Brennanfulton5770

Background Teratogenic potential has been linked to various industrial compounds. Methoxyacetic acid (MAA) is a primary metabolite of the widely used organic solvent and plasticizer, methoxyethanol and dimethoxyethyl phthalate, respectively. Studies using model animals have shown that MAA acts as the proximate teratogen that causes various malformations in developing embryos. Nonetheless, the molecular mechanisms by which MAA exerts its teratogenic effects are not fully understood. Methods Gastruloids of mouse P19C5 pluripotent stem cells, which recapitulate axial elongation morphogenesis of gastrulation-stage embryos, were explored as an in vitro model to investigate the teratogenic action of MAA. Morphometric parameters of gastruloids were measured to evaluate the morphogenetic effect, and transcript levels of various developmental regulator genes were examined to assess the impact on gene expression patterns. The effects of MAA on the level of retinoic acid (RA) signaling and histone deacetylase activity were also measured. Results MAA reduced axial elongation of gastruloids at concentrations comparable to the teratogenic plasma level (5 mM) in vivo. MAA at 4 mM significantly altered the expression profiles of developmental regulator genes. In particular, it upregulated the RA signaling target genes. The concomitant suppression of RA signaling using a pharmacological agent alleviated the morphogenetic effect of MAA. MAA at 4 mM also significantly reduced the activity of purified histone deacetylase protein. Conclusions MAA impaired axial elongation morphogenesis in a RA signaling-dependent manner in mouse gastruloids, possibly through the inhibition of histone deacetylase.Mathematical models can enable a predictive understanding of mechanism in cell biology by quantitatively describing complex networks of interactions, but such models are often poorly constrained by available data. Owing to its relative biochemical simplicity, the core circadian oscillator in Synechococcus elongatus has become a prototypical system for studying how collective dynamics emerge from molecular interactions. The oscillator consists of only three proteins, KaiA, KaiB, and KaiC, and near-24-h cycles of KaiC phosphorylation can be reconstituted in vitro. Here, we formulate a molecularly detailed but mechanistically naive model of the KaiA-KaiC subsystem and fit it directly to experimental data within a Bayesian parameter estimation framework. Analysis of the fits consistently reveals an ultrasensitive response for KaiC phosphorylation as a function of KaiA concentration, which we confirm experimentally. This ultrasensitivity primarily results from the differential affinity of KaiA for competing nucleotide-bound states of KaiC. We argue that the ultrasensitive stimulus-response relation likely plays an important role in metabolic compensation by suppressing premature phosphorylation at nighttime.Objectives To evaluate the effect of overactive bladder (OAB) and frailty on indoor fall events in community-dwelling adults aged 50 or older. Methods We conducted a cross-sectional study involving 723 adults between 2016 and 2017 in Hirosaki, Japan. OAB symptoms and sleep disturbance were assessed using the Overactive Bladder Symptom Score (OABSS) and the Pittsburgh Sleep Quality Index (PSQI). Indoor fall events (falls or near-falls) within 1 year were evaluated. Frailty was evaluated by the frailty discriminant score. We investigated the association of OAB symptoms with sleep disturbance, frailty, and indoor fall events. Multivariate logistic regression analysis was performed to investigate the effect of OAB symptoms on fall events controlling for confounding factors such as age, gender, comorbidity, frailty, and sleep disturbance. Results The median age was 64. We observed OABSS ≥6 in 98 participants (14%), nocturia ≥2 in 445 (62%), urgency score ≥3 in 80 (11%), urge incontinence score ≥3 in 36 (5.0%), PSQI ≥6 in 153 (21%), frailty in 169 (23%), and indoor fall events in 251 (35%). Older age, diabetes, OABSS, nocturia, urgency, urge incontinence, and the PSQI were significantly associated with indoor fall events. Multivariate logistic regression analyses showed that OAB symptoms and sleep disturbance were significantly associated with fall events. Conclusions The effect of OAB symptoms and sleep disturbance on indoor fall events was significant. The causal relationship between OAB and falls needs further study.O-GlcNAcylation is the dynamic and ubiquitous post-translational glycosylation of nucleocytoplasmic proteins on serine/threonine residues; it is implicated in regulation of the cell cycle. This protein modification is mainly governed by a pair of enzymes O-GlcNAc transferase (OGT) adds the N-acetylglucosamine moiety to acceptor proteins, and O-GlcNAcase (OGA) hydrolyses the sugar moiety from protein acceptors. Irregular O-GlcNAcylation is linked to several diseases including cancer, diabetes and neurodegeneration. Recently, the discovery of small-molecule OGA inhibitors has enabled the physiological function of O-GlcNAcylation to be investigated. However, the design of highly potent and selective inhibitors faces several challenges as no full structural data of human OGA has been discovered to date. Moreover, there are a number of mechanistically similar related enzymes such as β-hexosaminidases (Hex), and the concomitant inhibition of these enzymes leads to undesirable lysosomal-storage disorders. This review highlights recent insights into the structure of human O-GlcNAcase and its isoforms. We focus on the catalytic mechanism and substrate recognition by OGA. click here In addition, it presents an updated overview of small-molecule OGA inhibitors, with either carbohydrate or noncarbohydrate scaffolds. We discuss inhibitor structures, binding modes, and selectivity towards the enzyme, and potential outcomes in probing O-GlcNAcylation at cellular levels.Background Otolaryngologists are among the highest risk for COVID-19 exposure. Methods This is a cross-sectional, survey-based, national study evaluating academic otolaryngologists. Burnout, anxiety, distress, and depression were assessed by the single-item Mini-Z Burnout Assessment, 7-item Generalized Anxiety Disorder Scale, 15-item Impact of Event Scale, and 2-item Patient Health Questionnaire, respectively. Results A total of 349 physicians completed the survey. Of them, 165 (47.3%) were residents and 212 (60.7%) were males. Anxiety, distress, burnout, and depression were reported in 167 (47.9%), 210 (60.2%), 76 (21.8%), and 37 (10.6%) physicians, respectively. Attendings had decreased burnout relative to residents (odds ratio [OR] 0.28, confidence interval [CI] [0.11-0.68]; P = .005). Females had increased burnout (OR 1.93, CI [1.12.-3.32]; P = .018), anxiety (OR 2.53, CI [1.59-4.02]; P less then .005), and distress (OR 2.68, CI [1.64-4.37]; P less then .005). Physicians in states with greater than 20 000 positive cases had increased distress (OR 2.