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Background: X chromosome parent of origin (POX) has been proposed as a source of phenotypic variation within sex chromosome aneuploidies such as Klinefelter syndrome (XXY/KS) and between XX and XY individuals. However, previous studies have yielded conflicting results regarding the presence and nature of POX effects, which we sought to clarify in an expanded sample with deeper neurobehavioral phenotyping. Methods: A cohort of 58 individuals with XXY/KS underwent duo or trio genome sequencing with parents (n = 151), measurement of 66 neurobehavioral phenotypes by standardized research assessments, and measurement of over 1000 anatomical phenotypes by structural magnetic resonance imaging. We developed a novel algorithm, the uniparental disomy visualization for variant call format files, to determine proband POX and then systematically tested for POX associations with all neurobehavioral and neuroanatomical outcomes. Results: The uniparental disomy visualization for variant call format files algorithm showed maternal POX in 35 of 58 cases (60.3%). There were no statistically significant POX effects on any of the 66 subscale measures of cognition, psychopathology, or behavior. Neuroimaging analysis identified 2 regions in the right hemisphere with significantly higher surface area (mean effect size = 1.20) among individuals with paternal versus maternal POX (q = .021). Conclusions: Using deeper phenotyping in an expanded sample, we did not find evidence for substantial POX effects on neurobehavioral variability, except for localized unilateral modulations of surface area in the absence of co-occurring behavioral associations. These findings help to clarify previous inconsistencies in POX research and direct attention toward other sources of clinical variability in sex chromosome aneuploidies.

Objectives For eligible patient groups, hospital-at-home (HaH) programmes have been shown to deliver equivalent patient outcomes with cost reduction compared with standard care. This study aims to establish a benchmark of inpatient admissions that could potentially be substituted by HaH services.Design Descriptive retrospective cohort study.Setting Academic tertiary hospital in Singapore.Participants 124 253 medical admissions over 20 months (January 2016 to August 2017).Primary and secondary outcome measures The primary measure was the proportion of hospitalised patients who may be eligible for HaH, based on eligibility criteria adapted for the Singapore context. The secondary measures were the utilisation patterns and outcomes of these patients.Results Applying generalised eligibility criteria to the retrospective dataset showed that 53.0% of 124 253 medical admissions fitted the eligibility criteria for HaH based on administrative data. 46.8% of such patients had a length of stay

IntroductionThe combination of Myc-suppressed whole tumor cells with checkpoint inhibitors targeting CTLA-4 and PD-L1 generates a potent therapeutic cancer vaccine in a mouse neuroblastoma model. As immunotherapies translate from pre-clinical to clinical trials, the potential immune-related adverse events (irAEs) associated with induction of potent immunity must be addressed. The CD24-Siglec 10/G interaction is an innate checkpoint that abrogates inflammatory responses to molecules released by damaged cells, but its role in cancer immunology is not well defined. We investigate irAEs of an effective whole cell neuroblastoma vaccine and subsequently the effect of CD24-Fc, a CD24 and Fc fusion protein, on both the vaccine efficacy and induced irAEs in a mouse neuroblastoma model.MethodsTo test whether the whole tumor cell vaccination leads to autoimmune responses in other organ systems we harvested lung, heart, kidney and colon from naïve mice (n=3), unvaccinated tumor only mice (n=3), and vaccinated mice with CD24 Fc (n=12) or human IgG-Fc control (n=12) after tumor inoculation and vaccination therapy at day 30. The Immune cell infiltrates and immunogenic pathway signatures in different organ systems were investigated using NanoString Autoimmune Profiling arrays. Nanostring RNA transcript results were validated with immunohistochemistry staining.ResultsThe whole tumor cell vaccine combined with immune checkpoint therapy triggers occult organ specific immune cell infiltrates, primarily in cardiac tissue and to a lesser extent in the renal and lung tissue, but not in the colon. CD24-Fc administration with vaccination partially impedes anti-tumor immunity but delaying CD24-Fc administration after initial vaccination reverses this effect. CD24-Fc treatment also ameliorates the autoimmune response induced by effective tumor vaccination in the heart.DiscussionThis study illustrates that the combination of Myc suppressed whole tumor cell vaccination with checkpoint inhibitors is an effective therapy, but occult immune infiltrates are induced in several organ systems in a mouse neuroblastoma model. The systemic administration of CD24-Fc suppresses autoimmune tissue responses, but appropriate timing of administration is critical for maintaining efficacy of the therapeutic vaccine.

