arXiv subjects

Mark Gerstein

Publications and source records attributed to Mark Gerstein.

At least 19 recordsLinked to original sources

arXiv2026

MPP-GNN: Subject-Adaptive Community Detection for fMRI-Based Alzheimer's Disease Classification

Functional magnetic resonance imaging (fMRI) is a widely used technique for studying the brain. Recent methods that utilize graph neural networks (GNNs) for analysis of brain functional connectivity have shown great potential for the classification of brain disorders, such as Alzheimer's disease (AD). However, these methods often assume a preset number of functional modules across all subjects, which overlooks inter-subject variability. In addition, the discovered modules are rarely used to directly guide the learned connectivity patterns. Here, to address these issues, we propose a Meta Probabilistic Pooling GNN (MPP-GNN). We frame the model's task as a coupled, bilevel optimization that performs adaptive graph partitioning hierarchically to discover subject-specific modules and then uses the discovered brain modules as an explicit prior to guide edge refinement and representation learning. We validate MPP-GNN on two public datasets for AD classification, achieving the highest AUC in comparison to established baselines for both datasets. Furthermore, our analysis demonstrates that MPP-GNN shows significant alignment with the canonical functional-network organization defined by the Yeo brain atlas and reveals a network-level dedifferentiation pattern for AD.

cs.LG↗

arXiv2026

SurfDesign: Effective Protein Design on Molecular Surfaces

Protein function is largely determined by molecular surface geometry and physicochemical complementarity, yet most protein design methods condition only on backbone structure. We introduce SurfDesign, a surface-conditioned protein design framework that models molecular surfaces as continuous geometric manifolds and integrates them with pretrained protein language models. SurfDesign employs surface-based equivariant message passing to capture surface normals, curvature, and directional geometry, together with a parameter-efficient fine-tuning strategy. Focusing on functional protein design, we show that SurfDesign consistently outperforms prior surface-conditioned and backbone-only methods on de novo binder and enzyme design benchmarks. We also report strong performance on inverse-folding benchmarks as a diagnostic of structural compatibility. Our results highlight manifold-aware surface representations as a principled foundation for functional protein and enzyme design. Code is available at https://github.com/smiles724/SurfDesign.

q-bio.BM↗

arXiv2026

MIOFlow 2.0: A unified framework for inferring cellular stochastic dynamics from single cell and spatial transcriptomics data

Understanding cellular trajectories via time-resolved single-cell transcriptomics is vital for studying development, regeneration, and disease. A key challenge is inferring continuous trajectories from discrete snapshots. Biological complexity stems from stochastic cell fate decisions, temporal proliferation changes, and spatial environmental influences. Current methods often use deterministic interpolations treating cells in isolation, failing to capture the probabilistic branching, population shifts, and niche-dependent signaling driving real biological processes. We introduce Manifold Interpolating Optimal-Transport Flow (MIOFlow) 2.0. This framework learns biologically informed cellular trajectories by integrating manifold learning, optimal transport, and neural differential equations. It models three core processes: (1) stochasticity and branching via Neural Stochastic Differential Equations; (2) non-conservative population changes using a learned growth-rate model initialized with unbalanced optimal transport; and (3) environmental influence through a joint latent space unifying gene expression with spatial features like local cell type composition and signaling. By operating in a PHATE-distance matching autoencoder latent space, MIOFlow 2.0 ensures trajectories respect the data's intrinsic geometry. Empirical comparisons show expressive trajectory learning via neural differential equations outperforms existing generative models, including simulation-free flow matching. Validated on synthetic datasets, embryoid body differentiation, and spatially resolved axolotl brain regeneration, MIOFlow 2.0 improves trajectory accuracy and reveals hidden drivers of cellular transitions, like specific signaling niches. MIOFlow 2.0 thus bridges single-cell and spatial transcriptomics to uncover tissue-scale trajectories.

cs.LG↗

arXiv2026

Dispersion Loss Counteracts Embedding Condensation and Improves Generalization in Small Language Models

Large language models (LLMs) achieve remarkable performance through ever-increasing parameter counts, but scaling incurs steep computational costs. To better understand LLM scaling, we study representational differences between LLMs and their smaller counterparts, with the goal of replicating the representational qualities of larger models in smaller models. We observe a geometric phenomenon which we term $\textbf{embedding condensation}$, where token embeddings collapse into a narrow cone-like subspace in some language models. Through systematic analyses across multiple Transformer families, we show that small models such as $\texttt{GPT2}$ and $\texttt{Qwen3-0.6B}$ exhibit severe condensation, whereas larger models such as $\texttt{GPT2-xl}$ and $\texttt{Qwen3-32B}$ are more resistant to this phenomenon. Additional observations show that embedding condensation is not reliably mitigated by knowledge distillation from larger models. To fight against it, we formulate a dispersion loss that explicitly encourages embedding dispersion during training. Experiments demonstrate that it mitigates condensation, recovers dispersion patterns seen in larger models, and yields performance gains across 10 benchmarks. We believe this work offers a principled path toward improving smaller Transformers without additional parameters.

