DNA lesions pose a major obstacle during gene transcription by RNA polymerase II (RNAPII) enzymes. The transcription-coupled DNA repair (TCR) pathway eliminates such DNA lesions. Inherited defects in TCR cause severe clinical syndromes, including Cockayne syndrome (CS). The molecular mechanism of TCR and the molecular origin of CS have long remained enigmatic. Here we explore new advances in our understanding of how TCR complexes assemble through cooperative interactions between repair factors stimulated by RNAPII ubiquitylation. Mounting evidence suggests that RNAPII ubiquitylation activates TCR complex assembly during repair and, in parallel, promotes processing and degradation of RNAPII to prevent prolonged stalling. The fate of stalled RNAPII is therefore emerging as a crucial link between TCR and associated human diseases.The biosynthesis of about one third of the human proteome, including membrane receptors and secreted proteins, occurs in the endoplasmic reticulum (ER). Conditions that perturb ER homeostasis activate the unfolded protein response (UPR). An ‘optimistic’ UPR output aims at restoring homeostasis by reinforcement of machineries that guarantee efficiency and fidelity of protein biogenesis in the ER. Yet, once the UPR ‘deems’ that ER homeostatic readjustment fails, it transitions to a ‘pessimistic’ output, which, depending on the cell type, will result in apoptosis. In this article, we discuss emerging concepts on how the UPR ‘evaluates’ ER stress, how the UPR is repurposed, in particular in B cells, and how UPR-driven counter-selection of cells undergoing homeostatic failure serves organismal homeostasis and humoral immunity.Ubiquitin and ubiquitin-like proteins (UBLs) function as critical post-translational modifiers in the maintenance of genome stability. Ubiquitin/UBL-conjugating enzymes (E2s) are responsible, as part of a wider enzymatic cascade, for transferring single moieties or polychains of ubiquitin/UBLs to one or multiple residues on substrate proteins. Recent advances in structural and mechanistic understanding of how ubiquitin/UBL substrate attachment is orchestrated indicate that E2s can exert control over chain topology, substrate-site specificity, and downstream physiological effects to help maintain genome stability. Drug discovery efforts have typically focussed on modulating other members of the ubiquitin/UBL cascades or the ubiquitin-proteasome system. Here, we review the current standing of E2s in genome stability and revisit their potential as pharmacological targets for developing novel anti-cancer therapies.

The purpose of this study was to investigate the changes in serum irisin, fibroblast growth factor-21 (FGF21), visfatin, follistatin like protein-1 (FSTL1), and meteorin-like protein (Metrnl) levels in response to increased physical activity and/or diet interventions in overweight subjects with impaired glucose metabolism (IGM).

A total of 60 subjects (BMI > 25.0 kg/m

) with IGM were recruited in this single-centered interventional study. Twelve subjects dropped out during the study and the study was completed with 48 patients. Patients were divided into two groups as diet only (DI, n = 24) and diet and physical activity intervention (DPA, n = 24). Patients in DI group received a diet program while DPA group received a diet combined with a physical activity intervention for 12 weeks. Additional 24 healthy subjects were recruited to compare the baseline levels of proteins. Serum protein levels, anthropometric measurements, and biochemical parameters were assessed.

Irisin, FGF21, visfatin, and FSTL1 lcts with IGM, and these myokines might be related to glucose metabolism biomarkers.

The ideal cardiac risk stratification strategy for orthotopic liver transplantation (OLT) is unknown. Our institution performed coronary angiography for asymptomatic OLT candidates at high risk for CAD ≥65years of age, diabetic and ≥55years of age or diagnosed ≥5years, abnormal stress test, or at the discretion of the OLT committee.

The analysis included 301 consecutive, asymptomatic OLT candidates who underwent coronary angiography. Selleckchem Alofanib The primary outcome was the prevalence of obstructive CAD.

At 2-year follow-up, OLT was performed in 44.9%, and 42.2% died. The prevalence of obstructive CAD, involvement of the proximal or mid LAD, and 3-vessel CAD were 10.3%, 6.6%, and 0.7%, respectively. Percutaneous and surgical revascularization were performed in 7.0% and 1.3%, respectively. Stress test was performed in 54.8%. The sensitivity and specificity of stress testing were 0% and 87.1%, respectively. The negative and positive predictive values of stress testing were 91.4% and 0%, respectively. Chest computed tomography (CT) was performed in 83.1%. Moderate or severe coronary artery calcification (CAC) was present in 47.8%. The sensitivity and specificity of moderate or severe CAC were 88.9% and 57.3%, respectively. The negative and positive predictive values of moderate or severe CAC were 97.7% and 20.2%, respectively. Multivariate analysis demonstrated that CAC was an independent predictor of obstructive CAD (HR 10.7; 95% CI 3.2-37.9; p<0.001).

The prevalence of obstructive CAD in asymptomatic OLT candidates at high risk was uncommon. Alternative diagnostic strategies may be preferred to coronary angiography.

The prevalence of obstructive CAD in asymptomatic OLT candidates at high risk was uncommon. Alternative diagnostic strategies may be preferred to coronary angiography.

We aimed to evaluate the diagnostic performance of diffusion-weighted imaging (DWI) and dynamic susceptibility contrast-enhanced (DSC) magnetic resonance imaging (MRI) parameters in the noninvasive prediction of the isocitrate dehydrogenase (IDH) mutation status in high-grade gliomas (HGGs).

A total of 58 patients with histopathologically proved HGGs were included in this retrospective study. All patients underwent multiparametric MRI on 3-T, including DSC-MRI and DWI before surgery. The mean apparent diffusion coefficient (ADC), relative maximum cerebral blood volume (rCBV), and percentage signal recovery (PSR) of the tumor core were measured and compared depending on the IDH mutation status and tumor grade. The Mann-Whitney U test was used to detect statistically significant differences in parameters between IDH-mutant-type (IDH-m-type) and IDH-wild-type (IDH-w-type) HGGs. Receiver operating characteristic curve (ROC) analysis was performed to evaluate the diagnostic performance.

The rCBV was significantly higher, and the PSR value was significantly lower in IDH-w-type tumors than in the IDH-m group (p = 0.