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

VoidPadding: Let [VOID] Handle Padding in Masked Diffusion Language Models so that [EOS] Can Focus on Semantic Termination

MDLMs generate text by denoising a preallocated masked response canvas, making response-length modeling central to instruction tuning. Existing MDLMs often inherit the autoregressive convention of using repeated \texttt{[EOS]} tokens for padding during instruction tuning, giving \texttt{[EOS]} a dual role as both a semantic terminator and a padding token. We show that this dual role is a root cause of \texttt{[EOS]} overflow under large-block decoding. To decouple these roles, we propose VoidPadding, which introduces \texttt{[VOID]} for padding and reserves \texttt{[EOS]} for termination. During inference, the learned \texttt{[EOS]} signal enables early stopping, while the learned \texttt{[VOID]} signal guides adaptive response canvas expansion. On Dream-7B-Instruct, VoidPadding improves the block-size-averaged four-task mean across mathematical reasoning and code generation benchmarks by \(+17.84\) points over the original model and \(+6.95\) points over RainbowPadding, while reducing decoding NFE by 55.7\% on average. Code is available at https://github.com/Haru-LCY/VoidPadding.

02.
arXiv (quant-ph) 2026-06-12

Semi-Device-Independent Certification for Nonlocality without Entanglement

arXiv:2606.13667v1 Announce Type: new Abstract: In this work, we investigate maximum-confidence discrimination, which encompasses minimum-error and unambiguous discrimination, for ensembles of separable states by considering global and separable measurements. We demonstrate that global measurements outperform separable ones, thereby establishing nonlocality without entanglement (NLWE) in terms of confidence in a detection event, a fine-grained state-identification strategy that maximizes the probability of a correct guess given a measurement outcome. Conversely, verifying achievable confidence in measurement outcomes can certify global measurements, namely, semi-device-independent certification of NLWE. Our results make it feasible to experimentally demonstrate NLWE using present-day quantum measurement devices, even with non-unit detection efficiencies, since maximum-confidence measurements rely only on detected measurement outcomes.

03.
arXiv (CS.CL) 2026-06-16

ESBMC-PLC: Formal Verification of IEC 61131-3 Ladder Diagram Programs Using SMT-Based Model Checking

PLCs execute safety-critical programs across industrial sectors. The dominant PLC notation, ladder diagram (LD) per IEC 61131-3, remains absent from formal verification: SMT-based model checkers cannot process LD's rung-and-coil graphics. This paper presents ESBMC-PLC, the first open-source formal verifier with native LD support (PLCopen XML format), implemented as a new ESBMC frontend. ESBMC-PLC translates LD rungs to GOTO IR, models the PLC scan cycle as a while(true) loop with nondeterministic inputs, and checks safety properties via SMT-based bounded model checking or k-induction. A five-property YAML language (mutual_exclusion, invariant, absence, response, reachability) avoids temporal logic. A survey of 22 studies (2020-2026) identifies four research gaps; ESBMC-PLC closes two of them. Evaluation on 13 benchmarks (6 domains, 3 sources - including deployed CONTROLLINO PLCs and MathWorks Simulink PLC Coder) shows correct classification across 61 properties: all 9 author-constructed programs (Categories A/B) as expected, all 4 vendor programs (Category C) correctly unlabeled, with 8 bugs found (actionable counterexamples), 7 unbounded k-induction proofs, all runs under 60ms on Apple Silicon. Feature comparison with PLCverif shows that ESBMC-PLC is the only open-source tool that combines native LD, k-induction, and SMT bit-vector semantics.

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

The Safety-Aware Denoiser for Text Diffusion Models

arXiv:2605.08116v2 Announce Type: replace-cross Abstract: Recent work on text diffusion models offers a promising alternative to autoregressive generation, but controlling their safety remains underexplored. Existing safety approaches are geared toward autoregressive models and typically rely on post-hoc filtering or inference-time interventions. These are inadequate for effectively addressing safety risks in text diffusion models. We propose the Safety-Aware Denoiser (SAD), a safety-guidance framework in text diffusion models. The SAD modifies the iterative denoising process such that the text sample at the final denoising step is steered toward provably safe regions of the text space. This inference-time method can integrate safety constraints into the denoiser, avoiding computationally expensive retraining of the underlying diffusion model and enabling flexible, lightweight safety guidance. We evaluate the safety of the generated text using the SAD, with respect to hazard taxonomy, memorization, and jailbreak. Experimental results show that SAD substantially reduces unsafe generations while preserving generation quality, diversity, and fluency, outperforming existing methods. These results demonstrate that our safety guidance during denoising provides an effective and scalable mechanism for enforcing safety in text diffusion models.

