Showing papers by "Institute for Systems Biology published in 2014"
TL;DR: A comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project is described and a molecular classification dividing gastric cancer into four subtypes is proposed.
Abstract: Gastric cancer was the world’s third leading cause of cancer mortality in 2012, responsible for 723,000 deaths1. The vast majority of gastric cancers are adenocarcinomas, which can be further subdivided into intestinal and diffuse types according to the Lauren classification2. An alternative system, proposed by the World Health Organization, divides gastric cancer into papillary, tubular, mucinous (colloid) and poorly cohesive carcinomas3. These classification systems have little clinical utility, making the development of robust classifiers that can guide patient therapy an urgent priority.
The majority of gastric cancers are associated with infectious agents, including the bacterium Helicobacter pylori4 and Epstein–Barr virus (EBV). The distribution of histological subtypes of gastric cancer and the frequencies of H. pylori and EBV associated gastric cancer vary across the globe5. A small minority of gastric cancer cases are associated with germline mutation in E-cadherin (CDH1)6 or mismatch repair genes7 (Lynch syndrome), whereas sporadic mismatch repair-deficient gastric cancers have epigenetic silencing of MLH1 in the context of a CpG island methylator phenotype (CIMP)8. Molecular profiling of gastric cancer has been performed using gene expression or DNA sequencing9–12, but has not led to a clear biologic classification scheme. The goals of this study by The Cancer Genome Atlas (TCGA) were to develop a robust molecular classification of gastric cancer and to identify dysregulated pathways and candidate drivers of distinct classes of gastric cancer.
4,583 citations
European Bioinformatics Institute1, Institute for Systems Biology2, University of California, San Diego3, Swiss Institute of Bioinformatics4, Ruhr University Bochum5, University of Cambridge6, University of California, San Francisco7, Wiley-VCH8, Spanish National Research Council9, Ghent University10, University of Liverpool11
TL;DR: The PX submission tool simplifies the process of submitting data to PRIDE by automating the very labor-intensive and therefore time-heavy and expensive process of manually downloading and editing files.
Abstract: 5. Tools available and ways to submit data to PX ............................................................. 11 5.1. MS/MS data submissions to PRIDE .................................................................................... 11 5.1.1. Creation of supported files for “Complete” submissions .................................................. 11 5.1.1.1. PRIDE XML .................................................................................................................................. 11 5.1.1.2. mzIdentML ................................................................................................................................. 13 5.1.2. Checking the files before submission (initial quality assessment) ..................................... 14 5.1.3. File submission to PRIDE: the PX submission tool ............................................................. 15 5.1.3.1. General Information ................................................................................................................... 15 5.1.3.2. Functionality, Design and Implementation Details .................................................................... 15 5.1.3.3. New open source libraries made available with PX submission tool ......................................... 18 5.1.3.4. PX Submission Tool Java Web Start ............................................................................................ 18 5.1.4. File submission to PRIDE: Command line support using Aspera ........................................ 19 5.1.5. Examples of Partial submissions to PRIDE ......................................................................... 19 5.2. SRM data submissions via PASSEL ..................................................................................... 20
2,436 citations
TL;DR: Ch Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities.
Abstract: Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. To date, no molecularly targeted agents have been approved for the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#termsThis paper is distributed under the terms of the Creative Commons. Attribution-Non-Commercial-Share Alike license, and the online version of the paper is freely available to all readers.
2,257 citations
University of Texas Southwestern Medical Center1, Washington University in St. Louis2, Rockefeller University3, Institute for Systems Biology4, Seattle Biomed5, Columbia University6, University of Chicago7, University of St Andrews8, Icahn School of Medicine at Mount Sinai9, Leiden University Medical Center10
TL;DR: Comparative analysis reveals that the screened ISGs target positive-sense single-stranded RNA viruses more effectively than negative-sensesingle-strander RNA viruses.
Abstract: The type I interferon (IFN) response protects cells from viral infection by inducing hundreds of interferon-stimulated genes (ISGs), some of which encode direct antiviral effectors. Recent screening studies have begun to catalogue ISGs with antiviral activity against several RNA and DNA viruses. However, antiviral ISG specificity across multiple distinct classes of viruses remains largely unexplored. Here we used an ectopic expression assay to screen a library of more than 350 human ISGs for effects on 14 viruses representing 7 families and 11 genera. We show that 47 genes inhibit one or more viruses, and 25 genes enhance virus infectivity. Comparative analysis reveals that the screened ISGs target positive-sense single-stranded RNA viruses more effectively than negative-sense single-stranded RNA viruses. Gene clustering highlights the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS, also known as MB21D1) as a gene whose expression also broadly inhibits several RNA viruses. In vitro, lentiviral delivery of enzymatically active cGAS triggers a STING-dependent, IRF3-mediated antiviral program that functions independently of canonical IFN/STAT1 signalling. In vivo, genetic ablation of murine cGAS reveals its requirement in the antiviral response to two DNA viruses, and an unappreciated contribution to the innate control of an RNA virus. These studies uncover new paradigms for the preferential specificity of IFN-mediated antiviral pathways spanning several virus families.
