog, which determines the duration threshold in the network. Together our results suggest that the dynamic properties of positive feedback networks might determine how inputs are classified as signal or noise by stem cells.", "date": "2015-08-26", "date_type": "published", "publication": "Cell Systems", "volume": "1", "number": "2", "publisher": "Elsevier", "pagerange": "117-129", "id_number": "CaltechAUTHORS:20170206-125245319", "issn": "2405-4712", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170206-125245319", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "P50 GM081879" }, { "agency": "NIH", "grant_number": "DP5 OD012194" }, { "agency": "University of California, San Francisco (UCSF)" }, { "agency": "NIH", "grant_number": "DP5 OD017887" }, { "agency": "National Institute of Dental and Craniofacial Research (NIDCR)" } ] }, "doi": "10.1016/j.cels.2015.08.001", "pmcid": "PMC4576702", "primary_object": { "basename": "mmc4.mp4", "url": "https://authors.library.caltech.edu/records/j8q2p-50k32/files/mmc4.mp4" }, "related_objects": [ { "basename": "mmc5.mp4", "url": "https://authors.library.caltech.edu/records/j8q2p-50k32/files/mmc5.mp4" }, { "basename": "nihms714076.pdf", "url": "https://authors.library.caltech.edu/records/j8q2p-50k32/files/nihms714076.pdf" }, { "basename": "mmc1.pdf", "url": "https://authors.library.caltech.edu/records/j8q2p-50k32/files/mmc1.pdf" }, { "basename": "mmc2.mp4", "url": "https://authors.library.caltech.edu/records/j8q2p-50k32/files/mmc2.mp4" }, { "basename": "mmc3.mp4", "url": "https://authors.library.caltech.edu/records/j8q2p-50k32/files/mmc3.mp4" } ], "resource_type": "article", "pub_year": "2015", "author_list": "Sokolik, Cameron; Liu, Yanxia; et el." }, { "id": "https://authors.library.caltech.edu/records/tk9ge-wfm60", "eprint_id": 74413, "eprint_status": "archive", "datestamp": "2023-08-20 06:51:37", "lastmod": "2023-10-24 22:36:47", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Finkbeiner-S-R", "name": { "family": "Finkbeiner", "given": "Stacy R." } }, { "id": "Hill-D-R", "name": { "family": "Hill", "given": "David R." } }, { "id": "Altheim-C-H", "name": { "family": "Altheim", "given": "Christopher H." } }, { "id": "Dedhia-P-H", "name": { "family": "Dedhia", "given": "Priya H." } }, { "id": "Taylor-M-J", "name": { "family": "Taylor", "given": "Matthew J." } }, { "id": "Tsai-Yu-Hwai", "name": { "family": "Tsai", "given": "Yu-Hwai" } }, { "id": "Chin-Alana-M", "name": { "family": "Chin", "given": "Alana M." } }, { "id": "Mahe-M-M", "name": { "family": "Mahe", "given": "Maxime M." } }, { "id": "Watson-C-L", "name": { "family": "Watson", "given": "Carey L." } }, { "id": "Freeman-J-J", "name": { "family": "Freeman", "given": "Jennifer J." } }, { "id": "Nattiv-R", "name": { "family": "Nattiv", "given": "Roy" } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matthew" } }, { "id": "Klein-O-D", "name": { "family": "Klein", "given": "Ophir D." } }, { "id": "Shroyer-N-F", "name": { "family": "Shroyer", "given": "Noah F." } }, { "id": "Helmrath-M-A", "name": { "family": "Helmrath", "given": "Michael A." } }, { "id": "Teitelbaum-D-H", "name": { "family": "Teitelbaum", "given": "Daniel H." } }, { "id": "Dempsey-P-J", "name": { "family": "Dempsey", "given": "Peter J." } }, { "id": "Spence-J-R", "name": { "family": "Spence", "given": "Jason R." } } ] }, "title": "Transcriptome-wide Analysis Reveals Hallmarks of Human Intestine Development and Maturation In Vitro and In Vivo", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). \n\nReceived: December 16, 2014. Revised: April 22, 2015. Accepted: April 22, 2015. Published: June 4, 2015. \n\nWe thank Rich McEachin and Manjusha Pande at the University of Michigan Bioinformatics Core Facility. We also thank the Gift of Life, Michigan, for access to human intestinal tissue. This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, K01DK091415 and U01DK103141) to J.R.S. and by the University of Michigan Center for Gastrointestinal Research (UMCGR) (NIDDK, 5P30DK034933). Research reported in this publication and conducted by S.R.F. was supported by an NIDDK training grant, ''Training in Basic and Translational Digestive Sciences'' (T32DK094775), a postdoctoral fellowship from The Hartwell Foundation, and the National Center for Advancing Translational Sciences of the NIH (2UL1TR000433). Additionally, this work was supported by a grant from the California Institute for Regenerative Medicine (RN3-06525) to O.D.K. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.\n\nPublished - PIIS2213671115001228.pdf
Supplemental Material - mmc1.pdf
Supplemental Material - mmc2.xlsx
Supplemental Material - mmc3.xlsx
Supplemental Material - mmc4.xlsx
Supplemental Material - mmc5.xlsx
Supplemental Material - mmc6.xlsx
