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01.
bioRxiv (Bioinfo) 2026-06-10

When batch correction corrupts gene expression: uncovering distortions in correlation structures

Batch correction is essential for integrating datasets and enabling population-level insights into health and disease. Embedding-based approaches are among the most widely used solutions, but here we highlight a critical, overlooked limitation: these methods can distort feature-to-feature (e.g., gene gene) relationships, potentially undermining downstream analyses. We investigate this issue and introduce a novel metric to quantify it.

02.
Nature (Science) 2026-06-10

A first-in-class pulsatile FXR agonist for bile-acid-related liver diseases

作者:

Nuclear receptors are central regulators of metabolism1, yet therapeutic strategies that enforce continuous receptor activation frequently lead to reduced efficacy and unacceptable toxicity. Here we report a first-principles drug design strategy that aligns pharmacokinetics with physiological signalling cycles. We developed linafexor, a potent non-bile-acid agonist of the farnesoid X receptor (FXR)2; it is engineered for rapid systemic clearance, which enables pulsatile receptor activation that mirrors endogenous bile acid dynamics3–5. Linafexor has robust efficacy across multiple preclinical models of metabolic dysfunction-associated steatohepatitis6, liver fibrosis7, primary biliary cholangitis and primary sclerosing cholangitis8,9. Transcriptomic analyses reveal that, unlike long-acting FXR agonists10,11, linafexor preserves cyclic FXR signalling, avoids receptor downregulation and prevents broad transcriptional dysregulation. Direct manipulation of delivery patterns demonstrates that sustained FXR activation—independent of compound identity—induces severe toxicity, establishing activation duration as a determinant of therapeutic index. In phase 1 clinical studies (ClinicalTrials.gov; NCT05082779), linafexor administered once daily produces transient FXR pathway engagement, marked by (1) induction of FGF1912–14, a key endocrine mediator of bile acid feedback regulation; and (2) suppression of C415, an intermediate reflecting hepatic bile acid synthesis, with no treatment-related adverse events. Together, these findings identify pulsatile FXR activation as a mechanistically grounded and clinically translatable strategy, and establish linafexor as a first-in-class therapeutic for bile acid–related liver diseases. Linafexor is a rapidly cleared FXR agonist designed to mimic natural bile acid signalling, achieving transient receptor activation with strong efficacy and reduced toxicity in preclinical and early clinical studies.

03.
arXiv (CS.CL) 2026-06-15

Reward-SQL: Boosting Text-to-SQL via Stepwise Execution-Aware Reasoning and Process-Supervised Rewards

Recent advances in large language models (LLMs) trained with reinforcement learning (RL) have improved Text-to-SQL performance. However, RL-based approaches still struggle with complex queries due to two key limitations: insufficient stepwise execution-aware reasoning grounded in database feedback, and the lack of process-level rewards for guiding reasoning optimization. To address these issues, we propose CoCTE, a divide-and-conquer and execution-aware reasoning framework that progressively composes SQL queries through intermediate view validation and structured Common Table Expressions (CTEs), improving both accuracy and interpretability. To realize a CoCTE reasoning process, we develop Reward-SQL, a unified approach with three stages: (1) model initialization, which equips LLMs with structured CoCTE reasoning capabilities; (2) process reward design, which delivers fine-grained, execution-aware supervision; and (3) process-supervised RL and inference, which integrates process rewards into training and guides the inference stage by process rewards. This paper addresses the core challenges in Reward-SQL and makes the following contributions. We introduce a process reward model (PRM) that combines execution-aware trajectory scoring with entropy-based step weighting, providing dense and interpretable supervision across reasoning steps. We integrate PRM into both RL training and inference stages, stabilizing optimization and improving trajectory exploration with process-level signals. Experiments show that Reward-SQL significantly outperforms baselines with comparable model sizes, and exhibits strong cross-domain generalization.

