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Abstract microRNAs are crucial regulators of brain development, however, miRNA regulatory networks are not sufficiently well characterized. By performing small RNA-seq of the mouse embryonic cortex at E14, E17, and P0 as well as in neural progenitor cells and neurons, here we detected clusters of miRNAs that were co-regulated at distinct developmental stages. miRNAs such as miR-92a/b acted as hubs during early, and miR-124 and miR-137 during late neurogenesis. Notably, validated targets of P0 hub miRNAs were enriched for downregulated genes related to stem cell proliferation, negative regulation of neuronal differentiation and RNA splicing, among others, suggesting that miRNAs are particularly important for modulating transcriptional programs of crucial factors that guide the switch to neuronal differentiation. As most genes contain binding sites for more than one miRNA, we furthermore constructed a co-targeting network where numerous miRNAs shared more targets than expected by chance. Using luciferase reporter assays, we demonstrated that simultaneous binding of miRNA pairs to neurodevelopmentally relevant genes exerted an enhanced transcriptional silencing effect compared to single miRNAs. Taken together, we provide a comprehensive resource of miRNA longitudinal expression changes during murine corticogenesis. Furthermore, we highlight several potential mechanisms through which miRNA regulatory networks can shape embryonic brain development.

Abstract Background Gene expression and alternative splicing are strictly regulated processes that shape brain development and determine the cellular identity of differentiated neural cell populations. Despite the availability of multiple valuable datasets, many functional implications, especially those related to alternative splicing, remain poorly understood. Moreover, neuroscientists working primarily experimentally often lack the bioinformatics expertise required to process alternative splicing data and produce meaningful and interpretable results. Notably, re-analyzing publicly available datasets and integrating them with in-house data can provide substantial novel insights. However, such analyses necessitate developing harmonized data handling and processing pipelines which in turn require considerable computational resources and in-depth bioinformatics expertise. Results Here, we present Cortexa—a comprehensive web portal that incorporates RNA-sequencing datasets from the mouse cerebral cortex (longitudinal or cell-specific) and the hippocampus. Cortexa facilitates understandable visualization of the expression and alternative splicing patterns of individual genes. Our platform provides SplicePCA—a tool that allows users to integrate their alternative splicing dataset and compare it to cell-specific or developmental neocortical splicing patterns. All standardized gene expression and alternative splicing datasets can be downloaded for further in-depth downstream analysis without the need for extensive preprocessing. Conclusions Cortexa provides a robust and readily available resource for unraveling the complexity of gene expression and alternative splicing regulatory processes in the mouse brain. The data portal is available at https://cortexa-rna.com/

To compare the inter-rater reliability (IRR) of five clinical rating scales for video-based assessment of hemifacial spasm (HFS) motor severity. We evaluated the video recordings of 45 HFS participants recruited through the Dystonia Coalition. In Round 1, six clinicians with expertise in HFS assessed the participants motor severity with five scales used to measure motor severity of HFS: the Jankovic rating scale (JRS), Hemifacial Spasm Grading Scale (HSGS), Samsung Medical Center (SMC) grading system for severity of HFS spasms (Lees scale), clinical grading of spasm intensity (Chens scale), and a modified version of the Abnormal Involuntary Movement Scale (Tuncs scale). In Round 2, clinicians rated the same cohort with simplified scale wording after consensus training. For each round, we evaluated the IRR using the intraclass correlation coefficient [ICC (2,1) single-rater, absolute-agreement, 2-way random model]. The scales exhibited IRR that ranged from poor to moderate; the mean ICCs were 0.41, 0.43, 0.47, 0.43, and 0.65 for the JRS, HSGS, Lees, Chens, and Tuncs scales, respectively, for Round 1. In Round 2, the corresponding IRRs increased to 0.63, 0.60, 0.59, 0.53, and 0.71. In both rounds, Tuncs scale exhibited the highest IRR. For clinical assessments of HFS motor severity based on video observations, we recommend using Tuncs scale because of its comparative reliability and because clinicians interpret the scale easily without modifications or the need for consensus training.

Abstract Organic electrochemical transistors (OECTs) underpin a range of emerging technologies, from bioelectronics to neuromorphic computing, owing to their unique coupling of electronic and ionic charge carriers. In this context, various OECT systems exhibit significant hysteresis in their transfer curve, which is frequently leveraged to achieve non-volatility. Meanwhile, a general understanding of its physical origin is missing. Here, we introduce a thermodynamic framework that readily explains the emergence of bistable OECT operation via the interplay of enthalpy and entropy. We validate this model through temperature-resolved characterizations, material manipulation, and thermal imaging. Further, we reveal deviations from Boltzmann statistics for the subthreshold swing and reinterpret existing literature. Capitalizing on these findings, we finally demonstrate a single-OECT Schmitt trigger, thus compacting a multi-component circuit into a single device. These insights provide a fundamental advance for OECT physics and its application in non-conventional computing, where symmetry-breaking phenomena are pivotal to unlock new paradigms of information processing.

Abstract. Background. We report here the long-term outcomes of patients with intermediate-risk prostate cancer (PCa) treated with active surveillance (AS) in a daily routine setting. Material and methods. HAROW (2008–2013) was a noninterventional, health service research study investigating the management of localized PCa in a community setting. A substantial proportion of the study centers were office-based urologists. A follow-up examination of all intermediate-risk patients with AS was conducted. Overall, cancer-specific, metastasis-free, and treatment-free survival rates, as well as reasons for discontinuation, were determined and discussed. Results. Of the 2957 patients enrolled, 52 with intermediate-risk PCa were managed with AS and were available for evaluation. The median follow-up was 6.8 years (interquartile range, 3.4–8.6 years). Seven patients (13.5%) died of causes unrelated to PCa, of whom 4 were under AS or under watchful waiting. Two patients (3.8%) developed metastasis. The estimated 8-year overall, cancer-specific, metastasis-free, and treatment-free survival rates were 85% (95% confidence interval [CI], 72%–96%), 100%, 93% (95% CI, 82%–100%), and 31% (95% CI, 17%–45%), respectively. On multivariable analysis, prostate-specific antigen density of ≥0.2 ng/mL2 was significantly predictive of receiving invasive treatment (hazard ratio, 3.29; p = 0.006). Reasons for discontinuation were more often due to patient's or physician's concerns (36%) than due to observed clinical progression. Conclusions. Although survival outcome data for intermediate-risk patients managed with AS in real-life health care conditions were promising, rates of discontinuation were high, and discontinuation was often a patient's decision, even when the signs of disease progression were absent. This might be an indication of higher levels of mental burden and anxiety in this specific subgroup of patients, which should be considered when making treatment decisions. From a psychological perspective, not all intermediate-risk patients are optimal candidates for AS.

Background: Freezing of gait (FOG) is a debilitating symptom of Parkinson’s disease (PD) characterized by paroxysmal episodes in which patients are unable to step forward. A research priority is identifying cortical changes before freezing in PD-FOG. Methods: We tested 19 patients with PD who had been assessed for FOG (n=14 with FOG and 5 without FOG). While seated, patients stepped bilaterally on pedals to progress forward through a virtual hallway while 64-channel EEG was recorded. We assessed cortical activities before and during lower limb motor blocks (LLMB), defined as a break in rhythmic pedaling, and stops, defined as movement cessation following an auditory stop cue. This task was selected because LLMB correlates with FOG severity in PD and allows recording of high-quality EEG. Patients were tested after overnight withdrawal from dopaminergic medications (“off” state) and in the “on” medications state. EEG source activities were evaluated using individual MRI and standardized low resolution brain electromagnetic tomography (sLORETA). Functional connectivity was evaluated by phase lag index between seeds and pre-defined cortical regions of interest. Results: EEG source activities for LLMB vs. cued stops localized to right posterior parietal area (Brodmann area 39), lateral premotor area (Brodmann area 6), and inferior frontal gyrus (Brodmann area 47). In these areas, PD-FOG (n=14) increased alpha rhythms (8-12 Hz) before LLMB vs. typical stepping, whereas PD without FOG (n=5) decreased alpha power. Alpha rhythms were linearly correlated with LLMB severity, and the relationship became an inverted U-shape when assessing alpha rhythms as a function of percent time in LLMB in the “off” medication state. Right inferior frontal gyrus and supplementary motor area connectivity was observed before LLMB in the beta band (13-30 Hz). This same pattern of connectivity was seen before stops. Dopaminergic medication improved FOG and led to less alpha synchronization and increased functional connections between frontal and parietal areas. Conclusions: Right inferior parietofrontal structures are implicated in PD-FOG. The predominant changes were in the alpha rhythm, which increased before LLMB and with LLMB severity. Similar connectivity was observed for LLMB and stops between the right inferior frontal gyrus and supplementary motor area, suggesting that FOG may be a form of “unintended stopping.” These findings may inform approaches to neurorehabilitation of PD-FOG.

