Structure and stereochemistry of the base excision repair glycosylase MutY reveal a mechanism similar to retaining glycosidases.

MutY adenine glycosylases prevent DNA mutations by excising adenine from promutagenic 8-oxo-7,8-dihydroguanine (OG):A mismatches. Here, we describe structural features of the MutY active site bound to an azaribose transition state analog which indicate a catalytic role for Tyr126 and approach of the water nucleophile on the same side as the departing adenine base. The idea that Tyr126 participates in catalysis, recently predicted by modeling calculations, is strongly supported by mutagenesis and by seeing close contact between the hydroxyl group of this residue and the azaribose moiety of the transition state analog. NMR analysis of MutY methanolysis products corroborates a mechanism for adenine removal with retention of stereochemistry. Based on these results, we propose a revised mechanism for MutY that involves two nucleophilic displacement steps akin to the mechanisms accepted for 'retaining' O-glycosidases. This new-for-MutY yet familiar mechanism may also be operative in related base excision repair glycosylases and provides a critical framework for analysis of human MutY (MUTYH) variants associated with inherited colorectal cancer

DNA methylation age is accelerated in alcohol dependence.

Alcohol dependence (ALC) is a chronic, relapsing disorder that increases the burden of chronic disease and significantly contributes to numerous premature deaths each year. Previous research suggests that chronic, heavy alcohol consumption is associated with differential DNA methylation patterns. In addition, DNA methylation levels at certain CpG sites have been correlated with age. We used an epigenetic clock to investigate the potential role of excessive alcohol consumption in epigenetic aging. We explored this question in five independent cohorts, including DNA methylation data derived from datasets from blood (n = 129, n = 329), liver (n = 92, n = 49), and postmortem prefrontal cortex (n = 46). One blood dataset and one liver tissue dataset of individuals with ALC exhibited positive age acceleration (p < 0.0001 and p = 0.0069, respectively), whereas the other blood and liver tissue datasets both exhibited trends of positive age acceleration that were not significant (p = 0.83 and p = 0.57, respectively). Prefrontal cortex tissue exhibited a trend of negative age acceleration (p = 0.19). These results suggest that excessive alcohol consumption may be associated with epigenetic aging in a tissue-specific manner and warrants further investigation using multiple tissue samples from the same individuals

Cannabinoid receptor type 2 activation induces a microglial anti-inflammatory phenotype and reduces migration via MKP induction and ERK dephosphorylation

<p>Abstract</p> <p>Background</p> <p>Cannabinoid receptor type 2 (CBR2) inhibits microglial reactivity through a molecular mechanism yet to be elucidated. We hypothesized that CBR2 activation induces an anti-inflammatory phenotype in microglia by inhibiting extracellular signal-regulated kinase (ERK) pathway, via mitogen-activated protein kinase-phosphatase (MKP) induction. MKPs regulate mitogen activated protein kinases, but their role in the modulation of microglial phenotype is not fully understood.</p> <p>Results</p> <p>JWH015 (a CBR2 agonist) increased MKP-1 and MKP-3 expression, which in turn reduced p-ERK1/2 in LPS-stimulated primary microglia. These effects resulted in a significant reduction of tumor necrosis factor-α (TNF) expression and microglial migration. We confirmed the causative link of these findings by using MKP inhibitors. We found that the selective inhibition of MKP-1 by Ro-31-8220 and PSI2106, did not affect p-ERK expression in LPS+JWH015-treated microglia. However, the inhibition of both MKP-1 and MKP-3 by triptolide induced an increase in p-ERK expression and in microglial migration using LPS+JWH015-treated microglia.</p> <p>Conclusion</p> <p>Our results uncover a cellular microglial pathway triggered by CBR2 activation. These data suggest that the reduction of pro-inflammatory factors and microglial migration via MKP-3 induction is part of the mechanism of action of CBR2 agonists. These findings may have clinical implications for further drug development.</p

Accurate epigenetic aging in bottlenose dolphins (Tursiops truncatus), an essential step in the conservation of at-risk dolphins

Funding: This research was funded by SERDP grant RC20-C2-1097 awarded to Peter Tyack and Prescott Award NA20NMF4390132 awarded to Ashley Barratclough.Epigenetics, specifically DNA methylation, allows for the estimation of animal age from blood or remotely sampled skin. This multi-tissue epigenetic age estimation clock uses 110 longitudinal samples from 34 Navy bottlenose dolphins (Tursiops truncatus), identifying 195 cytosine-phosphate-guanine sites associated with chronological aging via cross-validation with one individual left out in each fold (R2 = 0.95). With a median absolute error of 2.5 years, this clock improves age estimation capacity in wild dolphins, helping conservation efforts and enabling a better understanding of population demographicsPublisher PDFPeer reviewe

