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

The KG-ER Conceptual Schema Language

arXiv:2508.02548v3 Announce Type: replace-cross Abstract: We propose KG-ER, a conceptual schema language for knowledge graphs that describes the structure of knowledge graphs independently of their representation (relational databases, property graphs, RDF) while helping to capture the semantics of the information stored in a knowledge graph.

02.
medRxiv (Medicine) 2026-06-22

Sequential Deep Learning to Predict Non-Central to Central Geographic Atrophy Progression from OCT Imaging

Purpose: To develop and validate a temporal deep learning framework for predicting geographic atrophy (GA) progression across multi-year horizons using longitudinal optical coherence tomography (OCT) sequences. Design: Retrospective longitudinal cohort study. Subjects, Participants, and/or Controls: A total of 91 patients with dry age-related macular degeneration (AMD) were identified from Wake Forest University School of Medicine (2013-2023), yielding 455 OCT volumes. Two prediction cohorts were defined: 32 patients with no GA (NGA) at baseline who subsequently developed GA, and 35 patients whose earliest GA manifestation was non-central GA (NCGA). Non-progressing patients served as negative controls. Methods: OCT B-scan volumes were encoded into visit-level feature representations using three pretrained architectures (ResNet-18, ResNet-50, ViT-B/16). Chronologically ordered visit embeddings, optionally augmented with inter-visit time intervals ({Delta}t), were processed through recurrent neural networks (RNN), long short-term memory networks (LSTM), and Transformer encoders to model longitudinal disease trajectories. Models were trained and evaluated independently for prediction horizons of 2, 3, 4, 5, and 6 years using patient-level stratified splits (80/20). Performance was assessed across five random seeds. Main Outcome Measures: Area under the receiver operating characteristic curve (ROC-AUC), F1-score, and accuracy for predicting two clinically critical transitions: NGA to GA onset and NCGA to central GA (CGA) involvement. Results: For NGA to GA prediction, models achieved ROC-AUC of 0.84-0.94 at 2-4 years and 1.00 at 5-6 years. For NCGA to CGA prediction, Transformer-based models achieved peak AUC of 0.95 at 4 years and 0.96 at 5 years. Longer input sequences (8 visits vs. 4 visits) consistently improved NCGA to CGA performance at extended horizons. Temporal interval encoding improved stability in several LSTM configurations.

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

Multi-Field Hybrid Retrieval-Augmented Generation for Maritime Accident Root Cause Analysis

arXiv:2606.13249v1 Announce Type: new Abstract: Maritime accident adjudication reports contain critical tribunal findings for root cause analysis (RCA), yet retrieving relevant precedents and drafting consistent reports from decades of records remains labor-intensive. This paper proposes a multi-field hybrid retrieval-augmented generation (RAG) framework for automated maritime RCA, utilizing a comprehensive dataset of 13,329 Korea Maritime Safety Tribunal (KMST) reports (1971-2025). We transform raw adjudications into a structured knowledge base of "incident cards", indexing three distinct fields-Summary, Causes, and Disposition-alongside a hierarchical L1/L2 cause taxonomy. Our retrieval strategy employs a field-aware hybrid approach, fusing sparse and dense rankings via Reciprocal Rank Fusion (RRF). Given the lack of large-scale expert relevance labels, we evaluate retrieval performance using ceiling-normalized recall and nDCG based on a metadata-derived proxy relevance score. Experimental results demonstrate that our proposed retrieval significantly outperforms baseline methods, improving NormRecall@100 from 0.18 to 0.55. Furthermore, grounding the generator on the retrieved precedents enhances RCA generation quality over an LLM-only baseline, increasing the LLM-as-a-judge score from 3.34 to 3.72. These findings suggest that field-aware RAG can substantially streamline maritime safety investigation workflows by enabling faster precedent search and more consistent, evidence-based RCA drafting.

