Showing papers by "Institute for Systems Biology published in 2020"
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TL;DR: The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.
Abstract: Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1,2,3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10,11,12,13,14,15,16,17,18.
1,600 citations
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TL;DR: This program brings substantial improvements over the original version of RepeatModeler, one of the most widely used tools for TE discovery, and incorporates a module for structural discovery of complete long terminal repeat (LTR) retroelements, which are widespread in eukaryotic genomes but recalcitrant to automated identification because of their size and sequence complexity.
Abstract: The accelerating pace of genome sequencing throughout the tree of life is driving the need for improved unsupervised annotation of genome components such as transposable elements (TEs). Because the types and sequences of TEs are highly variable across species, automated TE discovery and annotation are challenging and time-consuming tasks. A critical first step is the de novo identification and accurate compilation of sequence models representing all of the unique TE families dispersed in the genome. Here we introduce RepeatModeler2, a pipeline that greatly facilitates this process. This program brings substantial improvements over the original version of RepeatModeler, one of the most widely used tools for TE discovery. In particular, this version incorporates a module for structural discovery of complete long terminal repeat (LTR) retroelements, which are widespread in eukaryotic genomes but recalcitrant to automated identification because of their size and sequence complexity. We benchmarked RepeatModeler2 on three model species with diverse TE landscapes and high-quality, manually curated TE libraries: Drosophila melanogaster (fruit fly), Danio rerio (zebrafish), and Oryza sativa (rice). In these three species, RepeatModeler2 identified approximately 3 times more consensus sequences matching with >95% sequence identity and sequence coverage to the manually curated sequences than the original RepeatModeler. As expected, the greatest improvement is for LTR retroelements. Thus, RepeatModeler2 represents a valuable addition to the genome annotation toolkit that will enhance the identification and study of TEs in eukaryotic genome sequences. RepeatModeler2 is available as source code or a containerized package under an open license (https://github.com/Dfam-consortium/RepeatModeler, http://www.repeatmasker.org/RepeatModeler/).
949 citations
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TL;DR: The heads-and-hearts hypothesis, which holds that meaningful reductions in achievement gaps only occur when course designs combine deliberate practice with inclusive teaching, is proposed and supports calls to replace traditional lecturing with evidence-based, active-learning course designs across the STEM disciplines.
Abstract: We tested the hypothesis that underrepresented students in active-learning classrooms experience narrower achievement gaps than underrepresented students in traditional lecturing classrooms, averaged across all science, technology, engineering, and mathematics (STEM) fields and courses. We conducted a comprehensive search for both published and unpublished studies that compared the performance of underrepresented students to their overrepresented classmates in active-learning and traditional-lecturing treatments. This search resulted in data on student examination scores from 15 studies (9,238 total students) and data on student failure rates from 26 studies (44,606 total students). Bayesian regression analyses showed that on average, active learning reduced achievement gaps in examination scores by 33% and narrowed gaps in passing rates by 45%. The reported proportion of time that students spend on in-class activities was important, as only classes that implemented high-intensity active learning narrowed achievement gaps. Sensitivity analyses showed that the conclusions are robust to sampling bias and other issues. To explain the extensive variation in efficacy observed among studies, we propose the heads-and-hearts hypothesis, which holds that meaningful reductions in achievement gaps only occur when course designs combine deliberate practice with inclusive teaching. Our results support calls to replace traditional lecturing with evidence-based, active-learning course designs across the STEM disciplines and suggest that innovations in instructional strategies can increase equity in higher education.
478 citations
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TL;DR: It is suggested that moderate disease may provide the most effective setting for therapeutic intervention, at which point elevated inflammatory signaling is accompanied by the loss of specific classes of metabolites and metabolic processes at moderate disease.
407 citations
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TL;DR: By uncovering the interrelationships between host diet and lifestyle factors, clinical blood markers, and the human gut microbiome at the population-scale, the results serve as a roadmap for future studies on host-microbe interactions and interventions.
Abstract: Variation in the human gut microbiome can reflect host lifestyle and behaviors and influence disease biomarker levels in the blood. Understanding the relationships between gut microbes and host phenotypes are critical for understanding wellness and disease. Here, we examine associations between the gut microbiota and ~150 host phenotypic features across ~3,400 individuals. We identify major axes of taxonomic variance in the gut and a putative diversity maximum along the Firmicutes-to-Bacteroidetes axis. Our analyses reveal both known and unknown associations between microbiome composition and host clinical markers and lifestyle factors, including host-microbe associations that are composition-specific. These results suggest potential opportunities for targeted interventions that alter the composition of the microbiome to improve host health. By uncovering the interrelationships between host diet and lifestyle factors, clinical blood markers, and the human gut microbiome at the population-scale, our results serve as a roadmap for future studies on host-microbe interactions and interventions.
