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Early substance use initiation is associated with later substance use disorders, but the relative contributions of environmental, behavioral, and genetic factors during adolescence remain unclear. We analyzed 2,366 participants of European genetic ancestry from the Adolescent Brain Cognitive Development Study. Four outcomes were examined through four years of follow-up: initiation of alcohol, nicotine, cannabis, and any substance use. Time-varying Cox models screened predictors, followed by LASSO-selected multivariable Cox models adjusted for age, sex, ancestry principal components, and study site. Marginal structural models evaluated selected predictors. Environmental and behavioral factors were the strongest and most consistent predictors, including youth rule-breaking, impulsivity, parental alcohol-related problems, financial adversity, family context, phone use, negative life events, peer or romantic experiences, sleep, caffeine exposure, and parental monitoring. Polygenic risk scores for alcohol, cannabis, nicotine, and substance use disorder showed weaker and less consistent associations. Although some appeared in screening models, none remained robust after correction, multi

Motivation: Opioid use disorder (OUD) often arises after prescription opioid exposure and follows transitions among onset, remission, and relapse. Linked EHR-survey resources such as the All of Us Research Program enable stage-specific risk modeling and connection to intervention options. Results: We built a multi-stage framework to model time-to-onset, time-to-remission, and time-to-relapse after remission using All of Us EHR and survey data. For each participant we derived longitudinal predictors from clinical conditions and survey concepts, including recent (1/3/12-month) event counts, cumulative exposures, and time since last event. We fit regularized Cox models for each transition and aggregated selection frequencies and hazard ratios to identify a compact set of high-confidence predictors. Pain, mental health, and polysubstance use contributed across stages: chronic pain syndromes, tobacco/nicotine dependence, anxiety and depressive disorders, and cannabis dependence prominently predicted onset and relapse, whereas tobacco dependence during remission and other remission-coded conditions were strongly associated with transition to remission. To support therapeutic prioritizati

Understanding the development of adolescent behavioral and mental health outcomes requires integrating genetic predisposition, environmental exposures, and neurobiological processes over time. Here, we present a unified quantitative framework that models the human body as a dynamic system, where genetic factors form the foundational state, environmental exposures act as time-varying inputs, the brain might serve as a mediation processor, and behavioral phenotypes emerge as system outputs. Using longitudinal data from the Adolescent Brain Cognitive Development (ABCD) Study, we construct harmonized multi-domain representations across six phenotypes: externalizing behavior, internalizing behavior, and four substance use initiation outcomes (alcohol, nicotine, cannabis, and any substance use). We integrate polygenic risk scores (PRS), multi-domain environmental features, and multimodal neuroimaging representations derived through stability selection and dimensionality reduction. Our framework supports both continuous longitudinal modeling and survival-based event modeling through a unified data structure. We further develop interpretable domain-level representations using principal com

We present an open Molecular Crystal (MC) database of Machine-Learned Interatomic Potentials (MLIP) called MolCryst-MLIPs. The first release comprises fine-tuned MACE models for nine molecular crystal systems---Benzamide, Benzoic acid, Coumarin, Durene, Isonicotinamide, Nicotinic acid , Niacinamide, Pyrazinamide, and Resorcinol---developed using the Automated Machine Learning Pipeline (AMLP), which streamlines the entire MLIP development workflow, from reference data generation to model training and validation, into a reproducible and user-friendly pipeline. Models are fine-tuned from the MACE-MH-1 foundation model omol head), yielding a mean energy MAE of 0.141 kJ/mol/atom and a mean force MAE of 0.648 kJ/mol/Angstrom across all systems. Benchmarked against three state-of-the-art foundation models on the DFT-labelled polymorph set, only the fine-tuned models resolve the polymorphic energy landscape. Dynamical stability and structural integrity, as assessed through energy conservation, P2 orientational order parameters, and radial distribution functions, are evaluated using molecular dynamics simulations. The released models and datasets constitute a growing open database of valida

Understanding puffing topography (PT), which includes puff duration, intra-puff interval, and puff count per session, is critical for evaluating Electronic Nicotine Delivery Systems (ENDS) use, toxicant exposure, and informing regulatory decisions. We developed FRIENDS (Flexible Robust Instrumentation of ENDS), an open-source device that can be attached to ENDS and records puffing and touching events. This paper introduces the FRIENDS graphical user interface (GUI) that improves accessibility and interpretability of data collected by FRIENDS. The GUI is a Python-based opensource tool that extracts, decodes, and visualizes 24-hour puffing data from the FRIENDS device. Validation using 24-hour experimental data confirmed accurate timestamp conversion, reliable event decoding, and effective behavioral visualization. The software is freely available on GitHub for public use.