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

AI Pluralism and the Worlds It Misses

arXiv:2606.16167v1 Announce Type: new Abstract: AI pluralism is often framed as a problem of representing diverse values, preferences, users, or outputs. This paper argues that this framing is incomplete because AI systems also impose ontologies: they define what counts as an entity, relation, feature, harm, benefit, and valid form of evidence. We define ontological flattening as the conversion of situated, contested, and historically specific meanings into a restricted technical category, proxy, aggregation rule, or benchmark target that is treated as neutral and difficult to contest. The paper develops a bounded conceptual and qualitative synthesis across value pluralism, pluralistic alignment, participatory and democratic AI, procedural justice, science and technology studies, accountability research, aggregate themes from 11 expert interviews, and three urban AI companion cases. The cases illustrate how pluralistic methods can improve or structure model behavior while still compressing categories, proxies, aggregation rules, and revision rights before affected actors have procedural standing. We introduce Pluralistic Lifecycle Governance (PLG) as a preliminary qualitative audit scaffold for documenting ontological openness, epistemic inclusion, procedural authority, evaluation pluralism, and lifecycle accountability. PLG is not presented as a validated scoring instrument; it is a framework for making the evidence and governance conditions of pluralistic AI explicit.

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

A Convex Quasilinearization Method for Solving Nonlinear PDEs with Physics-Informed Neural Networks

arXiv:2606.18175v1 Announce Type: cross Abstract: We present a numerical method for the forward solution of nonlinear partial differential equations (PDEs) in which Bellman-Kalaba quasilinearization reduces the nonlinear problem to a sequence of linear subproblems, each discretized by collocation onto a trial space that is linear in its parameters and solved by a single direct linear least-squares QR factorization. The trial space, which we term Linear-in-Learnables (LiL), comprises representations whose trainable parameters enter linearly, including random-feature extreme learning machines, spectral polynomial bases, and trigonometric expansions, each implemented as a physics-informed neural network. The method thus replaces the nonconvex gradient-based training that limits standard PINNs with a convex per-step solve. We establish local Newton-Kantorovich convergence of the outer iteration to a residual-limited neighborhood under an explicit smallness condition, with the limiting accuracy governed by the best-approximation residual of the trial space rather than by an optimization tolerance. The method, denoted LiL-Q, is assessed on seven benchmarks spanning scalar nonlinear PDEs (Bratu, viscous Burgers, Buckley-Leverett), coupled systems (plane-strain elasticity and the incompressible Navier-Stokes equations in two and three spatial dimensions), and steady-state Darcy flow with heterogeneous permeability. Across these problems, LiL-Q converges in single-digit outer iterations in most cases, even at the coarsest basis sizes and independent of the parameter count. When the exact solution lies in the span of the trial space, the method recovers it to machine precision in a single solve. On the Navier-Stokes benchmarks, it matches or exceeds published PINN solvers with up to two orders of magnitude fewer trainable parameters, without gradient-based optimization.

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

Acquisition state behaves as a structured, measurable variable governing lung-nodule AI: kernel-driven measurement instability and noise-driven detection fragility, invisible to DICOM metadata

AI governance for medical imaging is formalizing: the 2026 ACR-SIIM Practice Parameter recommends local acceptance testing and ongoing drift monitoring, and the ACR Assess-AI registry monitors AI outputs using DICOM metadata for context. We argue that a necessary, currently unmonitored layer sits beneath output metrics: whether incoming studies remain within the acquisition envelope a model was validated on. Using a LUNA16-trained MONAI RetinaNet lung-nodule detector, we test whether acquisition state behaves as a structured, measurable variable. On real paired CT differing only in reconstruction kernel (NLST B30f vs B80f), kernel alone shifted AI-measured diameter and flipped a Fleischner size category in 5.2% (8 of 155) of nodules at fixed patient and acquisition, while detection confidence was unchanged (Wilcoxon p=0.22). Under controlled LIDC-IDRI perturbations the effects dissociated by axis: the noise axis degraded detection confidence (p=5.9e-32, concentrated in nodules under 6 mm) but not measurement, while the frequency/kernel axis corrupted measurement (p=8.6e-13) but not detection. A 4-feature pixel fingerprint recovered reconstruction identity (patient-level AUC about 0.95 on real CT, 0.995 on a QIBA phantom) where the ConvolutionKernel DICOM tag was uninformative (identical labels across reconstructions). The kernel axis transported across four manufacturers (leave-one-vendor-out AUC 0.94-0.98, matching the within-vendor ceiling). Acquisition state thus maps to distinct AI failure modes, frequency content to measurement reliability and noise to detection sensitivity, and is not recoverable from metadata. Acquisition-aware, input-side validation is the missing layer for the acceptance-testing and drift-monitoring requirements now entering imaging-AI accreditation.

