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In this work, we present a new imaging system to support real-time tumor tracking for surface-guided radiotherapy (SGRT). SGRT uses optical surface imaging (OSI) to acquire real-time surface topography images of the patient on the treatment couch. This serves as a surrogate for intra-fractional tumor motion tracking to guide radiation delivery. However, OSI cannot visualize internal anatomy, leading to motion tracking uncertainties for internal tumors, as body surface motion often does not have a good correlation with the internal tumor motion, particularly for lung cancer. This study proposes an Advanced Surface Imaging (A-SI) framework to address this issue. In the proposed A-SI framework, a high-speed surface imaging camera consistently captures surface images during radiation delivery, and a CBCT imager captures single-angle X-ray projections at low frequency. The A-SI then utilizes a generative model to generate real-time volumetric images with full anatomy, referred to as Optical Surface-Derived cone beam computed tomography (OSD-CBCT), based on the real-time high-frequent surface images and the low-frequency collected single-angle X-ray projections. The generated OSD-CBCT can provide accurate tumor motion for precise radiation delivery. The A-SI framework uses a patient-specific generative model: physics-integrated consistency-refinement denoising diffusion probabilistic model (PC-DDPM). This model leverages patient-specific anatomical structures and respiratory motion patterns derived from four-dimensional CT (4DCT) during treatment planning. It then employs a geometric transformation module (GTM) to extract volumetric anatomy information from the single-angle X-ray projection. A physics-integrated and cycle-consistency refinement strategy uses this information and the surface images to guide the DDPM, generating high quality OSD-CBCTs throughout the entire radiation delivery. A simulation study with 22 lung cancer patients evaluated the A-SI framework supported by PC-DDPM. The results showed that the framework produced real-time OSD-CBCT with high reconstruction fidelity and precise tumor localization. These results were validated through comprehensive intensity-, structural-, visual-, and clinical-level assessments. This study demonstrates the potential of A-SI to enable real-time tumor tracking with minimal imaging dose, advancing SGRT for motion-associated cancers and interventional procedures.

The success of machine learning models relies heavily on effectively representing high-dimensional data. However, ensuring data representations capture human-understandable concepts remains difficult, often requiring the incorporation of prior knowledge and decomposition of data into multiple subspaces. Traditional linear methods fall short in modeling more than one space, while more expressive deep learning approaches lack interpretability. Here, we introduce Supervised Independent Subspace Principal Component Analysis ($texttt{sisPCA}$), a PCA extension designed for multi-subspace learning. Leveraging the Hilbert-Schmidt Independence Criterion (HSIC), $texttt{sisPCA}$ incorporates supervision and simultaneously ensures subspace disentanglement. We demonstrate $texttt{sisPCA}$'s connections with autoencoders and regularized linear regression and showcase its ability to identify and separate hidden data structures through extensive applications, including breast cancer diagnosis from image features, learning aging-associated DNA methylation changes, and single-cell analysis of malaria infection. Our results reveal distinct functional pathways associated with malaria colonization, underscoring the essentiality of explainable representation in high-dimensional data analysis.

Stability in recurrent neural models poses a significant challenge, particularly in developing biologically plausible neurodynamical models that can be seamlessly trained. Traditional cortical circuit models are notoriously difficult to train due to expansive nonlinearities in the dynamical system, leading to an optimization problem with nonlinear stability constraints that are difficult to impose. Conversely, recurrent neural networks (RNNs) excel in tasks involving sequential data but lack biological plausibility and interpretability. In this work, we address these challenges by linking dynamic divisive normalization (DN) to the stability of "oscillatory recurrent gated neural integrator circuits" (ORGaNICs), a biologically plausible recurrent cortical circuit model that dynamically achieves DN and that has been shown to simulate a wide range of neurophysiological phenomena. By using the indirect method of Lyapunov, we prove the remarkable property of unconditional local stability for an arbitrary-dimensional ORGaNICs circuit when the recurrent weight matrix is the identity. We thus connect ORGaNICs to a system of coupled damped harmonic oscillators, which enables us to derive the circuit's energy function, providing a normative principle of what the circuit, and individual neurons, aim to accomplish. Further, for a generic recurrent weight matrix, we prove the stability of the 2D model and demonstrate empirically that stability holds in higher dimensions. Finally, we show that ORGaNICs can be trained by backpropagation through time without gradient clipping/scaling, thanks to its intrinsic stability property and adaptive time constants, which address the problems of exploding, vanishing, and oscillating gradients. By evaluating the model's performance on RNN benchmarks, we find that ORGaNICs outperform alternative neurodynamical models on static image classification tasks and perform comparably to LSTMs on sequential tasks.

