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01.
medRxiv (Medicine) 2026-06-18

Guiding the development of climate counterfactuals for health impact attribution studies

Climate change detection and attribution (D&A) methods have become vital for quantifying the influence of anthropogenic forcing on the Earth's systems, including human health. Health impact attribution (HIA) studies seek to disentangle climate-driven health effects from natural variability yet are often constrained by the availability of accessible counterfactual climate scenarios. This tutorial paper presents a flexible, reproducible framework for developing counterfactual climates without reliance on computationally intensive global circulation models. We provide practical, R-based methodologies for constructing both trend-based (temperature and non-temperature) and event-based counterfactual, using a variety of techniques including model residual detrending, data-driven decomposition (e.g., Singular Spectrum Analysis and Empirical Mode Decomposition) and stochastic weather generators. The tutorial also explores the incorporation of greenhouse gas concentrations as forcing variables, rather than global mean temperature anomalies. By operationalising these methods through worked examples and an open code repository, this paper aims to build capacity within the HIA community, enhance methodological transparency, and foster interdisciplinary collaboration between climate and health researchers.

02.
arXiv (CS.AI) 2026-06-15

Hy-Embodied-0.5-VLA: From Vision-Language-Action Models to a Real-World Robot Learning Stack

arXiv:2606.14409v1 Announce Type: cross Abstract: In this report, we present Hy-Embodied-0.5-VLA, abbreviated as HyVLA-0.5, an end-to-end system that spans the full robot learning stack: data collection, model design, continued pre-training and supervised fine-tuning, RL post-training, and real-world deployment. Each component serves a distinct role in this stack.

03.
Nature (Science) 2026-06-10

‘Hidden hero’ peptides guard crops against sudden cold

作者: 未知作者

A protein signal remains silent under normal conditions but is activated under cold stress to protect developing pollen. This ‘on-demand’ resilience mechanism could enable the development of ‘climate smart’ crops that maintain high yields in good years and food security under climate stress. A peptide signal ensures that, in cold conditions, developing pollen receives nutrients at the right time.

04.
arXiv (CS.LG) 2026-06-16

Learning the Geometry of Data: A Mathematical Review of Shape Space Analysis

arXiv:2606.17022v1 Announce Type: cross Abstract: A central objective of machine learning is to identify structure and patterns in data. Advances in data acquisition have increasingly produced datasets whose observations possess rich geometric form, giving rise to shape spaces that encode variability in object geometry. Such datasets arise across a wide range of disciplines, including biology, medicine, anthropology, and computer vision, where subtle geometric differences often carry important scientific information. Traditional machine learning methods, however, are frequently ill-equipped to account for the nonlinear geometric structure underlying these data. This survey synthesizes a rapidly growing body of work on shape space analysis, which provides a mathematical and computational framework for the study of geometric data. Drawing on ideas from differential geometry, statistics, and machine learning, we organize the literature around a common analytical pipeline: shape representation and parameterization, the rigorous construction of robust geodesic metrics, statistical analysis on shape spaces, and geometry-aware learning methods. We discuss how these tools enable the characterization of shape variability, the comparison of geometric objects, and the analysis of structural trajectories across populations and time. To illustrate the breadth of the field, we highlight applications spanning multiple scales of biological organization, including studies of subcellular morphology and primate tooth evolution. Across these and many other domains, researchers face common challenges arising from complex, nonlinear, and often unaligned geometric variation. The review concludes by identifying key theoretical and computational challenges, as well as emerging opportunities driven by increasingly large and diverse geometric datasets.

05.
arXiv (quant-ph) 2026-06-16

Long-range nonstabilizerness of topologically encoded states from mutual information

arXiv:2605.22424v2 Announce Type: replace Abstract: We study long-range nonstabilizerness (LRN), namely the obstruction to remove nonstabilizerness with shallow-depth local quantum circuits. In one-dimensional settings, the mutual information between disconnected spatial regions has proven to be a powerful tool to diagnose LRN. In this work, we focus on encoded states of two-dimensional topologically-ordered systems, and explore the ability of the mutual information to serve as a diagnostic of LRN. Focusing on the concrete setting of lattice models defined on a torus, we show that information about LRN can be gained from the analysis of the mutual information between non-overlapping regions containing non-contractible loops, and of the change of such mutual information under modular real-space transformations. We exemplify this idea in the toric code and the non-abelian string-net model with doubled Fibonacci topological order. In the former case, we show that the mutual information provides a full classification, certifying LRN for all encoded non-stabilizer states. In the latter case, instead, our approach does not lead to a full classification, as it detects LRN for all states except from a finite subset with special transformation properties under the modular group. Finally, we discuss how our results on LRN constrain the logical gates that can be implemented fault-tolerantly on the torus.