298 citations
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Technical University of Denmark1, VU University Amsterdam2, Heidelberg University3, École Polytechnique Fédérale de Lausanne4, RWTH Aachen University5, University of California, San Diego6, University of Toronto7, National Autonomous University of Mexico8, Institute for Systems Biology9, University of Tübingen10, University of Queensland11, Argonne National Laboratory12, Leiden University13, Spanish National Research Council14, Technical University of Madrid15, Norwegian University of Life Sciences16, Hanze University of Applied Sciences17, Wellcome Trust18, KAIST19, Max Planck Society20, Humboldt University of Berlin21, Wageningen University and Research Centre22, Agency for Science, Technology and Research23, Sungkyunkwan University24, King's College London25, Royal Institute of Technology26, Chinese Academy of Sciences27, University of Virginia28, Chalmers University of Technology29, University of Arkansas for Medical Sciences30, Oxford Brookes University31, University of Minho32, Nova Southeastern University33, University of Düsseldorf34
TL;DR: A community effort to develop a test suite named MEMOTE (for metabolic model tests) to assess GEM quality, and advocate adoption of the latest version of the Systems Biology Markup Language level 3 flux balance constraints (SBML3FBC) package as the primary description and exchange format.
Abstract: We acknowledge D. Dannaher and A. Lopez for their supporting work on the Angular parts of MEMOTE; resources and support from the DTU Computing Center; J. Cardoso, S. Gudmundsson, K. Jensen and D. Lappa for their feedback on conceptual details; and P. D. Karp and I. Thiele for critically reviewing the manuscript. We thank J. Daniel, T. Kristjansdottir, J. Saez-Saez, S. Sulheim, and P. Tubergen for being early adopters of MEMOTE and for providing written testimonials. J.O.V. received the Research Council of Norway grants 244164 (GenoSysFat), 248792 (DigiSal) and 248810 (Digital Life Norway); M.Z. received the Research Council of Norway grant 244164 (GenoSysFat); C.L. received funding from the Innovation Fund Denmark (project “Environmentally Friendly Protein Production (EFPro2)”); C.L., A.K., N. S., M.B., M.A., D.M., P.M, B.J.S., P.V., K.R.P. and M.H. received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement 686070 (DD-DeCaF); B.G.O., F.T.B. and A.D. acknowledge funding from the US National Institutes of Health (NIH, grant number 2R01GM070923-13); A.D. was supported by infrastructural funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections; N.E.L. received funding from NIGMS R35 GM119850, Novo Nordisk Foundation NNF10CC1016517 and the Keck Foundation; A.R. received a Lilly Innovation Fellowship Award; B.G.-J. and J. Nogales received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no 686585 for the project LIAR, and the Spanish Ministry of Economy and Competitivity through the RobDcode grant (BIO2014-59528-JIN); L.M.B. has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement 633962 for project P4SB; R.F. received funding from the US Department of Energy, Offices of Advanced Scientific Computing Research and the Biological and Environmental Research as part of the Scientific Discovery Through Advanced Computing program, grant DE-SC0010429; A.M., C.Z., S.L. and J. Nielsen received funding from The Knut and Alice Wallenberg Foundation, Advanced Computing program, grant #DE-SC0010429; S.K.’s work was in part supported by the German Federal Ministry of Education and Research (de.NBI partner project “ModSim” (FKZ: 031L104B)); E.K. and J.A.H.W. were supported by the German Federal Ministry of Education and Research (project “SysToxChip”, FKZ 031A303A); M.K. is supported by the Federal Ministry of Education and Research (BMBF, Germany) within the research network Systems Medicine of the Liver (LiSyM, grant number 031L0054); J.A.P. and G.L.M. acknowledge funding from US National Institutes of Health (T32-LM012416, R01-AT010253, R01-GM108501) and the Wagner Foundation; G.L.M. acknowledges funding from a Grand Challenges Exploration Phase I grant (OPP1211869) from the Bill & Melinda Gates Foundation; H.H. and R.S.M.S. received funding from the Biotechnology and Biological Sciences Research Council MultiMod (BB/N019482/1); H.U.K. and S.Y.L. received funding from the Technology Development Program to Solve Climate Changes on Systems Metabolic Engineering for Biorefineries (grants NRF-2012M1A2A2026556 and NRF-2012M1A2A2026557) from the Ministry of Science and ICT through the National Research Foundation (NRF) of Korea; H.U.K. received funding from the Bio & Medical Technology Development Program of the NRF, the Ministry of Science and ICT (NRF-2018M3A9H3020459); P.B., B.J.S., Z.K., B.O.P., C.L., M.B., N.S., M.H. and A.F. received funding through Novo Nordisk Foundation through the Center for Biosustainability at the Technical University of Denmark (NNF10CC1016517); D.-Y.L. received funding from the Next-Generation BioGreen 21 Program (SSAC, PJ01334605), Rural Development Administration, Republic of Korea; G.F. was supported by the RobustYeast within ERA net project via SystemsX.ch; V.H. received funding from the ETH Domain and Swiss National Science Foundation; M.P. acknowledges Oxford Brookes University; J.C.X. received support via European Research Council (666053) to W.F. Martin; B.E.E. acknowledges funding through the CSIRO-UQ Synthetic Biology Alliance; C.D. is supported by a Washington Research Foundation Distinguished Investigator Award. I.N. received funding from National Institutes of Health (NIH)/National Institute of General Medical Sciences (NIGMS) (grant P20GM125503).