04.
arXiv (quant-ph) 2026-06-12

Candidate overtone shear horizontal SAW resonators in thin-film lithium niobate for intermodal acousto-optic modulation

arXiv:2606.12853v1 Announce Type: cross Abstract: The merits of thin-film surface acoustic wave (SAW) devices are pivotal to develop the high-performance intermodal acousto-optic modulators. In this work, we have proposed shear-horizontal (SH) SAW resonators for anticipated intermodal acousto-optic modulation on the thin-film lithium niobate platform. Through optimization of the cut angle of LN films, the SAW wavelength, and the thickness of interdigital transducer (IDT) electrodes, the calculated acousto-optic overlap factors utilizing SH0 modes are improved by more than an order of magnitude compared with those of Rayleigh modes. Furthermore, we have fabricated and characterized three kinds of proof-of-principle SH0 mode devices without/with grating reflectors. The electromechanical coupling coefficients (keff^2) and quality factors (Q) in the overtone resonators with grating reflectors are systematically evaluated, featuring the highest Q of 843 with the compromised keff^2 of 0.96%-4.72%. The results reveal that the temperature coefficients of frequency (TCF) of Rayleigh modes vary across various overtones, whereas the SH0 modes exhibit TCFs in the range of 32.3-68.9 ppm/C. Our fabricated SH0-mode overtone resonators demonstrate the capability of operating at power levels up to 29 dBm without electrode damage, offering a promising paradigm for robust and high-efficiency intermodal acousto-optic modulators with potential applications in integrated optical signal processing, microwave photonics,and quantum information technologies.

05.
arXiv (CS.CV) 2026-06-11

Weakly Supervised Segmentation as Semantic-Based Regularization

Weakly supervised semantic segmentation (WSSS) trains dense pixel-level segmentation models from partial or coarse annotations such as bounding boxes, scribbles, or image-level tags. While recent work leverages foundation models such as the Segment Anything Model (SAM) to generate pseudo-labels, these approaches typically depend on heuristic prompt choices and offer limited ways to incorporate prior knowledge or heterogeneous labels. We address this gap by taking a neurosymbolic perspective: integrating differentiable fuzzy logic with deep segmentation models. Weak annotations and domain-specific priors are unified as continuous logical constraints that fine-tune SAM under weak supervision. The refined foundation model then produces improved pseudo-labels, from which we train a second-stage prompt-free segmentation model. Experiments on Pascal VOC 2012 and the REFUGE2 optic disc/cup segmentation dataset show that our logic-guided fine-tuning yields higher-quality pseudo-labels, leading to state-of-the-art segmentation accuracy that often exceeds densely supervised baselines.

06.
arXiv (CS.CL) 2026-06-12

ArogyaSutra: A Multi-Agent Framework for Multimodal Medical Reasoning in Indic Languages

Multimodal Large Language Models (MLLMs) have shown promising reasoning capabilities in general domains, yet their performance remains limited in specialized settings such as healthcare, especially in multilingual and low-resource scenarios. This gap is critical in regions like rural India, where patients often express complex medical queries in native Indic languages and rely on multimodal inputs such as medical images. Existing English-centric MLLMs struggle to support such use cases, limiting equitable access to AI-driven healthcare assistance. To address this challenge, we introduce ArogyaBodha, a large-scale multilingual multimodal medical question-answer dataset constructed from eight heterogeneous sources, covering 31 body systems, six imaging modalities, and 21 clinical domains across English and seven major Indian languages. We further propose ArogyaSutra, an actor-critic-based multi-agent framework that integrates tool grounding with dual-memory mechanisms for step-wise, reasoning-aware decision making, and uses stored actor-critic simulation trajectories for distillation. Experiments show that our dataset and framework improve multilingual medical reasoning accuracy across all Indic languages, with ablations validating the contribution of each component. The source code and dataset are available at: https://iitp-cse.github.io/ ArogyaSutra/