Climate conditions affect winter heating demand in areas that experience harsh winters. Skillful energy demand prediction provides useful information that may be a helpful component in ensuring a reliable energy supply, protecting vulnerable populations from cold weather, and reducing excess energy waste. Here, we develop a statistical model that predicts winter seasonal energy consumption over the United Kingdom using a multiple linear regression technique based on multiple sources of climate information from the previous fall season. We take the autumn conditions of Arctic sea-ice concentration, stratospheric circulation, and sea-surface temperature as predictors, which all influence North Atlantic oscillation (NAO) variability as reported in a previous study. The model predicts winter seasonal gas and electricity consumption two months in advance with a statistically significant correlation between the predicted and observed time series. To extend the analysis beyond the relatively short time scale of gas and electricity data availability, we also analyze predictability of an energy demand proxy, heating degree days (HDDs), for which the model also demonstrates skill. The predictability of energy consumption can be attributed to the predictability of the NAO and the significant correlation of energy consumption with surface air temperature, dew point depression, and wind speed. We further found skillful prediction of these surface climate variables and HDDs over many areas where the NAO is influential, implying the predictability of energy demand in these regions. The simple statistical model demonstrates the usefulness of fall climate observations for predicting winter season energy demand prediction with a wide range of potential applications across energy-related sectors.

Neuroblastoma is one of the most genomically heterogeneous childhood malignances studied to date, and the molecular events that occur during the course of the disease are not fully understood. Genomic studies in neuroblastoma have showed only a few recurrent mutations and a low somatic mutation burden. However, none of these studies has examined the mutations arising during the course of disease, nor have they systemically examined the expression of mutant genes. Here we performed genomic analyses on tumors taken during a 3.5 years disease course from a neuroblastoma patient (bone marrow biopsy at diagnosis, adrenal primary tumor taken at surgical resection, and a liver metastasis at autopsy). Whole genome sequencing of the index liver metastasis identified 44 non-synonymous somatic mutations in 42 genes (0.85 mutation/MB) and a large hemizygous deletion in the ATRX gene which has been recently reported in neuroblastoma. Of these 45 somatic alterations, 15 were also detected in the primary tumor and bone marrow biopsy, while the other 30 were unique to the index tumor, indicating accumulation of de novo mutations during therapy. Furthermore, transcriptome sequencing on the 3 tumors demonstrated only 3 out of the 15 commonly mutated genes (LPAR1, GATA2, and NUFIP1) had high level of expression of the mutant alleles, suggesting potential oncogenic driver roles of these mutated genes. Among them, the druggable G-protein coupled receptor LPAR1 was highly expressed in all tumors. Cells expressing the LPAR1 R163W mutant demonstrated a significantly increased motility through elevated Rho signaling, but had no effect on growth. Therefore, this study highlights the need for multiple biopsies and sequencing during progression of a cancer and combinatorial DNA and RNA sequencing approach for systematic identification of expressed driver mutations.

The heavy global demand for sand in various sectors of the economy subjects the Vietnamese Mekong Delta to correspondingly high amounts of sand mining—a process that started in the early 1990s contributing significantly to the Vietnamese economy. The impacts of intensive sand mining and mining-related industries damage the integrity of the river and local communities. Much of the literature focuses on the former, exposing people to the deleterious implications of sand mining on the physical environment. This study aims to fill the gap on the less explored latter through the lenses of place and landscape per human geography tradition, using qualitative methods of thirty-five interviews with locals, video recordings, and sound measurements to highlight the impacts of sand mining and mining-related industries. This study revealed that sand mining and its associated activities are responsible for people's perceptions of notable air, land, and noise pollution, as well as substantial harm to the urban environment. Over 80 percent of interviewed locals acknowledged the disruptions to their daily lives and a substantial loss of their sense of place. These findings shed light on narratives frequently overlooked by policymakers, emphasizing the urgency of addressing these issues for a sustainable future. [ABSTRACT FROM AUTHOR]