Psychosocial stress and epigenetic aging

Aging is the single most important risk factor for diseases that are currently the leading causes of morbidity and mortality. However, there is considerable inter-individual variability in risk for aging-related disease, and studies suggest that biological age can be influenced by multiple factors, including exposure to psychosocial stress. Among markers of biological age that can be affected by stress, the present article focuses on the so-called measures of epigenetic aging: DNA methylation-based age predictors that are measured in a range of tissues, including the brain, and can predict lifespan and healthspan. We review evidence linking exposure to diverse types of psychosocial stress, including early-life stress, cumulative stressful experiences, and low socioeconomic status, with accelerated epigenetic aging as a putative mediator of the effects of psychosocial environment on health and disease. The chapter also discusses methodologica

Testing the fixed-point QCD action and the construction of chiral currents

We present the first set of quenched QCD measurements using the recently parametrized fixed-point Dirac operator D^FP. We also give a general and practical construction of covariant densities and conserved currents for chiral lattice actions. The measurements include (a) hadron spectroscopy, (b) corrections of small chiral deviations, (c) the renormalized quark condensate from finite-size scaling and, independently, spectroscopy, (d) the topological susceptibility, (e) small eigenvalue distributions and random matrix theory, and (f) local chirality of near-zero modes and instanton-dominance.Comment: 50 pages, 19 figures; misprints corrected, discussion on covariant densities extended, new appendix adde

ERS/EAACI statement on adherence to international adult asthma guidelines

Clinical practice guidelines based on the best available evidence, aim to standardize and optimize asthma diagnosis and management. Nevertheless, there are concerns that particularly between different groups of healthcare professionals (HCPs), adherence to guidelines is suboptimal. Further to these concerns, the aims of this ERS/EAACI Statement were (1) via an international online survey, to evaluate and compare the understanding of and adherence to international asthma guidelines by HCPs of different specialties, (2) via systematic reviews of the literature, to assess effectiveness of strategies focused at improving implementation of guideline-recommended interventions, and compare process and clinical outcomes in patients managed by Specialists (respiratory physicians or allergists) or Generalists (internists or general practitioners). The online survey identified discrepancies between HCPs of different specialties which may be due to poor dissemination or lack of knowledge of the guidelines but also a reflection of the adaptations HCPs working in different clinical settings make, based on their resources. The systematic reviews demonstrated that multifaceted quality improvement initiatives addressing multiple challenges to guidelines adherence, or the input from additional specialized HCPs are most effective in improving guidelines adherence. More data are needed to evaluate differences in process and clinical outcomes among patients managed by Generalists or Specialists. Our results reveal a need for guidelines to consider the heterogeneity of real-life settings for asthma management and tailor their recommendations accordingly. Continuous, multifaceted quality improvement processes are required to optimize and maintain guidelines adherence. Validated referral pathways for uncontrolled asthma or for uncertain diagnosis are needed

The role of individual differences in the perceived job relatedness of a cognitive ability test and a multimedia situational judgment test

Abstract Although there is a growing number of publications concerning applicant reactions to different selection instruments, the relationships between individual differences and applicant reactions have largely remained unexplored. The aim of the present study was to examine the effects of several testing-related and general individual differences (anxiety, self-evaluations, and personality) on the most commonly studied dimension of applicant reactions, namely the perceived job relatedness of selection instruments. Participants were 153 psychology students, who completed a cognitive ability test and a multimedia SJT as part of their educational program. Our results indicated that computer anxiety negatively affected perceived job relatedness and core self-evaluations, subjective well-being, agreeableness, emotional stability, and openness to experience positively affected perceived job relatedness. Openness to experience was the most consistent predictor of perceived job relatedness. The results of our study suggest that certain individuals may be more predisposed to react positively to selection instruments. Therefore, we concluded that the nature of the applicant pool should be carefully considered when designing interventions to improve applicant reactions

Is human blood a good surrogate for brain tissue in transcriptional studies?

Abstract Background Since human brain tissue is often unavailable for transcriptional profiling studies, blood expression data is frequently used as a substitute. The underlying hypothesis in such studies is that genes expressed in brain tissue leave a transcriptional footprint in blood. We tested this hypothesis by relating three human brain expression data sets (from cortex, cerebellum and caudate nucleus) to two large human blood expression data sets (comprised of 1463 individuals). Results We found mean expression levels were weakly correlated between the brain and blood data (r range: [0.24,0.32]). Further, we tested whether co-expression relationships were preserved between the three brain regions and blood. Only a handful of brain co-expression modules showed strong evidence of preservation and these modules could be combined into a single large blood module. We also identified highly connected intramodular "hub" genes inside preserved modules. These preserved intramodular hub genes had the following properties: first, their expression levels tended to be significantly more heritable than those from non-preserved intramodular hub genes (p &lt; 10-90); second, they had highly significant positive correlations with the following cluster of differentiation genes: CD58, CD47, CD48, CD53 and CD164; third, a significant number of them were known to be involved in infection mechanisms, post-transcriptional and post-translational modification and other basic processes. Conclusions Overall, we find transcriptome organization is poorly preserved between brain and blood. However, the subset of preserved co-expression relationships characterized here may aid future efforts to identify blood biomarkers for neurological and neuropsychiatric diseases when brain tissue samples are unavailable