07.
arXiv (quant-ph) 2026-06-17

Quantum algorithm for dephasing of coupled systems: decoupling and IQP duality

arXiv:2601.06298v2 Announce Type: replace Abstract: Noise and decoherence are ubiquitous in the dynamics of quantum systems coupled to an external environment. In the regime where environmental correlations decay rapidly, the evolution of a subsytem is well described by a Lindblad quantum master equation. In this work, we introduce a quantum algorithm for simulating unital Lindbladian dynamics by sampling unitary quantum channels without extra ancillas. Using ancillary qubits we show that this algorithm allows approximating general Lindbladians as well. For interacting dephasing Lindbladians coupling two subsystems, we develop a decoupling scheme that reduces the circuit complexity of the simulation. This is achieved by sampling from a time-correlated probability distribution - determined by the evolution of one subsystem, which specifies the stochastic circuit implemented on the complementary subsystem. We demonstrate our approach by studying a model of bosons coupled to fermions via dephasing, which naturally arises from anharmonic effects in an electron-phonon system coupled to a bath. Our method enables tracing out the bosonic degrees of freedom, reducing part of the dynamics to sampling an IQP circuit. The sampled bitstrings then define a corresponding fermionic problem, which in the non-interacting case can be solved efficiently classically. We comment on the computational complexity of this class of dissipative problems, using the known fact that sampling from IQP circuits is believed to be difficult classically.

08.
medRxiv (Medicine) 2026-06-11

Computer Vision for Real-Time Anatomical Navigation in Neurosurgery: First-in-Human Clinical Evaluation and Iterative Development (IDEAL Stage 1)

Introduction: Precise anatomical navigation is fundamental to safe endoscopic pituitary surgery, a high-stakes procedure characterised by a challenging learning curve. While traditional navigation systems often rely on workflow-disrupting probes or static preoperative imaging, advancements in computer vision AI (CVAI) now enable dynamic, real-time anatomical segmentation directly from live surgical video1-3. Our group has previously conducted a series of preclinical human-computer interaction studies to refine the system's design, alongside digital and high-fidelity physical simulations demonstrating the benefit of AI assistance in improving overall performance, training, and safety4-8. Building on this foundation, the current study represents a first-in-human application of real-time CVAI assistance in the neurosurgical operating room, serving to assess feasibility and safety, and to iteratively improve the system. Method: Guided by DECIDE-AI and IDEAL frameworks, this single-centre evaluation comprises an initial proof-of-concept phase (n=6) for endoscopic transsphenoidal pituitary surgeries. The AI model utilised a DINOv3-derived vision transformer architecture, deployed via a high-performance edge computing unit to achieve low-latency, real-time inference without reliance on cloud infrastructure2. Given the high-risk nature of the procedure and the early stage of clinical AI integration, the system was initially deployed as an educational adjunct on a secondary monitor, ensuring the primary surgical feed remains uncompromised. Functionality and safety were assessed via structured questionnaire, prospective observation, and blinded retrospective review of the recordings of the endoscopic surgical video feed and wider operating room environment. Continuous multi-stakeholder feedback through validated human factors surveys drove iterative technical refinements between cases. Results: Six patients with pituitary adenomas were enrolled. The CVAI system was successfully deployed in four cases, demonstrating acceptable real-time sella segmentation accuracy. Deployment failed pre-operatively in two cases owing to a single recurring system reboot bug. Iterative refinement between cases were driven by our experience and surgical team feedback. This resulted in the integration of additional anatomical structure segmentations (e.g., carotid arteries), enhanced model accuracy via training dataset expansion, and hardware firmware upgrades. Multi-stakeholder surveys demonstrated satisfactory system feasibility, usability, and acceptability among the surgical team. Both prospective observation and retrospective video review confirmed the absence of adverse events, including no significant distraction to the primary surgeon, and there were no AI-related clinical complications. Conclusion: This first-in-human early clinical evaluation demonstrates the feasibility, safety and iterative development of real-time, CVAI-based anatomical navigation during high-stakes neurosurgery. Future work will include a larger single-centre case series (IDEAL Stage 2a) with more surgical teams to further iterate the system and explore its impact on training and workflow. As the underpinning technology improves, deployment will transition to direct intra-operative decision support and integration with other intra-operative navigational technologies.

