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01.
arXiv (CS.LG) 2026-06-18

Graph Instance Landscapes: When Structural Similarity Does (Not) Reflect Shortest-Path Performance

arXiv:2606.18267v1 Announce Type: cross Abstract: Benchmarking shortest-path algorithms is commonly based on aggregate performance over heterogeneous graph sets, which limits insight into how different search paradigms react to instance structure. We adopt an instance-landscape view of graph benchmarking by embedding graphs into a low-cost structural feature space and clustering them into regions of similar structure. Three benchmark suites are studied: weighted Erdős–Rényi graphs, random geometric (wireless) graphs, and real-world road networks. We evaluate four representative shortest-path solvers spanning uninformed exact search (Dijkstra), bidirectional exact search (bidirectional Dijkstra), heuristic-guided exact search (A$^{*}$), and deque-based strategies (DEQ). Clustering robustness is analyzed under multiple feature-selection schemes, and runtime distributions are compared across landscape regions using non-parametric tests. While generator parameters induce stable structural regions, we find that feature-space similarity does not necessarily imply performance similarity: significant runtime shifts are frequently observed even within the same landscape region. A merged-suite analysis further shows that different benchmark families occupy largely disjoint regions. These results highlight both the potential and the limits of structural landscapes for the structure-aware benchmarking of shortest-path algorithms.

02.
arXiv (CS.AI) 2026-06-18

Agentra: A Supervisable Multi-Agent Framework for Enterprise Intrusion Response

arXiv:2606.18325v1 Announce Type: cross Abstract: Enterprise intrusion response still depends on static playbooks and analyst-driven triage, creating delay between alert generation and containment. We present Agentra, a supervisable multi-agent Intrusion Response System (IRS) framework that converts alerts from IDS, EDR, and XDR platforms into structured incident response plans grounded in MITRE ATT&CK, MITRE D3FEND, and NIST CSF 2.0. Agentra decomposes response reasoning across role-scoped agents, validates proposed plans through a bounded Planner–Validator review loop, screens retrieved threat intelligence through a Moderator security gateway, gates actions through an Action Catalog and risk score, and records decisions in an append-only audit log. We evaluate Agentra against a static OASIS CACAO v2.0 cyber-playbook baseline on a 120-event corpus drawn from ThreatHunter-Playbook, Splunk BOTSv3, and DARPA OpTC. The strongest configuration improves FP-aware IRS F1 from 0.61 to 0.84 and restores the projected harmful-action rate to the static baseline level of 0.0% after Planner-only configurations introduce unsafe overreaction. These results indicate that multi-agent response planning can improve ontology-grounded IRS coverage while preserving analyst approval and auditability.

03.
arXiv (CS.LG) 2026-06-12

Toward General Digraph Contrastive Learning: A Dual Spatial Perspective

arXiv:2510.16311v2 Announce Type: replace Abstract: Graph Contrastive Learning (GCL) has emerged as a powerful tool for extracting consistent representations from graphs, independent of labeled information. However, existing methods predominantly focus on undirected graphs, disregarding the pivotal directional information that is fundamental and indispensable in real-world networks (e.g., social networks and recommendations).In this paper, we introduce S2-DiGCL, a novel framework that emphasizes spatial insights from complex and real domain perspectives for directed graph (digraph) contrastive learning. From the complex-domain perspective, S2-DiGCL introduces personalized perturbations into the magnetic Laplacian to adaptively modulate edge phases and directional semantics. From the real-domain perspective, it employs a path-based subgraph augmentation strategy to capture fine-grained local asymmetries and topological dependencies. By jointly leveraging these two complementary spatial views, S2-DiGCL constructs high-quality positive and negative samples, leading to more general and robust digraph contrastive learning. Extensive experiments on 7 real-world digraph datasets demonstrate the superiority of our approach, achieving SOTA performance with 4.41% improvement in node classification and 4.34% in link prediction under both supervised and unsupervised settings.