05.
arXiv (CS.AI) 2026-06-17

KFTD: Koopman-Fourier Time-Differentiable Network for Continuous Ocean Spatiotemporal Forecasting

arXiv:2606.17070v1 Announce Type: cross Abstract: Accurate oceanic forecasting is critical for climate monitoring and disaster early warning. However, ocean spatiotemporal forecasting encounters the double challenges of modeling complex dynamical systems and ensuring computational efficiency. We present Koopman Fourier Time-Differentiable (KFTD) Network, a time continuous twostage paradigm that decouples interpolation from prediction to achieve efficient and scalable spatiotemporal modeling. We map complex nonlinear dynamics into the Koopman linear space and exploit Fourier analysis to enable continuous time interpolation at arbitrary sub-steps. A lightweight residual network consumes the high fidelity intermediate states to yield the final forecast. Unlike diffusion models, KFTD eliminates multi step noise sampling and directly evolves the system in continuous time, yielding a 4 computational speedup. We further introduce a DPP Loss that supports arbitrary PDE constraints in an endtoend manner, breaking the physical consistency bottleneck of pure data-driven approaches. Empirical results on four ocean datasets confirm that our continuous time framework reduces MSE by an average of 5.6% (up to 12.7% for SST) and improves efficiency over MCVD by 76.25%.

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

Sustainable Face Recognition on Low-Power Devices with VQ-VAE Embeddings

Face recognition has become a cornerstone of modern AI applications, yet conventional approaches often rely on computationally intensive models deployed in cloud environments, leading to increased network traffic, high energy consumption, and a heavy carbon footprint. This work introduces a sustainable, edge-deployable face recognition framework based on Vector-Quantized Variational Autoencoders (VQ-VAE), which generates compact and semantically rich latent representations of facial images. By leveraging the compression capacity and reconstruction quality of VQ-VAE embeddings on the edge and combining them with the power of pre-trained face embeddings in a knowledge distillation setup, our system achieves comparable accuracy to state-of-the-art face embedding models while significantly reducing memory and computation requirements on the edge, making it suitable for low-power edge devices. The integration of VQ-VAE compression minimizes network overhead while keeping the matching accuracy high by retaining only the most informative facial features in the latent space. As a result, the reconstructed images preserve the key identity characteristics, improving the robustness and overall performance of the face embeddings.

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

Transformer-Guided Graph Attention for Direct Cardiac Mesh Reconstruction: A Structural Digital Twin Framework

Building patient-specific cardiac models sits at the heart of precision cardiology, yet getting those models into clinical use keeps running into the same wall: mesh generation is slow, messy, and frustrating. The standard workflow – segmenting the image, running Marching Cubes, and then manually cleaning up the result – is time-consuming, inconsistent across operators, and demands specialist knowledge most clinical teams do not have. We take a fundamentally different approach. Instead of treating segmentation and mesh generation as two separate problems, we train a single end-to-end network that goes directly from a raw 3D medical image to a smooth, simulation-ready cardiac surface mesh. The core is a 3D Swin Transformer encoder-decoder that extracts volumetric features from CT or MRI volumes, paired with a Graph Attention Network (GAT) head that iteratively deforms a template mesh to fit the patient's cardiac boundary. We tested on the MM-WHS 2017 benchmark using both CT and MRI. Segmentation scores were competitive (Dice of 0.84 on CT, 0.83 on MRI), but the primary focus is mesh quality: mean Chamfer distance of 1.8 mm, with 95th-percentile surface distance below 5 mm. Every mesh is produced in a single forward pass – no Marching Cubes, no smoothing filters, no manual cleanup. We argue that for cardiac digital twin pipelines, geometric fidelity and topological correctness matter more than pixel-level Dice scores. By removing the post-processing bottleneck, this approach makes patient-specific cardiac simulation substantially more accessible for clinical use.

