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01.
medRxiv (Medicine) 2026-06-11

Parent and physiotherapist perceptions about movement skills of young children with juvenile idiopathic arthritis

Objective: The onset of juvenile idiopathic arthritis (JIA) in the early years ([≤]5 years) may negatively impact movement skill (encompassing related concepts of gross motor skills, fundamental movement skills, and functional ability) development. Few studies have explored the perceptions and needs of parents and physiotherapists towards children's difficulty with these movement skills, essential to identify potential areas for added support. The objective of this study is to understand the perceptions of physiotherapists and parents towards movement skills of children with JIA. Methods: Seventeen parents and 24 physiotherapists completed an online questionnaire consisting of multiple choice and open-ended questions about the movement skills of young children with JIA. Demographic and multiple choice questions were quantitively analysed using descriptive statistics. Open-ended responses were analyzed using qualitative conventional content analysis. Results: About half (47%) of parents perceived their children to have movement difficulties, and 75% of physiotherapists described the movement skills of children with JIA as worse than other children of the same age. Our qualitative analysis revealed three general themes including: functional task difficulties; clinical variability in movement skills; and psychosocial components of movement skill difficulties. Conclusion: This study provides an analysis of perceptions of physiotherapists and parents towards the movement skills of young children with JIA. A significant proportion of parents and physiotherapists identify movement difficulties among children with JIA that impact daily life. Future interventions co-designed with both parents and care providers targeting movement skills are needed.

02.
arXiv (CS.CL) 2026-06-16

StagePilot: Stage-Level Planning for Long-Horizon Dialogue Simulation in Cybergrooming

Cybergrooming is an evolving threat to youth, requiring proactive educational interventions. We address this by modeling dialogue progression as a structured planning problem over stage-wise interactions. We propose StagePilot, a dialogue framework that separates stage-level planning from response generation, in which the model selects the next stage under constrained transitions and generates responses conditioned on it, enabling coherent and realistic progression. Reinforcement learning is used to learn stage-level policies from offline data, optimizing for both emotional alignment and goal-consistent progression. Our empirical experiments show that StagePilot generates more structured, coherent dialogue trajectories and reduces conversational stagnation compared to baselines; notably, the IQL+AWAC variant reaches the final stage more often while maintaining over 70% positive or neutral responses, yielding a 43% relative improvement.

03.
medRxiv (Medicine) 2026-06-15

Fanconi Anemia as a Window into Premalignant Field Cancerization of the Oral Mucosa

Head and neck squamous cell carcinoma (HNSCC) evolves through stepwise clonal expansion within genetically altered mucosa fields, yet actionable biomarkers remain undefined. Leveraging Fanconi anemia (FA), a cancer predisposition syndrome with extreme HNSCC risk due to defective DNA interstrand crosslink repair, we profiled premalignant changes in the oral cavity using noninvasive brush biopsies. Consistent with our prior demonstration of genomic instability in FA-associated SCCs, we detected pathogenic TP53 variants in 26% and copy number alterations in 60.5% in clinically normal-appearing oral mucosa of individuals with FA. These subclinical clonal expansions define candidate biomarkers of early clonal evolution amenable to serial sampling for risk stratification and prevention studies. Since FA-associated SCCs share genomic features with sporadic HNSCC, these findings may extend to the broader population. We also identify somatic reversion of a pathogenic FANCB variant, providing evidence of genomic self-correction and suggesting a potential avenue for gene-based cancer prevention in FA.

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

DeepRoot: A KG-Coordinated Multi-Agent System for Therapeutic Reasoning over Historical Medical Texts

arXiv:2606.15931v1 Announce Type: cross Abstract: Historical medical archives and traditional medicines hold immense potential for drug discovery and remain a primary source for current drug development. However, pre-ontological prose and idiosyncratic taxonomies prevent the standardization and medical modernization of the data for use in current biomedical pipelines. Furthermore, no existing LLM agent system, whether tool-calling, retrieval-augmented, or agentic deep-research, can convert such text into verifiable drug-discovery leads at scale. We close this gap with DeepRoot, a multi-agent LLM system that jointly builds and utilizes a verified knowledge graph, showing that grounding and reasoning – often conflated – are separable axes the system can compose for therapeutic reasoning. Applied to the Shen Nong Ben Cao Jing, DeepRoot recovers $10$ of $21$ held-out compound-disease treatment pairs at R@$20$ ($47.6\%$ vs $4.8\%$ for a raw corpus LLM and $\sim\!2.4\%$ random) and dominates an LLM-as-judge audit for reasoning quality over baseline LLMs and LLMs with direct tool-call access to the same APIs DeepRoot itself queries. Tool-using LLMs hallucinate evidence on $87\%$ of claims, versus 7-10% for DeepRoot. Graph-only inference hallucinates $0\%$ but ranks lowest on reasoning coherence; DeepRoot KG+LLM is the only condition to win on both axes, pointing toward a route for systematic mining and repurposing of historical medical knowledge.