Randomized controlled trials are the gold standard for evaluating the efficacy of an intervention. However, there is often a trade-off between selecting the most scientifically relevant primary endpoint versus a less relevant, but more powerful, endpoint. For example, in the context of tobacco regulatory science many trials evaluate cigarettes per day as the primary endpoint instead of abstinence from smoking due to limited power. Additionally, it is often of interest to consider subgroup analyses to answer additional questions; such analyses are rarely adequately powered. In practice, trials often collect multiple endpoints. Heuristically, if multiple endpoints demonstrate a similar treatment effect we would be more confident in the results of this trial. However, there is limited research on leveraging information from secondary endpoints besides using composite endpoints which can be difficult to interpret. In this paper, we develop an estimator for the treatment effect on the primary endpoint based on a joint model for primary and secondary efficacy endpoints. This estimator gains efficiency over the standard treatment effect estimator when the model is correctly specified but

Comorbidity networks, which capture disease-disease co-occurrence usually based on electronic health records, reveal structured patterns in how diseases cluster and progress across individuals. However, how these networks evolve across different age groups and how this evolution relates to properties like disease prevalence and mortality remains understudied. To address these issues, we used publicly available comorbidity networks extracted from a comprehensive dataset of 45 million Austrian hospital stays from 1997 to 2014, covering 8.9 million patients. These networks grow and become denser with age. We identified groups of diseases that exhibit similar patterns of structural centrality throughout the lifespan, revealing three dominant age-related components with peaks in early childhood, midlife, and late life. To uncover the drivers of this structural change, we examined the relationship between prevalence and degree. This allowed us to identify conditions that were disproportionately connected to other diseases. Using betweenness centrality in combination with mortality data, we further identified high-mortality bridging diseases. Several diseases show high connectivity relati

With the advance of high-throughput genotyping and sequencing technologies, it becomes feasible to comprehensive evaluate the role of massive genetic predictors in disease prediction. There exists, therefore, a critical need for developing appropriate statistical measurements to access the combined effects of these genetic variants in disease prediction. Predictiveness curve is commonly used as a graphical tool to measure the predictive ability of a risk prediction model on a single continuous biomarker. Yet, for most complex diseases, risk prediciton models are formed on multiple genetic variants. We therefore propose a multi-marker predictiveness curve and provide a non-parametric method to construct the curve for case-control studies. We further introduce a global predictiveness U and a partial predictiveness U to summarize prediction curve across the whole population and sub-population of clinical interest, respectively. We also demonstrate the connections of predictiveness curve with ROC curve and Lorenz curve. Through simulation, we compared the performance of the predictiveness U to other three summary indices: R square, Total Gain, and Average Entropy, and showed that Predi

My findings show what causes loss of awareness, anesthesia, memory replay, opioid induced respiratory depression (OIRD), and slow-wave sleep (SWS). Opiates are fast pain relievers and anesthetics that can cause respiratory arrest. I found how mu-opioids and anesthetics by activating medial habenula (MHb) and/or interpeduncular nucleus (IPN) induce unawareness and slowdown respiration. MHb projects to IPN and both increase their glucose intake during anesthesia (Herkenham, 1981). The question is: What is the MHb-IPN circuit doing? I found that it promotes SWS, memory replay, sharp-wave ripples, spindles, hippocampo-cortical replay, synaptogenesis, rest and recovery, by activating median raphe (MRN) serotonin, and by inhibiting the theta state circuit, new memories encoding, awareness, arousal, alert wakefulness, and REM sleep. It causes also natural slowdown of respiration and heart rate, while it inhibits locomotion and arousal. This extended model adds role of the dentate gyrus>posterior septum>MHb>IPN>MRN>hippocampus + BF + claustrum>cortical slow-waves in memory replay, ripples, loss of awareness, SWS, and anesthesia. It proposes new neural mechanism for anesth

