Comment on Cell. 2021 Apr 29;184(9):2454-2470.e26.

Comment in Dev Cell. 2021 Apr 19;56(8):1077-1079. Nat Rev Cancer. 2021 Jul;21(7):411.

Precision oncology has made significant advances, mainly by targeting actionable mutations in cancer driver genes. Aiming to expand treatment opportunities, recent studies have begun to explore the utility of tumor transcriptome to guide patient treatment. Here, we introduce SELECT (synthetic lethality and rescue-mediated precision oncology via the transcriptome), a precision oncology framework harnessing genetic interactions to predict patient response to cancer therapy from the tumor transcriptome. SELECT is tested on a broad collection of 35 published targeted and immunotherapy clinical trials from 10 different cancer types. It is predictive of patients' response in 80% of these clinical trials and in the recent multi-arm WINTHER trial. The predictive signatures and the code are made publicly available for academic use, laying a basis for future prospective clinical studies.

Comment in Cell. 2021 Apr 29;184(9):2281-2283.

Animals have co-evolved with a vast diversity of microorganisms, collectively named the microbiome, which are important modulators of host gastrointestinal, immune, metabolic, and behavioral functions. In this SnapShot, we provide an overview of the neurodevelopmental and functional influence of host-microbial interactions in the "microbiota-gut-brain axis," which refers to the bidirectional communication between the central nervous system and the gastrointestinal microbiome. To view this SnapShot, open or download the PDF.

Comment on Cell. 2021 Apr 29;184(9):2394-2411.e16.

Comment in Cell. 2021 Apr 29;184(9):2278-2281.

Comment in Cell Host Microbe. 2021 May 12;29(5):744-746.

Erratum in Cell. 2021 Apr 29;184(9):2523.

Comment in Cell. 2021 Apr 29;184(9):2276-2278.

The race to produce vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began when the first sequence was published, and this forms the basis for vaccines currently deployed globally. Independent lineages of SARS-CoV-2 have recently been reported: UK, B.1.1.7; South Africa, B.1.351; and Brazil, P.1. These variants have multiple changes in the immunodominant spike protein that facilitates viral cell entry via the angiotensin-converting enzyme-2 (ACE2) receptor. Mutations in the receptor recognition site on the spike are of great concern for their potential for immune escape. Here, we describe a structure-function analysis of B.1.351 using a large cohort of convalescent and vaccinee serum samples. The receptor-binding domain mutations provide tighter ACE2 binding and widespread escape from monoclonal antibody neutralization largely driven by E484K, although K417N and N501Y act together against some important antibody classes. In a number of cases, it would appear that convalescent and some vaccine serum offers limited protection against this variant.

Parent scientists lead a journey to bring surveillance severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing to public schools across the state of Massachusetts and beyond.

Comment in Cell. 2021 Apr 29;184(9):2261-2262.

Comment in J Cell Biol. 2021 Jun 7;220(6):

A fundamental challenge in synthetic biology is to create molecular circuits that can program complex cellular functions. Because proteins can bind, cleave, and chemically modify one another and interface directly and rapidly with endogenous pathways, they could extend the capabilities of synthetic circuits beyond what is possible with gene regulation alone. However, the very diversity that makes proteins so powerful also complicates efforts to harness them as well-controlled synthetic circuit components. Recent work has begun to address this challenge, focusing on principles such as orthogonality and composability that permit construction of diverse circuit-level functions from a limited set of engineered protein components. These approaches are now enabling the engineering of circuits that can sense, transmit, and process information; dynamically control cellular behaviors; and enable new therapeutic strategies, establishing a powerful paradigm for programming biology.

