Choikoefoed4543

Long non-coding RNAs (lncRNAs) have gained increasing attention as they exhibit highly tissue- and cell-type specific expression patterns. LncRNAs are highly expressed in the central nervous system and their roles in the brain have been studied intensively in recent years, but their roles in the spinal motor neurons (MNs) are largely unexplored. Spinal MN development is controlled by precise expression of a gene regulatory network mediated spatiotemporally by transcription factors, representing an elegant paradigm for deciphering the roles of lncRNAs during development. Moreover, many MN-related neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are associated with RNA metabolism, yet the link between MN-related diseases and lncRNAs remains obscure. In this review, we summarize lncRNAs known to be involved in MN development and disease, and discuss their potential future therapeutic applications.BACKGROUND Unstimulated whole saliva (UWS) flow rate is one of the ACR/EULAR 2016 criteria for primary Sjögren's syndrome (pSS). With a single threshold of ≤ 0.1 mL/min, UWS flow does not take into account the age- and sex-related physiological variations. Furthermore, it has a low sensitivity for the diagnosis of pSS (about 50%), contrary to the screening test for xerophthalmia, Schirmer's test (sensitivity of about 70%). We aimed to identify UWS thresholds allowing better performances for a screening test for pSS comparable to Schirmer's test, and considering age- and sex-related variations. METHODS A prospective cohort of 185 patients with oral and/or ocular dryness was classified into 3 groups men, women less then  50 ( less then  50 years old), and women ≥ 50 (≥ 50 years old). The diagnostic performances of UWS flow rate in these groups were compared in terms of sensitivity, specificity, positive and negative predictive values, and ROC curves. The identification of thresholds that optimize diagnostic performances was carried out using Youden's index. RESULTS The diagnostic performances of UWS flow rate varied according to age and sex. UWS had poor diagnostic performances whatever the threshold in the women ≥ 50 group. The threshold of 0.2 mL/min had a sensitivity of ≥ 70% and a specificity of ≥ 50% in both men and women less then  50 groups. In the whole population and compared to the current cutoff, a threshold of 0.2 mL/min increased sensitivity (+ 19.8%) and positive (+ 2.3%) and negative (+ 7.0%) predictive values, with a better specificity (65.2%) than Schirmer's test. CONCLUSION For objective assessment of xerostomia, raising the threshold of the UWS flow rate to 0.2 mL/min would optimize its screening performances for pSS.BACKGROUND In light of the vulnerability of the developing brain, mixture risk assessment (MRA) for the evaluation of developmental neurotoxicity (DNT) should be implemented, since infants and children are co-exposed to more than one chemical at a time. One possible approach to tackle MRA could be to cluster DNT chemicals in a mixture on the basis of their mode of action (MoA) into 'similar' and 'dissimilar', but still contributing to the same adverse outcome, and anchor DNT assays to common key events (CKEs) identified in DNT-specific adverse outcome pathways (AOPs). Moreover, the use of human in vitro models, such as induced pluripotent stem cell (hiPSC)-derived neuronal and glial cultures would enable mechanistic understanding of chemically-induced adverse effects, avoiding species extrapolation. METHODS HiPSC-derived neural progenitors differentiated into mixed cultures of neurons and astrocytes were used to assess the effects of acute (3 days) and repeated dose (14 days) treatments with single chemicals outgrowth and synaptogenesis (the most sensitive endpoint as confirmed by mathematical modelling) and increase of BDNF levels, to a certain extent reproducing autism-like cellular changes observed in the brain of autistic children. CONCLUSIONS Our findings suggest that the use of human iPSC-derived mixed neuronal/glial cultures applied to a battery of assays anchored to key events of an AOP network represents a valuable approach to identify mixtures of chemicals with potential to cause learning and memory impairment in children.BACKGROUND Driving under the influence of alcohol, illicit drugs and certain medicines is not allowed worldwide. Roadside drug testing is considered an important tool for determining such behavior. In Spain, mandatory roadside oral fluid drug testing is carried out regularly. The aim of this study was to determine the prevalence of benzodiazepines and benzodiazepines in combination with other drugs in drivers, examine benzodiazepine concentrations in drivers, and analyze the association of these factors with age and sex. OSI774 METHODS This study assessed data on Spanish drivers with confirmed drug-positive results recorded by the Spanish National Traffic Agency (Dirección General de Tráfico) between 2011 and 2016, accounting for 179,645 tests and 65,244 confirmed drug-positive tests. RESULTS Benzodiazepines were confirmed in 4.3% of all positive roadside drug tests. In most of those cases (97.1%), other substances were also detected, particularly cocaine (75.3%) and cannabis (64.0%). The frequency of benzodiazepine-positive drivers (OR, 1.094; 95% CI, 1.088-1.100) increased with age, while the frequency of drivers who tested positive for benzodiazepines in conjunction with other substances, compared with drivers who tested positive for benzodiazepines alone, decreased with age (OR, 0.903; 95% CI, 0.825-0.988). Nordiazepam (54.8%) and alprazolam (46.9%) were the most common