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01.
arXiv (CS.LG) 2026-06-16

Contrastive Regularization for Accent-Robust ASR

arXiv:2605.03297v2 Announce Type: replace-cross Abstract: ASR systems based on self-supervised acoustic pretraining and CTC fine-tuning achieve strong performance on native speech but remain sensitive to accent variability. We investigate supervised contrastive learning (SupCon) as a lightweight, accent-invariant auxiliary objective for CTC fine-tuning. An utterance-level contrastive loss regularizes encoder representations without architectural modification or explicit accent supervision. Experiments on the L2-ARCTIC benchmark show consistent WER reductions across multiple pretrained encoders, with up to 25 – 29\% relative reduction under unseen-accent evaluation. Analysis using within-transcript cosine dispersion indicates that SupCon promotes more compact and stable representation geometry under accent variability. Overall, SupCon provides an effective and model-agnostic regularization strategy for improving accent robustness.

02.
arXiv (CS.CV) 2026-06-17

AlignDrive: Aligned Lateral-Longitudinal Planning for End-to-End Autonomous Driving

Practical autonomous driving requires models that generalize by reasoning through spatial-temporal possibilities to exclude unsafe outcomes. While state-of-the-art (SOTA) methods use parallel planning architectures, they fail to explicitly couple speed decisions with agent behavior along the driving path, leading to suboptimal coordination. To address this, we propose a cascaded framework that transforms longitudinal planning from an independent prediction task into a path-conditioned reasoning process. On the model side, we introduce an anchor-based regression design that conditions longitudinal prediction on the lateral drive path, and reformulate longitudinal planning as 1D displacement prediction along the path. This reduces geometric uncertainty and sharpens the model's focus on interaction-driven dynamics. On the data side, we introduce a planning-oriented data augmentation strategy that simulates rare safety-critical events by programmatically inserting agents and relabeling longitudinal targets to enforce collision avoidance. Evaluated on the challenging Bench2Drive benchmark, our method achieves SOTA performance with a driving score of 89.07 and a success rate of 73.18%, demonstrating significantly improved coordination and safety. Further evaluation on Fail2Drive confirms strong generalization to rare edge cases where parallel formulations typically fail. Project page:https://yanhaowu.github.io/AlignDrive/.

03.
arXiv (CS.AI) 2026-06-19

JustDiag!: A Diagnostic Justification Engine for Accountable Root Cause Analysis

arXiv:2606.19407v1 Announce Type: cross Abstract: Large language models can produce fluent root cause analyses, but fluent final answers alone are insufficient evidence for accountability in high-stakes operations. In real incident response, engineers need to know what evidence supported a diagnosis, which alternatives were considered, where contradictions remained, and whether the system resolved the case or preserved uncertainty. We address this gap with JustDiag, a diagnostic justification engine for RCA that maintains an explicit process state over evidence, findings, competing hypotheses, conflicts, and next checks. We evaluated the system on 66 real-world incidents using a two-layer protocol that separately scores final-answer quality and process quality. Relative to a matched control without diagnostic justification, JustDiag achieved stronger outcome and process scores, while accepting slightly lower terminal completion due to more calibrated non-closure. These results suggest that accountable RCA requires explicit diagnostic justification artifacts and process-aware evaluation, not only fluent final answers.

04.
arXiv (CS.AI) 2026-06-17

Online LLM Selection via Constrained Bandits with Time-Varying Demand

arXiv:2606.17489v1 Announce Type: cross Abstract: Large Language Models (LLMs) are increasingly deployed in edge-cloud inference systems to handle diverse user tasks with heterogeneous accuracy, latency, and cost profiles. Selecting the appropriate LLM for each incoming task is critical for ensuring service quality and efficient resource utilization. However, model heterogeneity, stochastic and unknown performance characteristics, and time-varying task demands make static selection strategies inadequate. Real-world deployments often impose hard resource budgets such as monetary expenditure limits, along with soft service-level requirements such as latency guarantees. These constraints introduce additional challenges for online decision-making. We formulate this problem as a constrained stochastic bandit learning task, where the learner sequentially selects models under both packing-type (hard) and covering-type (soft) constraints, while adapting to time-varying task demand. The learner operates without access to the underlying reward, cost, or latency distributions and must rely on partial feedback. We develop a novel online learning algorithm that leverages confidence-bound estimates and demand predictions to balance reward maximization with long-term constraint satisfaction. We provide theoretical guarantees showing sublinear regret and sublinear covering constraint violations compared to an offline benchmark with full information. Experimental results on synthetic workloads demonstrate the effectiveness and robustness of our approach in dynamic, resource-constrained environments.

