Coxsackievirus B Type 4 Infection in beta Cells Downregulates the Chaperone Prefoldin URI to Induce a MODY4-like Diabetes via Pdx1 Silencing

Enteroviruses are suspected to contribute to insulin-producing beta cell loss and hyperglycemia-induced diabetes. However, mechanisms are not fully defined. Here, we show that coxsackievirus B type 4 (CVB4) infection in human islet-engrafted mice and in rat insulinoma cells displays loss of unconventional prefoldin RPB5 interactor (URI) and PDX1, affecting beta cell function and identity. Genetic URI ablation in the mouse pancreas causes PDX1 depletion in beta cells. Importantly, diabetic PDX1 heterozygous mice overexpressing URI in beta cells are more glucose tolerant. Mechanistically, URI loss triggers estrogen receptor nuclear translocation leading to DNA methyltransferase 1 (DNMT1) expression, which induces Pdx1 promoter hypermethylation and silencing. Consequently, demethylating agent procainamide-mediated DNMT1 inhibition reinstates PDX1 expression and protects against diabetes in pancreatic URI-depleted mice . Finally, the beta cells of human diabetes patients show correlations between viral protein 1 and URI, PDX1, and DNMT1 levels. URI and DNMT1 expression and PDX1 silencing provide a causal link between enterovirus infection and diabetes

SHARDS frontier fields: physical properties of a low-mass Lyα emitter at z = 5.75

We analyze the properties of a multiply-imaged Lyman-alpha (Lya) emitter at z=5.75 identified through SHARDS Frontier Fields intermediate-band imaging of the Hubble Frontier Fields (HFF) cluster Abell 370. The source, A370-L57, has low intrinsic luminosity (M_UV~-16.5), steep UV spectral index (\beta=-2.4+/-0.1), and extreme rest-frame equivalent width of Lya (EW(Lya)=420+180-120 \AA). Two different gravitational lens models predict high magnification (\mu~10--16) for the two detected counter-images, separated by 7", while a predicted third counter-image (\mu~3--4) is undetected. We find differences of ~50% in magnification between the two lens models, quantifying our current systematic uncertainties. Integral field spectroscopy of A370-L57 with MUSE shows a narrow (FWHM=204+/-10 km/s) and asymmetric Lya profile with an integrated luminosity L(Lya)~10^42 erg/s. The morphology in the HST bands comprises a compact clump (r_e<100 pc) that dominates the Lya and continuum emission and several fainter clumps at projected distances <1 kpc that coincide with an extension of the Lya emission in the SHARDS F823W17 and MUSE observations. The latter could be part of the same galaxy or an interacting companion. We find no evidence of contribution from AGN to the Lya emission. Fitting of the spectral energy distribution with stellar population models favors a very young (t<10 Myr), low mass (M*~10^6.5 Msun), and metal poor (Z<4x10^-3) stellar population. Its modest star formation rate (SFR~1.0 Msun/yr) implies high specific SFR (sSFR~2.5x10^-7 yr^-1) and SFR density (Sigma_SFR ~ 7-35 Msun/yr/kpc^2). The properties of A370-L57 make it a good representative of the population of galaxies responsible for cosmic reionization.Comment: 14 pages, 8 figures, 4 tables. Accepted for publication in Ap

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries

Background Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. Methods The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. Results A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P &lt; 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Conclusion Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov)