β(1,3)-Glucanosyl-Transferase Activity Is Essential for Cell Wall Integrity and Viability of Schizosaccharomyces pombe

13 páginas, 7 figuras, 2 tablas.[Background]: The formation of the cell wall in Schizosaccharomyces pombe requires the coordinated activity of enzymes involved in the biosynthesis and modification of b-glucans. The b(1,3)-glucan synthase complex synthesizes linear b(1,3)- glucans, which remain unorganized until they are cross-linked to other b(1,3)-glucans and other cell wall components. Transferases of the GH72 family play important roles in cell wall assembly and its rearrangement in Saccharomyces cerevisiae and Aspergillus fumigatus. Four genes encoding b(1,3)-glucanosyl-transferases -gas1+, gas2+, gas4+ and gas5+- are present in S. pombe, although their function has not been analyzed. [Methodology/Principal Findings]: Here, we report the characterization of the catalytic activity of gas1p, gas2p and gas5p together with studies directed to understand their function during vegetative growth. From the functional point of view, gas1p is essential for cell integrity and viability during vegetative growth, since gas1D mutants can only grow in osmotically supported media, while gas2p and gas5p play a minor role in cell wall construction. From the biochemical point of view, all of them display b(1,3)-glucanosyl-transferase activity, although they differ in their specificity for substrate length, cleavage point and product size. In light of all the above, together with the differences in expression profiles during the life cycle, the S. pombe GH72 proteins may accomplish complementary, non-overlapping functions in fission yeast. [Conclusions/Significance]: We conclude that b(1,3)-glucanosyl-transferase activity is essential for viability in fission yeast, being required to maintain cell integrity during vegetative growth.This research was supported by grants from the Comision Interministerial de Ciencia y Tecnologia (BFU2004-00778) and Junta de Castilla y Leon (GR231) to C.R.V-A and from the European Community (LSHB-CT-2004-511952) to C.R.V-A. and J.P.L. M.M-R. held a fellowship from the Ministerio de Educacion y Ciencia.Peer reviewe

How COVID-19 changed clinical research strategies: a global survey

Objective Clinical research has faced new challenges during the COVID-19 pandemic, leading to excessive operational demands affecting all stakeholders. We evaluated the impact of COVID-19 on clinical research strategies and compared different adaptations by regulatory bodies and academic research institutions in a global context, exploring what can be learned for possible future pandemics. Methods We conducted a cross-sectional online survey and identified and assessed different COVID-19-specific adaptation strategies used by academic research institutions and regulatory bodies. Results All 19 participating academic research institutions developed and followed similar strategies, including preventive measures, manpower recruitment, and prioritisation of COVID-19 projects. In contrast, measures for centralised management or coordination of COVID-19 projects, project preselection, and funding were handled differently amongst institutions. Regulatory bodies responded similarly to the pandemic by implementing fast-track authorisation procedures for COVID-19 projects and developing guidance documents. Quality and consistency of the information and advice provided was rated differently amongst institutions. Conclusion Both academic research institutions and regulatory bodies worldwide were able to cope with challenges during the COVID-19 pandemic by developing similar strategies. We identified some unique approaches to ensure fast and efficient responses to a pandemic. Ethical concerns should be addressed in any new decision-making process

Detection methods predict differences in biology and survival in breast cancer patients

BackgroundThe aim of this study was to measure the biological characteristics involved in tumorigenesis and the progression of breast cancer in symptomatic and screen-detected carcinomas to identify possible differences.MethodsFor this purpose, we evaluated clinical-pathological parameters and proliferative and apoptotic activities in a series of 130 symptomatic and 161 screen-detected tumors.ResultsAfter adjustment for the smaller size of the screen-detected carcinomas compared with symptomatic cancers, those detected in the screening program presented longer disease-free survival (RR = 0.43, CI = 0.19-0.96) and had high estrogen and progesterone receptor concentrations more often than did symptomatic cancers (OR = 3.38, CI = 1.72-6.63 and OR = 3.44, CI = 1.94-6.10, respectively). Furthermore, the expression of bcl-2, a marker of good prognosis in breast cancer, was higher and HER2/neu expression was lower in screen-detected cancers than in symptomatic cancers (OR = 1.77, CI = 1.01-3.23 and OR = 0.64, CI = 0.40-0.98, respectively). However, when comparing prevalent vs incident screen-detected carcinomas, prevalent tumors were larger (OR = 2.84, CI = 1.05-7.69), were less likely to be HER2/neu positive (OR = 0.22, CI = 0.08-0.61) and presented lower Ki67 expression (OR = 0.36, CI = 0.17-0.77). In addition, incident tumors presented a shorter survival time than did prevalent ones (RR = 4.88, CI = 1.12-21.19).ConclusionsIncident carcinomas include a variety of screen-detected carcinomas that exhibit differences in biology and prognosis relative to prevalent carcinomas. The detection method is important and should be taken into account when making therapy decisions

