Preserving neuromuscular synapses in ALS by stimulating MuSK with a therapeutic agonist antibody

In amyotrophic lateral sclerosis (ALS) and animal models of ALS, including SOD1-G93A mice, disassembly of the neuromuscular synapse precedes motor neuron loss and is sufficient to cause a decline in motor function that culminates in lethal respiratory paralysis. We treated SOD1-G93A mice with an agonist antibody to MuSK, a receptor tyrosine kinase essential for maintaining neuromuscular synapses, to determine whether increasing muscle retrograde signaling would slow nerve terminal detachment from muscle. The agonist antibody, delivered after disease onset, slowed muscle denervation, promoting motor neuron survival, improving motor system output, and extending the lifespan of SOD1-G93A mice. These findings suggest a novel therapeutic strategy for ALS, using an antibody format with clinical precedence, which targets a pathway essential for maintaining attachment of nerve terminals to muscle

Qualidade em agricultura: sistemas de certificação, desafios e perspectivas

Qualidade, quando referida ao sector agrícola, integra toda a cadeia produtiva, desde a provisão de matérias-primas até ao consumo e pode ser vista na óptica do produtor e do consumidor. Os sistemas de garantia e certificação da qualidade existentes na União Europeia, baseados numa abordagem holística, são particularmente complexos e variados, pela diversidade de consumidores existentes. A maioria aplica-se a um mercado diferenciado e apenas um reduzido número e muito diversificado vai além das normas legais, visando a diferenciação dos produtos e a manutenção de determinados padrões de qualidade. O seu desenvolvimento é influenciado por medidas de políticas distintas e, factores económicos e sociodemográficos. Podem classificar- se em função do objecto (produtos ou processos), dos objectivos (consumidor final ou os diferentes intervenientes na cadeia de comercialização alimentar), o conteúdo (rastreabilidade na origem ou modo de produção), os promotores (públicos ou privados), o contexto (local, regional, nacional ou internacional) e, o número de etapas envolvidas na cadeia agro-alimentar

The Regional Climate Change Hyper‐Matrix Framework

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95340/1/eost16593.pd

The first multi-model ensemble of regional climate simulations at kilometer-scale resolution, part I: evaluation of precipitation

Here we present the first multi-model ensemble of regional climate simulations at kilometer-scale horizontal grid spacing over a decade long period. A total of 23 simulations run with a horizontal grid spacing of ∼3 km, driven by ERA-Interim reanalysis, and performed by 22 European research groups are analysed. Six different regional climate models (RCMs) are represented in the ensemble. The simulations are compared against available high-resolution precipitation observations and coarse resolution (∼ 12 km) RCMs with parameterized convection. The model simulations and observations are compared with respect to mean precipitation, precipitation intensity and frequency, and heavy precipitation on daily and hourly timescales in different seasons. The results show that kilometer-scale models produce a more realistic representation of precipitation than the coarse resolution RCMs. The most significant improvements are found for heavy precipitation and precipitation frequency on both daily and hourly time scales in the summer season. In general, kilometer-scale models tend to produce more intense precipitation and reduced wet-hour frequency compared to coarse resolution models. On average, the multi-model mean shows a reduction of bias from ∼ −40% at 12 km to ∼ −3% at 3 km for heavy hourly precipitation in summer. Furthermore, the uncertainty ranges i.e. the variability between the models for wet hour frequency is reduced by half with the use of kilometer-scale models. Although differences between the model simulations at the kilometer-scale and observations still exist, it is evident that these simulations are superior to the coarse-resolution RCM simulations in the representing precipitation in the present-day climate, and thus offer a promising way forward for investigations of climate and climate change at local to regional scales

The first multi-model ensemble of regional climate simulations at kilometer-scale resolution. Part I: Evaluation of precipitation

Here we present the first multi-model ensemble of regional climate simulations at kilometer-scale horizontal grid spacing over a decade long period. A total of 23 simulations run with a horizontal grid spacing of ∼ 3 km, driven by ERA-Interim reanalysis, and performed by 22 European research groups are analysed. Six different regional climate models (RCMs) are represented in the ensemble. The simulations are compared against available high-resolution precipitation observations and coarse resolution (∼ 12 km) RCMs with parameterized convection. The model simulations and observations are compared with respect to mean precipitation, precipitation intensity and frequency, and heavy precipitation on daily and hourly timescales in different seasons. The results show that kilometer-scale models produce a more realistic representation of precipitation than the coarse resolution RCMs. The most significant improvements are found for heavy precipitation and precipitation frequency on both daily and hourly time scales in the summer season. In general, kilometer-scale models tend to produce more intense precipitation and reduced wet-hour frequency compared to coarse resolution models. On average, the multi-model mean shows a reduction of bias from ∼ −40 at 12 km to ∼ −3 at 3 km for heavy hourly precipitation in summer. Furthermore, the uncertainty ranges i.e. the variability between the models for wet hour frequency is reduced by half with the use of kilometer-scale models. Although differences between the model simulations at the kilometer-scale and observations still exist, it is evident that these simulations are superior to the coarse-resolution RCM simulations in the representing precipitation in the present-day climate, and thus offer a promising way forward for investigations of climate and climate change at local to regional scales. © 2021, The Author(s)

