The exocyst subunit Sec15 is critical for proper synaptic development and function at the Drosophila NMJ.

The exocyst protein complex is important for targeted vesicle fusion in a variety of cell types, however, its function in neurons is still not entirely known. We found that presynaptic knockdown (KD) of the exocyst component sec15 by transgenic RNAi expression caused a number of unexpected morphological and physiological defects in the synapse. These include the development of active zones (AZ) devoid of essential presynaptic proteins, an increase in the branching of the presynaptic arbor, the appearance of satellite boutons, and a decrease in the amplitude of stimulated postsynaptic currents as well as a decrease in the frequency of spontaneous synaptic vesicle release. We also found the release of extracellular vesicles from the presynaptic neuron was greatly diminished in the Sec15 KDs. These effects were mimicked by presynaptic knockdown of Rab11, a protein known to interact with the exocyst. sec15 RNAi expression caused an increase in phosphorylated Mothers against decapentaplegic (pMad) in the presynaptic terminal, an indication of enhanced bone morphogenic protein (BMP) signaling. Some morphological phenotypes caused by Sec15 knockdown were reduced by attenuation of BMP signaling through knockdown of wishful thinking (Wit), while other phenotypes were unaffected. Individual knockdown of multiple proteins of the exocyst complex also displayed a morphological phenotype similar to Sec15 KD. We conclude that Sec15, functioning as part of the exocyst complex, is critically important for proper formation and function of neuronal synapses. We propose a model in which Sec15 is involved in the trafficking of vesicles from the recycling endosome to the cell membrane as well as possibly trafficking extracellular vesicles for presynaptic release and these processes are necessary for the correct structure and function of the synapse.

Evaluation of Two Videos that Apply Evidence-Based Strategies to Increase Self-Efficacy and Reduce Opioid-Related Stigma Among Medical Students.

OBJECTIVE: This study evaluated the video-based application of evidence-based stigma reduction strategies to increase medical students' screening-diagnostic self-efficacy for opioid use disorder (OUD) and reduce stigma toward opioid use. METHODS: Formative qualitative research informed development of two videos for medical students. One uses an education strategy by including education regarding non-stigmatizing language use and OUD screening and diagnosis (Video A); the other uses an interpersonal contact strategy by presenting narratives regarding opioid use from three people who have a history of opioid use and three physicians (Video B). Both videos were administered to all respondents, with video order randomized. Effects on outcomes were evaluated using a pre-/post-test design with a 1-month follow-up. Participants also provided feedback on video content and design. RESULTS: Medical students (N = 103) watched the videos and completed the pre-/post-test, with 99% (N = 102) completing follow-up 1 month after viewing both videos. Self-efficacy increased directly following viewing Video A, and this increase was sustained at 1-month follow-up. Stigma toward opioid use decreased directly following viewing Video B, and this decrease was sustained at 1-month follow-up for participants who watched Video B first. Statistically significant improvements were observed in most secondary outcomes (e.g., harm reduction acceptability) directly following watching each video and most were sustained at 1-month follow-up. Feedback about the videos suggested the delivery of evidence-based strategies in each video was appropriate. CONCLUSIONS: Video-based applications of these evidence-based strategies were found acceptable by medical students and have potential to elicit sustained improvement in their screening-diagnostic self-efficacy and opioid-related stigma.

Emergent Criticality in Coupled Boolean Networks.

Early embryonic development involves forming all specialized cells from a fluid-like mass of identical stem cells. The differentiation process consists of a series of symmetry-breaking events, starting from a high-symmetry state (stem cells) to a low-symmetry state (specialized cells). This scenario closely resembles phase transitions in statistical mechanics. To theoretically study this hypothesis, we model embryonic stem cell (ESC) populations through a coupled Boolean network (BN) model. The interaction is applied using a multilayer Ising model that considers paracrine and autocrine signaling, along with external interventions. It is demonstrated that cell-to-cell variability can be interpreted as a mixture of steady-state probability distributions. Simulations have revealed that such models can undergo a series of first- and second-order phase transitions as a function of the system parameters that describe gene expression noise and interaction strengths. These phase transitions result in spontaneous symmetry-breaking events that generate new types of cells characterized by various steady-state distributions. Coupled BNs have also been shown to self-organize in states that allow spontaneous cell differentiation.

A machine learning-based prediction of hospital mortality in mechanically ventilated ICU patients.

