Meyercoleman8119
The manner in which newborn coding sequences and their transcriptional competency emerge during the process of gene evolution remains unclear. learn more Here, we experimentally simulated eukaryotic gene origination processes by mimicking horizontal gene transfer events in the plant genome. We mapped the precise position of the transcription start sites (TSSs) of hundreds of newly introduced promoterless firefly luciferase (LUC) coding sequences in the genome of Arabidopsis thaliana cultured cells. The systematic characterization of the LUC-TSSs revealed that 80% of them occurred under the influence of endogenous promoters, while the remainder underwent de novo activation in the intergenic regions, starting from pyrimidine-purine dinucleotides. These de novo TSSs obeyed unexpected rules; they predominantly occurred ∼100 bp upstream of the LUC inserts and did not overlap with Kozak-containing putative open reading frames (ORFs). These features were the output of the immediate responses to the sequence insertions, rather than a bias in the screening of the LUC gene function. Regarding the wild-type genic TSSs, they appeared to have evolved to lack any ORFs in their vicinities. Therefore, the repulsion by the de novo TSSs of Kozak-containing ORFs described above might be the first selection gate for the occurrence and evolution of TSSs in the plant genome. Based on these results, we characterized the de novo type of TSS identified in the plant genome and discuss its significance in genome evolution.Recent evidence has highlighted important associations between obstructive sleep apnea and the microbiome. Although the intricacies of the pathophysiologic mechanisms are not well understood, available evidence suggests a bidirectional relationship between OSA and microbiota composition. Sleep fragmentation, intermittent hypoxia, and intermittent hypercapnia all play significant roles in altering the microbiome, and initial evidence has shown that alterations of the microbiota affect sleep patterns. Animal model evidence strongly supports the idea that the microbiome mediates disease states associated with OSA including hypertension, atherosclerosis, and obesity. The majority of evidence focuses on changes in the gut microbiome, which may result from OSA as well as contribute to sleep pattern changes, OSA-related CVD, and obesity. Meanwhile, a developing body of work suggests changes in the upper airway microbiome may be associated with OSA and periodontitis-related oral cavity microbiome changes may have significance in OSA-related CVD. Lastly, while evidence is limited, several studies suggest there may be a role for treatment of OSA and OSA-related comorbidities through alteration of the microbiome with probiotics, prebiotics, and microbiota transplantation. These early animal and human studies begin to characterize the interrelationships of the microbiome and OSA and may lead to new avenues for treatment.This work aimed to evaluate if a radar sensor can distinguish sleep from wakefulness in real-time. The sensor detects body movements without direct physical contact with the subject, and can be embedded in the roof of a hospital room for completely unobtrusive monitoring. We conducted simultaneous recordings with polysomnography, actigraphy, and radar, on two groups healthy young adults (n=12, four nights per participant), and patients referred to a sleep exam (n=28, one night per participant). We developed models for sleep/wake classification based on principles commonly used by actigraphy, including real-time models, and tested them on both datasets. We estimated a set of commonly reported sleep parameters from this data, including total-sleep-time, sleep-onset-latency, sleep-efficiency, and wake-after-sleep-onset, and evaluated the inter-method reliability of these estimates. Classification results were on-par with, or exceeding, those often seen for actigraphy. For real-time models in healthy young adults, accuracies were above 92%, sensitivities above 95%, specificities above 83%, and all Cohen's kappa values were above 0.81 compared to polysomnography. For patients referred to a sleep exam, accuracies were above 81%, sensitivities about 89%, specificities above 53% and Cohen's kappa values above 0.44. Sleep variable estimates showed no significant inter-method bias, but the limits of agreement were quite wide for the group of patients referred to a sleep exam. Our results indicate that the radar has the potential to offer the benefits of contact-free real-time monitoring of sleep, both for in-patients and for ambulatory home monitoring.Workers of the Commissariat for Atomic Energy and Alternative Energy (CEA) may be potentially exposed to tritium over long periods. We aimed to assess the effect of tritium exposure on mortality in a cohort of employees followed by radiotoxicological monitoring. A total of 1,746 employees who worked for at least six months at one of three CEA centers were included between 1962 and 2011 (median follow-up 29.6 years). The cumulative dose of tritium was based on the quantification of tritium present from urinary excretion monitoring data from the beginning of occupational exposure to the end of such exposure or December 2011. Mortality was first compared to that in the French population using the standardized mortality ratio (SMR). Then, mortality risk ratios (RRs) per category of cumulative dose of tritium were estimated using categorical Poisson models adjusted for age at the onset of exposure, age, calendar period, sex, smoking, employment status, CEA center, and taking into account the number of person-yearsstudy underlines the need to continue following tritium-exposed workers and conducting multicenter studies.Elevated temperatures enhance alternative RNA splicing in maize (Zea mays) with the potential to expand the repertoire of plant responses to heat stress. Alternative RNA splicing generates multiple RNA isoforms for many maize genes, and here we observed changes in the pattern of RNA isoforms with temperature changes. Increases in maximum daily temperature elevated the frequency of the major modes of alternative splices, in particular retained introns and skipped exons. The genes most frequently targeted by increased alternative splicing with temperature encode factors involved in RNA processing and plant development. Genes encoding regulators of alternative RNA splicing were themselves among the principal alternative splicing targets in maize. Under controlled environmental conditions, daily changes in temperature comparable to field conditions altered the abundance of different RNA isoforms, including the RNAs encoding the splicing regulator SR45a, a member of the SR45 gene family. We established an "in protoplast" RNA splicing assay to show that during the afternoon on simulated hot summer days, SR45a RNA isoforms were produced with the potential to encode proteins efficient in splicing model substrates. With the RNA splicing assay, we also defined the exonic splicing enhancers that the splicing-efficient SR45a forms utilize to aid in the splicing of model substrates. Hence, with rising temperatures on hot summer days, SR45a RNA isoforms in maize are produced with the capability to encode proteins with greater RNA splicing potential.