04.
arXiv (CS.CV) 2026-06-24

NavWM: A Unified Navigation World Model for Foresight-Driven Planning

Conventional visual navigation policies often struggle with myopic decision-making and mode collapse in complex environments. While world models offer a promising alternative, existing paradigms typically isolate perception, generation, and control, failing to capture their shared spatio-temporal dynamics. In this paper, we propose NavWM, a unified navigation world model that seamlessly integrates latent world reasoning, multimodal action prediction, and controllable visual generation. At its core, NavWM leverages latent world tokens to distill geometric and semantic priors, endowing the agent with robust structural understanding. To overcome the limitations of deterministic policies, we introduce an anchor-based multimodal trajectory forecasting framework that generates a diverse action space. This inherent diversity explicitly empowers the generative world model to act as a robust closed-loop planner, utilizing visual foresight to evaluate and select the optimal path. Extensive experiments across diverse robotics datasets demonstrate that NavWM significantly advances the state-of-the-art, delivering remarkable improvements in both high-fidelity future state generation and zero-shot navigation success.

05.
arXiv (CS.LG) 2026-06-15

Curvature-Informed Potential Energy Surface for Protein-Ligand Binding Affinity Prediction

arXiv:2606.14217v1 Announce Type: new Abstract: Accurate prediction of protein-ligand binding affinity is essential for structure-based drug discovery. Recent geometric deep learning methods have achieved promising performance by representing protein-ligand complexes as three-dimensional graphs. However, most existing approaches mainly rely on static interaction geometry from a single bound conformation, while neglecting molecular flexibility and binding-induced conformational changes. To address this limitation, we propose a curvature-informed potential energy surface (CPES) graph neural network for protein-ligand binding affinity prediction, which incorporates physics-informed curvature representations to model conformational flexibility. CPES first derives curvature spectral descriptors from the Hessian of the potential energy surface evaluated at equilibrium configurations, whose eigenvalues define the local principal curvatures of the potential energy surface. It then uses spectral cross-attention to compare the unbound ligand and protein with the bound complex, thereby capturing binding-induced changes in conformational dynamics. In parallel, hierarchical protein-ligand interaction representations are learned from static structural features through geometry-aware message passing, soft clustering, and bidirectional cross-attention. Finally, CPES fuses the curvature-informed dynamic representations with static interaction representations for affinity regression. Extensive evaluations on multiple benchmark datasets demonstrate that CPES achieves improved predictive performance and offers physical interpretability.

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

Harmonic: Hierarchical State Space Models for Efficient Long-Context Language Modeling

作者:

We present Harmonic, a hierarchical state space model (SSM) for language modeling. The architecture stacks three recurrent levels at progressively slower timescales; each level receives the prediction error of the level below as input, rather than its raw hidden state. On enwiki8 with equal token budgets, Harmonic outperforms a comparable Transformer (28M params) by +1.4% at 1K tokens, +6.7% at 8K tokens, and +11.4% at 32K tokens (bpt, lower is better). It also outperforms Mamba at every tested length by 0.7–1.8%. At 64K tokens, both Mamba and Transformer run out of memory on an 80GB H100; Harmonic trains successfully, reaching 6.169 bpt. Results replicate on WikiText-103 (H-TF gap +1.7% to +7.2% across 1K–32K). At 1B parameter scale, replacing all attention layers in TinyLlama 1.1B with HarmonicBlock eliminates the RoPE positional encoding limit: the resulting Hallamonic model maintains stable loss across sequence lengths 1K–8K on two independent clean benchmarks (Lambada and fineweb-edu held-out), while TinyLlama degrades catastrophically past its 2K-token RoPE limit (gap: +9.4 bpt at seq=8K on Lambada). Compute is O(L) per forward pass vs. O(L^2) for attention. Logs: https://github.com/Omibranch/harmonic-logs.

