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

Visual-Seeker: Towards Visual-Native Multimodal Agentic Search via Active Visual Reasoning

arXiv:2606.15231v1 Announce Type: new Abstract: Multimodal large language models (MLLMs) have demonstrated impressive capabilities in many visual tasks, but they often struggle with factual grounding when confronted with complex, open-world scenarios. While recent multimodal deep search agents attempt to address this issue by utilizing external tools, the visual-native search paradigm remains underexplored. Existing methods primarily rely on simple images with explicit semantics and text-only evidence trajectories, limiting the agent's ability to perform multi-hop, cross-modal reasoning and search. To address these limitations, we propose Visual-Seeker, a visual-native multimodal deep search agent via active visual reasoning. Rather than treating vision as a static input, our agent actively attends to fine-grained visual details, dynamically harvests visual evidence throughout the search process. To unlock its visual-native potential, we design an active visual reasoning data pipeline and synthesize 5K high-quality multimodal trajectories for model training. Extensive experiments demonstrate the state-of-the-art performance across five challenging multimodal search benchmarks, even surpassing several proprietary models, validating robust visual-native reasoning and search in real-world web environments. The code and data can be accessed at: https://github.com/ZhengboZhang/Visual-Seeker.

02.
arXiv (CS.CV) 2026-06-25

Auto-Labelling-Based Domain Transfer for 3D Object Detection on a Bicycle-Mounted LiDAR Platform

Reliable 3D perception of vulnerable road users (VRUs) such as cyclists and pedestrians is essential for their safety in urban traffic and a core requirement for autonomous driving (AD). Alongside advances in vehicle-based perception, research increasingly equips bicycles with sensors to study traffic from a perspective native to VRUs. Such platforms still rely on LiDAR detectors originally trained on vehicle data, yet annotated 3D data from a cyclist's perspective is scarce. How well these detectors generalise to this setting has not been evaluated. We present a 3D object detection benchmark of 1,027 annotated LiDAR keyframes (over 18,000 3D bounding boxes) from the FUSE-Bike platform in urban Munich. We evaluate four nuScenes-pre-trained detectors against 1,854 human-verified ground-truth (GT) boxes both in their original form and after finetuning on training labels produced by a VRU-dedicated auto-labelling pipeline that requires no manual annotation. The zero-shot domain gap is concentrated on the VRU classes. Finetuning recovers most of it, improving mean average precision (mAP) by up to 23.4 points with the largest gains on pedestrians and cyclists, and the adapted detectors even surpass the quality of the auto-labels they were trained on. The benchmark provides a reproducible baseline for VRU-centric 3D detection and shows that auto-labels are a viable substitute for manual annotation when adapting vehicle-trained detectors to a cyclist platform.

03.
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.

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

Automated 3D Kinematic Monitoring for Circadian Activity and Anomaly Detection in Juvenile Fish

Precision aquaculture faces a "phenotyping bottleneck" in tracking high-resolution behavioral traits, as conventional methods cannot quantify instantaneous three-dimensional (3D) physical exertion. To address this, we present a high-throughput 3D behavioral phenotyping framework integrating deep learning object detection with binocular stereo vision for real-time monitoring of juvenile tilapia in high-density environments. The system automates non-contact body length estimation and reconstructs 3D swimming trajectories from absolute spatial coordinates. By eliminating 2D perspective distortions, this approach precisely quantifies 3D velocity and acceleration, marking the first estimation of true physical swimming speeds in free-roaming juveniles. Results show the framework successfully establishes circadian locomotor baselines, serving as an early warning system for physiological stress and providing an objective metric for fish vitality.