05.
arXiv (CS.CV) 2026-06-16

Variable-Rate Deep Image Compression based on Low-Rank Adaptation by Progressive Learning

In the digital age, image compression is crucial for numerous applications, including web media, streaming services, high-resolution medical imaging, and connected vehicle networks, enabling efficient data storage and transmission. With the increasing demand for high-quality image communication, the need for advanced compression techniques becomes increasingly critical. Numerous Deep Image Compression (DIC) techniques have recently been introduced, showing impressive performance compared to traditional standards. However, variable-rate image compression remains an unresolved issue. Specific DIC methods deploy multiple networks to attain different compression rates, whereas others use a single model, which often results in higher computational complexity and reduced performance. This work proposes a progressive learning approach for variable-rate image compression based on the parameter-efficient fine-tuning method, the Low-Rank Adaptation (LoRA). We introduce an additional LoRA Rate-Adaptive Module (LoRAM) in DIC methods. Due to the re-parameterized merging of LoRA, our proposed method does not introduce additional computational complexity during inference. Compared to methods utilizing multiple models, comprehensive experiments demonstrate that our approach achieves competitive performance, saving 99\% in parameter storage, 90% in datasets, and 97% in training steps.

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

Position: Stop Anthropomorphizing Intermediate Tokens as Reasoning/Thinking Traces!

arXiv:2504.09762v4 Announce Type: replace Abstract: Intermediate token generation (ITG), where a model produces output before the solution, has become a standard method to improve the performance of language models on reasoning tasks. These intermediate tokens have been called \say{reasoning traces} or even \say{thinking traces} – implicitly anthropomorphizing the traces, and implying that these traces resemble steps a human might take when solving a challenging problem, and as such can provide an interpretable window into the operation of the model's thinking process to the end user. In this position paper, we present evidence that this anthropomorphization isn't a harmless metaphor, and instead is quite dangerous – it confuses the nature of these models and how to use them effectively, and leads to questionable research. We call on the community to avoid such anthropomorphization of intermediate tokens.

07.
arXiv (CS.LG) 2026-06-12

Boltzmann Attention: Learnable Ising Couplings for Cooperative Attention

arXiv:2606.12478v1 Announce Type: new Abstract: Attention mechanisms are central to modern sequence models, yet standard attention computes relevance primarily through individual query–key similarities. Although softmax normalization introduces competition among positions, a standard attention layer does not explicitly parameterize learnable interactions between attention decisions. This limits its ability to directly model cooperative or antagonistic co-attention structure within the attention mechanism itself. We propose Boltzmann attention, an energy-based generalization in which attention patterns are governed by an interacting Ising model. The method augments the usual data-dependent local fields with learnable pairwise couplings, allowing the model to represent inter-position correlations beyond those captured by softmax or sigmoid attention. Experiments on character-level language modeling and synthetic bracket matching show that Boltzmann attention consistently improves over standard softmax attention within a standard Transformer architecture, with the advantage becoming more pronounced as sequence length increases. A four-way ablation confirms that the improvement arises from the learnable pairwise couplings. These results suggest that explicit inter-position interactions provide a principled enhancement for attention-based sequence modeling. Moreover, the Ising formulation opens a natural path toward quantum-computing-based sampling strategies: we demonstrate that diabatic quantum annealing provides a practical training method while maintaining competitive performance with exact Boltzmann computation.