", "abstract": "Human intestinal organoids (HIOs) are a tissue culture model in which small intestine-like tissue is generated from pluripotent stem cells. By carrying out unsupervised hierarchical clustering of RNA-sequencing data, we demonstrate that HIOs most closely resemble human fetal intestine.We observed that genes involved in digestive tract development are enriched in both fetal intestine and HIOs compared to adult tissue, whereas genes related to digestive function and Paneth cell host defense are expressed at higher levels in adult intestine. Our study also revealed that the intestinal stem cell marker OLFM4 is expressed at very low levels in fetal intestine and in HIOs, but is robust in adult crypts.We validated our findings using in vivo transplantation to show that HIOs become more adult-like after transplantation. Our study emphasizes important maturation events that occur in the intestine during human development and demonstrates that HIOs can be used to model fetal-to-adult maturation.", "date": "2015-06-09", "date_type": "published", "publication": "Stem Cell Reports", "volume": "4", "number": "6", "publisher": "Elsevier", "pagerange": "1140-1155", "id_number": "CaltechAUTHORS:20170217-155108581", "issn": "2213-6711", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170217-155108581", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "K01DK091415" }, { "agency": "NIH", "grant_number": "U01DK103141" }, { "agency": "NIH", "grant_number": "5P30DK034933" }, { "agency": "NIH Predoctoral Fellowship", "grant_number": "T32DK094775" }, { "agency": "Hartwell Foundation" }, { "agency": "NIH", "grant_number": "2UL1TR000433" }, { "agency": "California Institute for Regenerative Medicine (CIRM)", "grant_number": "RN3-06525" } ] }, "doi": "10.1016/j.stemcr.2015.04.010", "pmcid": "PMC4471827", "primary_object": { "basename": "mmc4.xlsx", "url": "https://authors.library.caltech.edu/records/tk9ge-wfm60/files/mmc4.xlsx" }, "related_objects": [ { "basename": "mmc5.xlsx", "url": "https://authors.library.caltech.edu/records/tk9ge-wfm60/files/mmc5.xlsx" }, { "basename": "mmc6.xlsx", "url": "https://authors.library.caltech.edu/records/tk9ge-wfm60/files/mmc6.xlsx" }, { "basename": "PIIS2213671115001228.pdf", "url": "https://authors.library.caltech.edu/records/tk9ge-wfm60/files/PIIS2213671115001228.pdf" }, { "basename": "mmc1.pdf", "url": "https://authors.library.caltech.edu/records/tk9ge-wfm60/files/mmc1.pdf" }, { "basename": "mmc2.xlsx", "url": "https://authors.library.caltech.edu/records/tk9ge-wfm60/files/mmc2.xlsx" }, { "basename": "mmc3.xlsx", "url": "https://authors.library.caltech.edu/records/tk9ge-wfm60/files/mmc3.xlsx" } ], "resource_type": "article", "pub_year": "2015", "author_list": "Finkbeiner, Stacy R.; Hill, David R.; et el." }, { "id": "https://authors.library.caltech.edu/records/tany3-s7t55", "eprint_id": 74083, "eprint_status": "archive", "datestamp": "2023-08-20 04:59:54", "lastmod": "2023-10-24 22:04:35", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Cerchiari-A-E", "name": { "family": "Cerchiari", "given": "Alec E." } }, { "id": "Garbe-J-C", "name": { "family": "Garbe", "given": "James C." } }, { "id": "Jee-Noel-Y", "name": { "family": "Jee", "given": "Noel Y." } }, { "id": "Todhunter-M-E", "name": { "family": "Todhunter", "given": "Michael E." } }, { "id": "Broaders-K-E", "name": { "family": "Broaders", "given": "Kyle E." } }, { "id": "Peehl-D-M", "name": { "family": "Peehl", "given": "Donna M." } }, { "id": "Desai-T-A", "name": { "family": "Desai", "given": "Tejal A." }, "orcid": "0000-0003-3409-9208" }, { "id": "LaBarge-M-A", "name": { "family": "LaBarge", "given": "Mark A." } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matthew" } }, { "id": "Gartner-Z-J", "name": { "family": "Gartner", "given": "Zev J." } } ] }, "title": "A strategy for tissue self-organization that is robust to cellular heterogeneity and plasticity", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2015 The Authors. \n\nEdited by Ken A. Dill, Stony Brook University, Stony Brook, NY, and approved December 30, 2014 (received for review June 9, 2014) \n\nThe authors thank Dr. Maija Valta for help in preparing primary prostate organoids, Dr. Jennifer Liu and Dr. Alba de Moniz for technical assistance and comments, Dr. Justin Farlow for help with data analysis, and an anonymous reviewer for helpful comments on the manuscript. This work was supported by a seed grant from the National Institutes of Health (NIH) Bay Area Physical Sciences and Oncology Center (to Z.J.G. and M.A.L.); Department of Defense Breast Cancer Research Program Grants W81XWH-10-1-1023 and W81XWH-13-1-0221 (to Z.J.G.); NIH common funds Grants DP5 OD012194-03 (to M.T.) and DP2 HD080351-01 (to Z.J.G.); the Sidney Kimmel Foundation; and the University of California, San Francisco (UCSF) Program in Breakthrough Biomedical Research. Z.J.G. and M.T. are supported by the UCSF Center for Systems and Synthetic Biology (National Institute of General Medical Sciences Systems Biology Center Grant P50 GM081879). A.E.C. was supported by the US Department of Defense through a National Defense Science and Engineering Graduate Fellowship.\n\nPublished - PNAS-2015-Cerchiari-2287-92.pdf
Supplemental Material - pnas.1410776112.sapp.pdf
Supplemental Material - pnas.1410776112.sm01.avi
Supplemental Material - pnas.1410776112.sm02.avi
Supplemental Material - pnas.201410776SI.pdf