765 citations
Broad Institute1, Eli Lilly and Company2, University of Victoria3, Institute for Systems Biology4, University of Washington5, ETH Zurich6, University of California, San Francisco7, University of South Florida8, Vanderbilt University9, Pacific Northwest National Laboratory10, Food and Drug Administration11, Pfizer12, Fred Hutchinson Cancer Research Center13, Purdue University14, National Institutes of Health15, Centers for Disease Control and Prevention16, Johns Hopkins University17, Korea University18, Harvard University19, Emory University20, Washington University in St. Louis21, Leidos22, University of Texas Health Science Center at San Antonio23
TL;DR: A workshop was held at the National Institutes of Health with representatives from the multiple communities developing and employing targeted MS assays and defined three tiers of assays distinguished by their performance and extent of analytical characterization.
476 citations
TL;DR: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases and reveals a general convergence of practices on most elements of the analysis and interpretation process.
Abstract: Background
There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance.
429 citations
TL;DR: In this paper, the authors present a compendium of highly specific assays covering more than 10,000 human proteins and enabling their targeted analysis in SWATH-MS datasets acquired from research or clinical specimens.
Abstract: Mass spectrometry is the method of choice for deep and reliable exploration of the (human) proteome. Targeted mass spectrometry reliably detects and quantifies pre-determined sets of proteins in a complex biological matrix and is used in studies that rely on the quantitatively accurate and reproducible measurement of proteins across multiple samples. It requires the one-time, a priori generation of a specific measurement assay for each targeted protein. SWATH-MS is a mass spectrometric method that combines data-independent acquisition (DIA) and targeted data analysis and vastly extends the throughput of proteins that can be targeted in a sample compared to selected reaction monitoring (SRM). Here we present a compendium of highly specific assays covering more than 10,000 human proteins and enabling their targeted analysis in SWATH-MS datasets acquired from research or clinical specimens. This resource supports the confident detection and quantification of 50.9% of all human proteins annotated by UniProtKB/Swiss-Prot and is therefore expected to find wide application in basic and clinical research. Data are available via ProteomeXchange (PXD000953-954) and SWATHAtlas (SAL00016-35).
378 citations
Oregon Health & Science University1, Baylor College of Medicine2, Stony Brook University3, University of Arizona4, Pompeu Fabra University5, Howard Hughes Medical Institute6, University of Washington7, University College London8, German Primate Center9, University of Bari10, Louisiana State University11, University of Toulouse12, Johns Hopkins University13, University of Utah14, Texas A&M University15, Babeș-Bolyai University16, Children's Hospital Oakland Research Institute17, University of Colorado Denver18, Max Delbrück Center for Molecular Medicine19, University of Barcelona20, Indiana University21, Washington University in St. Louis22, Institute for Systems Biology23, Pennsylvania State University24, University of Pittsburgh25, Harvard University26, Stanford University27, University of Cambridge28, University of California, San Francisco29, Paul Ehrlich Institute30, Gibbon Conservation Center31, University of Chicago32, Broad Institute33
TL;DR: The assembly and analysis of a northern white-cheeked gibbon genome is presented and the propensity for a gibbon-specific retrotransposon (LAVA) to insert into chromosome segregation genes and alter transcription by providing a premature termination site is described, suggesting a possible molecular mechanism for the genome plasticity of the gibbon lineage.
Abstract: Gibbons are small arboreal apes that display an accelerated rate of evolutionary chromosomal rearrangement and occupy a key node in the primate phylogeny between Old World monkeys and great apes. Here we present the assembly and analysis of a northern white-cheeked gibbon (Nomascus leucogenys) genome. We describe the propensity for a gibbon-specific retrotransposon (LAVA) to insert into chromosome segregation genes and alter transcription by providing a premature termination site, suggesting a possible molecular mechanism for the genome plasticity of the gibbon lineage. We further show that the gibbon genera (Nomascus, Hylobates, Hoolock and Symphalangus) experienced a near-instantaneous radiation ~5 million years ago, coincident with major geographical changes in southeast Asia that caused cycles of habitat compression and expansion. Finally, we identify signatures of positive selection in genes important for forelimb development (TBX5) and connective tissues (COL1A1) that may have been involved in the adaptation of gibbons to their arboreal habitat.
318 citations
University of California, Santa Cruz1, University of Florida2, Mississippi State University3, Pompeu Fabra University4, University of Texas at Arlington5, University of Colorado Denver6, University UCINF7, Austral University of Chile8, Genetic Information Research Institute9, Institute for Systems Biology10, University of Georgia11, University of Münster12, Uppsala University13, University of Sydney14, University of the Republic15, Occidental College16, University of Arizona17, Harvard University18, North Carolina State University19, Howard Hughes Medical Institute20, University of Copenhagen21, University of Tokyo22, University of Iowa23, University of Delaware24, Louisiana State University25, University of California, Los Angeles26, Catalan Institution for Research and Advanced Studies27, Texas Tech University28
TL;DR: An exceptionally slow rate of genome evolution within crocodilians at all levels is observed, consistent with a single underlying cause of a reduced rate of evolutionary change rather than intrinsic differences in base repair machinery.
