47 research outputs found

    Runx1 promotes scar deposition and inhibits myocardial proliferation and survival during zebrafish heart regeneration.

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    Runx1 is a transcription factor that plays a key role in determining the proliferative and differential state of multiple cell types, during both development and adulthood. Here, we report how Runx1 is specifically upregulated at the injury site during zebrafish heart regeneration, and that absence of runx1 results in increased myocardial survival and proliferation, and overall heart regeneration, accompanied by decreased fibrosis. Using single cell sequencing, we found that the wild-type injury site consists of Runx1-positive endocardial cells and thrombocytes that induce expression of smooth muscle and collagen genes. Both these populations cannot be identified in runx1 mutant wounds that contain less collagen and fibrin. The reduction in fibrin in the mutant is further explained by reduced myofibroblast formation and upregulation of components of the fibrin degradation pathway, including plasminogen receptor annexin 2A as well as downregulation of plasminogen activator inhibitor serpine1 in myocardium and endocardium, resulting in increased levels of plasminogen. Our findings suggest that Runx1 controls the regenerative response of multiple cardiac cell types and that targeting Runx1 is a novel therapeutic strategy for inducing endogenous heart repair.BHF, Wellcome, MR

    Response of the Great Barrier Reef to sea level and environmental changes over the past 30,000 years

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    Previous drilling through submerged fossil coral reefs has greatly improved our understanding of the general pattern of sea-level change since the Last Glacial Maximum, however, how reefs responded to these changes remains uncertain. Here we document the evolution of the Great Barrier Reef (GBR), the world\u27s largest reef system, to major, abrupt environmental changes over the past 30 thousand years based on comprehensive sedimentological, biological and geochronological records from fossil reef cores. We show that reefs migrated seaward as sea level fell to its lowest level during the most recent glaciation (~20.5-20.7 thousand years ago (ka)), then landward as the shelf flooded and ocean temperatures increased during the subsequent deglacial period (~20-10 ka). Growth was interrupted by five reef-death events caused by subaerial exposure or sea-level rise outpacing reef growth. Around 10 ka, the reef drowned as the sea level continued to rise, flooding more of the shelf and causing a higher sediment flux. The GBR\u27s capacity for rapid lateral migration at rates of 0.2-1.5 m yr−1 (and the ability to recruit locally) suggest that, as an ecosystem, the GBR has been more resilient to past sea-level and temperature fluctuations than previously thought, but it has been highly sensitive to increased sediment input over centennial-millennial timescales

    The Chiral Potts Models Revisited

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    In honor of Onsager's ninetieth birthday, we like to review some exact results obtained so far in the chiral Potts models and to translate these results into language more transparent to physicists, so that experts in Monte Carlo calculations, high and low temperature expansions, and various other methods, can use them. We shall pay special attention to the interfacial tension ϵr\epsilon_r between the kk state and the krk-r state. By examining the ground states, it is seen that the integrable line ends at a superwetting point, on which the relation ϵr=rϵ1\epsilon_r=r\epsilon_1 is satisfied, so that it is energetically neutral to have one interface or more. We present also some partial results on the meaning of the integrable line for low temperatures where it lives in the non-wet regime. We make Baxter's exact results more explicit for the symmetric case. By performing a Bethe Ansatz calculation with open boundary conditions we confirm a dilogarithm identity for the low-temperature expansion which may be new. We propose a new model for numerical studies. This model has only two variables and exhibits commensurate and incommensurate phase transitions and wetting transitions near zero temperature. It appears to be not integrable, except at one point, and at each temperature there is a point, where it is almost identical with the integrable chiral Potts model.Comment: J. Stat. Phys., LaTeX using psbox.tex and AMS fonts, 69 pages, 30 figure

    GHQ increases among Scottish 15 year olds 1987–2006

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    BACKGROUND: Increases in a number of psychosocial disorders have been identified among Western youth in the second half of the Twentieth century. However findings are not consistent, trends are complex, and comparisons over time are hampered by methodological problems. METHODS: Data were drawn from three samples identical in respect of age (15 years), school year (final year of statutory schooling) and geographical location (the West of Scotland). Each sample was administered the 12-item General Health Questionnaire, a measure of self-report psychological distress, in 1987 (N = 505), 1999 (N = 2,196) and 2006 (N = 3,194). Analyses were conducted to examine changes in: GHQ 'caseness'; individual items; and factors, derived via confirmatory factor analysis representing (a) 'negative' and 'positive' items, and (b) 'anxiety and depression', 'loss of confidence or self-esteem' and 'anhedonia and social dysfunction'. RESULTS: Based on the standard (2/3) cut-off, 'caseness' rates in 1987, 1999 and 2006 were 12.7, 15.1 and 21.5% (males) and 18.8, 32.5 and 44.1% (females). Similar increases were observed with more stringent 'caseness' cut-offs. Examination of individual items showed some to have increased much more markedly over time than others. There were larger increases among females for all except two items and some evidence, among both genders, of steeper increases among 'negative' items compared with 'positive' ones. However, the differences in slope were very small compared with the overall increases in both types. CONCLUSIONS: Data from three samples identical in respect of age, school year and geographical location, show marked increases in GHQ-12 'caseness' among females between 1987 and 1999 and among both males and females between 1999 and 2006. Although slightly steeper increases in 'negative' items raise the possibility that endorsing such symptoms may have become more acceptable, these were small in comparison with increases in all dimensions of psychological distress. The next step is to identify causal explanations for the increases reported here

    Genetic mechanisms of critical illness in COVID-19.

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    Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice
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