380 research outputs found

    Fusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified.

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    Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas with poor prognosis. Up to 30% of PTCL lack distinctive features and are classified as PTCL, not otherwise specified (PTCL-NOS). To further improve our understanding of the genetic landscape and biology of PTCL-NOS, we perform RNA-sequencing of 18 cases and validate results in an independent cohort of 37 PTCL cases. We identify FYN-TRAF3IP2, KHDRBS1-LCK and SIN3A-FOXO1 as new in-frame fusion transcripts, with FYN-TRAF3IP2 as a recurrent fusion detected in 8 of 55 cases. Using ex vivo and in vivo experiments, we demonstrate that FYN-TRAF3IP2 and KHDRBS1-LCK activate signaling pathways downstream of the T cell receptor (TCR) complex and confer therapeutic vulnerability to clinically available drugs

    Control and dysregulation of redox signalling in the gastrointestinal tract

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    Stabilizing effects of seagrass meadows on coastal water benthic food webs

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    Seagrass meadows ecosystem engineering effects are correlated to their density (which is in turn linked to seasonal cycles) and often cannot be perceived below a given threshold level of engineer density. The density and biomass of seagrass meadows (Z. marina) together with associated macrophytes undergo substantial seasonal changes, with clear declines in winter. The present study aims to test whether the seasonal changes in the density of recovering seagrass meadows affect the benthic food webs of the southern Baltic Sea (Puck Bay). It includes meiofauna, macrofauna and fish of vegetated and unvegetated habitats in summer and winter seasons. Two levels of organization have been tested – species-specific diet preferences using stable isotopes (δ13C, δ15N) in Bayesian mixing models (MixSIAR) and the community-scale food web characteristics by means of isotopic niches (SIBER). Between-habitat differences were observed for grazers, as a greater food source diversity in species from vegetated habitats was noted in both seasons. Larger between-habitat differences in winter were documented for suspension/detritus feeders. The community-wide approach showed that the differences between the habitats were greater in winter than in summer (as indicated by the lower overlap of the respective isotope niches). Overall, the presence of seagrass meadows increased ecological stability (in terms of the range of food sources utilized by consumers) in the faunal assemblage, while invertebrates from unvegetated areas shifted their diet to cope with winter conditions. Therefore, as a more complex system, not sensitive to seasonal changes, Z. marina meadows create a stable habitat with high resilience potential

    A library of human gut bacterial isolates paired with longitudinal multiomics data enables mechanistic microbiome research.

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    Our understanding of how the gut microbiome interacts with its human host has been restrained by limited access to longitudinal datasets to examine stability and dynamics, and by having only a few isolates to test mechanistic hypotheses. Here, we present the Broad Institute-OpenBiome Microbiome Library (BIO-ML), a comprehensive collection of 7,758 gut bacterial isolates paired with 3,632 genome sequences and longitudinal multi-omics data. We show that microbial species maintain stable population sizes within and across humans and that commonly used \u27omics\u27 survey methods are more reliable when using averages over multiple days of sampling. Variation of gut metabolites within people over time is associated with amino acid levels, and differences across people are associated with differences in bile acids. Finally, we show that genomic diversification can be used to infer eco-evolutionary dynamics and in vivo selection pressures for strains within individuals. The BIO-ML is a unique resource designed to enable hypothesis-driven microbiome research

    Ecological Drivers of and Responses by Arctic Benthic Communities, with an Emphasis on Kongsfjorden, Svalbard

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    Knowledge on the causes and consequences that structure benthic communities is essential to understand and conserve Arctic ecosystems. This review aims to summarize the current knowledge on the effects of abiotic and biotic factors on species interactions and community traits, i.e. diversity, structure, and functioning of Arctic coastal hard- and soft-bottom habitats, with emphasis on Kongsfjorden (Svalbard). Current evidence indicates that descriptive and mensurative studies on the distribution of species prevail and few studies allow inferences on the underlying processes generating observed patterns. Furthermore, Arctic hard- and soft-bottom communities show some fundamental differences in their ecology. The recovery in hard-bottom communities from disturbance, for instance, takes exceptionally long (i.e. > decadal) due to slow growth and/or sporadic recruitment, while it is considerably shorter in soft-bottom communities. Also, Arctic hard-bottom communities display strong competitive hierarchies that appear negligible in communities populating sedimentary shores. This review concludes with a suggestion to shift the focus in Arctic benthos research from pattern to processes and the identification of major research gaps. These include (i) the apparent demarcation of studies being devoted to either rocky or to sedimentary shores, which hamper studies on habitat connectivity, (ii) the lack of studies addressing the effects of pathogens and diseases on community ecology, and (iii) the incomplete assessment of potentially significant drivers of community ecology, such as trophic interactions, recruitment success, and competition

    Kelps and environmental changes in Kongsfjorden: Stress perception and responses

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    Frequent transmission of the Mycobacterium tuberculosis Beijing lineage and positive selection for the EsxW Beijing variant in Vietnam.

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    To examine the transmission dynamics of Mycobacterium tuberculosis (Mtb) isolated from tuberculosis patients in Ho Chi Minh City, Vietnam, we sequenced the whole genomes of 1,635 isolates and compared these with 3,144 isolates from elsewhere. The data identify an underlying burden of disease caused by the endemic Mtb lineage 1 associated with the activation of long-term latent infection, and a threefold higher burden associated with the more recently introduced Beijing lineage and lineage 4 Mtb strains. We find that Beijing lineage Mtb is frequently transferred between Vietnam and other countries, and detect higher levels of transmission of Beijing lineage strains within this host population than the endemic lineage 1 Mtb. Screening for parallel evolution of Beijing lineage-associated SNPs in other Mtb lineages as a signal of positive selection, we identify an alteration in the ESX-5 type VII-secreted protein EsxW, which could potentially contribute to the enhanced transmission of Beijing lineage Mtb in Vietnamese and other host populations

    Endothelial TLR4 and the microbiome drive cerebral cavernous malformations

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    Cerebral cavernous malformations (CCMs) are a cause of stroke and seizure for which no effective medical therapies yet exist. CCMs arise from the loss of an adaptor complex that negatively regulates MEKK3-KLF2/4 signalling in brain endothelial cells, but upstream activators of this disease pathway have yet to be identified. Here we identify endothelial Toll-like receptor 4 (TLR4) and the gut microbiome as critical stimulants of CCM formation. Activation of TLR4 by Gram-negative bacteria or lipopolysaccharide accelerates CCM formation, and genetic or pharmacologic blockade of TLR4 signalling prevents CCM formation in mice. Polymorphisms that increase expression of the TLR4 gene or the gene encoding its co-receptor CD14 are associated with higher CCM lesion burden in humans. Germ-free mice are protected from CCM formation, and a single course of antibiotics permanently alters CCM susceptibility in mice. These studies identify unexpected roles for the microbiome and innate immune signalling in the pathogenesis of a cerebrovascular disease, as well as strategies for its treatment
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