Role of the first WHO mutation catalogue in the diagnosis of antibiotic resistance in Mycobacterium tuberculosis in the Valencia Region, Spain: a retrospective genomic analysis

9 páginas, 2 figuras, 1 tablaBackground: In June, 2021, WHO published the most complete catalogue to date of resistance-conferring mutations in Mycobacterium tuberculosis. Here, we aimed to assess the performance of genome-based antimicrobial resistance prediction using the catalogue and its potential for improving diagnostics in a real low-burden setting. Methods: In this retrospective population-based genomic study M tuberculosis isolates were collected from 25 clinical laboratories in the low-burden setting of the Valencia Region, Spain. Culture-positive tuberculosis cases reported by regional public health authorities between Jan 1, 2014, and Dec 31, 2016, were included. The drug resistance profiles of these isolates were predicted by the genomic identification, via whole-genome sequencing (WGS), of the high-confidence resistance-causing variants included in the catalogue and compared with the phenotype. We determined the minimum inhibitory concentration (MIC) of the isolates with discordant resistance profiles using the resazurin microtitre assay. Findings: WGS was performed on 785 M tuberculosis complex culture-positive isolates, and the WGS resistance prediction sensitivities were: 85·4% (95% CI 70·8–94·4) for isoniazid, 73·3% (44·9–92·2) for rifampicin, 50·0% (21·1–78·9) for ethambutol, and 57·1% (34·0–78·2) for pyrazinamide; all specificities were more than 99·6%. Sensitivity values were lower than previously reported, but the overall pan-susceptibility accuracy was 96·4%. Genotypic analysis revealed that four phenotypically susceptible isolates carried mutations (rpoB Leu430Pro and rpoB Ile491Phe for rifampicin and fabG1 Leu203Leu for isoniazid) known to give borderline resistance in standard phenotypic tests. Additionally, we identified three putative resistance-associated mutations (inhA Ser94Ala, katG Leu48Pro, and katG Gly273Arg for isoniazid) in samples with substantially higher MICs than those of susceptible isolates. Combining both genomic and phenotypic data, in accordance with the WHO diagnostic guidelines, we could detect two new multidrug-resistant cases. Additionally, we detected 11 (1·6%) of 706 isolates to be monoresistant to fluoroquinolone, which had been previously undetected. Interpretation: We showed that the WHO catalogue enables the detection of resistant cases missed in phenotypic testing in a low-burden region, thus allowing for better patient-tailored treatment. We also identified mutations not included in the catalogue, relevant at the local level. Evidence from this study, together with future updates of the catalogue, will probably lead in the future to the partial replacement of culture testing with WGS-based drug susceptibility testing in our setting. Funding: European Research Council and the Spanish Ministerio de Ciencia.This project received funding from the European Research Council under the European Union’s Horizon 2020 Research and Innovation Program Grant 101001038 (TB-RECONNECT; awarded to IC), from Ministerio de Ciencia (Spanish Government) Project PID2019-104477RB-I00 (awarded to IC), and from Generalitat Valenciana Project AICO/2018/113 (awarded to IC). AMG-M is funded by a Formación deProfesorado Universitario grant programme (FPU19/04562) from Ministerio de Universidades (Spanish Government). IC is also supported by the European Commission–NextGenerationEU, through Centro Superior de Investigaciones Científicas Global Health Platform (PTI Salud Global). We thank all the members of the Valencia RegionTuberculosis Working Group

Fundamental Molecules and Mechanisms for Forming and Maintaining Neuromuscular Synapses

