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01.
arXiv (CS.CL) 2026-06-17

findsylls: A Language-Agnostic Toolkit for Syllable-Level Speech Tokenization and Embedding

Syllable-level units offer compact and linguistically meaningful representations for spoken language modeling and unsupervised word discovery, but research on syllabification remains fragmented across disparate implementations, datasets, and evaluation protocols. We introduce findsylls, a modular, language-agnostic toolkit that unifies classical syllable detectors and end-to-end syllabifiers under a common interface for syllable segmentation, embedding extraction, and multi-granular evaluation. The toolkit implements and standardizes widely used methods (e.g., Sylber, VG-HuBERT) and allows their components to be recombined, enabling controlled comparisons of representations, algorithms, and token rates. We demonstrate findsylls on English and Spanish corpora and on new hand-annotated data from Kono, an underdocumented Central Mande language, illustrating how a single framework can support reproducible syllable-level experiments across both high-resource and under-resourced settings.

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

Regular Fourier Features for Nonstationary Gaussian Processes

arXiv:2602.23006v2 Announce Type: replace-cross Abstract: Simulating a Gaussian process requires sampling from a high-dimensional Gaussian distribution, which scales cubically with the number of sample locations. Spectral methods address this challenge by exploiting the Fourier representation and treating the spectral density as a probability distribution suitable for Monte Carlo approximation. Although this probabilistic interpretation is valid for stationary processes, it is overly restrictive for the nonstationary case, where spectral densities are generally not probability measures. We propose regular Fourier features for harmonizable processes to avoid this limitation. Our method discretizes the spectral representation directly, preserving the correlation structure among spectral weights without requiring probability assumptions. Under a finite-spectral-support assumption, this yields an efficient low-rank approximation that is consistent and positive semi-definite by construction. When the spectral density is unknown, the framework extends naturally to kernel learning from data. We demonstrate the method on locally stationary and harmonizable mixture kernels, the latter with a complex-valued spectral density, and apply the kernel-learning extension to real and synthetic data.

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

Overhead Wildlife Locator (OWL): Benchmarking Weakly Supervised Learning for Aerial Wildlife Surveys

Automated aerial wildlife surveys increasingly rely on deep learning, yet standard object detectors require bounding-box annotations, reported to be up to seven times slower and three times more expensive to produce than point-level labels. To address this bottleneck, we introduce the Overhead Wildlife Locator (OWL), a weakly supervised density-estimation framework with three variants: OWL-C, a fully convolutional model for high-throughput screening; OWL-T, a Swin-augmented hybrid for heterogeneous, cluttered scenes; and OWL-D, built on a frozen DINOv3 ViT-H+/16 encoder with a DPT-style fusion decoder. We benchmark all three against POLO, YOLOv11n, and YOLOv11l across five public aerial datasets, from sparse fixed-wing savanna surveys to dense UAV paddock imagery, and against the published HerdNet baseline on its native Delplanque split. OWL-D sets a new state of the art on Delplanque (0.934 AP vs. HerdNet's 0.840) and records the highest AP on four of the five datasets. Performance is regime-dependent: on the extreme-density SheepCounter UAV dataset the hybrid OWL-T leads (0.978 AP) and the convolutional variants attain the lowest counting error, whereas the foundation-based OWL-D degrades, indicating which variant suits which survey type. We further validate operational readiness on the Alaska Department of Fish and Game's 2022 Central Arctic Caribou census: under cross-herd and cross-temporal transfer, OWL-C fine-tuned on the 2017 Porcupine Caribou Herd split attains F1 = 0.965 on a held-out patch test set, with a signed count error of +3.1% aggregated across the released test patches. We release the OWL code, model weights, and the annotated Porcupine Caribou Herd 2017 (PCH) and Central Arctic Herd 2022 (CAH) patches, the first open patch-level datasets for large-scale caribou aerial surveys, at https://github.com/microsoft/MegaDetector-Overhead.

