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01.
arXiv (CS.CL) 2026-06-19

The Voice Behind the Words: Quantifying Intersectional Bias in SpeechLLMs

Speech Large Language Models (SpeechLLMs) process spoken input directly, retaining cues such as accent and perceived gender that were previously removed in cascaded pipelines. This introduces speaker identity dependent variation in responses. We present a large-scale intersectional evaluation of accent and gender bias in three SpeechLLMs using 2,880 controlled interactions across six English accents and two gender presentations, keeping linguistic content constant through voice cloning. Using pointwise LLM-judge ratings, pairwise comparisons, and Best-Worst Scaling with human validation, we detect recurring directional disparities. Eastern European-accented speech receives lower helpfulness scores, particularly for female-presenting voices. Responses remain polite but differ in helpfulness. While LLM judges capture the directional trend of these biases, human evaluators exhibit significantly higher sensitivity, showing stronger accent-level contrasts.

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

PARSE: Provenance-Aware Retrieval Sanitization for Professional Domain LLM Agents

作者:

Prompt injection defenses evaluated on synthetic benchmarks do not generalize to real enterprise documents, which are longer, denser, and interleave legitimate authority language with factual content. We demonstrate this gap with a real-document benchmark of 122 tasks across five professional domains (financial, legal, medical, scientific, DevOps) using actual SEC filings, Federal Register rules, PubMed abstracts, arXiv papers, and GitHub postmortems. Paraphrasing, the strongest defense on synthetic benchmarks, shows no statistically significant attack success rate reduction on real documents (p=0.500) while degrading utility from 91.8% to 82.8%. We introduce PARSE (Provenance-Aware Retrieval Sanitization), a domain-aware, fact-preserving sanitization pipeline that classifies each sentence by injection likelihood, extracts structured facts before rewriting, and verifies fact preservation via a consistency-checking loop. A directiveness gate routes 59% of real enterprise documents to a lightweight path, concentrating computational cost on high-risk documents. PARSE achieves 15.6% attack success rate – a 38% reduction versus the 25.4% baseline – at 86.9% utility, the only condition that is both statistically significant (p=0.014, adequately powered) and maintains near-baseline utility. Practitioners should evaluate defenses on domain-matched real documents, not synthetic proxies.

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

Modality-Aware Feature Matching in Visual and Vision-Language Applications: A Comprehensive Survey

Feature matching is a cornerstone task in computer vision, essential for applications such as image retrieval, stereo matching, 3D reconstruction, and SLAM. This survey comprehensively reviews modality-based feature matching, exploring traditional handcrafted methods and emphasizing contemporary deep learning approaches across various modalities, including RGB images, depth images, 3D point clouds, LiDAR scans, medical images, and vision-language interactions. Traditional methods, leveraging detectors like Harris corners and descriptors such as SIFT and ORB, demonstrate robustness under moderate intra-modality variations but struggle with significant modality gaps. Contemporary deep learning-based methods, exemplified by detector-free strategies like CNN-based SuperPoint and transformer-based LoFTR, substantially improve robustness and adaptability across modalities. We highlight modality-aware advancements, such as geometric and depth-specific descriptors for depth images, sparse and dense learning methods for 3D point clouds, attention-enhanced neural networks for LiDAR scans, and specialized solutions like the MIND descriptor for complex medical image matching. Cross-modal applications, particularly in medical image registration and vision-language tasks, underscore the evolution of feature matching to handle increasingly diverse data interactions.

04.
arXiv (CS.LG) 2026-06-19

Judging to Improve: A De-biased VLM-as-3D-Judge Protocol for Single-Image 3D Generation