07.
arXiv (quant-ph) 2026-06-16

Noise-Adaptive Predictive Dynamical Decoupling

arXiv:2606.15769v1 Announce Type: new Abstract: Protecting quantum coherence against realistic environmental noise remains one of the fundamental obstacles to scalable quantum technologies. We develop a noise-adaptive dynamical decoupling framework that combines analytical open-quantum-system modeling with machine-learning-based forecasting for a qubit interacting with random telegraph noise. Unlike conventional dynamical decoupling protocols based on fixed pulse schedules, the proposed approach continuously forecasts short-time coherence evolution and adaptively applies control pulses according to the instantaneous noise dynamics. We investigate stationary and non-stationary environments spanning both Markovian and non-Markovian regimes. Numerical simulations demonstrate that the machine-learning-assisted adaptive control strategy substantially outperforms conventional periodic dynamical decoupling while using a comparable number of control pulses. The improvement becomes particularly pronounced in non-Markovian and non-stationary regimes, where memory effects, coherence revivals, and temporally evolving noise strongly limit the effectiveness of static pulse protocols. These results establish predictive machine-learning-assisted dynamical decoupling as a promising and scalable framework for adaptive quantum control in realistic noisy quantum devices.

08.
arXiv (math.PR) 2026-06-15

On a stochastic phase-field model of cell motility with singular diffusion

arXiv:2601.05881v2 Announce Type: replace Abstract: We study existence of solutions in the variational sense for a class of stochastic phase-field models describing moving boundary problems. The models consist of stochastic reaction-diffusion equations with singular diffusion forced by a phase-field. We investigate both the case of an independently evolving phase-field and of coupled phase-field evolution driven by a viscous Hamilton-Jacobi equation. Such systems are used in the modelling of single-cell chemotaxis, where the contour of the cell shape corresponds to a level set of the phase-field. The technical challenge lies in the singularities at zero level sets of the phase-field. For large classes of initial data, we establish global existence of probabilistically weak solutions in $L^2$-spaces with weights which compensate for the singularities.

09.
arXiv (CS.LG) 2026-06-24

Exact Schur-Sylvester Dimensionality Reductions for Non-Smooth Stochastic Complexity and Manifold Sampling

arXiv:2606.23867v1 Announce Type: new Abstract: The exact computation of the Normalized Maximum Likelihood (NML) codelength for regular non-smooth estimators (e.g., Lasso) has been historically limited by the cubic scaling walls of manifold-constrained projection and volume integration. At each step of the geometric Propose-and-Project Metropolis–Hastings (PPMH) sampler, evaluating the projection operator requires inverting an $(N+k) \times (N+k)$ generalized KKT matrix, while calculating the volume factor requires the determinant of an $(N-k) \times (N-k)$ Gram matrix. This paper presents an exact, mathematically equivalent formulation that bypasses both bottlenecks by utilizing the block Schur complement and Sylvester's determinant identity. We prove that the computational complexity of both operations collapses from $\mathcal{O}(N^3)$ to $\mathcal{O}(k^3 + N^2 k)$ per step. We generalize this reduction to Sparse Support Vector Machines (SVMs), Elastic Net, and Group Lasso. Finally, we provide a rigorous numerical stability analysis and evaluate the sampler's efficiency using the Effective Sample Size (ESS) per second. Our empirical benchmarks on high-dimensional datasets confirm a constant speedup exceeding $14{,}100\times$ while maintaining double-precision numerical equivalence, rendering exact non-smooth NML estimation highly tractable for large-scale statistical inference.

10.
medRxiv (Medicine) 2026-06-22

Associations of Chemical Exposures with Psychological Distress and Depression Diagnosis among Waste Pickers in Brasilia, Brazil: A Cross-Sectional Study

Introduction: Waste pickers face chemical exposures. We evaluated whether chemical exposure is associated with psychological distress and depression. Methods: A 2017 cross-sectional survey included 1,141 waste pickers working in the Estrutural open dump in Brasilia, Brazil. Participants self-reported occupational exposure to 11 chemical categories, 17 psychological distress symptoms, and depression diagnoses. Associations of chemical exposure with mean psychological distress scores and depression prevalence were assessed, adjusted for age, sex, marital status, and income. Results: Mean psychological distress score was higher among those exposed to any chemical (mean of 8.1 vs 6.1; adjusted mean difference [aMD]: 1.8 [0.9, 2.7]) and higher among those exposed to each of 11 chemical categories, for example, smoke (aMD: 1.2 [0.6, 1.7]), batteries (aMD: 1.5 [1.0, 1.9], and oils (aMD: 1.3 [0.9, 1.8]). Depression was more prevalent among those exposed to oils (16.6% vs 10.6%; adjusted prevalence difference [aPD]: 6.3% [95% CI: 2.3, 10.2]), cleaning products (aPD: 5.4% [1.2, 9.5]), medications (aPD: 4.7% [0.6, 8.8]), and aerosols (aPD: 5.3% [1.3, 9.3]) but, not smoke, batteries, greases, insecticides, solvents, paints, chemical containers, or any chemical. Conclusion: These associations highlight the need to consider policy level protections for waste pickers to reduce chemical exposure and guard against psychological distress. Further research is necessary to explore which specific chemicals, within broad chemical categories, are associated with psychological distress and depression.