By following up the gut microbiome, 51 human phenotypes and plasma levels of 1,183 metabolites in 338 individuals after 4 years, we characterize microbial stability and variation in relation to host physiology. Using these individual-specific and temporally stable microbial profiles, including bacterial SNPs and structural variations, we develop a microbial fingerprinting method that shows up to 85% accuracy in classifying metagenomic samples taken 4 years apart. Application of our fingerprinting method to the independent HMP cohort results in 95% accuracy for samples taken 1 year apart. We further observe temporal changes in the abundance of multiple bacterial species, metabolic pathways, and structural variation, as well as strain replacement. We report 190 longitudinal microbial associations with host phenotypes and 519 associations with plasma metabolites. These associations are enriched for cardiometabolic traits, vitamin B, and uremic toxins. Finally, mediation analysis suggests that the gut microbiome may influence cardiometabolic health through its metabolites.

Genomically minimal cells, such as JCVI-syn3.0, offer a platform to clarify genes underlying core physiological processes. Although this minimal cell includes genes essential for population growth, the physiology of its single cells remained uncharacterized. To investigate striking morphological variation in JCVI-syn3.0 cells, we present an approach to characterize cell propagation and determine genes affecting cell morphology. Microfluidic chemostats allowed observation of intrinsic cell dynamics that result in irregular morphologies. A genome with 19 genes not retained in JCVI-syn3.0 generated JCVI-syn3A, which presents morphology similar to that of JCVI-syn1.0. We further identified seven of these 19 genes, including two known cell division genes, ftsZ and sepF, a hydrolase of unknown substrate, and four genes that encode membrane-associated proteins of unknown function, which are required together to restore a phenotype similar to that of JCVI-syn1.0. This result emphasizes the polygenic nature of cell division and morphology in a genomically minimal cell.

The scientific world rewards the individual while often discouraging collaboration. However, times of crisis show us how much more we can accomplish when we work together. Here, we describe our approach to breaking down silos and fostering global collaborations and share the lessons we have learned, especially pertaining to research on SARS-CoV-2.

Comment in Signal Transduct Target Ther. 2021 Jul 27;6(1):284.

Comment on Cell. 2021 Apr 29;184(9):2503-2519.e17.

The global spread of SARS-CoV-2/COVID-19 is devastating health systems and economies worldwide. Recombinant or vaccine-induced neutralizing antibodies are used to combat the COVID-19 pandemic. However, the recently emerged SARS-CoV-2 variants B.1.1.7 (UK), B.1.351 (South Africa), and P.1 (Brazil) harbor mutations in the viral spike (S) protein that may alter virus-host cell interactions and confer resistance to inhibitors and antibodies. Here, using pseudoparticles, we show that entry of all variants into human cells is susceptible to blockade by the entry inhibitors soluble ACE2, Camostat, EK-1, and EK-1-C4. In contrast, entry of the B.1.351 and P.1 variant was partially (Casirivimab) or fully (Bamlanivimab) resistant to antibodies used for COVID-19 treatment. Moreover, entry of these variants was less efficiently inhibited by plasma from convalescent COVID-19 patients and sera from BNT162b2-vaccinated individuals. These results suggest that SARS-CoV-2 may escape neutralizing antibody responses, which has important implications for efforts to contain the pandemic.

Comment in Cell Host Microbe. 2021 May 12;29(5):744-746.

Comment in Cell Host Microbe. 2021 May 12;29(5):675-677.

Comment in Cell. 2021 Apr 15;184(8):1943-1944.

The α7 nicotinic acetylcholine receptor plays critical roles in the central nervous system and in the cholinergic inflammatory pathway. This ligand-gated ion channel assembles as a homopentamer, is exceptionally permeable to Ca2+, and desensitizes faster than any other Cys-loop receptor. The α7 receptor has served as a prototype for the Cys-loop superfamily yet has proven refractory to structural analysis. We present cryo-EM structures of the human α7 nicotinic receptor in a lipidic environment in resting, activated, and desensitized states, illuminating the principal steps in the gating cycle. The structures also reveal elements that contribute to its function, including a C-terminal latch that is permissive for channel opening, and an anionic ring in the extracellular vestibule that contributes to its high conductance and calcium permeability. Comparisons among the α7 structures provide a foundation for mapping the gating cycle and reveal divergence in gating mechanisms in the Cys-loop receptor superfamily.