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

3D Scene Graphs: Open Challenges and Future Directions

3D Scene Graphs (3DSGs) have emerged as a powerful representation for spatial AI by combining geometric grounding with semantic and relational abstractions of the environment. Their expressiveness has made them relevant to a broad range of problems in robotics and computer vision, including manipulation, navigation, task planning, scene understanding, and many others. However, the field remains fragmented: different communities adopt distinct formulations, construction pipelines, and evaluation protocols, making it difficult to compare methods, identify common assumptions, and assess remaining challenges for robust real-world deployment. This survey provides a unified and critical review of 3DSGs, with particular emphasis on open challenges and future directions. We first formalize 3DSGs under a common definition and analyze the principal modeling choices that characterize existing formulations, including node and edge attributes, hierarchical structure, dynamic scene representations, and affordance-aware extensions. We then review how 3DSGs are built from raw sensory observations, discussing the most common terminologies, conventions, and techniques. Finally, we examine downstream applications and evaluation strategies, from intrinsic graph quality to task-level performance. To support the community, we also provide a dedicated website that organizes and extends the surveyed content, accessible at https://3dscenegraphs.com/.

07.
arXiv (CS.AI) 2026-06-11

OmniBioTwin: A System-of-Twinned-Systems Framework for Health Digital Twins

arXiv:2606.11264v1 Announce Type: cross Abstract: Health digital twins (HDTs) promise patient-specific modeling and decision support but current approaches remain structurally fragmented: monolithic models that address a single organ or task lack cross-scale fidelity, while system-level twins lack generalizable architectural frameworks. We propose OmniBioTwin, a System-of-Twinned-Systems (SoTS) framework that organizes HDTs as modular computational entities coupled through explicit interaction operators within a multi-layer network architecture. The framework comprises seven coordinated layers - spanning data integration, autonomous twin modeling, cross-scale coupling, temporal synchronization, and human-in-the-loop decision support. We demonstrate OmniBioTwin by instantiating a multiscale twin for glucagon-like peptide-1 (GLP-1) signaling pathways in Alzheimer's disease, illustrating how molecular, cellular, and organ-level twins can be composed and coupled within a unified system.

08.
arXiv (CS.CV) 2026-06-15

Diffusion-Refined Segmentation and Vision-Language Interpretation for Pediatric Brain Tumor MRI

Accurate pediatric brain tumor segmentation remains challenging due to limited annotated data, heterogeneous imaging phenotypes, diffuse tumor boundaries, and class imbalance across tumor subregions. Here, we present a two-stage deep learning framework for improving multi-modal pediatric brain MRI segmentation and clinical interpretation. First, we evaluate 3D Res U-Net and Swin-UNETR baselines on BraTS-PEDs MRI scans, using four co-registered modalities to predict tumor core, whole tumor, and enhancing tumor regions. Second, we introduce diffusion-based refinement models conditioned on coarse Swin-UNETR predictions, including a 3D DDPM refiner and MedSegDiff. Conditioning substantially improves diffusion stability and performance, particularly for enhancing tumor boundary segmentation. Conditioned MedSegDiff achieves the strongest boundary agreement with the lowest HD95. Finally, predicted tumor volumes and representative segmentation overlays are integrated with a multimodal language model to generate structured radiology-style reports. Together, our results suggest that coarse-to-refined diffusion segmentation can improve pediatric tumor boundary delineation and support end-to-end interpretable AI-assisted neuro-oncology workflows.

09.
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.