Abstract Perceptual decisions should depend on sensory evidence. However, such decisions are also influenced by past choices and outcomes. These choice history biases may reflect advantageous strategies to exploit temporal regularities of natural environments. However, it is unclear whether and how observers can adapt their choice history biases to different temporal regularities, to exploit the multitude of temporal correlations that exist in nature. Here, we show that male mice adapt their perceptual choice history biases to different temporal regularities of visual stimuli. This adaptation was slow, evolving over hundreds of trials across several days. It occurred alongside a fast non-adaptive choice history bias, limited to a few trials. Both fast and slow trial history effects are well captured by a normative reinforcement learning algorithm with multi-trial belief states, comprising both current trial sensory and previous trial memory states. We demonstrate that dorsal striatal dopamine tracks predictions of the model and behavior, suggesting that striatal dopamine reports reward predictions associated with adaptive choice history biases. Our results reveal the adaptive nature of perceptual choice history biases and shed light on their underlying computational principles and neural correlates.

Abstract As genomic databases expand and artificial intelligence tools advance, there is a growing demand for efficient characterization of large numbers of proteins. To this end, here we describe a generalizable pipeline for high-throughput protein purification using small-scale expression in E. coli and an affordable liquid-handling robot. This low-cost platform enables the purification of 96 proteins in parallel with minimal waste and is scalable for processing hundreds of proteins weekly per user. We demonstrate the performance of this method with the expression and purification of the leading poly(ethylene terephthalate) hydrolases reported in the literature. Replicate experiments demonstrated reproducibility and enzyme purity and yields (up to 400 µg) sufficient for comprehensive analyses of both thermostability and activity, generating a standardized benchmark dataset for comparing these plastic-degrading enzymes. The cost-effectiveness and ease of implementation of this platform render it broadly applicable to diverse protein characterization challenges in the biological sciences.

Abstract Traditionally, aborted cardiac arrest (ACA) due to documented ventricular fibrillation (VF) in the absence of structural heart disease has been termed idiopathic VF. By careful evaluation, a specific etiology can be found in a substantial proportion of patients. The aim of this survey was to assess the yield of an advanced diagnostic work-up to reveal a causative etiology in a real-life clinical setting. Patients from the University Hospital Brno’s ACA database were analyzed (514 patients in total). Forty-six patients (31 males) fulfilled the inclusion criteria, which were: (1) absence of structural pathology on echocardiography; (2) absence of coronary artery disease; and (3) absence of reversible cause of ACA. The diagnostic work-up consisted in cardiac magnetic resonance imaging, stress testing, sodium channel blocker challenge, and genetic testing according to the availability of the method and patient compliance. A specific disease was found in 17 individuals (37.0%), although at least one diagnostic step was refused by 13 patients (28.3%). True idiopathic VF was confirmed in 7 patients (15.2%), for whom the entire diagnostic work-up did not reveal any specific pathology. Our real-life survey shows that, even with an incomplete diagnostic work-up (due to the unavailability of a particular method or variable patient compliance), a specific diagnosis can be identified in more than one third of the cases of “idiopathic” VF, which can thus enable targeted treatment and family screening.

Abstract A major challenge in protein design is to augment existing functional proteins with multiple property enhancements. Altering several properties likely necessitates numerous primary sequence changes, and novel methods are needed to accurately predict combinations of mutations that maintain or enhance function. Models of sequence co-variation (e.g., EVcouplings), which leverage extensive information about various protein properties and activities from homologous protein sequences, have proven effective for many applications including structure determination and mutation effect prediction. We apply EVcouplings to computationally design variants of the model protein TEM-1 β-lactamase. Nearly all the 14 experimentally characterized designs were functional, including one with 84 mutations from the nearest natural homolog. The designs also had large increases in thermostability, increased activity on multiple substrates, and nearly identical structure to the wild type enzyme. This study highlights the efficacy of evolutionary models in guiding large sequence alterations to generate functional diversity for protein design applications.