cs.LG↗

arXiv2026

Elign: Equivariant Diffusion Model Alignment from Foundational Machine Learning Force Fields

Generative models for 3D molecular conformations must respect Euclidean symmetries and concentrate probability mass on thermodynamically favorable, mechanically stable structures. However, E(3)-equivariant diffusion models often reproduce biases from semi-empirical training data rather than capturing the equilibrium distribution of a high-fidelity Hamiltonian. While physics-based guidance can correct this, it faces two computational bottlenecks: expensive quantum-chemical evaluations (e.g., DFT) and the need to repeat such queries at every sampling step. We present Elign, a post-training framework that amortizes both costs. First, we replace expensive DFT evaluations with a faster, pretrained foundational machine-learning force field (MLFF) to provide physical signals. Second, we eliminate repeated run-time queries by shifting physical steering to the training phase. To achieve the second amortization, we formulate reverse diffusion as a reinforcement learning problem and introduce Force--Energy Disentangled Group Relative Policy Optimization (FED-GRPO) to fine-tune the denoising policy. FED-GRPO includes a potential-based energy reward and a force-based stability reward, which are optimized and group-normalized independently. Experiments show that Elign generates conformations with lower gold-standard DFT energies and forces, while improving stability. Crucially, inference remains as fast as unguided sampling, since no energy evaluations are required during generation.

cs.LG↗

arXiv2025

Efficient Privacy-Preserving Training of Quantum Neural Networks by Using Mixed States to Represent Input Data Ensembles

Quantum neural networks (QNNs) are gaining increasing interest due to their potential to detect complex patterns in data by leveraging uniquely quantum phenomena. This makes them particularly promising for biomedical applications. In these applications and in other contexts, increasing statistical power often requires aggregating data from multiple participants. However, sharing data, especially sensitive information like personal genomic sequences, raises significant privacy concerns. Quantum federated learning offers a way to collaboratively train QNN models without exposing private data. However, it faces major limitations, including high communication overhead and the need to retrain models when the task is modified. To overcome these challenges, we propose a privacy-preserving QNN training scheme that utilizes mixed quantum states to encode ensembles of data. This approach allows for the secure sharing of statistical information while safeguarding individual data points. QNNs can be trained directly on these mixed states, eliminating the need to access raw data. Building on this foundation, we introduce protocols supporting multi-party collaborative QNN training applicable across diverse domains. Our approach enables secure QNN training with only a single round of communication per participant, provides high training speed and offers task generality, i.e., new analyses can be conducted without reacquiring information from participants. We present the theoretical foundation of our scheme's utility and privacy protections, which prevent the recovery of individual data points and resist membership inference attacks as measured by differential privacy. We then validate its effectiveness on three different datasets with a focus on genomic studies with an indication of how it can used in other domains without adaptation.

quant-ph↗

arXiv2025

CellForge: Agentic Design of Virtual Cell Models

Virtual cell modeling aims to predict cellular responses to diverse perturbations but faces challenges from biological complexity, multimodal data heterogeneity, and the need for interdisciplinary expertise. We introduce CellForge, a multi-agent framework that autonomously designs and synthesizes neural network architectures tailored to specific single-cell datasets and perturbation tasks. Given raw multi-omics data and task descriptions, CellForge discovers candidate architectures through collaborative reasoning among specialized agents, then generates executable implementations. Our core contribution is the framework itself: showing that multi-agent collaboration mechanisms - rather than manual human design or single-LLM prompting - can autonomously produce executable, high-quality computational methods. This approach goes beyond conventional hyperparameter tuning by enabling entirely new architectural components such as trajectory-aware encoders and perturbation diffusion modules to emerge from agentic deliberation. We evaluate CellForge on six datasets spanning gene knockouts, drug treatments, and cytokine stimulations across multiple modalities (scRNA-seq, scATAC-seq, CITE-seq). The results demonstrate that the models generated by CellForge are highly competitive with established baselines, while revealing systematic patterns of architectural innovation. CellForge highlights the scientific value of multi-agent frameworks: collaboration among specialized agents enables genuine methodological innovation and executable solutions that single agents or human experts cannot achieve. This represents a paradigm shift toward autonomous scientific method development in computational biology. Code is available at https://github.com/gersteinlab/CellForge.