Abstract: ?? To provide context for the diversification of archosaurs—the group that includes crocodilians, dinosaurs, and birds—we generated draft genomes of three crocodilians: Alligator mississippiensis (the American alligator), Crocodylus porosus (the saltwater crocodile), and Gavialis gangeticus (the Indian gharial). We observed an exceptionally slow rate of genome evolution within crocodilians at all levels, including nucleotide substitutions, indels, transposable element content and movement, gene family evolution, and chromosomal synteny. When placed within the context of related taxa including birds and turtles, this suggests that the common ancestor of all of these taxa also exhibited slow genome evolution and that the comparatively rapid evolution is derived in birds. The data also provided the opportunity to analyze heterozygosity in crocodilians, which indicates a likely reduction in population size for all three taxa through the Pleistocene. Finally, these data combined with newly published bird genomes allowed us to reconstruct the partial genome of the common ancestor of archosaurs, thereby providing a tool to investigate the genetic starting material of crocodilians, birds, and dinosaurs.
306 citations
TL;DR: Genome-wide analysis indicates that Ascl2 directly regulates TFH-related genes whereas it inhibits expression of T-helper cell 1 (TH1) and TH17 signature genes.
Abstract: In immune responses, activated T cells migrate to B-cell follicles and develop into follicular T-helper (TFH) cells, a recently identified subset of CD4(+) T cells specialized in providing help to B lymphocytes in the induction of germinal centres. Although Bcl6 has been shown to be essential in TFH-cell function, it may not regulate the initial migration of T cells or the induction of the TFH program, as exemplified by C-X-C chemokine receptor type 5 (CXCR5) upregulation. Here we show that expression of achaete-scute homologue 2 (Ascl2)--a basic helix-loop-helix (bHLH) transcription factor--is selectively upregulated in TFH cells. Ectopic expression of Ascl2 upregulates CXCR5 but not Bcl6, and downregulates C-C chemokine receptor 7 (CCR7) expression in T cells in vitro, as well as accelerating T-cell migration to the follicles and TFH-cell development in vivo in mice. Genome-wide analysis indicates that Ascl2 directly regulates TFH-related genes whereas it inhibits expression of T-helper cell 1 (TH1) and TH17 signature genes. Acute deletion of Ascl2, as well as blockade of its function with the Id3 protein in CD4(+) T cells, results in impaired TFH-cell development and germinal centre response. Conversely, mutation of Id3, known to cause antibody-mediated autoimmunity, greatly enhances TFH-cell generation. Thus, Ascl2 directly initiates TFH-cell development.
296 citations
TL;DR: How cell fate can be determined by glycolytic dynamics combined with cell heterogeneity purely at the metabolic level is revealed, extending fundamental knowledge of this central pathway that is dysfunctional in diseases such as diabetes and cancer.
Abstract: Cells need to adapt to dynamic environments. Yeast that fail to cope with dynamic changes in the abundance of glucose can undergo growth arrest. We show that this failure is caused by imbalanced reactions in glycolysis, the essential pathway in energy metabolism in most organisms. The imbalance arises largely from the fundamental design of glycolysis, making this state of glycolysis a generic risk. Cells with unbalanced glycolysis coexisted with vital cells. Spontaneous, nongenetic metabolic variability among individual cells determines which state is reached and, consequently, which cells survive. Transient ATP (adenosine 5'-triphosphate) hydrolysis through futile cycling reduces the probability of reaching the imbalanced state. Our results reveal dynamic behavior of glycolysis and indicate that cell fate can be determined by heterogeneity purely at the metabolic level.
TL;DR: It is shown that actually only a subpopulation is fit enough to partake in the second growth phase and present an evolutionary model, suggesting that this phenomenon might entail a bet-hedging strategy that helps bacteria adapt to the unexpectedly changing environment.
Abstract: When bacteria grow in a medium with two sugars, they first use the preferred sugar and only then start metabolizing the second one. After the first exponential growth phase, a short lag phase of nongrowth is observed, a period called the diauxie lag phase. It is commonly seen as a phase in which the bacteria prepare themselves to use the second sugar. Here we reveal that, in contrast to the established concept of metabolic adaptation in the lag phase, two stable cell types with alternative metabolic strategies emerge and coexist in a culture of the bacterium Lactococcus lactis. Only one of them continues to grow. The fraction of each metabolic phenotype depends on the level of catabolite repression and the metabolic state-dependent induction of stringent response, as well as on epigenetic cues. Furthermore, we show that the production of alternative metabolic phenotypes potentially entails a bet-hedging strategy. This study sheds new light on phenotypic heterogeneity during various lag phases occurring in microbiology and biotechnology and adjusts the generally accepted explanation of enzymatic adaptation proposed by Monod and shared by scientists for more than half a century.
TL;DR: Overall, the evidence indicates that a well-balanced diet is beneficial to all COPD patients, not only for its potential pulmonary benefits, but also for its proven benefits in metabolic and cardiovascular risk.