A literatura sobre impulsividade de compra tem negligenciado que a impulsividade pode fazer parte de processos criativos e lúdicos de descoberta. Para preencher essa lacuna, este estudo investiga as atitudes de consumidores que vivenciam impulsividade durante a prática de bricolagem em mercados de segunda mão. Por meio de um levantamento on-line e modelagem por equações estruturais, foram analisados dados de 775 consumidores, descobrindo que a atitude de caça ao tesouro dispara a impulsividade nesses mercados e a consciência de serendipidade, ambas sendo antecedentes de processos criativos na prática da bricolagem. Este estudo contribui para a literatura ao oferecer um modelo explicativo parcimonioso sobre como a impulsividade, a caça ao tesouro, a serendipidade e a prática da bricolagem podem fazer parte de processos criativos e lúdicos de consumo, promovendo uma visão positiva da impulsividade, em contraste com a visão tradicional majoritariamente negativa.

Detection and analysis of spontaneous synaptic events is an extremely common task in many neuroscience research labs. Various algorithms and tools have been developed over the years to improve the sensitivity of detecting synaptic events. However, the final stages of most procedures for detecting synaptic events still involve the manual selection of candidate events. This step in the analysis is laborious and requires care and attention to maintain consistency of event selection across the whole dataset. Manual selection can introduce bias and subjective selection criteria that cannot be shared with other labs in reporting methods. To address this, we have created Eventer, a standalone application for the detection of spontaneous synaptic events acquired by electrophysiology or imaging. This open-source application uses the freely available MATLAB Runtime and is deployed on Mac, Windows, and Linux systems. The principle of the Eventer application is to learn the user's “expert” strategy for classifying a set of detected event candidates from a small subset of the data and then automatically apply the same criterion to the remaining dataset. Eventer first uses a suitable model template to pull out event candidates using fast Fourier transform (FFT)-based deconvolution with a low threshold. Random forests are then created and trained to associate various features of the events with manual labeling. The stored model file can be reloaded and used to analyse large datasets with greater consistency. The availability of the source code and its user interface provide a framework with the scope to further tune the existing Random Forest implementation, or add additional, artificial intelligence classification methods. The Eventer website (https://eventerneuro.netlify.app/) includes a repository where researchers can upload and share their machine learning model files and thereby provide greater opportunities for enhancing reproducibility when analyzing datasets of spontaneous synaptic activity. In summary, Eventer, and the associated repository, could allow researchers studying synaptic transmission to increase throughput of their data analysis and address the increasing concerns of reproducibility in neuroscience research.

Abstract Tardigrades, microscopic animals that survive a broad range of environmental stresses, express a unique set of proteins termed tardigrade-specific intrinsically disordered proteins (TDPs). TDPs are often expressed at high levels in tardigrades upon desiccation, and appear to mediate stress adaptation. Here, we focus on the proteins belonging to the secreted family of tardigrade proteins termed secretory-abundant heat soluble (“SAHS”) proteins, and investigate their ability to protect diverse biological structures. Recombinantly expressed SAHS proteins prevent desiccated liposomes from fusion, and enhance desiccation tolerance of E. coli and Rhizobium tropici upon extracellular application. Molecular dynamics simulation and comparative structural analysis suggest a model by which SAHS proteins may undergo a structural transition upon desiccation, in which removal of water and solutes from a large internal cavity in SAHS proteins destabilizes the beta-sheet structure. These results highlight the potential application of SAHS proteins as stabilizing molecules for preservation of cells.

Aflatoxin levels increase during storage due to high humidity, temperature, and insect pests. The study determined the effectiveness of three levels of natural products in controlling aflatoxins at storage, done in 2023 at Kalro Njoro in Kenya. Maize grains were collected from Kilifi and weighed to 1 kg each and placed in polypropylene bags. Three levels of Moringa oleifera powder (10g/kg, 20g/kg and 30g/kg) from young moringa leaves, wood ash at (5g/kg, 7.5g/kg and 10g/kg) from Eucalyptus globulus from a dried log of wood from Eucalyptus globulus and diatomaceous earth (1g/kg, 2g/kg and 3g/kg) and a control (no treatment) were used. A completely randomized design replicated three times was used. Grains were stored for three and six months and total aflatoxin quantification was performed using ELISA. At six months aflatoxins levels had increased up to ten times from the three months storage. In the sixth month the total aflatoxins levels were 0.84 µg/kg for wood ash at 7.5 g/kg of maize with the lowest levels. The wood ash at all three levels reduced aflatoxins effectively. Additionally, for both diatomaceous earth and Moringa oleifera powder at low and medium levels were effective. These natural products should be used during storage because they reduce aflatoxins and not harmful to humans and animals.