BACKGROUND: Mechanical ventilation (MV) is vital for critically ill ICU patients but carries significant mortality risks. This study aims to develop a predictive model to estimate hospital mortality among MV patients, utilizing comprehensive health data to assist ICU physicians with early-stage alerts. METHODS: We developed a Machine Learning (ML) framework to predict hospital mortality in ICU patients receiving MV. Using the MIMIC-III database, we identified 25,202 eligible patients through ICD-9 codes. We employed backward elimination and the Lasso method, selecting 32 features based on clinical insights and literature. Data preprocessing included eliminating columns with over 90% missing data and using mean imputation for the remaining missing values. To address class imbalance, we used the Synthetic Minority Over-sampling Technique (SMOTE). We evaluated several ML models, including CatBoost, XGBoost, Decision Tree, Random Forest, Support Vector Machine (SVM), K-Nearest Neighbors (KNN), and Logistic Regression, using a 70/30 train-test split. The CatBoost model was chosen for its superior performance in terms of accuracy, precision, recall, F1-score, AUROC metrics, and calibration plots. RESULTS: The study involved a cohort of 25,202 patients on MV. The CatBoost model attained an AUROC of 0.862, an increase from an initial AUROC of 0.821, which was the best reported in the literature. It also demonstrated an accuracy of 0.789, an F1-score of 0.747, and better calibration, outperforming other models. These improvements are due to systematic feature selection and the robust gradient boosting architecture of CatBoost. CONCLUSION: The preprocessing methodology significantly reduced the number of relevant features, simplifying computational processes, and identified critical features previously overlooked. Integrating these features and tuning the parameters, our model demonstrated strong generalization to unseen data. This highlights the potential of ML as a crucial tool in ICUs, enhancing resource allocation and providing more personalized interventions for MV patients.

A single-cell transcriptomic atlas of sensory-dependent gene expression in developing mouse visual cortex.

Sensory experience drives the refinement and maturation of neural circuits during postnatal brain development through molecular mechanisms that remain to be fully elucidated. One likely mechanism involves the sensory-dependent expression of genes that encode direct mediators of circuit remodeling within developing cells. However, while studies in adult systems have begun to uncover crucial roles for sensory-induced genes in modifying circuit connectivity, the gene programs induced by brain cells in response to sensory experience during development remain to be fully characterized. Here, we present a single-nucleus RNA-sequencing dataset describing the transcriptional responses of cells in mouse visual cortex to sensory deprivation or sensory stimulation during a developmental window when visual input is necessary for circuit refinement. We sequenced 118,529 individual nuclei across sixteen neuronal and non-neuronal cortical cell types isolated from control, sensory deprived, and sensory stimulated mice, identifying 1,268 unique sensory-induced genes within the developing brain. To demonstrate the utility of this resource, we compared the architecture and ontology of sensory-induced gene programs between cell types, annotated transcriptional induction and repression events based upon RNA velocity, and discovered Neurexin and Neuregulin signaling networks that underlie cell-cell interactions via CellChat . We find that excitatory neurons, especially layer 2/3 pyramidal neurons, are highly sensitive to sensory stimulation, and that the sensory-induced genes in these cells are poised to strengthen synapse-to-nucleus crosstalk by heightening protein serine/threonine kinase activity. Altogether, we expect this dataset to significantly broaden our understanding of the molecular mechanisms through which sensory experience shapes neural circuit wiring in the developing brain.

Visual Functions Are Associated with Biomarker Changes in Alzheimer's Disease.

Background: While various biomarkers of Alzheimer's disease (AD) have been associated with general cognitive function, their association to visual-perceptive function across the AD spectrum warrant more attention due to its significant impact on quality of life. Thus, this study explores how AD biomarkers are associated with decline in this cognitive domain. Objective: To explore associations between various fluid and imaging biomarkers and visual-based cognitive assessments in participants across the AD spectrum. Methods: Data from participants (N = 1,460) in the Alzheimer's Disease Neuroimaging Initiative were analyzed, including fluid and imaging biomarkers. Along with the Mini-Mental State Examination (MMSE), three specific visual-based cognitive tests were investigated: Trail Making Test (TMT) A and TMT B, and the Boston Naming Test (BNT). Locally estimated scatterplot smoothing curves and Pearson correlation coefficients were used to examine associations. Results: MMSE showed the strongest correlations with most biomarkers, followed by TMT-B. The p-tau181/Aß1-42 ratio, along with the volume of the hippocampus and entorhinal cortex, had the strongest associations among the biomarkers. Conclusions: Several biomarkers are associated with visual processing across the disease spectrum, emphasizing their potential in assessing disease severity and contributing to progression models of visual function and cognition.

Effect of hydroxocobalamin on surface oximetry in nonexposed humans.