04.
arXiv (CS.AI) 2026-06-12

ToolSense: A Diagnostic Framework for Auditing Parametric Tool Knowledge in LLMs

arXiv:2606.12451v1 Announce Type: new Abstract: Large language models deployed as agents over large tool catalogs face a critical tool-retrieval bottleneck. As embedding-based retrieval approaches rely on compact encoders that may under-capture specialized tool semantics, parametric tool retrieval addresses this by encoding each tool as a virtual token appended to the LLM vocabulary, fine-tuned in two stages (memorization then retrieval SFT) to use the LLM as a retriever, achieving strong performance on standard ToolBench retrieval benchmarks. Yet these benchmarks use verbose, fully-specified queries, and their evaluation applies constrained decoding that restricts outputs to valid token paths, neither reveals whether the model actually understands its tools. We introduce ToolSense, an open-source LLM-powered diagnostic framework that takes any tool catalog as input and automatically generates three benchmarks: a Realistic Retrieval Benchmark (RRB) with queries at three ambiguity tiers, an MCQ probing benchmark, and a QA probing benchmark. Applying ToolSense to ToolBench (~47k tools) and evaluating five parametric model training configurations reveals a knowledge-retrieval dissociation: on RRB queries, several configurations collapse by ~50-64 percentage points compared to fully-specified ToolBench benchmarks, falling below the embedding-model baseline. Additionally, despite strong retrieval performance, some models score near-random on factual probes, suggesting a knowledge-retrieval dissociation. We open-source the ToolSense framework and the ToolBench diagnostic benchmarks at https://github.com/SAP/toolsense.

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

When to use what Schatten-$p$ norm in deep learning?

arXiv:2606.15268v1 Announce Type: new Abstract: Schatten-$\infty$ based optimizers such as Muon have shown promising empirical performance, but there remains seemingly conflicting observations regarding whether they are beneficial. We resolve this conflict by showing that the conclusion is regime dependent. Even when the objective is smooth in the Schatten-$\infty$ geometry, smaller Schatten-$p$ geometries can be optimal, specifically in the low-dimensional regime, which we show includes Chinchilla scaling. This conclusion follows from a new noise-robust acceleration result for the SODA framework for $p>2$. The same analysis explains why Muon-like methods do not require warmup, why they naturally favor large batches, and yields a batch size scaling rule for arbitrary $p$.

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

Enhancing Many-Body Chaos via Entropy Injection from Environment

arXiv:2606.11784v1 Announce Type: new Abstract: In closed quantum systems, local information spreads throughout the entire system and becomes highly complex under unitary evolution. In contrast, when the system is embedded in an environment, system-environment coupling can transfer information from the system into the environment, thereby reducing the rate of complexity growth within the system. This leads to the environment-induced scrambling transition established in previous works. In this work, we identify entropy injection from the environment as a different physical process that instead enhances many-body chaos. Our setup consists of coupling a system that is already in equilibrium with one environment to another environment, which serves as an entropy reservoir and drives the system into a non-equilibrium state. When entropy flows into the system through either heat transfer or particle transfer, the effective Hilbert space explored by the system enlarges, a mechanism that can enhance many-body chaos. We explicitly demonstrate this idea by constructing a solvable complex Brownian SYK model, in which both the relaxation toward the steady state and the steady-state quantum Lyapunov exponent can be computed analytically. Our results provide a controllable mechanism for tuning quantum scrambling through entropy flow in quantum many-body systems coupled to environments.

07.
arXiv (quant-ph) 2026-06-11

A Pfaffian quantum Hall state of ultracold bosons

arXiv:2606.12409v1 Announce Type: cross Abstract: Fractional quantum Hall states are a cornerstone of topological physics, hosting fractionally charged quasiparticles with exotic statistics that promise to enable topologically protected quantum information processing. Among these, the Pfaffian state introduced by Moore and Read implements a p-wave pairing structure that supports excitations with non-Abelian exchange statistics. Despite extensive study in electronic systems, direct access to its pairing structure has remained limited. Here we realize a three-particle bosonic Pfaffian state of ultracold $^{87}\mathrm{Rb}$ atoms in an optical lattice subject to a Floquet-engineered synthetic magnetic field. Using a Bayesian-optimized adiabatic protocol, we prepare a state exhibiting Pfaffian pairing correlations. Site-resolved measurements of multi-point density correlations reveal a pronounced suppression of short-range three-body coincidences, reflecting the underlying pairing structure. We further probe the state's transport response through Hall drift measurements. Our results establish a bottom-up approach to engineering non-Abelian topological order and lay the groundwork for future explorations of anyonic braiding in synthetic matter.