09.
bioRxiv (Bioinfo) 2026-06-22

Complex-valued representations of time-series gene expression profiles for network analysis

Time-series RNA sequencing provides a powerful framework for studying dynamic gene regulation, yet conventional analyses usually represent gene expression profiles as real-valued vectors in Euclidean space and quantify similarity using correlation or distance. Inspired by quantum information theory, we present a framework for encoding time-series gene expression profiles as complex-valued vectors comprising amplitude and phase components in Hilbert space. We designed multiple encoding models to represent gene expression in the amplitude of complex-valued vectors, encode temporal differences in the phase, and extend the phase representation to incorporate the direction of local expression changes. Gene-gene similarity was then quantified using fidelity, which measures the overlap between two encoded vectors. Evaluation using time-series RNA-seq datasets across diverse species and biological contexts showed that different encoding models produced distinct fidelity distributions that were related to, but distinct from, conventional correlation measures. We then constructed gene-gene networks using pairwise fidelity values and detected communities containing genes with similar temporal profiles. Although fidelity distributions differed across encoding models, the resulting communities captured major temporal expression programs, and functional annotations based on gene ontology and Kyoto encyclopedia of genes and genomes pathway analyses provided exploratory biological context. The detected communities were comparable to those obtained using conventional methods, including weighted correlation network analysis and fuzzy c-means clustering. Furthermore, as a proof-of-concept, we performed SWAP-test circuit simulations to mimic fidelity computation on a quantum computer; under noise-aware conditions, these simulations produced less accurate fidelity estimates with higher computational cost than classical computation. As a proof-of-concept, this study provides a complementary view of temporal transcriptome organization, rather than a uniformly superior alternative to conventional methods.

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

Phonikud: Overcoming Phonetic Underspecification for Hebrew Text-To-Speech

Text-to-speech (TTS) for Modern Hebrew is challenged by the language's orthographic complexity, with existing solutions ignoring underspecified phonetic features such as stress. We present a framework for more phonetically accurate Hebrew TTS with four contributions: (1) Phonikud, an open-source Hebrew grapheme-to-phoneme (G2P) system that outputs fully-specified International Phonetic Alphabet (IPA) transcriptions, designed by augmenting a base diacritizer. (2) The ILSpeech corpus of paired Hebrew audio, text, and expert IPA annotations. (3) A benchmark for the previously unmeasured task of Hebrew G2P conversion. (4) Hebrew audio-to-IPA models capturing previously disregarded phonetic details for automatic TTS evaluation. Our results show that Phonikud more accurately predicts Hebrew phonemes than prior methods, and that small, local TTS models with phonetic input from Phonikud approach large proprietary systems. We release our code, data, and models at https://phonikud.github.io.

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

VOiLA: Vectorized Online Planning with Learned Diffusion Model for POMDP Agents

arXiv:2606.19729v1 Announce Type: cross Abstract: Planning under uncertainty is an essential capability for autonomous robots. The Partially Observable Markov Decision Process (POMDP) provides a powerful framework for such a capability. Although POMDP-based planning has advanced significantly, its application to real-world problems is often limited by the difficulty of obtaining faithful POMDP models. We present Vectorized Online planning wIth Learned diffusion model for POMDP Agents (VOiLA), a framework that learns task-agnostic POMDP models for online planning under uncertainty. VOiLA learns transition and observation samplers using conditional diffusion models and learns observation-likelihood models for particle-based belief updates. To enable efficient online planning, the diffusion samplers are distilled into compact feedforward generators and integrated with Vectorized Online POMDP Planner (VOPP), an online POMDP planner designed to leverage GPU parallelization. Experimental results indicate the distillation strategy reduces sampling cost by up to nearly three orders of magnitude, making learned generative POMDP models practical for online planning. Evaluation of VOiLA on three benchmark problems indicate that VOiLA achieves equal or better performance than Recurrent Soft Actor Critic while using less than 10% training data, and generalizes much better to unseen environment configurations. Physical robot evaluation indicates VOiLA uses the models learned using only simulated data and generates a policy that successfully accomplish the task in 10 of 10 runs.