Abstract: Nutrition and metabolism have been the topic of extensive scientific research in chronic obstructive pulmonary disease (COPD) but clinical awareness of the impact dietary habits, nutritional status and nutritional interventions may have on COPD incidence, progression and outcome is limited. A multidisciplinary Task Force was created by the European Respiratory Society to deliver a summary of the evidence and description of current practice in nutritional assessment and therapy in COPD, and to provide directions for future research. Task Force members conducted focused reviews of the literature on relevant topics, advised by a methodologist. It is well established that nutritional status, and in particular abnormal body composition, is an important independent determinant of COPD outcome. The Task Force identified different metabolic phenotypes of COPD as a basis for nutritional risk profile assessment that is useful in clinical trial design and patient counselling. Nutritional intervention is probably effective in undernourished patients and probably most when combined with an exercise programme. Providing evidence of cost-effectiveness of nutritional intervention is required to support reimbursement and thus increase access to nutritional intervention. Overall, the evidence indicates that a well-balanced diet is beneficial to all COPD patients, not only for its potential pulmonary benefits, but also for its proven benefits in metabolic and cardiovascular risk.
Baylor College of Medicine1, University of Texas at San Antonio2, University of Bari3, Agency for Science, Technology and Research4, Louisiana State University5, Comenius University in Bratislava6, University of Wisconsin-Madison7, Indiana University8, Saint Louis University9, University of Illinois at Urbana–Champaign10, Children's Hospital Oakland Research Institute11, University of Washington12, Wellcome Trust Sanger Institute13, University of Geneva14, Boehringer Ingelheim15, University of Houston16, Harvard University17, University College London18, Institute for Systems Biology19, Massachusetts Institute of Technology20, University of Utah21, University of Oviedo22, Pompeu Fabra University23, Novartis24, University of California, Santa Cruz25, Howard Hughes Medical Institute26, Wayne State University27, Rutgers University28, Swiss Institute of Bioinformatics29, Imperial College London30
TL;DR: The whole-genome sequence of the common marmoset enables increased power for comparative analyses among available primate genomes and facilitates biomedical research application.
Abstract: Kim Worley and colleagues report the whole-genome sequence of the common marmoset, Callithrix jacchus, the first New World monkey to be sequenced.
TL;DR: A real-time, label-free, and quantitative method to detect and characterize tumor-derived exosomes without enrichment or purification is presented and a positive correlation between the metastatic potential of tumor cell lines and exosome secretion is found.
Abstract: Exosomes are endosome-derived membrane vesicles carrying proteins and nucleic acids that are involved in cellular functions such as intercellular communication, protein and RNA secretion, and antigen presentation. Therefore, exosomes serve as potential biomarkers for many diseases including cancer. Because exosomes are difficult to enrich or purify from biofluids, quantification of exosomes is tedious and inaccurate. Here, we present a real-time, label-free, and quantitative method to detect and characterize tumor-derived exosomes without enrichment or purification. Utilizing surface plasmon resonance imaging (SPRi) in combination with antibody microarrays specific to the extracellular domains of exosome membrane proteins, exosomes in tumor cell culture medium can be quantitatively detected. We found a positive correlation between the metastatic potential of tumor cell lines and exosome secretion. This method provides an easy, efficient, and novel way to detect exosome secretion and thus an avenue toward the diagnosis and prognosis prediction of cancer.
TL;DR: CTNNB1 exon 3 mutations are likely a driver that characterize an aggressive subset of low-grade and low-stage EEC occurring in younger women.
Abstract: Endometrial carcinoma (EC) is the most common gynecological cancer in the western world, with approximately 49560 EC cases estimated in the United States in 2013 (1). In contrast to many other cancers, the incidence of endometrial cancer is increasing, likely because of the fact that obesity is a major risk factor for EC (2). This increased incidence is also associated with increased mortality, as the deaths from EC in the US have increased dramatically, from 2900 deaths in 1987 to 8190 deaths in 2013, a 2.8x increase over 25 years. Endometrial cancer is clinically categorized into two subtypes that help to determine risk of recurrence and guide treatment (3). Type I carcinomas, which account for the majority of cases (70–80%), are typically associated with a good prognosis, early stage at diagnosis, estrogen signaling, obesity, and low-grade endometrioid histology (EEC). Type II cancers are characterized by high stage at time of diagnosis, nonendometrioid histology, and poor prognosis. Differences in molecular aberrations between these two types of EC have been previously reported (3–5). Clustering analysis of all EC samples together commonly segregates cases based largely on differences between serous vs endometrioid histologies (3,6). A more defined tumor classification for EEC, the largest histological group of EC, is needed.
Whereas type II EC invariably exhibits poor prognosis, the clinical course for type I EC can be unpredictable (7). Overall outcomes for EEC vary with International Federation of Gynecology and Obstetrics (FIGO) stage and tumor grade, but individual patients with endometrioid carcinomas have statistically significantly different clinical courses and show different responses to therapy, despite having tumors with similar histopathology (8). Histology is therefore insufficient to predict clinical course for EEC, and presently no clinical laboratory assay addresses this unmet need.
We propose that molecular subtyping of EEC may inform diagnosis and prognosis of women with low grade, early-stage disease by identifying molecular attributes defining EEC case patients at risk for a more aggressive clinical course; patients with such tumors may benefit from more aggressive management. We performed new analyses of whole-exome and RNA sequencing, RPPA profiling, and clinical data archived by TCGA for more than 200 EEC case patients. Reanalysis of the TCGA data of EEC samples and excluding those with serous histology identified four transcriptome subtypes in EEC that exhibited distinct clinicopathologic characteristics and mutation spectra. One of the subtypes identifies an aggressive variant of type I EEC previously not recognized.
