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01.
arXiv (CS.AI) 2026-06-12

Counterfactual Explanations for Deep Two-Sample Testing

arXiv:2606.04009v2 Announce Type: replace-cross Abstract: Two-sample testing is a fundamental tool for detecting distributional differences across scientific domains, but classical tests (including kernel-based tests) can be ineffective on high-dimensional structured data such as images. Recent deep two-sample tests improve sensitivity in these settings by learning informative representations, yet they provide limited insight into which data features drive rejection of the null hypothesis $H_0$. To address this issue, we propose a counterfactual explanation framework for deep two-sample testing that generates sample-level edits moving observations from a source group toward a target group while explicitly reducing the discrepancy measured by the test. Our method combines a diffusion autoencoder with a pretrained deep two-sample test model and optimizes a maximum mean discrepancy (MMD) objective in the test model's representation space to produce plausible counterfactuals. We quantify distribution-level effects through changes in the test statistic and the resulting two-sample p-values. We evaluate the method on synthetic 2D shape datasets and two MRI cohorts. Across both settings, the counterfactual transformations consistently increase p-values relative to the original samples, indicating that the edited source set becomes statistically closer to the target distribution under the test. We measure minimality using LPIPS to ensure the counterfactuals remain close to the original samples. The resulting edits provide interpretable evidence of the features associated with the detected group differences. On MRI, the localized changes are consistent with known anatomical differences between cohorts.

02.
medRxiv (Medicine) 2026-06-22

Three multimodal large language models fail at clinically actionable breast pathology in three different directions

Background. Breast cancer treatment depends on histopathological features, such as grade and receptor-defined subtype; however, specialist pathologist access is constrained when the workforce is limited. Commercial multimodal large language models (MLLMs) accept hematoxylin and eosin (H&E) image tiles through paid interfaces without local hardware or fine-tuning. However, prior pathology evaluations addressed only coarse tasks. Whether they reach treatment-determining accuracy and whether vendors agree remain unclear. Methods. We aimed to evaluate three vendor-designated flagship MLLMs (Claude Sonnet 4.6, Gemini 2.5 Pro, GPT-5.5) in 427 invasive breast cancer cases. Each case went to all three with identical H&E tiles and prompts, and the subtype was inferred in the second call. The reference was an institutional sign-out report of an immunohistochemistry-derived subtype. We calculated the concordance, sensitivity, specificity, Cohen's kappa, and pairwise McNemar and Bowker tests. Findings. Claude ranked highest by raw histologic-type concordance but lowest by kappa, classifying all 23 lobular and seven micropapillary carcinomas as invasive breast carcinoma of no special type. The models anchored the Nottingham grade to three modal grades. None of the models reliably identified human epidermal growth factor receptor 2-positive disease. The failure direction was vendor-specific: Claude and GPT-5.5 were under-detected, whereas Gemini was over-called. Twelve prompt variants (4,056 calls) did not recover sensitivity. Interpretation. No current commercial MLLM reaches deployment-ready accuracy for any treatment-determining feature of breast pathology. As each vendor fails in its own fixed direction, changing vendors alters the type of error rather than removing it; therefore, the value of these models is assistive rather than autonomous. At USD 0.20-0.50 per case, they may serve as supervised draft generators that leave the diagnosis with the pathologist.

03.
medRxiv (Medicine) 2026-06-16

A Poisson Process Life Expectancy framework for optimising patient lifetime during chemotherapy

Cancer therapy balances between two competing objectives - treatment efficacy against the tumour and the risk of treatment related severe adverse events, including patient death. Most existing optimal control theory (OCT) formulations rely on optimising heuristic cost functionals that lack direct clinical interpretability. In clinical practice treatment efficacy and patient tolerability are primarily assessed through survival metrics and adverse event rates. Here we introduce the Continuous Lifetime Payoff (CLP), a novel OCT objective functional that directly links treatment decisions to patient survival. It explicitly incorporates tumour dynamics, tumour eradication, and patient mortality from tumour progression, drug-related toxicity and age. We fit age-related mortality from life tables and infer parameters from simulated survival data. The CLP provides a clinically grounded framework for optimising chemotherapy regimens.

