Chromosome fusions threaten genome integrity and promote cancer by engaging catastrophic mutational processes, namely chromosome breakage-fusion-bridge cycles and chromothripsis. Chromosome fusions are frequent in cells incurring telomere dysfunctions or those exposed to DNA breakage. Their occurrence and therefore their contribution to genome instability in unchallenged cells is unknown. To address this issue, we constructed a genetic assay able to capture and quantify rare chromosome fusions in budding yeast. This chromosome fusion capture (CFC) assay relies on the controlled inactivation of one centromere to rescue unstable dicentric chromosome fusions. It is sensitive enough to quantify the basal rate of end-to-end chromosome fusions occurring in wild-type cells. These fusions depend on canonical nonhomologous end joining (NHEJ). Our results show that chromosome end protection results from a trade-off at telomeres between positive effectors (Rif2, Sir4, telomerase) and a negative effector partially antagonizing them (Rif1). The CFC assay also captures NHEJ-dependent chromosome fusions induced by ionizing radiation. It provides evidence for chromosomal rearrangements stemming from a single photon-matter interaction.
  To evaluate the impact of vitamin D and calcium supplementation(VitD/Ca) on lumbar spine bone mineral density(LSBMD) and bone metabolism among Thai adolescents with perinatally acquired HIV(PHIVA).
 
  A multicenter, randomized, active-control, open-labeled trial was conducted. PHIVA(aged10-20years) who were on stable cART were enrolled. Baseline LSBMD status was defined as low(z-score≤-2) and normal(z-score>-2). Eligible PHIVA were randomly assigned to receive standard-dose VitD/Ca (400IU/1,200mg daily), or high-dose VitD/Ca supplementation (400IU/1,200mg daily plus ergocalciferol 20,000IU weekly) for 48 weeks (ratio 11,stratified by baseline LSBMD). Study outcomes were the changes in LSBMD, LSBMD z-scores, and bone metabolism-related biomarkers (25-hydoxyvitamin D[25OHD], intact parathyroid hormone[iPTH], C-terminal telopeptide[CTX], procollagen type I amino-terminal propeptide[PINP]) from baseline to week48.
 
  Among 200 enrolled PHIVA, a median age was 16 (IQR14-18)years; 61% were on NNRTI-based cART. Tulation.
 Over the 48-week VitD/Ca supplementation, significant increase in LSBMD, and significant decreases in bone metabolism-related markers were observed among our Thai PHIVA in both treatment groups. The improvement in LSBMD z-score was more enhanced with high-dose VitD/Ca supplementation compared with standard-dose. High-dose VitD/Ca supplementation might be considered to promote bone health in this population.How aminoglycoside antibiotics limit bacterial growth and viability is not clearly understood. Here we employ fast kinetics to reveal the molecular mechanism of action of a clinically used, new-generation, semisynthetic aminoglycoside Arbekacin (ABK), which is designed to avoid enzyme-mediated deactivation common to other aminoglycosides. Our results portray complete picture of ABK inhibition of bacterial translation with precise quantitative characterizations. We find that ABK inhibits different steps of translation in nanomolar to micromolar concentrations by imparting pleotropic effects. ABK binding stalls elongating ribosomes to a state, which is unfavorable for EF-G binding. This prolongs individual translocation step from ∼50 ms to at least 2 s; the mean time of translocation increases inversely with EF-G concentration. ABK also inhibits translation termination by obstructing RF1/RF2 binding to the ribosome.  https://www.selleckchem.com/products/selonsertib-gs-4997.html  Furthermore, ABK decreases accuracy of mRNA decoding (UUC vs. CUC) by ∼80 000 fold, causing aberrant protein production. Importantly, translocation and termination events cannot be completely stopped even with high ABK concentration. Extrapolating our kinetic model of ABK action, we postulate that aminoglycosides impose bacteriostatic effect mainly by inhibiting translocation, while they become bactericidal in combination with decoding errors.As a result of the advent of high-throughput technologies, there has been rapid progress in our understanding of the genetics underlying biological processes. However, despite such advances, the genetic landscape of human diseases has only marginally been disclosed. Exploiting the present availability of large amounts of biological and phenotypic data, we can use our current understanding of disease genetics to train machine learning models to predict novel genetic factors associated with the disease. To this end, we developed DGLinker, a webserver for the prediction of novel candidate genes for human diseases given a set of known disease genes. DGLinker has a user-friendly interface that allows non-expert users to exploit biomedical information from a wide range of biological and phenotypic databases, and/or to upload their own data, to generate a knowledge-graph and use machine learning to predict new disease-associated genes. The webserver includes tools to explore and interpret the results and generates publication-ready figures. DGLinker is available at https//dglinker.rosalind.kcl.ac.uk. The webserver is free and open to all users without the need for registration.
  Vancomycin is a commonly used antimicrobial with the potential for renal toxicity. We evaluated vancomycin duration, changes in renal function after vancomycin initiation ("post-vancomycin" renal function changes), and associated mortality risk among hospitalized patients.
 
  We analyzed data from 76 hospitals and excluded patients with a baseline serum creatinine concentration (SCr) of >3.35mg/dL. We estimated mortality risk relative to vancomycin duration and the magnitude of post-vancomycin SCr change, controlling for demographics, baseline SCr, underlying diseases, clinical acuity, and comorbidities.
 
  Among 128,993 adult inpatients treated with vancomycin, 49.0% did not experience SCr elevation. Among the remaining patients, 26.0%, 11.4%, 8.8% and 4.8% experienced increases in post-vancomycin SCr of 1% to 20%, 21% to 40%, 41% to 100%, and greater than 100%, respectively. Compared to mortality risk among patients with a vancomycin therapy duration between 4 and 5 days (the lowest-mortality group), longer vancomycin therapy duration was not independently associated with higher mortality risk after adjusting for confounders.