Resolving the bias-precision paradox with stochastic causal representation learning for personalized medicine

Estimating individualized treatment effects from longitudinal observational data is central to data-driven medicine, yet existing methods face a fundamental limitation: reducing confounding bias often suppresses clinically informative heterogeneity, degrading patient-specific predictions. Here, we identify this tension as a bias-precision paradox in causal representation learning and introduce sampling-based maximum mean discrepancy (sMMD), a stochastic alignment strategy that replaces global adversarial balancing with subset-level matching. We instantiate this approach in a framework for counterfactual outcome prediction with attribution-grounded interpretability. Across two large-scale ICU cohorts (n = 27,783), our framework improves accuracy under distribution shift, reducing error by up to 11.5% and substantially increasing recall in high-risk tasks. Mechanistic analyses show that sMMD selectively preserves clinically decisive variables. In human-AI evaluation, our method outperforms clinicians-in-training and large language models, and improves clinician accuracy by 14.7% while reducing decision time, enabling interpretable, real-time clinical decision support.

RiboSphere: Learning Unified and Efficient Representations of RNA Structures

Accurate RNA structure modeling remains difficult because RNA backbones are highly flexible, non-canonical interactions are prevalent, and experimentally determined 3D structures are comparatively scarce. We introduce \emph{RiboSphere}, a framework that learns \emph{discrete} geometric representations of RNA by combining vector quantization with flow matching. Our design is motivated by the modular organization of RNA architecture: complex folds are composed from recurring structural motifs. RiboSphere uses a geometric transformer encoder to produce SE(3)-invariant (rotation/translation-invariant) features, which are discretized with finite scalar quantization (FSQ) into a finite vocabulary of latent codes. Conditioned on these discrete codes, a flow-matching decoder reconstructs atomic coordinates, enabling high-fidelity structure generation. We find that the learned code indices are enriched for specific RNA motifs, suggesting that the model captures motif-level compositional structure rather than acting as a purely compressive bottleneck. Across benchmarks, RiboSphere achieves strong performance in structure reconstruction (RMSD 1.25\,Å, TM-score 0.84), and its pretrained discrete representations transfer effectively to inverse folding and RNA--ligand binding prediction, with robust generalization in data-scarce regimes.

Does the Question Really Matter? Training-Free Data Selection for Vision-Language SFT

Visual instruction tuning is crucial for improving vision-language large models (VLLMs). However, many samples can be solved via linguistic patterns or common-sense shortcuts, without genuine cross-modal reasoning, limiting the effectiveness of multimodal learning. Prior data selection methods often rely on costly proxy model training and focus on difficulty or diversity, failing to capture a sample's true contribution to vision-language joint reasoning. In this paper, we propose CVS, a training-free data selection method based on the insight that, for high-quality multimodal samples, introducing the question should substantially alter the model's assessment of answer validity given an image. CVS leverages a frozen VLLM as an evaluator and measures the discrepancy in answer validity with and without conditioning on the question, enabling the identification of samples that require vision-language joint reasoning while filtering semantic-conflict noise. Experiments on Vision-Flan and The Cauldron show that CVS achieves solid performance across datasets. On Vision-Flan, CVS outperforms full-data training by 3.5% and 4.8% using only 10% and 15% of the data, respectively, and remains robust on the highly heterogeneous Cauldron dataset. Moreover, CVS reduces computational cost by 17.3% and 44.4% compared to COINCIDE and XMAS.

Preserving Continuous Symmetry in Discrete Spaces: Geometric-Aware Quantization for SO(3)-Equivariant GNNs

