Activity-dependent competition regulates motor neuron axon pathfinding via PlexinA3

The role of electrical activity in axon guidance has been extensively studied in vitro. To better understand its role in the intact nervous system, we imaged intracellular Ca2+ in zebrafish primary motor neurons (PMN) during axon pathfinding in vivo. We found that PMN generate specific patterns of Ca2+ spikes at different developmental stages. Spikes arose in the distal axon of PMN and were propagated to the cell body. Suppression of Ca2+ spiking activity in single PMN led to stereotyped errors, but silencing all electrical activity had no effect on axon guidance, indicating that an activity-based competition rule regulates this process. This competition was not mediated by synaptic transmission. Combination of PlexinA3 knockdown with suppression of Ca2+ activity in single PMN produced a synergistic increase in the incidence of pathfinding errors. However, expression of PlexinA3 transcripts was not regulated by activity. Our results provide an in vivo demonstration of the intersection of spontaneous electrical activity with the PlexinA3 guidance molecule receptor in regulation of axon pathfinding.Fil: Plazas, Paola Viviana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. University of California at San Diego. Kavli Institute for Brain and Mind. Division of Biological Sciences. Neurobiology Section and Center for Neural Circuits and Behavior; Estados UnidosFil: Nicol, Xavier. University of California at San Diego. Kavli Institute for Brain and Mind. Division of Biological Sciences. Neurobiology Section and Center for Neural Circuits and Behavior; Estados UnidosFil: Spitzer, Nicholas C.. University of California at San Diego. Kavli Institute for Brain and Mind. Division of Biological Sciences. Neurobiology Section and Center for Neural Circuits and Behavior; Estados Unido

Discriminaci?n de precios como mecanismo para promover la demanda de servicios de entretenimiento en el consumidor adulto joven

La presente tesis es una investigaci?n aplicada que tiene como objetivo general dise?ar un modelo de discriminaci?n de precios, al cual se ha llegado luego de realizar un modelo econom?trico que permite predecir el gasto de los consumidores adultos j?venes en actividades de entretenimiento por semana y compararlo con el gasto promedio de este grupo etario, lo que permite calificar a estas personas en diversos grupos para el otorgamiento de un precio diferenciado (descuento sobre precio de lista). El modelo propuesto puede ser de gran utilidad para las empresas del sector entretenimiento que cuentan con capacidad instalada subutilizada, y costos marginales cercanos a cero, ya que el incremento de uno o m?s consumidores adicionales incrementar?a sus beneficios, pues mejorar?a sus ingresos sin tener implicancias significativas en sus costos totales de operaci?n

Modeling Activity and Target-Dependent Developmental Cell Death of Mouse Retinal Ganglion Cells Ex Vivo

Programmed cell death is widespread during the development of the central nervous system and serves multiple purposes including the establishment of neural connections. In the mouse retina a substantial reduction of retinal ganglion cells (RGCs) occurs during the first postnatal week, coinciding with the formation of retinotopic maps in the superior colliculus (SC). We previously established a retino-collicular culture preparation which recapitulates the progressive topographic ordering of RGC projections during early post-natal life. Here, we questioned whether this model could also be suitable to examine the mechanisms underlying developmental cell death of RGCs. Brn3a was used as a marker of the RGCs. A developmental decline in the number of Brn3a-immunolabelled neurons was found in the retinal explant with a timing that paralleled that observed in vivo. In contrast, the density of photoreceptors or of starburst amacrine cells increased, mimicking the evolution of these cell populations in vivo. Blockade of neural activity with tetrodotoxin increased the number of surviving Brn3a-labelled neurons in the retinal explant, as did the increase in target availability when one retinal explant was confronted with 2 or 4 collicular slices. Thus, this ex vivo model reproduces the developmental reduction of RGCs and recapitulates its regulation by neural activity and target availability. It therefore offers a simple way to analyze developmental cell death in this classic system. Using this model, we show that ephrin-A signaling does not participate to the regulation of the Brn3a population size in the retina, indicating that eprhin-A-mediated elimination of exuberant projections does not involve developmental cell death

Observations and models to support the first Marine Ecosystem Assessment for the Southern Ocean (MEASO)