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

Quantization Robustness of Monotone Operator Equilibrium Networks

arXiv:2603.10562v2 Announce Type: replace-cross Abstract: Monotone operator equilibrium networks are implicit-layer models whose output is the unique equilibrium of a monotone operator, guaranteeing existence, uniqueness, and convergence. When deployed on low-precision hardware, weights are quantized, potentially destroying these guarantees. We analyze weight quantization as a spectral perturbation of the underlying monotone inclusion. Convergence of the quantized solver is guaranteed whenever the spectral-norm weight perturbation is smaller than the monotonicity margin; the displacement between quantized and full-precision equilibria is bounded in terms of the perturbation size and margin; and a condition number characterizing the ratio of the operator norm to the margin links quantization precision to forward error. MNIST experiments confirm a phase transition at the predicted threshold: three- and four-bit post-training quantization diverge, while five-bit and above converge. The backward-pass guarantee enables quantization-aware training, which recovers provable convergence at four bits.

13.
arXiv (CS.AI) 2026-06-15

FreoStream:Enhancing Stream Guardrails via Future-Aware Reasoning and Safety-Aligned Optimization

arXiv:2606.13737v1 Announce Type: cross Abstract: Stream guardrails enable token-level safety detection before full responses are generated. However, they often make overly conservative judgements and block those sensitive but safe tokens, which is known as over-refusal. Due to lack of full context, they also fail to detect implicitly harmful content from jailbreaking. To address these challenges, we propose FreoStream, a novel streaming guardrail framework. Specifically, FreoStream fine-tunes a LoRA module to perform Future-Aware Reasoning when the base guardrail detects unsafe tokens. The reasoning process follows a Future-Reason-Judge paradigm: predict the future, reason about the full context and give the final judgement. This design can effectively reduce over-refusal by incorporating the future information. Moreover, we introduce the Safety-Aligned Optimization module that extracts the safety-aligned component from the reasoning gradients to update the base guardrail model, thereby enhancing streaming safety detection. Extensive experiments on various safety benchmarks demonstrate that FreoStream achieves lower over-refusal rates and better jailbreak defense compared to existing streaming guardrails.

14.
medRxiv (Medicine) 2026-06-22

T Cell Receptor repertoire analysis reveals antigenic convergence and immunotherapeutic opportunities in Prostate Cancer

Background: The T-cell receptor {beta} (TCR{beta}) repertoire reflects antigen-driven adaptive immune responses and provides insight into tumor-immune interaction. In prostate cancer (PCa), the immunosuppressive tumor microenvironment limits effective T-cell activation, and the antigenic drivers shaping intratumoral TCR repertoires remains poorly defined. This study aimed to characterize matched tumor and peripheral TCR{beta} repertoires from treatment-naive PCa patients and to identify shared clonotypes and antigenic specificities associated with disease severity. Methods: Next-generation sequencing was used to profile TCR{beta} repertoires from matched tumor biopsies and peripheral blood mononuclear cells obtained from treatment-naive PCa patients. Repertoires clonality, diversity, and was assessed using established metrics. Antigenic convergence was evaluated using GLIPH2 to identify shared CDR3{beta} motifs and predicted tumor-associated antigen (TAA) recognition, followed by functional validation using IFN-{gamma} ELISpot and T-cell expansion assays. Results: Tumor-derived TCR{beta} repertoires displayed reduced richness and increased clonality compared with peripheral blood mononuclear cells, consistent with local antigen-driven expansion. High-grade tumors demonstrated greater interpatient clonotype sharing and motif-level convergence, indicative of recognition of common TAAs. GLIPH2 analysis associated expanded clonotypes with epitopes derived from prostate-specific G-protein coupled receptor (PSGR), prostate-specific membrane antigen (PSMA), and prostate-specific antigen (PSA). Functional validation confirmed that peptide pools containing PSGR- and PSMA-derived epitopes induced IFN-{gamma} production and antigen-specific T-cell proliferation in vitro. Conclusions: These findings reveal an oligoclonal, antigen-driven intratumoral TCR{beta} landscape and identify PSGR and PSMA as immunogenic, potentially actionable targets. Integration of TCR profiling with antigen discovery pipelines may support the development of TCR-based biomarkers and precision immunotherapeutic strategies in prostate cancer.