07.
arXiv (CS.AI) 2026-06-17

ARVO: Atlas of Reproducible Vulnerabilities for Open-Source Software

arXiv:2606.17283v1 Announce Type: cross Abstract: Achieving reproducibility, quantity, and diversity in vulnerability datasets has long been viewed as an inherent three-way trade-off, where improving one dimension often comes at the cost of the others. In practice, reproducibility has been the dimension most often neglected. This has limited what can be automatically extracted from historical bug datasets, and has reduced their utility for downstream security research. In this work, we propose a method to produce a new security dataset which ensures reproducibility for diverse vulnerabilities at scale by identifying the key obstacles to large-scale bug reproduction and addressing them with general solutions. Using this method, we introduce full reproducibility to the largest open source software vulnerability dataset (OSS-Fuzz) and construct the ARVO dataset (an Atlas of Reproducible Vulnerabilities in Open-source software). ARVO is a large-scale dataset consisting of over 6,100 real-world vulnerabilities across 311 projects. Focusing on reproducibility, ARVO differs from existing datasets by providing each vulnerability in a form that can be consistently rebuilt, triggered, and analyzed across versions. Reproducibility also enables automatic identification of the corresponding patch for each vulnerability and supports direct interaction with vulnerabilities after code changes, capabilities that existing large-scale datasets do not provide. In our evaluation, ARVO successfully reproduces 81% of vulnerabilities and achieves 89.4% accuracy on the located patches. We also discuss ARVO's influence on both upstream practices and downstream security research.

08.
arXiv (CS.AI) 2026-06-16

Beyond Case Law: Evaluating Structure-Aware Retrieval and Safety in Statute-Centric Legal QA

arXiv:2604.06173v2 Announce Type: replace-cross Abstract: Legal QA benchmarks have predominantly focused on case law, overlooking the unique challenges of statute-centric regulatory reasoning. In statutory domains, relevant evidence is distributed across hierarchically linked documents, creating a statutory retrieval gap where conventional retrievers fail and models often hallucinate under incomplete context. We introduce SearchFireSafety, a structure- and safety-aware benchmark for statute-centric legal QA. Instantiated on fire-safety regulations as a representative case, the benchmark evaluates whether models can retrieve hierarchically fragmented evidence and safely abstain when statutory context is insufficient. SearchFireSafety adopts a dual-source evaluation framework combining real-world questions that require citation-aware retrieval and synthetic partial-context scenarios that stress-test hallucination and refusal behavior. Experiments across multiple large language models show that graph-guided retrieval substantially improves performance, but also reveal a critical safety trade-off: domain-adapted models are more likely to hallucinate when key statutory evidence is missing. Our findings highlight the need for benchmarks that jointly evaluate hierarchical retrieval and model safety in statute-centric regulatory settings.

09.
arXiv (quant-ph) 2026-06-12

A ribbon ZX calculus for gauge theory

arXiv:2606.13551v1 Announce Type: cross Abstract: ZX calculus provides a graphical formalism for reasoning about quantum processes, built from two interacting Frobenius algebras associated with the Z and X bases of a qubit. While it has found widespread application in quantum information and computing, its relationship to quantum field theory has only recently begun to be explored. In this work, we further develop this connection by providing a generalization of ZX calculus to two-dimensional Yang Mills theory with a compact gauge group. The key observation is that both frameworks can be organized around the Hopf Frobenius algebraic structure associated with a group algebra, which can in turn be described by the diagrammatics of two dimensional topological quantum field theory. Given the well known relationship between gauge theory and gravity in two and three dimensions, our work paves the way for applications of ZX to low dimensional gravity.

10.
arXiv (CS.CV) 2026-06-11

CellNet – Localizing Cells using Sparse and Noisy Point Annotations

Counting living cells is an important step in many biological research workflows. Our collaborators at the Wellcome Sanger Institute study vital genes in humans via large scale saturation genome editing screening, which requires repeatedly counting cells a great number of times. Computer Vision based automation is crucial for high throughput and resource efficiency. In this work, we develop a regression-based deep learning computer vision algorithm to detect and count cells in phase-contrast microscopy images. To reduce annotation effort, which in practice often becomes a bottleneck, we focus on counting cells only using sparse point annotations, which are fast and easy to acquire. By comparison to state-of-the-art 0-shot methods, we show that regression-based counting is a promising alternative in low data regimes. Through developing methods to automatically count living cells in microscopy images, we contribute to valuable research on the human genome. The code is available at https://github.com/beijn/cellnet.