255 citations
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Daniel K. Wells, Marit M. van Buuren1, Kristen K. Dang2, Vanessa M. Hubbard-Lucey +146 more•Institutions (15)
TL;DR: A model of tumor epitope immunogenicity was developed that filtered out 98% of non-immunogenic peptides with a precision above 0.70 and was validated in an independent cohort of 310 epitopes prioritized from tumor sequencing data and assessed for T cell binding.
240 citations
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Baylor College of Medicine1, Boston Children's Hospital2, Sage Bionetworks3, University of California, Irvine4, Institute for Systems Biology5, Rush University Medical Center6, Mayo Clinic7, Icahn School of Medicine at Mount Sinai8, GlaxoSmithKline9, Johns Hopkins University School of Medicine10, Massachusetts Institute of Technology11, Picower Institute for Learning and Memory12, University of Florida13, Emory University14, University of Sheffield15, University of Manchester16, Durham University17, Beth Israel Deaconess Medical Center18, Biogen Idec19, Eli Lilly and Company20, University of British Columbia21, Broad Institute22, Columbia University23
TL;DR: A consensus atlas of the human brain transcriptome in Alzheimer’s disease (AD), based on meta-analysis of differential gene expression in 2,114 postmortem samples, is presented, highlighting transcriptional networks altered by human brain pathophysiology and identifying correspondences with mouse models for AD preclinical studies.
167 citations
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TL;DR: Both SPMs and sEH inhibitors may promote the resolution of inflammation in COVID-19, thereby reducing acute respiratory distress syndrome (ARDS) and other life-threatening complications associated with robust viral-induced inflammation.
Abstract: Severe coronavirus disease (COVID-19) is characterized by pulmonary hyper-inflammation and potentially life-threatening "cytokine storms". Controlling the local and systemic inflammatory response in COVID-19 may be as important as anti-viral therapies. Endogenous lipid autacoid mediators, referred to as eicosanoids, play a critical role in the induction of inflammation and pro-inflammatory cytokine production. SARS-CoV-2 may trigger a cell death ("debris")-induced "eicosanoid storm", including prostaglandins and leukotrienes, which in turn initiates a robust inflammatory response. A paradigm shift is emerging in our understanding of the resolution of inflammation as an active biochemical process with the discovery of novel endogenous specialized pro-resolving lipid autacoid mediators (SPMs), such as resolvins. Resolvins and other SPMs stimulate macrophage-mediated clearance of debris and counter pro-inflammatory cytokine production, a process called inflammation resolution. SPMs and their lipid precursors exhibit anti-viral activity at nanogram doses in the setting of influenza without being immunosuppressive. SPMs also promote anti-viral B cell antibodies and lymphocyte activity, highlighting their potential use in the treatment of COVID-19. Soluble epoxide hydrolase (sEH) inhibitors stabilize arachidonic acid-derived epoxyeicosatrienoic acids (EETs), which also stimulate inflammation resolution by promoting the production of pro-resolution mediators, activating anti-inflammatory processes, and preventing the cytokine storm. Both resolvins and EETs also attenuate pathological thrombosis and promote clot removal, which is emerging as a key pathology of COVID-19 infection. Thus, both SPMs and sEH inhibitors may promote the resolution of inflammation in COVID-19, thereby reducing acute respiratory distress syndrome (ARDS) and other life-threatening complications associated with robust viral-induced inflammation. While most COVID-19 clinical trials focus on "anti-viral" and "anti-inflammatory" strategies, stimulating inflammation resolution is a novel host-centric therapeutic avenue. Importantly, SPMs and sEH inhibitors are currently in clinical trials for other inflammatory diseases and could be rapidly translated for the management of COVID-19 via debris clearance and inflammatory cytokine suppression. Here, we discuss using pro-resolution mediators as a potential complement to current anti-viral strategies for COVID-19.