15.
arXiv (CS.AI) 2026-06-24

SAFARI: Scaling Long Horizon Agentic Fault Attribution via Active Investigation

arXiv:2606.24626v1 Announce Type: new Abstract: As autonomous agents tackle increasingly complex multi-step, multi-agent tasks, their execution trajectories have scaled beyond the constraints of even the largest context windows. Current methods for effectively diagnosing agent failures load the full trajectory into an LLM's context window, which suffers from attention dilution and fails when agentic traces inevitably exceed context limits. To address this, we introduce SAFARI (Scaling long-horizon Agentic Fault AttRibution via active Investigation), a framework that replaces linear context loading with a tool-augmented diagnostic loop. By equipping LLMs with a specialized toolbox to read and search trajectory segments alongside a persistent Short-Term Memory (STM) for cross-turn reasoning, SAFARI effectively decouples diagnostic accuracy from architectural context limits. Our experiments demonstrate that SAFARI outperforms state-of-the-art results by 20% on the Who&When dataset within a 1M token budget, and by 19% on TRAIL GAIA subset on a 25K token budget. Most significantly, SAFARI maintains a 0.58 precision even when the target fault resides 5x beyond the model's native context window, a scenario where traditional evaluators fail entirely.

16.
arXiv (math.PR) 2026-06-18

On the Singular Control of a Diffusion and its Running Infimum or Supremum

arXiv:2501.17577v2 Announce Type: replace-cross Abstract: We study a class of singular stochastic control problems for a one-dimensional diffusion $X$ in which the performance criterion to be optimised depends explicitly on the running infimum $I$ (or supremum $S$) of the controlled process. We introduce two novel integral operators that are consistent with the Hamilton-Jacobi-Bellman equation for the resulting two-dimensional singular control problems. The first operator involves integrals where the integrator is the control process of the two-dimensional process $(X,I)$ or $(X,S)$; the second operator concerns integrals where the integrator is the running infimum or supremum process itself. Using these definitions, we prove a general verification theorem for problems involving two-dimensional state-dependent running costs, costs of controlling the process, costs of increasing the running infimum (or supremum) and exit times. Finally, we apply our results to explicitly solve an optimal dividend problem in which the manager's time-preferences depend on the company's historical worst performance.

17.
bioRxiv (Bioinfo) 2026-06-11

HoloCell: A Generative Foundation Model for Holistic Cellular Modeling

Single-cell multi-omics technologies have recently advanced to enable the profiling of epigenomic, transcriptomic, and proteomic layers within individual cells, offering new opportunities to characterize cellular states as integrated biological systems. However, developing a unified framework that can seamlessly integrate diverse omics modalities and remain robust to heterogeneous modality missingness remains challenging. Here we present HoloCell, to our knowledge the first generative foundation model for joint representation learning and generative modeling across all three major single-cell omics modalities, i.e., epigenomics, transcriptomics, and proteomics. HoloCell contains over 860 million parameters and is pretrained on the Human-Multi-Omics-Corpus, which comprises approximately 468 million single-cell profiles across these three omics layers, corresponding to over 425 billion tokens. HoloCell introduces a simple yet biologically grounded hierarchical tokenization strategy that encodes cis-regulatory elements, genes, and proteins as structured tokens within a shared modeling framework. We evaluated HoloCell across single-omics representation learning, paired multi-omics integration, unpaired multi-omics alignment, and cross-modal generation via iterative diffusion and remasking, demonstrating its superior performance and flexibility across diverse omics tasks. From a representation perspective, HoloCell provides a unified digital mapping of cellular states across multiple omics layers, capturing cell heterogeneity as an integrated system. From a generation perspective, its iterative diffusion and remasking framework accounts for the inherently unordered nature of biological features, enabling in silico simulation of multi-omics information flow. Together, these capabilities position HoloCell as a versatile foundation model toward the emerging concept of a virtual cell, offering both systematic characterization and generative simulation of cellular systems within a unified framework.