11.
arXiv (CS.CL) 2026-06-19

Beyond Global Replanning: Hierarchical Recovery for Cross-Device Agent Systems

Real-world computer-use tasks often span multiple applications and devices, requiring agents to coordinate heterogeneous environments under dynamic runtime failures. Existing multi-device agent systems support task decomposition and cross-device assignment, but recovery remains largely coarse-grained: when execution fails, they typically retry the same strategy, reassign the subtask, or revise the global plan, without systematically modeling the device-local strategy space. This limits their ability to distinguish failures that can be repaired within the current device from those that require cross-device replanning. We propose H-RePlan, a hierarchical replanning framework for multi-device agents with unified API–CLI–GUI execution. H-RePlan equips each device with interchangeable execution strategies and separates device-local strategy recovery from orchestrator-level global replanning through a compact cross-layer failure abstraction. To evaluate this capability, we introduce HeraBench, a fault-injected benchmark that constructs cross-device workflows over Linux and Android devices and injects strategy- and device-level failures. Experiments show that H-RePlan substantially outperforms single-strategy and coarse-grained multi-device baselines, achieving higher completion, instruction adherence, and perfect-pass rates while reducing the token cost required for reliable end-to-end success. These results demonstrate that scope-aware hierarchical recovery is essential for robust multi-device agent execution.

12.
arXiv (CS.AI) 2026-06-18

A Taxonomy of Mental Health and Technology Needs for Alzheimer's and Dementia Caregivers

arXiv:2606.19247v1 Announce Type: cross Abstract: Family members caring for individuals with Alzheimer's disease and related dementias (AD/ADRD) provide the foundation of long-term care worldwide. In 2023, more than 11 million U.S. family and friends contributed 18 billion hours of unpaid care, often at the cost of their own physical and mental health. These informal caregivers – also referred as the "invisible second patients" – experience elevated rates of mental health problems. Yet research commonly reduces their complex psychosocial experiences to a single construct of caregiver burden, obscuring which specific needs are unmet or effectively supported. At the same time, digital and AI-enabled technologies are rapidly expanding, from smartphone apps and videoconferencing to sensor platforms and AI chatbots. However, the absence of shared frameworks across medicine, psychology, and technology research limits cumulative progress. This study introduces a Caregiver Mental Health and Technology Taxonomy that systematically links AD/ADRD caregiver needs with corresponding classes of technology-based interventions. Drawing from an interdisciplinary literature review and two qualitative studies with caregivers, the taxonomy identifies mismatches between caregiver priorities and existing technological support, highlights under-served domains such as relational strain and compassion fatigue, and proposes design directions for adaptive, responsive systems. The framework offers a shared vocabulary to guide clinicians, researchers, and technology designers in developing more person-centered and clinically grounded innovation in dementia care.