Comment on Cell. 2021 Apr 15;184(8):2151-2166.e16.

Comment on Cell. 2021 Apr 15;184(8):2084-2102.e19.

Erratum in Cell. 2021 Jul 22;184(15):4105.

The population is aging at a rate never seen before in human history. As the number of elderly adults grows, it is imperative we expand our understanding of the underpinnings of aging biology. Human lungs are composed of a unique panoply of cell types that face ongoing chemical, mechanical, biological, immunological, and xenobiotic stress over a lifetime. Yet, we do not fully appreciate the mechanistic drivers of lung aging and why age increases the risk of parenchymal lung disease, fatal respiratory infection, and primary lung cancer. Here, we review the molecular and cellular aspects of lung aging, local stress response pathways, and how the aging process predisposes to the pathogenesis of pulmonary disease. We place these insights into context of the COVID-19 pandemic and discuss how innate and adaptive immunity within the lung is altered with age.

Comment in Nat Rev Cancer. 2021 Jun;21(6):343. Nat Cancer. 2021 Dec;2(12):1284.

During cell migration or differentiation, cell surface receptors are simultaneously exposed to different ligands. However, it is often unclear how these extracellular signals are integrated. Neogenin (NEO1) acts as an attractive guidance receptor when the Netrin-1 (NET1) ligand binds, but it mediates repulsion via repulsive guidance molecule (RGM) ligands. Here, we show that signal integration occurs through the formation of a ternary NEO1-NET1-RGM complex, which triggers reciprocal silencing of downstream signaling. Our NEO1-NET1-RGM structures reveal a "trimer-of-trimers" super-assembly, which exists in the cell membrane. Super-assembly formation results in inhibition of RGMA-NEO1-mediated growth cone collapse and RGMA- or NET1-NEO1-mediated neuron migration, by preventing formation of signaling-compatible RGM-NEO1 complexes and NET1-induced NEO1 ectodomain clustering. These results illustrate how simultaneous binding of ligands with opposing functions, to a single receptor, does not lead to competition for binding, but to formation of a super-complex that diminishes their functional outputs.

Comment in Nat Rev Mol Cell Biol. 2021 May;22(5):304-305. Cell. 2021 Apr 15;184(8):1965-1967.

Comment in Cell. 2021 Apr 15;184(8):1964-1965.