18.
arXiv (CS.AI) 2026-06-19

ProMUSE: Progressive Multi-modal Uncertainty-guided Staged Evidential Alzheimer Disease Classification

arXiv:2606.19371v1 Announce Type: cross Abstract: Alzheimer's disease (AD) is a fatal disorder that destroys memory and cognitive skills in the elderly population. Most treatments for AD are effective in the early stage, leading to an increasing demand for early AD diagnosis. AD diagnosis increasingly relies on multimodal data such as clinical assessments, structural Magnetic Resonance Imaging (MRI), and Positron Emission Tomography (PET) imaging. However, MRI and PET acquisition remain costly and not universally accessible, making full-modality inference impractical in real-world clinical workflows. We propose ProMUSE, a Progressive Multi-modal Uncertainty Guided Staged Evidential Network that adaptively determines when additional modalities are necessary, helping reduce the overall cost of data acquisition while maintaining accuracy. ProMUSE first performs evidential classification using low-cost clinical data and quantifies uncertainty via a Dirichlet-based subjective logic model. When uncertainty exceeds a learned threshold, ProMUSE progressively incorporates MRI or PET features, fusing modality-wise belief and uncertainty through Dempster-Shafer theory to obtain a calibrated multimodal prediction. This staged acquisition strategy enables accurate diagnosis while minimizing reliance on expensive imaging. Experiments on ADNI, AIBL, and OASIS across CN-AD, CN-MCI, and MCI-AD tasks demonstrate that ProMUSE achieves competitive or superior accuracy compared to full-modality baselines while reducing MRI/PET usage by 50-90%, yielding substantial cost savings. These results highlight ProMUSE as a practical, uncertainty-aware, and resource-efficient solution for real-world AD screening.

19.
arXiv (CS.AI) 2026-06-16

Relational Structural Causal Models

arXiv:2606.14892v1 Announce Type: new Abstract: An artificial intelligence must have a model of its environment that is causal, supporting reasoning about interventions and counterfactuals, and also combinatorial, supporting generalization to unseen combinations of objects. In this work, we formally study when and how such a model can be learned. We develop relational structural causal models, extending structural causal models (Pearl 2009) to settings where objects and their relations vary. First, we show how answers to not only causal but also observational queries about unseen combinations of objects can not be identified without further assumptions. To enable such identification–including in the presence of unobserved confounding–we define relational causal graphs and derive symbolic identification criteria. Finally, we propose relational neural causal models, a provably correct approach that outperforms non-relational baselines on simulated traffic scenes with varying cars, signals, and pedestrians.

20.
arXiv (CS.AI) 2026-06-18

Better Adherence, Richer Context: A Field Evaluation of LLM-Powered Conversational Voice Diaries for Sleep

arXiv:2606.18596v1 Announce Type: cross Abstract: Sleep diaries are central to behavioral sleep medicine and cognitive behavioral therapy for insomnia, yet daily completion is difficult to sustain, and static forms often provide limited context for interpreting night-to-night sleep variation. We designed an LLM-powered conversational voice diary that delivers clinically grounded morning and evening sleep diary questions through proactive smart-speaker prompts, structured conversational intake, and adaptive follow-up dialogue. We evaluated the system in a four-week between-subjects field study with 30 university students, comparing it with a text-based mobile diary using matched diary items, reporting windows, and reminder intervals. Compared with the text-based diary, the conversational voice diary showed higher adherence and elicited more detailed contextual self-report about routines, stressors, environmental conditions, and other sleep-related factors. Participants also described the voice diary as easier to integrate into daily routines, despite longer perceived completion time. However, voice-based conversational intake produced lower completeness for some structured diary fields, revealing a trade-off between expressive richness and structured precision. These findings show both the promise and the challenge of using LLM-powered conversational voice assistants for longitudinal health self-report.