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

Enhancing Visual Feature Attribution via Weighted Integrated Gradients

arXiv:2505.03201v4 Announce Type: replace-cross Abstract: Integrated Gradients (IG) is a widely used attribution method in explainable AI, particularly in computer vision applications where reliable feature attribution is essential. A key limitation of IG is its sensitivity to the choice of baseline (reference) images. Multi-baseline extensions such as Expected Gradients (EG) assume uniform weighting over baselines, implicitly treating all baseline images as equally informative. In high-dimensional vision models, this assumption often leads to noisy or unstable explanations. This paper proposes Weighted Integrated Gradients (WG), a principled approach that evaluates and weights baselines to enhance attribution reliability. WG introduces an unsupervised criterion for baseline suitability, enabling adaptive selection and weighting of baselines on a per-input basis. The method preserves the core axiomatic properties of IG in a generalized weighted-baseline form. Under an expected, proxy-based fitness–relevance monotonicity assumption, WG provides a probabilistic justification for assigning larger weights to more informative baselines. Experiments on commonly used image datasets and models show that WG improves over EG under our protocol, with up to 36% gains across evaluated convolutional and Transformer architectures. These gains come with additional fitness-evaluation cost, so WG should be viewed as an attribution-fidelity trade-off rather than a faster alternative to EG. By moving beyond the assumption that all baselines contribute equally, Weighted Integrated Gradients offers a clearer and more reliable approach to explaining computer-vision models, improving both understanding and practical usability in explainable AI.

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

The Shrinking Lifespan of LLMs in Science

arXiv:2604.07530v2 Announce Type: replace-cross Abstract: Scaling laws describe how language model capabilities grow with compute and data, but say nothing about how long a model matters once released. We introduce time-to-peak and lifespan as measures of model obsolescence and use them to characterize the scientific adoption trajectories of 62 LLMs across more than 108k citing papers (2019-2025), separating active adoption from background citation to recover per-model trajectories that citation counts cannot resolve. We find that a model's longevity is shaped more by when it was released than by its characteristics: release year predicts time-to-peak and lifespan more strongly than architecture, openness, or scale. LLM adoption follows an inverted-U curve (rising after release, peaking, and then declining), but this pattern is rapidly compressing. Each successive release year is associated with a 27% shorter time-to-peak and a 23% shorter lifespan ($p < 0.001$), robust to minimum-age thresholds and controls for model size. These adoption-side dynamics are invisible to scaling laws and suggest that specialization on any single model may be a depreciating investment, with costs falling on reproducibility and migration.

07.
arXiv (CS.CL) 2026-06-19

Segment-Level Mandarin Chinese Speech-Based Cognitive Impairment Detection via an Autoencoder with Contrastive Learning

\noindentBackground and Objective: Speech has emerged as a low-cost and non-invasive digital biomarker with considerable potential for cognitive impairment detection. However, limited labeled data and cross-dataset variability remain major challenges for robust speech-based screening systems. \par\noindentMethods: We developed a segment-level representation learning framework for speech-based cognitive impairment detection. Speech recordings were divided into short segments and converted into spectrogram representations. To improve robustness under limited-data conditions, offline and online augmentation strategies were combined with autoencoder-based representation learning and contrastive objectives to enhance discriminative latent representations. \par\noindentResults: Experiments conducted on four independent Mandarin Chinese speech datasets demonstrated stable and competitive performance in both binary and three-class classification tasks, with particularly notable improvements in the clinically challenging three-class setting. Ablation studies further supported the effectiveness of the proposed framework. \par\noindentConclusions: The findings suggest that segment-level speech representation learning may provide a scalable and practical approach for cognitive impairment screening in resource-constrained clinical settings.