BACKGROUND. Severe, early-onset fetal growth restriction (FGR) causes significant fetal and neonatal mortality and morbidity. Predicting the outcome of affected pregnancies at the time of diagnosis is difficult, thus preventing accurate patient counseling. We investigated the use of maternal serum protein and ultrasound measurements at diagnosis to predict fetal or neonatal death and 3 secondary outcomes: fetal death or delivery at or before 28+0 weeks, development of abnormal umbilical artery (UmA) Doppler velocimetry, and slow fetal growth. METHODS. Women with singleton pregnancies (n = 142, estimated fetal weights [EFWs] below the third centile, less than 600 g, 20+0 to 26+6 weeks of gestation, no known chromosomal, genetic, or major structural abnormalities) were recruited from 4 European centers. Maternal serum from the discovery set (n = 63) was analyzed for 7 proteins linked to angiogenesis, 90 additional proteins associated with cardiovascular disease, and 5 proteins identified through pooled liquid chromatography and tandem mass spectrometry. Patient and clinician stakeholder priorities were used to select models tested in the validation set (n = 60), with final models calculated from combined data. RESULTS. The most discriminative model for fetal or neonatal death included the EFW z score (Hadlock 3 formula/Marsal chart), gestational age, and UmA Doppler category (AUC, 0.91; 95% CI, 0.86-0.97) but was less well calibrated than the model containing only the EFW z score (Hadlock 3/Marsal). The most discriminative model for fetal death or delivery at or before 28+0 weeks included maternal serum placental growth factor (PlGF) concentration and UmA Doppler category (AUC, 0.89; 95% CI, 0.83-0.94). CONCLUSION. Ultrasound measurements and maternal serum PlGF concentration at diagnosis of severe, early-onset FGR predicted pregnancy outcomes of importance to patients and clinicians. TRIAL REGISTRATION. ClinicalTrials.gov NCT02097667. FUNDING. The European Union, Rosetrees Trust, Mitchell Charitable Trust., Introduction The survival and growth of a fetus depends on placental provision of nutrients and waste exchange with the mother. When this system is impaired by inadequate transformation of the [...]

Abstract Background Regular physical activity has multiple health benefits, especially in older people. Therefore, the World Health Organization recommends at least 2.5 h of moderate physical activity per week. The aim of the POWER Study was to investigate whether volunteer-assisted walking improves the physical performance and health of older people. Methods We approached people aged 65 years and older with restricted mobility due to physical limitations and asked them to participate in this multicentre randomised controlled trial. The recruitment took place in nursing homes and the community setting. Participants randomly assigned to the intervention group were accompanied by volunteer companions for a 30–50 min walk up to three times a week for 6 months. Participants in the control group received two lectures that included health-related topics. The primary endpoint was physical function as measured with the Short Physical Performance Battery (SPPB) at baseline and 6 and 12 months. The secondary and safety endpoints were quality of life (EQ-5D-5L), fear of falling (Falls Efficacy Scale), cognitive executive function (the Clock Drawing Test), falls, hospitalisations and death. Results The sample comprised 224 participants (79% female). We failed to show superiority of the intervention with regard to physical function (SPPB) or other health outcomes in the intention-to-treat analyses. However, additional exploratory analyses suggest benefits in those who undertook regular walks. The intervention appears to be safe regarding falls. Conclusions Regular physical activity is essential to preserve function and to improve health and quality of life. Against the background of a smaller-than-planned sample size, resulting in low power, and the interference of the COVID-19 pandemic, we suggest that community based low-threshold interventions deserve further exploration. Trial registration The trial was registered with the German Clinical Trials Register ( www.germanctr.de ), with number DRKS00015188 on 31/08/2018.