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

Beyond Native Success: Auditing Deployment-Interface Exposure of CLIP Backdoors

Contrastive Language-Image Pre-training models are widely reused across downstream interfaces, including feature extraction, retrieval, reranking, and selection. Existing CLIP backdoor, however, usually validate attacks on a small attack-native task, leaving unclear whether the same poisoned checkpoint remains exposed, weakens, or becomes not applicable when reused through other interfaces. We introduce DIFE, a Deployment-Interface Footprint Evaluation framework that audits backdoored CLIP checkpoints across deployment interfaces. DIFE makes various evaluations comparable by specifying each interface's component readout, trigger channel, target event, reference condition, and metric. DIFE also introduces effective-footprint diagnosis to identify the reusable CLIP component or component combination that carries exposure and explains where risk transfers. Auditing reproduced CLIP backdoors with DIFE reveals a structured landscape: native success is not a checkpoint-level risk certificate, exposure follows component footprints, text-side poisoning does not yield textual-encoder control, and some coupled attacks remain mechanism-bound. This audit reveals a import gapin existing CLIP backdoors: a textual encoder that itself becomes a reusable carrier of adversarial behavior. We therefore introduce BadTextTower to fill this gap. BadTextTower produces strong text-conditioned retrieval, reranking, and selection exposure while leaving visual-only reuse nearly clean.

13.
arXiv (quant-ph) 2026-06-15

Fulde-Ferrell superfluids in an asymmetric three-component Fermi Gas

arXiv:2602.24006v2 Announce Type: replace-cross Abstract: An asymmetric three-component Fermi gas, featuring Raman-induced spin-orbit coupling between the first and second components and contact interaction only between the first and third components, introduces both spin-orbit coupling and population imbalance-two mechanisms known to stabilize the Fulde-Ferrell superfluids.We systematically study Fulde-Ferrell superfluids in an asymmetric three-component Fermi gas { in two dimensions and at zero temperature} by finding the global minima of the thermodynamic potential. We reveal a new class of composite Fulde-Ferrell superfluids that emerges when strong spin-orbit coupling generates a double-well structure in momentum space within the lower spin-orbit-coupled band. The key features of these composite superfluids are identified.

14.
arXiv (quant-ph) 2026-06-12

Proper and improper mixed states serve as different prior beliefs for quantum state retrodiction

arXiv:2502.10030v2 Announce Type: replace Abstract: A mixed quantum state can be taken as capturing an unspecified form of ignorance; or as describing the lack of knowledge about the true pure state of the system ("proper mixture"); or as arising from entanglement with another system that has been disregarded ("improper mixture"). These different views yield identical density matrices and therefore identical predictions for future measurements. But when used as prior beliefs for inferring the past state from later observations ("retrodiction"), they lead to different updated beliefs. This is a purely quantum feature of Bayesian agency. Based on this observation, we establish a framework for retrodicting on any quantum belief and we prove a necessary and sufficient condition for the equivalence of beliefs. We also illustrate how these differences have operational consequences in quantum state recovery.

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

Text-Vision Co-Instructed Image Editing

Existing image editing methods can be generally categorized into textual instruction-based and visual prompt-based ones. Textual instructions are semantically expressive, but are limited by the coarse granularity of spatial control of the editing results. In contrast, visual prompts such as drag and point can provide precise spatial guidance, but are limited by the inherent ambiguity in semantic intent. To unify the strength of textual and visual prompts, we present Text-Vision Co-Instructed Image Editing, which jointly models textual instructions as semantic intent and sparse visual instructions as spatial guidance, aiming to achieve precise and intent-faithful image manipulation. To this end, we first construct a textual-visual instruction paired dataset with more than 23K samples derived from dynamic videos, enabling aligned supervision for cross-modal instruction. We then propose TV-Edit, a Textual-Visual instruction unified Editing framework to contextualize drag or point-based visual instructions with image-text semantics and lift them into semantic-aware control representations for pretrained editing backbones. By integrating semantic intent and spatial constraints, TV-Edit leads to more precise spatial control, less instruction ambiguity, and stronger structural consistency than text-only or drag-based alternatives. Finally, we establish TV-Edit-Bench, a deliberately designed benchmark to evaluate semantic faithfulness, spatial alignment, and visual consistency with ground-truth references and controlled textual-visual variations for reliable assessment. Our experiments across multiple editing backbones demonstrate that TV-Edit consistently yields more precise and intent-faithful edits, significantly outperforming state-of-the-art instruction-based and drag-based baselines.