", "abstract": "Developing tissues contain motile populations of cells that can self-organize into spatially ordered tissues based on differences in their interfacial surface energies. However, it is unclear how self-organization by this mechanism remains robust when interfacial energies become heterogeneous in either time or space. The ducts and acini of the human mammary gland are prototypical heterogeneous and dynamic tissues comprising two concentrically arranged cell types. To investigate the consequences of cellular heterogeneity and plasticity on cell positioning in the mammary gland, we reconstituted its self-organization from aggregates of primary cells in vitro. We find that self-organization is dominated by the interfacial energy of the tissue\u2013ECM boundary, rather than by differential homo- and heterotypic energies of cell\u2013cell interaction. Surprisingly, interactions with the tissue\u2013ECM boundary are binary, in that only one cell type interacts appreciably with the boundary. Using mathematical modeling and cell-type-specific knockdown of key regulators of cell\u2013cell cohesion, we show that this strategy of self-organization is robust to severe perturbations affecting cell\u2013cell contact formation. We also find that this mechanism of self-organization is conserved in the human prostate. Therefore, a binary interfacial interaction with the tissue boundary provides a flexible and generalizable strategy for forming and maintaining the structure of two-component tissues that exhibit abundant heterogeneity and plasticity. Our model also predicts that mutations affecting binary cell\u2013ECM interactions are catastrophic and could contribute to loss of tissue architecture in diseases such as breast cancer.", "date": "2015-02-17", "date_type": "published", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "volume": "112", "number": "7", "publisher": "National Academy of Sciences", "pagerange": "2287-2292", "id_number": "CaltechAUTHORS:20170206-125245656", "issn": "0027-8424", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170206-125245656", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Department of Defense", "grant_number": "W81XWH-10-1-1023" }, { "agency": "Department of Defense", "grant_number": "W81XWH-13-1-0221" }, { "agency": "NIH", "grant_number": "DP5 OD012194-03" }, { "agency": "NIH", "grant_number": "DP2 HD080351-01" }, { "agency": "Sidney Kimmel Foundation" }, { "agency": "University of California, San Francisco (UCSF)" }, { "agency": "NIH", "grant_number": "P50 GM081879" }, { "agency": "National Defense Science and Engineering Graduate (NDSEG) Fellowship" } ] }, "doi": "10.1073/pnas.1410776112", "pmcid": "PMC4343104", "primary_object": { "basename": "PNAS-2015-Cerchiari-2287-92.pdf", "url": "https://authors.library.caltech.edu/records/tany3-s7t55/files/PNAS-2015-Cerchiari-2287-92.pdf" }, "related_objects": [ { "basename": "pnas.1410776112.sapp.pdf", "url": "https://authors.library.caltech.edu/records/tany3-s7t55/files/pnas.1410776112.sapp.pdf" }, { "basename": "pnas.1410776112.sm01.avi", "url": "https://authors.library.caltech.edu/records/tany3-s7t55/files/pnas.1410776112.sm01.avi" }, { "basename": "pnas.1410776112.sm02.avi", "url": "https://authors.library.caltech.edu/records/tany3-s7t55/files/pnas.1410776112.sm02.avi" }, { "basename": "pnas.201410776SI.pdf", "url": "https://authors.library.caltech.edu/records/tany3-s7t55/files/pnas.201410776SI.pdf" } ], "resource_type": "article", "pub_year": "2015", "author_list": "Cerchiari, Alec E.; Garbe, James C.; et el." }, { "id": "https://authors.library.caltech.edu/records/h17dy-k1z79", "eprint_id": 74407, "eprint_status": "archive", "datestamp": "2023-08-20 04:40:20", "lastmod": "2023-10-24 22:36:27", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Sivak-D-A", "name": { "family": "Sivak", "given": "David A." } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" } } ] }, "title": "Environmental Statistics and Optimal Regulation", "ispublished": "pub", "full_text_status": "restricted", "note": "\u00a9 2015 Biophysical Society. \n\n1830-Plat \n\nConference: 59th Annual Meeting of the Biophysical-Society Location: Baltimore, MD Date: FEB 07-11, 2015 \nSponsor(s): Biophys Soc", "abstract": "[no abstract]", "date": "2015-01-27", "date_type": "published", "publication": "Biophysical Journal", "volume": "108", "number": "2, Supp. 1", "publisher": "Biophysical Society", "pagerange": "364a-365a", "id_number": "CaltechAUTHORS:20170217-150644261", "issn": "0006-3495", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170217-150644261", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1016/j.bpj.2014.11.1999", "resource_type": "article", "pub_year": "2015", "author_list": "Sivak, David A. and Thomson, Matt" }, { "id": "https://authors.library.caltech.edu/records/eqsfg-syx61", "eprint_id": 74105, "eprint_status": "archive", "datestamp": "2023-08-20 02:48:31", "lastmod": "2023-10-24 22:06:16", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Sivak-D-A", "name": { "family": "Sivak", "given": "David A." } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" } } ] }, "title": "Environmental Statistics and Optimal Regulation", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2014 Sivak, Thomson. 