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

SACE: Concept Erasure at the Semantic Singularity in Visual Autoregressive Models

The rapid progress of visual autoregressive (VAR) models has unlocked a transformative frontier for high-fidelity text-to-image synthesis, while heightening concerns over the safety alignment of generated content. Naive application of existing erasure techniques to VAR models causes catastrophic semantic collapse and visual artifacts, since they are predominantly designed for the homogeneous denoising steps of diffusion models. To address this foundational challenge, we first propose the Semantic Singularity Axiom, which posits that any target semantic concept embedded within a prompt is definitively locked at Scale-0. Then rigorously validate this axiom through our proposed Incremental Semantic Saliency Analysis (ISSA),which also enable the community to transparently inspect the coarse-to-fine semantic injection process. Guided by this insight, we introduce the first scale-aware concept erasure framework (SACE) for VAR models. By strictly confining interventions to the first scale, our approach couples an Entropy-Regularized Erasure Objective to prevent high-entropy sampling degeneration, alongside a restorative preservation loss to safely anchor the integrity of entangled benign priors. Extensive experiments demonstrate that our method achieves surgical concept erasure performance across various domains with minimal training overhead, timely and elegently resolute the critical safety vulnerabilities inherent in emerging VAR architectures. Code is available at: https://github.com/limerenceysy/SACE}{https://github.com/limerenceysy/SACE.

05.
arXiv (CS.LG) 2026-06-18

Stochastic Thermodynamics and SDE-based Generative Models

作者:

arXiv:2606.18290v1 Announce Type: cross Abstract: SDE-based generative models, including diffusion models and the Schrödinger bridge, have found broad applications in signal processing tasks such as speech enhancement, image restoration, and time-series generation. This note presents a modeling framework for such models within the context of stochastic thermodynamics. The main results of this note are trajectory-level definitions of work, heat, and entropy production, along with a generalized Jarzynski identity and a second-law-like inequality. The proposed framework extends the original Jarzynski setup to accommodate time-dependent bath temperature and nonconservative driving forces. This thermodynamic perspective may deepen our understanding of diffusion models and the Schrödinger bridge from a nonequilibrium statistical mechanics viewpoint.

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

A PubMed-Scale Dataset of Structured Biomedical Abstracts

Structured abstracts are important for biomedical literature processing, by facilitating information retrieval, text mining, and knowledge synthesis. However, a vast portion of abstracts indexed in PubMed remain unstructured, presenting a significant bottleneck for downstream text-processing workflows and applications. To resolve this limitation, we introduce Structured PubMed, a comprehensive corpus of section-labeled biomedical abstracts compiled from the complete PubMed database, encompassing over 23.2 million research-article records. The corpus is divided into two distinct subsets: a collection of 5.9 million author-structured abstracts parsed from official XML files, and an automatically labeled collection of 17.2 million originally unstructured abstracts structured via a verbatim-extraction Large Language Model pipeline. Every record is harmonized under a unified five-section schema and mapped to its original PubMed identifier, publication type, and publication date. This dataset can be utilized to train sentence-classification models, benchmark text-segmentation architectures, and perform large-scale, section-specific information extraction at an unprecedented PubMed-wide scale.

08.
arXiv (CS.CV) 2026-06-17

Reload-Mamba: Hierarchical Anti-Dilution State-Space Modeling for Multi-Class Semantic Segmentation