Data increasingly take the form of a multi-way array, or tensor, in several biomedical domains. Such tensors are often incompletely observed. For example, we are motivated by longitudinal microbiome studies in which several timepoints are missing for several subjects. There is a growing literature on missing data imputation for tensors. However, existing methods give a point estimate for missing values without capturing uncertainty. We propose a multiple imputation approach for tensors in a flexible Bayesian framework, that yields realistic simulated values for missing entries and can propagate uncertainty through subsequent analyses. Our model uses efficient and widely applicable conjugate priors for a CANDECOMP/PARAFAC (CP) factorization, with a separable residual covariance structure. This approach is shown to perform well with respect to both imputation accuracy and uncertainty calibration, for scenarios in which either single entries or entire fibers of the tensor are missing. For two microbiome applications, it is shown to accurately capture uncertainty in the full microbiome profile at missing timepoints and used to infer trends in species diversity for the population. Documented R code to perform our multiple imputation approach is available at https://github.com/lockEF/MultiwayImputation.

Abrupt changes in behavior can often be associated with changes in underlying behavioral states. When placed off food, the foraging behavior of C. elegans can be described as a change between an initial local-search behavior characterized by a high rate of reorientations, followed by a global-search behavior characterized by sparse reorientations. This is commonly observed in individual worms, but when numerous worms are characterized, only about half appear to exhibit this behavior. We propose an alternative model that predicts both abrupt and continuous changes to reorientation that does not rely on behavioral states. This model is inspired by molecular dynamics modeling that defines the foraging reorientation rate as a decaying parameter. By stochastically sampling from the probability distribution defined by this rate, both abrupt and gradual changes to reorientation rates can occur, matching experimentally observed results. Crucially, this model does not depend on behavioral states or information accumulation. Even though abrupt behavioral changes do occur, they are not necessarily indicative of abrupt changes in behavioral states, especially when abrupt changes are not universally observed in the population.

Electron cryomicroscopy (cryo-EM) is an imaging technique widely used in structural biology to determine the three-dimensional structure of biological molecules from noisy two-dimensional projections with unknown orientations. As the typical pipeline involves processing large amounts of data, efficient algorithms are crucial for fast and reliable results. The stochastic gradient descent (SGD) algorithm has been used to improve the speed of ab initio reconstruction, which results in a first, low-resolution estimation of the volume representing the molecule of interest, but has yet to be applied successfully in the high-resolution regime, where expectation-maximization algorithms achieve state-of-the-art results, at a high computational cost. In this article, we investigate the conditioning of the optimization problem and show that the large condition number prevents the successful application of gradient descent-based methods at high resolution. Our results include a theoretical analysis of the condition number of the optimization problem in a simplified setting where the individual projection directions are known, an algorithm based on computing a diagonal preconditioner using Hutchinson's diagonal estimator, and numerical experiments showing the improvement in the convergence speed when using the estimated preconditioner with SGD. The preconditioned SGD approach can potentially enable a simple and unified approach to ab initio reconstruction and high-resolution refinement with faster convergence speed and higher flexibility, and our results are a promising step in this direction.