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: May 12, 2014; Accepted: July 26, 2014; Published: September 25, 2014. \n\nWe thank Hana El-Samad, Wendell Lim, Amir Mitchell, Michael Fischbach, and Hao Li for enlightening discussions, and especially Hyun Youk for detailed feedback on the manuscript. \n\nDAS and MT were funded by National Institute of General Medical Sciences Systems Biology Center grant P50 GM081879. MT also acknowledges support from NIH 5DP5OD012194. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\nThis article was republished on October 10, 2014, to correct errors in the formatting of the equations and paragraphs. These errors were introduced during the typesetting process. Please download this article again to view the correct version. The originally published, uncorrected article and the republished, corrected article are provided here for reference.\n\nPublished - journal.pcbi.1003826.PDF
Published - journal.pcbi.1003826.s002.PDF
Supplemental Material - journal.pcbi.1003826.s001.PDF
", "abstract": "Any organism is embedded in an environment that changes over time. The timescale for and statistics of environmental change, the precision with which the organism can detect its environment, and the costs and benefits of particular protein expression levels all will affect the suitability of different strategies\u2013such as constitutive expression or graded response\u2013for regulating protein levels in response to environmental inputs. We propose a general framework\u2013here specifically applied to the enzymatic regulation of metabolism in response to changing concentrations of a basic nutrient\u2013to predict the optimal regulatory strategy given the statistics of fluctuations in the environment and measurement apparatus, respectively, and the costs associated with enzyme production. We use this framework to address three fundamental questions: (i) when a cell should prefer thresholding to a graded response; (ii) when there is a fitness advantage to implementing a Bayesian decision rule; and (iii) when retaining memory of the past provides a selective advantage. We specifically find that: (i) relative convexity of enzyme expression cost and benefit influences the fitness of thresholding or graded responses; (ii) intermediate levels of measurement uncertainty call for a sophisticated Bayesian decision rule; and (iii) in dynamic contexts, intermediate levels of uncertainty call for retaining memory of the past. Statistical properties of the environment, such as variability and correlation times, set optimal biochemical parameters, such as thresholds and decay rates in signaling pathways. Our framework provides a theoretical basis for interpreting molecular signal processing algorithms and a classification scheme that organizes known regulatory strategies and may help conceptualize heretofore unknown ones.", "date": "2014-09", "date_type": "published", "publication": "PLOS Computational Biology", "volume": "10", "number": "9", "publisher": "Public Library of Science", "pagerange": "Art. No. e1003826", "id_number": "CaltechAUTHORS:20170206-153034371", "issn": "1553-7358", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170206-153034371", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "P50 GM081879" }, { "agency": "NIH", "grant_number": "5DP5OD012194" } ] }, "doi": "10.1371/journal.pcbi.1003826", "pmcid": "PMC4177669", "primary_object": { "basename": "journal.pcbi.1003826.PDF", "url": "https://authors.library.caltech.edu/records/eqsfg-syx61/files/journal.pcbi.1003826.PDF" }, "related_objects": [ { "basename": "journal.pcbi.1003826.s001.PDF", "url": "https://authors.library.caltech.edu/records/eqsfg-syx61/files/journal.pcbi.1003826.s001.PDF" }, { "basename": "journal.pcbi.1003826.s002.PDF", "url": "https://authors.library.caltech.edu/records/eqsfg-syx61/files/journal.pcbi.1003826.s002.PDF" } ], "resource_type": "article", "pub_year": "2014", "author_list": "Sivak, David A. and Thomson, Matt" }, { "id": "https://authors.library.caltech.edu/records/yedxt-2ne26", "eprint_id": 73810, "eprint_status": "archive", "datestamp": "2023-08-19 07:09:10", "lastmod": "2023-10-24 16:28:49", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matt" } }, { "id": "Liu-Siyuan-John", "name": { "family": "Liu", "given": "Siyuan John" } }, { "id": "Zou-Ling-Nan", "name": { "family": "Zou", "given": "Ling-Nan" } }, { "id": "Smith-Zack", "name": { "family": "Smith", "given": "Zack" } }, { "id": "Meissner-A", "name": { "family": "Meissner", "given": "Alexander" } }, { "id": "Ramanathan-S", "name": { "family": "Ramanathan", "given": "Sharad" } } ] }, "title": "Pluripotency Factors in Embryonic Stem Cells Regulate Differentiation into Germ Layers", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2011 Elsevier Inc. Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) \n\nReceived: October 15, 2010. Revised: March 3, 2011. Accepted: May 16, 2011. Published: June 9, 2011. \n\nWe thank Doug Melton, Sean Eddy, Areez Mody, and Alexander Schier for scientific discussions and Rene Maehr, Masa Yamagata, and Dawen Cai for discussions and technical assistance. We thank Manfred Baetscher and the Harvard Genome Modification Facility for assistance with the cell line generation. We thank Bodo Stern, Nicole Francis, and in particular Sean Eddy and three anonymous referees for extensive comments on the manuscript. We thank the Harvard Stem Cell Institute Seed Grant (S.R.) and the Massachusetts Life Science Center (A.M.) for support. Microarray hybridization and measurements were performed by the Molecular Genetics Core Facility at Children's Hospital Boston supported by NIH-P50-NS40828, and NIH-P30-HD18655. M.T. and S.R. conceived the project. M.T. established the experimental system and performed the immunofluorescence and perturbation experiments. S.J.L. and M.T. built the cell lines and performed microarray experiments. L.N.Z. performed the FACS experiments and established techniques for long term microscopy of ESCs on glass. M.T. and S.J.L. performed the time-lapse microscopy experiments. Z.S. and A.M. did the ChIP for Oct4 and Sox2. S.J.L., M.T., and S.R. performed the tiling qPCR experiments. M.T., S.R., and S.J.L. performed the data and mathematical analyses and wrote the manuscript. \n\nAccession Numbers: Microarray data are available in the Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo/) under the accession number GSE29005.\n\nPublished - PIIS0092867411005435.pdf
Supplemental Material - mmc1.pdf
", "abstract": "Cell fate decisions are fundamental for development, but we do not know how transcriptional networks reorganize during the transition from a pluripotent to a differentiated cell state. Here, we asked how mouse embryonic stem cells (ESCs) leave the pluripotent state and choose between germ layer fates. By analyzing the dynamics of the transcriptional circuit that maintains pluripotency, we found that Oct4 and Sox2, proteins that maintain ESC identity, also orchestrate germ layer fate selection. Oct4 suppresses neural ectodermal differentiation and promotes mesendodermal differentiation; Sox2 inhibits mesendodermal differentiation and promotes neural ectodermal differentiation. Differentiation signals continuously and asymmetrically modulate Oct4 and Sox2 protein levels, altering their binding pattern in the genome, and leading to cell fate choice. The same factors that maintain pluripotency thus also integrate external signals and control lineage selection. Our study provides a framework for understanding how complex transcription factor networks control cell fate decisions in progenitor cells.", "date": "2011-06-10", "date_type": "published", "publication": "Cell", "volume": "145", "number": "6", "publisher": "Elsevier", "pagerange": "875-889", "id_number": "CaltechAUTHORS:20170127-224411366", "issn": "0092-8674", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170127-224411366", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "P50-NS40828" }, { "agency": "NIH", "grant_number": "P30-HD18655" } ] }, "doi": "10.1016/j.cell.2011.05.017", "primary_object": { "basename": "PIIS0092867411005435.pdf", "url": "https://authors.library.caltech.edu/records/yedxt-2ne26/files/PIIS0092867411005435.pdf" }, "related_objects": [ { "basename": "mmc1.pdf", "url": "https://authors.library.caltech.edu/records/yedxt-2ne26/files/mmc1.pdf" } ], "resource_type": "article", "pub_year": "2011", "author_list": "Thomson, Matt; Liu, Siyuan John; et el." }, { "id": "https://authors.library.caltech.edu/records/jt54h-2yp89", "eprint_id": 74108, "eprint_status": "archive", "datestamp": "2023-08-19 00:54:39", "lastmod": "2024-03-05 18:30:03", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matthew" }, "orcid": "0000-0003-1021-1234" }, { "id": "Gunawardena-J", "name": { "family": "Gunawardena", "given": "Jeremy" } } ] }, "title": "The rational parameterisation theorem for multisite post-translational modification systems", "ispublished": "pub", "full_text_status": "public", "keywords": "Algebraic geometry, King\u2013Altman, Matrix-Treetheorem, Multisite PTM, Rational variety, Systems biology", "note": "\u00a9 2009 Elsevier Ltd. \n\nReceived 30 May 2009. Accepted 3 September 2009. Available online 16 September 2009. \n\nThe research undertaken here was supported in part by NIH under Grant R01-GM081578. We thank Bernd Sturmfels for pointing us to the Matrix-Tree theorem, Alicia Dickenstein for many stimulating scientific discussions and the Statistical and Applied Mathematical Sciences Institute (SAMSI) for supporting an extended visit by J.G. to the Program on Algebraic Methods in Systems Biology and Statistics, during which this paper was drafted.\n\nAccepted Version - nihms146463.pdf