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

Organize then Retrieve: Hierarchical Memory Navigation for Efficient Agents

Large language model (LLM) agents struggle with long-horizon tasks due to their inherent statelessness, requiring all task-relevant information to be encoded in growing input contexts. The resulting degraded reasoning quality, increased inference cost, and higher latency necessitate efficient working memory mechanisms. However, existing approaches either rely on lossy compression or similarity-based retrieval, which often fail to capture temporal structure and causal dependencies required for multi-step agentic tasks. In this work, we present HORMA, a Hierarchical Organize-and-Retrieve Memory Agent that organizes experience into a file-system-like hierarchical structure, where summarized entities are linked to the corresponding raw trajectories, enabling efficient access without losing detailed information. HORMA decomposes working memory into two stages: structured memory construction and navigation-based retrieval. The construction module iteratively refines how experiences are structured by distinguishing between failures caused by missing information and those caused by misleading or overloaded context. The navigation module retrieves task-relevant context by traversing the hierarchy using a lightweight agent trained with reinforcement learning to select minimal yet sufficient context, thereby reducing latency along the critical execution path. Across ALFWorld, LoCoMo, and LongMemEval, HORMA improves task performance under constrained context budgets while requiring at most 22.17% of the baseline token usage in long conversation tasks. Compared to existing methods, it consistently achieves better efficiency-performance trade-offs and generalizes effectively to unseen tasks.

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

Silent Failures in Federated Personalization of Foundation Models

arXiv:2606.00947v2 Announce Type: replace-cross Abstract: Foundation models are increasingly personalized on decentralized private data through federated learning and are now deployed at scale under growing regulatory requirements for post-market monitoring. We argue that this convergence creates a distinct and under-recognized class of trustworthiness failures, which we term "Silent Failures." These include amplified bias, fairness collapse, and alignment erosion that may remain difficult to detect because federated learning's privacy constraints limit visibility into model behavior. A landscape analysis of existing benchmarks reveals a structural divide. Federated benchmarks evaluate system performance but provide limited insight into model behavior, whereas centralized trustworthiness benchmarks assess behavior but require model access incompatible with federated privacy. We introduce a taxonomy of six silent failure modes arising from the interaction of foundation model personalization, dataset shift, and core federated constraints. Our analysis shows that privacy-preserving training alone is insufficient for trustworthy deployment. We conclude with a research agenda for privacy-preserving behavioral evaluation and propose that silent failures become a standard diagnostic category for trustworthy federated artificial intelligence.

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

Generating Natural and Expressive Robot Gestures through Iterative Reinforcement Learning with Human Feedback using LLMs

arXiv:2606.18747v1 Announce Type: cross Abstract: Expressive gestures are essential for natural and effective communication, complementing speech when verbal cues alone are insufficient (e.g., pointing). For social robots such as the humanoid Pepper, producing natural and expressive movements is critical for improving human-robot interaction (HRI) and long-term acceptance. However, generating gestures remains challenging due to reliance on expert-authored animations, resulting in rigid behaviors that are impractical for dynamic and diverse environments. Alternatively, machine learning approaches often struggle to capture perceived naturalness, becoming increasingly challenging with more degrees of freedom. Consequently, producing expressive robot gestures requires a system that can adapt to the environment while adhering to social norms and physical constraints. Recent advances in large language models (LLMs) enable dynamic code generation, offering new opportunities for runtime gesture synthesis from natural language. In this paper, we integrate ChatGPT into the humanoid robot Pepper to generate co-speech gestures aligned with conversational output. While this baseline enables flexible gesture generation, the resulting motions are often perceived as stiff and unnatural. To address this limitation, we introduce an iterative reinforcement learning with human feedback (RLHF) system that finetunes gesture generation based on user evaluations, leveraging an iterative user study to compare Pepper's generated gestures. Our results show that RLHF improved the LLM's co-speech generative capabilities, producing more expressive, relevant and fluid movements.

13.
Nature (Science) 2026-06-10

Diverse binding poses of agonistic neurotoxins on human Na<sub>v</sub>1.6

作者:

Voltage-gated sodium (Nav) channels are key targets of various venomous toxins. Deciphering the binding poses and mechanisms of action of representative toxins will help to dissect the functional mechanism of the channels and facilitate therapeutic development targeting Nav channels1,2. Here we present cryo-electron microscopy&nbsp;(cryo-EM) structures of distinct binding poses of three agonistic peptide toxins on the human Nav1.6–β1 channel complex. The globular β-scorpion toxin Cn2 nestles between the extracellular segment of voltage-sensing domain (VSD)&nbsp;in the second repeat of the Nav1.6 core α-unit (VSDII) and the pore extracellular loops in the third repeat of the Nav1.6 core α-unit (ECLIII), where it is stabilized by interactions with both protein regions and the branched N1372-glycan. Cone&nbsp;snail ι-conotoxin RXIA adopts an elongated conformation, spanning VSDI and VSDIV to wrap around the shoulder of the pore domain (PD). The bullet&nbsp;ant-derived toxin δ-paraponeritoxin-Pc1a exists as a transmembrane helix that stands between VSDII and PDIII. Our findings, corroborated by functional characterizations, illustrate the diversity in peptide toxin binding poses and mechanisms of action, link stabilization of the up state of VSDI or VSDII to channel activation, and provide clues to the rational design of selective Nav channel modulators. Structures of the distinct binding poses of three agonistic peptide toxins—bullet-ant-derived toxin δ-paraponeritoxin-Pc1a, cone&nbsp;snail ι-conotoxin RXIA and the globular β-scorpion toxin Cn2—on the human Nav1.6–β1 channel complex illustrate a diversity in binding poses and mechanisms of action.

14.
arXiv (CS.AI) 2026-06-12

Cluster Aggregated GAN (CAG): A Cluster-Based Hybrid Model for Appliance Pattern Generation

arXiv:2512.22287v3 Announce Type: replace-cross Abstract: Synthetic appliance data are essential for developing non-intrusive load monitoring algorithms and enabling privacy preserving energy research, yet the scarcity of labeled datasets remains a significant barrier. Recent GAN-based methods have demonstrated the feasibility of synthesizing load patterns, but most existing approaches treat all devices uniformly within a single model, neglecting the behavioral differences between intermittent and continuous appliances and resulting in unstable training and limited output fidelity. To address these limitations, we propose the Cluster Aggregated GAN framework, a hybrid generative approach that routes each appliance to a specialized branch based on its behavioral characteristics. For intermittent appliances, a clustering module groups similar activation patterns and allocates dedicated generators for each cluster, ensuring that both common and rare operational modes receive adequate modeling capacity. Continuous appliances follow a separate branch that employs an LSTM-based generator to capture gradual temporal evolution while maintaining training stability through sequence compression. Extensive experiments on the UVIC smart plug dataset demonstrate that the proposed framework consistently outperforms baseline methods across metrics measuring realism, diversity, and training stability, and that integrating clustering as an active generative component substantially improves both interpretability and scalability. These findings establish the proposed framework as an effective approach for synthetic load generation in non-intrusive load monitoring research.

15.
arXiv (CS.AI) 2026-06-18

Synthetic Resonance: A Framework for Growth-Oriented Human-AI Relationships

arXiv:2606.18265v1 Announce Type: cross Abstract: As human relationships with artificial intelligence systems become increasingly frequent and sustained, existing language and theory fail to accurately capture the nature of these affiliations. Common descriptors such as mutual understanding, connection, or friendship risk anthropomorphizing systems that lack subjective experience, while dominant frameworks tend to reduce AI to either a tool or a threat. In this paper, I introduce the concept of synthetic resonance as an integrative framework for understanding human-AI relationships. Synthetic resonance describes how relationships humans define as meaningful can emerge between a human and an AI system without the need to attribute shared feelings or mutual awareness. I argue that synthetic resonance is best understood as a structured, dynamic pattern of interaction that can produce a sense of relationship without the presence of a second experiencing subject. By clarifying this distinction, the concept of synthetic resonance offers a more precise way of conceptualizing human-AI relationships and highlights their potential value and ethical implications. I also call for more research that tests the processes and outcomes of synthetic resonance.

16.
arXiv (CS.LG) 2026-06-12

Hölder++: Improving the Quality-Coherence Trade-off in Multimodal VAEs

arXiv:2606.13381v1 Announce Type: new Abstract: Existing approaches for multimodal variational autoencoders (VAEs) face a trade-off between generative quality and coherence-i.e., they struggle to generate realistic and diverse samples that, at the same time, are semantically consistent across modalities. A recent work shows that using a simple approximation to Hölder pooling as an aggregation method improves coherence over the SOTA MMVAE+, despite assuming a single shared representation across all modalities. Yet, it slightly compromises sample diversity. Inspired by this insight, we propose Hölder++, a novel multimodal VAE that improves the generative quality-coherence trade-off through: (i) the first implementation of Hölder pooling without any approximation for multimodal VAEs; (ii) an extended architecture that models distinct shared and private (i.e., modality-specific) representations (Hölder+); and (iii) hierarchical inference that further enhances the disentanglement between the shared and private representations (Hölder++). Our experiments corroborate that Hölder++ consistently improves the generative quality-coherence trade-off, yields more structured latent spaces, and learns shared representations that are informative for downstream tasks.

