Publications

The randomized SVD is a method to compute an inexpensive, yet accurate, low-rank approximation of a matrix. The algorithm assumes access to the matrix through matrix-vector products (matvecs). Therefore, when we would like to apply the randomized SVD to a matrix function, f(A), one needs to approximate matvecs with f(A) using some other algorithm, which is typically treated as a black-box. Chen and Hallman (SIMAX 2023) argued that, in the common setting where matvecs with f(A) are approximated using Krylov subspace methods (KSMs), a more efficient low-rank approximation is possible if we open this black-box. They present an alternative approach that significantly outperforms the naive combination of KSMs with the randomized SVD, although the method lacked theoretical justification. In this work, we take a closer look at the method, and provide strong and intuitive error bounds that justify its excellent performance for low-rank approximation of matrix functions.

We present a spectrally accurate fast algorithm for evaluating the solution to the scalar wave equation in free space driven by a large collection of point sources in a bounded domain. With $M$ sources temporally discretized by $N_t$ time steps of size $\Delta t$, a naive potential evaluation at $M$ targets on the same time grid requires $\mathcal O(M^2 N_t)$ work. Our scheme requires $\mathcal{O}\left((M + N^3\log N)N_t\right)$ work, where $N$ scales as $\mathcal O(1/\Delta t)$, i.e., the maximum signal frequency. This is achieved by using the recently-proposed windowed Fourier projection (WFP) method to split the potential into a local part, evaluated directly, plus a smooth history part approximated by an $N^3$-point equispaced discretization of the Fourier transform, where each Fourier coefficient obeys a simple recursion relation. The growing oscillations in the spectral representation (which would be present with a naive use of the Fourier transform) are controlled by spatially truncating the hyperbolic Green's function itself. Thus, the method avoids the need for absorbing boundary conditions. We demonstrate the performance of our algorithm with up to a million sources and targets at 6-digit accuracy. We believe it can serve as a key component in addressing time-domain wave equation scattering problems.

Recent advances in mechanistic interpretability have revealed that large language models (LLMs) develop internal representations corresponding not only to concrete entities but also distinct, human-understandable abstract concepts and behaviour. Moreover, these hidden features can be directly manipulated to steer model behaviour. However, it remains an open question whether this phenomenon is unique to models trained on inherently structured data (ie. language, images) or if it is a general property of foundation models. In this work, we investigate the internal representations of a large physics-focused foundation model. Inspired by recent work identifying single directions in activation space for complex behaviours in LLMs, we extract activation vectors from the model during forward passes over simulation datasets for different physical regimes. We then compute "delta" representations between the two regimes. These delta tensors act as concept directions in activation space, encoding specific physical features. By injecting these concept directions back into the model during inference, we can steer its predictions, demonstrating causal control over physical behaviours, such as inducing or removing some particular physical feature from a simulation. These results suggest that scientific foundation models learn generalised representations of physical principles. They do not merely rely on superficial correlations and patterns in the simulations. Our findings open new avenues for understanding and controlling scientific foundation models and has implications for AI-enabled scientific discovery

Color discrimination thresholds—the smallest detectable color differences—provide a benchmark for models of color vision, enable quantitative evaluation of eye diseases, and inform the design of display technologies. Despite their importance, a comprehensive characterization of these thresholds has long been considered intractable due to the psychophysical curse of dimensionality. Here, we address this challenge using a novel semi-parametric Wishart Process Psychophysical Model (WPPM), which leverages the feature that the internal noise limiting color discrimination varies smoothly across stimulus space. The model was fit to data collected with a non-parametric adaptive trial-placement procedure, enabling efficient stimulus selection. Together, through the combination of adaptive trial placement and post hoc WPPM fitting, we achieved comprehensive characterization of color discrimination in the isoluminant plane with only ~6,000 trials per participant (N = 8). Once fit, the WPPM allows readouts of discrimination performance for any stimulus pair. We validated these readouts against 25 probe psychometric functions, measured with an additional 6,000 trials per participant held out from model fitting. In conclusion, our study provides a foundational dataset for color vision, and our approach generalizes beyond color to any domain in which the internal noise limiting performance varies smoothly across stimulus space, offering a powerful and efficient method for comprehensively characterizing various perceptual discrimination thresholds.