arXiv:2606.20364v1 Announce Type: new Abstract: A companion study established a de-biased, cross-model VLM-as-3D-judge that reliably ranks single-image-to-3D mesh quality where cheap geometry and CLIP proxies fall short. This paper asks: can that judge's preferences specialize a strong open generator, TRELLIS, on one asset class (furniture), cheaply and without human labels? Taking the judge from ranking to optimization is where the work lives. Pushing a VLM judge into the training and evaluation loop exposes failure modes ranking never triggered, so our contribution is an optimization-grade hardening of the judge: a training judge (Qwen2.5-VL-7B) held distinct from an evaluation judge (InternVL3-8B) to break circularity; position-bias correction; and fixes for three failure modes (image overload, geometry-hiding splat renders, and reference-free judging that rewards clean-but-wrong outputs), with calibration evidence (clear-gap win-rate 0.83-1.0; base-vs-base ~0.5). Using this protocol as an independent evaluator, and working only from public models and data with lightweight parameter-efficient adaptation, we find our methods match the strong base rather than exceed it. Independent base samples carry essentially no learnable preference (0.94 order-flip rate), so signal must be engineered by quality-contrastive construction. Across six adaptation methods, two input regimes, and a severity sweep, the most targeted - conditioner repair under severe degradation - reaches parity (0.50) with the base, while no method clears the >=65% win-rate target. The result is mechanistic: clean inputs saturate the judge, flow-DIT fine-tuning washes out through the sampler, and conditioning repair is the locus that moves geometry. Win-rates are directional at n=8 objects. Matching a strong public-data base with cheap adaptation is itself informative: exceeding it needs more than lightweight PEFT on public data, and the judge protocol is reusable.

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

Few-Shot Resampling for Scalable Statistically-Sound Data Mining

arXiv:2606.11235v1 Announce Type: new Abstract: A key step in knowledge discovery is the evaluation of data mining results. In several applications, including pattern mining, graph analysis, and others, this step includes the evaluation of the statistical significance of the results, to avoid spurious discoveries due only to noise or random fluctuations in the data. While specialized procedures have been developed for some specific applications, resampling-based approaches are widely used, in particular for complex analyses where analytical results cannot be derived. However, current resampling-based approaches require the generation and analysis of thousands of resampled datasets, and are therefore impractical for large datasets or computationally intensive analyses. In this paper, we introduce FewRS, a simple and effective resampling-based approach to assess the statistical significance of data mining results with rigorous guarantees on the probability of false discoveries. Our approach can be used in every situation where resampling-based approaches are applied. FewRS builds on our derivation of a novel bound to the supremum deviation of test statistics representing the quality of data mining results. We prove that FewRS needs to generate and analyze an extremely small number of resampled datasets, leading to a highly scalable approach with wide applicability. We test our approach on common tasks such as pattern mining and network analysis. In all cases, our approach results in a reduction of up to two orders of magnitude in running time compared to the state of the art, while preserving high statistical power, enabling the statistical validation of data mining results on large-scale real-world datasets.

06.
bioRxiv (Bioinfo) 2026-06-10

Promera: a unified model for biomolecular structure prediction, filtering, and design

Generative models have become staple tools for modeling and designing biomolecular structures. However, although these tools have improved in structural prediction accuracy, their ability to filter designed binders—an essential use case—remains insufficient; whereas design methods have focused more on unconstrained binder generation rather than capabilities enabled by controllable design. We introduce Promera, a unified generative model that combines all-atom structure prediction with improved filtering and controllable design. We find that Promera's confidence metrics are more accurate for filtering binders from non-binders for both miniproteins and nanobodies, while its co-folding performance surpasses popular open-source models (OpenFold3-p2, Boltz-2) on therapeutically relevant categories. As a design model, Promera generates binders by predicting masked protein sequences with optional epitope, paratope, and template constraints. Remarkably, our nanobody designs match the in silico success rates from backprop-based techniques (mBER) when evaluated under co-folding confidence filters. We further provide two in silico demonstrations of the the versatile capabilities of our design method: epitope targeting of the Andes hantavirus glycoprotein with VHHs and active state stabilization of the beta-2 andrenergic GPCR. We conclude by proposing a scaling law for co-folding models, suggesting a path for further performance improvement.

07.
arXiv (CS.AI) 2026-06-15

TRACE: Trajectory-Routed Causal Memory for Delayed-Evidence Visuomotor Imitation

arXiv:2606.14551v1 Announce Type: cross Abstract: Robots under autonomous operation may require decisions based on evidence that is no longer visible. We study delayed-evidence tasks, where an early cue disappears before a later decision point, so visually similar observations can require different actions. In these settings, the current observation is not a sufficient state for control. We introduce TRAjectory-routed Causal Evidence (TRACE), a memory framework for visuomotor imitation policies. TRACE stores task-relevant visual and robot-state evidence, such as object identity, target choice, or route-dependent state, in a fixed-size latent memory that remains bounded over long episodes. Instead of indexing memory by raw time or manually provided task labels, TRACE uses path signatures: compact, order-sensitive features of the executed robot-state trajectory. These signatures do not store the visual cue itself; rather, they provide trajectory-conditioned keys for writing and retrieving the evidence stored when the cue was visible. When the robot later reaches an ambiguous observation, the policy conditions on TRACE memory to recover the missing context and choose the correct branch. TRACE attaches through lightweight adapters to policies, without changing the policy backbone, action head, or imitation objective. Across real-world long-horizon manipulation tasks with visually ambiguous branch points, TRACE improves branch selection and task success over alternative baselines, including short-history and recurrent memory. Project page: https://jeong-zju.github.io/trace