University of Tübingen1, Katholieke Universiteit Leuven2, University of Luxembourg3, Institute for Systems Biology4, University of Rennes5, University of Kiel6, University of Antwerp7, Boston Children's Hospital8, Utrecht University9, University of Cologne10, Max Delbrück Center for Molecular Medicine11, Centre national de la recherche scientifique12, University of Southern Denmark13, University of Ulm14
TL;DR: The results thus implicate STX1B and the presynaptic release machinery in fever-associated epilepsy syndromes.
Abstract: Febrile seizures affect 2-4% of all children and have a strong genetic component. Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2) have been identified that cause febrile seizures with or without epilepsy. Here we report the identification of mutations in STX1B, encoding syntaxin-1B, that are associated with both febrile seizures and epilepsy. Whole-exome sequencing in independent large pedigrees identified cosegregating STX1B mutations predicted to cause an early truncation or an in-frame insertion or deletion. Three additional nonsense or missense mutations and a de novo microdeletion encompassing STX1B were then identified in 449 familial or sporadic cases. Video and local field potential analyses of zebrafish larvae with antisense knockdown of stx1b showed seizure-like behavior and epileptiform discharges that were highly sensitive to increased temperature. Wild-type human syntaxin-1B but not a mutated protein rescued the effects of stx1b knockdown in zebrafish. Our results thus implicate STX1B and the presynaptic release machinery in fever-associated epilepsy syndromes.
TL;DR: It is shown that Ctcf hemizygous knockout mice are markedly susceptible to spontaneous, radiation-, and chemically induced cancer in a broad range of tissues and point to CTCF-mediated epigenetic stability as a major barrier to neoplastic progression.
TL;DR: It is suggested that mutations in NOTCH1 are the most common cause of AOS and add to a growing list of human diseases that have a vascular and/or bony component and are caused by alterations in the Notch signaling pathway.
Abstract: Notch signaling determines and reinforces cell fate in bilaterally symmetric multicellular eukaryotes Despite the involvement of Notch in many key developmental systems, human mutations in Notch signaling components have mainly been described in disorders with vascular and bone effects Here, we report five heterozygous NOTCH1 variants in unrelated individuals with Adams-Oliver syndrome (AOS), a rare disease with major features of aplasia cutis of the scalp and terminal transverse limb defects Using whole-genome sequencing in a cohort of 11 families lacking mutations in the four genes with known roles in AOS pathology (ARHGAP31, RBPJ, DOCK6, and EOGT), we found a heterozygous de novo 85 kb deletion spanning the NOTCH1 5′ region and three coding variants (c1285T>C [pCys429Arg], c4487G>A [pCys1496Tyr], and c5965G>A [pAsp1989Asn]), two of which are de novo, in four unrelated probands In a fifth family, we identified a heterozygous canonical splice-site variant (c743−1 G>T) in an affected father and daughter These variants were not present in 5,077 in-house control genomes or in public databases In keeping with the prominent developmental role described for Notch1 in mouse vasculature, we observed cardiac and multiple vascular defects in four of the five families We propose that the limb and scalp defects might also be due to a vasculopathy in NOTCH1-related AOS Our results suggest that mutations in NOTCH1 are the most common cause of AOS and add to a growing list of human diseases that have a vascular and/or bony component and are caused by alterations in the Notch signaling pathway
Stockholm University1, University of Leeds2, Environment Canada3, University of Toronto4, University of Helsinki5, Finnish Meteorological Institute6, National Research Council7, Remote Sensing Center8, Geophysical Institute, University of Bergen9, University of Innsbruck10, Leibniz Association11, University of Bayreuth12, Bigelow Laboratory For Ocean Sciences13, University of Colorado Boulder14, National Oceanic and Atmospheric Administration15, ETH Zurich16, Max Planck Society17, Institute for Systems Biology18, Queensland University of Technology19, Swedish Meteorological and Hydrological Institute20, Bjerknes Centre for Climate Research21, Lund University22, University of Miami23, University of Eastern Finland24
TL;DR: The Arctic Summer Cloud Ocean Study (ASCOS) was the most extensive central Arctic Ocean expedition with an atmospheric focus during the International Polar Year (IPY) 2007-2008 as discussed by the authors, which focused on the formation and life cycle of low-level Arctic clouds.
