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The weighted ensemble (WE) method stands out as a widely used segment-based sampling technique renowned for its rigorous treatment of kinetics. The WE framework typically involves initially mapping the configuration space onto a low-dimensional collective variable (CV) space and then partitioning it into bins. The efficacy of WE simulations heavily depends on the selection of CVs and binning schemes. The recently proposed State Predictive Information Bottleneck (SPIB) method has emerged as a promising tool for automatically constructing CVs from data and guiding enhanced sampling through an iterative manner. In this work, we advance this data-driven pipeline by incorporating prior expert knowledge. Our hybrid approach combines SPIB-learned CVs to enhance sampling in explored regions with expert-based CVs to guide exploration in regions of interest, synergizing the strengths of both methods. Through benchmarking on alanine dipeptide and chignoin systems, we demonstrate that our hybrid approach effectively guides WE simulations to sample states of interest, and reduces run-to-run variances. Moreover, our integration of the SPIB model also enhances the analysis and interpretation of WE simulation data by effectively identifying metastable states and pathways, and offering direct visualization of dynamics.

Recent advancements in protein docking site prediction have highlighted the limitations of traditional rigid docking algorithms, like PIPER, which often neglect critical stochastic elements such as solvent-induced fluctuations. These oversights can lead to inaccuracies in identifying viable docking sites due to the complexity of high-dimensional, stochastic energy manifolds with low regularity. To address this issue, our research introduces a novel model where the molecular shapes of ligands and receptors are represented using multi-variate Karhunen-Lo `eve (KL) expansions. This method effectively captures the stochastic nature of energy manifolds, allowing for a more accurate representation of molecular interactions.Developed as a plugin for PIPER, our scientific computing software enhances the platform, delivering robust uncertainty measures for the energy manifolds of ranked binding sites. Our results demonstrate that top-ranked binding sites, characterized by lower uncertainty in the stochastic energy manifold, align closely with actual docking sites. Conversely, sites with higher uncertainty correlate with less optimal docking positions. This distinction not only validates our approach but also sets a new standard in protein docking predictions, offering substantial implications for future molecular interaction research and drug development.

Purpose: Many approaches have been used to model chordae tendineae geometries in finite element simulations of atrioventricular heart valves. Unfortunately, current "functional" chordae tendineae geometries lack fidelity (e.g., branching) that would be helpful when informing clinical decisions. The objectives of this work are (i) to improve synthetic chordae tendineae geometry fidelity to consider branching and (ii) to define how the chordae tendineae geometry affects finite element simulations of valve closure.

Methods: In this work, we develop an open-source method to construct synthetic chordae tendineae geometries in the SlicerHeart Extension of 3D Slicer. The generated geometries are then used in FEBio finite element simulations of atrioventricular valve function to evaluate how variations in chordae tendineae geometry influence valve behavior. Effects are evaluated using functional and mechanical metrics.

Results: Our findings demonstrated that altering the chordae tendineae geometry of a stereotypical mitral valve led to changes in clinically relevant valve metrics (regurgitant orifice area, contact area, and billowing volume) and valve mechanics (first principal strains). Specifically, cross sectional area had the most influence over valve closure metrics, followed by chordae tendineae density, length, radius and branches. We then used this information to showcase the flexibility of our new workflow by altering the chordae tendineae geometry of two additional geometries (mitral valve with annular dilation and tricuspid valve) to improve finite element predictions.

Conclusion: This study presents a flexible, open-source method for generating synthetic chordae tendineae with realistic branching structures. Further, we establish relationships between the chordae tendineae geometry and valve functional/mechanical metrics. This research contribution helps enrich our opensource workflow and brings the finite element simulations closer to use in a patient-specific clinical setting.