09.
medRxiv (Medicine) 2026-06-17

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

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

10.
arXiv (quant-ph) 2026-06-16

TENSO: Software Package for Numerically Exact Open Quantum Dynamics Based on Efficient Tree Tensor Network Decomposition of the Hierarchical Equations of Motion

arXiv:2603.17711v2 Announce Type: replace-cross Abstract: TENSO is a versatile and powerful open-source software package for numerically exact simulations of the dynamics of quantum systems immersed in structured thermal environments. It is based on a tree tensor network decomposition of the hierarchical equations of motion (HEOM) that efficiently curbs its curse of dimensionality with bath complexity. As such, TENSO enables exact non-Markovian open quantum dynamics simulations even with complex environments typical of chemistry and quantum information science. TENSO allows for time-dependent drive in the system, and for non-commuting fluctuations. More generally, TENSO efficiently propagates the dynamics for any method with a generator of the dynamics that can be expressed in a sum-of-products form, including the HEOM and multi-layer multiconfigurational time-dependent Hartree methods. TENSO enables simulations using tensor trees and trains of arbitrary order, and implements three propagation strategies for the coupled master equations; two fixed-rank methods that require a constant memory footprint during the dynamics and one adaptive rank method with a variable memory footprint controlled by the target level of computational error. In contrast to the accompanying theory and algorithmic paper [J. Chem. Phys. 163, 104109 (2025)] the focus here is on the practical usage and applications of TENSO with underlying theoretical concepts introduced only as needed.

11.
arXiv (math.PR) 2026-06-17

Cutoff for asymmetric shelf shuffle

arXiv:2606.18039v1 Announce Type: new Abstract: A mechanical shuffler consists of $m$ shelves. A deck of $n$ cards, arranged in increasing order, is dealt from the bottom sequentially. Each card is assigned a shelf uniformly at random and placed on the top (bottom) of the existing pile with probability $p$ ($1-p$) independently. We refer to this as asymmetric shelf-shuffle. We find the law $\nu_{n, m}^{(p)}$ of the permutation induced by the asymmetric shelf-shuffle and show that the pair consisting of the number of descents and the number of valleys is a sufficient statistic. This generalizes a result of Diaconis, Fulman, and Holmes (Ann. Appl. Prob., 2013) corresponding to the case $p=1/2$. For $p=1/2$, Chen and Ottolini (ECP, 2025) established the cutoff in the total variation distance near $\lfloor n^{5/4}\rfloor$. We establish the cutoff for the asymmetric shelf shuffle. Let $\nu_n$ be the uniform measure on the set of all permutations $S_n$ of $\{1, \ldots, n\}$. For a fixed $p\neq 1/2$ and $c>0$, we show that \[\operatorname{TV}\left(\nu_{n, \lfloor cn^{3/2}\rfloor }^{(p)}, \nu_n\right)=1-2\Phi\left(-\frac{|2p-1|}{4\sqrt{3}c}\right)+O_{c, p}(n^{-1/2})\;.\] We also establish the cutoff in the separation distance near $m\approx n^{2}$ and in the relative entropy near $m=n^{3/2}$. In both cases, we also obtain the cutoff profile explicitly.

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

Can LLMs Be CEOs? Benchmarking Strategic Resource Reallocation with Multi-Role Agent Simulation

arXiv:2606.17459v1 Announce Type: new Abstract: Evaluating the decision-making capabilities of large language models (LLMs) is a growing research priority, yet existing benchmarks focus on isolated cognitive tasks such as reasoning, knowledge retrieval, and economic rationality in stylized settings. These evaluations overlook the defining challenge of real executive decision-making: integrating conflicting recommendations from specialized stakeholders under information asymmetry, organizational constraints, and temporal dependencies. We introduce \textsc{CEO-Bench}, a multi-agent benchmark that evaluates LLMs on CEO-level strategic resource reallocation – the process of redirecting capital across business units in a multi-round, constraint-rich organizational environment. In \textsc{CEO-Bench}, LLM agents receive conflicting advice from four role-conditioned C-suite advisors (CFO, CTO, COO, CMO), each with private signals and distinct priorities, and must synthesize these into a concrete allocation plan evaluated along four dimensions: role integration, conditional boldness, history-sensitive judgment, and plan validity. Experiments across five frontier models on 13 scenarios reveal that all models achieve high structural validity but diverge sharply on strategic calibration – the hardest capability layer. We identify systematic failure modes including single-advisor capture, conservative default under ambiguity, and historical amnesia, and uncover a structural integration-boldness tradeoff: models that engage more deeply with conflicting perspectives tend to produce less decisive action. These findings delineate the current capability boundary of LLMs as organizational decision-makers and inform the design of future AI-assisted executive systems.

