Medical Research Council

About: Medical Research Council is a government organization based out in London, United Kingdom. It is known for research contribution in the topics: Population & Malaria. The organization has 16430 authors who have published 19150 publications receiving 1475494 citations.

Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection

Abstract: Sepsis is a systemic inflammatory condition following bacterial infection with a high mortality rate and limited therapeutic options. Here we show that interleukin-33 (IL-33) reduces mortality in mice with experimental sepsis from cecal ligation and puncture (CLP). IL-33-treated mice developed increased neutrophil influx into the peritoneal cavity and more efficient bacterial clearance than untreated mice. IL-33 reduced the systemic but not the local proinflammatory response, and it did not induce a T helper type 1 (T(H)1) to T(H)2 shift. The chemokine receptor CXCR2 is crucial for recruitment of neutrophils from the circulation to the site of infection. Activation of Toll-like receptors (TLRs) in neutrophils downregulates CXCR2 expression and impairs neutrophil migration. We show here that IL-33 prevents the downregulation of CXCR2 and inhibition of chemotaxis induced by the activation of TLR4 in mouse and human neutrophils. Furthermore, we show that IL-33 reverses the TLR4-induced reduction of CXCR2 expression in neutrophils via the inhibition of expression of G protein-coupled receptor kinase-2 (GRK2), a serine-threonine protein kinase that induces internalization of chemokine receptors. Finally, we find that individuals who did not recover from sepsis had significantly more soluble ST2 (sST2, the decoy receptor of IL-33) than those who did recover. Together, our results indicate a previously undescribed mechanism of action of IL-33 and suggest a therapeutic potential of IL-33 in sepsis.

Mechanism of corepressor binding and release from nuclear hormone receptors.

Abstract: The association of transcription corepressors SMRT and N-CoR with retinoid and thyroid receptors results in suppression of basal transcriptional activity. A key event in nuclear receptor signaling is the hormone-dependent release of corepressor and the recruitment of coactivator. Biochemical and structural studies have identified a universal motif in coactivator proteins that mediates association with receptor LBDs. We report here the identity of complementary acting signature motifs in SMRT and N-CoR that are sufficient for receptor binding and ligand-induced release. Interestingly, the motif contains a hydrophobic core (PhixxPhiPhi) similar to that found in NR coactivators. Surprisingly, mutations in the amino acids that directly participate in coactivator binding disrupt the corepressor association. These results indicate a direct mechanistic link between activation and repression via competition for a common or at least partially overlapping binding site.

Emotion Regulation Strategies in Depressive and Anxiety Symptoms in Youth: A Meta-Analytic Review

Abstract: The role of emotion regulation in subclinical symptoms of mental disorders in adolescence is not yet well understood. This meta-analytic review examines the relationship between the habitual use of prominent adaptive emotion regulation strategies (cognitive reappraisal, problem solving, and acceptance) and maladaptive emotion regulation strategies (avoidance, suppression, and rumination) with depressive and anxiety symptoms in adolescence. Analyzing 68 effect sizes from 35 studies, we calculated overall outcomes across depressive and anxiety symptoms as well as psychopathology-specific outcomes. Age was examined as a continuous moderator via meta-regression models. The results from random effects analyses revealed that the habitual use of all emotion regulation strategies was significantly related to depressive and anxiety symptoms overall, with the adaptive emotion regulation strategies showing negative associations (i.e., less symptoms) with depressive and anxiety symptoms whereas the maladaptive emotion regulation strategies showed positive associations (i.e., more symptoms). A less frequent use of adaptive and a more frequent use of maladaptive emotion regulation strategies were associated with depressive and anxiety symptoms comparably in the respective directions. Regarding the psychopathology-specific outcomes, depressive and anxiety symptoms displayed similar patterns across emotion regulation strategies showing the strongest negative associations with acceptance, and strongest positive associations with avoidance and rumination. The findings underscore the relevance of adaptive and also maladaptive emotion regulation strategies in depressive and anxiety symptoms in youth, and highlight the need to further investigate the patterns of emotion regulation as a potential transdiagnostic factor.

Mutation in Brca2 stimulates error‐prone homology‐directed repair of DNA double‐strand breaks occurring between repeated sequences

Abstract: Mutation of BRCA2 causes familial early onset breast and ovarian cancer. BRCA2 has been suggested to be important for the maintenance of genome integrity and to have a role in DNA repair by homology- directed double-strand break (DSB) repair. By studying the repair of a specific induced chromosomal DSB we show that loss of Brca2 leads to a substantial increase in error-prone repair by homology-directed single-strand annealing and a reduction in DSB repair by conservative gene conversion. These data demonstrate that loss of Brca2 causes misrepair of chromosomal DSBs occurring between repeated sequences by stimulating use of an error-prone homologous recombination pathway. Furthermore, loss of Brca2 causes a large increase in genome-wide error-prone repair of both spontaneous DNA damage and mitomycin C-induced DNA cross-links at the expense of error-free repair by sister chromatid recombination. This provides insight into the mechanisms that induce genome instability in tumour cells lacking BRCA2.