There is a short gamma-ray burst prompt phase at the beginning of each long one

We compare the prompt intrinsic spectral properties of a sample of short Gamma--ray Burst (GRB) with the first 0.3 seconds (rest frame) of long GRBs observed by Fermi/GBM. We find that short GRBs and the first part of long GRBs lie on the same E_p--E_iso correlation, that is parallel to the relation for the time averaged spectra of long GRBs. Moreover, they are indistinguishable in the E_p--L_iso plane. This suggests that the emission mechanism is the same for short and for the beginning of long events, and both short and long GRBs are very similar phenomena, occurring on different timescales. If the central engine of a long GRB would stop after ~0.3 * (1+z) seconds the resulting event would be spectrally indistinguishable from a short GRB.Comment: 14 pages, 6 figures, MNRAS accepte

A structure-based proposal for the catalytic mechanism of the bacterial acid phosphatase AphA belonging to the DDDD superfamily of phosphohydrolases

The Escherichia coli gene aphA codes for a periplasmic acid phosphatase called AphA, belonging to class B bacterial phosphatases, which is part of the DDDD superfamily of phosphohydrolases. After our first report about its crystal structure, we have started a series of crystallographic studies aimed at understanding of the catalytic mechanism of the enzyme. Here, we report three crystal structures of the AphA enzyme in complex with the hydrolysis products of nucleoside monophosphate substrates and a fourth with a proposed intermediate analogue that appears to be covalently bound to the enzyme. Comparison with the native enzyme structure and with the available X-ray structures of different phosphatases provides clues about the enzyme chemistry and allows us to propose a catalytic mechanism for AphA, and to discuss it with respect to the mechanism of other bacterial and human phosphatases. (c) 2005 Elsevier Ltd. All rights reserved

DBATE: database of alternative transcripts expression

The use of high-throughput RNA sequencing technology (RNA-seq) allows whole transcriptome analysis, providing an unbiased and unabridged view of alternative transcript expression. Coupling splicing variant-specific expression with its functional inference is still an open and difficult issue for which we created the DataBase of Alternative Transcripts Expression (DBATE), a web-based repository storing expression values and functional annotation of alternative splicing variants. We processed 13 large RNA-seq panels from human healthy tissues and in disease conditions, reporting expression levels and functional annotations gathered and integrated from different sources for each splicing variant, using a variant-specific annotation transfer pipeline. The possibility to perform complex queries by cross-referencing different functional annotations permits the retrieval of desired subsets of splicing variant expression values that can be visualized in several ways, from simple to more informative. DBATE is intended as a novel tool to help appreciate how, and possibly why, the transcriptome expression is shaped. DATABASE URL: http://bioinformatica.uniroma2.it/DBATE/

Changes in eggshell ultrastructure of Falco naumanni and Tyto alba exposed to pesticides and polychlorinated biphenyls (PCBs)

Changes in the quality of eggs of birds exposed to environmental contaminants have been described, but few reports concern eggshell ultrastructure. In this study, infertile or addled Lesser Kestrels (Falco naumanni) and Barn owls (Tyto alba) eggs were collected from the polluted area of Gela plain (Sicily) during 2007, and compared in terms of organophosphate and organochlorine pesticides, and PCBs levels, and eggshell ultrastructure as determined by scanning electron microscopy. Pesticide and PCB residues in eggs were determined by Gas chromatography/ mass spectrometry (GC/MS) [GC Agilent 7890A/MS Agilent 5975C (Agilent technologies) using a DB-5 capillary column in the selected ion monitoring mode]. The GC/MS analysis revealed that eggs contained measurable amounts of some pesticides and PCBs. There was a low detection of organophosphate pesticides while the most abundant organochlorine residues detected were p,p’ DDT, p,p’ DDE, and Hexachlorobenzene. While, the most abundant PCBs detected congeners were PCB 138, 153, 170, 180, and 187. Although the general structure of the eggshell layers was maintained, the results showed ultrastructural differences in mammillary and palisade eggshell layers between high level and low level contaminated eggs in Tyto alba. Furthermore, mammillary cores of the eggshell had an increased distance between themselves with respect to well organized structures present in uncontaminated egg. In this paper we verify the presence of environmental contaminants in the eggs and document structural changes in bird of prey eggshells. The data could suggest that some contaminants can contribute to reduced reproductive performance (infertile or addled egg) by structural changes in the eggshell. The alteration in morphological disposition of mammillary cores could also suggest an impairment of gas exchange

A magnetar powering the ordinary monster GRB 130427A?