13.
arXiv (CS.CV) 2026-06-18

OneCanvas: 3D Scene Understanding via Panoramic Reprojection

Existing approaches to 3D scene understanding in Vision-Language Models (VLMs) either rely on complex, model-specific geometry encoders or large training budgets in pursuit of spatial reasoning. Instead, OneCanvas aggregates patch features from all views onto a single equirectangular panoramic canvas. Namely, each patch is unprojected to a 3D world coordinate using its depth and camera pose, then placed on the canvas at the continuous longitude and latitude of that point as seen from the canvas origin, with no rasterization or aggregation across overlapping views. A 3D position embedding of the patch's metric coordinates is added to its feature, restoring the depth lost when collapsing the world position to an angular canvas coordinate. Patches from all frames thus share one spatial coordinate system with no fusion or major architectural modifications of the backbone. The pretrained VLM consumes this representation as if it were an ordinary image. Because the canvas can be centered on any pose of interest, the same representation directly supports situated reasoning from a specific viewpoint, a common requirement in robotics and embodied AI. Thanks to this representation, we can also introduce a spatial pretraining curriculum: by procedurally placing patch features of objects, drawn from real images, at chosen 3D world positions on an otherwise empty canvas, we generate on-the-fly supervision spanning a broad range of spatial reasoning tasks, with answer distributions controlled to reduce spatial reasoning shortcuts. OneCanvas achieves state-of-the-art accuracy on SQA3D and VSI-Bench, and generalizes to out-of-distribution data on SPBench, using an order of magnitude less training compute than the strongest competing methods.

14.
arXiv (CS.CL) 2026-06-18

PreUnlearn: Auditing Collateral Knowledge Damage Before Large Language Model Unlearning

Machine unlearning for large language models (LLMs) aims to remove specified knowledge while preserving the rest of the model's capabilities. However, the boundary between knowledge to forget and knowledge to retain is often unclear, since related and even distant information may be entangled in the model. In this paper, we study LLM unlearning from a data-centric perspective and measure how unlearning effects propagate from the forget set to same-domain and distant-domain knowledge. We find a consistent decay pattern: collateral damage is strongest near the forget set, weakens with semantic distance, but does not disappear at domain boundaries. We further ask whether such damage can be audited before unlearning is executed. We formulate forget-set auditing as a pre-unlearning prediction task and analyze which data features are most predictive of downstream damage. Our results show that interaction features between the forget set and evaluation set provide the strongest signals, suggesting that collateral damage is partly reflected in data geometry before model updates occur. These findings position forget-set auditing as an early warning tool for identifying risky unlearning runs and designing more reliable unlearning procedures.

15.
arXiv (CS.LG) 2026-06-11

Renewable Lasso without Batch-Number Constraints: A Gradient-Enhanced Approach

arXiv:2606.11738v1 Announce Type: cross Abstract: We study online estimation for high-dimensional generalized linear models with streaming data. First, for the non-distributed setting, we propose a gradient-enhanced surrogate loss that approximates the cumulative loss using only historical summaries, which modifies and improves upon the existing renewable estimation approach for the same model in the high-dimensional setting, and removes the batch-number constraint in previous studies. We then extend the method to distributed streaming data under the master-client architecture, where batches are partitioned across sites and only summaries (gradient vectors) are exchanged. Instead of directing applying the popular method of Jordan et al. (2019) to the surrogate quadratic loss, our adjusted approach does not require the clients to compute the full surrogate loss. We derive non-asymptotic error bounds under the high-dimensional scaling, without the stringent constraint on the number of batches in the previous studies. Simulation results under linear and logistic models, together with a real-data application, show improved accuracy over existing renewable estimators.

16.
PLOS Computational Biology 2026-06-09

Evolution of phenocopying in a dynamical model of developmental trajectories

by Yuuki Matsushita, Archishman Raju Developmental trajectories are known to be canalized, or robust to both environmental and genetic perturbations. However, even when these trajectories are decanalized by an environmental perturbation outside the range of conditions to which they are robust, they often produce phenotypes similar to known mutants, called phenocopies. This correspondence between the effects of environmental and genetic perturbations has received little theoretical attention. Here, we study an abstract regulatory model that is evolved to follow a specific trajectory. We then study the effects of small and large perturbations to the trajectory, both by changing parameters and by perturbing the state at specific times. We find that the phenomenon of phenocopying emerges in evolved trajectories and is not present in a null model of randomly sampled trajectories. Our results suggest that, in this class of dynamic models, evolution can allow high-dimensional phenotypic landscapes to simultaneously exhibit robustness and phenocopying.