05.
arXiv (quant-ph) 2026-06-12

More efficient Clifford+T synthesis for small-angle rotations and application to Trotterization

arXiv:2605.31544v2 Announce Type: replace Abstract: Clifford+T synthesis of rotation gates is an important routine in fault-tolerant quantum compilation. While Clifford+T synthesis is scalable, it has a high overhead of tens of T gates per rotation in practice, translating to high resource estimates for many fault-tolerant algorithms. However, these well-known results, including those using probabilistic mixtures [Quantum 7, 1208 (2023)], are independent of the rotation angle $\theta$, requiring $O(\log 1/\delta)$ T gates. We show that it is possible to do much better for small angles, reducing the T cost to $\tilde{O}(\theta^2/\delta)$, and returning to existing $O(\log1/\delta)$ results in the worst case. This is particularly important since many algorithms, such as Trotterization, are dominated by small-angle rotations. Further, we perform a detailed theoretical and numerical study of quasi-probabilities, which can further reduce the total T cost of large circuits by orders of magnitude with only a small overhead in sample complexity. We also develop a scheme based on quasi-probability mixtures of Clifford+T fallback channels. We derive new $\theta$-dependent formulas that can be used for resource estimation of fault-tolerant quantum algorithms. As an application of our results, we show that the gate cost of Trotterization circuits compiled to a Clifford+T gate set is constant in the small Trotter step size limit, and can be reduced by orders of magnitude even for large step sizes. The cost of fault-tolerant Trotterization for a variety of applications should be re-examined in light of these results. Our work dispels the widely-stated claim that Clifford+T rotation synthesis has a high cost independent of $\theta$, and further develops a scalable quasi-probability method for rotation synthesis. We also expect our results to bring forward useful early fault-tolerant quantum computing by reducing required magic state resources.

06.
PLOS Computational Biology 2026-06-15

A multilevel hierarchical framework for quantification of experimental heterogeneity in population snapshot data

by David J. Warne, Xiangrun Zhu, Thomas P. Steele, Stuart T. Johnston, Scott A. Sisson, Matthew Faria, Ryan J. Murphy, Alexander P. Browning Biological systems exhibit substantial heterogeneity: that is, variation in specific characteristics of individuals within a population. As a result, it is of critical importance to appropriately account for biological heterogeneity when calibrating mathematical models to infer cellular processes and predict behaviour. Recent approaches consider ordinary differential equations with random parameters to quantify heterogeneity in dynamical processes of cells. In this setting, statistical inference is performed to characterise the distribution of these random parameters within a cell population. One significant limitation of this approach is the tacit assumption that there are no substantial deviations in these distributions across experimental replicates. In this work, we propose a flexible Bayesian hierarchical differential equation modelling framework that quantifies and distinguishes both inter-experimental heterogeneity (heterogeneity between experimental replicates) and intra-experimental heterogeneity (biological heterogeneity within replicate populations). We consider two recent studies that employ mathematical models to interpret flow cytometry snap-shot data and quantify heterogeneity in nano-particle cell interactions and cell internalisation processes. Using simulation data, we demonstrate that substantial inaccuracy in the inferred dynamics can arise when experimental heterogeneity is not accounted for. By contrast, our hierarchical approach is robust to variability in inter-experimental and intra-experimental heterogeneity and our method simplifies to previous methods when inter-experimental heterogeneity is negligible. Our approach is flexible and widely applicable to applications involving replicate populations and snapshot data. We provide open-source implementations of our methods on GitHub.