We present the analysis of the extraordinarily bright Gamma-Ray Burst (GRB) 130427A under the hypothesis that the GRB central engine is an accretion-powered magnetar. In this framework, initially proposed to explain GRBs with precursor activity, the prompt emission is produced by accretion of matter onto a newly-born magnetar, and the observed power is related to the accretion rate. The emission is eventually halted if the centrifugal forces are able to pause accretion. We show that the X-ray and optical afterglow is well explained as the forward shock emission with a jet break plus a contribution from the spin-down of the magnetar. Our modelling does not require any contribution from the reverse shock, that may still influence the afterglow light curve at radio and mm frequencies, or in the optical at early times. We derive the magnetic field ($B\sim 10^{16}$ G) and the spin period ($P\sim 20$ ms) of the magnetar and obtain an independent estimate of the minimum luminosity for accretion. This minimum luminosity results well below the prompt emission luminosity of GRB 130427A, providing a strong consistency check for the scenario where the entire prompt emission is the result of continuous accretion onto the magnetar. This is in agreement with the relatively long spin period of the magnetar. GRB 130427A was a well monitored GRB showing a very standard behavior and, thus, is a well-suited benchmark to show that an accretion-powered magnetar gives a unique view of the properties of long GRBs.Comment: 5 pages, 1 figure, accepted for publication in MNRAS Letter

Transcription Impacts the Efficiency of mRNA Translation via Co-transcriptional N6-adenosine Methylation

Transcription and translation are two main pillars of gene expression. Due to the different timings, spots of action, and mechanisms of regulation, these processes are mainly regarded as distinct and generally uncoupled, despite serving a common purpose. Here, we sought for a possible connection between transcription and translation. Employing an unbiased screen of multiple human promoters, we identified a positive effect of TATA box on translation and a general coupling between mRNA expression and translational efficiency. Using a CRISPR-Cas9-mediated approach, genome-wide analyses, and in vitro experiments, we show that the rate of transcription regulates the efficiency of translation. Furthermore, we demonstrate that m6A modification of mRNAs is co-transcriptional and depends upon the dynamics of the transcribing RNAPII. Suboptimal transcription rates lead to elevated m6A content, which may result in reduced translation. This study uncovers a general and widespread link between transcription and translation that is governed by epigenetic modification of mRNAs

Nutraceutical Value of Citrus Flavanones and Their Implications in Cardiovascular Disease

Background- Cardiovascular diseases, including myocardial infarction, dyslipidaemia and coronary artery pathology, are a major cause of illness and death in Western countries. Therefore, identifying effective therapeutic approaches and their cellular signalling pathways is a challenging goal for medicine. In this regard, several epidemiological studies demonstrate a relationship between the intake of flavonoid-rich foods and the reduction of cardiovascular risk factors and mortality. In particular, flavonoids present in citrus fruits, such as oranges, bergamots, lemons and grapefruit (95% from flavanones), are emerging for their considerable nutraceutical value. Methods- In this review an examination of literature was performed while considering both epidemiological, clinical and pre-clinical evidence supporting the beneficial role of the flavanone class. We evaluated studies in which citrus fruit juices or single flavanone administration and cardiovascular risk factors were analysed; to identify these studies, an electronic search was conducted in PUBMED for papers fulfilling these criteria and written in English. Results- In addition to epidemiological evidence and clinical studies demonstrating that fruits in the Citrus genus significantly reduce the incidence of cardiovascular disease risk, pre-clinical investigations highlight cellular and subcellular targets that are responsible for these beneficial effects. There has been special attention on evaluating intracellular pathways involved in direct cardiovascular and cardiometabolic effects mediated by naringenin, hesperetin and eriodictyol or their glycosylated derivatives. Conclusions- Although some mechanisms of action remain unclear and bioavailability problems remain to be solved, the current evidence supports the use of a nutraceutical approach with citrus fruits to prevent and cure several aspects of cardiovascular disease

Erucin exhibits vasorelaxing effects and antihypertensive activity by H2 S-releasing properties.