08.
arXiv (CS.LG) 2026-06-11

Bergson: An Open Source Library for Data Attribution

arXiv:2606.11660v1 Announce Type: new Abstract: Data attribution is a promising field in interpretability that aims to explain model behavior through the influence of its training data, with applications including debugging undesirable model behavior and training dataset curation. However, significant engineering effort is required to perform it at scale, and many cutting edge techniques lack open-source tooling and support. Bergson is an open source library that aims to enable faster progress in the field by providing a host of techniques that scale to very large language models and pre-training datasets. The library natively supports on-disk gradient stores and multi-node distributed training, and provides quality of life tools for researchers. Finally, we introduce the first open-source implementations of three leading data attribution methods: MAGIC, SOURCE, and TrackStar. The library is available at https://github.com/EleutherAI/bergson .

09.
arXiv (CS.CV) 2026-06-16

Conditional Multi-Event Temporal Grounding in Long-Form Video

Multimodal large language models have made rapid progress in video temporal grounding, yet real-world applications routinely require localizing every event that satisfies compositional temporal and spatial conditions. Existing benchmarks fall short: they localize only a single moment per query, count without temporal conditions, or treat grounding and counting as disjoint tasks. We introduce CoMET-Bench for Conditional Multi-Event Temporal Grounding in long-form video, comprising 2789 queries over 600 videos averaging 33.8 minutes across five real-world domains, with each query composed from 4 temporal conditions, 3 spatial conditions, and a dedicated negative-query subset. We further propose a unified evaluation protocol jointly measuring counting, grounding, and negative-query recognition, including a new Rejection-F1 metric that prevents trivial gaming by lazy "always-empty" models. Benchmarking a broad suite of MLLMs, agent-based, and grounding-specialized methods reveals that existing approaches remain far from solving this task. Building on these findings, we propose CoMET-Agent, a training-free agentic framework that reformulates the task as structured search-and-aggregate, improving F1@0.5 by 6.1% over GPT-5 purely through structural reasoning. Failure analysis further surfaces three open directions: fine-grained entity tracking, position-uniform retrieval, and causal event pairing.

10.
arXiv (CS.LG) 2026-06-18

A Guide to Estimating Conditional Average Treatment Effects in Competing Risks Settings

arXiv:2606.18281v1 Announce Type: cross Abstract: Conditional average treatment effects (CATEs) are central to treatment decision-making in personalized medicine. In competing risks settings, estimating CATEs from survival data allows for patient-specific assessments of treatment effectiveness for a specific event of interest while properly accounting for alternative event types. This distinction is essential in the presence of comorbidities, where competing causes of death may otherwise confound the therapeutic benefit. Focusing on right-censored survival times with binary treatment, we examine CATEs defined as covariate-conditional differences in the absolute risk for the event of interest at a fixed time. To this end, we study meta-learners which adapt machine learning algorithms for CATE estimation in competing risks scenarios. We systematically compare six meta-learners, combining Cox regression or random survival forests for risk modeling with elastic net regression or random forests for direct CATE modeling. To provide practical guidance on model selection, we evaluate their performance in multiple simulation settings, that differ in hazard complexity, treatment heterogeneity, treatment assignment, event type distribution and censoring. To facilitate applied use, we provide the R package, crsurvlearners, which implements all considered approaches.