Abstract: The climate in the Arctic is changing faster than anywhere else on earth. Poorly understood feedback processes relating to Arctic clouds and aerosol-cloud interactions contribute to a poor understanding of the present changes in the Arctic climate system, and also to a large spread in projections of future climate in the Arctic. The problem is exacerbated by the paucity of research-quality observations in the central Arctic. Improved formulations in climate models require such observations, which can only come from measurements in situ in this difficult-to-reach region with logistically demanding environmental conditions. The Arctic Summer Cloud Ocean Study (ASCOS) was the most extensive central Arctic Ocean expedition with an atmospheric focus during the International Polar Year (IPY) 2007-2008. ASCOS focused on the study of the formation and life cycle of low-level Arctic clouds. ASCOS departed from Longyearbyen on Svalbard on 2 August and returned on 9 September 2008. In transit into and out of the pack ice, four short research stations were undertaken in the Fram Strait: two in open water and two in the marginal ice zone. After traversing the pack ice northward, an ice camp was set up on 12 August at 87°21′ N, 01°29′ W and remained in operation through 1 September, drifting with the ice. During this time, extensive measurements were taken of atmospheric gas and particle chemistry and physics, mesoscale and boundary-layer meteorology, marine biology and chemistry, and upper ocean physics. ASCOS provides a unique interdisciplinary data set for development and testing of new hypotheses on cloud processes, their interactions with the sea ice and ocean and associated physical, chemical, and biological processes and interactions. For example, the first-ever quantitative observation of bubbles in Arctic leads, combined with the unique discovery of marine organic material, polymer gels with an origin in the ocean, inside cloud droplets suggests the possibility of primary marine organically derived cloud condensation nuclei in Arctic stratocumulus clouds. Direct observations of surface fluxes of aerosols could, however, not explain observed variability in aerosol concentrations, and the balance between local and remote aerosols sources remains open. Lack of cloud condensation nuclei (CCN) was at times a controlling factor in low-level cloud formation, and hence for the impact of clouds on the surface energy budget. ASCOS provided detailed measurements of the surface energy balance from late summer melt into the initial autumn freeze-up, and documented the effects of clouds and storms on the surface energy balance during this transition. In addition to such process-level studies, the unique, independent ASCOS data set can and is being used for validation of satellite retrievals, operational models, and reanalysis data sets. © Author(s) 2014.
TL;DR: Together with previous studies that implicated several PARPs in immunity, as well as those that demonstrated a role for virally encoded macrodomains in host immune evasion, the evolutionary analyses suggest that addition, recognition and removal of ADP-ribosylation is a critical, underappreciated currency in host-virus conflicts.
Abstract: Post-translational protein modifications such as phosphorylation and ubiquitinylation are common molecular targets of conflict between viruses and their hosts. However, the role of other post-translational modifications, such as ADP-ribosylation, in host-virus interactions is less well characterized. ADP-ribosylation is carried out by proteins encoded by the PARP (also called ARTD) gene family. The majority of the 17 human PARP genes are poorly characterized. However, one PARP protein, PARP13/ZAP, has broad antiviral activity and has evolved under positive (diversifying) selection in primates. Such evolution is typical of domains that are locked in antagonistic ‘arms races’ with viral factors. To identify additional PARP genes that may be involved in host-virus interactions, we performed evolutionary analyses on all primate PARP genes to search for signatures of rapid evolution. Contrary to expectations that most PARP genes are involved in ‘housekeeping’ functions, we found that nearly one-third of PARP genes are evolving under strong recurrent positive selection. We identified a >300 amino acid disordered region of PARP4, a component of cytoplasmic vault structures, to be rapidly evolving in several mammalian lineages, suggesting this region serves as an important host-pathogen specificity interface. We also found positive selection of PARP9, 14 and 15, the only three human genes that contain both PARP domains and macrodomains. Macrodomains uniquely recognize, and in some cases can reverse, protein mono-ADP-ribosylation, and we observed strong signatures of recurrent positive selection throughout the macro-PARP macrodomains. Furthermore, PARP14 and PARP15 have undergone repeated rounds of gene birth and loss during vertebrate evolution, consistent with recurrent gene innovation. Together with previous studies that implicated several PARPs in immunity, as well as those that demonstrated a role for virally encoded macrodomains in host immune evasion, our evolutionary analyses suggest that addition, recognition and removal of ADP-ribosylation is a critical, underappreciated currency in host-virus conflicts.
TL;DR: The Crux mass spectrometry analysis software toolkit is an open source project that aims to provide users with a cross-platform suite of analysis tools for interpreting protein mass Spectrometry data.
Abstract: Efficiently and accurately analyzing big protein tandem mass spectrometry data sets requires robust software that incorporates state-of-the-art computational, machine learning, and statistical methods. The Crux mass spectrometry analysis software toolkit (http://cruxtoolkit.sourceforge.net) is an open source project that aims to provide users with a cross-platform suite of analysis tools for interpreting protein mass spectrometry data.
TL;DR: It is demonstrated that abundances are correlated between plasma and urine, and the most abundant urine proteins not derived from either plasma or kidney are examined, to consider the biomarker potential of proteins associated with renal decline.
Abstract: The kidney, urine, and plasma proteomes are intimately related: proteins and metabolic waste products are filtered from the plasma by the kidney and excreted via the urine, while kidney proteins may be secreted into the circulation or released into the urine. Shotgun proteomics data sets derived from human kidney, urine, and plasma samples were collated and processed using a uniform software pipeline, and relative protein abundances were estimated by spectral counting. The resulting PeptideAtlas builds yielded 4005, 2491, and 3553 nonredundant proteins at 1% FDR for the kidney, urine, and plasma proteomes, respectively - for kidney and plasma, the largest high-confidence protein sets to date. The same pipeline applied to all available human data yielded a 2013 Human PeptideAtlas build containing 12,644 nonredundant proteins and at least one peptide for each of ∼14,000 Swiss-Prot entries, an increase over 2012 of ∼7.5% of the predicted human proteome. We demonstrate that abundances are correlated between plasma and urine, examine the most abundant urine proteins not derived from either plasma or kidney, and consider the biomarker potential of proteins associated with renal decline. This analysis forms part of the Biology and Disease-driven Human Proteome Project (B/D-HPP) and is a contribution to the Chromosome-centric Human Proteome Project (C-HPP) special issue.