17.
arXiv (CS.LG) 2026-06-12

Contrastive Geometric Learning Unlocks Unified Structure- and Ligand-Based Drug Design

arXiv:2601.09693v3 Announce Type: replace Abstract: Structure-based and ligand-based computational drug design have traditionally relied on disjoint data sources and modeling assumptions, limiting their joint use at scale. In this work, we introduce Contrastive Geometric Learning for Unified Computational Drug Design (ConGLUDe), a single contrastive geometric model that unifies structure- and ligand-based training. ConGLUDe couples a geometric protein encoder that produces whole-protein representations and implicit embeddings of predicted binding sites with a fast ligand encoder, removing the need for predefined pockets. By aligning ligands with both global protein representations and multiple candidate binding sites through contrastive learning, ConGLUDe supports ligand-conditioned pocket prediction in addition to virtual screening and target fishing, while being trained jointly on protein-ligand complexes and large-scale bioactivity data. Across diverse benchmarks, ConGLUDe achieves competitive zero-shot virtual screening performance, substantially outperforms existing methods on a challenging target fishing task, and demonstrates state-of-the-art ligand-conditioned pocket selection. These results highlight the advantages of unified structure-ligand training and position ConGLUDe as a step toward general-purpose foundation models for drug discovery.

18.
arXiv (CS.AI) 2026-06-16

SorryDB: Can AI Provers Complete Real-World Lean Theorems?

arXiv:2603.02668v2 Announce Type: replace Abstract: We present SorryDB, a dynamically-updating benchmark of open Lean tasks drawn from 78 real world formalization projects on GitHub. Unlike existing static benchmarks, often composed of competition problems, hillclimbing the SorryDB benchmark will yield tools that are aligned to the community needs, more usable by mathematicians, and more capable of understanding complex dependencies. Moreover, by providing a continuously updated stream of tasks, SorryDB mitigates test-set contamination and offers a robust metric for an agent's ability to contribute to novel formal mathematics projects. We evaluate a collection of approaches, including generalist large language models, agentic approaches, and specialized symbolic provers, over a selected snapshot of 1000 tasks from SorryDB. We show that current approaches are complementary: even though an agentic approach based on Gemini Flash is the most performant, it is not strictly better than other off-the-shelf large-language models, specialized provers, or even a curated list of Lean tactics.

19.
arXiv (CS.CV) 2026-06-11

EvoLMM: Self-Evolving Large Multimodal Models with Continuous Rewards

Recent advances in large multimodal models (LMMs) have enabled impressive reasoning and perception abilities, yet most existing training pipelines still depend on human-curated data or externally verified reward models, limiting their autonomy and scalability. In this work, we strive to improve LMM reasoning capabilities in a purely unsupervised fashion (without any annotated data or reward distillation). To this end, we propose a self-evolving framework, named EvoLMM, that instantiates two cooperative agents from a single backbone model: a Proposer, which generates diverse, image-grounded questions, and a Solver, which solves them through internal consistency, where learning proceeds through a continuous self-rewarding process. This dynamic feedback encourages both the generation of informative queries and the refinement of structured reasoning without relying on ground-truth or human judgments. When using the popular Qwen2.5-VL as the base model, our EvoLMM yields consistent gains upto $\sim$3\% on multimodal math-reasoning benchmarks, including ChartQA, MathVista, and MathVision, using only raw training images. We hope our simple yet effective approach will serve as a solid baseline easing future research in self-improving LMMs in a fully-unsupervised fashion. Our code and models are available at https://github.com/mbzuai-oryx/EvoLMM.

