114 research outputs found
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Unique and Overlapping Actions of Type I and III IFNs in Influenza A Virus Infection and Implications for Therapy
Influenza A virus (IAV) poses a significant public health burden. Severe disease is characterised by infected lung airway epithelial cells (AECs), inflammation and tissue damage. However, disease severity differs between individuals and this cannot be entirely explained by inter-individual differences in pre-existing immunity or comorbidities. Host-specific, genetically determined factors must contribute to susceptibility. Type I interferon (IFNαβ) is known to have antiviral function in vitro, but its role in restricting IAV infection in vivo is controversial. We demonstrate that responsiveness to IFNαβ signalling is a host-specific determinant with protective or pathogenic potential which determines the severity of IAV-induced disease. IAV infected 129, CBA/J and DBA mouse strains showed dramatically increased mortality and lung damage, yet higher levels of pulmonary IFNαβ, compared to C57BL/6 or BALB/C mice. Ablation of IFNαβR signalling in 129 mice markedly reduced mortality, levels of proinflammatory cytokines, inflammatory cell recruitment and AEC apoptosis. Susceptibility to IAV-induced disease is influenced by the number of functional alleles for the IFNαβR subunit, IFNAR1, within the genome. IFNAR1+/-(129) mice were less susceptible than wild type 129s yet more so than IFNαβR-/-(129) mice. Conversely, triplication of a section of murine chromosome 16 that includes IFNAR1 in C57BL/6 mice enhanced IFNα response to IAV infection and downstream immunopathology. Finally, IFNα therapy of infected B6. A2G-Mxl mice reduced IAV titers, yet increased secretion of proinflammatory cytokines, innate cell recruitment and AEC apoptosis in the lung, due to the potent immunostimulatory capability to IFNα. In contrast, treatment with IFNλ, whose receptor is largely restricted to AECs, promoted IAV control without exacerbating IAV-induced inflammation. Thus, by manipulating the IFNαβ signal in various ways, we demonstrate that excessive IFNαβ in IAV infection can increase AEC death and enhance proinflammatory responses that ultimately increase disease severity. Our findings have important implications for prediction and treatment of severe influenza
“Experience First”: Investigating Co-creation Experience in Social Product Development Networks
Social product development (SPD) is a network-based innovation model in which firms or platforms use social mechanisms and social technologies to mobilize organizationally independent individuals––co-creators––to co-create new products. SPD networks require the maintenance of external participation across the innovation cycle to survive competition and thrive in the innovation sector. While prior research suggests that the viability, survivability, and productivity of social networks generally depend on user experience, we have limited evidence on the particular role of user experience in the context of SPD networks. Responding to this need, we introduce a conceptual model to theorize and operationalize co-creation experience in SPD networks. Through validating the proposed model, we demonstrate why co-creation experience is critical for predicting co-creators’ behavioral intentions and maintaining their actual contribution. Finally, we explore the theoretical and practical implications of the results. Future studies can leverage the findings to better capture co-creation experience and contribute to designing successful SPD networks
Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis
Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small-molecule PKM2 activators inhibits the growth of xenograft tumors. Structural studies reveal that small-molecule activators bind PKM2 at the subunit interaction interface, a site that is distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small-molecule activation of PKM2 can interfere with anabolic metabolism.National Institutes of Health (U.S.) (NIH grant R01 GM56203)National Institutes of Health (U.S.) (grant NIH 5P01CA120964)Dana-Farber/Harvard Cancer Center (NIH 5P30CA006516)National Institutes of Health (U.S.) (NIH grant R03MH085679)National Human Genome Research Institute (U.S.) (Intramural Research Program)National Institutes of Health (U.S.) (Molecular Libraries Initiative of the NIH Roadmap for Medical Research
Variable levels of drift in tunicate cardiopharyngeal gene regulatory elements.
Background: Mutations in gene regulatory networks often lead to genetic divergence without impacting gene expression or developmental patterning. The rules governing this process of developmental systems drift, including the variable impact of selective constraints on different nodes in a gene regulatory network, remain poorly delineated.
Results: Here we examine developmental systems drift within the cardiopharyngeal gene regulatory networks of two tunicate species, Corella inflata and Ciona robusta. Cross-species analysis of regulatory elements suggests that trans-regulatory architecture is largely conserved between these highly divergent species. In contrast, cis-regulatory elements within this network exhibit distinct levels of conservation. In particular, while most of the regulatory elements we analyzed showed extensive rearrangements of functional binding sites, the enhancer for the cardiopharyngeal transcription factor FoxF is remarkably well-conserved. Even minor alterations in spacing between binding sites lead to loss of FoxF enhancer function, suggesting that bound trans-factors form position-dependent complexes.