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

NEST: Narrative Event Structures in Time for Long Video Understanding

Recent progress in vision-language models has enabled the processing of increasingly long video sequences, but the ability to handle extended token streams does not translate to understanding of narrative structure in long videos. Existing long video benchmarks focus on needle-in-a-haystack retrieval rather than evaluating how low-level actions form events, how events interact across time, and how narratives progress, for example, whether a model can connect an early setback, such as a job loss to a later relationship breakup, despite long gaps, intervening scenes, or flashbacks that reframe what occurred. We introduce NEST (Narrative Event Structures in Time for Long Video Understanding), a dataset of 1005 full-length movies (avg. 98 minutes), each annotated with 102 multimodal narrative events grounded in visual content, dialogue, and audio. NEST captures multimodal narrative events with structured annotations grounded in visual content, dialogue, and audio, and links them through relations that reflect narrative structure, including temporal ordering, hierarchical composition, and long-range dependencies. We introduce baselines for event trigger detection (ETD), event localization (EL), event argument extraction (EAE), and event relation extraction (ERE). The benchmark is highly challenging for grounded event discovery, with ETD below 8%, EL under 6%, and EAE below 11%. In contrast, ERE is more tractable once events are given, reaching 35.45% F1 zero-shot and 44.42% F1 after fine-tuning.

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

A Mechanistic Understanding of Pronoun Fidelity in LLMs

Faithful and robust pronoun use is important for fair and coherent generations, yet large language models largely fail when multiple referents use different pronouns. To study the interplay of reasoning, repetition, and bias in this task, prior work relies exclusively on behavioural approaches, which may not reflect a model's internal workings. Therefore, we provide a mechanistic, model-internal perspective on pronoun fidelity, testing whether three mechanisms – group entity binding (G), recency bias (R), and stereotypical bias (S) – are causally implemented across several SOTA language models. Using Boundless Distributed Alignment Search, we find all three coexist as causal subspaces distributed across network depth. No single mechanism fully explains model behaviour, but a combination of the three consistently accounts for 91-99.5%. An attention head analysis further reveals two competing copying routes; group binding and stereotype share a localized concept-level route that retrieves a bound occupation-pronoun unit, while recency uses a distributed token-level route that repeats surface forms. In sum, pronoun fidelity arises from competition between simultaneously active causal subspaces.

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

Graph-based Target Back-Propagation for Context Adaptation in Multi-LLM Agentic Systems

Context adaptation automates prompt engineering in LLM-based systems by iteratively revising tunable prompts from task feedback, without modifying model weights. Extending this paradigm to multi-LLM agentic systems is crucial: existing methods suffer from inaccurate credit assignment and lack convergence guarantees. We propose Graph-based Target Back-Propagation (GTBP), a context adaptation framework for agentic workflows modeled as directed acyclic graphs. GTBP propagates local target outputs backward through the workflow graph and uses target–output discrepancies to guide a stage-wise prompt update mechanism. Theoretically, we show that GTBP's stage-wise prompt updates become stable over iterations, and that a sufficiently capable LLM optimizer can decrease the overall objective. Empirically, GTBP consistently outperforms strong baselines across three benchmarks while maintaining comparable computational cost.

14.
medRxiv (Medicine) 2026-06-16

Doctors, Wellness Influencers, and Probiotic Gummies: A Cross-Sectional Analysis of Gut Health Claims and Financial Conflicts on TikTok

TikTok has emerged as a major source of health information, yet concerns persist regarding the accuracy of content and influence of financial conflicts. Gut health content is particularly vulnerable to misinformation. This study examined the relationship between creator profession ("medical" versus "non-medical") and the quality of gut health claims and the presence of financial conflicts on TikTok. We conducted a cross-sectional study of 412 TikTok creator accounts identified using the search terms "guthealth," "gutcleansing," and "digestion." One video per creator was analyzed. Creator profession was categorized as medical or non-medical. Health claim quality was coded as high, moderate, or poor. Financial conflicts (Showcase, Subscription, external links) were assessed. Modified Poisson regression was used to estimate prevalence ratios (PRs) of health claim quality (high versus poor- or moderate-quality) and financial conflicts between medical and non-medical creators, and negative binomial regression was used to evaluate associations between claim quality and number of video likes. Non-medical creators were more likely than medical creators to present poor- or moderate-quality health claims (adjusted PR: 2.33; 95% CI: 1.50-3.62). Most creators (92%) exhibited at least one financial conflict, and Showcase use was greater among non-medical creators (adjusted PR: 1.57; 95% CI: 1.02-2.42). Videos containing moderate- and poor-quality health claims received three times as many likes as videos containing high-quality claims. Non-medical creators disproportionately produced lower-quality gut health content on TikTok, and misleading claims received greater engagement. These findings highlight a misalignment between information quality and visibility, emphasizing the need for interventions promoting evidence-based health communication.