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

STaR-DRO: Stateful Tsallis Reweighting for Group-Robust Structured Prediction

arXiv:2604.09737v2 Announce Type: replace-cross Abstract: Structured prediction with large language models requires outputs that are label-accurate, ontology-constrained, structurally valid, and evidence-grounded under label imbalance and heterogeneous group difficulty. We present a unified framework for ontology-constrained generation. First, we introduce a modular prompt-engineering architecture combining XML-style structure, expert disambiguation rules, chain-of-thought reasoning, metadata-aware decision logic, schema contracts, and a self-validation gate. It targets recurrent in-context failures, including format drift, label ambiguity, evidence hallucination, and metadata-conditioned confusion. Second, we propose STaR-DRO, combining Tsallis mirror ascent, sparse entmax-style primal mapback, EMA-smoothed group-loss tracking, rescaled ascent signals, and bounded excess-only multipliers. Unlike conventional DRO, which relies on dense Shannon-entropy exponentiated-gradient updates, can introduce high-variance stochastic reweighting, assigns positive adversarial mass to groups that are not persistently hard, and incurs costs through simplex competition, STaR-DRO upweights only persistently hard groups without suppressing easier ones. We evaluate the framework on EPPC Miner, a clinically grounded high-stakes structured-prediction task requiring hierarchical label prediction and evidence-span extraction from patient-provider secure messages. Across 1B-70B Llama models, prompt engineering improves zero-shot extraction, yielding an average label F1 gain of +14.46 and a Span F1 gain of +17.40. Building on supervised fine-tuning, STaR-DRO further improves accuracy and robustness, increasing average label F1 by +1.08 and +2.20 while reducing mean groupwise validation cross-entropy by 21.3% and 14.8% relative to SFT and standard DRO, respectively. These results advance reliable automated communication mining for patient-centered clinical care analysis.

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

An Extensible and Lightweight Unified Architecture for Demosaicing Pixel-bin Image Sensors

Pixel-bin image sensors are becoming the default choice for smartphone cameras due to their resolution vs light-gathering trade-off. However, their larger inter-color separation compared to the Bayer color filter array (CFA) makes them challenging to demosaic. Furthermore, existing deep learning-based demosaicing methods are CFA-specific, requiring multiple individual models that take up precious onboard resources and demand larger development and maintenance efforts. In this work, we propose a modular unified architecture for demosaicing various pixel-bin sensors that provides higher image quality while being extensible and lightweight. Additionally, to enable plug-and-play operation, we introduce a learning-free CFA-identification module to detect the CFA type of raw data accurately.

10.
arXiv (CS.CV) 2026-06-16

No One Knows the State of the Art in Geospatial Foundation Models

Geospatial foundation models (GFMs) have been proposed as generalizable backbones for disaster response, land-cover mapping, food-security monitoring, and other high-stakes Earth-observation tasks. Yet the published work about these models does not give reviewers or users enough information to tell which model fits a given task. We argue that nobody knows what the current state of the art is in geospatial foundation models. The methods may be useful, but the GFM literature does not standardize evaluations, training and testing protocols, released weights, or pretraining controls well enough for anyone to compare or rank them. In a 152-paper audit, we find 46 cross-paper disagreements of at least 10 points for the same model, benchmark, and protocol; 94/126 papers with extractable pretraining data use a configuration no other paper uses; and 39% of GFM papers release no model weights. This lack of community standards can be solved. We propose six concrete expectations: named-license weight release, shared core evaluations, copied-versus-rerun baseline annotations, variance reporting, one shared evaluation harness, and data-vs-architecture-vs-algorithm controls. These gaps are a coordination failure, not a fault of any individual lab; the authors of this paper, like many others in the GFM community, have contributed to them. Rather than just critiquing the community, we aim to provide concrete steps toward a shared understanding of how to innovate GFMs.

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

Right Regions, Wrong Labels: Semantic Label Flips in Segmentation under Correlation Shift