benzodiazepines detected. CONCLUSION Concomitant use of benzodiazepines and other psychoactive substances was found to be a common behavior among drivers who tested positive on the road. It is important to raise awareness of all those involved in the consumption of driving-impairing substances (authorities, healthcare providers, patients and their families, etc.) roadside detection of driving-impairing substances is suggested, in addition to promoting the use of fewer driving-impairing medications and the provision of clear information to patients.BACKGROUND Idiopathic membranous nephropathy (IMN) remains the leading cause of adult nephrotic syndrome. Immunosuppressive therapy with cyclophosphamide (CTX) is often successful in reducing proteinuria, but its use is associated with severe side effects. link2 Tacrolimus (TAC) is effective in achieving complete remission (CR) in patients with IMN. However, whether it is as effective as CTX in inducing and maintaining complete or partial remission in these patients is unknown. This trial aims to test TAC monotherapy for its non-inferiority to CTX in inducing long-term remission of proteinuria. METHODS Patients with biopsy-proven IMN with nephrotic syndrome will be randomized into a 12-month treatment period with oral TAC of 0.05-0.1 mg/kg/day for 6 months or with CTX + glucocorticoid. The efficacy of the treatment will be assessed by the remission status (based on changes in proteinuria) and relapse rate. DISCUSSION This study will test whether treatment with TAC monotherapy is superior to CTX with glucocorticoid in inducing long-term remission of proteinuria in patients with adult IMN. The role of serum anti-PLA2R antibodies in the early assessment of the response to therapy using different therapeutic regimens will also be clarified. TRIAL REGISTRATION ClinicalTrials.gov ChiCTR1800016140. link3 Registered 12 June 2017. http//www.chictr.org.cn.BACKGROUND An extreme and persistent dysbiosis occurs among critically ill patients, regardless of the heterogeneity of disease. Dysbiosis in critically ill patients may make them prone to hospital-acquired infections, sepsis, multi-organ failure (MOF), energy homeostasis disturbance, muscle wasting, and cachexia. Modulation of gut microbiota through synbiotics can be considered as a potential treatment for muscle wasting and macronutrient homeostasis disturbances. METHODS This is a prospective, single-center, double-blind, parallel randomized controlled trial with the aim to evaluate the effects of synbiotic supplementation on energy and macronutrient homeostasis and muscle wasting in critically ill patients. A total of 40 hemodynamically stable, adult, critically ill patients who receive enteral nutrition via a nasogasteric tube (NGT) in the 24-48 h after admission to critical care will be included in this study. Eligible patients will be randomly assigned to receive Lactocare (ZistTakhmir) capsules 500 mg every 12 h or a placebo capsule, which contains only the sterile maize starch and is similar to synbiotic capsules for 14 days. The synbiotic and placebo capsules will be given through the nasogastric tube, separately from gavage, after feeding. DISCUSSION Gut microbiota modulation through synbiotics is proposed to improve clinical prognosis and reduce infectious complications, ventilator dependency, and length of ICU stay by improving energy and macronutrient homeostasis and reducing muscle protein catabolism. TRIAL REGISTRATION Iranian Registry of Clinical Trials, IRCT20190227042857N1. Registered on 17 March 2019.The pore-forming protein epsilon toxin (Etx) from Clostridium perfringens produces acute perivascular edema affecting several organs, especially the brain and lungs. Despite the toxin evident effect on microvasculature and endothelial cells, the underlying molecular and cellular mechanisms remain obscure. Moreover, no Etx-sensitive endothelial cell model has been identified to date. Here, we characterize the mouse lung endothelial cell line 1G11 as an Etx-sensitive cell line and compare it with the well-characterized Etx-sensitive Madin-Darby canine kidney epithelial cell line. Several experimental approaches, including morphological and cytotoxic assays, clearly demonstrate that the 1G11 cell line is highly sensitive to Etx and show the specific binding, oligomerization, and pore-forming activity of the toxin in these cells. Recently, the myelin and lymphocyte (MAL) protein has been postulated as a putative receptor for Etx. Here, we show the presence of Mal mRNA in the 1G11 cell line and the presence of the MAL protein in the endothelium of some mouse lung vessels, supporting the hypothesis that this protein is a key element in the Etx intoxication pathway. The existence of an Etx-sensitive cell line of endothelial origin would help shed light on the cellular and molecular mechanisms underlying Etx-induced edema and its consequences.Recently, several non-classical functions of histone modification regulators (HMRs), independent of their known histone modification substrates and products, have been reported to be essential for specific cellular processes. However, there is no framework designed for identifying such functions systematically. Here, we develop ncHMR detector, the first computational framework to predict non-classical functions and cofactors of a given HMR, based on ChIP-seq data mining. We apply ncHMR detector in ChIP-seq data-rich cell types and predict non-classical functions of HMRs. Finally, we experimentally reveal that the predicted non-classical function of CBX7 is biologically significant for the maintenance of pluripotency.