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

Sample-Efficient Hypergradient Estimation for Decentralized Bi-Level Reinforcement Learning

arXiv:2603.14867v4 Announce Type: replace-cross Abstract: Many strategic decision-making problems, such as environment design for warehouse robots, can be naturally formulated as bi-level reinforcement learning (RL), where a leader agent optimizes its objective while a follower solves a Markov decision process (MDP) conditioned on the leader's decisions. In many situations, a fundamental challenge arises when the leader cannot intervene in the follower's optimization process; it can only observe the optimization outcome. We address this decentralized setting by deriving the hypergradient of the leader's objective, i.e., the gradient of the leader's strategy that accounts for changes in the follower's optimal policy. Unlike prior hypergradient-based methods that require extensive data for repeated state visits or rely on gradient estimators whose complexity can increase substantially with the high-dimensional leader's decision space, we leverage the Boltzmann covariance trick to derive an alternative hypergradient formulation. This enables efficient hypergradient estimation solely from interaction samples, even when the leader's decision space is high-dimensional. Additionally, to our knowledge, this is the first method that enables hypergradient-based optimization for 2-player Markov games in decentralized settings. Experiments highlight the impact of hypergradient updates and demonstrate our method's effectiveness in both discrete and continuous state tasks.

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

The Periodic Table of LLM Reasoning: A Structured Survey of Reasoning Paradigms, Methods, and Failure Modes

Large Language Models (LLMs) have achieved strong performance across natural language processing tasks, yet reliable reasoning remains an open challenge. Although modern LLMs show progress in structured inference, multi-step problem solving, and contextual understanding, their reasoning behavior is often inconsistent and sensitive to prompting strategies, task design, and model scale. This survey provides a systematic analysis of more than 300 recent papers from arXiv, Semantic Scholar, Google Scholar, Papers with Code, and the ACL Anthology to examine how reasoning capabilities emerge in LLMs and where they fail. We make three main contributions. First, we introduce a structured taxonomy of LLM reasoning research, covering Chain-of-Thought reasoning, multi-hop reasoning, mathematical reasoning, common sense reasoning, visual and temporal reasoning, code and algorithmic reasoning, retrieval-augmented reasoning, tool-augmented and agentic reasoning, and reinforcement learning-based reasoning. Second, we analyze methodological trends across these paradigms, including prompting methods, model architectures, training objectives, reward modeling, and evaluation benchmarks. Third, we synthesize recurring limitations and failure modes, such as reasoning hallucinations, brittle multi-step inference, weak causal abstraction, and poor cross-domain generalization. By organizing a rapidly expanding literature, this survey offers a unified view of the current capabilities and limitations of reasoning in LLMs. We also identify emerging research directions, including meta-reasoning, self-evolving reasoning frameworks, multimodal reasoning, and socially grounded reasoning. Overall, this work aims to serve as a reference for developing more robust, interpretable, and generalizable reasoning systems in future language models.

17.
arXiv (quant-ph) 2026-06-11

Controlled ion-ion interactions and cavity-enhanced emission of a coherent dinuclear Eu$^{3+}$ complex

arXiv:2606.11947v1 Announce Type: new Abstract: Molecular rare-earth-ion complexes offer unique opportunities for quantum technologies by combining the intrinsic coherence properties of rare-earth ions with chemically tunable molecular environments. A crucial capability is the realization of multi-qubit architectures with defined qubit couplings to enable two-qubit quantum gates. Here, we investigate the optical coherence properties and excitation-induced interactions of two Eu$^{3+}$-based molecular complexes, comparing a mononuclear reference system with a dinuclear analogue in which two Eu$^{3+}$ ions are positioned at a well-defined intramolecular distance of about 7 Angstrom. Using cryogenic ensemble spectroscopy, including spectral hole burning, free-induction decay, and photon echo measurements at temperatures down to 100 mK, we demonstrate long optical coherence times $T_{2,o}$ of up to 9 $\mu$s. As a key step toward scalable multi-qubit architectures, a control-target sequence was implemented to probe conditional ion-ion interactions, revealing a stronger interaction-induced dephasing in the dinuclear complex. Finally, we show the integration of the dinuclear complex into a fiber-based optical microcavity, and observe an 380-fold emission enhancement of the $\mathrm{}^5\mathrm{D}_0\rightarrow\mathrm{}^7\mathrm{F}_0$ transition. Together, these results position molecular rare-earth complexes as versatile and chemically tunable building blocks for scalable quantum technologies.