08.
medRxiv (Medicine) 2026-06-11

Long-term exposure to PM2.5 components and lipid profiles in WTC Health Program general responders

Fine particulate matter (PM2.5) was found to be associated with elevated blood lipids, but fewer studies have examined the associations with specific constituents of PM2.5. We studied the associations between exposure to annual PM2.5 and its 14 constituents, and repeated blood lipid measurements among general responders enrolled in the World Trade Center Health Program between 2003 and 2019 (n = 44,876). We used generalized additive mixed effect models to investigate the single-pollutant associations with repeated measures of blood total cholesterol (TC), high and low-density lipoprotein (HDL-C and LDL-C) levels. We then used linear generalized weighted quantile sum regression with a random intercept for participant ID to account for the clustering of repeated measures and evaluate the combined associations with the component mixture. A decile increase in the mixture of 14 PM2.5 chemical components was associated with 0.375 mg/dL increase in TC levels (95% confidence Interval (CI): 0.174-0.577) and 0.302 mg/dL increase in LDL-C (95% CI: 0.063, 0.540). Lead, organic carbon, and iron were major drivers of both associations. Component-specific models also show higher TC and LDL levels associated with interquartile range increases in organic carbon (0.472, 95% CI [0.027, 0.918] and 0.648 95% CI [0.136, 1.160]) and iron exposure (1.081, 95% CI [0.630, 1.532] and 0.748, 95% CI [0.318, 1.178]). In conclusion, we found PM2.5 exposure to be associated with elevated lipid levels. The associations differed by PM2.5 composition, highlighting organic carbon, lead, and iron and major drivers. These findings are highly significant for a population exposed to extreme air pollution event and susceptible to lipid alterations that might trigger cardiovascular events.

09.
arXiv (CS.AI) 2026-06-18

A Variational Framework for LLM Generator-Regulator Games

作者:

arXiv:2606.18424v1 Announce Type: cross Abstract: This paper develops a variational framework for regulated language generation. Starting from autoregressive token sampling, we derive the induced distribution over complete messages and relate it to an entropy-regularized Gibbs law. Regulation is modeled as an optimal discriminator whose convex-dual value is an f-divergence, and the generator-regulator interaction is formulated as a saddle-point problem. The framework applies to moderation, censorship, AI deception detection, compliance auditing, phishing defense, and manipulation control, where regulation concerns a distribution over possible messages rather than a single output. The equilibrium clarifies the tradeoff among utility, entropy, regulatory alignment, and finite-length detectability. Two finite-vocabulary case studies, censorship filtering and phishing defense, illustrate how the theory can be evaluated through utility, entropy, divergence, receiver-side scores, and detection probability.

10.
arXiv (quant-ph) 2026-06-17

Quantum conditional entropies from convex trace functionals

arXiv:2410.21976v4 Announce Type: replace Abstract: We study geometric properties of trace functionals that generalize those in [Zhang, Adv. Math. 365:107053 (2020)], arising from a novel family of conditional entropies with applications in quantum information. Building on new convexity results for these functionals, we establish data-processing inequalities and additivity properties for our entropies, demonstrating their operational significance. We further prove completeness under duality, chain rules, and various monotonicity properties for this family. Our proofs draw on tools from complex interpolation theory, multivariate Araki–Lieb and Lieb–Thirring inequalities, variational characterizations of trace functionals, and spectral pinching techniques.

11.
arXiv (quant-ph) 2026-06-19

Charge-Conjugation Violation and Population Asymmetry in Bipartite Fermionic Lattices

arXiv:2606.06138v2 Announce Type: replace-cross Abstract: Charge conjugation violation (CCV) is a central concept in particle physics and appears also for quasiparticles in quantum many-body systems, which typically relies on an embedded external symmetry breaking to the underlying system. An open question is how an intrinsic CCV mechanism could emerge and what its macroscopic consequences would be. We establish sublattice kinks in bipartite fermionic lattices as a concrete setup showing intrinsic CCV. The intrinsic CCV of the sublattice kink is based on the graph-topological nature of the underlying Hamiltonian, with no explicit symmetry breaking taking place. It leads to a population asymmetry of different configurations and imprints a hidden leaf-like structure in the eigenenergy spectrum. The population asymmetry also leads to an imbalanced sublattice-kink production triggered by the vacuum-instability in the quench dynamics. Our work demonstrates the graph topology as the microscopic origin of intrinsic CCV, with the population asymmetry as the macroscopic consequence, of which the proposed setup is highly amenable to experimental implementation via cold-atom quantum simulators.