The discovery and identification of molecules in biological and environmental samples is crucial for advancing biomedical and chemical sciences. Tandem mass spectrometry (MS/MS) is the leading technique for high-throughput elucidation of molecular structures. However, decoding a molecular structure from its mass spectrum is exceptionally challenging, even when performed by human experts. As a result, the vast majority of acquired MS/MS spectra remain uninterpreted, thereby limiting our understanding of the underlying (bio)chemical processes. Despite decades of progress in machine learning applications for predicting molecular structures from MS/MS spectra, the development of new methods is severely hindered by the lack of standard datasets and evaluation protocols. To address this problem, we propose MassSpecGym -- the first comprehensive benchmark for the discovery and identification of molecules from MS/MS data. Our benchmark comprises the largest publicly available collection of high-quality labeled MS/MS spectra and defines three MS/MS annotation challenges: textit{de novo} molecular structure generation, molecule retrieval, and spectrum simulation. It includes new evaluation metrics and a generalization-demanding data split, therefore standardizing the MS/MS annotation tasks and rendering the problem accessible to the broad machine learning community. MassSpecGym is publicly available at url{https://github.com/pluskal-lab/MassSpecGym}.

Understanding the relationship between cognition and intrinsic brain activity through purely data-driven approaches remains a significant challenge in neuroscience. Resting-state functional magnetic resonance imaging (rs-fMRI) offers a non-invasive method to monitor regional neural activity, providing a rich and complex spatiotemporal data structure. Deep learning has shown promise in capturing these intricate representations. However, the limited availability of large datasets, especially for disease-specific groups such as Alzheimer's Disease (AD), constrains the generalizability of deep learning models. In this study, we focus on multivariate time series forecasting of independent component networks derived from rs-fMRI as a form of data augmentation, using both a conventional LSTM-based model and the novel Transformer-based BrainLM model. We assess their utility in AD classification, demonstrating how generative forecasting enhances classification performance. Post-hoc interpretation of BrainLM reveals class-specific brain network sensitivities associated with AD.

The promise of large-scale, high-resolution datasets from Electron Microscopy (EM) and X-ray Microtomography (XRM) lies in their ability to reveal neural structures and synaptic connectivity, which is critical for understanding the brain. Effectively managing these complex and rapidly increasing datasets will enable new scientific insights, facilitate querying, and support secondary use across the neuroscience community. However, without effective neurodata standards that permit use of these data across multiple systems and workflows, these valuable and costly datasets risk being underutilized especially as they surpass petascale levels. These standards will promote data sharing through accessible interfaces, allow researchers to build on each other's work, and guide the development of tools and capabilities that are interoperable. Herein we outline a standards framework for creating and managing annotations originating and derived from high-resolution volumetric imaging and connectomic datasets, focusing on ensuring Findable, Accessible, Interoperable, and Reusable (FAIR) practices. The goal is to enhance collaborative efforts, boost the reliability of findings, and enable comparative analysis across growing datasets of different species and modalities. We have formed a global working group with academic and industry partners in the high-resolution volumetric data generation and analysis community, focused on identifying gaps in current EM and XRM data pipelines, and refining outlines and platforms for standardizing EM and XRM methods. This focus considers existing and past community approaches and includes examining neuronal entities, biological components, and associated metadata, while emphasizing adaptability and fostering collaboration.

Understanding the genetic basis of complex traits is a longstanding challenge in the field of genomics. Genome-wide association studies (GWAS) have identified thousands of variant-trait associations, but most of these variants are located in non-coding regions, making the link to biological function elusive. While traditional approaches, such as transcriptome-wide association studies (TWAS), have advanced our understanding by linking genetic variants to gene expression, they often overlook gene-gene interactions. Here, we review current approaches to integrate different molecular data, leveraging machine learning methods to identify gene modules based on co-expression and functional relationships. These integrative approaches, like PhenoPLIER, combine TWAS and drug-induced transcriptional profiles to effectively capture biologically meaningful gene networks. This integration provides a context-specific understanding of disease processes while highlighting both core and peripheral genes. These insights pave the way for novel therapeutic targets and enhance the interpretability of genetic studies in personalized medicine.