Human Tra2 proteins jointly control a CHEK1 splicing switch among alternative and constitutive target exons

Alternative splicing—the production of multiple messenger RNA isoforms from a single gene—is regulated in part by RNA binding proteins. While the RBPs transformer2 alpha (Tra2α) and Tra2β have both been implicated in the regulation of alternative splicing, their relative contributions to this process are not well understood. Here we find simultaneous—but not individual—depletion of Tra2α and Tra2β induces substantial shifts in splicing of endogenous Tra2β target exons, and that both constitutive and alternative target exons are under dual Tra2α–Tra2β control. Target exons are enriched in genes associated with chromosome biology including CHEK1, which encodes a key DNA damage response protein. Dual Tra2 protein depletion reduces expression of full-length CHK1 protein, results in the accumulation of the DNA damage marker γH2AX and decreased cell viability. We conclude Tra2 proteins jointly control constitutive and alternative splicing patterns via paralog compensation to control pathways essential to the maintenance of cell viability

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Aortic length measurements for pulse wave velocity calculation:manual 2D vs automated 3D centreline extraction

BACKGROUND: Pulse wave velocity (PWV) is a biomarker for the intrinsic stiffness of the aortic wall, and has been shown to be predictive for cardiovascular events. It can be assessed using cardiovascular magnetic resonance (CMR) from the delay between phase-contrast flow waveforms at two or more locations in the aorta, and the distance on CMR images between those locations. This study aimed to investigate the impact of different distance measurement methods on PWV. We present and evaluate an algorithm for automated centreline tracking in 3D images, and compare PWV calculations using distances derived from 3D images to those obtained from a conventional 2D oblique-sagittal image of the aorta. METHODS: We included 35 patients from a twin cohort, and 20 post-coarctation repair patients. Phase-contrast flow was acquired in the ascending, descending and diaphragmatic aorta. A 3D centreline tracking algorithm is presented and evaluated on a subset of 30 subjects, on three CMR sequences: balanced steady-state free precession (SSFP), black-blood double inversion recovery turbo spin echo, and contrast-enhanced CMR angiography. Aortic lengths are subsequently compared between measurements from a 2D oblique-sagittal plane, and a 3D geometry. RESULTS: The error in length of automated 3D centreline tracking compared with manual annotations ranged from 2.4 [1.8-4.3] mm (mean [IQR], black-blood) to 6.4 [4.7-8.9] mm (SSFP). The impact on PWV was below 0.5m/s (<5%). Differences between 2D and 3D centreline length were significant for the majority of our experiments (p < 0.05). Individual differences in PWV were larger than 0.5m/s in 15% of all cases (thoracic aorta) and 37% when studying the aortic arch only. Finally, the difference between end-diastolic and end-systolic 2D centreline lengths was statistically significant (p < 0.01), but resulted in small differences in PWV (0.08 [0.04 - 0.10]m/s). CONCLUSIONS: Automatic aortic centreline tracking in three commonly used CMR sequences is possible with good accuracy. The 3D length obtained from such sequences can differ considerably from lengths obtained from a 2D oblique-sagittal plane, depending on aortic curvature, adequate planning of the oblique-sagittal plane, and patient motion between acquisitions. For accurate PWV measurements we recommend using 3D centrelines

Comparative effect of calcium and EDTA on arsenic uptake and physiological attributes of Pisum sativum.

In this study, we determined the effect of ethylenediaminetetraacetic acid (EDTA) and calcium (Ca) on arsenic (As) uptake and toxicity to Pisum sativum. Plants were treated with three levels of As (25, 125, 250 µM) in the presence and absence of three levels of Ca (1, 5, 10 mM) and EDTA (25, 125, 250 µM). Exposure to As caused an overproduction of hydrogen peroxide (H2O2) in roots and leaves, which induced lipid peroxidation and decreased pigment contents. Application of both Ca and EDTA significantly reduced As accumulation by pea, Ca being more effective in reducing As accumulation. Both Ca and EDTA enhanced As-induced H2O2 production, but reduced lipid peroxidation. In the case of pigment contents, EDTA significantly reduced pigment contents, whereas Ca significantly enhanced pigment contents compared to As alone. The effect of As treatment in the presence and absence of EDTA and Ca was more pronounced in younger leaves compared to older leaves. The effect of amendments varied greatly with their applied levels, as well as type and age of plant organs. Importantly, due to possible precipitation of Ca-As compounds, the soils with higher levels of Ca ions are likely to be less prone to food chain contamination

Chromium speciation, bioavailability, uptake, toxicity and detoxification in soil-plant system: A review