Author information: (1)Cancer Genomics Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK; Big Data Institute, University of Oxford, Oxford OX3 7LF, UK. (2)Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (3)Cancer Genomics Laboratory, The Francis Crick Institute, London NW1 1AT, UK. (4)Cancer Genomics Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK. (5)University of Toronto, Toronto, ON M5S 3E1, Canada; Vector Institute, Toronto, ON M5G 1L7, Canada. (6)The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (7)Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK. (8)Cancer Genomics Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Department of Human Genetics, University of Leuven, 3000 Leuven, Belgium. (9)Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK; University of Cambridge, Cambridge CB2 0QQ, UK; Computational Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Irving Institute for Cancer Dynamics, Columbia University, New York, NY 10027, USA. (10)German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Heidelberg University, 69120 Heidelberg, Germany. (11)Cancer Data Science Laboratory, National Cancer Institute, NIH, Bethesda, MD 20892, USA. (12)Simon Fraser University, Burnaby, BC V5A 1S6, Canada; Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada. (13)NorthShore University HealthSystem, Evanston, IL 60201, USA. (14)Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97231, USA. (15)University of Melbourne, Melbourne, VIC 3010, Australia; Walter + Eliza Hall Institute, Melbourne, VIC 3000, Australia. (16)Weill Cornell Medicine, New York, NY 10065, USA; New York Genome Center, New York, NY 10013, USA. (17)Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London NW1 1AT, UK. (18)University of California, Santa Cruz, Santa Cruz, CA 95064, USA. (19)German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (20)Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK. (21)Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK; Cancer Genome Evolution Research Group, University College London Cancer Institute, London WC1E 6DD, UK. (22)Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK; Department of Medical Oncology, University College London Hospitals, London NW1 2BU, UK. (23)Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Massachusetts General Hospital Center for Cancer Research, Charlestown, MA 02129, USA; Massachusetts General Hospital, Department of Pathology, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02215, USA. (24)University of Toronto, Toronto, ON M5S 3E1, Canada; Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; University of California, Los Angeles, Los Angeles, CA 90095, USA. (25)Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Dana-Farber Cancer Institute, Boston, MA 02215, USA. (26)NorthShore University HealthSystem, Evanston, IL 60201, USA; The University of Chicago, Chicago, IL 60637, USA. (27)Department of Translational Genomics, Center for Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany. (28)Organismal and Evolutionary Biology Research Programme, Department of Computer Science, Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland. (29)Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; School of Computing Science, University of Glasgow, Glasgow G12 8RZ, UK. (30)Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK; European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Cambridge CB10 1SD, UK; European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany. (31)University of Toronto, Toronto, ON M5S 3E1, Canada; Vector Institute, Toronto, ON M5G 1L7, Canada; Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Computational and Systems Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (32)Big Data Institute, University of Oxford, Oxford OX3 7LF, UK; Oxford NIHR Biomedical Research Centre, Oxford OX4 2PG, UK; Manchester Cancer Research Centre, University of Manchester, Manchester M20 4GJ, UK. (33)Cancer Genomics Laboratory, The Francis Crick Institute, London NW1 1AT, UK. Electronic address: peter.vanloo@crick.ac.uk.

Comment in Nat Rev Cardiol. 2021 Jun;18(6):387.

Industrialization has impacted the human gut ecosystem, resulting in altered microbiome composition and diversity. Whether bacterial genomes may also adapt to the industrialization of their host populations remains largely unexplored. Here, we investigate the extent to which the rates and targets of horizontal gene transfer (HGT) vary across thousands of bacterial strains from 15 human populations spanning a range of industrialization. We show that HGTs have accumulated in the microbiome over recent host generations and that HGT occurs at high frequency within individuals. Comparison across human populations reveals that industrialized lifestyles are associated with higher HGT rates and that the functions of HGTs are related to the level of host industrialization. Our results suggest that gut bacteria continuously acquire new functionality based on host lifestyle and that high rates of HGT may be a recent development in human history linked to industrialization.

Sarcomeres are force-generating and load-bearing devices of muscles. A precise molecular picture of how sarcomeres are built underpins understanding their role in health and disease. Here, we determine the molecular architecture of native vertebrate skeletal sarcomeres by electron cryo-tomography. Our reconstruction reveals molecular details of the three-dimensional organization and interaction of actin and myosin in the A-band, I-band, and Z-disc and demonstrates that α-actinin cross-links antiparallel actin filaments by forming doublets with 6-nm spacing. Structures of myosin, tropomyosin, and actin at ~10 Å further reveal two conformations of the "double-head" myosin, where the flexible orientation of the lever arm and light chains enable myosin not only to interact with the same actin filament, but also to split between two actin filaments. Our results provide unexpected insights into the fundamental organization of vertebrate skeletal muscle and serve as a strong foundation for future investigations of muscle diseases.

Comment in Cell. 2021 Apr 15;184(8):1968-1970.

Comment in Signal Transduct Target Ther. 2021 Apr 10;6(1):151.

Comment in Nat Rev Nephrol. 2021 May;17(5):297. Br J Anaesth. 2021 Oct;127(4):e146-e148. Cell. 2022 May 26;185(11):1837-1839. Cell. 2022 May 26;185(11):1840-1841.

Erratum in Cell. 2021 Jun 24;184(13):3589.