Mamba-based state space models offer linear-time long-range modeling for high-resolution dense prediction, but sequential state-space propagation can attenuate boundary-sensitive and detail-sensitive responses that are critical in multi-class semantic segmentation. We propose Reload-Mamba, a semantic segmentation framework that addresses this propagation-induced response dilution through three segmentation-specific designs: (i) a boundary-supervised local detail prior that is explicitly trained with ground-truth boundary masks to identify regions requiring response restoration; (ii) a class-uncertainty-aware Reload Gate that incorporates per-pixel class entropy from a pre-reload auxiliary head as an additional gating signal, a formulation that is informative only under multi-class dense prediction; and (iii) a hierarchical multi-level Reload mechanism that applies anti-dilution refinement at three decoder levels and fuses the restored representations top-down. Built upon a ConvNeXt-Tiny encoder with a multi-scale decoder and four-directional Mamba scanning with pixel-wise directional attention, Reload-Mamba achieves 47.9% single-scale (48.9% multi-scale) mIoU on ADE20K and 83.2% single-scale mIoU on Cityscapes. With ResNet-101 + COCO pre-training under the standard DeepLab-style protocol, Reload-Mamba reaches 87.8% mIoU on PASCAL VOC 2012 val. Controlled ablations show that each of the three segmentation-specific designs contributes beyond a direct port of the prior anti-dilution architecture proposed for binarization, cumulatively improving over the direct-port baseline by +2.2 mIoU on ADE20K.

09.
arXiv (CS.CL) 2026-06-12

NaturalFlow: Reducing Disruptive Pauses for Natural Speech Flow in Simultaneous Speech-to-Speech Translation

Simultaneous speech-to-speech translation aims to enable near-real-time communication by minimizing latency, offering a compelling, real-time alternative to the high latency of consecutive translation. However, the excessive pursuit of low latency often results in fragmented chunk-wise speech. Consequently, listeners are subjected to an unnatural acoustic flow punctuated by frequent pauses, which could increase their cognitive load. To bridge this gap, we introduce a fluency-aware optimization framework designed to discover the sweet spot between the low-latency benefits of simultaneous translation and the natural flow of consecutive translation. Our framework minimizes inter-chunk silences by leveraging model-internal signals, including linguistic diversity and induced temporal variability in speech durations. Experiments on short- and long-form benchmarks show that our framework produces natural speech flow while maintaining competitive latency and translation quality.

10.
arXiv (quant-ph) 2026-06-12

Achieving Heisenberg limit under noisy conditions with quantum Zeno dynamics and dynamical decoupling

arXiv:2606.13205v1 Announce Type: new Abstract: Quantum Zeno dynamics (QZD) and dynamical decoupling (DD) are useful tools that enable the effective suppression of noise in quantum systems. We consider the problem of when (i) noise can be suppressed and (ii) Heisenberg limit (HL) can be achieved in quantum metrology, and prove necessary and sufficient conditions for when QZD and DD are useful for achieving these two goals. We also show that in the Markovian regime, there are scenarios where preventing errors using QZD/DD may enable HL to be achieved where current QEC methods may not. Finally, we demonstrate that the combination of both techniques can allow individually imperfect QZD and DD strategies to saturate HL.

11.
bioRxiv (Bioinfo) 2026-06-11

SPARK: A Systems-level Computational Framework for Reconstructing Transcriptomic State Organisation in Lung Adenocarcinoma

Lung adenocarcinoma (LUAD) exhibits substantial molecular heterogeneity, which complicates tumour stratification and limits the ability of mutation-centric models to capture tumour behaviour and predict patient outcomes. This study investigates whether coordinated transcriptomic programs can provide a systems-level representation of tumour states. Bulk RNA-sequencing data from the TCGA-LUAD cohort were analysed to reconstruct pathway-level transcriptomic organisation using a stability-optimised network framework (SPARK). This analysis identified eight transcriptomic modules representing coordinated biological processes active across tumours. Module activity scores were subsequently used to derive a composite Transcriptomic Risk Score through elastic-net Cox proportional hazards modelling. The resulting risk score showed a significant association with overall survival in the discovery cohort and improved prognostic discrimination beyond clinical variables. An independent evaluation in the CPTAC-LUAD cohort confirmed the prognostic signal and preserved risk stratification across patient groups. Unsupervised clustering of module activity further revealed three transcriptomic patient groups characterised by distinct biological programs, genomic alteration patterns, and survival outcomes. Single-cell analysis also demonstrated that the identified transcriptomic modules reflect coordinated organisation of the tumour-immune-stromal ecosystem across cellular compartments. Together, these findings suggest that LUAD heterogeneity can be organised into coordinated transcriptomic programs with measurable clinical relevance, providing a systems-level framework for representing tumour molecular states.