17.
arXiv (CS.CL) 2026-06-16

Can Agents Read the Room? Benchmarking Visual Social Intelligence in Multimodal Simulation

Social interaction depends on both language and visible social signals, such as facial expressions, posture, gaze, and emotional shifts. Yet existing social-agent benchmarks are largely text-based and rarely test whether multimodal agents can use visual cues to guide interaction. We introduce \textsc{\benchmarkname{}}, a benchmark evaluating visual social intelligence in multimodal social simulation. It contains 240 scenarios, 585 role instances, and 2,340 role-task instances, combining aligned textual-visual evidence, structured role profiles, and four role-level tasks: expression task, characteristic task, interaction regulation task, and interaction outcome task. Evaluating seven recent MLLMs under verbalized-vision and direct-vision reveals a clear gap between local role enactment and interaction management: role-specific expression and conflict handling are near saturation, whereas interaction regulation and visually grounded outcome achievement remain substantially more difficult. The code is released at https://github.com/JunsWan/AgentViSS, and the dataset is available at https://huggingface.co/datasets/JunsWan/AgentViSS.

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

A Human-in-the-Loop Label Error Detection Framework Applied to Arabic-Script HTR Datasets

Despite recent advances, Handwritten Text Recognition (HTR) for Arabic-script languages still lags behind Latin-script HTR. Part of the problem is dataset quality. To help closing this gap, we propose a two-stage framework (CER-HV) for detecting label errors. Stage 1 (CER) is a Character-Error-Rate-based noise detector built on a Convolutional Recurrent Neural Network (CRNN) architecture. Stage 2 (HV) is the Human-In-The-Loop (HITL) Verification of noisy samples detected by the first stage. Applying the CER-HV framework on multiple Arabic-script datasets can identify samples with label errors including transcription, segmentation, orientation, and non-text content errors that can markedly affect HTR performance. These errors were identified by the first stage of the framework with up to 90percent (top-50) precision. We also show that our CRNN achieves state-of-the-art performance across five of the six evaluated datasets, reaching 8.46 percent Character Error Rate (CER) on KHATT (Arabic), 8.22 percent on PHTI (Pashto), 10.59 percent on Ajami, and 10.11% on Muharaf (Arabic), all without any data cleaning. We establish a new baseline of 11.3 percent CER on the PHTD (Persian) dataset. Applying CER-HV improves evaluation CER by up to 1.8 percentage points after dataset cleaning and retraining. Although our experiments focus on documents written in an Arabic-script language, the framework is general and can be applied to other text recognition datasets

19.
bioRxiv (Bioinfo) 2026-06-19

OmniPath Metabo: chemical structures, interactions and mechanisms to study the metabolome

Mechanistic and functional analysis of omics data largely relies on the incorporation of prior knowledge; however, connecting metabolomics data and knowledge is a major methodological challenge. This is largely driven by the diverse prior knowledge being fragmented across many databases requiring the merging of different database records across chemical structures, identifiers, and varying levels of structural specificity. Hence, this limits mechanistic interpretation and functional characterisation of the metabolome. Here, we present OmniPath Metabo, a comprehensive, harmonized, metabolome-centric database covering metabolites, lipids, food-derived compounds, and small molecule drugs, along with their associated receptors, transporters, enzymes, reactions, allosteric regulators, and disease associations. OmniPath Metabo harmonizes attributes using controlled vocabularies and ontologies, structures and built-in cheminformatics to map identifiers and track ambiguity. OmniPath Metabo is built directly from 40+ original resources and is freely accessible via an interactive web app and API at metabo.omnipathdb.org. OmniPath Metabo enables dynamic, context-specific construction of subnetworks to serve dedicated purposes, such as cell-cell communication or integrated multi-omics metabolite-driven regulation, connecting reactions, allosteric regulation, metabolite-receptor and metabolite-transporter interactions. Combining it with the over 170 other resources in OmniPath, it can be used for integrated networks of signaling, gene regulation, and metabolism. We showcase the application of OmniPath Metabo by analysing publicly available metabolomics data of lung cancer cell lines and metabolic footprints to mutational patterns. In summary, OmniPath Metabo transforms fragmented resources into a harmonised prior knowledge framework for a mechanistic and functional analysis of the metabolome.