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

SupraBench: A Benchmark for Supramolecular Chemistry

Supramolecular chemistry, which includes the study of non-covalent host-guest assemblies, has advanced various applications. However, designing host-guest systems remains time-consuming, requiring days of dry-lab verification per candidate pair. Although LLMs have emerged as a fast alternative with strong performance on molecular binding tasks, no benchmark currently systematically evaluates LLMs for host-guest reasoning across fundamental supramolecular chemistry tasks, e.g., binding affinity prediction. To this end, we collaborate with domain experts to release the first Supramolecular Benchmark, called SupraBench, to evaluate LLMs in chemistry reasoning. Specifically, we design four fundamental tasks, i.e., binding affinity prediction, top-binder selection, solvent identification, and host-guest description, plus an auxiliary vision-based task for molecular identification. We also release SupraPMC, a curated 16M-token corpus of Supramolecular chemistry articles distilled from Europe PMC, to support the adaptation to the supramolecular domain. We benchmark a broad range of open and proprietary LLMs and find that LLMs leave substantial headroom across all tasks. Domain adaptation pretraining over SupraPMC transfers cleanly to in-distribution regression but trades off against strict letter-format output. Moreover, the difficulty profile differs sharply across task families, revealing distinct failure modes that indicate specific gaps in current supramolecular chemistry reasoning. Our source codes and benchmark datasets are available at https://github.com/Tianyi-Billy-Ma/SupraBench.

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

Agentic Discovery of Non-Canonical Antimicrobial Peptides with AMPGAN v3

arXiv:2606.17127v1 Announce Type: cross Abstract: Antimicrobial resistance causes to over a million deaths annually. Antimicrobial peptides (AMPs) are a promising solution, but generative AMP models are not yet ready to design peptides with non-natural amino acids and/or chemical modifications, which are essential for real-world peptide drugs. We present AMPGAN v3, a multi-objective conditional GAN that expands the generative vocabulary to D-amino acids and N/C-terminus modifications such as amidation. By separating adversarial and activity-aware supervision across two specialized discriminators, AMPGAN v3 substantially improves training stability and outperforms prior generative AMP models on external classifiers. We validated five candidates spanning three structural classes in vitro; two showed activity against Gram-positive strains, with the best candidate reaching MIC 8 {\mu}g/mL against B. subtilis. To support downstream curation, we further present PepCraft, a multi-agent framework for end-to-end AMP discovery in which a Planning Agent orchestrates specialized executors for generation, filtering, and verification. Its prioritization recommendations align with our in vitro outcomes. Together, these contributions let us examine, on a small but real scale, how generative and agentic AI compose in therapeutic peptide discovery. Code: https://github.com/marszzibros/AMPGANv3

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

MDForge: Agentic Molecular Dynamics Pipeline Design under Sparse Simulator Feedback

Molecular dynamics (MD) is the canonical in-silico method for atomistic molecular science, simulating molecular behavior from first-principle physics. Designing an MD pipeline for a new system requires substantial expert knowledge: running it on even one molecule is expensive, ruling out trial-and-error. We automate this expert pipeline-design process with an LLM agent. Unlike existing MD agents that orchestrate a predefined tool set, we treat pipeline design as open-ended code generation in which the agent's behavior is reshaped online by verbal reward. Specifically, we build MDForge, an LLM agent whose in-context update rule densifies the sparse reward via a multi-agent debate among physics experts. On three SAMPL host-guest binding free-energy benchmarks, MDForge automatically designs MD pipelines competitive with human experts. Deployed on a library of unseen candidate guests, its CB[7] pipeline discovers a novel binder that wet-lab competition NMR confirms is a high-affinity, picomolar CB[7] binder. Our data and code are available at https://github.com/Zehong-Wang/MDForge.

10.
medRxiv (Medicine) 2026-06-10

Prediction of immunotherapy response using live tumor fragments from routine clinical biopsies

Functional ex vivo assays using live tumor tissues have demonstrated strong predictive accuracy for response to immune checkpoint inhibitors (ICIs) but are not scalable, requiring manual processing of large resections collected at academic centers. Here, an ex vivo live tumor fragment (LTF) platform was developed using standard-of-care biopsies from 228 patients with suspected malignancy collected across prospective, multicenter observational trials and biobanks. Hierarchical clustering of ICI-mediated changes in cytokine production identified two groups: responders and nonresponders. A binary classifier (elive index) using 8 cytokines achieved an AUC of 0.99 for cluster prediction. elive index correctly predicted clinical benefit in 93% (26/28) of patients (P = 3.2x10-5) and accurately identified 83% (10/12) of objective responders. Critically, elive responders were identified among biomarker-negative patients, highlighting the platform as a scalable approach that complements existing companion diagnostics and expands the population of patients identified to benefit from ICI therapy.