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

FloatDoor: Platform-Triggered Backdoors in LLMs

arXiv:2606.19535v1 Announce Type: cross Abstract: Large language models (LLMs) are increasingly deployed in sensitive settings such as software engineering, where their outputs directly shape downstream artifacts. Recent work has shown that an identical model can produce measurably different outputs depending on the deployment platform, a consequence of non-associative floating-point arithmetic and divergent kernel implementations. We study the security implications of this platform-dependent variability and uncover a novel attack surface on LLM deployments. We introduce FloatDoor, the first input-independent, platform-triggered backdoor attack against generative LLMs. The compromised model exhibits adversary-chosen behavior when served on a target platform and is otherwise benign. FloatDoor is realized through two lightweight LoRA adapters, one that amplifies inter-platform numerical divergence and one that binds the resulting platform signature to a malicious downstream task, while leaving aggregate model utility largely intact. FloatDoor exploits a pronounced time-of-check, time-of-use gap between model auditing and serving. We demonstrate FloatDoor on Qwen3-4B across a broad range of deployment targets, including NVIDIA GPUs, Google TPUs, AWS Graviton, and Alibaba Yitian-710. As a final case study, we show that FloatDoor reliably induces exploitable code vulnerabilities on a chosen target platform. Our results establish a new class of attacks on LLM deployments and underscore the pressing need for trusted model supply chains in sensitive, LLM-powered applications.

20.
arXiv (quant-ph) 2026-06-19

Scalable quantum circuit knitting using a weak-coupling approximation

arXiv:2606.19035v2 Announce Type: replace Abstract: We present a method for performing distributed quantum computing with controlled approximations. Exact distributed quantum computing requires exponential classical information to reconstruct the quantum process. However, we show how the classical cost is reduced to polynomial if the quantum procedure can be partitioned between a qubit that is weakly coupled the other qubits. We demonstrate our method for a layered circuit based on the circuits used for the quantum approximate optimization algorithm.

21.
arXiv (CS.AI) 2026-06-16

MiroBench: Benchmarking Realism in Agentic Simulation of Real-world Discussions

arXiv:2606.14715v1 Announce Type: cross Abstract: LLM agents are increasingly used to simulate real world interactions, but it remains unclear whether simulated behaviors preserve the content patterns and interaction dynamics of real human behaviors. Existing evaluations remain fragmented, which makes it difficult to compare systems or measure progress. In this paper, we focus on Reddit discussions as a concrete first step toward evaluating real-world social simulation. Reddit threads provide public, topic-grounded, multi-party interactions where people share experiences, debate, seek advice, express emotion, and collectively respond to products, events, and social issues. These discussions offer an observable window into broader social behavior, making them a useful setting for testing whether LLM agents can reproduce not only fluent text, but also the distributional patterns and interaction dynamics of real online communities. We introduce MiroBench, a benchmark for Reddit discussion simulation built from 4,292 real Reddit threads. MiroBench uses statistical tests to compare generated and real discussions across four major aspects: repetition and semantic uniformity, narrative content, toxicity and aggression, and structural complexity. Experiments across five domains and five models show that current simulators remain distributionally mismatched with real Reddit threads, while a lightweight prompt-based improvement procedure provides only limited gains. MiroBench offers a concrete benchmark for measuring, diagnosing, and improving realism in LLM-based social simulation.

22.
Nature (Science) 2026-06-10

Molecular glue degraders of HuR suppress BRAF-mutant colorectal cancer

作者:

BRAF gain-of-function mutations, particularly BRAF(V600E), affect roughly 10% of all patients with colorectal cancer (CRC), and portend poor prognosis with limited therapeutic interventions. BRAF inhibitors such as encorafenib are ineffective due to MAPK pathway reactivation driven by BRAF dimerization. Combined inhibition of BRAF and EGFR, although approved therapies, results in short survival benefits and frequent treatment resistance and relapse1–3. Here, through rational chemical library design coupled with parallel proteomic screening, we identified dHuR as a molecular glue degrader of human antigen R (HuR), an RNA-binding protein that drives tumour growth, invasion and therapy resistance. dHuR binds to the CRBN ubiquitin ligase to create a unique benzofuran-tethered composite surface to recruit HuR as a neosubstrate by engaging its β-hairpin G-loop degron, as revealed by the cryo-electron microscopy structure of the ternary complex. dHuR abrogated BRAF expression by inducing its exon 18 skipping, and demonstrated superior suppression of BRAF-mutant CRC tumours including those gaining resistance to BRAF inhibitors. Finally, we performed kinome library CRISPR screening and revealed that inactivation of EGFR or MEK enhanced dHuR cytotoxicity, thus establishing a combinatorial strategy to treat patients with refractory BRAF-mutant CRC. Molecular glue degraders of the RNA-binding protein HuR have therapeutic potential for BRAF-mutant cancers.