", "abstract": "Post-translational modification of proteins plays a central role in cellular regulation but its study has been hampered by the exponential increase in substrate modification forms (\"modforms\") with increasing numbers of sites. We consider here biochemical networks arising from post-translational modification under mass-action kinetics, allowing for multiple substrates, having different types of modification (phosphorylation, methylation, acetylation, etc.) on multiple sites, acted upon by multiple forward and reverse enzymes (in total number L), using general enzymatic mechanisms. These assumptions are substantially more general than in previous studies. We show that the steady-state modform concentrations constitute an algebraic variety that can be parameterised by rational functions of the L free enzyme concentrations, with coefficients which are rational functions of the rate constants. The parameterisation allows steady states to be calculated by solving L algebraic equations, a dramatic reduction compared to simulating an exponentially large number of differential equations. This complexity collapse enables analysis in contexts that were previously intractable and leads to biological predictions that we review. Our results lay a foundation for the systems biology of post-translational modification and suggest deeper connections between biochemical networks and algebraic geometry.", "date": "2009-12-21", "date_type": "published", "publication": "Journal of Theoretical Biology", "volume": "261", "number": "4", "publisher": "Elsevier", "pagerange": "626-636", "id_number": "CaltechAUTHORS:20170206-154848264", "issn": "0022-5193", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170206-154848264", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01-GM081578" }, { "agency": "Statistical and Applied Mathematical Sciences Institute (SAMSI)" } ] }, "collection": "CaltechAUTHORS", "doi": "10.1016/j.jtbi.2009.09.003", "pmcid": "PMC2800989", "primary_object": { "basename": "nihms146463.pdf", "url": "https://authors.library.caltech.edu/records/jt54h-2yp89/files/nihms146463.pdf" }, "resource_type": "article", "pub_year": "2009", "author_list": "Thomson, Matthew and Gunawardena, Jeremy" }, { "id": "https://authors.library.caltech.edu/records/q50de-jv517", "eprint_id": 74109, "eprint_status": "archive", "datestamp": "2023-08-20 02:16:25", "lastmod": "2023-10-24 22:06:51", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matthew" } }, { "id": "Gunawardena-J", "name": { "family": "Gunawardena", "given": "Jeremy" } } ] }, "title": "Unlimited multistability in multisite phosphorylation systems", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2009 Macmillan Publishers Limited. \n\nReceived 10 November 2008; accepted 24 April 2009. Published online 17 June 2009. \n\nThis work was supported in part by the NIH under grant R01-GM081578. We thank A. Manrai for scientific discussions, R. Ward for editorial help and HMS RITG for support with cluster computing. We acknowledge the encouragement of the late Stephen Thomson (1946\u20132006) and Charles Gunawardena (1929\u20132007).\n\nAccepted Version - nihms-184849.pdf
Supplemental Material - nature08102-s1.pdf
", "abstract": "Reversible phosphorylation on serine, threonine and tyrosine is the most widely studied posttranslational modification of proteins (1, 2). The number of phosphorylated sites on a protein (n) shows a significant increase from prokaryotes, with n less than or equal to 7 sites, to eukaryotes, with examples having n greater than or equal to 150 sites (3). Multisite phosphorylation has many roles (4, 5) and site conservation indicates that increasing numbers of sites cannot be due merely to promiscuous phosphorylation. A substrate with n sites has an exponential number (2^n) of phospho-forms and individual phospho-forms may have distinct biological effects (6, 7). The distribution of these phospho-forms and how this distribution is regulated have remained unknown. Here we show that, when kinase and phosphatase act in opposition on a multisite substrate, the system can exhibit distinct stable phospho-form distributions at steady state and that the maximum number of such distributions increases with n. Whereas some stable distributions are focused on a single phospho-form, others are more diffuse, giving the phospho-proteome the potential to behave as a fluid regulatory network able to encode information and flexibly respond to varying demands. Such plasticity may underlie complex information processing in eukaryotic cells (8) and suggests a functional advantage in having many sites. Our results follow from the unusual geometry of the steady-state phospho-form concentrations, which we show to constitute a rational algebraic curve, irrespective of n. We thereby reduce the complexity of calculating steady states from simulating 3 times 2^n differential equations to solving two algebraic equations, while treating parameters symbolically. We anticipate that these methods can be extended to systems with multiple substrates and multiple enzymes catalysing different modifications, as found in posttranslational modification 'codes' (9) such as the histone code (10, 11). Whereas simulations struggle with exponentially increasing molecular complexity, mathematical methods of the kind developed here can provide a new language in which to articulate the principles of cellular information processing (12).", "date": "2009-07-09", "date_type": "published", "publication": "Nature", "volume": "460", "number": "7252", "publisher": "Nature Publishing