The robustness of machine learning models can be compromised by spurious correlations between non-causal features in the input data and target labels. A common way to test for such correlations is to train on data where the label is strongly tied to some non-causal cue, then evaluate on examples where that tie no longer holds. This idea is well established for classification tasks, but for semantic segmentation the specific failure modes are not well understood. We show that a model may achieve reasonable overlap while assigning the wrong semantic label, swapping one plausible foreground class for another, even when object boundaries are largely correct. We focus on this semantic label-flip behaviour and quantify it with a simple diagnostic (Flip) that counts how often ground truth foreground pixels are assigned the wrong foreground identity while remaining predicted as foreground. In a setting where category and scene are correlated during training, increasing the correlation consistently widens the gap between common and rare test conditions and increases these within-object label swaps on counterfactual groups. Overall, our results motivate assessing segmentation robustness under distribution shift beyond overlap by decomposing foreground errors into correct pixels, flipped-identity pixels, and missed-to-background pixels. We also propose an entropy-based, ground truth label-free `flip-risk' score, which is computed from foreground identity uncertainty, and show that it can flag flip-prone cases at inference time. Code is available at https://github.com/acharaakshit/label-flips.

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

Latent Thought Flow: Efficient Latent Reasoning in Large Language Models

arXiv:2606.16222v1 Announce Type: new Abstract: Large Language Models (LLMs) increasingly rely on intermediate reasoning, yet explicit Chain-of-Thought (CoT) suffers from a linguistic space bottleneck: each thought must be decoded into tokens, causing high inference overhead. Latent reasoning moves deliberation into continuous space, but existing methods mostly learn deterministic or reward-maximizing paths, lacking a principled way to allocate probability across trajectories with different correctness and costs. We propose Latent Thought Flow (LTF), which models reasoning as variable-length continuous trajectories and trains a sampler to match a reward-induced posterior over answer quality and computation cost. We instantiate this with a continuous GFlowNet using stochastic latent transitions. To handle sparse answer supervision, we introduce an Entropy-Weighted Subtrajectory Balance objective for intermediate rewards and a reference-prior regularizer to anchor exploration. Experiments under finetuning and transfer learning settings show that LTF outperforms explicit CoT and latent reasoning baselines, improving accuracy by 9.5% while reducing reasoning length by 27.2% on average compared with strong latent reasoning baselines.

13.
arXiv (CS.CL) 2026-06-19

Self-Preference Is Weak or Absent in Verifiable Instruction-Following Revision: A Four-Model Test Under Genuine Authorship

Large language models (LLMs) increasingly review and revise text, including their own. A documented self-preference bias (models favoring their own generations when acting as judges) raises the question of whether models also resist valid corrections to their own writing. We test this in a setting where "valid" is decided not by another model but by a deterministic verifier: instruction-following revision on IFEval. A model writes a draft; the official IFEval checker confirms the draft violates a constraint and that a candidate edit fixes it; the model then accepts or rejects that edit either as the genuine in-context author or as a fresh model that sees the draft neutrally. Across four mid-tier model families and 85 author-versus-fresh comparisons, we find no detectable self-preference: authors reject verified-good fixes to their own drafts at essentially the same rate as fresh models judging the same drafts (gap -5.1 pp, 95% CI [-12.9, +2.7]). A self-skepticism hint from a smaller pilot did not replicate at scale. The one robust observation is qualitative: when authors do reject a verified-good fix, 97% of their stated reasons are flaw-catching rather than preference, that is, about the character of rejections, not an elevated rate. Effects smaller than ~13 pp cannot be excluded at this sample size.

14.
arXiv (CS.LG) 2026-06-12

Accelerating Speculative Diffusions via Block Verification

arXiv:2606.13426v1 Announce Type: new Abstract: Speculative decoding speeds up LLM inference by using a draft model to generate tokens, with an acceptance-rejection scheme that ensures that the output matches the target distribution. Adapting this to continuous diffusions is difficult because speculative sampling requires drawing from a residual distribution. While straightforward in discrete spaces, efficiently sampling this residual in continuous space is non-trivial. Consequently, existing diffusion adaptations either use computationally inefficient sampling techniques or rely on an alternative scheme. In this work, we introduce a novel scheme that efficiently implements the original speculative sampling mechanism for diffusion models. Our approach offers a critical advantage over current methods: it enables us to adapt block verification from LLMs to diffusions – which provably improves the acceptance rate of drafts. Furthermore, we formalize and analyze the Free Drafter, a heuristic self-speculative drafter for diffusions that requires no training. By enabling block verification, our Free Drafter yields up to a 6.3% speedup over existing speculative methods with no additional training and negligible overhead beyond the existing parallel verification pass.