13.
arXiv (CS.CL) 2026-06-12

Unraveling Syntax: Language Modeling and the Substructure of Grammars

While language models achieve impressive results, their learning dynamics are far from understood. Many domains of interest – such as natural language syntax, coding languages, arithmetic – are captured by context-free grammars (CFGs). In this work, we extend prior work on neural language modeling of CFGs in a novel direction: how language modeling behaves with respect to CFG substructure, namely subgrammars. We define subgrammars, and prove a set of fundamental theorems connecting language modeling and subgrammars. We show that language modeling loss recurses linearly over its top-level subgrammars; applied recursively, the loss decomposes into losses for "irreducible" subgrammars. Under additional assumptions, and empirically, parametrized models learn subgrammars in parallel, unlike children who first master simple substructures. We find that subgrammar pretraining can improve final performance, but only for tiny models relative to the grammar, while alignment analyses show that pretraining consistently leads to internal representations that better reflect the grammar's substructure.

14.
Nature Medicine 2026-06-08

Apitegromab for lean mass preservation during tirzepatide-induced weight loss: a randomized, double-blind, placebo-controlled phase 2 trial

Loss of lean mass in proportion to total weight loss is observed with incretin mimetic therapies such as tirzepatide and has the potential to adversely affect health and function. Apitegromab is an investigational, fully human monoclonal antibody that selectively inhibits myostatin activation and is, thereby, capable of increasing muscle mass. In the randomized, double-blind, placebo-controlled phase 2 EMBRAZE study, adults with overweight or obesity (n = 102) were randomized 1:1 to receive tirzepatide plus apitegromab (10 mg kg−1) or tirzepatide plus placebo. At week 24, apitegromab resulted in a least square mean (80% confidence interval (CI)) of 1.9 (1.2−2.7) kg less lean mass loss than placebo (P = 0.001), despite similar total body weight loss between groups, representing a 54.9% retention of lean mass relative to placebo. In participants receiving apitegromab, trough concentrations of apitegromab and total latent myostatin, a pharmacodynamic marker, both increased over time and reached a plateau after approximately 16 weeks. Incidence of adverse events (AEs) (% (95% CI)) was generally similar across apitegromab-treated participants and placebo-treated participants, with 39 of 51 (76% (63−86%)) and 36 of 51 (71% (57−81%)) participants experiencing an AE, respectively. Serious adverse events (SAEs) were balanced and experienced by one of 51 (2% (0−10%)) participants in each arm. In summary, this proof-of-concept study demonstrated that selective targeting of myostatin by apitegromab was well tolerated and effective in preserving lean mass when combined with tirzepatide. ClinicalTrials.gov identifier: NCT06445075 . In the phase 2 EMBRAZE study, participants receiving tirzepatide and apitegromab lost less lean mass compared to participants receiving tirzepatide and placebo.

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

Generative AI and the future of scientometrics: current topics and future questions

In this paper, we contribute to the debate on generative artificial intelligence (GenAI) in scientometrics. We argue that moving from a trial-and-error approach to an explainable and actionable use requires a principled understanding of strengths and weaknesses of GenAI as compared with other techniques and with human judgment. To this end, we introduce a conceptual framework based on the distinction between the semantic dimensions of texts, i.e. the meanings attributed to words, and their pragmatic dimension, i.e. their embedding within communicative situations. We leverage this framework to interpret the results of applications of GenAI in scientometrics and to provide guidance to users. Specifically, we conclude that key parameters to be considered are the nature of the task, the level of granularity of the analysis and whether the goal was descriptive, inferential or evaluative. These parameters lead to different strategies for using GenAI and human-machine integration. Finally, we suggest that, by generating large amounts of scientific language, GenAI might affect textual characteristics used to measure science, such as authors, words, and references. We argue that careful empirical work and theoretical reflection will be essential to remain capable of interpreting the evolving patterns of knowledge production in the age of AI.