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

Proprioceptive-visual correspondence enables self-other distinction in humanoid robots

arXiv:2606.13222v1 Announce Type: cross Abstract: Distinguishing self from others is a prerequisite for social intelligence, yet humanoid robots that increasingly share workspaces with humans still lack this ability. Here we show that a humanoid robot can learn self-other distinction from proprioceptive-visual correspondence, without any identity labels or kinematic models. Once established, this distinction bootstraps a predictive self-model that maps joint configurations to three-dimensional body occupancy, capturing how the robot's body changes with action. In multi-agent scenes involving humans or morphologically identical robots, the system reliably identifies itself, learns a 3D self-model, and supports downstream tasks including target reaching, collision-aware motion planning, and human-to-robot motion retargeting. Together, these results outline a route toward bodily self-representation in robots that act and coordinate alongside others in shared physical environments. Project page: https://euron-zc.github.io/humanoid-self-model/.

13.
arXiv (CS.LG) 2026-06-12

Auditing Discriminatory Patterns in Mortgage Lending Through Association Rules and Fair Binning

arXiv:2606.12435v1 Announce Type: cross Abstract: Mortgage lending in the United States exhibits persistent racial and gender disparities. We investigate whether standard data preprocessing steps, specifically attribute binning, amplify these disparities in downstream pattern mining. Using 103,481 cleaned mortgage applications from the HMDA 2023 dataset (Chicago metropolitan area), we build a three-stage pipeline: (1) a PySpark data cleaning and binning pipeline that implements both standard equal-frequency binning and the epsilon-biased fair binning algorithm from Asudeh et al. [1], (2) FP-Growth association rule mining that compares denial patterns under both binning regimes, and (3) K-Means clustering with a per-cluster disparate impact audit. Our standard binning shows 9.63% racial bias in income discretization, consistent with the 8-10% reported in prior work. Fair binning with seven race groups is infeasible at epsilon=0.03 and only succeeds at epsilon=0.08 with a Price of Fairness of 29.4%. FP-Growth reveals that high debt-to-income ratio is the dominant denial predictor (67.2% confidence, 2.81 lift), while racial bias does not appear as explicit high-support rules. However, K-Means clustering followed by a disparate impact audit flags 10 out of 45 cluster-group pairs, showing that Black applicants face significantly higher denial rates than White applicants even among financially similar groups.

14.
arXiv (CS.CV) 2026-06-16

Semantic Flip: Synthetic OOD Generation for Robust Refusal in Embodied Question Answering and Spatial Localization

Detecting unanswerable user queries remains essential for the reliable deployment of real-world embodied agents. However, modern vision-language models (VLMs) often generate overly confident answers even when the available visual memory cannot support the query. Such overconfidence poses various task-dependent risks. The agent may provide misleading information to the user in Embodied Question Answering and select an arbitrary coordinate and physically guide the user there in spatial reasoning for navigation. Despite these high stakes, only a few prior studies directly address when and how an embodied VLM should respond with "I do not know." This work proposes Semantic Flip, a simple yet effective framework that synthesizes auxiliary out-of-distribution (OOD) samples for embodied refusal without requiring external OOD annotations. The key idea is to independently transform the query and video memory to construct auxiliary OOD pairs that lack sufficient visual grounding. These synthesized pairs enable training a lightweight rejection module on top of a frozen pretrained VLM. The module attaches to any existing VLM-based pipeline without retraining the underlying model. Across two complementary benchmarks, Semantic Flip consistently outperforms strong prompting baselines. This work also introduces SpaceReject, a new refusal benchmark for spatial localization with deliberately unanswerable queries over long video memory, where Semantic Flip achieves an $F_1$ score of 0.9559. The source codes and datasets are publicly available at https://github.com/ndb796/SemanticFlip.