Comment on Cell. 2021 Apr 15;184(8):2068-2083.e11.

Comment on Cell. 2021 Apr 15;184(8):2020-2032.e14.

How are individual cell behaviors coordinated toward invariant large-scale anatomical outcomes in development and regeneration despite unpredictable perturbations? Endogenous distributions of membrane potentials, produced by ion channels and gap junctions, are present across all tissues. These bioelectrical networks process morphogenetic information that controls gene expression, enabling cell collectives to make decisions about large-scale growth and form. Recent progress in the analysis and computational modeling of developmental bioelectric circuits and channelopathies reveals how cellular collectives cooperate toward organ-level structural order. These advances suggest a roadmap for exploiting bioelectric signaling for interventions addressing developmental disorders, regenerative medicine, cancer reprogramming, and synthetic bioengineering.

Antibodies are crucial to immune protection against SARS-CoV-2, with some in emergency use as therapeutics. Here, we identify 377 human monoclonal antibodies (mAbs) recognizing the virus spike and focus mainly on 80 that bind the receptor binding domain (RBD). We devise a competition data-driven method to map RBD binding sites. We find that although antibody binding sites are widely dispersed, neutralizing antibody binding is focused, with nearly all highly inhibitory mAbs (IC50 < 0.1 μg/mL) blocking receptor interaction, except for one that binds a unique epitope in the N-terminal domain. Many of these neutralizing mAbs use public V-genes and are close to germline. We dissect the structural basis of recognition for this large panel of antibodies through X-ray crystallography and cryoelectron microscopy of 19 Fab-antigen structures. We find novel binding modes for some potently inhibitory antibodies and demonstrate that strongly neutralizing mAbs protect, prophylactically or therapeutically, in animal models.

Update of bioRxiv. 2021 Jan 19;:

The central pathogen-immune interface in tuberculosis is the granuloma, a complex host immune structure that dictates infection trajectory and physiology. Granuloma macrophages undergo a dramatic transition in which entire epithelial modules are induced and define granuloma architecture. In tuberculosis, relatively little is known about the host signals that trigger this transition. Using the zebrafish-Mycobacterium marinum model, we identify the basis of granuloma macrophage transformation. Single-cell RNA-sequencing analysis of zebrafish granulomas and analysis of Mycobacterium tuberculosis-infected macaques reveal that, even in the presence of robust type 1 immune responses, countervailing type 2 signals associate with macrophage epithelialization. We find that type 2 immune signaling, mediated via stat6, is absolutely required for epithelialization and granuloma formation. In mixed chimeras, stat6 acts cell autonomously within macrophages, where it is required for epithelioid transformation and incorporation into necrotic granulomas. These findings establish the signaling pathway that produces the hallmark structure of mycobacterial infection.

Comment in Mol Cell. 2021 Apr 15;81(8):1598-1600.

Divergence of gene function is a hallmark of evolution, but assessing functional divergence over deep time is not trivial. The few alleles available for cross-species studies often fail to expose the entire functional spectrum of genes, potentially obscuring deeply conserved pleiotropic roles. Here, we explore the functional divergence of WUSCHEL HOMEOBOX9 (WOX9), suggested to have species-specific roles in embryo and inflorescence development. Using a cis-regulatory editing drive system, we generate a comprehensive allelic series in tomato, which revealed hidden pleiotropic roles for WOX9. Analysis of accessible chromatin and conserved cis-regulatory sequences identifies the regions responsible for this pleiotropic activity, the functions of which are conserved in groundcherry, a tomato relative. Mimicking these alleles in Arabidopsis, distantly related to tomato and groundcherry, reveals new inflorescence phenotypes, exposing a deeply conserved pleiotropy. We suggest that targeted cis-regulatory mutations can uncover conserved gene functions and reduce undesirable effects in crop improvement.