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

Can Machine Learning Forecast Rice Yields in Data-Constrained Settings? Satellite Climate Data, National Crop Statistics, and Lessons from Sierra Leone

arXiv:2606.13959v1 Announce Type: new Abstract: Sierra Leone's agriculture operates with almost no data-driven decision support, and no published machine learning study has examined the country's crop yields. We ask whether rice yield can be forecast from data Sierra Leone currently has. Using 25 years of FAOSTAT production data (2000-2024) for nine major crops, we train XGBoost, Gradient Boosting, and Random Forest under a strict anti-leakage protocol with expanding-window walk-forward evaluation across seven held-out years, benchmarked against naive persistence. No model trained on crop statistics alone outperforms persistence. Augmenting with free satellite climate data (CHIRPS rainfall, NASA POWER temperature) reverses this result: a climate-only XGBoost reduces forecast error by one third (RMSE 284 vs 428 kg/ha), a gain that holds for a linear model and is robust to excluding the anomalous 2018 season. Early-season (May-June) rainfall is the dominant predictor, implying seasonal yield risk is observable months before harvest. No model anticipated the 2018 collapse, whose origins were institutional rather than climatic. We translate the findings into policy recommendations for Sierra Leone's Feed Salone Strategy, with a fully open-source pipeline.

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

GenTrack: A New Generation of Multi-Object Tracking

This paper introduces a novel multi-object tracking (MOT) method, dubbed GenTrack, whose main contributions include: first-a hybrid tracking approach employing both stochastic and deterministic manners to robustly handle unknown and time-varying numbers of targets, particularly in maintaining target identity (ID) consistency and managing nonlinear dynamics, second-leveraging particle swarm optimization (PSO) with some proposed fitness measures to guide stochastic particles toward their target distribution modes, enabling effective tracking even with weak and noisy object detectors, third-integration of social interactions among targets to enhance PSO-guided particles as well as improve continuous updates of both strong (matched) and weak (unmatched) tracks, thereby reducing ID switches and track loss, especially during occlusions, fourth-a GenTrack-based redefined visual MOT baseline incorporating a comprehensive state and observation model based on space consistency, appearance, detection confidence, track penalties, and social scores for systematic and efficient target updates, and five-the first ever publicly available source-code reference implementation with minimal dependencies, featuring three variants, including GenTrack Simple, Strengthen, and Super, facilitating flexible reimplementation. Experimental results have shown that GenTrack provides superior performance on standard benchmarks and real-world scenarios compared to state-of-the-art trackers, with integrated implementations of baselines for fair comparison. Potential directions for future work are also discussed. The source-code reference implementations of both the proposed method and compared-trackers are provided on GitHub: https://github.com/SDU-VelKoTek/GenTrack

19.
Nature (Science) 2026-06-10

A first-in-class pulsatile FXR agonist for bile-acid-related liver diseases

Authors:

Nuclear receptors are central regulators of metabolism1, yet therapeutic strategies that enforce continuous receptor activation frequently lead to reduced efficacy and unacceptable toxicity. Here we report a first-principles drug design strategy that aligns pharmacokinetics with physiological signalling cycles. We developed linafexor, a potent non-bile-acid agonist of the farnesoid X receptor (FXR)2; it is engineered for rapid systemic clearance, which enables pulsatile receptor activation that mirrors endogenous bile acid dynamics3–5. Linafexor has robust efficacy across multiple preclinical models of metabolic dysfunction-associated steatohepatitis6, liver fibrosis7, primary biliary cholangitis and primary sclerosing cholangitis8,9. Transcriptomic analyses reveal that, unlike long-acting FXR agonists10,11, linafexor preserves cyclic FXR signalling, avoids receptor downregulation and prevents broad transcriptional dysregulation. Direct manipulation of delivery patterns demonstrates that sustained FXR activation—independent of compound identity—induces severe toxicity, establishing activation duration as a determinant of therapeutic index. In phase 1 clinical studies (ClinicalTrials.gov; NCT05082779), linafexor administered once daily produces transient FXR pathway engagement, marked by (1) induction of FGF1912–14, a key endocrine mediator of bile acid feedback regulation; and (2) suppression of C415, an intermediate reflecting hepatic bile acid synthesis, with no treatment-related adverse events. Together, these findings identify pulsatile FXR activation as a mechanistically grounded and clinically translatable strategy, and establish linafexor as a first-in-class therapeutic for bile acid–related liver diseases. Linafexor is a rapidly cleared FXR agonist designed to mimic natural bile acid signalling, achieving transient receptor activation with strong efficacy and reduced toxicity in preclinical and early clinical studies.