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

What Drives Test-Time Adaptation for CLIP? A Controlled Empirical Study from an Update Perspective

Vision-Language Models (VLMs) such as CLIP have become a standard backbone for open-vocabulary recognition, yet their zero-shot predictions remain vulnerable to distribution shifts encountered at deployment. Test-Time Adaptation (TTA) has recently been extended to CLIP as a lightweight solution, leading to a rapidly growing body of TTA4CLIP methods. However, empirical progress in this area has largely outpaced our understanding of what truly drives adaptation, where their gains originate, and under which shifts they remain reliable. In this paper, we take a step back from the pursuit of state-of-the-art accuracy and conduct a systematic controlled study of TTA4CLIP. We first organize existing methods into three unified paradigms according to what is updated at test time. We then introduce TTABC, an open-source TTA Benchmark for CLIP, which standardizes evaluation protocols and integrates more than 20 representative methods. Our controlled empirical analysis focuses on three key areas. First, we determine the driving factors in parameter-based methods, revealing that adaptation gains are primarily driven by test-time evidence and reliable proxies rather than heavy optimization. Second, we explore evidence utilization beyond heavy parameter tuning, showing that competitive and efficient performance can be achieved through cross- or current-sample evidence and lightweight prototype updates. Finally, we demonstrate that there is no silver bullet for TTA: no single adaptation paradigm is universally optimal, and the preferred paradigm depends on the nature of shift. We hope our benchmark and study provide a clearer understanding of the current TTA4CLIP landscape and establish a foundation for further research.

16.
arXiv (CS.CL) 2026-06-24

Cross-Lingual Exploration for Parametric Knowledge

Parametric knowledge in Large Language Models is not equally accessible across languages. As a result, standard inference techniques often struggle to surface localized facts, leading to failures in cross-lingual knowledge transfer and consistency. In this work, we investigate techniques for accessing hidden factual knowledge by exploring cross-lingual prompting strategies. We identify four inherent dimensions of cross-lingual exploration that directly govern parametric knowledge retrieval and evaluate them on multilingual factual benchmarks covering 17 typologically diverse languages. Our results demonstrate that cross-lingual exploration significantly improves knowledge transfer and factual recall, representing a more efficient compute Pareto frontier than native-language scaling. Furthermore, we observe corresponding improvements in cross-lingual consistency, exceeding what can be explained by accuracy gains alone. Overall, our work establishes multilingual prompt exploration as a highly effective inference-time strategy for unlocking latent parametric knowledge.

17.
arXiv (quant-ph) 2026-06-16

Initiation of Superradiance from Different Collective Spin States

arXiv:2606.14949v1 Announce Type: new Abstract: Superradiance is an extensive cooperative spontaneous emission phenomenon. Some atomic collective spin states exhibit it. However, distinct initial states differ in their decay dynamics. Dicke states with different numbers of excitations have their peak emission intensity shifted in time depending on the number of excitations. Emission intensity in atomic coherent states depends on their polarization. Some specific states undergo a squeezing controlled crossover, making the emission character dependent on the amount of squeezing in the state. We present detailed results on the superradiant dynamics of a representative selection of Dicke states. For large N, we are able to predict fairly accurately the pulse profile in each case using the mean field approximation, an approach based on the Fokker Planck Equation. We also present results on the intensity correlation function of the emission.

