Suchergebnisse

Lymph node stromal cells (LNSCs) closely regulate immunity and self-tolerance, yet key aspects of their biology remain poorly elucidated. Here, comparative transcriptomic analyses of mouse LNSC subsets demonstrated the expression of important immune mediators, growth factors and previously unknown structural components. Pairwise analyses of ligands and cognate receptors across hematopoietic and stromal subsets suggested a complex web of crosstalk. Fibroblastic reticular cells (FRCs) showed enrichment for higher expression of genes relevant to cytokine signaling, relative to their expression in skin and thymic fibroblasts. LNSCs from inflamed lymph nodes upregulated expression of genes encoding chemokines and molecules involved in the acute-phase response and the antigen-processing and antigen-presentation machinery. Poorly studied podoplanin (gp38)-negative CD31− LNSCs showed similarities to FRCs but lacked expression of interleukin 7 (IL-7) and were identified as myofibroblastic pericytes that expressed integrin α7. Together our data comprehensively describe the transcriptional characteristics of LNSC subsets. ; National Institutes of Health (U.S.) (grant R01 DK074500) ; National Institutes of Health (U.S.) (grant P01 AI045757) ; National Institutes of Health (U.S.) (grant R24 AI072073) ; National Institutes of Health (U.S.) (grant R01 AI063428-06) ; National Institutes of Health (U.S.) (grant R01 DE019917) ; National Institutes of Health (U.S.) (grant GM38903) ; Dana-Farber Cancer Institute ; Seventh Framework Programme of the European Union (Marie Curie International Outgoing Fellowship 220044)

The ongoing pandemic of SARS-CoV-2, a novel coronavirus, caused over 3 million reported cases of coronavirus disease 2019 (COVID-19) and 200,000 reported deaths between December 2019 and April 2020(1). Cases and deaths will increase as the virus continues its global march outward. In the absence of effective pharmaceutical interventions or a vaccine, wide-spread virological screening is required to inform where restrictive isolation measures should be targeted and when they can be lifted(2–6). However, limitations on testing capacity have restricted the ability of governments and institutions to identify individual clinical cases, appropriately measure community prevalence, and mitigate transmission. Group testing offers a way to increase efficiency, by combining samples and testing a small number of pools(7–9). Here, we evaluate the effectiveness of group testing designs for individual identification or prevalence estimation of SARS-CoV-2 infection when testing capacity is limited. To do this, we developed mathematical models for epidemic spread, incorporating empirically measured individual-level viral kinetics to simulate changing viral loads in a large population over the course of an epidemic. We used these to construct representative populations and assess pooling strategies for community screening, accounting for variability in viral load samples, dilution effects, changing prevalence and resource constraints. We confirmed our group testing framework through pooled tests on de-identified human nasopharyngeal specimens with viral loads representative of the larger population. We show that group testing designs can both accurately estimate overall prevalence using a small number of measurements and substantially increase the identification rate of infected individuals in resource-limited settings.

Human organoids – three-dimensional structures of cells that recapitulate important aspects of organ development in vitro – hold tremendous potential for biomedical applications. To help deliver on the promises of combining human organoids with single-cell technology, we have launched an Organoid Cell Atlas pilot project, as a 'Biological Network' within the Human Cell Atlas (HCA), focusing on single-cell profiling of organoids and in vitro cell models (https://www.humancellatlas.org/coordinators/). The Organoid Cell Atlas will foster the production, quality control, dissemination, and utilization of single-cell and spatial genomics data for human organoids, and it will connect such datasets with the comprehensive profiles of primary tissue that are being generated within the HCA. A first step toward establishing the Organoid Cell Atlas has recently been funded by the European Union Horizon 2020 call for "Pilot actions to build the foundations of a human cell atlas" through the "HCA|Organoid" project (http://hca-organoid.eu/). This preprint outlines the rationale for combining human organoids with single-cell technology and the concrete plans for established the Organoid Cell Atlas as a Rosetta Stone for biomedical discovery and regenerative therapy.

Gut dysmotility is associated with constipation, diarrhea, and functional gastrointestinal disorders like irritable bowel syndrome (IBS), although its molecular underpinnings are poorly characterized. We studied stool frequency (defined by the number of bowel movements per day, based on questionnaire data) as a proxy for gut motility in a GWAS meta-analysis including 167,875 individuals from UK Biobank and four smaller population-based cohorts. We identify 14 loci associated with stool frequency (p = 5.0 × 10-8). Gene set and pathway analyses detected enrichment for genes involved in neurotransmitter/neuropeptide signaling and preferentially expressed in enteric motor neurons controlling peristalsis. PheWAS identified pleiotropic associations with dysmotility syndromes and the response to their pharmacological treatment. The genetic architecture of stool frequency correlates with that of IBS, and UK Biobank participants from the top 1% of stool frequency polygenic score distribution were associated with 5× higher risk of IBS with diarrhea. These findings pave the way for the identification of actionable pathological mechanisms in IBS and the dysmotility syndromes. ; Funding agencies: he Swedish Research Council (VR 2017-02403), the Health Department of the Basque Government (2015111133), and the Spanish Ministry of Economy and Competitiveness (FIS PI17/00308) to M.D.; the research leading to these results has received funding from the EU FP7 under grant nr. 313010 (BBMRI-LPC); the FGFP project received support from the Flemish government (IWT130359), the Research Fund–Flanders (FWO) Odysseus program (G.0924.09), the King Baudouin Foundation (2012-J80000-004), FP7 METACARDIS HEALTH-F4-2012-305312, VIB, the Rega Institute for Medical Research, and KU Leuven. R.B. is funded by the Research Fund–Flanders (FWO) through a postdoctoral fellowship (1221620N). A.Z. is supported by the ERC Starting Grant 715772, Netherlands Organization for Scientific Research NWO-VIDI grant 016.178.056, the Netherlands Heart Foundation ...