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

Value-order Decomposition for Generalist Anomaly Detection

Industrial anomaly detection suffers from limited data, making cross-domain generalization particularly challenging. Generalist Anomaly Detection (GAD) aims to train a unified model on a source domain that can effectively detect anomalies in unseen target domains. In the initial semantic feature space, strong entanglement between anomalies and object categories or defect types hinders effective generalization across domains. Recent works address this issue by projecting features into a residual space; however, such methods primarily increase cross-domain overlap for normal features, while anomalous features remain specific to object categories, defect types and data domains, leading to poor alignment and generalization. To address this limitation, we propose Value-order Decomposition (VOD), a simple yet effective technique that bridges three types of generalization gaps across object categories, defect types (including real and synthetic defects), and data domains. VOD disentangles and suppresses object-category-, defect-type-, and domain-specific information, promoting alignment within normal and abnormal samples while preserving their separability, thereby enabling robust generalization across the three gaps. Leveraging the strong alignment between real and synthetic defects within the same object, we perform anomaly detection using only normal and synthetic-abnormal reference, and effectively generalize to unseen real defect types. Experiments on diverse industrial and medical benchmarks demonstrate that our method, using a simple cut-and-paste anomaly simulation strategy, achieves strong generalization across the three gaps.

09.
arXiv (CS.CL) 2026-06-19

NAMESAKES: Probing Identity Memorization in Text-to-Image Models

Text-to-image (T2I) models generate realistic likenesses of some individuals when prompted with their names, raising privacy concerns. However, distinguishing whether a generated face is memorized or fabricated currently requires ground-truth photos, access to training data, or white-box access to model internals, limiting applicability. We introduce a fully black-box behavioral probe that distinguishes between these regimes while requiring no reference photos or prior knowledge of training data. To benchmark this task, we present the NAMESAKES dataset of over one thousand names and faces of public figures spanning a wide range of fame levels, along with perturbed, less famous names. Experiments on state-of-the-art T2I models show that our probe substantially predicts identity memorization and separates memorized from unrecognized names, with further insights into differences across model families.

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

PROJECTMEM: A Local-First, Event-Sourced Memory and Judgment Layer for AI Coding Agents

arXiv:2606.12329v1 Announce Type: new Abstract: AI coding assistants now support a growing share of software work, from quick scripts to production applications. Yet these agents remain largely stateless: each new session re-reads project files, re-derives prior decisions, and - most costly - may repeat debugging attempts that already failed. Reconstructing this context can consume an estimated 5,000-20,000 tokens per session; the bottleneck is often not model capability but missing project memory. We present projectmem, an open-source, local-first memory and judgment layer for AI coding agents. projectmem records development as an append-only, plain-text event log of typed events - issues, attempts, fixes, decisions, and notes - and deterministically projects that log into compact, AI-readable summaries served through the Model Context Protocol (MCP). Beyond storage, projectmem adds a deterministic pre-action gate that warns an agent before it repeats a previously failed fix or edits a known-fragile file. We frame this as Memory-as-Governance: memory that does not merely answer the agent but acts on its next action. The system runs fully offline with no telemetry; its immutable log also serves as a provenance trail for reproducible, auditable AI-assisted development. projectmem ships as a three-dependency Python package (14 MCP tools, 19 CLI commands, 37 automated tests) and is evaluated through a two-month self-study across 10 projects comprising 207 logged events. Source code: https://github.com/riponcm/projectmem.

11.
arXiv (CS.AI) 2026-06-16

HAMON: Passive Optical Sequence Mixing for Long-Horizon Forecasting

arXiv:2606.17028v1 Announce Type: cross Abstract: Simple linear and frequency-domain models remain surprisingly competitive in long-horizon time-series forecasting, and recent mechanistic evidence suggests that standard forecasting benchmarks may not require the dense superposed representations that make transformers powerful in other domains. This raises a substrate-level question: if the core forecasting operator is often low-complexity and approximately linear, does it need to be implemented as learned digital temporal mixing? We introduce HAMON, a passive diffractive optical forecasting core in which historical values are encoded onto an optical aperture, future positions are left dark, and cascaded trainable phase masks with free-space diffraction shape the forecast directly in the output field. At inference, prediction is performed by a single passive optical propagation pass with no trainable digital sequence-mixing layer. Across standard benchmarks, HAMON outperforms the strongest digital baselines considered on ETTm2 at all horizons and on ETTh2 at all but the longest horizon, improving MSE by up to 14\% and doing so consistently across horizons rather than at isolated points. It is competitive on Weather and trails the strongest baselines on the remaining ETT settings and on the high-channel-count Traffic and Electricity datasets. Phase encoding, intensity-compatible readout, and phase-scrambling ablations, together with a TorchOptics cross-simulator check, indicate that the forecasts arise from the data-bearing optical field rather than from a digital forecasting head. Because the passive core uses standard Fourier optics, HAMON defines a concrete target for optical hardware and for passive physical sequence mixing.