Group", "pagerange": "274-277", "id_number": "CaltechAUTHORS:20170206-154848538", "issn": "0028-0836", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170206-154848538", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "NIH", "grant_number": "R01GM081578" }, { "agency": "Harvard Medical School" } ] }, "doi": "10.1038/nature08102", "pmcid": "PMC2859978", "primary_object": { "basename": "nature08102-s1.pdf", "url": "https://authors.library.caltech.edu/records/q50de-jv517/files/nature08102-s1.pdf" }, "related_objects": [ { "basename": "nihms-184849.pdf", "url": "https://authors.library.caltech.edu/records/q50de-jv517/files/nihms-184849.pdf" } ], "resource_type": "article", "pub_year": "2009", "author_list": "Thomson, Matthew and Gunawardena, Jeremy" }, { "id": "https://authors.library.caltech.edu/records/222s0-j1978", "eprint_id": 74110, "eprint_status": "archive", "datestamp": "2023-08-21 21:00:32", "lastmod": "2023-10-24 22:06:56", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Mallavarapu-A", "name": { "family": "Mallavarapu", "given": "Aneil" } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matthew" } }, { "id": "Ullian-B", "name": { "family": "Ullian", "given": "Benjamin" } }, { "id": "Gunawardena-J", "name": { "family": "Gunawardena", "given": "Jeremy" } } ] }, "title": "Programming with models: modularity and abstraction provide powerful capabilities for systems biology", "ispublished": "pub", "full_text_status": "public", "keywords": "model building; systems biology; modularity; abstraction", "note": "\u00a9 2008 The Royal Society. \n\nReceived May 15, 2008. Accepted June 20, 2008. \n\nWe are grateful to the Bauer Center for Genomics Research and to Craig Muir for support during the initial phase of this work. We thank, especially, Steve Harrison, Ed Harlow, Marc Kirschner and Rebecca Ward of the Harvard Medical School for enabling this work to come to fruition through their support for the Virtual Cell Program. We thank Peter Lawrence for the Drosophila image in figure 6a, Radhika Nagpal for access to material in press, David Young for his open source implementation of LISA and Dave Fox of LispWorks for his assistance with the Lisp environment. We thank Carl Pabo, Brian Seed and Rebecca Ward for their insightful comments and the other members of the Virtual Cell Program for their assistance. The authors declare that they have no competing financial interests.\n\nAccepted Version - rsif20080205.pdf
", "abstract": "Mathematical models are increasingly used to understand how phenotypes emerge from systems of molecular interactions. However, their current construction as monolithic sets of equations presents a fundamental barrier to progress. Overcoming this requires modularity, enabling sub-systems to be specified independently and combined incrementally, and abstraction, enabling generic properties of biological processes to be specified independently of specific instances. These, in turn, require models to be represented as programs rather than as datatypes. Programmable modularity and abstraction enables libraries of modules to be created, which can be instantiated and reused repeatedly in different contexts with different components. We have developed a computational infrastructure that accomplishes this. We show here why such capabilities are needed, what is required to implement them and what can be accomplished with them that could not be done previously.", "date": "2009-03-06", "date_type": "published", "publication": "Journal of the Royal Society Interface", "volume": "6", "number": "32", "publisher": "The Royal Society", "pagerange": "257-270", "id_number": "CaltechAUTHORS:20170206-154848804", "issn": "1742-5689", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170206-154848804", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "doi": "10.1098/rsif.2008.0205", "pmcid": "PMC2659579", "primary_object": { "basename": "rsif20080205.pdf", "url": "https://authors.library.caltech.edu/records/222s0-j1978/files/rsif20080205.pdf" }, "resource_type": "article", "pub_year": "2009", "author_list": "Mallavarapu, Aneil; Thomson, Matthew; et el." }, { "id": "https://authors.library.caltech.edu/records/0pa0n-jye66", "eprint_id": 74406, "eprint_status": "archive", "datestamp": "2023-08-19 22:38:21", "lastmod": "2023-10-24 22:36:24", "type": "article", "metadata_visibility": "show", "creators": { "items": [ { "id": "Ben-Porath-I", "name": { "family": "Ben-Porath", "given": "Ittai" } }, { "id": "Thomson-M-W", "name": { "family": "Thomson", "given": "Matthew W." } }, { "id": "Carey-V-J", "name": { "family": "Carey", "given": "Vincent J." } }, { "id": "Ge-Ruping", "name": { "family": "Ge", "given": "Ruping" } }, { "id": "Bell-G-W", "name": { "family": "Bell", "given": "George W." } }, { "id": "Regev-A", "name": { "family": "Regev", "given": "Aviv" }, "orcid": "0000-0003-3293-3158" }, { "id": "Weinberg-R-A", "name": { "family": "Weinberg", "given": "Robert A." } } ] }, "title": "An embryonic stem cell\u2013like gene expression signature in poorly differentiated aggressive human tumors", "ispublished": "pub", "full_text_status": "public", "note": "\u00a9 2008 Nature Publishing Group. \n\nWe thank C. Fan and C. Perou for assistance with the intrinsic subtype classification and the proliferation cluster, J. Foekens for tumor data, K. Gurdziel and J. Rodriguez for bioinformatics assistance, and Y. Dor, T. Brummelkamp, W. Guo, H. Cedar, N. Friedman and E. Pikarsky for reviewing of the manuscript and helpful discussions. I.B.