Causal variable selection in time-varying treatment settings is challenging due to evolving confounding effects. Existing methods mainly focus on time-fixed exposures and are not directly applicable to time-varying scenarios. We propose a novel two-step procedure for variable selection when modeling the treatment probability at each time point. We first introduce a novel approach to longitudinal confounder selection using a Longitudinal Outcome Adaptive LASSO (LOAL) that will data-adaptively select covariates with theoretical justification of variance reduction of the estimator of the causal effect. We then propose an Adaptive Fused LASSO that can collapse treatment model parameters over time points with the goal of simplifying the models in order to improve the efficiency of the estimator while minimizing model misspecification bias compared with naive pooled logistic regression models. Our simulation studies highlight the need for and usefulness of the proposed approach in practice. We implemented our method on data from the Nicotine Dependence in Teens study to estimate the effect of the timing of alcohol initiation during adolescence on depressive symptoms in early adulthood.

Common psychiatric and brain disorders are highly heritable and affected by a number of genetic risk factors, yet the mechanism by which these genetic factors contribute to the disorders through alterations in brain structure and function remain poorly understood. Contemporary imaging genetic studies integrate genetic and neuroimaging data to investigate how genetic variation contributes to brain disorders via intermediate neuroimaging endophenotypes. However, the large number of potential exposures (genes) and mediators (neuroimaging features) pose new challenges to the traditional mediation analysis. In this paper, we propose a novel multi-exposure-to-multi-mediator mediation model that integrates genetic, neuroimaging and phenotypic data to investigate the "geneneuroimaging-brain disorder" mediation pathway. Our method jointly reduces the dimensions of exposures and mediators into low-dimensional aggregators where the mediation effect is maximized. We further introduce sparsity into the loadings to improve the interpretability. To target the bi-convex optimization problem, we implement an efficient alternating direction method of multipliers algorithm with block coordinate updat

Target-specific peptides, such as conotoxins, exhibit exceptional binding affinity and selectivity toward ion channels and receptors. However, their therapeutic potential remains underutilized due to the limited diversity of natural variants and the labor-intensive nature of traditional optimization strategies. Here, we present CreoPep, a deep learning-based conditional generative framework that integrates masked language modeling with a progressive masking scheme to design high-affinity peptide mutants while uncovering novel structural motifs. CreoPep employs an integrative augmentation pipeline, combining FoldX-based energy screening with temperature-controlled multinomial sampling, to generate structurally and functionally diverse peptides that retain key pharmacological properties. We validate this approach by designing conotoxin inhibitors targeting the $α$7 nicotinic acetylcholine receptor, achieving submicromolar potency in electrophysiological assays. Structural analysis reveals that CreoPep-generated variants engage in both conserved and novel binding modes, including disulfide-deficient forms, thus expanding beyond conventional design paradigms. Overall, CreoPep offers a

Predicting signed interactions in biological networks is crucial for understanding drug mechanisms and facilitating drug repurposing. While deep graph models have demonstrated success in modeling complex biological systems, existing approaches often fail to distinguish between positive and negative interactions, limiting their utility for precise pharmacological predictions. In this study, we propose a novel deep graph model, PAMR (polarity-aware multi-relational model), designed to predict both polar (e.g., activation, inhibition) and non-polar (e.g., binding, affect) chemical-gene interactions. Our model integrates graph convolutional networks with tensor decomposition to enhance feature representation and incorporates a conflict-aware sampling strategy to resolve polarity ambiguities. We introduce new evaluation metrics, polarity discrimination score (PDS) and CP@100, to assess the model's ability to differentiate interaction types. Experimental results demonstrate that PAMR outperforms baseline models, achieving superior classification accuracy and improved discrimination of polar edges. Specifically, PAMR-CL attains a Macro AUROC of 0.9072 and CP@100 of 0.974, surpassing RGCN,