12.
arXiv (math.PR) 2026-06-15

A random approach to the multibonacci sequence

arXiv:2606.14294v1 Announce Type: cross Abstract: This paper presents a random approach to the multibonacci sequence. We generalise the model introduced by Benjamin, Levin, Mahlburg, and Quinn, which is based on a random tiling method using dominoes and squares that leads to the Fibonacci sequence, and which was extended to the tribonacci case in a previous work by the authors. Our approach employs tiling with linear $k$-ominoes, $k=1,\ldots,s$, combined with specific colouring, to generate a weighted multibonacci sequence. For a natural random variable~$X$ defined by this model, we establish the distribution of $X$ in terms of multibonacci numbers and compute $\mathbb{E}[X] = 2^{s+1}-3$.

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

Connections Between Pairs of Filters Improve the Accuracy of Convolutional Neural Networks

While researchers continue to find new and improved network structures for CNNs, most of the newly invented architectures still rely on the traditional pattern of stacking convolutional blocks and separating them with pointwise activation functions. However, there are drawbacks to a network purely building on pointwise nonlinearities. One alternative is to introduce a pairwise connection between two filters of a network. Typical connection functions use multiplications or the minimum operation to realize logical AND connections. In this paper, we go one step further by demonstrating that CNNs can benefit from more general connections, which include parameters that are learned. With such parameters, the network is able to implement different connections in different network layers and better adapt the connection function to the task at hand.

14.
arXiv (quant-ph) 2026-06-19

Passive-User Bell-State Loop-Back Key Establishment without Quantum Detectors at the User Nodes

arXiv:2606.19551v1 Announce Type: new Abstract: We propose and analyze a Bell-state extension of the Loop-Back quantum key distribution architecture for secret-key establishment between two passive users that do not require quantum transmitters or quantum detectors. In the proposed setting, a single active station, Alice, provides the entangled-state infrastructure, retains one qubit of an initially prepared Bell pair, and sends the traveling subsystem through two passive users, denoted by $B_1$ and $B_2$. Each passive user applies a local Pauli operation to the same traveling subsystem, so that the operation observed by Alice is only the effective composition $U_{\mathrm{eff}}=U_2U_1$. After the subsystem returns, Alice performs a Bell-state measurement and, using her private knowledge of the initial Bell state, deterministically identifies the effective Pauli operation. However, the individual factors $U_1$ and $U_2$ remain algebraically hidden from Alice whenever the local choices are uniformly and independently selected. The public effective operation acts as a parity-like constraint: each passive user can infer the operation applied by the other from its own private choice, while the active station learns only the global composition. This construction transfers the essential distributed-transformation mechanism of passive-user Loop-Back QKD to the entangled-state regime. Unlike single-qubit passive-user schemes, whose useful events are intrinsically post-selected, the Bell-state version is limited primarily by the success probability of the Bell-state measurement. We discuss the algebraic structure of the protocol, its interpretation as an infrastructure-assisted mediated key-establishment mechanism, and the physical assumptions required to protect passive Pauli modulators against active injection or Trojan-horse-type attacks.

15.
arXiv (CS.AI) 2026-06-16

Retrieve, Don't Retrain: Extending Vision Language Action Models to New Tasks at Test Time

arXiv:2606.15631v1 Announce Type: cross Abstract: Extending a vision-language-action (VLA) policy to a new task typically requires task-specific teleoperated demonstrations and per-task fine-tuning, making adaptation costly in both data collection and compute. In this paper, we show that this target-side per-task adaptation cost can be replaced by retrieval. Our retrieval-augmented policy is trained once on paired demonstrations from the target embodiment (query) and a cheaper embodiment (pool, e.g., human-hand video), then frozen. New tasks are added at deployment by appending pool-side demonstrations to a retrieval pool. The frozen policy conditions on retrieved trajectories at every control step, so new tasks are absorbed by indexing data rather than updating parameters. Fine-tuning is needed only to take on a new, unseen embodiment, not for each new task. We show that retrieval improves policies beyond a specific backbone, including standard VLA policies, but its effect is especially pronounced in Cosmos Policy, a video-generation-based world-action model (WAM). In this setting, retrieval supplies coarse task progression, while the WAM's future-image objective provides an additional visual consistency signal that strengthens the retrieval-conditioned actions. On PushT, we study how retrieval provides a reusable high-level motion prior for cross-embodiment generalization to unseen goal angles, while on RoboTwin 2.0 our method outperforms cross-embodiment baselines on unseen tasks, and we additionally demonstrate the method on a real robot.