Conclusions: Our findings reveal heterogeneous levels of divergence across cardiopharyngeal cis-regulatory elements. These distinct levels of divergence presumably reflect constraints that are not clearly associated with gene function or position within the regulatory network. Thus, levels of cis-regulatory divergence or drift appear to be governed by distinct structural constraints that will be difficult to predict based on network architectur
Consensus coding sequence (CCDS) database: a standardized set of human and mouse protein-coding regions supported by expert curation.
The Consensus Coding Sequence (CCDS) project provides a dataset of protein-coding regions that are identically annotated on the human and mouse reference genome assembly in genome annotations produced independently by NCBI and the Ensembl group at EMBL-EBI. This dataset is the product of an international collaboration that includes NCBI, Ensembl, HUGO Gene Nomenclature Committee, Mouse Genome Informatics and University of California, Santa Cruz. Identically annotated coding regions, which are generated using an automated pipeline and pass multiple quality assurance checks, are assigned a stable and tracked identifier (CCDS ID). Additionally, coordinated manual review by expert curators from the CCDS collaboration helps in maintaining the integrity and high quality of the dataset. The CCDS data are available through an interactive web page (https://www.ncbi.nlm.nih.gov/CCDS/CcdsBrowse.cgi) and an FTP site (ftp://ftp.ncbi.nlm.nih.gov/pub/CCDS/). In this paper, we outline the ongoing work, growth and stability of the CCDS dataset and provide updates on new collaboration members and new features added to the CCDS user interface. We also present expert curation scenarios, with specific examples highlighting the importance of an accurate reference genome assembly and the crucial role played by input from the research community. Nucleic Acids Res 2018 Jan 4; 46(D1):D221-D228
Discovery of directional and nondirectional pioneer transcription factors by modeling DNase profile magnitude and shape
We describe protein interaction quantitation (PIQ), a computational method for modeling the magnitude and shape of genome-wide DNase I hypersensitivity profiles to identify transcription factor (TF) binding sites. Through the use of machine-learning techniques, PIQ identified binding sites for >700 TFs from one DNase I hypersensitivity analysis followed by sequencing (DNase-seq) experiment with accuracy comparable to that of chromatin immunoprecipitation followed by sequencing (ChIP-seq). We applied PIQ to analyze DNase-seq data from mouse embryonic stem cells differentiating into prepancreatic and intestinal endoderm. We identified 120 and experimentally validated eight 'pioneer' TF families that dynamically open chromatin. Four pioneer TF families only opened chromatin in one direction from their motifs. Furthermore, we identified 'settler' TFs whose genomic binding is principally governed by proximity to open chromatin. Our results support a model of hierarchical TF binding in which directional and nondirectional pioneer activity shapes the chromatin landscape for population by settler TFs.National Institutes of Health (U.S.) (Common Fund 5UL1DE019581)National Institutes of Health (U.S.) (Common Fund RL1DE019021)National Institutes of Health (U.S.) (Common Fund 5TL1EB008540)National Institutes of Health (U.S.) (Grant 1U01HG007037)National Institutes of Health (U.S.) (Grant 5P01NS055923
Investigation of type 1 diabetes and coeliac disease susceptibility loci for association with juvenile idiopathic arthritis
BACKGROUND: There is strong evidence suggesting that juvenile idiopathic arthritis (JIA) shares many susceptibility loci with other autoimmune diseases. OBJECTIVE: To investigate variants robustly associated with type 1 diabetes (T1D) or coeliac disease (CD) for association with JIA. METHODS: Sixteen single-nucleotide polymorphisms (SNPs) already identified as susceptibility loci for T1D/CD were selected for genotyping in patients with JIA (n=1054) and healthy controls (n=3129). Genotype and allele frequencies were compared using the Cochrane-Armitage trend test implemented in PLINK. RESULTS: One SNP in the LPP gene, rs1464510, showed significant association with JIA (p(trend)=0.002, OR=1.18, 95% CI 1.06 to 1.30). A second SNP, rs653178 in ATXN2, also showed nominal evidence for association with JIA (p(trend)=0.02, OR=1.13, 95% CI 1.02 to 1.25). The SNP, rs17810546, in IL12A showed subtype-specific association with enthesitis-related arthritis (ERA) subtype (p(trend)=0.005, OR=1.88, 95% CI 1.2 to 2.94). CONCLUSIONS: Evidence for a novel JIA susceptibility locus, LPP, is presented. Association at the SH2B3/ATXN2 locus, previously reported to be associated with JIA in a US series, also supports this region as contributing to JIA susceptibility. In addition, a subtype-specific association of IL12A with ERA is identified. All findings will require validation in independent JIA cohorts
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