11.
medRxiv (Medicine) 2026-06-18

Distinct Neuronal, Proliferative, and Secretory Pathways are Perturbed in Cancer Survivors with Depressive Symptoms

Introduction Depression is highly prevalent among cancer survivors and may be biologically distinct, although clinical studies investigating these mechanisms remain limited. Thus, the aims of this study were to (1) identify perturbed biological pathways associated with depressive symptom severity in cancer survivors, and (2) investigate whether these pathways are common or distinct to those perturbed in an age-matched non-cancer cohort. Methods We analyzed cross-sectional self-reported and transcriptomic data from the Multi-Ethnic Study of Atherosclerosis (PHD #39341). Cancer survivors and an age-matched non-cancer cohort (target ratio 1:2) were identified. The 20-item Center for Epidemiologic Studies Depression Scale (CES-D) was used to split participants into low (CES-D

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

Emyx: Fast and efficient all-atom protein generation

arXiv:2606.19377v1 Announce Type: cross Abstract: Computational enzyme design requires generating proteins that scaffold catalytic residues and ligands, a task that demands both geometric accuracy and structural diversity from the underlying generative model. Current all-atom generators inherit expensive architectures from structure prediction, leading to high training costs and limited sample diversity. We argue that much of this complexity is unnecessary for generators, which condition on sparse geometric constraints rather than rich co-evolutionary signals. Emyx is a 140M-parameter conditional flow matching model that concentrates capacity within standard transformer blocks, replacing heavy embedding stacks with lightweight conditional representations and sparse connectivity. We additionally derive an exact reparametrisation of the flow matching interpolant into the EDM noise-level framework, bridging flow matching training efficiency with state-of-the-art sampling methods designed for diffusion models without retraining. Despite being the smallest model, Emyx outperforms both Proteína-Complexa and RFdiffusion3 against the AME enzyme design benchmark across success rate under strict evaluation requiring both global fold recovery and catalytic geometry accuracy, structural novelty, scaffold diversity, and geometric validity, while training in just $682$ GPU-hours, roughly $4\times$ less than RFdiffusion3.

13.
medRxiv (Medicine) 2026-06-11

Two modes of aversive control in suicidality: joint computational modelling exposes regime-specific clinical signatures invisible to symptom-based stratification

Suicidal thoughts and behaviours (STBs) are heterogeneous in their proximal dynamics, planning, and stress-sensitivity, yet most subtyping efforts remain symptom-driven and rarely validated across independent datasets. Computational mixture modelling offers a principled alternative: by fitting explicit models of learning and action selection and partitioning individuals by their latent parameter profiles, it can identify mechanistically distinct control strategies invisible to cross-sectional symptom measurement. We applied this approach to aversive Go/NoGo performance, jointly clustering two independently collected STB-enriched samples (N = 50 and N = 184) using tasks with the same structure but different duration, reversal timing, and clinical instrumentation. Two recurrent behavioural regimes emerged: a fast/adaptive regime characterised by rapid policy updating and elevated feedback reactivity, and a slow/perseverative regime characterised by slow updating, high choice determinism, and a pronounced cost following contingency reversal. These regimes were stable across initialisations, recovered more parsimoniously in joint than independent solutions, and were largely orthogonal to symptom-based stratification. Critically, stratification by regime exposed clinical-computational coupling structures substantially attenuated in pooled analyses. Pooled, population-level associations were modest and anchored by a broad affective burden axis. Within the slow/perseverative regime, coupling reorganised around learning dynamics and internalizing burden (depression, hopelessness, and active suicidal ideation) with markedly larger effect sizes. Within the fast/adaptive regime, a dissociation between anxious-compulsive and antisocial-disinhibitory profiles emerged along the same computational axis, invisible at the population level. These findings support a view of suicidality heterogeneity in which clinically similar individuals differ in the control strategies they recruit under aversive uncertainty - variation that symptom measurement alone cannot capture.

