Mal Mediates TLR-Induced Activation of CREB and Expression of IL-10

TLRs initiate immune responses by direct detection of molecular motifs that distinguish invading microbes from host cells. Five intracellular adaptor proteins, each containing a Toll/IL-1R (TIR) domain, are used by TLRs and play key roles in dictating gene expression patterns that are tailored to the invader. Such gene expression is mediated by transcription factors, and although TIR adaptor-induced activation of NF-kB and the IFN regulatory factors have been intensively studied, there is a dearth of information on the role of TIR adaptors in regulating CREB. In this paper, we describe a role for the TIR adaptor Mal in enhancing activation of CREB. Mal-deficient murine bone marrow-derived macrophages show a loss in responsiveness to TLR2 and TLR4 ligands with respect to activation of CREB. Mal-deficient cells also fail to express the CREB-responsive genes IL-10 and cyclooxygenase 2 in response to Pam2Cys-Ser-(Lys)4 and LPS. We reveal that Mal-mediated activation of CREB is dependent on Pellino3 and TNFR-associated factor 6, because CREB activation is greatly diminished in Pellino3 knockdown cells and TNFRassociated factor 6-deficient cells. We also demonstrate the importance of p38 MAPK in this pathway with the p38 inhibitor SB203580 abolishing activation of CREB in murine macrophages. MAPK-activated protein kinase 2 (MK2), a substrate for p38 MAPK, is the likely downstream mediator of p38 MAPK in this pathway, because Mal is shown to activate MK2 and inhibition of MK2 decreases TLR4-induced activation of CREB. Overall, these studies demonstrate a new role for Mal as a key upstream regulator of CREB and as a contributor to the expression of both pro- and anti-inflammatory gen

Mal Mediates TLR-Induced Activation of CREB and Expression of IL-10

TLRs initiate immune responses by direct detection of molecular motifs that distinguish invading microbes from host cells. Five intracellular adaptor proteins, each containing a Toll/IL-1R (TIR) domain, are used by TLRs and play key roles in dictating gene expression patterns that are tailored to the invader. Such gene expression is mediated by transcription factors, and although TIR adaptor-induced activation of NF-kB and the IFN regulatory factors have been intensively studied, there is a dearth of information on the role of TIR adaptors in regulating CREB. In this paper, we describe a role for the TIR adaptor Mal in enhancing activation of CREB. Mal-deficient murine bone marrow-derived macrophages show a loss in responsiveness to TLR2 and TLR4 ligands with respect to activation of CREB. Mal-deficient cells also fail to express the CREB-responsive genes IL-10 and cyclooxygenase 2 in response to Pam2Cys-Ser-(Lys)4 and LPS. We reveal that Mal-mediated activation of CREB is dependent on Pellino3 and TNFR-associated factor 6, because CREB activation is greatly diminished in Pellino3 knockdown cells and TNFRassociated factor 6-deficient cells. We also demonstrate the importance of p38 MAPK in this pathway with the p38 inhibitor SB203580 abolishing activation of CREB in murine macrophages. MAPK-activated protein kinase 2 (MK2), a substrate for p38 MAPK, is the likely downstream mediator of p38 MAPK in this pathway, because Mal is shown to activate MK2 and inhibition of MK2 decreases TLR4-induced activation of CREB. Overall, these studies demonstrate a new role for Mal as a key upstream regulator of CREB and as a contributor to the expression of both pro- and anti-inflammatory gen

The impact of the COVID-19 pandemic on self-harm and suicidal behaviour: a living systematic review

Background: The COVID-19 pandemic has caused widespread morbidity and mortality as well as disruption to people’s lives and livelihoods around the world; this has occurred as a result of both infection with the virus itself and the health protection measures taken to curb its spread. There are concerns that rates of suicide, suicidal behaviours and self-harm may rise during and in the aftermath of the pandemic. Given the likely rapidly expanding research evidence base on the pandemic’s impact on rates of suicide, suicidal behaviours and self-harm and emerging evidence about how best to mitigate such effects, it is important that the best available knowledge is made readily available to policymakers, public health specialists and clinicians as soon as is possible. To facilitate this, we plan to undertake a living systematic review focusing on suicide prevention in relation to COVID-19.Method: Regular automated searches will feed into a web-based screening system which will also host the data extraction form for included articles. Our eligibility criteria are wide and include aspects of incidence and prevalence of suicidal behaviour, effects of exposures and effects of interventions in relation to the COVID-19 pandemic, with minimal restrictions on the types of study design to be included. The outcomes assessed will be death by suicide; self-harm or attempted suicide (including hospital attendance and/or admission for these reasons); and suicidal thoughts/ideation. There will be no restriction on study type, except for single case reports. There will be no restriction on language of publication. The review will be updated at three-monthly intervals if a sufficient volume of new evidence justifies doing so.Conclusions: Our living review will provide a regular synthesis of the most up-to-date research evidence to guide public health and clinical policy to mitigate the impact of COVID-19 on suicide.Protocol registration: PROSPERO CRD42020183326 01/05/202