cs.LG↗

arXiv2025

STAGED: A Multi-Agent Neural Network for Learning Cellular Interaction Dynamics

The advent of single-cell technology has significantly improved our understanding of cellular states and subpopulations in various tissues under normal and diseased conditions by employing data-driven approaches such as clustering and trajectory inference. However, these methods consider cells as independent data points of population distributions. With spatial transcriptomics, we can represent cellular organization, along with dynamic cell-cell interactions that lead to changes in cell state. Still, key computational advances are necessary to enable the data-driven learning of such complex interactive cellular dynamics. While agent-based modeling (ABM) provides a powerful framework, traditional approaches rely on handcrafted rules derived from domain knowledge rather than data-driven approaches. To address this, we introduce Spatio Temporal Agent-Based Graph Evolution Dynamics(STAGED) integrating ABM with deep learning to model intercellular communication, and its effect on the intracellular gene regulatory network. Using graph ODE networks (GDEs) with shared weights per cell type, our approach represents genes as vertices and interactions as directed edges, dynamically learning their strengths through a designed attention mechanism. Trained to match continuous trajectories of simulated as well as inferred trajectories from spatial transcriptomics data, the model captures both intercellular and intracellular interactions, enabling a more adaptive and accurate representation of cellular dynamics.

cs.LG↗

arXiv2025

Med-PRM: Medical Reasoning Models with Stepwise, Guideline-verified Process Rewards

Large language models have shown promise in clinical decision making, but current approaches struggle to localize and correct errors at specific steps of the reasoning process. This limitation is critical in medicine, where identifying and addressing reasoning errors is essential for accurate diagnosis and effective patient care. We introduce Med-PRM, a process reward modeling framework that leverages retrieval-augmented generation to verify each reasoning step against established medical knowledge bases. By verifying intermediate reasoning steps with evidence retrieved from clinical guidelines and literature, our model can precisely assess the reasoning quality in a fine-grained manner. Evaluations on five medical QA benchmarks and two open-ended diagnostic tasks demonstrate that Med-PRM achieves state-of-the-art performance, with improving the performance of base models by up to 13.50% using Med-PRM. Moreover, we demonstrate the generality of Med-PRM by integrating it in a plug-and-play fashion with strong policy models such as Meerkat, achieving over 80\% accuracy on MedQA for the first time using small-scale models of 8 billion parameters. Our code and data are available at: https://med-prm.github.io/

cs.CL↗

arXiv2025

Advancing AI Research Assistants with Expert-Involved Learning

Large language models (LLMs) and large multimodal models (LMMs) promise to accelerate biomedical discovery, yet their reliability remains unclear. We introduce ARIEL (AI Research Assistant for Expert-in-the-Loop Learning), an open-source evaluation and optimization framework that pairs a curated multimodal biomedical corpus with expert-vetted tasks to probe two capabilities: full-length article summarization and fine-grained figure interpretation. Using uniform protocols and blinded PhD-level evaluation, we find that state-of-the-art models generate fluent but incomplete summaries, whereas LMMs struggle with detailed visual reasoning. We later observe that prompt engineering and lightweight fine-tuning substantially improve textual coverage, and a compute-scaled inference strategy enhances visual question answering. We build an ARIEL agent that integrates textual and visual cues, and we show it can propose testable mechanistic hypotheses. ARIEL delineates current strengths and limitations of foundation models, and provides a reproducible platform for advancing trustworthy AI in biomedicine.

cs.AI↗

arXiv2025

MedicalAgentsBench for Complex Medical Reasoning: Comparing Internalized Reasoning Models versus Externalized Agent-based Frameworks

Complex medical reasoning requires integrating heterogeneous clinical evidence across multiple inference steps. Large language models (LLMs) now approach this through two routes: internalized reasoning and externalized agent scaffolding (frameworks that decompose problems collaboratively amongst multiple LLMs). To determine whether these routes are exclusive or complementary, we introduce MedicalAgentsBench, a filtered benchmark of 862 complex clinical questions drawn from the union of eight medical datasets via difficulty-aware curation and contamination screening. Evaluating three internalized reasoning models (DeepSeek-R1, o1-mini, and o3-mini), seven base models, and nine externalized agent-based methods, we find that internalized and externalized approaches each independently improve performance, and that their benefits compound: the highest accuracy is achieved by layering agent workflows onto an internalized reasoning model (i.e., o3-mini + MDAgents with 35.1%). Pareto analysis shows this combination dominates the cost-performance frontier; moreover, lightweight optimization on inexpensive models offers an entry point for resource-constrained settings. Our benchmark is at https://github.com/gersteinlab/MedicalAgentsBench.