20.
arXiv (CS.CV) 2026-06-11

ReMoT: Reinforcement Learning with Motion Contrast Triplets

We present ReMoT, a unified training paradigm to systematically address the fundamental shortcomings of VLMs in spatio-temporal consistency – a critical failure point in navigation, robotics, and autonomous driving. ReMoT integrates two core components: (1) A rule-based automatic framework that generates ReMoT-16K, a large-scale (16.5K triplets) motion-contrast dataset derived from video meta-annotations, surpassing costly manual or model-based generation. (2) Group Relative Policy Optimization, which we empirically validate yields optimal performance and data efficiency for learning this contrastive reasoning, far exceeding standard Supervised Fine-Tuning. We also construct the first benchmark for fine-grained motion contrast triplets to measure a VLM's discrimination of subtle motion attributes (e.g., opposing directions). The resulting model achieves state-of-the-art performance on our new benchmark and multiple standard VLM benchmarks, culminating in a remarkable 25.1% performance leap on spatio-temporal reasoning tasks.

21.
arXiv (CS.CL) 2026-06-12

RAGPPI: RAG Benchmark for Protein-Protein Interactions in Drug Discovery

Retrieving the biological impacts of protein-protein interactions (PPIs) is essential for target identification (Target ID) in drug development. Given the vast number of proteins involved, this process remains time-consuming and challenging. Large Language Models (LLMs) and Retrieval-Augmented Generation (RAG) frameworks have supported Target ID; however, no benchmark currently exists for identifying the biological impacts of PPIs. To bridge this gap, we introduce the RAG Benchmark for PPIs (RAGPPI), a factual question-answer benchmark of 4,420 question-answer pairs that focus on the potential biological impacts of PPIs. Through interviews with experts, we identified criteria for a benchmark dataset, such as a type of QA and source. We built a gold-standard dataset (500 QA pairs) through expert-driven data annotation. We developed an ensemble auto-evaluation LLM that incorporates expert labeling characteristics, average fact-abstract similarity (F1), and low-similarity fact counts (F2), enabling the construction of a silver-standard dataset (3,720 QA pairs). We are committed to maintaining RAGPPI as a resource to support the research community in advancing RAG systems for drug discovery QA solutions.

22.
bioRxiv (Bioinfo) 2026-06-21

Expanding the GUSome: Structure-guided identification and characterization of gut microbial β-glucuronidases

The gut microbiome-encoded {beta}-glucuronidase (GUS) enzymes have a significant effect on human physiology through their deglucuronidation activity on endogenous and exogenous glucuronides. GUS activity also significantly influences the pharmacokinetics, efficacy and toxicity of various drugs including chemotherapeutic drugs. Given their crucial role in drug metabolism, GUS enzymes have emerged as promising targets for therapeutic intervention. Here, we have identified and characterized 79 unique GUS enzymes through a structure-guided approach. Structural modelling of these GUS enzymes revealed a conserved core and active-site residues with significant variations in the number and nature of the C-terminal domains. A new classification system based on the number and type of additional C-terminal domains is presented for the GUS proteins. Further, GUS enzymes have been categorized into different loop categories linked to their substrate preferences. The relationship between domain architecture and loop-type is explored by sequence similarity network analysis. We could successfully express, purify and validate GUS processing capability of a panel of identified GUS proteins. The nature of oligomer organization has been deciphered by SEC and DLS studies. Further, we have identified additional GUS enzymes capable of processing SN-38G, glucuronidated form of anticancer drug, irinotecan. These newly identified GUS enzymes will offer valuable insights into gut microbial GUS diversity and their role in understanding the population-specific drug-induced adverse effects on human health.