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

Trust-Region Diffusion Policies for Massively Parallel On-Policy RL

arXiv:2606.15260v1 Announce Type: cross Abstract: Reinforcement learning with massively parallel simulations has become a standard framework for developing robust, deployable policies; however, most existing approaches still rely on simple Gaussian policy parameterizations. Diffusion models provide a more expressive policy class and have shown strong performance on challenging control problems, yet most diffusion-based RL methods are designed for offline or off-policy training. In this work, we ask whether diffusion policies can be trained effectively in the massively parallel, on-policy regime. To this end, we introduce Trust-region Diffusion Policies (TruDi), which enables diffusion policies for on-policy RL with massively parallel simulations. This setting is particularly challenging because the data distribution changes quickly across updates, making stable training with complex policies difficult. TruDi addresses this by integrating a trust-region optimization rule to enforce a KL-divergence constraint over the entire diffusion trajectory. Empirically, we evaluate TruDi on a diverse set of 4 massively parallel RL benchmarks comprising a total of 73 tasks. Across these tasks, TruDi consistently outperforms or is on-par with strong baselines on standard tasks and achieves clear gains on more challenging humanoid control tasks, establishing a strong new baseline for massively parallel on-policy RL.

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

PANDA: An LLM-Enhanced Performance-Driven Analog Design Framework Bridging Design Intent and Layout Generation

arXiv:2606.15052v1 Announce Type: cross Abstract: Traditional design of analog circuits heavily relies on manual interventions across topology, sizing, and layout, with prior automation addressing stages in isolation. In this work, we propose PANDA, an LLM-enhanced framework that bridges high-level design intent to final layout by actively managing cross-stage dependencies through guided topology synthesis, substructure-aware sizing, and constraint-driven layout generation. This shifts automation from algorithm-centric execution to intent-centric co-design, reducing turnaround time from days or weeks to hours while improving design performance.

18.
arXiv (CS.CV) 2026-06-11

A Turbo-Inference Strategy for Object Detection and Instance Segmentation

Object detection and instance segmentation tasks are closely related. Existing top-down instance segmentation methods usually follow a detect-then-segment paradigm, where an initial detector is used to recognize and localize objects with bounding boxes, followed by the segmentation of an instance mask within each bounding box. In such methods, the detection accuracy directly influences the subsequent segmentation performance. However, previous research has seldom explored the impact of the instance segmentation task on object detection. In this paper, we present a turbo-inference strategy for the top-down methods that leverages the complementary information between detection and segmentation tasks iteratively. Specifically we design two modules: turbo-detection head and turbo-segmentation head, which facilitate communication between the tasks. The two modules form a closed loop that interlaces the detection and segmentation results without retraining the model. Comprehensive experiments on the COCO, iFLYTEK, and Cityscapes datasets demonstrate that our method substantially enhances both detection and segmentation accuracies with a certain increase in computational cost. The proposed method represents a tradeoff between prediction accuracy and inference speed. Codes are available at https://github.com/zhaozhen2333/Turbo-Learning.git.

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

Addressing Detail Bottlenecks in Latent Diffusion for RGB-to-SWIR Image Translation

Latent diffusion models (LDMs) enable efficient image-to-image translation but discard fine spatial details during compression, degrading downstream perception tasks. We identify two bottlenecks: the autoencoder, which loses spatial information, and the conditioning pathway, which further degrades the source signal through naive downsampling. We propose two lightweight, backbone-agnostic fixes: a Source-Conditioned Autoencoder (SCAE) that injects high-resolution source features into the decoder via skip connections, and a Learnable Guidance Encoder (LGE) that replaces naive downsampling with a learned conditioning signal. Evaluated on RGB-to-SWIR translation for driving scenes with two denoiser backbones (U-Net and DiT), our approach improves detection mAP by up to 2x over the latent diffusion baseline, with up to 3.4x gains on small objects (COCO-small,

21.
arXiv (CS.CL) 2026-06-11

Pretrained self-supervised speech models can recognize unseen consonants

Modern pretrained self-supervised automatic speech recognition models are trained on large-scale audio data to encode speech into contextualized representations. However, their training data are heavily skewed toward high-resource languages with little data from low-resource languages, raising concerns about the potential underrepresentation of typologically uncommon speech sounds such as click consonants primarily found in Khoisan languages. This leads to our central research question: Can these models recognize click consonants as accurately as other speech sounds? To address this question, we fine-tune and compare pretrained self-supervised speech models (Wav2Vec2 and HuBERT) on data from two click-rich Khoisan languages (G|ui and West !Xoon). Our results reveal that the fine-tuned models consistently recognize clicks more accurately than non-clicks, suggesting that self-supervision enables generalization across human speech sounds including rare phonemes.