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

Scalable Training of Spatially Grounded 2D Vision-Language Models for Radiology

We study how to train visually grounded vision-language models (VLMs) for radiology without manual spatial annotations. We introduce RefRad2D, a large-scale bilingual (German/English) dataset of 1.2M CT and MR image-text pairs derived from clinical practice, with task-specific VQA and spatial grounding subsets generated automatically via LLM-based curation and automated segmentation. Trained on this data, our model RadGrounder jointly performs report generation, visual question answering, and spatial grounding via bounding-box detection or segmentation. On external VQA benchmarks (Slake, VQA-RAD), RadGrounder achieves competitive results with specialized medical VLMs. Adding our clinical data to the training mixture improves open-ended VQA over fine-tuning on the downstream datasets alone, showing the transferability of our dataset. Crucially, adding grounding supervision does not degrade language quality, enabling spatially verifiable outputs at no cost to VQA performance.

19.
arXiv (CS.AI) 2026-06-24

RAVEN: A Regime-Aware Variable-context Expert Network for Financial Time Series Forecasting

arXiv:2606.24062v1 Announce Type: cross Abstract: Financial time series forecasting presents structural challenges absent from standard benchmarks. Log-returns are non-stationary, exhibit exceptionally low signal-to-noise (SNR) ratios, and are governed by regime-dependent temporal dependencies. We identify a key limitation of state-of-the-art (SOTA) time series models in financial settings. A fixed context window is mismatched to the time-varying optimal look-back of non-stationary price processes. We propose the Regime-Aware Variable-context Expert Network (RAVEN), a Mixture-of-Experts framework designed to adaptively determine the temporal context for each input sample. Instead of relying on a fixed look-back horizon, RAVEN constructs a hierarchy of nested contiguous windows whose lengths are determined by the data itself. Specifically, RAVEN scores patches by learned importance in reverse chronological order and applies the Cumulative Importance Thresholding (CIT) mechanism to derive nested prefix windows, each routed to a scale-specialized expert. A Global Compressed Representation (GCR) branch runs in parallel over the full context, preserving global temporal coherence that local experts cannot guarantee. Because the nested routing induces structured overlap among expert inputs, we introduce a Correlation-Aware Weighting (CAW) to align variable-length expert outputs and penalize pairwise cosine similarity prior to aggregation. Experiments on cumulative log-return prediction (HS300, S&P500) and fund sales forecasting demonstrate that RAVEN achieves SOTA performances, improves Pearson correlation by 9.2% on HS300 and 20.2% on S&P500, and reduces MSE by 18.2% on fund sales forecasting, while achieving the best results in 14 of 16 metrics on four PEMS traffic benchmarks.

20.
arXiv (CS.AI) 2026-06-25

Agentic System as Compressor: Quantifying System Intelligence in Bits

arXiv:2606.25960v1 Announce Type: new Abstract: Large language models are turning from isolated predictors into agentic systems: they call tools, retrieve evidence, obey environment constraints, use verifiers, and complete tasks through search and multi-turn interaction. We adopts an analytical viewpoint based on "compression is intelligence": under a fixed task distribution, interface, and compute budget, a stronger agentic system lets a target object be reconstructed with fewer bits. We operationalize the measure with arithmetic coding, seed coding, and a fallback, and evaluate it in five settings: reversed text, chess moves, protein sequences, retrieval-augmented question answering, and semantic story compression; in all of them agentic components reduce codelength. These small, controlled experiments cover component types typical of real agentic systems, show that codelength can analyze how components, observers, and budgets change residual uncertainty, and offer guidance for evaluating real agent systems.

21.
arXiv (CS.AI) 2026-06-17

Comprehensive pKa Data Augmentation from Limited Real Data through an Engineered Models-Quantum Framework