TL;DR: It is proposed to remove 638 genes from the denominator that are "uncertain" or "dubious" in Ensembl, UniProt/SwissProt, and neXtProt to leave 3844 "missing proteins", currently having no or inadequate documentation, to be found from a new denominator of 19,490 protein-coding genes.
Abstract: One year ago the Human Proteome Project (HPP) leadership designated the baseline metrics for the Human Proteome Project to be based on neXtProt with a total of 13 664 proteins validated at protein evidence level 1 (PE1) by mass spectrometry, antibody-capture, Edman sequencing, or 3D structures. Corresponding chromosome-specific data were provided from PeptideAtlas, GPMdb, and Human Protein Atlas. This year, the neXtProt total is 15 646 and the other resources, which are inputs to neXtProt, have high-quality identifications and additional annotations for 14 012 in PeptideAtlas, 14 869 in GPMdb, and 10 976 in HPA. We propose to remove 638 genes from the denominator that are “uncertain” or “dubious” in Ensembl, UniProt/SwissProt, and neXtProt. That leaves 3844 “missing proteins”, currently having no or inadequate documentation, to be found from a new denominator of 19 490 protein-coding genes. We present those tabulations and web links and discuss current strategies to find the missing proteins.
TL;DR: A systems-level framework describing the transcriptome of a devastating bacterial pathogen is described, the transcriptional influence of nearly all individual transcription factors in M. tuberculosis is characterized, and the phenotype of a regulator that reduces susceptibility to a first line anti-tubercular drug is validated.
Abstract: Mycobacterium tuberculosis senses and responds to the shifting and hostile landscape of the host. To characterize the underlying intertwined gene regulatory network governed by approximately 200 transcription factors of M. tuberculosis, we have assayed the global transcriptional consequences of overexpressing each transcription factor from an inducible promoter. We cloned and overexpressed 206 transcription factors in M. tuberculosis to identify the regulatory signature of each. We identified 9,335 regulatory consequences of overexpressing each of 183 transcription factors, providing evidence of regulation for 70% of the M. tuberculosis genome. These transcriptional signatures agree well with previously described M. tuberculosis regulons. The number of genes differentially regulated by transcription factor overexpression varied from hundreds of genes to none, with the majority of expression changes repressing basal transcription. Exploring the global transcriptional maps of transcription factor overexpressing (TFOE) strains, we predicted and validated the phenotype of a regulator that reduces susceptibility to a first line anti-tubercular drug, isoniazid. We also combined the TFOE data with an existing model of M. tuberculosis metabolism to predict the growth rates of individual TFOE strains with high fidelity. This work has led to a systems-level framework describing the transcriptome of a devastating bacterial pathogen, characterized the transcriptional influence of nearly all individual transcription factors in M. tuberculosis, and demonstrated the utility of this resource. These results will stimulate additional systems-level and hypothesis-driven efforts to understand M. tuberculosis adaptations that promote disease.
TL;DR: The systems genomics approach showed consistency across different biological levels (DNA, RNA and protein concentrations).
Abstract: The human neuroblastoma cell line, SH-SY5Y, is a commonly used cell line in studies related to neurotoxicity, oxidative stress, and neurodegenerative diseases. Although this cell line is often used as a cellular model for Parkinson’s disease, the relevance of this cellular model in the context of Parkinson’s disease (PD) and other neurodegenerative diseases has not yet been systematically evaluated. We have used a systems genomics approach to characterize the SH-SY5Y cell line using whole-genome sequencing to determine the genetic content of the cell line and used transcriptomics and proteomics data to determine molecular correlations. Further, we integrated genomic variants using a network analysis approach to evaluate the suitability of the SH-SY5Y cell line for perturbation experiments in the context of neurodegenerative diseases, including PD. The systems genomics approach showed consistency across different biological levels (DNA, RNA and protein concentrations). Most of the genes belonging to the major Parkinson’s disease pathways and modules were intact in the SH-SY5Y genome. Specifically, each analysed gene related to PD has at least one intact copy in SH-SY5Y. The disease-specific network analysis approach ranked the genetic integrity of SH-SY5Y as higher for PD than for Alzheimer’s disease but lower than for Huntington’s disease and Amyotrophic Lateral Sclerosis for loss of function perturbation experiments.
TL;DR: The post-transcriptional regulatory network that is involved in EMT and MET is discussed and how targeting E MT and MET may provide effective therapeutics for human disease is discussed.
