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The impacts of individual commensal microbes on immunity and disease can differ dramatically depending on the surrounding microbial context; however, the specific bacterial combinations that dictate divergent immunological outcomes remain largely undefined. Here, we characterize an immunostimulatory Allobaculum species from an inflammatory bowel disease patient that exacerbates colitis in gnotobiotic mice. Allobaculum inversely associates with the taxonomically divergent immunostimulatory species Akkermansia muciniphila in human-microbiota-associated mice and human cohorts. Co-colonization with A. muciniphila ameliorates Allobaculum -induced intestinal epithelial cell activation and colitis in mice, whereas Allobaculum blunts the A.muciniphila -specific systemic antibody response and reprograms the immunological milieu in mesenteric lymph nodes by blocking A.muciniphila -induced dendritic cell activation and T cell expansion. These studies thus identify a pairwise reciprocal interaction between human gut bacteria that dictates divergent immunological outcomes. Furthermore, they establish a generalizable framework to define the contextual cues contributing to the "incomplete penetrance" of microbial impacts on human disease. [Display omitted] • Allobaculum isolates from ulcerative colitis patients exacerbate colitis in mice • Immunostimulatory Allo. sp. are inversely correlated with Akkermansia muciniphila • Co-colonization uniquely alters immune responses elicited by Allo. or A. muc. alone • "Epistatic" interspecies interactions have nonlinear impacts on host immunity Microbial community context can critically alter commensal-induced immune responses. Here, Rice et al. describe a reciprocal interaction between a novel colitogenic human Allobaculum species and Akkermansia muciniphila that uniquely reprograms the immune responses elicited by either microbe alone, revealing nonlinear impacts of interspecies interactions on host immunity. [ABSTRACT FROM AUTHOR]

Summary Single-cell RNA sequencing technologies suffer from many sources of technical noise, including under-sampling of mRNA molecules, often termed “dropout,” which can severely obscure important gene-gene relationships. To address this, we developed MAGIC (Markov affinity-based graph imputation of cells), a method that shares information across similar cells, via data diffusion, to denoise the cell count matrix and fill in missing transcripts. We validate MAGIC on several biological systems and find it effective at recovering gene-gene relationships and additional structures. Applied to the epithilial to mesenchymal transition, MAGIC reveals a phenotypic continuum, with the majority of cells residing in intermediate states that display stem-like signatures, and infers known and previously uncharacterized regulatory interactions, demonstrating that our approach can successfully uncover regulatory relations without perturbations. [ABSTRACT FROM AUTHOR]

Summary: The number of applicants vastly outnumbers the available academic faculty positions. What makes a successful academic job market candidate is the subject of much current discussion [1–4]. Yet, so far there has been no quantitative analysis of who becomes a principal investigator (PI). We here use a machine-learning approach to predict who becomes a PI, based on data from over 25,000 scientists in PubMed. We show that success in academia is predictable. It depends on the number of publications, the impact factor (IF) of the journals in which those papers are published, and the number of papers that receive more citations than average for the journal in which they were published (citations/IF). However, both the scientist’s gender and the rank of their university are also of importance, suggesting that non-publication features play a statistically significant role in the academic hiring process. Our model (www.pipredictor.com) allows anyone to calculate their likelihood of becoming a PI. [Copyright &y& Elsevier]

Understanding the drivers and markers of clonally expanding HIV-1-infected CD4+ T cells is essential for HIV-1 eradication. We used single-cell ECCITE-seq, which captures surface protein expression, cellular transcriptome, HIV-1 RNA, and TCR sequences within the same single cell to track clonal expansion dynamics in longitudinally archived samples from six HIV-1-infected individuals (during viremia and after suppressive antiretroviral therapy) and two uninfected individuals, in unstimulated conditions and after CMV and HIV-1 antigen stimulation. Despite antiretroviral therapy, persistent antigen and TNF responses shaped T cell clonal expansion. HIV-1 resided in Th1-polarized, antigen-responding T cells expressing BCL2 and SERPINB9 that may resist cell death. HIV-1 RNA+ T cell clones were larger in clone size, established during viremia, persistent after viral suppression, and enriched in GZMB + cytotoxic effector memory Th1 cells. Targeting HIV-1-infected cytotoxic CD4+ T cells and drivers of clonal expansion provides another direction for HIV-1 eradication. [Display omitted] • Most HIV-1 RNA+ T cell clones are large, stable, GZMB + cytotoxic effector memory Th1s • Some HIV-1 RNA+ cells express SERPINB9 and may be shielded from CD8+ T cell killing • Antigen stimulation, TNF, and cytotoxic T cell responses determine T cell clone size • Early ART cannot fully reduce chronic immune activation, and TNF responses persist Using single-cell ECCITE-seq, Collora et al. profiled 267 HIV-1 RNA+ cells and 68 expanded HIV-1 RNA+ T cell clones from 215,458 CD4+ T cells. HIV-1 resides in GZMB + cytotoxic Th1 effector memory CD4+ T cell clones that are large and persistent. HIV-1-infected cytotoxic CD4+ T cells may evade cytotoxic CD8+ T cell killing through Seprin B9 degradation of granzyme B. [ABSTRACT FROM AUTHOR]