Equivariant Graph Neural Networks (GNNs) are essential for physically consistent molecular simulations but suffer from high computational costs and memory bottlenecks, especially with high-order representations. While low-bit quantization offers a solution, applying it naively to rotation-sensitive features destroys the SO(3)-equivariant structure, leading to significant errors and violations of conservation laws. To address this issue, in this work, we propose a Geometric-Aware Quantization (GAQ) framework that compresses and accelerates equivariant models while rigorously preserving continuous symmetry in discrete spaces. Our approach introduces three key contributions: (1) a Magnitude-Direction Decoupled Quantization (MDDQ) scheme that separates invariant lengths from equivariant orientations to maintain geometric fidelity; (2) a symmetry-aware training strategy that treats scalar and vector features with distinct quantization schedules; and (3) a robust attention normalization mechanism to stabilize gradients in low-bit regimes. Experiments on the rMD17 benchmark demonstrate that our W4A8 models match the accuracy of FP32 baselines (9.31 meV vs. 23.20 meV) while reducing Local Equivariance Error (LEE) by over 30x compared to naive quantization. On consumer hardware, GAQ achieves 2.39x inference speedup and 4x memory reduction, enabling stable, energy-conserving molecular dynamics simulations for nanosecond timescales.

NMRTrans: Structure Elucidation from Experimental NMR Spectra via Set Transformers

Nuclear Magnetic Resonance (NMR) spectroscopy is fundamental for molecular structure elucidation, yet interpreting spectra at scale remains time-consuming and highly expertise-dependent. While recent spectrum-as-language modeling and retrieval-based methods have shown promise, they rely heavily on large corpora of computed spectra and exhibit notable performance drops when applied to experimental measurements. To address these issues, we build NMRSpec, a large-scale corpus of experimental $^1$H and $^{13}$C spectra mined from chemical literature, and propose NMRTrans, which models spectra as unordered peak sets and aligns the model's inductive bias with the physical nature of NMR. To our best knowledge, NMRTrans is the first NMR Transformer trained solely on large-scale experimental spectra and achieves state-of-the-art performance on experimental benchmarks, improving Top-10 Accuracy over the strongest baseline by +17.82 points (61.15% vs. 43.33%), and underscoring the importance of experimental data and structure-aware architectures for reliable NMR structure elucidation.

EnzyPGM: Pocket-conditioned Generative Model for Substrate-specific Enzyme Design

Designing enzymes with substrate-binding pockets is a critical challenge in protein engineering, as catalytic activity depends on the precise interaction between pockets and substrates. Currently, generative models dominate functional protein design but cannot model pocket-substrate interactions, which limits the generation of enzymes with precise catalytic environments. To address this issue, we propose EnzyPGM, a unified framework that jointly generates enzymes and substrate-binding pockets conditioned on functional priors and substrates, with a particular focus on learning accurate pocket-substrate interactions. At its core, EnzyPGM includes two main modules: a Residue-atom Bi-scale Attention (RBA) that jointly models intra-residue dependencies and fine-grained interactions between pocket residues and substrate atoms, and a Residue Function Fusion (RFF) that incorporates enzyme function priors into residue representations. Also, we curate EnzyPock, an enzyme-pocket dataset comprising 83,062 enzyme-substrate pairs across 1,036 four-level enzyme families. Extensive experiments demonstrate that EnzyPGM achieves state-of-the-art performance on EnzyPock. Notably, EnzyPGM reduces the average binding energy of 0.47 kcal/mol over EnzyGen, showing its superior performance on substrate-specific enzyme design. The code and dataset will be released later.

Beyond Affinity: A Benchmark of 1D, 2D, and 3D Methods Reveals Critical Trade-offs in Structure-Based Drug Design

Currently, the field of structure-based drug design is dominated by three main types of algorithms: search-based algorithms, deep generative models, and reinforcement learning. While existing works have typically focused on comparing models within a single algorithmic category, cross-algorithm comparisons remain scarce. In this paper, to fill the gap, we establish a benchmark to evaluate the performance of fifteen models across these different algorithmic foundations by assessing the pharmaceutical properties of the generated molecules and their docking affinities and poses with specified target proteins. We highlight the unique advantages of each algorithmic approach and offer recommendations for the design of future SBDD models. We emphasize that 1D/2D ligand-centric drug design methods can be used in SBDD by treating the docking function as a black-box oracle, which is typically neglected. Our evaluation reveals distinct patterns across model categories. 3D structure-based models excel in binding affinities but show inconsistencies in chemical validity and pose quality. 1D models demonstrate reliable performance in standard molecular metrics but rarely achieve optimal binding affinities. 2D models offer balanced performance, maintaining high chemical validity while achieving moderate binding scores. Through detailed analysis across multiple protein targets, we identify key improvement areas for each model category, providing insights for researchers to combine strengths of different approaches while addressing their limitations. All the code that are used for benchmarking is available in https://github.com/zkysfls/2025-sbdd-benchmark