22.
arXiv (CS.LG) 2026-06-19

The Representational Limit of Scalar Interactions: An Interventional Decomposition

arXiv:2606.19410v1 Announce Type: cross Abstract: Signed pairwise interaction scores fundamentally conflate uniqueness (U), redundancy (R), and synergy (S). We prove this on a minimal 3-way XOR structural causal model: faithful indices such as Shapley-Taylor return zero per pair, whereas projective indices such as Shapley Interaction spread the third-order effect into pair scalars that conflate the three mechanisms. We introduce Stochastic Hi-Fi, a post-hoc, retraining-free predictability decomposition that estimates per-feature U/R/S profiles by interventional masked inference. The estimator provides exact interventional semantics, finite-sample Monte Carlo bounds, strict variance reduction from coupled diamond sampling, and uniform finite-vocabulary convergence. Across tabular SCMs, Stochastic Hi-Fi recovers structure missed by scalar baselines (up to 411x larger interaction-magnitude recovery ratios). It also separates redundant and synergistic heads in the GPT-2 IOI circuit. On NIH ChestX-ray14, Stochastic Hi-Fi matches GradCAM on Pointing Game and improves substantially on Deletion AUC.

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

Multi-Modal Agents for Power Distribution Defect Detection: An Evaluation of Foundation Models

作者:

arXiv:2606.12969v1 Announce Type: new Abstract: The power distribution network is critical to reliable electricity delivery, yet traditional inspection methods face limitations in semantic understanding, generalization, and closed-loop automation. To address these challenges, this paper proposes a Multi-Modal Agent framework specifically for power distribution defect detection. Central to this study is the systematic evaluation of multimodal foundation models as unified cognitive engines. We rigorously assess their integrated performance across three critical capabilities: (1) Perception, where the model must accurately identify equipment and generate expert-level descriptions of defects; (2) Reasoning, where the model interprets visual findings to diagnose causes, assess severity, and plan maintenance strategies based on domain knowledge; and (3) Tool Usage, where the model acts as an autonomous operator to execute actions – such as querying knowledge bases or generating work orders – to achieve closed-loop maintenance. To support this evaluation, a domain-specific evaluation dataset and a comprehensive benchmark are developed. Experimental results demonstrate the strengths and limitations of current foundation models in these three dimensions, providing empirical evidence for deploying autonomous agents in high-stakes industrial environments.

24.
medRxiv (Medicine) 2026-06-18

AlphaGenome identifies a deep intronic variant in a family with PLA2G6-associated neurodegeneration: Closing the diagnostic gap in rare genetic diseases

A molecular diagnosis remains out of reach for a substantial subset of patients with clinically recognizable Mendelian disorders, even after comprehensive next-generation sequencing. Causal variants in non-coding regions are difficult to detect and interpret using standard pipelines. Deep intronic variants that disrupt splicing are a known but underexplored source of pathogenic alleles, and systematic tools to evaluate them at scale have only recently emerged. We aimed to resolve an incomplete genetic diagnosis in two siblings with early-onset parkinsonism, prominent neuropsychiatric features, and autonomic dysfunction consistent with PLA2G6-associated neurodegeneration (PLAN), an autosomal recessive condition. Prior clinical exome sequencing, genome sequencing, Multiplex Ligation-dependent Probe Amplification (MLPA), and long-read sequencing had identified only a single heterozygous PLA2G6 missense variant, c.2132C>G (p.Pro711Arg). We used AlphaGenome to score 91 non-coding variants shared among the affected siblings and their father within 1 megabase of the PLA2G6 locus. The deep-learning model identified an intronic variant (c.2034+355G>A) that was predicted to create a cryptic splice acceptor site that could result in inclusion of a 160-bp cryptic exon. Tissue-specific predictions indicated the aberrant splicing would be detectable in blood, confirmed by junction-spanning RNA-seq reads from an unrelated carrier. This analysis completed a compound heterozygous PLAN diagnosis nearly two decades after symptom onset and demonstrates the utility of sequence-to-function models. Systematic integration of tools like AlphaGenome into rare disease workflows offers a practical, low-barrier route to closing the diagnostic gap for patients with compelling Mendelian phenotypes and incomplete genetic diagnoses.

25.
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.