BACKGROUND AND PURPOSE: Hydrogen sulfide (H2 S)-releasing agents are viewed as potential antihypertensive drugs. Recently, natural isothiocyanates emerged as original H2 S-donor agents. Among them, erucin, present in some edible cruciferous plants, shows suitable H2 S-releasing properties and features of "druggability." The aim of this work was to investigate the erucin-mediated release of H2 S inside vascular cells, its vasorelaxing effects, and activity on BP of normo and hypertensive animals. EXPERIMENTAL APPROACH: Intracellular H2 S-release and the hyperpolarizing effect of erucin were tested using fluorescent dye, in human aortic smooth muscle cells (HASMCs). Its direct vasorelaxing effect and ability to inhibit noradrenaline-induced vasoconstriction were evaluated on endothelium-intact or -denuded rat aortic rings. Its vasodilator properties were tested in coronary arteries using Langendorff-perfused rat hearts. Finally, erucin's antihypertensive activity was evaluated in vivo in normotensive and spontaneously hypertensive rats (SHRs) by recording systolic BP using the tail-cuff method. KEY RESULTS: Erucin induced the release of H2 S inside HASMCs. Moreover, erucin hyperpolarized the membrane of HASMCs membrane in a concentration-dependent manner. It induced vasodilatation of rat aortic rings, in endothelium-denuded vessels. This effect was further improved by the presence of endothelial NO. When pre-incubated with rat aortic rings, erucin induced concentration-dependent inhibition of noradrenaline-induced vasoconstriction. Erucin did not affect basal coronary flow but restored the flow to normal in pre-contracted coronary vessels. Finally, in vivo, erucin decreased systolic BP in SHRs by about 25%, and restored the BP to values observed in normotensive rats. CONCLUSIONS AND IMPLICATIONS: Erucin is an H2 S donor endowed with vasorelaxing and antihypertensive effects

Selective estrogen receptor modulators in COVID-19. a possible therapeutic option

Male and female genders exhibit significant differences in the outcome of infective diseases caused by several viral pathogens. Along with behavioral or social factors which can affect the exposure to infection and the availability of therapies, it is widely accepted that genetic and physiological factors can markedly influence sex-related differences in immune responses. In particular, receptors for gonadal hormones are expressed in many immune cell types and, consistently, sex-related differences in immune function are likely to be strongly influenced by circulating sex steroid hormones (Klein and Huber, 2010). Concerning coronaviruses, epidemiological data from SARS epidemic (severe acute respiratory syndrome caused by SARS-CoV in 2002–2003) and MERS epidemic (Middle East respiratory syndrome, caused by MERS-CoV in 2012–2013) showed evident sex-dependent differences in disease outcome (Karlberg et al., 2004). Notably, such a sex-dependent difference is presently observed in the new SARS pandemic, broken out in 2019 and caused by SARS-CoV-2 (COVID-19). In particular, susceptibility to SARS-CoV-2 infection is almost similar in both genders, but higher severity and mortality are observed in male patients (Wenham et al., 2020)

Multicentre randomised placebo-controlled trial of oral anticoagulation with apixaban in systemic sclerosis-related pulmonary arterial hypertension: the SPHInX study protocol

Introduction: Systemic sclerosis (SSc) is a severe and costly multiorgan autoimmune connective tissue disease characterised by vasculopathy and fibrosis. One of the major causes of SSc-related death is pulmonary arterial hypertension (PAH), which develops in 12–15% of patients with SSc and accounts for 30– 40% of deaths. In situ thrombosis in the small calibre peripheral pulmonary vessels resulting from endothelial dysfunction and an imbalance of anticoagulant and prothrombotic mediators has been implicated in the complex pathophysiology of SSc-related PAH (SSc- PAH), with international clinical guidelines recommending the use of anticoagulants for some types of PAH, such as idiopathic PAH. However, anticoagulation has not become part of standard clinical care for patients with SSc-PAH as only observational evidence exists to support its use. Therefore, we present the rationale and methodology of a phase III randomised controlled trial (RCT) to evaluate the efficacy, safety and cost-effectiveness of anticoagulation in SSc-PAH. Methods and analysis: This Australian multicentre RCT will compare 2.5 mg apixaban with placebo, in parallel treatment groups randomised in a 1:1 ratio, both administered twice daily for 3 years as adjunct therapy to stable oral PAH therapy. The composite primary outcome measure will be the time to death or clinical worsening of PAH. Secondary outcomes will include functional capacity, health-related quality of life measures and adverse events. A cost-effectiveness analysis of anticoagulation versus placebo will also be undertaken. Ethics and dissemination: Ethical approval for this RCT has been granted by the Human Research Ethics Committees of all participating centres. An independent data safety monitoring board will review safety and tolerability data for the duration of the trial. The findings of this RCT are to be published in open access journals.Alicia Calderone, Wendy Stevens, David Prior, Harshal Nandurkar, Eli Gabbay, Susanna M Proudman, Trevor Williams, David Celermajer, Joanne Sahhar, Peter K K Wong, Vivek Thakkar, Nathan Dwyer, Jeremy Wrobel, Weng Chin, Danny Liew, Margaret Staples, Rachelle Buchbinder, Mandana Nikpou