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

Neural Network Implementation of the Renormalization Group for Fault Diagnosis with Class Imbalance

arXiv:2606.18326v1 Announce Type: new Abstract: The application of machine learning models in practical tasks faces challenges such as class imbalance and multidimensional noise. This paper proposes RGNet, a neural network architecture based on the concept of the renormalization group (RG), for hierarchical coarse-graining of the feature space. The model sequentially compresses the input dimensionality and concatenates all scales before classification, allowing it to capture both local details and global patterns. The notion of RG-flows is introduced - interpretable low-dimensional representations whose visualization via t-SNE reveals a discrete curvilinear structure confirming the effectiveness of coarse-graining. Experimental results are presented on the imbalanced AI4I dataset. The obtained results demonstrate that RGNet is a universal, interpretable, and competitive solution for fault prediction in applications with imbalanced classes.

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

Perceptual compensation for tonal context in self-supervised speech models

This study examines the extent to which the wav2vec2.0 architecture exhibits evidence of compensation for phonological context. We conducted a pseudo-replication of a perceptional compensation experiment on Mandarin Chinese tones, and compared the embedding similarities and probing classifier outputs between a purely self-supervised pre-trained model and a model fine-tuned for Mandarin ASR. No evidence of compensation was found in the embedding similarities of the purely pre-trained model. Probing classifiers showed some evidence of compensation in addition to the expected layer-wise improvements in categorization, but failed to replicate human performance on isolated test syllables. Our findings contrast with previous reports of sensitivity to phonological structure emerging through pre-training alone, and suggest that supervised objectives may be necessary to encourage the abstraction of at least some types of phonological regularities.

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

AfroScope: A Framework for Studying the Linguistic Landscape of Africa

Language Identification (LID), the task of determining the language of a given text, is a fundamental preprocessing step that shapes the reliability of downstream NLP applications. While recent work has expanded African LID, existing systems remain limited in both language coverage and fine-grained discrimination among closely related languages and varieties. We introduce AfroScope, a unified framework for African LID that includes AfroScope-Data, a dataset covering 640 languages, and AfroScope-Models, a suite of strong LID models with broad African language coverage. To address persistent confusions among closely related languages, we propose a hierarchical classification approach that leverages AfroScope-Mirror, a specialized embedding model for targeted disambiguation, improving macro-F1 by 1.57 points on the confusable subset compared to our best base model. We further analyze cross-lingual transfer and domain effects, showing how language-family structure, script compatibility, and domain coverage shape LID performance. We position African LID as an enabling technology for large-scale measurement of Africa's linguistic landscape in digital text, and release AfroScope-Data and AfroScope-Models online.

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

Revisiting Vehicle Color Recognition in Long-Tailed Surveillance Scenarios

Vehicle color recognition is an important cue for vehicle identification in surveillance systems, especially when license plates are illegible due to low resolution, occlusion, motion blur, or poor illumination. However, real-world vehicle color distributions are highly imbalanced, making overall accuracy insufficient to assess performance on rare but operationally relevant colors. This paper presents a comprehensive study of vehicle color recognition under severe class imbalance using UFPR-VeSV, a challenging real-world surveillance dataset. We investigate synthetic minority-class augmentation through two off-the-shelf generative strategies: text-conditioned image generation with RunDiffusion/JuggernautXL and image-conditioned color editing with Gemini 2.0 Flash. The curated synthetic data are combined with modern visual representations, loss reweighting, learning-rate scheduling, color-safe augmentation, foreground-aware preprocessing, and ensemble fusion. The bestperforming approach achieves 94.6% micro accuracy and 79.7% macro accuracy, improving macro accuracy by 8.2 percentage points over recent literature. A manual error analysis further shows that many remaining failures are visually ambiguous even for human annotators, highlighting the practical limits of color-based vehicle identification in unconstrained surveillance imagery. The generated images and source code are publicly available at https://github.com/viniciusorru/vcr-synthetic