arXiv:2606.17077v1 Announce Type: cross Abstract: Proton dissociation constants (pKa) are critical for functional molecule discovery and molecular modeling. Building on iBonD, the largest experimental pKa database established, we and other researchers have developed several methods including machine-learning-based empirical prediction and high-accuracy energy calculations. Despite this foundation, the rapid augmentation of high-quality pKa data remains fundamentally constrained. As part of this work, we performed large-scale regression-based pKa prediction on unlabeled molecular datasets using a collection of extensively optimized machine-learning models. The results indicate that, since the feature distributions of unlabeled molecular datasets, the pKa data distribution approximates normality, with extreme scarcity of tail-region samples. Although such augmentation is highly valuable for improving overall data availability and predictive modeling, it remains insufficient for efficiently discovering molecules with broad-spectrum pKa properties. To address this, we explore the targeted generation of molecules with sparse pKa properties from the vast chemical space. Given that traditional continuous latent space VAE-RNN methods for molecular generation suffer from insufficient stability and fail to demonstrate clear advantages in complementing sparse data, we design and implement a quantum-assisted sparse-pKa molecular generation. Feasibility is validated on a simulated quantum annealer, and superior extreme-value sampling is further achieved on physical coherent Ising machines (CIMs). (to be continued)

22.
bioRxiv (Bioinfo) 2026-06-24

BATTLE-AMP: Benchmarking Antimicrobial Peptide Predictors

As antimicrobial resistance outpaces antibiotic development, antimicrobial peptides (AMPs) have emerged as a promising class of alternative antibacterials, and computational predictors are increasingly used to prioritize AMP candidates. Such predictors are typically evaluated on binary AMP/non-AMP classification, which does not test whether they can identify peptides with clinically relevant potency against specific pathogens. We present BATTLE-AMP, a benchmarking framework that evaluates AMP predictors against experimentally measured minimum inhibitory concentrations (MICs) across clinically relevant bacterial species and strains. We surveyed 48 published methods, finding fewer than 25% reproducible, and benchmarked 10 model families (21 variants) using experimental MIC data, synthetic sequence perturbations, activity cliff analyses, and all-atom molecular dynamics (MD) simulations. Four findings emerge: (i) models trained on MIC data outperform binary classifiers regardless of architecture; (ii) the best model depends on the target pathogen, so model selection must be guided by the biological question; (iii) most models cannot distinguish active peptides from inactive sequences with identical amino acid composition; and (iv) activity cliffs remain unresolved by both machine learning and MD, marking a limit of current computational methods. BATTLE-AMP is released as an open Snakemake framework at https://github.com/szczurek-lab/battleamp-snakemake for benchmarking new models and scoring novel candidate libraries.

23.
PLOS Computational Biology 2026-06-16

Evolution and the ultimatum game: An agent-based model with interbirth intervals and population structure

by Jeffrey C. Schank, Matt L. Miller The ultimatum game (UG) is widely used to study mutually beneficial exchanges, fairness, and prosocial behavior across different societies. However, human behavior in UG experiments does not align with the game-theoretical prediction that proposers should offer the least positive amount and responders should accept such offers. Instead, proposers make generous offers that are greater than the minimum responders are willing to accept, resulting in generous offers with wide offer-acceptance gaps. Numerous evolutionary models of the UG have been created and studied to explain human behavior, particularly generous offers made in UG experiments. These models have recently faced criticism for lacking biological realism and not adequately explaining the data. Here, we present an agent-based model inspired by our hunter-gatherer ancestors and with a biologically more realistic selection process. We assume that (1) agents exist in group-structured and group-clustered populations, where reproduction (2) depends on resource accumulation, but (3) is limited by interbirth intervals. We ran simulations to assess whether this biologically more realistic model evolves patterns of behavior consistent with patterns in the data from meta-analyses of human behavior in the UG. For the proposed model, we show that generous offers robustly evolve, as well as the difficult-to-explain offer-acceptance gaps, only in group-structured populations with interbirth intervals. We demonstrate that these results are robust and may help explain variation in data across societies. We discuss how interbirth intervals interact with group structure to modulate offer and rejection costs, favoring the evolution of generous offers, offer-acceptance gaps, and other patterns in the data on human behavior in the UG. We also discuss why weak selection and/or high mutation rate models cannot explain all the patterns in UG experimental data. We discuss biological realism and conclude that group structure and interbirth intervals may be essential for explaining prosocial behavior across societies.

