PhyleasProg: a user-oriented web server for wide evolutionary analyses

Evolutionary analyses of biological data are becoming a prerequisite in many fields of biology. At a time of high-throughput data analysis, phylogenetics is often a necessary complementary tool for biologists to understand, compare and identify the functions of sequences. But available bioinformatics tools are frequently not easy for non-specialists to use. We developed PhyleasProg (http://phyleasprog.inra.fr), a user-friendly web server as a turnkey tool dedicated to evolutionary analyses. PhyleasProg can help biologists with little experience in evolutionary methodologies by analysing their data in a simple and robust way, using methods corresponding to robust standards. Via a very intuitive web interface, users only need to enter a list of Ensembl protein IDs and a list of species as inputs. After dynamic computations, users have access to phylogenetic trees, positive/purifying selection data (on site and branch-site models), with a display of these results on the protein sequence and on a 3D structure model, and the synteny environment of related genes. This connection between different domains of phylogenetics opens the way to new biological analyses for the discovery of the function and structure of proteins

Antithrombotic Treatment in Transcatheter Aortic Valve Implantation Insights for Cerebrovascular and Bleeding Events

Transcatheter aortic valve implantation (TAVI) has emerged as a therapeutic alternative for patients with symptomatic aortic stenosis at high or prohibitive surgical risk. However, patients undergoing TAVI are also at high risk for both bleeding and stroke complications, and specific mechanical aspects of the procedure itself can increase the risk of these complications. The mechanisms of periprocedural bleeding complications seem to relate mainly to vascular/access site complications (related to the use of large catheters in a very old and frail elderly population), whereas the pathophysiology of cerebrovascular events remains largely unknown. Further, although mechanical complications, especially the interaction between the valve prosthesis and the native aortic valve, may play a major role in events that occur during TAVI, post-procedural events might also be related to a prothrombotic environment or state generated by the implanted valve, the occurrence of atrial arrhythmias, and associated comorbidities. Antithrombotic therapy in the setting of TAVI has been empirically determined, and unfractionated heparin during the procedure followed by dual antiplatelet therapy with aspirin (indefinitely) and clopidogrel (1 to 6 months) is the most commonly recommended treatment. However, bleeding and cerebrovascular events are common; these may be modifiable with optimization of periprocedural and post-procedural pharmacology. Further, as the field of antiplatelet and anticoagulant therapy evolves, potential drug combinations will multiply, introducing variability in treatment. Randomized trials are the best path forward to determine the balance between the efficacy and risks of antithrombotic treatment in this high risk-population

The sterlet sturgeon genome sequence and the mechanisms of segmental rediploidization.

Sturgeons seem to be frozen in time. The archaic characteristics of this ancient fish lineage place it in a key phylogenetic position at the base of the ~30,000 modern teleost fish species. Moreover, sturgeons are notoriously polyploid, providing unique opportunities to investigate the evolution of polyploid genomes. We assembled a high-quality chromosome-level reference genome for the sterlet, Acipenser ruthenus. Our analysis revealed a very low protein evolution rate that is at least as slow as in other deep branches of the vertebrate tree, such as that of the coelacanth. We uncovered a whole-genome duplication that occurred in the Jurassic, early in the evolution of the entire sturgeon lineage. Following this polyploidization, the rediploidization of the genome included the loss of whole chromosomes in a segmental deduplication process. While known adaptive processes helped conserve a high degree of structural and functional tetraploidy over more than 180 million years, the reduction of redundancy of the polyploid genome seems to have been remarkably random

Androgen receptor condensates as drug targets

Transcription factors are among the most attractive therapeutic targets, but are considered largely undruggable. Here we provide evidence that small molecule-mediated partitioning of the androgen receptor, an oncogenic transcription factor, into phase-separated condensates has therapeutic effect in prostate cancer models. We show that the phase separation capacity of the androgen receptor is driven by aromatic residues and short unstable helices in its intrinsically disordered activation domain. Based on this knowledge, we developed tool compounds that covalently attach aromatic moieties to cysteines in the receptors’ activation domain. The compounds enhanced partitioning of the receptor into condensates, facilitated degradation of the receptor, inhibited androgen receptor-dependent transcriptional programs, and had antitumorigenic effect in models of prostate cancer and castration-resistant prostate cancer in vitro and in vivo. These results establish a generalizable framework to target the phase- separation capacity of intrinsically disordered regions in oncogenic transcription factors and other disease-associated proteins with therapeutic intent

Macro-language planning for multilingual education : focus on programmes and provision

This overview identifies some common features of macro-level language planning and briefly summarises the changing approaches to the analysis of macro-planning in the field. It previews six cases of language-in-education planning in response to linguistic diversity presented by the contributors to this issue. The cases show how macro-planning can either fail to recognise diverse ethnolinguistic identities or work to acknowledge them. Three common themes in language planning for multilingual education can be identified from the contributions: (i) top-down definitions of what counts as mother tongue can have both intended and unintended outcomes; (ii) language-as-problem responses to linguistic diversity can work to reinforce social exclusion; and (iii) the acknowledgement of diversity and minority language rights needs to flow through from statements of intent to on-the-ground implementation if they are to become a reality

Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial

IMPORTANCE: Secretory phospholipase A2(sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measurewas a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95%CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95%CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246. Copyright 2014 American Medical Association. All rights reserved

Incidence and Sequelae of Prosthesis-Patient Mismatch in Transcatheter Versus Surgical Valve Replacement in High-Risk Patients With Severe Aortic Stenosis A PARTNER Trial Cohort-A Analysis

AbstractBackgroundLittle is known about the incidence of prosthesis-patient mismatch (PPM) and its impact on outcomes after transcatheter aortic valve replacement (TAVR).ObjectivesThe objectives of this study were: 1) to compare the incidence of PPM in the TAVR and surgical aortic valve replacement (SAVR) randomized control trial (RCT) arms of the PARTNER (Placement of AoRTic TraNscathetER Valves) I Trial cohort A; and 2) to assess the impact of PPM on regression of left ventricular (LV) hypertrophy and mortality in these 2 arms and in the TAVR nonrandomized continued access (NRCA) registry cohort.MethodsThe PARTNER Trial cohort A randomized patients 1:1 to TAVR or bioprosthetic SAVR. Postoperative PPM was defined as absent if the indexed effective orifice area (EOA) was >0.85 cm2/m2, moderate if the indexed EOA was ≥0.65 but ≤0.85 cm2/m2, or severe if the indexed EOA was <0.65 cm2/m2. LV mass regression and mortality were analyzed using the SAVR-RCT (n = 270), TAVR-RCT (n = 304), and TAVR-NRCA (n = 1,637) cohorts.ResultsThe incidence of PPM was 60.0% (severe: 28.1%) in the SAVR-RCT cohort versus 46.4% (severe: 19.7%) in the TAVR-RCT cohort (p < 0.001) and 43.8% (severe: 13.6%) in the TAVR-NRCA cohort. In patients with an aortic annulus diameter <20 mm, severe PPM developed in 33.7% undergoing SAVR compared with 19.0% undergoing TAVR (p = 0.002). PPM was an independent predictor of less LV mass regression at 1 year in the SAVR-RCT (p = 0.017) and TAVR-NRCA (p = 0.012) cohorts but not in the TAVR-RCT cohort (p = 0.35). Severe PPM was an independent predictor of 2-year mortality in the SAVR-RCT cohort (hazard ratio [HR]: 1.78; p = 0.041) but not in the TAVR-RCT cohort (HR: 0.58; p = 0.11). In the TAVR-NRCA cohort, severe PPM was not a predictor of 1-year mortality in all patients (HR: 1.05; p = 0.60) but did independently predict mortality in the subset of patients with no post-procedural aortic regurgitation (HR: 1.88; p = 0.02).ConclusionsIn patients with severe aortic stenosis and high surgical risk, PPM is more frequent and more often severe after SAVR than TAVR. Patients with PPM after SAVR have worse survival and less LV mass regression than those without PPM. Severe PPM also has a significant impact on survival after TAVR in the subset of patients with no post-procedural aortic regurgitation. TAVR may be preferable to SAVR in patients with a small aortic annulus who are susceptible to PPM to avoid its adverse impact on LV mass regression and survival. (The PARTNER Trial: Placement of AoRTic TraNscathetER Valve Trial; NCT00530894

Incidence and severity of paravalvular aortic regurgitation with multidetector computed tomography nominal area oversizing or undersizing after transcatheter heart valve replacement with the Sapien 3 : a comparison with the Sapien XT.

Objectives : This study sought to compare the influence of the extent of multidetector computed tomography (MDCT) area oversizing on the incidence of paravalvular aortic regurgitation (PAR) between the Sapien 3 and the Sapien XT transcatheter heart valve (THV) to define a new MDCT sizing guideline suitable for the Sapien 3 platform. Background : The inverse relationship of PAR occurrence and oversizing has been demonstrated for the Sapien XT but the incidence of PAR with comparable oversizing with the Sapien 3 is not known. Methods : Sixty-one prospectively enrolled patients who underwent transcatheter aortic valve replacement with the Sapien 3 THV were compared with 92 patients who underwent transcatheter aortic valve replacement with the Sapien XT THV. Patients were categorized depending on the degree of MDCT area oversizing percentage: undersizing (below 0%), 0% to 5%, 5% to 10%, and above 10%. The primary endpoint was mild or greater PAR on transthoracic echocardiography. Results : Mild or greater PAR was present in 19.7% of patients (12 of 61) in the Sapien 3 group and in 54.3% of patients (50 of 92) in the Sapien XT group (p 10% (p for interaction = 0.54). Moderate or severe PAR rates were also lower in the Sapien 3 group than in the Sapien XT group (3.3% vs. 13.0%, p = 0.04). In the Sapien 3 group, a MDCT area oversizing percentage value of =4.17% was identified as the optimal cutoff value to discriminate patients with or without mild or greater PAR. Conclusions : Our retrospective analysis suggests that the Sapien 3 THV displays significantly lower rates of PAR than does the Sapien XT THV. A lesser degree of MDCT area oversizing may be employed for this new balloon-expandable THV

Биофизика зрительной сенсорной системы человека

Зрительная сенсорная система – это система, которая воспринимает излучение видимого спектра, после чего формируется изображение предметов окружающей среды в виде определенных ощущений (сенсорных чувств)