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

A Fully First-Order Layer for Differentiable Optimization

arXiv:2512.02494v2 Announce Type: replace Abstract: Differentiable optimization layers enable learning systems to make decisions by solving embedded optimization problems. However, computing gradients via implicit differentiation requires solving a linear system with Hessian terms, which is both compute- and memory-intensive. To address this challenge, we propose a novel algorithm that computes the gradient using only first-order information. The key insight is to rewrite the differentiable optimization as a bilevel optimization problem and leverage recent advances in bilevel methods. Specifically, we introduce an active-set Lagrangian hypergradient oracle that avoids Hessian evaluations and provides finite-time, non-asymptotic approximation guarantees. We show that an approximate hypergradient can be computed using only first-order information in $\tilde{O}(1)$ time, leading to an overall complexity of $\tilde{O}(\delta^{-1}\epsilon^{-3})$ for constrained bilevel optimization, which matches the best known rate for non-smooth non-convex optimization. Furthermore, we release an open-source Python library that can be easily adapted from existing solvers. The source code is available at https://github.com/guaguakai/FFOLayer.

20.
arXiv (CS.AI) 2026-06-19

Charting the Future of Scholarly Knowledge with AI: A Community Perspective

arXiv:2509.02581v2 Announce Type: replace-cross Abstract: Despite the growing availability of tools designed to support scholarly knowledge extraction and organization, many researchers still rely on manual methods, sometimes due to unfamiliarity with existing technologies or limited access to domain-adapted solutions. Meanwhile, the rapid increase in scholarly publications across disciplines has made it increasingly difficult to stay current, further underscoring the need for scalable, AI-enabled approaches to structuring and synthesizing scholarly knowledge. Various research communities have begun addressing this challenge independently, developing tools and frameworks aimed at building reliable, dynamic, and queryable scholarly knowledge bases. However, limited interaction across these communities has hindered the exchange of methods, models, and best practices, slowing progress toward more integrated solutions. This manuscript identifies ways to foster cross-disciplinary dialogue, identify shared challenges, categorize new collaboration and shape future research directions in scholarly knowledge and organization.

21.
bioRxiv (Bioinfo) 2026-06-13

Reinforcement learning-driven unified generative framework for multi-objective RNA codon design

Current RNA codon design methods are limited by inefficient long-sequence processing and poor generalizability, often relying on a decoupled "generate-or-optimize" paradigm. We introduce RNARL, a reinforcement learning-driven framework that unifies sequence generation with multi-objective optimization. RNARL directly learns to generate high-performance sequences, effectively optimizing sequences over 3,900 nucleotides and demonstrating superior performance and universality across six species and five RNA types. RNARL thus establishes an effective and generalizable framework for RNA codon design. Finally, a user-friendly web platform is freely available to facilitate its application for RNA therapeutic design.

22.
arXiv (CS.CV) 2026-06-15

Pano3D: Unified 3D Reconstruction and Panoptic Segmentation

Recent advances in 3D feedforward reconstruction neural networks have achieved remarkable success in dense reconstruction from images without any camera parameters. Yet, equipping these models with robust semantic understanding remains an open problem. Here we introduce an approach that performs 3D reconstruction and 3D panoptic segmentation in a unified framework. We build on existing 3D reconstruction models and augment them with a set-based mask decoder. The approach is jointly trained with a geometric and semantic loss, which are shown to be mutually beneficial. More precisely, the features are initialized from the geometric information and then finetuned to capture jointly geometry and semantics. We demonstrate the generality of our approach by successfully applying our framework both to online and all-to-all attention reconstruction backbones. Our method achieves state-of-the-art performance in 3D panoptic segmentation across ScanNet, ScanNet200, and ScanNet++ datasets. Ablation studies show that such joint training of a unified model equips 3D feedforward reconstruction neural networks with panoptic segmentation and yields mutually beneficial improvements.