When it comes to precision oncology, proteogenomics may provide better prospects to the clinical characterization of tumors, help make a more accurate diagnosis of cancer, and improve treatment for patients with cancer. This perspective describes the significant contributions of The Cancer Genome Atlas and the Clinical Proteomic Tumor Analysis Consortium to precision oncology and makes the case that proteogenomics needs to be fully integrated into clinical trials and patient care in order for precision oncology to deliver the right cancer treatment to the right patient at the right dose and at the right time.

Comment on Cell. 2021 Apr 1;184(7):1884-1894.e14.

The recently enriched genomic history of Indigenous groups in the Americas is still meager concerning continental Central America. Here, we report ten pre-Hispanic (plus two early colonial) genomes and 84 genome-wide profiles from seven groups presently living in Panama. Our analyses reveal that pre-Hispanic demographic events contributed to the extensive genetic structure currently seen in the area, which is also characterized by a distinctive Isthmo-Colombian Indigenous component. This component drives these populations on a specific variability axis and derives from the local admixture of different ancestries of northern North American origin(s). Two of these ancestries were differentially associated to Pleistocene Indigenous groups that also moved into South America, leaving heterogenous genetic footprints. An additional Pleistocene ancestry was brought by a still unsampled population of the Isthmus (UPopI) that remained restricted to the Isthmian area, expanded locally during the early Holocene, and left genomic traces up to the present day.

Author information: (1)Multiscale Systems Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD 20892, USA; Graduate Program in Biological Sciences, University of Maryland, College Park, MD 20742, USA. (2)Multiscale Systems Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD 20892, USA. (3)Multiscale Systems Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD 20892, USA; Office of Intramural Research, CIT, NIH, Bethesda, MD 20892, USA. (4)NIH Center for Human Immunology, NIAID, NIH, Bethesda, MD 20892, USA. (5)CREA Laboratory, Diagnostic Department, ASST Spedali Civili di Brescia, Brescia 25123, Italy. (6)Neutrophil Monitoring Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 20701, USA. (7)National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD 20892, USA. (8)Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD 20892, USA. (9)Department of Infectious and Tropical Diseases, University of Brescia and ASST Spedali Civili di Brescia, Brescia 25123, Italy. (10)Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD 20892, USA. (11)ASST Spedali Civili di Brescia, Brescia 25123, Italy. (12)Laboratory of Infectious Diseases, NIAID, NIH, Bethesda, MD 20892, USA. (13)Multiscale Systems Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD 20892, USA; NIH Center for Human Immunology, NIAID, NIH, Bethesda, MD 20892, USA. Electronic address: john.tsang@nih.gov.

Erratum in Cell. 2021 Nov 11;184(23):5838.

Author information: (1)Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA; Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA, USA. Electronic address: zon@enders.tch.childrens.harvard.edu. (2)Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA; Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA, USA.

Comment in Cell. 2021 Apr 1;184(7):1652-1653.

Comment in Cell. 2021 Apr 1;184(7):1659-1660.

Regulatory T cells prevent the emergence of autoantibodies and excessive IgE, but the precise mechanisms are unclear. Here, we show that BCL6-expressing Tregs, known as follicular regulatory T (Tfr) cells, produce abundant neuritin protein that targets B cells. Mice lacking Tfr cells or neuritin in Foxp3-expressing cells accumulated early plasma cells in germinal centers (GCs) and developed autoantibodies against histones and tissue-specific self-antigens. Upon immunization, these mice also produced increased plasma IgE and IgG1. We show that neuritin is taken up by B cells, causes phosphorylation of numerous proteins, and dampens IgE class switching. Neuritin reduced differentiation of mouse and human GC B cells into plasma cells, downregulated BLIMP-1, and upregulated BCL6. Administration of neuritin to Tfr-deficient mice prevented the accumulation of early plasma cells in GCs. Production of neuritin by Tfr cells emerges as a central mechanism to suppress B cell-driven autoimmunity and IgE-mediated allergies.