Quantized SO(3)-Equivariant Graph Neural Networks for Efficient Molecular Property Prediction

Deploying 3D graph neural networks (GNNs) that are equivariant to 3D rotations (the group SO(3)) on edge devices is challenging due to their high computational cost. This paper addresses the problem by compressing and accelerating an SO(3)-equivariant GNN using low-bit quantization techniques. Specifically, we introduce three innovations for quantized equivariant transformers: (1) a magnitude-direction decoupled quantization scheme that separately quantizes the norm and orientation of equivariant (vector) features, (2) a branch-separated quantization-aware training strategy that treats invariant and equivariant feature channels differently in an attention-based $SO(3)$-GNN, and (3) a robustness-enhancing attention normalization mechanism that stabilizes low-precision attention computations. Experiments on the QM9 and rMD17 molecular benchmarks demonstrate that our 8-bit models achieve accuracy on energy and force predictions comparable to full-precision baselines with markedly improved efficiency. We also conduct ablation studies to quantify the contribution of each component to maintain accuracy and equivariance under quantization, using the Local error of equivariance (LEE) metric. The proposed techniques enable the deployment of symmetry-aware GNNs in practical chemistry applications with 2.37--2.73x faster inference and 4x smaller model size, without sacrificing accuracy or physical symmetry.

ClinicalReTrial: A Self-Evolving AI Agent for Clinical Trial Protocol Optimization

Clinical trial failure remains a central bottleneck in drug development, where minor protocol design flaws can irreversibly compromise outcomes despite promising therapeutics. Although cutting-edge AI methods achieve strong performance in predicting trial success, they are inherently reactive for merely diagnosing risk without offering actionable remedies once failure is anticipated. To fill this gap, this paper proposes ClinicalReTrial, a self-evolving AI agent framework that addresses this gap by casting clinical trial reasoning as an iterative protocol redesign problem. Our method integrates failure diagnosis, safety-aware modification, and candidate evaluation in a closed-loop, reward-driven optimization framework. Serving the outcome prediction model as a simulation environment, ClinicalReTrial enables low-cost evaluation of protocol modifications and provides dense reward signals for continuous self-improvement. To support efficient exploration, the framework maintains hierarchical memory that captures iteration-level feedback within trials and distills transferable redesign patterns across trials. Empirically, ClinicalReTrial improves 83.3% of trial protocols with a mean success probability gain of 5.7%, and retrospective case studies demonstrate strong alignment between the discovered redesign strategies and real-world clinical trial modifications.

MolAct: An Agentic RL Framework for Molecular Editing and Property Optimization

Molecular editing and optimization are multi-step problems that require iteratively improving properties while keeping molecules chemically valid and structurally similar. We frame both tasks as sequential, tool-guided decisions and introduce MolAct, an agentic reinforcement learning framework that employs a two-stage training paradigm: first building editing capability, then optimizing properties while reusing the learned editing behaviors. To the best of our knowledge, this is the first work to formalize molecular design as an Agentic Reinforcement Learning problem, where an LLM agent learns to interleave reasoning, tool-use, and molecular optimization. The framework enables agents to interact in multiple turns, invoking chemical tools for validity checking, property assessment, and similarity control, and leverages their feedback to refine subsequent edits. We instantiate the MolAct framework to train two model families: MolEditAgent for molecular editing tasks and MolOptAgent for molecular optimization tasks. In molecular editing, MolEditAgent-7B delivers 100, 95, and 98 valid add, delete, and substitute edits, outperforming strong closed "thinking" baselines such as DeepSeek-R1; MolEditAgent-3B approaches the performance of much larger open "thinking" models like Qwen3-32B-think. In molecular optimization, MolOptAgent-7B (trained on MolEditAgent-7B) surpasses the best closed "thinking" baseline (e.g., Claude 3.7) on LogP and remains competitive on solubility, while maintaining balanced performance across other objectives. These results highlight that treating molecular design as a multi-step, tool-augmented process is key to reliable and interpretable improvements.