23.
arXiv (CS.AI) 2026-06-15

Discovery under Hypothesis Redundancy: A Geometric Theory of Discovery Bottlenecks

arXiv:2606.14386v1 Announce Type: cross Abstract: Scientific discovery saturates when new hypotheses cease to provide independent information, even if the nominal hypothesis space remains large. We study hybrid discovery systems that combine structured local search with LLM-generated non-local proposals and pose the Search Compression Hypothesis: non-local exploration helps only when three geometric conditions co-occur: spectral compression, orthogonal escape from the explored span, and residual signal alignment with the target. We formalize these conditions, derive necessary conditions for hybrid advantage, and test the mechanism in controlled synthetic environments, large-scale A-share factor discovery, and symbolic-regression benchmarks; a public tabular operational sanity check tests the associated budget-allocation implication. Signal-planting and directed-versus-random experiments show that novelty alone is insufficient: random orthogonal jumps expand coverage but do not improve yield without predictive alignment. Across compression sweeps, real factor archives, and LLM-SRBench tasks, hybrid gains concentrate in weakly represented but target-bearing directions and vanish as the hypothesis space approaches full rank. The framework turns LLM-guided discovery from generic novelty search into a diagnostic procedure for deciding when directed non-local exploration is warranted.

24.
medRxiv (Medicine) 2026-06-12

An integrative multi-omics framework identifies epigenetic dysregulation of HAND2 as a potential primary driver of impaired enteric neural crest cell differentiation in Hirschsprung Disease

Hirschsprung disease (HSCR) is a congenital neurodevelopmental disorder characterized by segmental aganglionosis due to impaired developmental processes of enteric neural crest cells (NCCs). Despite being the leading genetic cause of functional intestinal obstruction in early childhood, HSCR represents a paradigmatic challenge in precision medicine: its multifactorial etiology, complex gene-environment interactions and limited resolution of single-modality analyses have long hindered mechanistic understanding and therapeutic translation. Here, we applied an integrative multi-omics approach combining genetic, phenotypic, epigenomic and transcriptomic analyses of matched ganglionic and aganglionic formalin-fixed paraffin-embedded (FFPE) patient tissues, complemented by patient-specific in vitro models. Beyond established genetic contributors, our integrative approach reveals novel regulatory pathways predominantly affecting enteric NCC differentiation, with convergent evidence pointing to epigenetic dysregulation as a primary disease mechanism. Notably, we identified over 1,300 differentially methylated positions between ganglionic and aganglionic FFPE samples, with HAND2 emerging as a key candidate due to multiple hypermethylated sites and consistently reduced expression levels in aganglionic tissues and in vitro models, suggesting a potential role in HSCR pathophysiology. We propose that our multi-omics approach offers a powerful and comprehensive framework for dissecting disease mechanisms. Beyond advancing biological understanding, this strategy holds promise for paving the way for molecularly informed patient stratification and supporting the development of personalized treatment and postoperative management strategies.

25.
arXiv (quant-ph) 2026-06-16

Achieving double-logarithmic precision dependence in optimization-based quantum unstructured search

arXiv:2603.26039v3 Announce Type: replace Abstract: Grover's algorithm is a fundamental quantum algorithm that achieves a quadratic speedup for unstructured search problems of size $N$. Recent studies have reformulated this task as a maximization problem on the unitary manifold and solved it via linearly convergent Riemannian gradient ascent (RGA) methods, resulting in a complexity of $O(\sqrt{N/M}\log (1/\varepsilon))$, where $M$ denotes the number of target items and $\varepsilon$ denotes the success probability error. In this work, we adopt the Riemannian modified Newton (RMN) method to solve the quantum search problem, under the assumption that the ratio $ M/N$ is known. We show that, in this setting, the Riemannian Newton direction is collinear with the Riemannian gradient in the sense that the Riemannian gradient is always an eigenvector of the corresponding Riemannian Hessian. This structure removes the overhead of Hessian inversion and allows the proposed RMN method to retain the local quadratic convergence in terms of the error $\varepsilon$. More precisely, we rigorously prove an overall complexity of $O(\sqrt{N/M}+\log\log(1/\varepsilon))$. Furthermore, our approach remains Grover-compatible, namely, it relies exclusively on the standard Grover diffusion and oracle operators to ensure algorithmic implementability, and its parameter update process can be efficiently precomputed on classical computers.