20.
arXiv (CS.CV) 2026-06-15

Stream3D: Sequential Multi-View 3D Generation via Evidential Memory

View-conditioned 3D generators such as SAM 3D, TRELLIS, and Hunyuan3D produce high-quality object reconstructions from a single view, but real-world visual observation often arrives as long monocular streams. Naively applying these generators to each streaming frame independently leads to severe temporal inconsistency in the generated results. To address this problem, we propose Stream3D, the first training-free streaming mechanism that turns a frozen view-conditioned 3D generator into a streaming generator with constant cross-chunk memory. Stream3D achieves this by maintaining a compact evidential memory, which selectively caches the most informative historical frames based on a proposed evidence score mechanism. As the stream progresses, the memory dynamically updates to retain a fixed number of informative frames, preventing the memory footprint from growing linearly with sequence length. This also prevents degradation over long sequences and keeps the underlying generator completely unchanged without retraining, architectural modifications, or auxiliary losses. Evaluated on both realistic and synthetic streaming benchmarks, Stream3D outperforms latent-transport baselines, including KV-cache reuse and flow-based feature editing, across both photometric and geometric metrics. More details can be found at: https://stream-3d.github.io/stream3d.github.io/.

21.
arXiv (CS.LG) 2026-06-19

Towards Modality-imbalanced Federated Graph Learning: A Data Synthesis-based Approach

arXiv:2606.20382v1 Announce Type: new Abstract: MultiModal Federated Graph Learning (MM-FGL) offers a natural collaborative training paradigm, but its practical deployment is challenged by two granularities of modality imbalance. Client-level imbalance occurs when certain clients lack entire modalities, while node-level imbalance occurs when individual nodes exhibit missing visual or textual attributes. While several relevant studies exist, our investigation reveals that they predominantly target graph-agnostic or centralized scenarios, rendering them difficult to adapt directly. To address these challenges, we formalize modality-imbalanced MM-FGL as an implicit graph-aware latent semantic representation synthesis problem. This paradigm recovers missing modal semantics directly within the representation space, thereby maximizing alignment with the original data's semantic distribution and mitigating the high variance induced by missing modalities. To this end, we propose FedMGS (Federated Modality-aware Graph Synthesis), which integrates three core components. The availability-aware graph encoder prevents missing modalities from contaminating local structural propagation. The prototype-guided latent semantic synthesizer establishes cross-client semantic anchors for unavailable modalities. The reliability-calibrated semantic fusion mechanism regulates the impact of recovered latent representations prior to predictive readout. Extensive experiments on four tasks show that FedMGS consistently outperforms competitive baselines with gains up to 17.41% with best efficiency-performance tradeoff.

22.
bioRxiv (Bioinfo) 2026-06-13

ProtAff: Protein Binding Affinity Prediction via LoRA-Finetuned ESM-2

Predicting the binding affinity of protein–protein interactions remains a central challenge in computational biology. Structure prediction models such as AlphaFold3 (AF3) and Boltz-2 can produce high-quality docking poses, and their confidence scores indicate structure quality, but these same scores fail to rank binding affinity among confirmed binders. Here we present ProtAff, a sequence-only affinity prediction model built on ESM-2 (650M parameters) with low-rank adaptation (LoRA) fine-tuning and a cross-attention module. ProtAff is trained using a margin ranking loss on 362,567 affinity measurements spanning 20 heterogeneous data sources, and we removed all training samples whose target sequence exceeds 50% similarity to the test target EGFR. On the AdaptyvBio EGFR benchmark (N = 55), ProtAff achieves a Spearman correlation coefficient {rho} = 0.413, outperforming the best AF3 metric ({rho} = 0.054), the best Boltz-2 metric ({rho} = -0.046), and ML-based predictors MINT ({rho} = 0.242) and CrossAffinity ({rho} = 0.216). Applied to the AdaptyvBio Nipah virus binder design competition, a pipeline incorporating ProtAff for affinity ranking produced a design with KD = 0.132 nM (2 of 5 designs confirmed binding), a 2.8-fold improvement over the competition winner. On a cross-target discrimination benchmark of 91 VHH-antigen crystal structures, ProtAff underperforms structural methods for distinguishing cognate from non-cognate pairings, indicating that sequence-based affinity models are effective for within-target ranking but not for cross-target specificity.