23.
bioRxiv (Bioinfo) 2026-06-12

CAREPath: Semantic Context-Aware Reasoning Paths with Mechanism-Augmented Embeddings for Drug Repurposing

Biomedical knowledge graphs (BKGs) that include drugs, genes, and diseases support drug repurposing by connecting drugs to diseases through gene-mediated multi-hop paths, thereby enabling mechanism-of-action reasoning. However, deeper traversal does not necessarily improve mechanistic reasoning: long paths grow combinatorially and frequently pass through hub genes, producing irrelevant gene regulatory signals, whereas overly constrained or sparse paths may miss broader biological context. We propose CAREPath, a KG-LLM framework inspired by depth-first search (DFS)-like and breadth-first search (BFS)-like reasoning to balance mechanistic specificity, scalability, and context recovery. The DFS-like module constrains traversal to short disease-gene-drug paths, converts each path into a structured prompt, and encodes it with a biomedical language model to generate semantic path embeddings. Complementarily, the BFS-like module constructs entity-level mechanism-context embeddings from one-hop gene neighborhoods and enriches them through similarity-guided augmentation using pharmacologically related drugs and gene-signature-similar diseases. Across five biomedical KGs, CAREPath achieves the best overall AUPRC among 18 baselines, improving performance by up to 3.8%. Additional analyses show that semantic short-path encoding contributes most to performance, while mechanism-context augmentation improves robustness under sparse evidence and strengthens Gene Ontology functional agreement. Case studies and recently FDAapproved indications further demonstrate its practical relevance, positioning CAREPath as an interpretable framework for scalable and mechanism-aware drug repurposing. Source code is available at https://github.com/hamppy-song/CAREPath.

24.
arXiv (CS.LG) 2026-06-16

The Reverse Telescoping Coordinate System for Positive Definite Matrices: Geometry, Computation, and Generative Modeling

arXiv:2606.15442v1 Announce Type: cross Abstract: We design a new unconstrained coordinate system where a $p\times p$ symmetric positive definite (SPD) matrix $\Theta$ is represented by a reverse telescoping map $\Theta(x)=\rm{RT}(x)$, with $x=(v,d,r)\in\mathbb{R}\times\mathbb{R}^{(p-1)}\times\mathbb{R}^{p(p-1)/2}$, representing respectively the log volume or log determinant; and the shape, as encoded by log relative diagonal scales and partial covariances among the nodes. This construction results in important properties not available in other charts, e.g., matrix logarithm, such as Jacobian depending on only the log-determinant. A useful feature of our construction is $x$ contains a lossless symbolic representation of both the matrix and its inverse. Many important computations involving a matrix and its inverse can be performed in $O(p^2)$ in the transformed domain, while it is the rendering of results in matrix forms (on demand) that must incur an $O(p^3)$ cost. Moreover, two unit-determinant matrices in the transformed domain can be joined by a straight line with pathwise unit determinant. For generative modeling, this allows designing a split volume-shape flow model trained by conditional flow matching for transporting the shape over the unit-determinant path, with a separate one-dimensional flow for transporting the volume or the determinant. The forbidding SPD constraint, tamed thus into a powerful guiding force, leads to the surprising insight that it is in some sense easier to design a volume-normalized shape flow for SPD compared to the unconstrained $\mathbb{R}^{p\times p}$, with no intrinsic notion of volume to aid normalization, unlike the determinant of SPD matrices. We apply our construction for up to $p=200$ in generative modeling of SPD matrices on a difficult synthetic bimodal target, and in generating brain connectivity networks by models trained on fMRI data; as well as in intrinsic diffusion on the SPD manifold.

25.
arXiv (CS.AI) 2026-06-19

PrefSQA: Pairwise Preference Prediction for Speech Quality Assessment and the Critical Role of High Quality Datasets

arXiv:2606.19597v1 Announce Type: cross Abstract: Mean opinion scores (MOS) are widely used for speech quality assessment, yet scalar labels are sensitive to rater variability and listening test differences. This introduces labeling noise, which limits the reliability of MOS prediction. Preference prediction reduces this variability as listeners compare signals directly, producing cleaner labels. We study MOS-free preference prediction and propose PrefSQA, which incorporates uncertainty-aware logits, an impairment attention head, and a module based on non-matching-reference comparisons. We use and refine five datasets, including MOS-derived and low-noise simulated sets with matching and non-matching content, experiment with human preference sets, and test on unseen data. Experiments show small improvements on MOS-derived data, while other sets reveal clear improvement over the baselines, highlighting the value of high-quality preference data and demonstrating the effectiveness of the proposed method.