cs.CL↗

arXiv2025

E2Former: An Efficient and Equivariant Transformer with Linear-Scaling Tensor Products

Equivariant Graph Neural Networks (EGNNs) have demonstrated significant success in modeling microscale systems, including those in chemistry, biology and materials science. However, EGNNs face substantial computational challenges due to the high cost of constructing edge features via spherical tensor products, making them impractical for large-scale systems. To address this limitation, we introduce E2Former, an equivariant and efficient transformer architecture that incorporates the Wigner $6j$ convolution (Wigner $6j$ Conv). By shifting the computational burden from edges to nodes, the Wigner $6j$ Conv reduces the complexity from $O(|\mathcal{E}|)$ to $ O(| \mathcal{V}|)$ while preserving both the model's expressive power and rotational equivariance. We show that this approach achieves a 7x-30x speedup compared to conventional $\mathrm{SO}(3)$ convolutions. Furthermore, our empirical results demonstrate that the derived E2Former mitigates the computational challenges of existing approaches without compromising the ability to capture detailed geometric information. This development could suggest a promising direction for scalable and efficient molecular modeling.

cs.LG↗

arXiv2025

ChemAgent: Self-updating Library in Large Language Models Improves Chemical Reasoning

Chemical reasoning usually involves complex, multi-step processes that demand precise calculations, where even minor errors can lead to cascading failures. Furthermore, large language models (LLMs) encounter difficulties handling domain-specific formulas, executing reasoning steps accurately, and integrating code effectively when tackling chemical reasoning tasks. To address these challenges, we present ChemAgent, a novel framework designed to improve the performance of LLMs through a dynamic, self-updating library. This library is developed by decomposing chemical tasks into sub-tasks and compiling these sub-tasks into a structured collection that can be referenced for future queries. Then, when presented with a new problem, ChemAgent retrieves and refines pertinent information from the library, which we call memory, facilitating effective task decomposition and the generation of solutions. Our method designs three types of memory and a library-enhanced reasoning component, enabling LLMs to improve over time through experience. Experimental results on four chemical reasoning datasets from SciBench demonstrate that ChemAgent achieves performance gains of up to 46% (GPT-4), significantly outperforming existing methods. Our findings suggest substantial potential for future applications, including tasks such as drug discovery and materials science. Our code can be found at https://github.com/gersteinlab/chemagent

cs.CL↗

arXiv2024

ChemSafetyBench: Benchmarking LLM Safety on Chemistry Domain

The advancement and extensive application of large language models (LLMs) have been remarkable, including their use in scientific research assistance. However, these models often generate scientifically incorrect or unsafe responses, and in some cases, they may encourage users to engage in dangerous behavior. To address this issue in the field of chemistry, we introduce ChemSafetyBench, a benchmark designed to evaluate the accuracy and safety of LLM responses. ChemSafetyBench encompasses three key tasks: querying chemical properties, assessing the legality of chemical uses, and describing synthesis methods, each requiring increasingly deeper chemical knowledge. Our dataset has more than 30K samples across various chemical materials. We incorporate handcrafted templates and advanced jailbreaking scenarios to enhance task diversity. Our automated evaluation framework thoroughly assesses the safety, accuracy, and appropriateness of LLM responses. Extensive experiments with state-of-the-art LLMs reveal notable strengths and critical vulnerabilities, underscoring the need for robust safety measures. ChemSafetyBench aims to be a pivotal tool in developing safer AI technologies in chemistry. Our code and dataset are available at https://github.com/HaochenZhao/SafeAgent4Chem. Warning: this paper contains discussions on the synthesis of controlled chemicals using AI models.