23.
arXiv (CS.CL) 2026-06-12

Marginal Alignment Does Not Guarantee Joint-Distribution Fidelity: An Official-Reference Audit of Nemotron-Personas-Korea with Cross-Locale Replication

Synthetic persona datasets cite alignment with official demographics as a basis for trust, yet downstream users consume them as joint structures across age, sex, region, occupation, education, name, and institutional status. Marginal alignment does not imply that these joints are preserved. We propose the Independence-Assumption Footprint (IAF), an audit primitive that operates on the attribute combinations a dataset card itself documents as treated independently. For each such combination, IAF compares the synthetic joint against an external official or institutional reference, using direct joint tables where available and rule-implied checks otherwise. Applied to NVIDIA Nemotron-Personas-Korea (one million Korean synthetic personas), IAF finds that NPK aligns with KOSIS marginals while three joints fail. The major-by-occupation distribution against the KEIS graduate universe carries a large conditional mismatch. The age profile of military service is institutionally inconsistent. Female representation in male-dominated occupations is substantially over-flattened toward parity, with the strict screening verdict mapping-dependent and age-robust under direct standardisation. A transferability demonstration across six further NPK locales finds locale-dependent rather than universal diagnostics, with reference-taxonomy cardinality confounding cross-locale flag counts. For synthetic personas used as silicon samples, marginal claims must therefore be paired with disclosure-anchored joint audits before reuse. The released audit artefacts (reference manifests, occupational crosswalks, derived metrics, reproducibility scripts) instantiate this protocol on the NPK family and are released for retargeting at other synthetic persona resources.

24.
arXiv (CS.CL) 2026-06-12

MARD: Mirror-Augmented Reasoning Distillation for Mechanism-Level Drug-Drug Interaction Prediction

Mechanism-level drug-drug interaction (DDI) prediction requires identifying which enzyme or pharmacodynamic axis is implicated, in which direction, and with which evidence – not merely whether two drugs interact. We introduce a reproducible mechanism-level DDI labelling and evaluation protocol with a structured 7-family/147-subtype taxonomy, leakage-safe cold-split protocols, and auditable reasoning metrics for evaluating pharmacological prediction beyond flat interaction classification. We propose a pipeline that produces a 7B reasoning MARD (Mirror-Augmented Reasoning Distillation), combining three training innovations: a single-token KL divergence on direction tag that ties the model's prediction, per-loss PRM-weighted DPO with programmatic hard negatives, and a leakage-safe mechanism-aware retrieval channel. Process-reward step labels are automatically verifiable against DrugBank-structured fields, requiring no human or LLM judges. On the April-2026 DrugBank release, our MARD-7B is the only system in a 32-system comparison whose accuracy survives drug-pair novelty, beating the best baseline by +13.9 pp and GPT-4o by +6.7 pp at ~1% of frontier API cost. Further analysis reveals an anti-memorisation signature where accuracy improves on rarely seen drugs, suggesting that gain comes from structured pharmacological reasoning rather than drug-frequency memorisation. We release corpus, DDI-PRM, retrieval index, and training code.

25.
arXiv (quant-ph) 2026-06-15

Certifying Macroscopic Quantum Mechanics via Hypothesis Testing with Finite Data

arXiv:2506.22092v2 Announce Type: replace Abstract: We address the challenge of certifying quantum behavior with single macroscopic massive particles, subject to decoherence and finite data. We propose a hypothesis testing framework that distinguishes between classical and quantum mechanics based on position measurements. While interference pattern visibility in single-particle quantum superposition experiments has been commonly used as a sufficient criterion to falsify classical mechanics, we show that, from a hypothesis testing perspective, it is neither necessary nor efficient. Focusing on recent proposals to prepare macroscopic superposition states of levitated nanoparticles, we show that the likelihood ratio test – which leverages differences across the entire probability distribution – provides an exponential reduction in measurements needed to reach a given confidence level. These results generalize to a broad class of quantum states, and offer a principled, efficient method to falsify classical mechanics in interference experiments, relaxing the experimental constraints faced by current efforts to test quantum mechanics at the macroscopic scale.