12.
arXiv (CS.AI) 2026-06-19

Editorial Alignment: A Participatory Approach to Engaging Editorial Expertise in LLM-mediated Knowledge Dissemination

arXiv:2606.20258v1 Announce Type: cross Abstract: The emergence of LLM-driven information services is reshaping the conditions under which public knowledge institutions operate, threatening to absorb the editorial function these institutions exist to exercise. While LLMs offer powerful new affordances for knowledge dissemination, editorial authority is challenged by pretrained LLMs that arrive already aligned with the values and dissemination strategies of their commercial developers. This paper investigates editor participation in re-aligning LLM interfaces to editorial standards through design workshops, in a case study where we design and implement an LLM-enabled encyclopedia interface with a Nordic public knowledge institution. We introduce editorial alignment as a design practice within Participatory AI, framing AI alignment as a design process and positioning the editorial standard as a design artefact that translates editorial practice and values into alignment objectives for technical implementation. Last, we discuss how editorial alignment can create space for ongoing participation and give editors agency in LLM-mediated knowledge dissemination.

13.
arXiv (CS.LG) 2026-06-11

Loss Landscape Diagnosis for Gradient-Based Gray-Scott System Inversion: Disentangling the Roles of PINN Components

作者:

arXiv:2606.11258v1 Announce Type: new Abstract: Gradient-based inversion of reaction-diffusion systems is typically approached via surrogate models or physics-informed neural networks (PINNs), while the most direct route, backpropagation through the PDE's structure itself, has largely been avoided. We pursue this direct route as a diagnostic probe, backpropagating a steady-state loss through unrolled Gray-Scott simulation to recover its parameters, with no surrogate or neural-network augmentation. Optimization fails to converge, and plotting the landscape directly locates the failure in its geometry – flat plateaus with no gradient signal, bounded by sharp cliffs that align with bifurcation boundaries – a structure that recurs across loss functions and is inherited however the gradients are routed to parameters. Reading this minimal setup as an ablation of PINN, we disentangle each component's role: with the neural network fixed, the residual loss is quadratic in the PDE parameters and yields a smooth landscape, so it alone already avoids the pathology, by implicitly encoding the full PDE dynamics across all initial conditions. The neural network, for its part, cannot repair an ill-posed parameter subspace, and so serves only to complete the observed data – a division of labor not previously made explicit. These findings carry concrete design implications for PINN-type methods and a broader heuristic on when added dimensions actually help.

14.
Nature (Science) 2026-06-17

<i>CHPO</i> coordinates chilling recovery and nitrogen use in rice

作者:

Global rice production faces mounting challenges from abnormal temperature fluctuations and nitrogen-fertilizer-driven environmental pollution1–7. Developing varieties that balance chilling resilience and nitrogen-use efficiency (NUE) offers a promising solution, but the molecular networks coordinating these traits remain poorly understood. Here we identify CHILLING PHOENIX (CHPO), a major gene underlying the quantitative trait locus shared by both chilling tolerance and resilience. It encodes a MYB transcription factor that acts as a key regulator coordinating post-chilling recovery with nitrogen use in rice. Natural variation in a GCG-repeat-encoded polyalanine tract alters CHPO DNA-binding preference and redirects regulatory outputs between the japonica-type (CHPOjap) and indica-type (CHPOind), causing opposing effects on chilling tolerance and resilience. This allelic variation is shaped by domestication selection, with the CHPOjap allele probably derived from Chinese wild rice. CHPOjap directly targets OsTCP19 and OsNRT2.4 to fine-tune NUE, thereby enhancing chilling tolerance and resilience. These findings provide a mechanistic framework for a chilling-induced high-nitrogen-utilization module that alleviates the damage caused by chilling stress, and a potential molecular design&nbsp;strategy for breeding rice varieties with both chilling resilience and high NUE at the&nbsp;recovery stage. A rice gene, CHPO, links chilling resilience with nitrogen-use efficiency, revealing a domestication-shaped regulatory mechanism that could guide breeding of climate-resilient, sustainable rice varieties.