BackgroundPrimary care research networks can generate important information in the setting where most patients are seen and treated. However, this requires a suitable IT infrastructure (ITI), which the North Rhine-Westphalian general practice research network is looking to implement. ObjectiveThis mixed methods research study aims to evaluate (study 1) requirements for an ITI and (study 2) the usability of an IT solution already available on the market, the FallAkte Plus (FA+) system for the North Rhine-Westphalian general practice research network, which comprises 8 primary care university institutes in Germany’s largest state. MethodsIn study 1, a survey was conducted among researchers from the institutes to identify the requirements for a suitable ITI. The questionnaire consisted of standardized questions with open-ended responses. In study 2, a mixed method approach combining a think-aloud approach and a quantitative survey was used to evaluate the usability and acceptance of the FA+ system among 3 user groups: researchers, general practitioners, and practice assistants. Respondents were asked to assess the usability with the validated system usability scale and to test a short questionnaire on vaccination management through FA+. ResultsIn study 1, five of 8 institutes participated in the requirements survey. A total of 32 user requirements related primarily to study management were identified, including data entry, data storage, and user access management. In study 2, a total of 36 participants (24 researchers and 12 general practitioners or practice assistants) were surveyed in the mixed methods study of an already existing IT solution. The tutorial video and handouts explaining how to use the FA+ system were well received. Researchers, unlike practice personnel, were concerned about data security and data protection regarding the system’s emergency feature, which enables access to all patient data. The median overall system usability scale rating was 60 (IQR 33.0-85.0), whereby practice personnel (median 82, IQR 58.0-94.0) assigned higher ratings than researchers (median 44, IQR 14.0-61.5). Users appreciated the option to integrate data from practices and other health care facilities. However, they voted against the use of the FA+ system due to a lack of support for various study formats. ConclusionsUsability assessments vary markedly by professional group and role. In its current stage of development, the FA+ system does not fully meet the requirements for a suitable ITI. Improvements in the user interface, performance, interoperability, security, and advanced features are necessary to make it more effective and user-friendly. Collaborating with end users and incorporating their feedback are crucial for the successful development of any practice network research ITI.

ABSTRACTBK polyomavirus (BKPyV) is a double-stranded DNA virus causing nephropathy, hemorrhagic cystitis, and urothelial cancer in transplant patients. The BKPyV-encoded capsid protein Vp1 and large T-antigen (LTag) are key targets of neutralizing antibodies and cytotoxic T-cells, respectively. Our single-center data suggested that variability in Vp1 and LTag may contribute to failing BKPyV-specific immune control and impact vaccine design. We, therefore, analyzed all available entries in GenBank (1516 VP1; 742 LTAG) and explored potential structural effects using computational approaches. BKPyV-genotype (gt)1 was found in 71.18% of entries, followed by BKPyV-gt4 (19.26%), BKPyV-gt2 (8.11%), and BKPyV-gt3 (1.45%), but rates differed according to country and specimen type. Vp1-mutations matched a serotype different than the assigned one or were serotype-independent in 43%, 18% affected more than one amino acid. Notable Vp1-mutations altered antibody-binding domains, interactions with sialic acid receptors, or were predicted to change conformation. LTag-sequences were more conserved, with only 16 mutations detectable in more than one entry and without significant effects on LTag-structure or interaction domains. However, LTag changes were predicted to affect HLA-class I presentation of immunodominant 9mers to cytotoxic T-cells. These global data strengthen single center observations and specifically our earlier findings revealing mutant 9mer epitopes conferring immune escape from HLA-I cytotoxic T cells. We conclude that variability of BKPyV-Vp1 and LTag may have important implications for diagnostic assays assessing BKPyV-specific immune control and for vaccine design.IMPORTANCEType and rate of amino acid variations in BKPyV may provide important insights into BKPyV diversity in human populations and an important step toward defining determinants of BKPyV-specific immunity needed to protect vulnerable patients from BKPyV diseases. Our analysis of BKPyV sequences obtained from human specimens reveals an unexpectedly high genetic variability for this double-stranded DNA virus that strongly relies on host cell DNA replication machinery with its proof reading and error correction mechanisms. BKPyV variability and immune escape should be taken into account when designing further approaches to antivirals, monoclonal antibodies, and vaccines for patients at risk of BKPyV diseases.

O presente artigo de natureza bibliográfica e documental analisa os desafios, limites e possibilidades da inclusão social de adolescentes, que são autores de atos infracionais, por meio das políticas socioeducativas. A questão de fundo é como essas políticas dão conta de uma inclusão emancipatória desses adolescentes, em outras palavras, como as políticas da socioeducação articulam-se às políticas educacionais visando a emancipação desses adolescentes? Para contextualizar essa problemática, serão analisados elementos da formação socioeconômica brasileira, que gerou e reproduz a exclusão de milhares de adolescentes das condições mínimas de cidadania. Na sequência, são examinadas as políticas socioeducativas destinadas aos adolescentes, que são autores de atos infracionais, especialmente o Sistema Nacional de Atendimento Socioeducativo (BRASIL, 2012), e os desafios de uma inclusão emancipadora desses sujeitos. Na conclusão, defendemos a tese que as políticas socioeducativas avançaram de forma substancial, especialmente, com a aprovação do SINASE, mas, uma socioeducação emancipadora na prática ainda continua sendo um desafio.