Neurodegeneration is a protracted process involving progressive changes in myriad cell types that ultimately results in the death of vulnerable neuronal populations. To dissect how individual cell types within a heterogeneous tissue contribute to the pathogenesis and progression of a neurodegenerative disorder, we performed longitudinal single-nucleus RNA sequencing of mouse and human spinocerebellar ataxia type 1 (SCA1) cerebellar tissue, establishing continuous dynamic trajectories of each cell population. Importantly, we defined the precise transcriptional changes that precede loss of Purkinje cells and, for the first time, identified robust early transcriptional dysregulation in unipolar brush cells and oligodendroglia. Finally, we applied a deep learning method to predict disease state accurately and identified specific features that enable accurate distinction of wild-type and SCA1 cells. Together, this work reveals new roles for diverse cerebellar cell types in SCA1 and provides a generalizable analysis framework for studying neurodegeneration., Competing Interests: Declaration of interests S.W. is an inventor on a patent applied for by Harvard University related to MERFISH and a consultant and shareholder of Translura, Inc., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening post-infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV-2 infection. We profiled MIS-C, adult COVID-19, and healthy pediatric and adult individuals using single-cell RNA sequencing, flow cytometry, antigen receptor repertoire analysis, and unbiased serum proteomics, which collectively identified a signature in MIS-C patients that correlated with disease severity. Despite having no evidence of active infection, MIS-C patients had elevated S100A-family alarmins and decreased antigen presentation signatures, indicative of myeloid dysfunction. MIS-C patients showed elevated expression of cytotoxicity genes in NK and CD8 + T cells and expansion of specific IgG-expressing plasmablasts. Clinically severe MIS-C patients displayed skewed memory T cell TCR repertoires and autoimmunity characterized by endothelium-reactive IgG. The alarmin, cytotoxicity, TCR repertoire, and plasmablast signatures we defined have potential for application in the clinic to better diagnose and potentially predict disease severity early in the course of MIS-C., Competing Interests: Declaration of interests D.A.H. has received research funding from Bristol-Myers Squibb, Novartis, Sanofi, and Genentech. He has been a consultant for Bayer Pharmaceuticals, Bristol Myers Squibb, Compass Therapeutics, EMD Serono, Genentech, Juno Therapeutics, Novartis Pharmaceuticals, Proclara Biosciences, Sage Therapeutics, and Sanofi Genzyme. Further information regarding funding is available on: https://openpaymentsdata.cms.gov/physician/166753/general-payments. N.K. reports personal fees from Boehringer Ingelheim, Third Rock, Pliant, Samumed, NuMedii, Indalo, Theravance, LifeMax, Three Lake Partners, RohBar in the last 36 months, and Equity in Pliant. N.K. is also a recipient of a grant from Veracyte and non-financial support from Miragen. All outside the submitted work; In addition, N.K. has patents on New Therapies in Pulmonary Fibrosis and ARDS (unlicensed) and Peripheral Blood Gene Expression as biomarkers in IPF (licensed to biotech). S.H.K. receives consulting fees from Northrop Grumman. K.B.H. receives consulting fees from Prellis Biologics. B.S. is a former SomaLogic, Inc. (Boulder, CO, USA) employee and a company shareholder. All other authors declared that they have no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Identification of host genes essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may reveal novel therapeutic targets and inform our understanding of coronavirus disease 2019 (COVID-19) pathogenesis. Here we performed genome-wide CRISPR screens in Vero-E6 cells with SARS-CoV-2, Middle East respiratory syndrome CoV (MERS-CoV), bat CoV HKU5 expressing the SARS-CoV-1 spike, and vesicular stomatitis virus (VSV) expressing the SARS-CoV-2 spike. We identified known SARS-CoV-2 host factors, including the receptor ACE2 and protease Cathepsin L. We additionally discovered pro-viral genes and pathways, including HMGB1 and the SWI/SNF chromatin remodeling complex, that are SARS lineage and pan-coronavirus specific, respectively. We show that HMGB1 regulates ACE2 expression and is critical for entry of SARS-CoV-2, SARS-CoV-1, and NL63. We also show that small-molecule antagonists of identified gene products inhibited SARS-CoV-2 infection in monkey and human cells, demonstrating the conserved role of these genetic hits across species. This identifies potential therapeutic targets for SARS-CoV-2 and reveals SARS lineage-specific and pan-CoV host factors that regulate susceptibility to highly pathogenic CoVs., Competing Interests: Declaration of Interests Yale University (C.B.W.) has a patent pending related to this work entitled “Compounds and Compositions for Treating, Ameliorating, and/or Preventing SARS-CoV-2 Infection and/or Complications Thereof.” Yale University has committed to rapidly executable non-exclusive royalty-free licenses to intellectual property rights for the purpose of making and distributing products to prevent, diagnose, and treat COVID-19 infection during the pandemic and for a short period thereafter. J.G.D. consults for Foghorn Therapeutics, Maze Therapeutics, Merck, Agios, and Pfizer. J.G.D. consults for and has equity in Tango Therapeutics. C.K. is the Scientific Founder, Board of Directors member, Scientific Advisory Board member, shareholder, and consultant for Foghorn Therapeutics, Inc. (Cambridge, MA)., (Copyright © 2020 Elsevier Inc. All rights reserved.)