While deep learning has revolutionized computer-aided drug discovery, the AI community has predominantly focused on model innovation and placed less emphasis on establishing best benchmarking practices. We posit that without a sound model evaluation framework, the AI community's efforts cannot reach their full potential, thereby slowing the progress and transfer of innovation into real-world drug discovery. Thus, in this paper, we seek to establish a new gold standard for small molecule drug discovery benchmarking, WelQrate. Specifically, our contributions are threefold: WelQrate Dataset Collection - we introduce a meticulously curated collection of 9 datasets spanning 5 therapeutic target classes. Our hierarchical curation pipelines, designed by drug discovery experts, go beyond the primary high-throughput screen by leveraging additional confirmatory and counter screens along with rigorous domain-driven preprocessing, such as Pan-Assay Interference Compounds (PAINS) filtering, to ensure the high-quality data in the datasets; WelQrate Evaluation Framework - we propose a standardized model evaluation framework considering high-quality datasets, featurization, 3D conformation generation, evaluation metrics, and data splits, which provides a reliable benchmarking for drug discovery experts conducting real-world virtual screening; Benchmarking - we evaluate model performance through various research questions using the WelQrate dataset collection, exploring the effects of different models, dataset quality, featurization methods, and data splitting strategies on the results. In summary, we recommend adopting our proposed WelQrate as the gold standard in small molecule drug discovery benchmarking. The WelQrate dataset collection, along with the curation codes, and experimental scripts are all publicly available at WelQrate.org.

Alzheimer's disease (AD) is the most prevalent form of dementia, affecting millions worldwide with a progressive decline in cognitive abilities. The AD continuum encompasses a prodromal stage known as Mild Cognitive Impairment (MCI), where patients may either progress to AD (MCIc) or remain stable (MCInc). Understanding the underlying mechanisms of AD requires complementary analyses relying on different data sources, leading to the development of multimodal deep learning models. In this study, we leveraged structural and functional Magnetic Resonance Imaging (sMRI/fMRI) to investigate the disease-induced grey matter and functional network connectivity changes. Moreover, considering AD's strong genetic component, we introduced Single Nucleotide Polymorphisms (SNPs) as a third channel. Given such diverse inputs, missing one or more modalities is a typical concern of multimodal methods. We hence propose a novel deep learning-based classification framework where a generative module employing Cycle Generative Adversarial Networks (cGAN) was adopted for imputing missing data within the latent space. Additionally, we adopted an Explainable Artificial Intelligence (XAI) method, Integrated Gradients (IG), to extract input features' relevance, enhancing our understanding of the learned representations. Two critical tasks were addressed: AD detection and MCI conversion prediction. Experimental results showed that our framework was able to reach the state-of-the-art in the classification of CN vs AD with an average test accuracy of 0.926 ± 0.02. For the MCInc vs MCIc task, we achieved an average prediction accuracy of 0.711 ± 0.01 using the pre-trained model for CN and AD. The interpretability analysis revealed that the classification performance was led by significant grey matter modulations in cortical and subcortical brain areas well known for their association with AD. Moreover, impairments in sensory-motor and visual resting state network connectivity along the disease continuum, as well as mutations in SNPs defining biological processes linked to endocytosis, amyloid-beta, and cholesterol, were identified as contributors to the achieved performance. Overall, our integrative deep learning approach shows promise for AD detection and MCI prediction, while shading light on important biological insights.

White matter alterations are increasingly implicated in neurological diseases and their progression. International-scale studies use diffusion-weighted magnetic resonance imaging (DW-MRI) to qualitatively identify changes in white matter microstructure and connectivity. Yet, quantitative analysis of DW-MRI data is hindered by inconsistencies stemming from varying acquisition protocols. Specifically, there is a pressing need to harmonize the preprocessing of DW-MRI datasets to ensure the derivation of robust quantitative diffusion metrics across acquisitions. In the MICCAI-CDMRI 2023 QuantConn challenge, participants were provided raw data from the same individuals collected on the same scanner but with two different acquisitions and tasked with preprocessing the DW-MRI to minimize acquisition differences while retaining biological variation. Harmonized submissions are evaluated on the reproducibility and comparability of cross-acquisition bundle-wise microstructure measures, bundle shape features, and connectomics. The key innovations of the QuantConn challenge are that (1) we assess bundles and tractography in the context of harmonization for the first time, (2) we assess connectomics in the context of harmonization for the first time, and (3) we have 10x additional subjects over prior harmonization challenge, MUSHAC and 100x over SuperMUDI. We find that bundle surface area, fractional anisotropy, connectome assortativity, betweenness centrality, edge count, modularity, nodal strength, and participation coefficient measures are most biased by acquisition and that machine learning voxel-wise correction, RISH mapping, and NeSH methods effectively reduce these biases. In addition, microstructure measures AD, MD, RD, bundle length, connectome density, efficiency, and path length are least biased by these acquisition differences. A machine learning approach that learned voxel-wise cross-acquisition relationships was the most effective at harmonizing connectomic, microstructure, and macrostructure features, but requires the same subject be scanned at each site co-registered. NeSH, a spatial and angular resampling method, was also effective and has generalizable framework not reliant co-registration. Our code is available at https://github.com/nancynewlin-masi/QuantConn/.