Distinct Mechanisms for Induction and Tolerance Regulate the Immediate Early Genes Encoding Interleukin 1β and Tumor Necrosis Factor α

Interleukin-1β and Tumor Necrosis Factor α play related, but distinct, roles in immunity and disease. Our study revealed major mechanistic distinctions in the Toll-like receptor (TLR) signaling-dependent induction for the rapidly expressed genes (IL1B and TNF) coding for these two cytokines. Prior to induction, TNF exhibited pre-bound TATA Binding Protein (TBP) and paused RNA Polymerase II (Pol II), hallmarks of poised immediate-early (IE) genes. In contrast, unstimulated IL1B displayed very low levels of both TBP and paused Pol II, requiring the lineage-specific Spi-1/PU.1 (Spi1) transcription factor as an anchor for induction-dependent interaction with two TLR-activated transcription factors, C/EBPβ and NF-κB. Activation and DNA binding of these two pre-expressed factors resulted in de novo recruitment of TBP and Pol II to IL1B in concert with a permissive state for elongation mediated by the recruitment of elongation factor P-TEFb. This Spi1-dependent mechanism for IL1B transcription, which is unique for a rapidly-induced/poised IE gene, was more dependent upon P-TEFb than was the case for the TNF gene. Furthermore, the dependence on phosphoinositide 3-kinase for P-TEFb recruitment to IL1B paralleled a greater sensitivity to the metabolic state of the cell and a lower sensitivity to the phenomenon of endotoxin tolerance than was evident for TNF. Such differences in induction mechanisms argue against the prevailing paradigm that all IE genes possess paused Pol II and may further delineate the specific roles played by each of these rapidly expressed immune modulators. © 2013 Adamik et al

One way or another? Criminal investigators' beliefs regarding the disclosure of evidence in interviews with suspects in England and Wales

The research base concerning interviews with suspects remains to be comprehensively developed. For example, the extant literature provides differing views regarding how best to undertake the important interview task of disclosing evidence. In the current study, using a self-report questionnaire, 224 investigators based in England and Wales were asked as to their own preferred methods. Most respondents advocated a gradual method of disclosing evidence, stating that this approach would better reveal inconsistencies and obtain a complete version of events (similar to the reasoning of those who preferred disclosing evidence later). Those who advocated revealing evidence early stated this approach would more likely elicit confessions. Several respondents would not commit to one single method, arguing that their chosen strategy was contextually dependent. The study’s findings suggest that it remains arguable as to whether there is one best approach to evidence disclosure and/or whether particular circumstances should influence interviewing strategies

Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome

MicroRNA (miRNA)-mediated RNA interference regulates many immune processes, but how miRNA circuits orchestrate aberrant intestinal inflammation during inflammatory bowel disease (IBD) is poorly defined. Here, we report that miR-223 limits intestinal inflammation by constraining the nlrp3 inflammasome. miR-223 was increased in intestinal biopsies from patients with active IBD and in preclinical models of intestinal inflammation. miR-223-/y mice presented with exacerbated myeloid-driven experimental colitis with heightened clinical, histopathological, and cytokine readouts. Mechanistically, enhanced NLRP3 inflammasome expression with elevated IL-1β was a predominant feature during the initiation of colitis with miR-223 deficiency. Depletion of CCR2+ inflammatory monocytes and pharmacologic blockade of IL-1β or NLRP3 abrogated this phenotype. Generation of a novel mouse line, with deletion of the miR-223 binding site in the NLRP3 3′ untranslated region, phenocopied the characteristics of miR-223-/y mice. Finally, nanoparticle-mediated overexpression of miR-223 attenuated experimental colitis, NLRP3 levels, and IL-1β release. Collectively, our data reveal a previously unappreciated role for miR-223 in regulating the innate immune response during intestinal inflammation

Mapping the decision pathways of acute infection management in secondary care among UK medical physicians: a qualitative study.