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

Contextual Bandits for Maximizing Stimulated Word-of-Mouth Rewards

arXiv:2606.15146v1 Announce Type: new Abstract: Stimulated word-of-mouth is a strategy that promotes information sharing through prompts or incentives. Optimizing stimulated word-of-mouth through social networks requires identifying and targeting connected users who are most susceptible to spillover, a phenomenon where the influence of recommendations extends beyond the immediate audience to impact their connected users. The probability of spillover varies across individuals, and their connections, leading to heterogeneity. Understanding and accurately estimating the spillover probabilities among users in social networks is crucial for improving the effectiveness of stimulated word-of-mouth. To address this, we present a novel contextual multi-armed bandit framework that learns individual spillover probabilities and ranks connected users to maximize rewards from stimulated word-of-mouth. Experiments on real-world network datasets demonstrate that accounting for spillover heterogeneity enhances the targeting precision of top-$k$ connected users, boosting rewards and outperforming baseline methods that do not learn individual spillover effects.

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

See-and-Reach: Precise Vision-Language Navigation for UAVs within the Field of View

arXiv:2606.20045v1 Announce Type: cross Abstract: UAV Vision-Language Navigation (UAV-VLN) is typically formulated as a holistic search-and-reach problem, where long-range target discovery and final target approach are optimized and evaluated jointly. This formulation makes it difficult to assess a critical capability of aerial embodied agents, namely whether a UAV can accurately ground a visible target and translate vision-language evidence into precise 3D motion once the target enters its field of view. To address this limitation, we introduce UAV-VLN-FOV, a target-visible navigation task that isolates the see-and-reach stage and enables a more diagnostic evaluation of terminal reaching ability. We further propose 3DG-VLN, a vision-language waypoint prediction framework guided by dynamic 3D direction cues to enhance fine-grained visual grounding and spatial direction alignment for precise target reaching. Specifically, 3DG-VLN adaptively processes high-resolution front-view and downward-view observations to preserve fine-grained visual and geometric details for target grounding. It also updates the target-relative direction online during closed-loop navigation, allowing the agent to maintain spatial alignment with the target and reduce accumulated direction drift. To support this task, we construct a dedicated high-resolution benchmark which contains 2,717 trajectories with target-oriented high-level instructions, high-resolution front-view and downward-view egocentric observations, and continuous 3D waypoint annotations. Experiments show that 3DG-VLN outperforms competitive UAV-VLN baselines, achieving a 13.82\% improvement in success rate. Real-world trials further demonstrate the potential of 3DG-VLN for practical see-and-reach navigation. The source code and benchmark are available at https://github.com/xuefanfu/3DG-VLN.

17.
arXiv (math.PR) 2026-06-12

Mixing times of one-sided $k$-transposition shuffles

arXiv:2112.05085v2 Announce Type: replace Abstract: We study mixing times of the one-sided $k$-transposition shuffle. We prove that this shuffle mixes relatively slowly, even for $k$ big. Using the recent ``lifting eigenvectors'' technique of Dieker and Saliola and applying the $\ell^2$ bound, we prove different mixing behaviors and explore the occurrence of cutoff depending on $k$.

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

The Tao of Agency: Autotelic AI, Embedded Agency and Dissolution of the Self

arXiv:2606.19924v1 Announce Type: new Abstract: Most artificial intelligence systems are built on the assumption that goals are exogenous and specified by the designer. Exploring what happens when an agent begins generating its own goals opens the field of autotelic AI. Agents are expected not merely to pursue objectives but to discover them. In this article, we trace its consequences through intrinsic motivation, resource-driven priors, causal-interventional learning, homeostasis, and embeddedness; the last of which is found to be a necessary but not sufficient condition for autotelic agency. Embeddedness individuates the agent at the cost of revealing that the individuation is non-unique, such that the same dynamics admit many valid partitions, each defining a different candidate self. The deepest problem with autotelic AI is therefore not how the agent generates goals, but how it generates and relativizes the self to which the goals are assigned. The agent must believe in its own boundary in order to act, and see through that boundary in order to understand. We consolidate these developments into a single framework and extend it along three directions: a quantum formulation in which the agent-environment cut becomes physical, a philosophical reading against non-dual contemplative traditions, and a concrete LLM-based agentic instantiation.