14.
arXiv (CS.CV) 2026-06-19

Prediction of Alzheimer's Disease Risk Factors from Retinal Images via Deep Learning: Development and Validation of Biologically Relevant Morphological Associations in the UK Biobank

The systemic, metabolic, lifestyle factors have established associations with Alzheimer's Disease (AD) through epidemiologic and AD-specific biomarker studies. Whether colored fundus photography (CFP) contains retinal structural signatures corresponding to these AD-related risk domains remains unclear. To determine whether deep learning (DL) models can predict 12 AD-related risk factors from CFP and to characterize the retinal structures underlying these predictions, thereby assessing whether CFP reflects pathways to AD vulnerability. Using 62,876 CFPs from 44,501 unique participants from the UK Biobank, DL models were trained to predict 12 factors linked to AD incidence: 6 categorical (sex, smoking, sleeplessness, economic status, alcohol use, depression) and 6 continuous (age, age at completing education, BMI, systolic, diastolic blood pressure, HbA1c). Model performance, model saliency, and saliency-derived scores (CAM-Score) were evaluated and compared to retinal morphometry. The scores were also compared between incident-AD cases (average 8.55 years before onset) and matched controls. Performance of DL ranged from AUROC= 0.5654-0.9480 for categorical and R2=-0.0291-0.7620 for continuous factors, outperforming most of the morphometry-machine learning models. Saliency-based score consistently highlighted biologically meaningful regions, particularly the optic nerve head and retinal vasculature. It also aligned with present morphometric variations. Several saliency-based scores differed significantly between incident AD and matched controls, suggesting potential overlap between retinal correlates of risk factors and preclinical AD-associated changes. CFP encodes retinal signatures linked to AD risk factors. Although not diagnostic, DL-derived retinal representations may uncover biologically meaningful risk-related structural changes mirroring the potential AD vulnerability.

15.
medRxiv (Medicine) 2026-06-15

Association of Genetic Liability to Psychiatric Disorders with Peripheral Metabolic Dysregulation

Importance: Individuals with psychiatric disorders face elevated cardiometabolic risk which is linked to increased mortality. The extent to which this reflects shared pathogenesis or the downstream effects of illness and treatment remains poorly understood. Objective: To characterize the direct pleiotropic effects of psychiatric genetic liability on circulating metabolites and aggregate cardiometabolic risk, independent of psychiatric diagnosis and psychotropic medication use. Design: Cohort study. Setting: Mass General Brigham Biobank (MGBB). Participants: MGBB participants with metabolomic profiling, genomic data, and linked electronic health records. Exposures: Genetic liability to nine psychiatric disorders quantified using polygenic risk scores (PRS): attention deficit/hyperactivity disorder (ADHD), anorexia nervosa (ANO), anxiety disorder (ANX), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), PTSD, schizophrenia (SCZ), and substance use disorder (SUD). Main Outcomes and Measures: 249 circulating metabolites and four metabolomic risk scores (MRS) for type 2 diabetes, myocardial infarction, ischemic stroke, and vascular dementia. PRS-metabolite associations were estimated using nested models adjusting for lifetime psychiatric diagnosis and psychotropic medication use. Results: Across 25,290 participants, we identified 604 significant PRS-metabolite associations (Bonferroni p< 1.36 x 10-4), of which 89% persisted after adjustment for lifetime diagnosis and medication use, suggesting that the direct genetic effects on metabolism are largely independent of illness or treatment. PRS for MDD, PTSD, and ADHD showed the most extensive dysregulation, with a transdiagnostic pattern of elevated lipids and systemic inflammation, specifically triglycerides ({beta} = 0.04 to 0.05, all p< 4.4 x10-13) and glycoprotein acetyls ({beta} = 0.05, all p< 2.2 x10-16). Notably, PRS for SCZ and BD showed minimal metabolite dysregulation despite having the strongest association with their target diagnoses. PRS for MDD, PTSD, ADHD, and SUD were associated with increased MRS across cardiometabolic conditions ({beta} = 0.03 to 0.08, all p< 2.1 x10-4). Sensitivity analyses controlling for BMI or excluding participants without any psychiatric history (N: 21,305 and 11,150, respectively) showed a similar pattern. Conclusions and Relevance: Psychiatric genetic liability is associated with systemic metabolic dysregulation independent of illness onset or treatment, supporting a partially pleiotropic basis for psychiatric-cardiometabolic comorbidity.