BACKGROUND: The inappropriate use of antimicrobials drives antimicrobial resistance. We conducted a study to map physician decision-making processes for acute infection management in secondary care to identify potential targets for quality improvement interventions. METHODS: Physicians newly qualified to consultant level participated in semi-structured interviews. Interviews were audio recorded and transcribed verbatim for analysis using NVIVO11.0 software. Grounded theory methodology was applied. Analytical categories were created using constant comparison approach to the data and participants were recruited to the study until thematic saturation was reached. RESULTS: Twenty physicians were interviewed. The decision pathway for the management of acute infections follows a Bayesian-like step-wise approach, with information processed and systematically added to prior assumptions to guide management. The main emerging themes identified as determinants of the decision-making of individual physicians were (1) perceptions of providing 'optimal' care for the patient with infection by providing rapid and often intravenous therapy; (2) perceptions that stopping/de-escalating therapy was a senior doctor decision with junior trainees not expected to contribute; and (3) expectation of interactions with local guidelines and microbiology service advice. Feedback on review of junior doctor prescribing decisions was often lacking, causing frustration and confusion on appropriate practice within this cohort. CONCLUSION: Interventions to improve infection management must incorporate mechanisms to promote distribution of responsibility for decisions made. The disparity between expectations of prescribers to start but not review/stop therapy must be urgently addressed with mechanisms to improve communication and feedback to junior prescribers to facilitate their continued development as prudent antimicrobial prescribers

Boreal forest soil carbon fluxes one year after a wildfire: Effects of burn severity and management

The extreme 2018 hot drought that affected central and northern Europe led to the worst wildfire season in Sweden in over a century. The Ljusdal fire complex, the largest area burnt that year (8995 ha), offered a rare opportunity to quantify the combined impacts of wildfire and post-fire management on Scandinavian boreal forests. We present chamber measurements of soil CO2 and CH4 fluxes, soil microclimate and nutrient content from five Pinus sylvestris sites for the first growing season after the fire. We analysed the effects of three factors on forest soils: burn severity, salvage-logging and stand age. None of these caused significant differences in soil CH4 uptake. Soil respiration, however, declined significantly after a high-severity fire (complete tree mortality) but not after a low-severity fire (no tree mortality), despite substantial losses of the organic layer. Tree root respiration is thus key in determining post-fire soil CO2 emissions and may benefit, along with heterotrophic respiration, from the nutrient pulse after a low-severity fire. Salvage-logging after a high-severity fire had no significant effects on soil carbon fluxes, microclimate or nutrient content compared with leaving the dead trees standing, although differences are expected to emerge in the long term. In contrast, the impact of stand age was substantial: a young burnt stand experienced more extreme microclimate, lower soil nutrient supply and significantly lower soil respiration than a mature burnt stand, due to a thinner organic layer and the decade-long effects of a previous clear-cut and soil scarification. Disturbance history and burn severity are, therefore, important factors for predicting changes in the boreal forest carbon sink after wildfires. The presented short-term effects and ongoing monitoring will provide essential information for sustainable management strategies in response to the increasing risk of wildfire

Measurement of the B -> D^* l nu Branching Fractions and |Vcb|

We study the exclusive semileptonic B meson decays B- -> D*0 l- nu and B0 -> D*+ l- nu using data collected with the CLEO II detector at CESR. We present measurements of the branching fractions B(B0 -> D*+ l-nu) = 0.5/f00* [4.49+/-0.32+/-0.39]% and B(B- -> D*0 l-nu) = 0.5/f+-*[5.13+/-0.54+/-0.64]%, where f00 and f+- are the neutral and charged B meson production fractions at the Upsilon(4s) resonance. Assuming isospion invariance and taking the charged to neutral B meson lifetimes measured at higher energy machines, we determine the ratio f+-/f00=1.04+/-0.14+/-0.13+-/-0.10; further assuming f+- + f00 = 1 we also determine the partial width G(B->D* l nu) = 29.9+/-1.9+/-2.7+/-2.0 ns-1 (independent of f+-/f00). From this partial width we calculate B -> D* l nu branching fractions that do not depend on f+-/f00, nor the individual B lifetimes, but only on the charged to neutral lifetime ratio. The product of the CKM matrix element |Vcb| times the normalization of the decay form factor at the point of zero recoil of the D* meson, F(y=1), is determined from a linear fit to the combined differential decay rate of the exclusive B->D* l nu decays: |Vcb|F(y) = 0.0351 +/- 0.0019 +/- 0.0018 +/- 0.0008. Using theoretical calculations of the form factor normalization we extract a value for |Vcb|. LATEX (REVTEX style) file with uuencoded figures attached (uses PSBOX). Available on WWW http://w4.lns.cornell.edu/public/CLNS/Comment: 42 pages,CLNS 94/1285, CLEO 94-2