19.
medRxiv (Medicine) 2026-06-11

Effects of Resveratrol as an Adjunct to a Low-Calorie Diet in Postmenopausal Women with Obesity and Knee Osteoarthritis

Background. Obesity is a modifiable risk factor for osteoarthritis and may contribute to pain, functional impairment, inflammation, and cartilage degradation. Resveratrol has potential anti-inflammatory and chondroprotective effects, but its efficacy as an adjunct to dietary intervention remains unclear. Objective. This study evaluated whether resveratrol supplementation provides additional benefits when combined with a low-calorie diet in postmenopausal women with obesity and knee osteoarthritis. Methods. A total of 97 postmenopausal women with obesity and knee osteoarthritis were included in this randomized controlled clinical study. Participants received either a 10-day low-calorie diet alone or the same diet combined with 150 mg/day trans-resveratrol. Anthropometric parameters, body composition, biochemical markers, pain intensity, functional status, and urinary CTX-II were assessed at baseline and follow-up. Results. Both interventions were associated with reductions in body weight, BMI, waist and hip circumferences, fat mass, glucose, HOMA-IR, lipid parameters, hsCRP, VAS, WOMAC, LAI, and urinary CTX-II. Compared with diet alone, resveratrol supplementation did not provide additional benefits for anthropometric parameters, glucose metabolism, lipid profile, or WOMAC score. However, the resveratrol group showed a greater reduction in hsCRP and urinary CTX-II. The obesity class did not modify the treatment effect. Conclusion. A short-term low-calorie diet improved metabolic, inflammatory, and osteoarthritis-related parameters in postmenopausal women with obesity and knee osteoarthritis. The addition of resveratrol did not enhance weight loss or improve most metabolic outcomes but was associated with greater reductions in hsCRP and urinary CTX-II. These findings suggest a potential anti-inflammatory and cartilage-related effect of resveratrol, which requires confirmation in longer randomized trials.

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

LSTM based IoT Device Identification

arXiv:2304.13905v2 Announce Type: replace-cross Abstract: While the use of the Internet of Things is becoming more and more popular, many security vulnerabilities are emerging with the large number of devices being introduced to the market. In this environment, IoT device identification methods provide a preventive security measure as an important factor in identifying these devices and detecting the vulnerabilities they suffer from. In this study, we present an end-to-end machine learning pipeline that identifies IoT devices in the Aalto university dataset (IoT devices captures) using Long Short-Term Memory (LSTM) networks. Raw network packet captures (PCAP) are processed into 25 engineered features, which are then arranged as sliding-window time-series sequences. We systematically evaluate sequence lengths from 2 to 20, reporting that performance improves approximately linearly up to length 6 and thereafter in a wave-like pattern, reaching its peak at length 18. On the final held-out test set with the optimal configuration, the model achieves an accuracy of 79.85% and a macro-averaged F1-score of 75.70% across 27 device classes.

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

Training-Free Open-Vocabulary Visual Grounding for Remote Sensing Images and Videos

Remote sensing visual grounding (RSVG) aims to localize a referred target in a remote sensing image or video according to a natural language expression. Existing RSVG methods usually rely on task-specific manual annotations, which are costly to collect and inevitably limited in covering the diversity of real-world geospatial scenarios. As a result, they often struggle to generalize to open-vocabulary queries involving novel objects, fine-grained attributes, complex spatial relationships, and functional semantics. In this paper, we propose RSVG-ZeroOV, a training-free framework that leverages frozen generic foundation models for zero-shot open-vocabulary RSVG. RSVG-ZeroOV follows an Overview-Focus-Evolve paradigm, which exploits the distinct yet complementary attention patterns of vision-language models (VLMs) and diffusion models (DMs) to progressively generate precise grounding results. Specifically, (i) Overview utilizes a VLM to extract cross-attention maps that capture semantic correlations between the referring expression and visual regions; (ii) Focus leverages the fine-grained modeling priors of a DM to compensate for object structure and shape information often overlooked by VLM attention; and (iii) Evolve introduces a simple yet effective attention evolution module to suppress irrelevant activations, yielding purified object masks. To handle video inputs, we further present Video RSVG-ZeroOV, which extends image-level grounding to spatio-temporal grounding through a query-relevant key-frame selector and a temporal propagator, enabling efficient and temporally coherent video grounding without video annotations or fine-tuning. Extensive experiments on six image and video grounding benchmarks show that RSVG-ZeroOV consistently outperforms existing zero-shot baselines and achieves competitive or superior performance compared with weakly- and fully-supervised methods.