162 citations
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Memorial Sloan Kettering Cancer Center1, University of Michigan2, Clarkson University3, General Electric4, University of South Carolina5, University of Chicago6, Indiana University7, University of Massachusetts Medical School8, Institute for Systems Biology9, City University of New York10, Northern Arizona University11, George Washington University12, Thomas Jefferson University13, University of Puerto Rico14, University of Minnesota15, University of California, Irvine16, Boston Children's Hospital17, Virginia Tech18, Mayo Clinic19, Columbia University20, Pacific Northwest National Laboratory21, Georgia Institute of Technology22, Boston University23, University of Florida24, University of Illinois at Urbana–Champaign25, University of Texas Southwestern Medical Center26, Toyota Technological Institute at Chicago27, Yeshiva University28, University of Texas MD Anderson Cancer Center29
TL;DR: Understanding the role of host-associated microbial communities in cancer systems will require a multidisciplinary approach combining microbial ecology, immunology, cancer cell biology, and computational biology - a systems biology approach.
Abstract: The collection of microbes that live in and on the human body - the human microbiome - can impact on cancer initiation, progression, and response to therapy, including cancer immunotherapy. The mechanisms by which microbiomes impact on cancers can yield new diagnostics and treatments, but much remains unknown. The interactions between microbes, diet, host factors, drugs, and cell-cell interactions within the cancer itself likely involve intricate feedbacks, and no single component can explain all the behavior of the system. Understanding the role of host-associated microbial communities in cancer systems will require a multidisciplinary approach combining microbial ecology, immunology, cancer cell biology, and computational biology - a systems biology approach.
151 citations
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TL;DR: A blood-based molecular approach to characterizing the cellular immune response has applications in vaccine development as well as clinical diagnostics and monitoring and demonstrates an approach to reliably assess the adaptive immune response both soon after viral antigenic exposure (before antibodies are typically detectable) aswell as at later time points.
Abstract: T cells are involved in the early identification and clearance of viral infections and also support the development of antibodies by B cells. This central role for T cells makes them a desirable target for assessing the immune response to SARS-CoV-2 infection. Here, we combined two high-throughput immune profiling methods to create a quantitative picture of the T-cell response to SARS-CoV-2. First, at the individual level, we deeply characterized 3 acutely infected and 58 recovered COVID-19 subjects by experimentally mapping their CD8 T-cell response through antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I presented viral peptides (class II data in a forthcoming study). Then, at the population level, we performed T-cell repertoire sequencing on 1,815 samples (from 1,521 COVID-19 subjects) as well as 3,500 controls to identify shared "public" T-cell receptors (TCRs) associated with SARS-CoV-2 infection from both CD8 and CD4 T cells. Collectively, our data reveal that CD8 T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the T-cell response to SARS-CoV-2 peaks about one to two weeks after infection and is detectable for at least several months after recovery. As an application of these data, we trained a classifier to diagnose SARS-CoV-2 infection based solely on TCR sequencing from blood samples, and observed, at 99.8% specificity, high early sensitivity soon after diagnosis (Day 3-7 = 85.1% [95% CI = 79.9-89.7]; Day 8-14 = 94.8% [90.7-98.4]) as well as lasting sensitivity after recovery (Day 29+/convalescent = 95.4% [92.1-98.3]). These results demonstrate an approach to reliably assess the adaptive immune response both soon after viral antigenic exposure (before antibodies are typically detectable) as well as at later time points. This blood-based molecular approach to characterizing the cellular immune response has applications in clinical diagnostics as well as in vaccine development and monitoring.
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Harvard University1, Institute for Systems Biology2, University of North Carolina at Chapel Hill3, Buck Institute for Research on Aging4, Van Andel Institute5, Icahn School of Medicine at Mount Sinai6, Foundation Medicine7, Washington University in St. Louis8, University of Trento9, University of California, San Francisco10, University of Texas MD Anderson Cancer Center11, St. Jude Children's Research Hospital12, University of California, Santa Cruz13, Brigham and Women's Hospital14
TL;DR: Analysis of ancestry effects on mutation rates, DNA methylation, and mRNA and miRNA expression among 10,678 patients across 33 cancer types from The Cancer Genome Atlas demonstrated that cancer subtypes and ancestry-related technical artifacts are important confounders that have been insufficiently accounted for.
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TL;DR: A method to efficiently generate DIA-only chromatogram libraries is illustrated and best practices for how to acquire, queue, and validate DIA data without spectrum libraries are demonstrated.