Building and surroundings: thermal coupling

Energy building performance can be different according to outdoor conditions or urban environment, at the same time that this last assess, buildings are also affected by the building envelope, as obvious consequence of the thermal and Aeraulic coupling existing between the indoor and outdoor conditions in buildings. Thus, in this coupling is fundamental to typify the transmission phenomenon through the building envelope. Doing this, it is possible to estimate transmission heating losses and gains and also the superficial temperatures of the envelope. In order to assess the transient behaviour of the building envelope it is necessary to develop a predictive model, precise enough, to be integrated in a simulating tool. Detailed and multidimensional models, based in numerical methods, like Finite Element Method (FEM), has a high precision, but its complexity imply resources consumption and computational time, too high to be integrated in these kind of tools. On the contrary, simplified methods are good enough because they are simple and fast, with an acceptable precision in almost all the situations. The present work is focused: (a) Firstly, to develop a simplified RC-network model. The aim of the model is to characterize and to implement with precision the behaviour of a wall in a simulating software tool based on urban environment, (b) secondly, to express in form of equivalences, the different indoor and outdoor excitations that can exist in the building envelope, and (c) finally, to calibrate the simplified model through its characteristic parameters. For a homogeneous wall and two types of excitations, it has been obtained the characteristic parameters of the model that represent the better adjustment to the real wall. In a first step, it has been obtained the results of the proposal model and a reference model based on FEM, in terms of wall external surface heat flow. Results of both models have been compared, and the resultant characteristic parameters of the model have been obtained through an optimisation method. Results for the wall and for the excitations under analysis show: (1) Characteristic longitude ec, or capacitive node position, it is determined according to a certain value of Fo equal to 2 for both excitations, this value remains constant in time, (2) useful wall thickness, on the contrary, vary as time function, according to a logarithmic law for both excitations, although this function is different depending on the considered excitation, (3) using a constant excitation, coefficients from the previous logarithmic function depends on the range of the excitation, while these are practically independent of the lineal excitation gradient

Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy:Study protocol of a cluster randomized clinical trial (Multi-PAP project)

This study was funded by the Fondo de Investigaciones Sanitarias ISCIII (Grant Numbers PI15/00276, PI15/00572, PI15/00996), REDISSEC (Project Numbers RD12/0001/0012, RD16/0001/0005), and the European Regional Development Fund ("A way to build Europe").Background: Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT02866799Publisher PDFPeer reviewe

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Repositioning of the global epicentre of non-optimal cholesterol

High blood cholesterol is typically considered a feature of wealthy western countries(1,2). However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world(3) and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health(4,5). However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol-which is a marker of cardiovascular riskchanged from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million-4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.Peer reviewe

Measurement of the top quark forward-backward production asymmetry and the anomalous chromoelectric and chromomagnetic moments in pp collisions at √s = 13 TeV

Abstract The parton-level top quark (t) forward-backward asymmetry and the anomalous chromoelectric (d̂ t) and chromomagnetic (μ̂ t) moments have been measured using LHC pp collisions at a center-of-mass energy of 13 TeV, collected in the CMS detector in a data sample corresponding to an integrated luminosity of 35.9 fb−1. The linearized variable AFB(1) is used to approximate the asymmetry. Candidate t t ¯ events decaying to a muon or electron and jets in final states with low and high Lorentz boosts are selected and reconstructed using a fit of the kinematic distributions of the decay products to those expected for t t ¯ final states. The values found for the parameters are AFB(1)=0.048−0.087+0.095(stat)−0.029+0.020(syst),μ̂t=−0.024−0.009+0.013(stat)−0.011+0.016(syst), and a limit is placed on the magnitude of | d̂ t| < 0.03 at 95% confidence level. [Figure not available: see fulltext.