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

Interpretable Factor Decomposition for Decision Intelligence in Large-Scale Financial Markets: Evidence from China's A-Share Market

arXiv:2606.12843v1 Announce Type: new Abstract: We present an interpretable machine learning pipeline to decompose Cross-Sectional Equity Return Predictability into auditable factor contribution. We apply an XGBoost model with TreeSHAP attribution and conduct stress testing on 3632 Chinese A-share stocks from 2009 until 2019. Using 60-month, rolling windows over 55 months of out-of-sample data, XGBoost obtains a mean AUC of 0.547 and +2.38%/month (Newey-West t = 5.94; Annualized Sharpe 2.23) long-short spread for the top vs bottom quintiles. This alpha is persistent after adjusting for the Carhart four-factor model (+2.31%/month; t = 7.48). SHAP Decomposition indicates that behavioral signals (turnover and momentum) account for 58.2% of predictive attribution compared to 10.7% for valuation ratios, on average, across 55 industry groups. Ablation analysis serves to cross-validate this ranking and provides evidence that SHAP and ablation diverge in a manner that highlights feature substitutability structure that is largely invisible to either method used in isolation.

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

SUP-MCRL: Subject-aware Unified Pseudo-feature Coded Multimodal Contrastive Representation Learning for EEG Visual Decoding

Non-invasive brain-computer interfaces suffer severe fidelity degradation in neural visual decoding when generalizing to natural visual experiences. Conventional multimodal contrastive representation learning solely optimizes geometric distance alignment, neglecting semantic consistency and subject selectivity, causing spurious zero-shot alignment. We propose SUP-MCRL, a unified framework integrating three collaborative mechanisms: (1) Semantic-entity Aware Visual Encoder (SAVE), learning spatial attention to extract semantic content without pre-trained saliency models; (2 Unified EEG Enhancer (UEE), employing multi-scale atrous convolutions and inter-band attention for adaptive cross-subject robustness; and (3) Prototype-based Progressive Augmenter (PPA), maintaining an EMA-updated pseudo-feature pool to prevent representation collapse. Zero-shot experiments on THINGS-EEG achieve 66.0%/91.9% (Top-1/Top-5) intra-subject and 24.0%/52.9% LOSO accuracy, surpassing state-of-the-art methods. Code is available at https://github.com/NZWANG/SUP-MCRL.

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

SAE Interventions are Unreliable: Post-Intervention Recovery of Suppressed Behavior

arXiv:2606.18322v1 Announce Type: cross Abstract: Sparse Autoencoders (SAEs) decompose residual-stream activations into interpretable features. Recent latent-space defenses increasingly rely on these decompositions, assuming that identified "unsafe" SAE features serve as actionable handles for monitoring and intervention. In this paradigm, clamping a specific harmful feature is expected to reliably prevent model misbehavior. However, we show that this success may hide a recoverable failure mode: the clamp may block one visible route to a behavior without eliminating the behavior itself. We formulate this vulnerability as post-intervention recovery, a constrained residual-space optimization problem. Starting from the post-intervention residual state, we optimize residual perturbations to recover the pre-intervention behavior while preserving the post-intervention values of the targeted SAE features. Even under a strong threat model where the intervention remains active throughout optimization and generation, recovery remains possible. To rule out that recovery simply undoes the intervention, we use encoder-orthogonal updates for single-layer interventions and the corresponding feature-map Jacobian in the cross-layer setting. Across TPP, unlearning, IOI, and refusal steering experiments, this stress test reveals recoverable behavior despite successful feature-level intervention. Especially in the safety-critical refusal-steering setting, we achieve a 95.8% recovery rate on valid samples while keeping defended-feature relative drift to 0.131, substantially below suffix-based baselines. A recovery-path attribution analysis further localizes this recovery to the SAE reconstruction residual, the component left unexplained by the SAE. These results expose a gap between feature-level control and behavioral completeness: SAE features can support causal intervention, but controlling them does not guarantee control over the underlying behavior.