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Macquarie University1, Monash University2, Institute for Systems Biology3, University of Geneva4, University of Michigan5, University College Dublin6, Yonsei University7, University of British Columbia8, Carlos III Health Institute9, Princeton University10, Cedars-Sinai Medical Center11, Royal Institute of Technology12, Uppsala University13, Johns Hopkins University14, Arizona State University15, National Institutes of Health16, Protein Sciences17, University of California, Los Angeles18, University of Nebraska Medical Center19, Royal Prince Alfred Hospital20, Indian Institute of Technology Bombay21, Federal University of Rio de Janeiro22, University of Grenoble23, Anschutz Medical Campus24, University of New South Wales25, University of California, San Diego26, Lund University27, University of Texas Health Science Center at San Antonio28, French Institute of Health and Medical Research29, Leiden University30, Stanford University31, University of Zurich32
TL;DR: On the occasion of the Human Proteome Project’s tenth anniversary, a 90.4% complete high-stringency human proteome blueprint is reported, highlighting potential roles the human proteomes plays in the understanding, diagnosis and treatment of cancers, cardiovascular and infectious diseases.
Abstract: The Human Proteome Organization (HUPO) launched the Human Proteome Project (HPP) in 2010, creating an international framework for global collaboration, data sharing, quality assurance and enhancing accurate annotation of the genome-encoded proteome. During the subsequent decade, the HPP established collaborations, developed guidelines and metrics, and undertook reanalysis of previously deposited community data, continuously increasing the coverage of the human proteome. On the occasion of the HPP’s tenth anniversary, we here report a 90.4% complete high-stringency human proteome blueprint. This knowledge is essential for discerning molecular processes in health and disease, as we demonstrate by highlighting potential roles the human proteome plays in our understanding, diagnosis and treatment of cancers, cardiovascular and infectious diseases.
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TL;DR: A library generation workflow that leverages fragmentation and retention time prediction to build libraries containing every peptide in a proteome, and then refines those libraries with empirical data is demonstrated.
Abstract: Data-independent acquisition approaches typically rely on experiment-specific spectrum libraries, requiring offline fractionation and tens to hundreds of injections. We demonstrate a library generation workflow that leverages fragmentation and retention time prediction to build libraries containing every peptide in a proteome, and then refines those libraries with empirical data. Our method specifically enables rapid, experiment-specific library generation for non-model organisms, which we demonstrate using the malaria parasite Plasmodium falciparum, and non-canonical databases, which we show by detecting missense variants in HeLa.
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21 Jan 2020
TL;DR: In this article, a customizable metabolic model of the human gut microbiome is presented, based on a heuristic optimization approach based on L2 regularization, which is able to obtain a unique set of realistic growth rates that corresponded well with observed replication rates.
Abstract: Compositional changes in the gut microbiota have been associated with a variety of medical conditions such as obesity, Crohn's disease, and diabetes. However, connecting microbial community composition to ecosystem function remains a challenge. Here, we introduce MICOM, a customizable metabolic model of the human gut microbiome. By using a heuristic optimization approach based on L2 regularization, we were able to obtain a unique set of realistic growth rates that corresponded well with observed replication rates. We integrated adjustable dietary and taxon abundance constraints to generate personalized metabolic models for individual metagenomic samples. We applied MICOM to a balanced cohort of metagenomes from 186 people, including a metabolically healthy population and individuals with type 1 and type 2 diabetes. Model results showed that individual bacterial genera maintained conserved niche structures across humans, while the community-level production of short-chain fatty acids (SCFAs) was heterogeneous and highly individual specific. Model output revealed complex cross-feeding interactions that would be difficult to measure in vivo Metabolic interaction networks differed somewhat consistently between healthy and diabetic subjects. In particular, MICOM predicted reduced butyrate and propionate production in a diabetic cohort, with restoration of SCFA production profiles found in healthy subjects following metformin treatment. Overall, we found that changes in diet or taxon abundances have highly personalized effects. We believe MICOM can serve as a useful tool for generating mechanistic hypotheses for how diet and microbiome composition influence community function. All methods are implemented in an open-source Python package, which is available at https://github.com/micom-dev/micomIMPORTANCE The bacterial communities that live within the human gut have been linked to health and disease. However, we are still just beginning to understand how those bacteria interact and what potential interventions to our gut microbiome can make us healthier. Here, we present a mathematical modeling framework (named MICOM) that can recapitulate the growth rates of diverse bacterial species in the gut and can simulate metabolic interactions within microbial communities. We show that MICOM can unravel the ecological rules that shape the microbial landscape in our gut and that a given dietary or probiotic intervention can have widely different effects in different people.