20.
medRxiv (Medicine) 2026-06-15

High Demand, Low Possession: Dilemmas and Strategies for Research Capability Cultivation in Clinical Medicine Postgraduates

Most previous studies have examined medical postgraduate research training from a single dimension, lacking a full-chain analysis that integrates capability demand, actual possession, obstacles, and output. Consequently, the measurement of capability gaps and the analysis of underlying training model deficiencies remain insufficient. To address this gap, we administered a self-designed multidimensional questionnaire to 86 clinical medicine postgraduates at a medical school, covering research cognition, interest, capability demand and possession, participation pathways, difficulties, and outputs. The aim was to systematically characterize the current situation, identify problems, and propose optimization strategies. Over 90% of participants expressed interest in research, yet only 1.16% self-rated as very knowledgeable. The largest demand-possess gap was for writing and publication (86.05% vs. 16.28%), followed by independent research capability (75.58% vs. 11.63%). A total of 59.30% cited lack of foundational knowledge, making experiments very difficult, as the greatest challenge, and 66.28% had no research achievements. The primary source of research topics was supervisor assignment (54.65%), with only 4.65% choosing topics independently. No statistically significant differences were found across grades or training types (P > 0.05). These findings reveal a structural high demand, low possession gap in medical postgraduate research training, with early research experience deficit and a passive research model as key constraining factors. Accordingly, an integrated bachelor-postgraduate progressive research competency training system is proposed.

21.
medRxiv (Medicine) 2026-06-17

Clinical Study Protocol of the 'Biomarkers of Severity of COVID-19 Patients' (BIOMARCOVID) Project

Introduction The coronavirus disease 2019 (COVID-19) pandemic has challenged health care systems worldwide, in certain areas exceeding hospital capacities and human resources. This has underscored the importance of having better tools to predict the outcome of potentially severe respiratory infections such as SARS-CoV-2. Predicting COVID-19 severity may allow physicians to better manage ICU beds and increase the chances of patient survival through appropriate management. During the toughest months of the pandemic, most physicians tried to identify patients that might develop severe forms based primarily on clinical features on admission (e.g., BMI, age). In this context, significant research has focused on identifying comorbidities, clinical manifestations, and routine blood biomarkers to predict disease severity. However, despite the demonstrated value of untargeted metabolomics in assessing severity, limited data exist on its use for identifying novel metabolite biomarkers that could improve both the sensitivity and specificity of outcome prediction. Our goal is to identify metabolite biomarkers that could enhance the predictive accuracy of standard medical biology data and clinical parameters. Methods and analysis This is a retrospective, observational, monocentric cohort study conducted at the Centre Hospitalier Universitaire Grenoble Alpes (CHUGA). The maximum number of eligible patients admitted for PCR-confirmed COVID-19 between March and December 2020 will be included. Severity outcome is defined using the WHO 10-category ordinal scale (mild: categories 4-5; severe: >5). Blood samples were collected within 48 hours of admission and analyzed for 62 routine blood tests and untargeted multiplatform LC-MS/MS metabolomics across four national platforms. Statistical analysis will include logistic regression with variable selection for the primary aim, and multi-block chemometric integration of clinical, biological, and metabolomics data as a secondary aim. Ethics and dissemination A study steering committee has been formed to ensure the accuracy of the collected data by thoroughly reviewing it prior to the data lock. All aspects of the study comply with ethical standards, including approval by the CHUGA institutional review board and adherence to CNIL Reference Methodology MR004 for the protection of participants' rights, privacy, and confidentiality. This study is registered on the French Health Data Hub (number F20210218154851). Results will be disseminated through peer-reviewed publications, presentations at national and international scientific and clinical conferences, and reports shared with key healthcare system stakeholders.

22.
arXiv (CS.AI) 2026-06-17

Physics-Informed Attention Mechanism and Generalization Capability of Deep Learning-Based Grain Growth Evolution Prediction

arXiv:2606.17235v1 Announce Type: cross Abstract: Machine Learning (ML) models for grain growth prediction are typically trained on idealized synthetic data, yet practical applications require generalization to conditions outside the training distribution. This study evaluated the Out-Of-Distribution (OOD) generalization capability of the trained model from our previous study across three test cases, including experimental microstructures, microstructures characterized by a bimodal grain size distribution, and abnormal grain growth. To further probe whether physics-informed architectural design could improve robustness under these different conditions, a boundary-masked attention mechanism was proposed specifically for grain growth, constraining attention to grain boundary pixels. Both the baseline and the proposed physics-informed attention model were evaluated without retraining or fine-tuning on the OOD data. Both models successfully generalized to all three test cases, yet the boundary-masked attention mechanism provided substantial improvements, with the most notable gains for microstructures characterized by a bimodal grain size distribution, where Structural Similarity Index Measure (SSIM) improved from \num{0.6221} to \num{0.7609} and mean grain size ($\overline{R}$) error decreased from \operatorname{SI}{8.75}{\percent} to \operatorname{SI}{3.57}{\percent}. The attention heatmap analysis revealed that the boundary-masked attention model learned to concentrate attention on large grain boundaries in a manner consistent with curvature-driven grain growth physics, emerging from training without being explicitly encoded into the architecture. These results indicate that models trained on synthetic data can generalize to diverse OOD conditions without retraining, and that physics-informed attention may improve accuracy when the boundary morphology matches the training domain.

23.
arXiv (CS.AI) 2026-06-17

Riemann-Bench: A Benchmark for Moonshot Mathematics

arXiv:2604.06802v2 Announce Type: replace Abstract: Recent AI systems have achieved gold-medal-level performance on the International Mathematical Olympiad, demonstrating remarkable proficiency at competition-style problem solving. However, competition mathematics represents only a narrow slice of mathematical reasoning: problems are drawn from limited domains, require minimal advanced machinery, and can often reward insightful tricks over deep theoretical knowledge. We introduce Riemann-Bench, a private benchmark of expert-curated problems designed to evaluate AI systems on research-level mathematics that goes far beyond the olympiad frontier. Problems are authored by Ivy League mathematics professors, graduate students, and PhD-holding IMO medalists, and routinely took their authors weeks to solve independently. Each problem undergoes double-blind verification by two independent domain experts who must solve the problem from scratch, and yields a unique, closed-form solution assessed by programmatic verifiers. We evaluate frontier models as unconstrained research agents, with full access to coding tools, search, and open-ended reasoning, using an unbiased statistical estimator computed over 100 independent runs per problem. Our results reveal that all frontier models currently score below 10%, exposing a substantial gap between olympiad-level problem solving and genuine research-level mathematical reasoning. By keeping the benchmark fully private, we ensure that measured performance reflects authentic mathematical capability rather than memorization of training data.

24.
arXiv (CS.CV) 2026-06-18

SegmentAnyTreeV2: Scaling Transformer-Based Tree Instance Segmentation Across Sensors, Platforms, and Forests

We present SegmentAnyTreeV2, a sensor- and platform-agnostic framework for semantic and instance segmentation of forest point clouds. The model combines a serialization-based Point Transformer v3 backbone with a lightweight semantic head and a tree-focused cross-attention mask decoder. Semantic predictions restrict instance decoding to tree-class voxels, while instance-aware query initialization, one-to-many seed supervision, and asymmetric mask scoring improve separation in dense and structurally complex stands. We further introduce FOR-instance v3, an expanded benchmark comprising 427 scenes and 26,496 annotated trees across diverse biomes, forest structures, and LiDAR platforms. On the FOR-instanceV2 test split, SegmentAnyTreeV2 achieves 90.5% precision, 80.2% recall, 85.0% F1, 90.7% coverage, and 87.6% semantic mIoU, outperforming previous learning-based methods in both instance detection and mask completeness. Zero-shot evaluation on independent sites further demonstrates strong cross-domain generalization.

25.
arXiv (CS.AI) 2026-06-18

Data Intelligence Agents: Interpreting, Modeling, and Querying Enterprise Data via Autonomous Coding Agents

arXiv:2606.19319v1 Announce Type: cross Abstract: Production data integration is bottlenecked by repeated, lossy handoffs between data owners, engineers, and analysts who must collaboratively discover, structure, and query enterprise data. We present Data Intelligence Agents (DIA), a system of three agents (Data Interpreter, Schema Creator, and Query Generator) that compresses this workflow by treating autonomous coding agents (ACAs) as a first-class abstraction: rather than emitting text, the agents generate, execute, validate, and repair concrete artifacts, draw on a shared memory for experience reuse, and surface each for review by domain experts. DIA is deployed in production for enterprise customers. We study the Query Generator in depth and evaluate it in fully autonomous mode across seven SQL benchmarks spanning four task categories and four dialects. It matches or surpasses the best published results on all seven, demonstrating that an architecture grounded in execution, built on ACAs and a shared memory, generalizes across the data intelligence workload with adaptation confined to natural-language instructions.