INTRODUCTION: The newer cyanide antidote, hydroxocobalamin, due to its pigmentation, has been found to cause interferences in some laboratory assays. Co-oximetry may also be affected by hydroxocobalamin, leading to false elevations in hemoglobin concentration, methemoglobin, carboxyhemoglobin, and false decreases in oxyhemoglobin. The Masimo Radical-7 is a medical device that performs noninvasive oximetry and estimates hemoglobin (Hb) concentration and percent carboxyhemoglobin (COHb), methemoglobin (MetHb), and oxyhemoglobin saturation (O2Hb). STUDY OBJECTIVES: The study sought to determine the effect of hydroxocobalamin on noninvasive measurement of hemoglobin indices using the Masimo Radical-7 monitor. METHODS: Seven asymptomatic volunteers who were unexposed to cyanide had baseline heart rate (HR), blood pressure (BP), and oximeter measurements recorded followed by an infusion of five grams of hydroxocobalamin over 15 minutes. The above parameters were subsequently recorded at: 5, 10, 15, 30 and 60 minutes post infusion. Data were analyzed by calculating the area under the curve (AUC) for each variable and comparing the results to expected values by paired t tests. Expected AUC values were calculated by extrapolating baseline values across the entire time period. RESULTS: The mean differences from baseline values with 95% confidence intervals and t tests of mean difference were: SBP: 11 mm Hg (95% CI, 0-22; P = .051); HR: -9 (95% CI, -15 to -3; P = .01); Hb: -0.1 (95% CI, -0.7 to 0.4; P = .57); O2Hb: 0 g/dL (95% CI, -1 to 1; P = .41); COHb: -1 (95% CI, -3 to 1; P = .25); MetHb: -0.2 (95% CI, -0.3 to 0; P = .03). DISCUSSION: After infusion of hydroxocobalamin there was a significant elevation of systolic blood pressure and decrease in heart rate. There were no significant differences in Hb, O2Hb, and COHb. Although percent methemoglobin concentrations were statistically lower, the authors feel this difference is of trivial clinical significance. CONCLUSION: The administration of hydroxocobalamin does not significantly impact noninvasive oximetry.

Emergence of diversity in homogeneous coupled Boolean networks.

The origin of multicellularity in metazoa is one of the fundamental questions of evolutionary biology. We have modeled the generic behaviors of gene regulatory networks in isogenic cells as stochastic nonlinear dynamical systems-coupled Boolean networks with perturbation. Model simulations under a variety of dynamical regimes suggest that the central characteristic of multicellularity, permanent spatial differentiation (diversification), indeed can arise. Additionally, we observe that diversification is more likely to occur near the critical regime of Lyapunov stability.

Article Commentary: A Psychospiritual Integration frame of Reference for Occupational Therapy. Part 2: Transformative Occupations and the Change Process.

This paper builds upon the first in the series on psychospiritual integration (PSI) and examines the concept of transformative occupations and the process of change underpinning occupational therapy from a PSI perspective. A repertoire of new terms highlighting finer distinctions in the concept of occupation will be introduced and explained, as will the dynamic for transformation inherent in the psychospiritual integration change process. Suggestions for PSI-informed occupational therapy practice will be explored.

Lithium-Ion Insertion Properties of Solution-Exfoliated Germanane.

The high theoretical energy density of alloyed lithium and germanium (Li15Ge4), 1384 mAh/g, makes germanium a promising anode material for lithium-ion batteries. However, common alloy anode architectures suffer from long-term instability upon repetitive charge-discharge cycles that arise from stress-induced degradation upon lithiation (volume expansion >300%). Here, we explore the use of the two-dimensional nanosheet structure of germanane to mitigate stress from high volume expansion and present a facile method for producing stable single-to-multisheet dispersions of pure germanane. Purity and degree of exfoliation were assessed with scanning electron microscopy, transmission electron microscopy, and Raman spectroscopy. We measured representative germanane battery electrodes to have a reversible Li-ion capacity of 1108 mAh/g when cycled between 0.1 and 2 V vs Li/Li+. These results indicate germanane anodes are capable of near-theoretical-maximum energy storage, perform well at high cycling rates, and can maintain capacity over 100 cycles.

Ordered mesoporous silicon through magnesium reduction of polymer templated silica thin films.

This paper describes the process of making ordered mesoporous silicon (Si) thin films. The process begins with mesoporous silica (SiO 2) thin films that are produced via evaporation induced self-assembly (EISA) using sol-gel silica precursors with a diblock copolymer template. This results in a film with a cubic lattice of 15 nm diameter pores and 10 nm thick walls. The silicon is produced through reduction of the silica thin films in a magnesium (Mg) vapor at 675 degrees C. Magnesium reduction preserves the ordered pore-solid architecture but replaces the dense silica walls with 10-17 nm silicon crystallites. The resulting porous silicon films are characterized by a combination of low and high angle X-ray diffraction, combined with direct SEM imaging. The result is a straightforward route to the production of ordered nanoporous silicon.