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University of Luxembourg1, Institute for Systems Biology2, Ontario Institute for Cancer Research3, St. John's University4, PSL Research University5, University of Paris6, European Bioinformatics Institute7, Gladstone Institutes8, Maastricht University9, Technische Universität München10, University of Bonn11, Monash University12, University of Konstanz13, University of Tübingen14, Oregon Health & Science University15, University of Rostock16, Stellenbosch University17, Pompeu Fabra University18, Pasteur Institute19, Catalan Institution for Research and Advanced Studies20, Barcelona Supercomputing Center21, Keio University22, Okinawa Institute of Science and Technology23
TL;DR: Researchers around the world join forces to reconstruct the molecular processes of the virus-host interactions aiming to combat the cause of the ongoing pandemic.
Abstract: Researchers around the world join forces to reconstruct the molecular processes of the virus-host interactions aiming to combat the cause of the ongoing pandemic.
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TL;DR: It is shown that, for a range of assumptions on the action and efficacy of the vaccine, targeting older age groups first is optimal and can avoid a second wave if the vaccine prevents transmission as well as disease.
Abstract: The COVID-19 outbreak has highlighted our vulnerability to novel infections. Faced with this threat and no effective treatment, in line with many other countries, the UK adopted enforced social distancing (lockdown) to reduce transmission- successfully reducing the reproductive number, R, below one. However, given the large pool of susceptible individuals that remain, complete relaxation of controls is likely to generate a substantial second wave. Vaccination remains the only foreseeable means of both containing the infection and returning to normal interactions and behaviour. Here, we consider the optimal targeting of vaccination within the UK, with the aim of minimising future deaths or quality adjusted life year (QALY) losses. We show that, for a range of assumptions on the action and efficacy of the vaccine, targeting older age groups first is optimal and can avoid a second wave if the vaccine prevents transmission as well as disease.
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University of London1, Canterbury Christ Church University2, University of Oxford3, University College London4, The Turing Institute5, University of Liverpool6, University of Bath7, Stockholm University8, University of Exeter9, National University of Singapore10, University of Cambridge11, Imperial College London12, University of Surrey13, University of Manchester14, Utrecht University15, University of Warwick16, IBM17, Institute for Systems Biology18, University of Sussex19, North Carolina State University20, Australian Institute of Tropical Health and Medicine21, University of Melbourne22, La Trobe University23, University of Washington24, University of Nottingham25, Stellenbosch University26, University of Adelaide27, University of Rome Tor Vergata28, Fundação Getúlio Vargas29, Heriot-Watt University30
TL;DR: A roadmap to facilitate the development of reliable models to guide exit strategies is proposed, and has three parts: improve estimation of key epidemiological parameters; understand sources of heterogeneity in populations; and focus on requirements for data collection, particularly in low-to-middle-income countries.
Abstract: Combinations of intense non-pharmaceutical interventions (lockdowns) were introduced worldwide to reduce SARS-CoV-2 transmission. Many governments have begun to implement exit strategies that relax restrictions while attempting to control the risk of a surge in cases. Mathematical modelling has played a central role in guiding interventions, but the challenge of designing optimal exit strategies in the face of ongoing transmission is unprecedented. Here, we report discussions from the Isaac Newton Institute 'Models for an exit strategy' workshop (11-15 May 2020). A diverse community of modellers who are providing evidence to governments worldwide were asked to identify the main questions that, if answered, would allow for more accurate predictions of the effects of different exit strategies. Based on these questions, we propose a roadmap to facilitate the development of reliable models to guide exit strategies. This roadmap requires a global collaborative effort from the scientific community and policymakers, and has three parts: (i) improve estimation of key epidemiological parameters; (ii) understand sources of heterogeneity in populations; and (iii) focus on requirements for data collection, particularly in low-to-middle-income countries. This will provide important information for planning exit strategies that balance socio-economic benefits with public health.
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TL;DR: In this paper, the tumor microenvironment of Gastroesophageal adenocarcinomas (GEAs) was characterized using RNAseq data and the Cancer Genome Atlas.
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TL;DR: This work sequenced viruses from two distinct episodes of symptomatic COVID-19 separated by 144 days in a single patient, to conclusively describe reinfection with a new strain harboring the spike variant D614G.
Abstract: Recovery from COVID-19 is associated with production of anti-SARS-CoV-2 antibodies, but it is uncertain whether these confer immunity. We describe viral RNA shedding duration in hospitalized patients and identify patients with recurrent shedding. We sequenced viruses from two distinct episodes of symptomatic COVID-19 separated by 144 days in a single patient, to conclusively describe reinfection with a new strain harboring the spike variant D614G. With antibody and B cell analytics, we show correlates of adaptive immunity, including a differential response to D614G. Finally, we discuss implications for vaccine programs and begin to define benchmarks for protection against reinfection from SARS-CoV-2.