The neuromuscular synapse is a relatively large synapse with hundreds of active zones in presynaptic motor nerve terminals and more than ten million acetylcholine receptors (AChRs) in the postsynaptic membrane. The enrichment of proteins in presynaptic and postsynaptic membranes ensures a rapid, robust, and reliable synaptic transmission. Over fifty years ago, classic studies of the neuromuscular synapse led to a comprehensive understanding of how a synapse looks and works, but these landmark studies did not reveal the molecular mechanisms responsible for building and maintaining a synapse. During the past two-dozen years, the critical molecular players, responsible for assembling the specialized postsynaptic membrane and regulating nerve terminal differentiation, have begun to be identified and their mechanism of action better understood. Here, we describe and discuss five of these key molecular players, paying heed to their discovery as well as describing their currently understood mechanisms of action. In addition, we discuss the important gaps that remain to better understand how these proteins act to control synaptic differentiation and maintenance

Kontinuierliche Herstellung von Profilen mit faserverstärkten Decklagen und Schaumkern durch Pultrusion mit Polyurethan

The importance of physical exercise practice in the treatment of diabetes has been reported in many studies recently, but only limited data can be found regarding its benefits on liver morphology and protein content of hepatocytes. In order to assess the changes arising from the development of type I diabetes and the benefits of a training protocol, Wistar rats were divided into four groups: sedentary control (SC), trained control (TC), sedentary diabetic (SD) and trained diabetic (TD). The training protocol consisted of swimming for 60 min a day, 5 days/week, during 8 weeks. Liver samples were collected, processed and analyzed by histochemical and ultrastructural techniques. Biochemical tests were also conducted to examine the protein content and quantity of DNA in the liver. In morphological assessment, the presence of areas of cytoplasmic basophilia observed in control subjects was not visualized in sedentary diabetics. It was related to differences in the amount of mitochondria in the cytosol. The mitochondrial structure has not undergone relevant changes, and the number of rough endoplasmic reticulum cisterns was clearly inferior in sedentary diabetics, suggesting lower protein production. However, the biochemical analysis of protein content indicated no statistical differences between groups. The exercise, in turn, was not responsible for major changes in these characteristics. on the whole, the morphological damages arising from type I diabetes were noteworthy. Nevertheless, regular physical training was not responsible for significant improvements in some respects, making evident the need for combined application of a distinct form of treatment. (C) 2011 Elsevier Ltd. All rights reserved.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES

The Chronology of Angiostrongylus vasorum (Baillet, 1866), Kamensky, 1905: Infection in Biomphalaria glabrata (Say, 1818)

The intermediate hosts of the French heartworm Angiostrongylus vasorum are aquatic and terrestrial gastropods. The present work is aimed at clarifying the sites of penetration and the migratory routes of A. vasorum in Biomphalaria glabrata snail tissues and evaluating their perilarval reaction with regard to the cellular composition and histological alterations involved in the gastropod response to infection. Biomphalaria glabrata snails were individually infected with 1000 first-stage larvae (L1) of A. vasorum each and killed at predetermined times after infection. Percutaneous infection occurred simultaneously with oral infection. Despite larval tropism to the fibromuscular tissue, some larvae were located in different tissues and organs. A perilarval reaction was observed around the larvae in a fibromuscular layer, appearing later around the larvae located in the viscera. The number of hemocytes surrounding the larvae increased gradually, forming a pregranuloma. Larval death and degeneration were not observed. No defined migratory pattern occurred, and larval development was apparently not associated with particular tissues or organs. In addition, the infection by A. vasorum induces a systemic mobilization of hemocytes in perilarval reaction

Downstream effect of Hengduan Mountains on East China in the REMO regional climate model

The Hengduan Mountains and Tibetan Plateau possess unique topographical characteristics that serve as an effective blocking of the movement of the westerly wind in the middle and lower troposphere towards East China. This study examines results from a regional climate model (REMO) at the resolutions of 25 and 50 km for the period 1980--2012. The model is run using lateral boundary conditions from ERA-Interim (European Centre for Medium-Range Weather Forecasts interim reanalysis). There are only a few differences between 25 and 50 km in land surface/vegetation characteristics, but the major differences in this region are due to the orography. Results show that the high-resolution simulation performance is poor in winter, when southwesterly wind prevails, whereas it performs well in summer, when the westerly wind is substantially weakened in southern China. In comparison to the ERA-Interim wind field, the high-resolution simulation overestimates the air flow over the Hengduan Mountains near the ground surface, which influences the transport of atmospheric water vapor in the downstream region, i.e., over southern China. Specifically, with the help of the overestimated southwesterly wind, the amount of atmospheric water vapor transported increases considerably perennially by up to 20%} in southern China, while it decreases remarkably by more than 5{% throughout the year in a large area of Central and North China. These features lead to excessive precipitation and underestimated cloud cover in southern China, which probably causes the overestimated 2-m temperature in southern China. Our study emphasizes that, in such high-resolution-model studies for East Asia, special attention should be paid to the near-surface winds over the Hengduan Mountains