21.
PLOS Computational Biology 2026-05-29

Structural and dynamic basis of NOD2 tandem CARD association and NOD1/2–RIP2 signaling complexes

by Jitendra Maharana, Aritra Bej, Debasish Biswal, Debashis Panda, Arjun Sharma NOD1 and NOD2, founding members of the NOD-like receptor (NLR) family, play a crucial role in host defense against bacterial infections. Recognition of peptidoglycan-derived ligands triggers ATP-dependent oligomerization of the NACHT domain, exposing the CARD domains that recruit the adaptor protein RIP2 via CARD–CARD interactions to activate the NF-κB signaling cascade. Although NOD1/2-RIP2 interactions and RIP2CARD filament assembly are established, the precise interfaces that stabilize hetero–CARD filaments remain poorly defined. Here, we integrate in silico structural modeling with molecular dynamics (MD) simulations to elucidate structurally compatible arrangements of NOD1–RIP2 and NOD2–RIP2 hetero–CARD filaments. Our results reveal that NOD1CARD subunits form a structurally compatible homomeric scaffold via canonical (type-I–III) interfaces, accommodating multiple tiers of RIP2CARD rings at both filament termini. Meanwhile, the NOD2 tandem CARDs adopt multiple discrete conformations, reflecting a more intricate structural mechanism. In stable filament conformations, tandem CARDs converge at the type-II interface, with RIP2CARD rings stacking onto CARDa (top-down) and CARDb (bottom-up) interfaces, highlighting the structural role of NOD2CARDb in RIP2-mediated CARD–CARD interaction. In silico mutagenesis, involving charge-reversal and alanine scanning of key interfacial residues, disrupts NOD1–RIP2 and NOD2–RIP2 interactions at both top-down and bottom-up interfaces, leading to rapid interface destabilization within 0.1–0.4 μs of simulation. Together, these results reveal conserved and receptor-specific mechanisms governing NOD1/2–RIP2 CARD–CARD interactions and provide deeper structural and dynamic insights into the complex structural mechanisms for NLR-mediated inflammatory signaling.

22.
arXiv (CS.AI) 2026-06-18

Efficient Zeroth-Order Federated Finetuning of Language Models on Resource-Constrained Devices

arXiv:2502.10239v3 Announce Type: replace-cross Abstract: Federated Learning (FL) is a promising paradigm for finetuning Large Language Models (LLMs) across distributed data sources while preserving data privacy. However, finetuning such large models is challenging on edge devices due to its high resource demand. Zeroth-order Optimization (ZO) estimates gradients through finite-difference approximations, which rely on function evaluations under random perturbations of the model parameters. Consequently, ZO with task alignment provides a potential solution, allowing finetuning using only forward passes with inference-level memory requirements and low communication overhead, but it suffers from slow convergence and higher computational demand. In this paper, we propose a new ZO-based method that applies a more efficient technique to reduce the computational demand associated with using a large number of perturbations while preserving their convergence benefits. This is achieved by splitting the model into consecutive blocks and allocating a higher number of perturbations to the second block, enabling efficient reuse of intermediate activations to update the full network with fewer forward evaluations. Our evaluation on RoBERTa-large, OPT1.3B, LLaMa-3-3.2B models shows up to $3\times$ reduction in computation compared to the other ZO-based techniques, while retaining the memory and communication benefits over first-order federated learning techniques.