22.
bioRxiv (Bioinfo) 2026-06-08

DDI_single: Single-Sequence-Based Protein Domain Assembly

作者:

Domains are the basic units of protein structure and function. Appropriate inter-domain organization is critical to enable cooperative execution of multiple related functions. It is thus a crucial step to determine the full-length structure of multi-domain proteins for the purpose of elucidating their functions and designing new drugs to regulate these functions. Existing structure prediction algorithms are generally better at solving the internal conformation of domains, rather than modeling the relative positions between domains. To address the challenge of accurately determining multi-domain protein conformations, we develop a single-sequence-based domain assembly algorithm called DDI_single. DDI_single directly extracts features from the amino acid sequence using the protein language model ESM-1b, and accurately predicts the interactions between residue pairs of structural domains through a novel gated cross-attention module, thus achieving the correct assembly of structural domains. With the knowledge of domain definition, DDI_single achieves more than 20% higher accuracy in the task of predicting the relative distances of residue pairs between domains than that of the single-sequence-based structure prediction algorithm trRosettaX_single. When assembling domains with known spatial conformations, DDI_single correctly assembles 74.4% of the samples in the test set (TM-score>0.5). When assembling domains with unknown spatial conformations, in cases where the internal spatial conformations of domains are correctly modeled, DDI_single correctly assembles 73.9% of the samples.

23.
medRxiv (Medicine) 2026-06-15

Dysplasia-Stratified Management of Barrett's Esophagus: An Incidence-Based U.S. Cost-Effectiveness Analysis

作者:

Background and Aims Barrett's esophagus (BE) is the principal precursor of esophageal adenocarcinoma (EAC), whose incidence has risen sharply in Western countries since the 1960s. Effective, dysplasia stratified surveillance strategies are needed to prevent progression. This study evaluated the cost effectiveness of dysplasia stratified surveillance intervals and endoscopic eradication therapy (EET) across the BE spectrum. Methods We developed an incidence-based Markov state transition model of BE progression calibrated to U.S. epidemiologic data from a healthcare sector perspective over a lifetime horizon. Four hypothetical cohorts of 50-year-old individuals with short segment BE (SSBE), nondysplastic BE (NDBE), low grade dysplasia (LGD), or high-grade dysplasia (HGD) were evaluated. Strategies included no surveillance; surveillance at 1-, 2-, 3-, 4-, 5-, or 10-year intervals; standard or AI assisted endoscopy; non endoscopic screening (sponge, breath, miRNA tests); and EET for LGD and HGD. Outcomes included costs, quality adjusted life years (QALYs), incremental cost effectiveness ratios (ICERs), net monetary benefits (NMBs), EAC cases, and EAC-related deaths. Sensitivity analyses used a willingness to pay threshold of US$100,000 per QALY. Results No surveillance was the most cost-effective strategy for SSBE and NDBE. For LGD, upfront EET was more cost effective than all surveillance strategies, with results sensitive to EAC incidence and recurrence. For HGD, EET was cost saving and yielded the greatest QALYs, with findings robust in 99.9% of simulations. EET prevented 12,614 and 44,295 EAC related deaths per 100,000 individuals with LGD and HGD, respectively. Conclusion Dysplasia-stratified management is essential for optimizing surveillance and treatment strategies in BE. Any degree of dysplasia should receive EET followed by targeted post-treatment monitoring, establishing EET as the central therapeutic pathway for dysplastic BE.