cs.CL↗

arXiv2024

D-Flow: Multi-modality Flow Matching for D-peptide Design

Among these, D-peptides are resistant to proteolysis, exhibit greater in vivo stability, and are easier to synthesize. Despite advances in deep learning for peptide discovery, the scarcity of natural D-protein data limits the transfer of existing generative models to the D-peptide chemical space. We propose D-Flow, a full-atom flow-based framework for de novo D-peptide design. Conditioned on receptor binding, D-Flow uses structural representations incorporating backbone frames, side-chain angles, and discrete amino acid types. A mirror-image algorithm is implemented to address the lack of training data for D-proteins by converting the chirality of L-receptors. Furthermore, we enhance D-Flow's capacity by integrating protein language models (PLMs) with structural awareness through a lightweight structural adapter that injects structural representations into PLM embeddings. This enables D-Flow to learn conformational priors in the D-peptide chemical space and to accommodate the chiral selectivity of binding sites, thereby mitigating the scarcity of D-peptide data. A two-stage training pipeline and a control toolkit enable D-Flow to transition from general protein design to targeted binder design while preserving pre-training knowledge. Results on the PepMerge benchmark show D-Flow's effectiveness. D-peptides generated by D-Flow align more closely with native sequences and structures, with sequence identity improving by 10.2% over the best baseline, and the top affinity score reaching 24.31%. Overall, D-Flow shows potential for D-peptide design, facilitating the development of bioorthogonal and stable molecular tools and diagnostics. Code is available at https://github.com/smiles724/PeptideDesign.

cs.CE↗

arXiv2024

Step-Back Profiling: Distilling User History for Personalized Scientific Writing

Large language models (LLM) excel at a variety of natural language processing tasks, yet they struggle to generate personalized content for individuals, particularly in real-world scenarios like scientific writing. Addressing this challenge, we introduce STEP-BACK PROFILING to personalize LLMs by distilling user history into concise profiles, including essential traits and preferences of users. To conduct the experiments, we construct a Personalized Scientific Writing (PSW) dataset to study multi-user personalization. PSW requires the models to write scientific papers given specialized author groups with diverse academic backgrounds. As for the results, we demonstrate the effectiveness of capturing user characteristics via STEP-BACK PROFILING for collaborative writing. Moreover, our approach outperforms the baselines by up to 3.6 points on the general personalization benchmark (LaMP), including 7 personalization LLM tasks. Our ablation studies validate the contributions of different components in our method and provide insights into our task definition. Our dataset and code are available at \url{https://github.com/gersteinlab/step-back-profiling}.

cs.CL↗

arXiv2024

MIMIR: A Streamlined Platform for Personalized Agent Tuning in Domain Expertise

Recently, large language models (LLMs) have evolved into interactive agents, proficient in planning, tool use, and task execution across a wide variety of tasks. However, without specific agent tuning, open-source models like LLaMA currently struggle to match the efficiency of GPT- 4, particularly given the scarcity of agent-tuning datasets for fine-tuning. In response, we introduce \textsc{Mimir}: a streamlined platform offering a customizable pipeline that enables users to leverage both private knowledge and publicly available, legally compliant datasets at scale for \textbf{personalized agent tuning}. Additionally, \textsc{Mimir} supports the generation of general instruction-tuning datasets from the same input. This dual capability ensures that language agents developed through the platform possess both specific agent abilities and general competencies. \textsc{Mimir} integrates these features into a cohesive end-to-end platform, facilitating everything from the uploading of personalized files to one-click agent fine-tuning.

cs.CL↗

arXiv2024

$\zeta$-QVAE: A Quantum Variational Autoencoder utilizing Regularized Mixed-state Latent Representations

A major challenge in quantum computing is its application to large real-world datasets due to scarce quantum hardware resources. One approach to enabling tractable quantum models for such datasets involves finding low-dimensional representations that preserve essential information for downstream analysis. In classical machine learning, variational autoencoders (VAEs) facilitate efficient data compression, representation learning for subsequent tasks, and novel data generation. However, no quantum model has been proposed that captures these features for direct application to quantum data on quantum computers. Some existing quantum models for data compression lack regularization of latent representations. Others are hybrid models with only some internal quantum components, impeding direct training on quantum data. To address this, we present a fully quantum framework, $\zeta$-QVAE, which encompasses all the capabilities of classical VAEs and can be directly applied to map both classical and quantum data to a lower-dimensional space, while effectively reconstructing much of the original state from it. Our model utilizes regularized mixed states to attain optimal latent representations. It accommodates various divergences for reconstruction and regularization. Furthermore, by accommodating mixed states at every stage, it can utilize the full-data density matrix and allow for a training objective defined on probabilistic mixtures of input data. Doing so, in turn, makes efficient optimization possible and has potential implications for private and federated learning. In addition to exploring the theoretical properties of $\zeta$-QVAE, we demonstrate its performance on genomics and synthetic data. Our results indicate that $\zeta$-QVAE learns representations that better utilize the capacity of the latent space and exhibits similar or better performance compared to matched classical models.

quant-ph↗