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

Pyramid Self-Contrastive Learning for Single-shot Test-time Ultrasound Image Denoising

The inherent electronic and speckle noise complicates clinical interpretation of ultrasound images. Conventional denoising methods rely on explicit noise assumptions whose validity diminishes under composite noise conditions. Learning-based methods are usually pretrained in a limited image domain using a labeled dataset, which implies inevitable domain shift in complex in vivo environments. This study proposes a Pyramid Self-Contrastive Learning (PSCL) framework for test-time ultrasound image denoising without pretraining. Given multiple noisy samples from only one-shot imaging, PSCL disentangles anatomical similarity and noise randomness into separate pyramid latent spaces. The clean image is then decoded from the anatomy space while discarding the noise space. We first apply PSCL to synthetic aperture ultrasound (SAU), where an Aperture-to-Aperture loop serves as a self-supervised proxy task to ensure denoising fidelity. Simulation experiments, including noise levels from 0 to 30 dB and inclusion geometries from simple to complex, demonstrated improvements of 69.3% in SNR and 34.4% in CNR. The in vivo results showed 84.8% SNR and 25.7% CNR gains using only two aperture data of the heart in six echocardiographic views, liver, and kidney. PSCL delivers clear images across diverse imaging targets and configurations, paving the way for more reliable anatomical visualization without domain shift and pretraining costs.

20.
arXiv (CS.CL) 2026-06-17

Beyond Domains: Reusing Web Skills via Transferable Interaction Patterns

Large language model (LLM) web agents are usually deployed as tool callers: each turn, the model reads a fresh page observation and emits one structured tool action. When every action is a low-level primitive, horizons grow quickly and so do policy-facing LLM completions, dominating latency and cost on benchmarks such as Mind2Web and WebArena. Recent systems therefore wrap repeated interaction fragments as web skills: callable tools built from successful trajectories or induced programs, so one call can replace several primitives. However, prior skill libraries are still triggered mainly by instruction similarity or coarse site metadata, which yields low skill reuse on held-out sites and leaves much of the potential step and token reduction on the table. We present SkillMigrator, an agent that learns reusable web skills and transfers them across sites by matching layout structure rather than specific element references. Each induced skill is stored as a transferable interaction pattern (TIP): the skill paired with a structural sketch of the snapshot at induction time. At test time, SkillMigrator retrieves TIPs by layout similarity and grounds their references on the live page. The rest of the stack is standard: accessibility-snapshot observations with stable references, and fixed tool calling over primitives plus skill invocations. Compared with the state-of-the-art approaches, SkillMigrator reduces the average LLM-action count on successful trajectories by 8-10% across both WebArena and Mind2Web at matched success rate.

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

A Unified Definition of Hallucination: It's The World Model, Stupid!

Despite numerous attempts at mitigation since the inception of language models, hallucinations remain a persistent problem even in today's frontier LLMs. Why is this? We review existing definitions of hallucination and fold them into a single, unified definition wherein prior definitions are subsumed. We argue that hallucination can be unified by defining it as simply inaccurate (internal) world modeling, in a form where it is observable to the user. For example, stating a fact which contradicts a knowledge base OR producing a summary which contradicts the source. By varying the reference world model and conflict policy, our framework unifies prior definitions. We argue that this unified view is useful because it forces evaluations to clarify their assumed reference "world", distinguishes true hallucinations from planning or reward errors, and provides a common language for comparison across benchmarks and discussion of mitigation strategies. Building on this definition, we also connect our framework to HalluWorld, a complementary benchmark that instantiates fully specified reference world models for stress-testing model hallucinations.

22.
Nature (Science) 2026-06-12

Daily briefing: How Venus flytraps snap shut

作者:

Softening cells enable flytraps to shut with astonishing speed. Plus, the cutting-edge science happening at the World Cup and why scientists shouldn’t ignore the Pope’s AI message. Softening cells enable flytraps to shut with astonishing speed. Plus, the cutting-edge science happening at the World Cup and why scientists shouldn’t ignore the Pope’s AI message.

23.
medRxiv (Medicine) 2026-06-15

Sociodemographic Disparities in Tafamidis Initiation and Clinical Outcomes in ATTR-CM Across the United States