Pose estimation is a general problem in computer vision with wide applications. The relative orientation of a 3D reference object can be determined from a 3D rotated version of that object, or from a projection of the rotated object to a 2D planar image. This projection can be a perspective projection (the PnP problem) or an orthographic projection (the OnP problem). We restrict our attention here to the OnP problem and the full 3D pose estimation task (the EnP problem). Here we solve the least squares systems for both the error-free EnP and OnP problems in terms of the determinant ratio matrix (DRaM) approach. The noisy-data case can be addressed with a straightforward rotation correction scheme. While the SVD and optimal quaternion eigensystem methods solve the noisy EnP 3D-3D alignment exactly, the noisy 3D-2D orthographic (OnP) task has no known comparable closed form, and can be solved by DRaM-class methods. We note that while previous similar work has been presented in the literature exploiting both the QR decomposition and the Moore-Penrose pseudoinverse transformations, here we place these methods in a larger context that has not previously been fully recognized in the absence of the corresponding DRaM solution. We term this class of solutions as the DRaM family, and conduct comparisons of the behavior of the families of solutions for the EnP and OnP rotation estimation problems. Overall, this work presents both a new solution to the 3D and 2D orthographic pose estimation problems and provides valuable insight into these classes of problems. With hindsight, we are able to show that our DRaM solutions to the exact EnP and OnP problems possess derivations that could have been discovered in the time of Gauss, and in fact generalize to all analogous N-dimensional Euclidean pose estimation problems.

Building upon a foundational Human Kidney resource, we present a comprehensive multi-modal atlas that defines spatially resolved versus unresolved repair states and mechanisms in human kidney disease. Homeostatic interactions between injured kidney epithelium and its surrounding milieu determine successful repair outcomes, while pathogenic signaling promotes unresolved inflammation and fibrosis leading to chronic disease. We integrated multiple single-cell and spatial modalities across ∼700 samples from >350 patients (∼250 research biopsies), analyzing ∼1.7 million cells alongside complementary mouse multi-omic profiles spanning acute-to-chronic injury and aging (>300,000 cells) and spatial transcriptomic analysis of >150 human biopsies. This cross-species atlas delineates functional pathways and druggable targets across the nephron and defines gene regulatory networks and chromatin landscapes governing tubular, fibroblast, and immune cell transitions from injury to either recovery or failed repair states. We identified distinct cellular states associated with specific pathological features that show dynamic distributions between acute kidney injury (AKI) and chronic kidney disease (CKD), organized within unique spatial niches that reveal progression mechanisms from early injury to unresolved disease. Gene regulatory analyses prioritized key transcription factor activities (SOX4, SOX9, NFKB1, REL, KLFs) and their target networks establishing disease states and tissue microenvironments. These regulatory programs were directly linked to clinical outcomes, identifying molecular signatures of recovery and secreted biomarkers predictive of AKI-to-CKD progression, providing a key resource for therapeutic development and precision medicine approaches in kidney disease.

Ongoing efforts over the last 50 years have made data and methods more reproducible and transparent across the life sciences. This openness has led to transformative insights and vastly accelerated scientific progress (Gražulis et al., 2012; Munafó et al., 2017). For example, structural biology (Bruno and Groom, 2014) and genomics (Benson et al., 2013; Porter and Hajibabaei, 2018) have undertaken systematic collection and publication of protein sequences and structures over the past half century. These data, in turn, have led to scientific breakthroughs that were unthinkable when data collection first began (Jumper et al., 2021). We believe that neuroscience is poised to follow the same path, and that principles of open data and open science will transform our understanding of the nervous system in ways that are impossible to predict at the moment. New social structures supporting an active and open scientific community are essential (Saunders, 2022) to facilitate and expand the still limited adoption of open science practices in our field (Schottdorf et al., 2024). Unified by shared values of openness, we set out to organize a symposium for open data in neurophysiology (ODIN) to strengthen our community and facilitate transformative open neuroscience research at large. In this report, we synthesize insights from this first ODIN event. We also lay out plans for how to grow this movement, document emerging conversations, and propose a path toward a better and more transparent science of tomorrow.