Abstract: Epithelial-to-mesenchymal transition (EMT) and its reverse process, mesenchymal-to-epithelial transition (MET), play important roles in embryogenesis, stem cell biology, and cancer progression. EMT can be regulated by many signaling pathways and regulatory transcriptional networks. Furthermore, post-transcriptional regulatory networks regulate EMT; these networks include the long non-coding RNA (lncRNA) and microRNA (miRNA) families. Specifically, the miR-200 family, miR-101, miR-506, and several lncRNAs have been found to regulate EMT. Recent studies have illustrated that several lncRNAs are overexpressed in various cancers and that they can promote tumor metastasis by inducing EMT. MiRNA controls EMT by regulating EMT transcription factors or other EMT regulators, suggesting that lncRNAs and miRNA are novel therapeutic targets for the treatment of cancer. Further efforts have shown that non-coding-mediated EMT regulation is closely associated with epigenetic regulation through promoter methylation (e.g., miR-200 or miR-506) and protein regulation (e.g., SET8 via miR-502). The formation of gene fusions has also been found to promote EMT in prostate cancer. In this review, we discuss the post-transcriptional regulatory network that is involved in EMT and MET and how targeting EMT and MET may provide effective therapeutics for human disease.
TL;DR: ITEP harnesses the power of comparative genomics to build confidence in links between genotype and phenotype and helps disambiguate gene annotations when they are evaluated in both evolutionary and metabolic network contexts.
Abstract: Comparative genomics is a powerful approach for studying variation in physiological traits as well as the evolution and ecology of microorganisms. Recent technological advances have enabled sequencing large numbers of related genomes in a single project, requiring computational tools for their integrated analysis. In particular, accurate annotations and identification of gene presence and absence are critical for understanding and modeling the cellular physiology of newly sequenced genomes. Although many tools are available to compare the gene contents of related genomes, new tools are necessary to enable close examination and curation of protein families from large numbers of closely related organisms, to integrate curation with the analysis of gain and loss, and to generate metabolic networks linking the annotations to observed phenotypes. We have developed ITEP, an Integrated Toolkit for Exploration of microbial Pan-genomes, to curate protein families, compute similarities to externally-defined domains, analyze gene gain and loss, and generate draft metabolic networks from one or more curated reference network reconstructions in groups of related microbial species among which the combination of core and variable genes constitute the their "pan-genomes". The ITEP toolkit consists of: (1) a series of modular command-line scripts for identification, comparison, curation, and analysis of protein families and their distribution across many genomes; (2) a set of Python libraries for programmatic access to the same data; and (3) pre-packaged scripts to perform common analysis workflows on a collection of genomes. ITEP’s capabilities include de novo protein family prediction, ortholog detection, analysis of functional domains, identification of core and variable genes and gene regions, sequence alignments and tree generation, annotation curation, and the integration of cross-genome analysis and metabolic networks for study of metabolic network evolution. ITEP is a powerful, flexible toolkit for generation and curation of protein families. ITEP's modular design allows for straightforward extension as analysis methods and tools evolve. By integrating comparative genomics with the development of draft metabolic networks, ITEP harnesses the power of comparative genomics to build confidence in links between genotype and phenotype and helps disambiguate gene annotations when they are evaluated in both evolutionary and metabolic network contexts.
TL;DR: It is found that deregulation of miR‐506 in ovarian carcinoma promotes an aggressive phenotype, and it is demonstrated that CDK4 and CDK6 are direct targets of mi R‐506, and that miR-506 can inhibit CDK 4/6–FOXM1 signalling, which is activated in the majority of serous ovarian carcinomas.
Abstract: Ovarian carcinoma is the most lethal gynaecological malignancy. Better understanding of the molecular pathogenesis of this disease and effective targeted therapies are needed to improve patient outcomes. MicroRNAs play important roles in cancer progression and have the potential for use as either therapeutic agents or targets. Studies in other cancers have suggested that miR-506 has anti-tumour activity, but its function has yet to be elucidated. We found that deregulation of miR-506 in ovarian carcinoma promotes an aggressive phenotype. Ectopic over-expression of miR-506 in ovarian cancer cells was sufficient to inhibit proliferation and to promote senescence. We also demonstrated that CDK4 and CDK6 are direct targets of miR-506, and that miR-506 can inhibit CDK4/6–FOXM1 signalling, which is activated in the majority of serous ovarian carcinomas. This newly recognized miR-506–CDK4/6–FOXM1 axis provides further insight into the pathogenesis of ovarian carcinoma and identifies a potential novel therapeutic agent. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd
TL;DR: The structural pocket around S184 is employed as a docking site to screen the NCI library of small molecules using the UCSF-DOCK program suite and offers a strategy for the treatment of lung cancer and other Bax-expressing malignancies.
Abstract: Bax, a central death regulator, is required at the decisional stage of apoptosis. We recently identified serine 184 (S184) of Bax as a critical functional switch controlling its proapoptotic activity. Here we used the structural pocket around S184 as a docking site to screen the NCI library of small molecules using the UCSF-DOCK programme suite. Three compounds, small-molecule Bax agonists SMBA1, SMBA2 and SMBA3, induce conformational changes in Bax by blocking S184 phosphorylation, facilitating Bax insertion into mitochondrial membranes and forming Bax oligomers. The latter leads to cytochrome c release and apoptosis in human lung cancer cells, which occurs in a Bax- but not Bak-dependent fashion. SMBA1 potently suppresses lung tumour growth via apoptosis by selectively activating Bax in vivo without significant normal tissue toxicity. Development of Bax agonists as a new class of anticancer drugs offers a strategy for the treatment of lung cancer and other Bax-expressing malignancies.