-P. is a Leukemia and Lymphoma Special Fellow; V.J.C. was supported in part by NIH P41 HG 004059 and in part by the Whitehead Institute Bioinformatics Department; A.R. is supported by the Burroughs Wellcome Career Award at the Scientific Interface; R.A.W. is supported by US National Institutes of Health/National Cancer Institute grant R01 CA078461, the Breast Cancer Research Foundation and the Ludwig Cancer Center for Molecular Oncology at the Massachusetts Institute of Technology. \n\nAuthor Contributions: I.B.-P. conceived the study, collected and processed datasets, performed gene set expression analyses and wrote the manuscript. M.W.T. contributed to the design of the study, collected and processed many of the datasets and performed multiple analyses including gene set expression and nearest neighbor. V.J.C. supervised the statistical aspects of the study and performed the patient survival analyses. R.G. and G.W.B. processed datasets and performed various analyses, including transcription factor clustering and gene function assignment; G.W.B. set up the study website. A.R. designed the study together with I.B.-P., provided the analytical framework, supervised the analyses and reviewed the manuscript. R.A.W. contributed to the conception of the study, provided guidance and supervision of study design and goals and assisted in the writing of the manuscript.\n\nAccepted Version - nihms214217.pdf
Supplemental Material - ng.127-S1.pdf
Supplemental Material - ng.127-S2.xls
Supplemental Material - ng.127-S3.xls
Supplemental Material - ng.127-S4.xls
Supplemental Material - ng.127-S5.xls
Supplemental Material - ng.127-S6.xls
", "abstract": "Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear, however, whether these phenotypic similarities reflect the activity of common molecular pathways. Here, we analyze the enrichment patterns of gene sets associated with embryonic stem (ES) cell identity in the expression profiles of various human tumor types. We find that histologically poorly differentiated tumors show preferential overexpression of genes normally enriched in ES cells, combined with preferential repression of Polycomb-regulated genes. Moreover, activation targets of Nanog, Oct4, Sox2 and c-Myc are more frequently overexpressed in poorly differentiated tumors than in well-differentiated tumors. In breast cancers, this ES-like signature is associated with high-grade estrogen receptor (ER)-negative tumors, often of the basal-like subtype, and with poor clinical outcome. The ES signature is also present in poorly differentiated glioblastomas and bladder carcinomas. We identify a subset of ES cell-associated transcription regulators that are highly expressed in poorly differentiated tumors. Our results reveal a previously unknown link between genes associated with ES cell identity and the histopathological traits of tumors and support the possibility that these genes contribute to stem cell\u2013like phenotypes shown by many tumors.", "date": "2008-05", "date_type": "published", "publication": "Nature Genetics", "volume": "40", "number": "5", "publisher": "Nature Publishing Group", "pagerange": "499-507", "id_number": "CaltechAUTHORS:20170217-132836548", "issn": "1061-4036", "official_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170217-132836548", "rights": "No commercial reproduction, distribution, display or performance rights in this work are provided.", "funders": { "items": [ { "agency": "Leukemia and Lymphoma Society" }, { "agency": "NIH", "grant_number": "P41HG004059" }, { "agency": "Whitehead Institute" }, { "agency": "Burroughs Wellcome Fund" }, { "agency": "NIH", "grant_number": "R01CA078461" }, { "agency": "Breast Cancer Research Foundation" }, { "agency": "Massachusetts Institute of Technology (MIT)" } ] }, "doi": "10.1038/ng.127", "pmcid": "PMC2912221", "primary_object": { "basename": "nihms214217.pdf", "url": "https://authors.library.caltech.edu/records/0pa0n-jye66/files/nihms214217.pdf" }, "related_objects": [ { "basename": "ng.127-S1.pdf", "url": "https://authors.library.caltech.edu/records/0pa0n-jye66/files/ng.127-S1.pdf" }, { "basename": "ng.127-S2.xls", "url": "https://authors.library.caltech.edu/records/0pa0n-jye66/files/ng.127-S2.xls" }, { "basename": "ng.127-S3.xls", "url": "https://authors.library.caltech.edu/records/0pa0n-jye66/files/ng.127-S3.xls" }, { "basename": "ng.127-S4.xls", "url": "https://authors.library.caltech.edu/records/0pa0n-jye66/files/ng.127-S4.xls" }, { "basename": "ng.127-S5.xls", "url": "https://authors.library.caltech.edu/records/0pa0n-jye66/files/ng.127-S5.xls" }, { "basename": "ng.127-S6.xls", "url": "https://authors.library.caltech.edu/records/0pa0n-jye66/files/ng.127-S6.xls" } ], "resource_type": "article", "pub_year": "2008", "author_list": "Ben-Porath, Ittai; Thomson, Matthew W.; et el." } ]