Assessments of the status and trends of habitats, species and ecosystems are needed for effective ecosystem-based management in marine ecosystems. Knowledge on imminent ecosystem changes (climate change impacts) set in train by existing climate forcings are needed for adapting management practices to achieve conservation and sustainabililty targets into the future. Here, we describe a process for enabling a marine ecosystem assessment (MEA) by the broader scientific community to support managers in this way, using a MEA for the Southern Ocean (MEASO) as an example. We develop a framework and undertake an audit to support a MEASO, involving three parts. First, we review available syntheses and assessments of the Southern Ocean ecosystem and its parts, paying special attention to building on the SCAR Antarctic Climate Change and Environment report and the SCAR Biogeographic Atlas of the Southern Ocean. Second, we audit available field observations of habitats and densities and/or abundances of taxa, using the literature as well as a survey of scientists as to their current and recent activities. Third, we audit available system models that can form a nested ensemble for making, with available data, circumpolar assessments of habitats, species and food webs. We conclude that there is sufficient data and models to undertake, at least, a circumpolar assessment of the krill-based system. The auditing framework provides the basis for the first MEASO but also provides a repository (www.SOKI.aq/display/MEASO) for easily amending the audit for future MEASOs. We note that an important outcome of the first MEASO will not only be the assessment but also to advise on priorities in observations and models for improving subsequent MEASOs

Predição do índice de conforto térmico em edificíos de escritório na Alemanha

Ladrões internacionais indicam quais são as exigências sobre conforto térmico que devem ser alcançadas em espaços de escritório. Elas se baseiam em um modelo desenvolvido pelo Prof. Paul Ole Fanger, no Centre for Indoor Environment and Energy, na Dinamarca. Hoje, quarenta anos de pesquisa mostram uma evolução desses indicadores. Este trabalho consiste no desenvolvimento de uma ferramenta para avaliar o conforto térmico em espaços de trabalho de edifícios de escritório. A metodologia baseia-se em medições e questionários realizados no local. Para o estudo de campo utiliza-se uma unidade móvel equipada com sensores e um questionário pelos quais se obtêm respostas dos usuários sobre a qualidade térmica do ambiente de trabalho. Levantam-se as condições térmicas de trinta edifícios de escritório na Alemanha com diferentes sistemas de climatização. A correlação entre os dados objetivos e subjetivos permite desenvolver uma fórmula que calcula o nível de insatisfação térmica em um ambiente determinado, em função de aspectos locais. Para os edifícios estudados, a temperatura de conforto é 23,3 ºC e o percentual mínimo de usuários insatisfeitos é de 7%, sendo 2,3 K (Kelvin) menor que o modelo de Fanger, o que é significativo no balanço energético dos edifícios localizados em um clima da Europa central

COVID-19: Rapid antigen detection for SARS-CoV-2 by lateral flow assay: A national systematic evaluation of sensitivity and specificity for mass-testing

Background Lateral flow device (LFD) viral antigen immunoassays have been developed around the world as diagnostic tests for SARS-CoV-2 infection. They have been proposed to deliver an infrastructure-light, cost-economical solution giving results within half an hour. Methods LFDs were initially reviewed by a Department of Health and Social Care team, part of the UK government, from which 64 were selected for further evaluation from 1st August to 15th December 2020. Standardised laboratory evaluations, and for those that met the published criteria, field testing in the Falcon-C19 research study and UK pilots were performed (UK COVID-19 testing centres, hospital, schools, armed forces). Findings 4/64 LFDs so far have desirable performance characteristics (orient Gene, Deepblue, Abbott and Innova SARS-CoV-2 Antigen Rapid Qualitative Test). All these LFDs have a viral antigen detection of >90% at 100,000 RNA copies/ml. 8951 Innova LFD tests were performed with a kit failure rate of 5.6% (502/8951, 95% CI: 5.1–6.1), false positive rate of 0.32% (22/6954, 95% CI: 0.20–0.48). Viral antigen detection/sensitivity across the sampling cohort when performed by laboratory scientists was 78.8% (156/198, 95% CI 72.4–84.3). Interpretation Our results suggest LFDs have promising performance characteristics for mass population testing and can be used to identify infectious positive individuals. The Innova LFD shows good viral antigen detection/sensitivity with excellent specificity, although kit failure rates and the impact of training are potential issues. These results support the expanded evaluation of LFDs, and assessment of greater access to testing on COVID-19 transmission. Funding Department of Health and Social Care. University of Oxford. Public Health England Porton Down, Manchester University NHS Foundation Trust, National Institute of Health Research

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research