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17 Nov 2020
TL;DR: Intriguingly, some bile acids measured in brain tissue cannot be explained by the presence of enzymes responsible for their synthesis, suggesting that they may originate from the gut microbiome and are transported to the brain.
Abstract: Increasing evidence suggests Alzheimer's disease (AD) pathophysiology is influenced by primary and secondary bile acids, the end product of cholesterol metabolism. We analyze 2,114 post-mortem brain transcriptomes and identify genes in the alternative bile acid synthesis pathway to be expressed in the brain. A targeted metabolomic analysis of primary and secondary bile acids measured from post-mortem brain samples of 111 individuals supports these results. Our metabolic network analysis suggests that taurine transport, bile acid synthesis, and cholesterol metabolism differ in AD and cognitively normal individuals. We also identify putative transcription factors regulating metabolic genes and influencing altered metabolism in AD. Intriguingly, some bile acids measured in brain tissue cannot be explained by the presence of enzymes responsible for their synthesis, suggesting that they may originate from the gut microbiome and are transported to the brain. These findings motivate further research into bile acid metabolism in AD to elucidate their possible connection to cognitive decline.
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TL;DR: RAFs are consistent with an autotrophic origin of metabolism and indicate that autocatalytic chemical networks preceded proteins and RNA in evolution, and RAFs uncover intermediate stages in the emergence of metabolic networks, narrowing the gaps between early Earth chemistry and life.
Abstract: Modern cells embody metabolic networks containing thousands of elements and form autocatalytic sets of molecules that produce copies of themselves. How the first self-sustaining metabolic networks arose at life's origin is a major open question. Autocatalytic sets smaller than metabolic networks were proposed as transitory intermediates at the origin of life, but evidence for their role in prebiotic evolution is lacking. Here, we identify reflexively autocatalytic food-generated networks (RAFs)-self-sustaining networks that collectively catalyse all their reactions-embedded within microbial metabolism. RAFs in the metabolism of ancient anaerobic autotrophs that live from H2 and CO2 provided with small-molecule catalysts generate acetyl-CoA as well as amino acids and bases, the monomeric components of protein and RNA, but amino acids and bases without organic catalysts do not generate metabolic RAFs. This suggests that RAFs identify attributes of biochemical origins conserved in metabolic networks. RAFs are consistent with an autotrophic origin of metabolism and furthermore indicate that autocatalytic chemical networks preceded proteins and RNA in evolution. RAFs uncover intermediate stages in the emergence of metabolic networks, narrowing the gaps between early Earth chemistry and life.
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TL;DR: A structural model of the endogenously purified human canonical BAF complex bound to the nucleosome, generated using cryoelectron microscopy, cross-linking mass spectrometry, and homology modeling provides important biophysical foundations for understanding the mechanisms of BAFcomplex function in normal and disease states.
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University of Missouri1, Baylor College of Medicine2, University of California, Santa Cruz3, University of Washington4, Institute for Systems Biology5, Louisiana State University6, Washington University in St. Louis7, University of Bari8, Pacific Biosciences9, University of Wisconsin-Madison10, Oregon National Primate Research Center11, Tulane University12, Boston University13, University of Texas MD Anderson Cancer Center14, Emory University15, Yerkes National Primate Research Center16, University of California, Davis17, California National Primate Research Center18, Duke University19, University of Pennsylvania20, Texas Biomedical Research Institute21
TL;DR: A new reference genome for the rhesus macaque, a model nonhuman primate, in which most gaps were closed and most protein-coding genes were annotated is generated, improving gene mapping for biomedical and comparative genetic studies.
Abstract: The rhesus macaque (Macaca mulatta) is the most widely studied nonhuman primate (NHP) in biomedical research. We present an updated reference genome assembly (Mmul_10, contig N50 = 46 Mbp) that increases the sequence contiguity 120-fold and annotate it using 6.5 million full-length transcripts, thus improving our understanding of gene content, isoform diversity, and repeat organization. With the improved assembly of segmental duplications, we discovered new lineage-specific genes and expanded gene families that are potentially informative in studies of evolution and disease susceptibility. Whole-genome sequencing (WGS) data from 853 rhesus macaques identified 85.7 million single-nucleotide variants (SNVs) and 10.5 million indel variants, including potentially damaging variants in genes associated with human autism and developmental delay, providing a framework for developing noninvasive NHP models of human disease.
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TL;DR: The model revealed quantitative imbalances in TFs' cross-antagonistic relationships that underlie lineage determination and made the surprising discovery that, in the nucleus, co-repressors are dramatically more abundant than co-activators at the protein level, but not at the RNA level, with profound implications for understanding transcriptional regulation.