23.
medRxiv (Medicine) 2026-06-22

Repeat expansions in Parkinson's disease and parkinsonism across ancestries: insights from a global genetic cohort

Expanded short tandem repeats contribute to a broad spectrum of neurodegenerative diseases, yet their roles in Parkinson's disease (PD) and parkinsonism remain incompletely characterized, especially across diverse ancestries. We analyzed short-read whole-genome (WGS) and clinical exome sequencing (CES) data from 38,365 individuals (28,861 WGS; 9,504 CES), encompassing 23,242 patients with PD, 4,729 patients with atypical parkinsonism and 10,394 healthy controls from 11 genetic ancestries. To determine carrier frequencies and characterize repeat structures across diverse ancestries, we genotyped 12 established pathogenic loci where normal, intermediate, and pathogenic alleles can be reliably differentiated using short-read sequencing data. Additionally, we conducted threshold-based associations to determine the minimum threshold associated with increased PD risk in 15,995 individuals (8,591 PD, 7,404 controls) of European ancestry. Pathogenic repeat expansions were detected in 62 patients (56 PD and 6 atypical parkinsonism) and 5 controls across seven loci (AR, ATXN1, ATXN2, ATXN3, CACNA1A, HTT and THAP11), spanning seven ancestries. Among these, ATXN2 expansions were the most frequently observed in PD and were present in African, East Asian, European and Middle Eastern ancestries. Additionally, intermediate ATXN2 repeat expansions exhibited a strong, length-dependent association with PD risk in the European population, with individuals with [≥]32 repeats having a more than four-fold increased risk (odds ratio 4.25, 95% confidence interval 1.80-12.05). Overall, >92% of expanded alleles harbor CAA interruptions within the CAG tract. Pathogenic expansions at other loci, such as ATXN3 and THAP11, showed more ancestry-specific distributions. Clinically, individuals with pathogenic ATXN2 and ATXN3 expansions most often presented with typical PD features but frequently showed earlier disease onset and a strong family history of PD. This large-scale, multi-ancestry study comprehensively maps the genetic landscape of pathogenic and intermediate repeat expansions in PD. Our findings confirm a length- and structure-dependent risk association for ATXN2 with PD in the European population, and highlight the pleiotropic effects of repeat expansions across the parkinsonian spectrum.

24.
arXiv (CS.AI) 2026-06-19

Towards Engineering Scaling Laws with Pretraining Data Composition

arXiv:2606.19781v1 Announce Type: cross Abstract: Neural scaling laws describe how model performance improves as a power law in compute, model size, and dataset size. While well-established for large language models, these relationships are emerging for large models in particle physics. As with language, empirical studies show that the performance scales as a power law. However, unlike natural language or image domains, fundamental physics has high-fidelity simulators that produce synthetic data cheaply. This favors scaling regimes where additional data is cheaper than additional parameters, and allows the pretraining dataset itself to be engineered to influence the scaling. For the task of classifying hadronic jets produced in collisions of high-energy particle beams, we show that the scaling behavior can be engineered towards requiring more data rather than larger models by inclusion of pretraining data which is more diverse and better aligned with the downstream classification task.

25.
arXiv (CS.AI) 2026-06-16

Multi-Grade Deep Learning for Partial Differential Equations with Applications to the Burgers Equation

arXiv:2309.07401v2 Announce Type: replace-cross Abstract: Deep neural networks (DNNs) show great promise for solving partial differential equations (PDEs), but their deep architectures introduce complex, large-scale, non-convex optimization challenges. Nonlinear PDEs, like the viscous Burgers' equation, compound these difficulties due to steep gradients and shock-like solutions. To address this, we propose a two-stage multi-grade deep learning (TS-MGDL) method. In the first stage, shallow networks are trained progressively grade by grade to fit the target function from low- to high-frequency components; previously learned grades are frozen, and each new residual block is trained solely to minimize the remaining approximation error. The second stage unfreezes and retrains selected layers using the first-stage network as initialization, achieving an interpretable, stable hierarchical refinement while mitigating optimization complexity. Furthermore, we theoretically prove that each grade and stage in TS-MGDL monotonically reduces the loss function under an appropriate optimization strategy. Numerical experiments on 1D, 2D, and 3D viscous Burgers' equations demonstrate that TS-MGDL significantly outperforms single-grade learning (SGL), reducing predictive errors by up to a factor of 60.