24.
Nature Medicine 2026-06-09

Adjuvanted inactivated rabies virus-vectored Lassa virus vaccine in healthy adults: a phase 1 trial

Lassa fever causes substantial morbidity and mortality in West Africa, and no licensed vaccine is available. We evaluated LASSARAB, an inactivated rabies virus-vectored Lassa virus (Josiah strain) glycoprotein complex vaccine. We conducted a randomized, controlled, dose-escalation phase 1 trial. Participants (total n = 54) received two intramuscular doses of LASSARAB containing 700 (n = 15), 1,400 (n = 15) or 2,800 (n = 14) relative units of antigen formulated with the TLR-4 agonist 3D-6-acyl PHAD-SE adjuvant, or licensed rabies vaccine control (n = 10), administered 28 days apart. This protocol-defined interim analysis reports the primary safety evaluation and secondary immunogenicity assessments through day 61. There were no prespecified hypotheses or formal power calculations. All primary safety end points demonstrated an acceptable safety profile. After dose 1, local solicited adverse events occurred in 86.7–100.0% of LASSARAB groups and 80% of controls; systemic events in 33.3–71.4% and 60.0% of controls. After dose 2, local solicited adverse events occurred in 66.7–86.7% of LASSARAB groups and 55.6% of controls; systemic events in 53.3–71.4% of LASSARAB groups and 55.6% of controls. Events were predominantly mild and self-limited. Unsolicited adverse events occurred in 28.6–60.0% of LASSARAB groups and 20.0% of controls. No serious adverse event, immune-mediated condition or sensorineural hearing loss occurred. Safety laboratory abnormalities occurred in 13.3–66.7% of LASSARAB groups and 30.0% of controls (14 mild, 6 moderate and none severe). After two doses, Lassa virus GPC IgG ELISA seroconversion (≥fourfold rise) was achieved in 100.0% (44 of 44) of LASSARAB recipients and 0.0% (0 of 10) of controls. Rabies glycoprotein IgG ELISA seroconversion (≥fourfold rise) and neutralizing antibody by rapid fluorescent focus inhibition test (RFFIT) seroprotection (≥0.5 IU ml−1) were also 100% across all groups, including controls. LASSARAB + 3D-6-acyl phosphorylated hexaacyl disaccharide (PHAD)-SE demonstrated a favorable safety profile and immunogenicity against Lassa and rabies viruses. The per-protocol final study report will include safety and durability through day 394. ClinicalTrials.gov identifier NCT06546709 . An interim report of a first-in-human phase 1 trial found an adjuvanted, combination inactivated rabies-vectored, Lassa fever vaccine (LASSARAB + 3D-6-acyl PHAD-SE) to be safe and induced immunogenicity to both Lassa and rabies viruses in healthy participants.

25.
Nature (Science) 2026-06-17

Cucurbituril-based anion-conducting membranes with supramolecular nanopores

作者:

Nanoporous anion-conducting membranes have gained considerable interest for their potential to reduce resistance in electrochemical devices1–4. Current pore-forming methods, such as backbone engineering through polymers of intrinsic microporosity5,6 or covalent organic and metal–organic frameworks7,8, however, suffer from limited structural control, mechanical fragility or demanding synthesis. Here we establish a supramolecular strategy that overcomes these limitations by constructing uniform, dynamic nanopores. Co-assembly of the rigid macrocyclic host cucurbit[7]uril with the cationic polymer guest quaternized poly(piperidinium-terphenyl) yields a robust network of nanometre-scale channels while simultaneously enhancing mechanical and chemical stability. The dynamic host–guest interactions allow the pore structure to fluctuate on picosecond and angstrom scales. This transient environment supports low-friction hydroxide migration through a Grotthuss mechanism, producing a marked enhancement in ionic conductivity. This bottom-up design principle provides a versatile new tool for molecularly engineering transport pathways and promises to advance electrochemical reactors with respect to energy efficiency, operational stability and the production of high-purity products. A supramolecular strategy, in which uniform, dynamic nanopores are constructed, overcomes the limitations of limited structural control, mechanical fragility or demanding synthesis in nanoporous anion-conducting membranes, providing a versatile tool for molecularly engineering transport pathways.