BACKGROUND Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, life-threatening disease. Sociodemographic factors may influence time to treatment initiation and resulting clinical outcomes, yet these relationships are poorly characterized. OBJECTIVE Assess the effects of sex and race on tafamidis initiation and subsequent outcomes and their interaction with factors such as ATTR-CM type and social deprivation measures. METHODS A retrospective cohort analysis was conducted using the US Komodo Healthcare Map (01/2016-06/2024) among patients with amyloidosis, identified by ICD-10-CM diagnosis codes. Cumulative incidence of treatment initiation and survival probabilities for cardiovascular-related hospitalization (CVH) or death were estimated by Kaplan-Meier, stratified by sex and race. Cox proportional hazards models were fitted for both endpoints to estimate hazard ratios, adjusting for demographics and clinical characteristics. RESULTS Of 11,311 patients identified, White and Black patients (n=9,223) were included in subsequent analyses. Within 12 months of diagnosis, White women had the lowest cumulative incidence of tafamidis initiation (11.4%), followed by Black women (22.0%), Black men (26.7%), and White men (31.0%). Event-free survival at 12 months was lowest in Black women (42.9%), followed by Black men (46.8%), White women (48.6%), and White men (54.4%). Median (95% CI) time to CVH or death was shortest for Black women (8.0 months [6.8-10.0]) followed by Black men (9.9 months [8.8-12.0]), White women (11.0 months [9.6-13.0]), and White men (15.0 months [14.0-16.0]). CONCLUSIONS In this large, real-world cohort of US patients with ATTR-CM, sex and race contributed to disparities in tafamidis initiation and survival, underscoring compounded disparities in both access and outcomes.

24.
bioRxiv (Bioinfo) 2026-06-12

From Proteome Mining to Structural Validation: Phosphopyruvate Hydratase as a Structurally Tractable Drug Target in Kinetoplastid Parasites

Chagas disease, caused by Trypanosoma cruzi, demands novel therapeutic strategies that overcome the toxicity and limited efficacy of current treatments. To address this need, herein we report an integrative, target-centric strategy that combines parasite proteome mining, structural modeling, and experimental validation. Functional enrichment and druggability analyses identified phosphopyruvate hydratase (PPH) as a promising candidate due to its essential metabolic role and limited similarity to human homologs. Notably, proteome mining revealed the presence and conservation of PPH across kinetoplastid parasites, including Leishmania donovani, supporting its evaluation beyond T. cruzi. For the selected PPH sequences, AlphaFold-derived three-dimensional models underwent extensive molecular dynamics refinement, yielding stable conformational ensembles suitable for structure-based studies. Using this validated model, virtual screening of the Latin American Natural Products Database - LANaPDB - identified aptosimon as a top-ranked compound candidate. Molecular dynamics simulations further showed ligand-dependent binding behavior, suggesting alternative binding modes distinct from the canonical substrate configuration. In vitro assays demonstrated consistent antiparasitic activity against intracellular T. cruzi amastigotes (IC50 = 3.52 ug/mL) and Leishmania donovani promastigotes (IC50 = 13.06 ug/mL), supporting the biological relevance of the aptosimon-related lignan chemotype, hinokinin, across two kinetoplastid parasite models. Together, these results support PPH as a structurally tractable and biologically relevant candidate target, while identifying an aptosimon-related lignan chemotype, represented experimentally by hinokinin, as a cross-species antiparasitic scaffold that warrants further biochemical target-validation studies.

25.
medRxiv (Medicine) 2026-06-11

Polygenic risk scores associate with asthma phenotypes and proteomic analyses implicate IL1R1 in two family-based studies

Despite its high prevalence and the discovery of hundreds of genetic associations, the genetic determinants and heterogeneous manifestations of asthma remain incompletely understood. Incorporating polygenic risk scores (PRS) into asthma research offers a powerful approach to quantify inherited susceptibility, refine risk profiles, and advance mechanistic understanding of disease development. For this study, we leveraged whole-genome sequencing (WGS) data from two family-based cohorts of childhood asthma - the Genetics of Asthma in Costa Rica Study (GACRS) and the Childhood Asthma Management Program (CAMP) - to examine the transmission profiles of externally derived asthma PRS and their associations with clinical phenotypes in children with asthma. To further elucidate molecular mechanisms, we integrated large-scale external genome-wide association study (GWAS) summary statistics and genetic prediction models of protein abundance in a two-step proteome-wide association study (PWAS) of asthma. Our findings provide robust evidence supporting the validity of externally derived asthma PRS (asthma PRS association p-value p={10}^{-24} [GACRS and CAMP trios combined] for the Global Biobank Meta-analysis Initiative [GBMI]) and reveal consistent associations with spirometry measures and atopy markers across both studies, as 13 of 21 traits (62%) were significantly associated with the GBMI-PRS in the meta-analysis after multiple-testing correction. Moreover, the results of the integrative proteomic analysis implicate IL-1 signaling in the etiology of asthma, reinforcing the candidacy of IL1R1 antagonists for drug repurposing.