Laparoscopic sleeve gastrectomy (LSG) is a recognized effective procedure of bariatric surgery but a poor response in weight loss may still represent a clinical problem. To date there are no validated predictors useful to better perform patient selection.
to establish the association of baseline anthropometric, metabolic and psychologic features with the percent total (%TWL) and excess (%EWL) weight loss 12 months after surgery.
retrospective longitudinal analysis of a set of data about obese attending the outpatients service of a single obesity center from June 2016 to June 2019.
106 obese patients underwent LSG with pre-surgery evaluation and follow-up at 12 months after surgery.
weight loss 12 months after LSG.
patients who achieved a %TWL higher than the observed median (≥34%) were younger, with a lower fasting plasma glucose and HbA1c, with a lower prevalence of hypertension and with a lower score in the impulsiveness scale, compared to the patients with a %TWL <34%. Similar findings were found when was considered %EWL. Multivariable stepwise regression analysis showed that younger age, lower impulsiveness, higher than normal urinary free cortisol and lower HbA1c were associates with higher %TWL, explaining about 31.5% of the outcome.
metabolic and psychologic features at baseline were independently associated with weight loss and explained a non-negligible effect on the response to LSG. These data suggest that careful metabolic and psychologic profiling could help in sharper indications and personalized pre- and post-surgical follow-up protocols in candidates for LSG.
metabolic and psychologic features at baseline were independently associated with weight loss and explained a non-negligible effect on the response to LSG. These data suggest that careful metabolic and psychologic profiling could help in sharper indications and personalized pre- and post-surgical follow-up protocols in candidates for LSG.
Genome-wide association studies have identified associations between a common single nucleotide polymorphism (SNP, rs267738) in CERS2 - a gene that encodes a (dihydro)ceramide synthase involved in the biosynthesis of very-long chain sphingolipids (e.g. C20-C26) - and indices of metabolic dysfunction (e.g. impaired glucose homeostasis). However, the biological consequences of this mutation on enzyme activity and its causal roles in metabolic disease are unresolved.
The studies described herein aimed to characterize the effects of rs267738 on CERS2 enzyme activity, sphingolipid profiles, and metabolic outcomes.
We performed in-depth lipidomic and metabolic characterization of a novel CRISPR knock-in mouse modeling the rs267738 variant. In parallel, we conducted mass spectrometry-based, targeted lipidomics on 567 serum samples collected through the Utah Coronary Artery Disease study, which included 185 patients harboring one (n = 163) or both (n = 22) rs267738 alleles.
In-silico analysis of the amino acid substitution within CERS2 caused by the rs267738 mutation suggested that rs267738 is deleterious for enzyme function. Homozygous knock-in mice had reduced liver CERS2 activity and enhanced diet-induced glucose intolerance and hepatic steatosis. However, human serum sphingolipids and a ceramide-based CERT1 risk score of cardiovascular disease were not significantly affected by rs267738 allele count.
The rs267738 SNP leads to a partial loss-of-function of CERS2, which worsened metabolic parameters in knock-in mice. However, rs267738 was insufficient to effect changes in serum sphingolipid profiles in subjects from the Utah Coronary Artery Disease Study.
The rs267738 SNP leads to a partial loss-of-function of CERS2, which worsened metabolic parameters in knock-in mice. However, rs267738 was insufficient to effect changes in serum sphingolipid profiles in subjects from the Utah Coronary Artery Disease Study.
Accumulated evidence supports the existence of sex-associated differences in immune systems. Understanding the role of sex in immune-related adverse events (irAEs) is important for management of irAE in patients receiving immunotherapy.
We performed meta-analysis on published clinical study data and multivariable logistic regression on pharmacovigilance data and applied a propensity algorithm to The Cancer Genome Atlas (TCGA) omics data. We further validated our observations in two independent in-house cohorts of 179 and 767 cancer patients treated with immune checkpoint inhibitors.
A meta-analysis using 13 clinical studies that reported on 1,096 female patients (36.8%, 95% confidence interval [CI] = 35.0%-38.5%) and 1,886 male patients (63.2%, 95% CI = 61.5%-65.0%) demonstrated no statistically significant irAE risk difference between the sexes (odds ratio [OR] = 1.19; 95% CI = 0.91-1.54; 2-sided P = 0.21). Multivariable logistic regression analysis of 12,225 patients from FAERS and 10,979 patients from VigiBase showed no statistically significant difference in irAEs by sex.