Foundation models have transformed machine learning for language and vision, but achieving comparable impact in physical simulation remains a challenge. Data heterogeneity and unstable long-term dynamics inhibit learning from sufficiently diverse dynamics, while varying resolutions and dimensionalities challenge efficient training on modern hardware. Through empirical and theoretical analysis, we incorporate new approaches to mitigate these obstacles, including a harmonic-analysis-based stabilization method, load-balanced distributed 2D and 3D training strategies, and compute-adaptive tokenization. Using these tools, we develop Walrus, a transformer-based foundation model developed primarily for fluid-like continuum dynamics. Walrus is pretrained on nineteen diverse scenarios spanning astrophysics, geoscience, rheology, plasma physics, acoustics, and classical fluids. Experiments show that Walrus outperforms prior foundation models on both short and long term prediction horizons on downstream tasks and across the breadth of pretraining data, while ablation studies confirm the value of our contributions to forecast stability, training throughput, and transfer performance over conventional approaches. Code and weights are released for community use.

Phase separation of proteins plays a critical role in cellular organization. How phase-separated protein condensates underpin biological function and how condensates achieve specificity remain elusive. We investigated the phase separation of MUT-16, a scaffold protein in Mutator foci, and its role in recruiting the client protein MUT-8, a key component in RNA silencing in Caenorhabditis elegans. We employed a multi-scale approach that combined coarse-grained (residue-level CALVADOS2 and near-atomistic Martini3) and atomistic simulations. Simulations across different resolutions provide a consistent perspective on how MUT-16 condensates recruit MUT-8, enabling the fine-tuning of chemical details and balancing the computational cost. Both coarse-grained models (CALVADOS2 and Martini3) predicted the relative phase-separation propensities of MUT-16’s disordered regions, which we confirmed through in vitro experiments. Simulations also identified key sequence features and residues driving phase separation and revealed differences in residue interaction propensities between CALVADOS2 and Martini3. Furthermore, Martini3 and 350-μs atomistic simulations on Folding@Home of MUT-8’s N-terminal prion-like domain with MUT-16 M8BR cluster highlighted the importance of cation-interactions between Tyr residues of MUT-8 and Arg residues of MUT-16 M8BR. Lys residues were observed to be more prone to interact in Martini3. Atomistic simulations revealed that the guanidinium group of Arg also engages in interactions and hydrogen bonds with the backbone of Tyr, possibly contributing to the greater strength of Arg-Tyr interactions compared to Lys-Tyr, where these additional favorable contacts are absent. In agreement with our simulations, in vitro co-expression pull-down experiments demonstrated a progressive loss of MUT-8 recruitment after the mutation of Arg in MUT-16 M8BR to Lys or Ala, confirming the critical role of Arg in this interaction. These findings advance our understanding of MUT-16 phase separation and subsequent MUT-8 recruitment, key processes in assembling Mutator foci that drive RNA silencing in C. elegans.

Phase separation of proteins plays a critical role in cellular organization. How phase-separated protein condensates underpin biological function and how condensates achieve specificity remain elusive. We investigated the phase separation of MUT-16, a scaffold protein in Mutator foci, and its role in recruiting the client protein MUT-8, a key component in RNA silencing in Caenorhabditis elegans. We employed a multi-scale approach that combined coarse-grained (residue-level CALVADOS2 and near-atomistic Martini3) and atomistic simulations. Simulations across different resolutions provide a consistent perspective on how MUT-16 condensates recruit MUT-8, enabling the fine-tuning of chemical details and balancing the computational cost. Both coarse-grained models (CALVADOS2 and Martini3) predicted the relative phase-separation propensities of MUT-16’s disordered regions, which we confirmed through in vitro experiments. Simulations also identified key sequence features and residues driving phase separation and revealed differences in residue interaction propensities between CALVADOS2 and Martini3. Furthermore, Martini3 and 350-μs atomistic simulations on Folding@Home of MUT-8’s N-terminal prion-like domain with MUT-16 M8BR cluster highlighted the importance of cation-interactions between Tyr residues of MUT-8 and Arg residues of MUT-16 M8BR. Lys residues were observed to be more prone to interact in Martini3. Atomistic simulations revealed that the guanidinium group of Arg also engages in interactions and hydrogen bonds with the backbone of Tyr, possibly contributing to the greater strength of Arg-Tyr interactions compared to Lys-Tyr, where these additional favorable contacts are absent. In agreement with our simulations, in vitro co-expression pull-down experiments demonstrated a progressive loss of MUT-8 recruitment after the mutation of Arg in MUT-16 M8BR to Lys or Ala, confirming the critical role of Arg in this interaction. These findings advance our understanding of MUT-16 phase separation and subsequent MUT-8 recruitment, key processes in assembling Mutator foci that drive RNA silencing in C. elegans.