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TL;DR: It is uncovered that isogenic BRAF mutant melanoma cells can take two distinct paths to become tolerant to BRAF inhibition, thus updating the paradigm of adaptive resistance development in an isogenic cell population.
Abstract: The determination of individual cell trajectories through a high-dimensional cell-state space is an outstanding challenge for understanding biological changes ranging from cellular differentiation to epigenetic responses of diseased cells upon drugging. We integrate experiments and theory to determine the trajectories that single BRAFV600E mutant melanoma cancer cells take between drug-naive and drug-tolerant states. Although single-cell omics tools can yield snapshots of the cell-state landscape, the determination of individual cell trajectories through that space can be confounded by stochastic cell-state switching. We assayed for a panel of signaling, phenotypic, and metabolic regulators at points across 5 days of drug treatment to uncover a cell-state landscape with two paths connecting drug-naive and drug-tolerant states. The trajectory a given cell takes depends upon the drug-naive level of a lineage-restricted transcription factor. Each trajectory exhibits unique druggable susceptibilities, thus updating the paradigm of adaptive resistance development in an isogenic cell population.
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TL;DR: A long-term perspective of the field is provided and how applying quantitative immunopeptidomics at population scale may provide a new look at individual predisposition to common immune diseases as well as responsiveness to vaccines and immunotherapies is highlighted.
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TL;DR: This work utilizes Raman spectro-microscopy for spatial mapping of metabolites within single cells, with the specific goal of identifying druggable metabolic susceptibilities from a series of patient-derived melanoma cell lines, to provide a general approach in spatially-resolved single cell metabolomics studies.
Abstract: Non-invasively probing metabolites within single live cells is highly desired but challenging. Here we utilize Raman spectro-microscopy for spatial mapping of metabolites within single cells, with the specific goal of identifying druggable metabolic susceptibilities from a series of patient-derived melanoma cell lines. Each cell line represents a different characteristic level of cancer cell de-differentiation. First, with Raman spectroscopy, followed by stimulated Raman scattering (SRS) microscopy and transcriptomics analysis, we identify the fatty acid synthesis pathway as a druggable susceptibility for differentiated melanocytic cells. We then utilize hyperspectral-SRS imaging of intracellular lipid droplets to identify a previously unknown susceptibility of lipid mono-unsaturation within de-differentiated mesenchymal cells with innate resistance to BRAF inhibition. Drugging this target leads to cellular apoptosis accompanied by the formation of phase-separated intracellular membrane domains. The integration of subcellular Raman spectro-microscopy with lipidomics and transcriptomics suggests possible lipid regulatory mechanisms underlying this pharmacological treatment. Our method should provide a general approach in spatially-resolved single cell metabolomics studies.
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Harvard University1, United States Department of the Army2, University of California, San Francisco3, Veterans Health Administration4, Icahn School of Medicine at Mount Sinai5, McLean Hospital6, Institute for Systems Biology7, University of Memphis8, Emory University9, Sapienza University of Rome10, Lund University11
TL;DR: The identification and validation of this diverse diagnostic panel represents a powerful and novel approach to improve accuracy and reduce bias in diagnosing combat-related PTSD.
Abstract: Post-traumatic stress disorder (PTSD) impacts many veterans and active duty soldiers, but diagnosis can be problematic due to biases in self-disclosure of symptoms, stigma within military populations, and limitations identifying those at risk. Prior studies suggest that PTSD may be a systemic illness, affecting not just the brain, but the entire body. Therefore, disease signals likely span multiple biological domains, including genes, proteins, cells, tissues, and organism-level physiological changes. Identification of these signals could aid in diagnostics, treatment decision-making, and risk evaluation. In the search for PTSD diagnostic biomarkers, we ascertained over one million molecular, cellular, physiological, and clinical features from three cohorts of male veterans. In a discovery cohort of 83 warzone-related PTSD cases and 82 warzone-exposed controls, we identified a set of 343 candidate biomarkers. These candidate biomarkers were selected from an integrated approach using (1) data-driven methods, including Support Vector Machine with Recursive Feature Elimination and other standard or published methodologies, and (2) hypothesis-driven approaches, using previous genetic studies for polygenic risk, or other PTSD-related literature. After reassessment of ~30% of these participants, we refined this set of markers from 343 to 28, based on their performance and ability to track changes in phenotype over time. The final diagnostic panel of 28 features was validated in an independent cohort (26 cases, 26 controls) with good performance (AUC = 0.80, 81% accuracy, 85% sensitivity, and 77% specificity). The identification and validation of this diverse diagnostic panel represents a powerful and novel approach to improve accuracy and reduce bias in diagnosing combat-related PTSD.