Chromium (Cr) is a potentially toxic heavy metal which does not have any essential metabolic function in plants. Various past and recent studies highlight the biogeochemistry of Cr in the soil-plant system. This review traces a plausible link among Cr speciation, bioavailability, phytouptake, phytotoxicity and detoxification based on available data, especially published from 2010 to 2016. Chromium occurs in different chemical forms (primarily as chromite (Cr(III)) and chromate (Cr(VI)) in soil which vary markedly in term of their biogeochemical behavior. Chromium behavior in soil, its soil-plant transfer and accumulation in different plant parts vary with its chemical form, plant type and soil physico-chemical properties. Soil microbial community plays a key role in governing Cr speciation and behavior in soil. Chromium does not have any specific transporter for its uptake by plants and it primarily enters the plants through specific and non-specific channels of essential ions. Chromium accumulates predominantly in plant root tissues with very limited translocation to shoots. Inside plants, Cr provokes numerous deleterious effects to several physiological, morphological, and biochemical processes. Chromium induces phytotoxicity by interfering plant growth, nutrient uptake and photosynthesis, inducing enhanced generation of reactive oxygen species, causing lipid peroxidation and altering the antioxidant activities. Plants tolerate Cr toxicity via various defense mechanisms such as complexation by organic ligands, compartmentation into the vacuole, and scavenging ROS via antioxidative enzymes. Consumption of Cr-contaminated-food can cause human health risks by inducing severe clinical conditions. Therefore, there is a dire need to monitor biogeochemical behavior of Cr in soil-plant system

A comparative study to evaluate efficiency of EDTA and calcium in alleviating arsenic toxicity to germinating and young Vicia faba L. seedlings

Purpose: This study delineated the effect of calcium (Ca) and ethylenediaminetetraacetic acid (EDTA) addition on arsenic (As) accumulation and physiological attributes of Vicia faba L. Materials and methods: Two separate experiments were performed. In the first experiment, V. faba seedlings, grown under hydroponic conditions, were exposed to three levels of As (25, 125 and 250 μM) in the presence and absence of three levels of EDTA (25, 125, 250 μM) and calcium (CaCl2: 1, 5 and 10 mM). The effect of EDTA and Ca on As accumulation and physiological attributes of V. faba was assessed by determining As contents in roots and shoot, chlorophyll contents, H2O2 contents, and lipid peroxidation in young and old leaves. In the second experiment, V. faba seeds were grown in Ascontaminated sand culture using the same treatment plan. Results and discussion: The accumulation and toxicity of As to V. faba plants increased with increasing As levels in nutrient solution. Arsenic exposure enhanced the production of reactive oxygen species (ROS) in both roots and leaves, which resulted in lipid peroxidation and decreased chlorophyll contents. The presence of both EDTA and Ca, in general, significantly decreased As accumulation by V. faba seedlings, Ca being more effective than EDTA. Both the amendments decreased As-induced reactive oxygen species (ROS) production and lipid peroxidation. In the case of chlorophyll contents, EDTA significantly decreased chlorophyll contents, while Ca significantly increased chlorophyll contents compared to As. The effect of all the treatments was more pronounced in roots than leaves and in young leaves compared to old leaves. Conclusions: It is proposed that EDTA and Ca greatly affect As accumulation and toxicity to V. faba, and the effect varies greatly with their applied levels as well as type and age of plant organs. The germinating seedlings of V. faba may be preferred for risk assessment studies, while transplanting 1-week-old V. faba seedlings to As-contaminated soils can decrease its toxicity

Comparative effect of organic amendments on physio-biochemical traits of young and old bean leaves grown under cadmium stress : a multivariate analysis

The current study investigated the influence of organic amendments on cadmium (Cd) uptake and its effects on biochemical attributes of young and old leaves of bean. Bean seedlings were exposed to two levels of Cd (25 and 100 μM) in the presence and absence of different levels of ethylenediaminetetraacetic acid (EDTA) and citric acid (CA). An increase in Cd concentration in growth medium significantly enhanced Cd accumulation in bean roots and shoot. Cadmium stress increased the production of H2O2 which resulted in lipid peroxidation and decreased chlorophyll contents. The presence of organic amendments significantly affected Cd accumulation and toxicity to bean plants. Application of EDTA alleviated Cd toxicity in terms of chlorophyll contents, H2O2 contents, and lipid peroxidation possibly by chelating toxic Cd ions, and as such forming Cd-EDTA complexes. The presence of CA decreased Cd toxicity by decreasing its uptake. The biochemical responses (H2O2 contents, lipid peroxidation, and chlorophyll contents) of bean plants were more severely affected by Cd treatments in old leaves compared to young leaves. This study shows that the effect of CA and EDTA on biochemical behavior of Cd varies greatly with applied levels of Cd and amendments as well as the age of leaves. Based on the results, it is proposed that the presence of organic amendments can greatly affect biogeochemical behavior of Cd in the soil-plant system (ecosystem)