23.
medRxiv (Medicine) 2026-06-17

High burden of subclinical TB in Africa revealed from a postmortem cohort.

Tuberculosis (TB) is increasingly recognised as a spectrum of infection and disease, yet the prevalence of viable, asymptomatic Mycobacterium tuberculosis (M.tb) infection remains uncertain. Subclinical Tuberculosis (scTB), defined as microbiologically confirmed M.tb infection in the absence of recognised symptoms, is under detected by symptom, sputum and imaging-based approaches. We conducted postmortem examinations of 94 adults who died from non-infectious causes, none of whom were clinically suspected of TB or reported TB related symptoms prior to death. Lung and extrapulmonary tissues were cultured for M.tb. Viable M.tb was confirmed in six individuals, corresponding to a prevalence of 6.4% (95% CI: 2.4 to 13.4%). These findings provide direct tissue-based evidence that viable, asymptomatic M.tb infection can persist beyond the reach of conventional clinical detection. Our data suggest that a biologically active reservoir of infection may exist undetected within high-burden settings, with implications for surveillance strategies aimed at TB elimination.

24.
arXiv (quant-ph) 2026-06-16

Diagonal-Budgeted Trotterization for Efficient Quantum Hamiltonian Simulation

arXiv:2606.16959v1 Announce Type: new Abstract: Efficient classical simulation of quantum Hamiltonian dynamics is often bottlenecked by exponential state growth and the overhead of generic sparse linear algebra. We introduce diagonal-budgeted Trotterization, a structure-aware strategy that decomposes Hamiltonians into factors preserving diagonal sparsity while tightly controlling fidelity loss. Our implementation, HamSim, utilizes a compact diagonal-sparse data layout and specialized C++/CUDA kernels to bypass the overheads of generic formats like CSR. By leveraging SIMD vectorization, multithreading, and GPU acceleration, HamSim achieves high performance across heterogeneous architectures. Benchmarks on the HamLib suite show that HamSim significantly outperforms Qiskit-Aer. On CPUs, HamSim attains speedups of $182$–$1,269\times$ on optimization instances (TSP, MaxCut) and $4.8$–$841\times$ on physical models (TFIM, Heisenberg). On GPUs, it achieves up to $178\times$ speedup for $12$–$16$ qubit problems. Unlike traditional Trotterization, HamSim maintains near-perfect fidelity without requiring exponential steps. This demonstrates that diagonal-aware numerical kernels provide a scalable foundation for high-fidelity classical Hamiltonian simulation.

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

Think Again or Think Longer? Selective Verification for Budget-Aware Reasoning

Test-time reasoning is increasingly used as a serving-time control knob, but extra reasoning is not uniformly valuable: it can repair failed attempts, waste compute on already-correct answers, or introduce harmful answer changes. We study this as a deployment allocation problem rather than a new-verifier problem. We introduce \sevra, Selective Verification for Reasoning Allocation, a serving-layer controller that decides whether to preserve a frozen solver's initial answer or invoke active verification. Using a frozen Qwen3-4B solver, we log intervention outcomes and train recoverability-aware gates from serving-visible attempt state. On \mathfive, selective verification reaches 76.3\% accuracy, compared with 75.5\% for always verifying, while reducing post-generation tokens by 26.8\% and harmful flips from 2.2\% to 1.0\%. However, an 8,192-token initial solve reaches 76.0\% accuracy with 28\% fewer total model tokens, showing that selective recovery is useful but not the best tested cost frontier. In frozen transfer to \gsm, the selective policy verifies only 3.0\% of examples, improves accuracy from 93.4\% to 94.5\%, and reduces verification tokens by 91.2\% relative to always verifying; again, a longer initial solve matches its accuracy with fewer realized tokens. On CommonsenseQA, always-on verification hurts, while Self-Consistency@5 improves accuracy at about five times the realized token cost. The resulting deployment rule is: tune the initial budget first, then use selective recovery when explicit checks, bounded retries, auditability, or regression-risk control matter.