Cerebral autoregulation plays a key physiological role by limiting blood flow changes in the face of pressure fluctuations. Although the involved cellular processes are mechanically driven, the quantification of haemodynamic forces in in-vivo settings remains extremely difficult and uncertain. In this work, we propose a novel computational framework for evaluating the blood flow dynamics across networks of myogenically active cerebral arteries, which can modulate their muscular tone to stabilize flow (and perfusion pressure) as well as to limit vascular intramural stress. The introduced framework is built on contractile (myogenically active) vascular wall mechanics and blood flow dynamics models, which can be numerically coupled in either a weak or strong way. We investigate the time dependency of the vascular wall response to pressure changes at both single vessel and network levels. The robustness of the model was assessed by considering different types of inlet signals and numerical settings in an idealized vascular network formed by a middle cerebral artery and its three generations. For the vessel size and boundary conditions considered, weak coupling ensured accurate results with a lower computational cost. To complete the analysis, we evaluated the effect of an upstream pressure surge on the haemodynamics of the vascular network. This provided a clear quantitative picture of how pressure and flow are redistributed across each vessel generation upon inlet pressure changes. This work paves the way for future combined experimental-computational studies aiming to decipher cerebral autoregulation.

Single-cell RNA sequencing (scRNA-seq) data are often confounded by technical or biological batch effects. Existing deep learning models mitigate these effects but often discard batch-specific information, potentially losing valuable biological insights. We propose a Mixed Effects Deep Learning (MEDL) autoencoder framework that separately models batch-invariant (fixed effects) and batch-specific (random effects) components. By decoupling batch-invariant biological states from batch variations, our framework integrates both into predictive models. Our approach also generates 2D visualizations of how the same cell appears across batches, enhancing interpretability. Retaining both fixed and random effect latent spaces improves classification accuracy. We applied our framework to three datasets spanning the cardiovascular system (Healthy Heart), Autism Spectrum Disorder (ASD), and Acute Myeloid Leukemia (AML). With 147 batches in the Healthy Heart dataset-far exceeding typical numbers-we tested our framework's ability to handle many batches. In the ASD dataset, our approach captured donor heterogeneity between autistic and healthy individuals. In the AML dataset, it distinguished donor heterogeneity despite missing cell types and diseased donors exhibiting both healthy and malignant cells. These results highlight our framework's ability to characterize fixed and random effects, enhance batch effect visualization, and improve prediction accuracy across diverse datasets.

The structure and function of a protein are determined by its amino acid sequence. While random mutations change a protein's sequence, evolutionary forces shape its structural fold and biological activity. Studies have shown that neutral networks can connect a local region of sequence space by single residue mutations that preserve viability. However, the larger-scale connectedness of protein morphospace remains poorly understood. Recent advances in artificial intelligence have enabled us to computationally predict a protein's structure and quantify its functional plausibility. Here we build on these tools to develop an algorithm that generates viable paths between distantly related extant protein pairs. The intermediate sequences in these paths differ by single residue changes over subsequent steps - substitutions, insertions and deletions are admissible moves. Their fitness is evaluated using the protein language model ESM2, and maintained as high as possible subject to the constraints of the traversal. We document the qualitative variation across paths generated between progressively divergent protein pairs, some of which do not even acquire the same structural fold. The ease of interpolating between two sequences could be used as a proxy for the likelihood of homology between them.