24.
Nature Medicine 2026-06-08

Effects of SGLT2 inhibition on incident heart failure in carriers of cardiomyopathy-associated genetic variants

Although the beneficial effects of sodium–glucose cotransporter 2 (SGLT2) inhibition in heart failure (HF) have been well established, it is unknown whether SGLT2 inhibition confers benefit in carriers of rare variants in cardiomyopathy-associated genes. Here we evaluated whole-exome sequencing data from the randomized DECLARE-TIMI 58 trial, in which adults with type 2 diabetes and increased cardiovascular risk were randomized to dapagliflozin or placebo treatment. Pathogenic or likely pathogenic variants (P/LP) in high-confidence cardiomyopathy genes were identified, and treatment effects on hospitalization for HF (HHF) were compared between carriers of such variants and noncarriers. Among 12,685 patients for whom sequence data were obtained, 121 carried a cardiomyopathy variant (76 dilated cardiomyopathy, 25 hypertrophic cardiomyopathy and 25 arrhythmogenic cardiomyopathy). Over a median follow-up of 4.2 years, dapagliflozin lowered the risk of HHF more strongly in carriers (hazard ratio 0.18, 95% confidence interval 0.04–0.86) than in noncarriers (hazard ratio 0.70, 95% confidence interval 0.57–0.86; P interaction 0.03). Absolute risk reduction was 13.0% in carriers and 1.0% in noncarriers (P interaction 0.03). Most carriers (82%) had no prior HF, and in carriers without prior HF, treatment with dapagliflozin reduced the absolute risk of HHF by 12.8%, compared with a reduction of 0.6% in noncarriers (P interaction 0.01). The findings from this cohort of older and high-risk patients raise the possibility that SGLT2 inhibitor treatment should be started early to prevent HF in individuals who carry P/LP cardiomyopathy variants. These results need to be confirmed in a prospective, dedicated trial of preventive HF treatments in carriers of P/LP cardiomyopathy-associated variants. In a whole-exome sequencing analysis, the beneficial effects of the SGLT2 inhibitor dapagliflozin in reducing the risk of future heart failure hospitalization in individuals with type 2 diabetes were markedly greater in individuals who carried a cardiomyopathy-associated genetic variant compared with noncarriers, suggesting a personalized preventative therapy based on genetic information.

25.
medRxiv (Medicine) 2026-06-24

Cognitive-emotional responses to ultrasonic neuromodulation of anterior cingulate cortex

The anterior cingulate cortex (ACC) is a key brain center involved in cognitive and emotional processing that is implicated in a variety of neuropsychiatric disorders including chronic pain and depression. Circuit-targeted diagnosis and treatment of these disorders will require the capacity to precisely modulate ACC subregions. Toward that end, we recently developed and validated a novel low-intensity transcranial focused ultrasound device that can noninvasively and directly modulate ACC subdivisions in humans with millimeter precision. Here we describe the subjective reports of 36 individuals diagnosed with either chronic pain or major depression who received repeated brief stimulation trials (807 active, 797 sham; duration 30s-3min) spanning the dorsoventral extent of the ACC. Sonication immediately altered cognitive-emotional states (odds ratio 5.6, active versus sham), eliciting a positive-valence experience more often than negative (29% versus 8%) in both diagnostic groups. Sham-adjusted response rate varied across ACC targets, with the largest effects (Cohen's d ~ 0.8) observed in pregenual and subgenual ACC in subjects with chronic pain and depression, respectively. These rapid trial-by-trial responses to ACC stimulation predicted subsequent improvements in pain and depression severity at 24 hours. Collectively, these findings reveal that transcranial ultrasound can robustly evoke immediate, target-specific, clinically meaningful changes in cognitive-emotional state, demonstrating the potential of ultrasonic neuromodulation as a tool for individualized probing of circuit function and dysfunction.