Human induced pluripotent stem cell (iPSC) lines were generated from peripheral blood mononuclear cells (PBMCs) isolated from two related patients diagnosed with either idiopathic ventricular fibrillation or catecholaminergic polymorphic ventricular tachycardia, carrying an unknown variant in the RYR2 gene, c.14201A>G (p.Y4734C) and one healthy related individual. Reprogramming was done using a commercially available Epi5 Reprogramming Kit. The pluripotency of the iPSC lines was verified by the expression of pluripotency markers and by their capacity to differentiate into all three embryonic germ layers in vitro. These iPSC lines are available for functional analysis and in vitro studies of RYR2 channelopathy.

Introduction There is a need for evidence-based prevention programming that can reduce head impacts and increase reporting and disclosure of concussion. This study assessed an intervention to decrease concussion risk and improve concussion management through improving concussion-related knowledge, attitudes, intentions, and self-efficacy among parents in the middle school (MS) sport setting.Patients and methods This randomized controlled trial (NCT04841473) examined parents of MS-aged children. Participants were randomized into one of two study arms: (1) CDC, which completed an education training module that compiled concussion education from the Centers for Disease Control and Prevention (CDC); and (2) TRAIN + CDC, which completed the CDC training module and an additional TRAIN educational module that provided strategies (originating from the Popular Opinion Leader framework) on communicating such information with one’s personal peer networks and children. Validated measures of concussion-related knowledge, attitudes, intentions, and self-efficacy were collected before completing the training modules and one week following completion. Linear mixed model analyses examined differences in outcomes between study arms.Results Overall, 103 parents completed the training modules and had valid pre- and post-intervention data (TRAIN + CDC n = 49; CDC n = 54). Analyses found that the study arms did not differ in the change scores from pre- to post-intervention across concussion-related outcomes. However, scores from pre- to post-intervention improved across both study arms for knowledge metrics, such as ‘Concussions are less likely to happen when athletes play by the rules of the sport’ (p

Estudo acerca da configuração do excesso na prosa hilstiana, suas encruzilhadas e bifurcações estético-sociais. Por meio do “transbordamento”, “experiência” e “desregramento”, a operação do excesso ocorre nos (des)limites da representação do território corporal, reivindicando uma cartografia do corpo e da linguagem erótico-pornográfica.

Objetivo: relatar experiência vivenciada pelos acadêmicos de enfermagem no processo de territorialização da atenção primária à saúde. Materiais e Métodos: trata- se de um relato de experiência de uma intervenção promovida em uma Unidade de Saúde da Família, no Município de Montes Claros - Minas Gerais, por acadêmicos do 3° período de enfermagem, nos meses de março e abril de 2023. A realização da intervenção iniciou-se com a escolha da área de abrangência quando foi realizado o mapeamento de uma microárea, a fim de conhecer os territórios solo e processo. Após, foi realizada uma estimativa rápida para identificar, através de entrevista com usuários o perfil sociodemográfico do território. Finalizou-se com a identificação das comorbidades mais comuns na microárea e o conhecimento do Sistema de informação E-SUS. Resultados: através da territorialização, com o auxílio do Agente Comunitário de Saúde e demais membros da Equipe de Saúde, foi possível reconhecer os aspectos geográficos, estruturais, sociais e culturais da microárea, além de suas fragilidades, possibilitando identificar e auxiliar esses profissionais a planejar suas melhorias e ações pelo método mais eficaz da assistência à saúde. Conclusão: a partir da construção do mapa e a atualização da região de abrangência, a identificação da quantidade de pessoas residentes e suas enfermidades se tornaram-se evidentemente mais clara. Tal processo facilitou a compreensão e atuação dos agentes e corroborando em atendimentos nas diferentes fases da vida e nos acompanhamentos das doenças crônicas, de forma mais eficaz e acessível, aproximando os acadêmicos na prática dos conhecimentos aprendidos na academia.