Comment on Cell. 2021 Apr 1;184(7):1693-1705.e17.

Erratum in Cell. 2021 Jun 24;184(13):3588.

The introduction of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the human population represents a tremendous medical and economic crisis. Innate immunity-as the first line of defense of our immune system-plays a central role in combating this novel virus. Here, we provide a conceptual framework for the interaction of the human innate immune system with SARS-CoV-2 to link the clinical observations with experimental findings that have been made during the first year of the pandemic. We review evidence that variability in innate immune system components among humans is a main contributor to the heterogeneous disease courses observed for coronavirus disease 2019 (COVID-19), the disease spectrum induced by SARS-CoV-2. A better understanding of the pathophysiological mechanisms observed for cells and soluble mediators involved in innate immunity is a prerequisite for the development of diagnostic markers and therapeutic strategies targeting COVID-19. However, this will also require additional studies addressing causality of events, which so far are lagging behind.

Embryo morphogenesis is impacted by dynamic changes in tissue material properties, which have been proposed to occur via processes akin to phase transitions (PTs). Here, we show that rigidity percolation provides a simple and robust theoretical framework to predict material/structural PTs of embryonic tissues from local cell connectivity. By using percolation theory, combined with directly monitoring dynamic changes in tissue rheology and cell contact mechanics, we demonstrate that the zebrafish blastoderm undergoes a genuine rigidity PT, brought about by a small reduction in adhesion-dependent cell connectivity below a critical value. We quantitatively predict and experimentally verify hallmarks of PTs, including power-law exponents and associated discontinuities of macroscopic observables. Finally, we show that this uniform PT depends on blastoderm cells undergoing meta-synchronous divisions causing random and, consequently, uniform changes in cell connectivity. Collectively, our theoretical and experimental findings reveal the structural basis of material PTs in an organismal context.

Comment in Cell Rep Med. 2021 Apr 20;2(4):100256. Cell Res. 2021 Aug;31(8):832-833.

Update of bioRxiv. 2020 Dec 28;:

Human monoclonal antibodies are safe, preventive, and therapeutic tools that can be rapidly developed to help restore the massive health and economic disruption caused by the coronavirus disease 2019 (COVID-19) pandemic. By single-cell sorting 4,277 SARS-CoV-2 spike protein-specific memory B cells from 14 COVID-19 survivors, 453 neutralizing antibodies were identified. The most potent neutralizing antibodies recognized the spike protein receptor-binding domain, followed in potency by antibodies that recognize the S1 domain, the spike protein trimer, and the S2 subunit. Only 1.4% of them neutralized the authentic virus with a potency of 1-10 ng/mL. The most potent monoclonal antibody, engineered to reduce the risk of antibody-dependent enhancement and prolong half-life, neutralized the authentic wild-type virus and emerging variants containing D614G, E484K, and N501Y substitutions. Prophylactic and therapeutic efficacy in the hamster model was observed at 0.25 and 4 mg/kg respectively in absence of Fc functions.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Understanding of the RNA virus and its interactions with host proteins could improve therapeutic interventions for COVID-19. By using icSHAPE, we determined the structural landscape of SARS-CoV-2 RNA in infected human cells and from refolded RNAs, as well as the regulatory untranslated regions of SARS-CoV-2 and six other coronaviruses. We validated several structural elements predicted in silico and discovered structural features that affect the translation and abundance of subgenomic viral RNAs in cells. The structural data informed a deep-learning tool to predict 42 host proteins that bind to SARS-CoV-2 RNA. Strikingly, antisense oligonucleotides targeting the structural elements and FDA-approved drugs inhibiting the SARS-CoV-2 RNA binding proteins dramatically reduced SARS-CoV-2 infection in cells derived from human liver and lung tumors. Our findings thus shed light on coronavirus and reveal multiple candidate therapeutics for COVID-19 treatment.

Update of medRxiv. 2020 Nov 10;: