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01.
arXiv (CS.CL) 2026-06-15

Incentives Of EdTech: A Systematic Review Of EduNLP Research

While the Natural Language Processing community has dedicated significant resources in developing educational technologies (EdTech) that support this shift, it remains unclear whose interests are being best served among the stakeholders of education. In this paper, we present a systematic literature review of 204 papers published in venues of the Association for Computational Linguistics' Special Interest Group on Building Educational Applications in 2024 and 2025, and validate these against EdTech papers from the wider ACL Anthology. By examining stakeholder inclusion and the prioritisation of research tasks, our findings reveal a critical tension: a push and pull between private-sector incentives and the foundational needs of educational infrastructure. Our analysis reveals that teachers are systematically under-represented as beneficiaries of research (33.3%) despite being the most affected, that real-world deployment remains rare (9.8%), and that ethical engagement tends toward acknowledgement rather than action. Drawing on exemplary papers in our corpus, we offer concrete recommendations for more responsible EduNLP research practices.

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

Separable Neural Architectures as Physical World Models: from Mathematical Theory to Applications

arXiv:2606.14934v1 Announce Type: cross Abstract: This work introduces the Separable Neural Architecture (SNA), a function representational class combining neural approximation with tensor decomposition. The SNA decouples localized coordinate functions (atoms) from global interactions governed by a sparse, low-rank interaction object. This architecture possesses a compact and smooth inductive bias well-suited for solving partial differential equations (PDEs). When viewed as a Galerkin trial space under the variational SNA (VSNA) framework, the formulation satisfies classical variational guarantees under Lax-Milgram: well-posedness, quasi-optimality, convergence, and stability. In high-dimensional spatiotemporal–parametric PDEs, the VSNA mitigates the curse of dimensionality by scaling algebraically rather than exponentially. Exploiting an entirely factorized, tensor-native alternating least squares (ALS) optimization framework reduces this cost to linear in dimension. The VSNA is validated across elliptic, hyperbolic, and parabolic systems, demonstrating close alignment with predicted algebraic and spectral scaling rates. We showcase the SNA as a "solve once, query anywhere" physical world model via two engineering case studies: a 7D parametric manufacturing simulation and an experimental thermal-to-property inversion pipeline for Inconel 718. The VSNA executes a 1,000,000-query Monte Carlo sweep in 102s on a standard laptop CPU, yielding a 150,000x speedup over a full-grid finite element baseline hosted on an NVIDIA A100 GPU. It further enables real-time generative inverse-mode reconstructions under 100ms. These results demonstrate that the SNA serves as a compact mathematical substrate for continuous parameter manifolds to enable real-time inversion, optimization loops, and rapid uncertainty propagation.

03.
arXiv (CS.LG) 2026-06-18

ChronoSurv: A Clinical Pathway-Guided Graph Framework for Multimodal Survival Analysis

arXiv:2606.19140v1 Announce Type: new Abstract: Accurate survival prediction is essential for personalized treatment planning in head and neck cancer, yet remains challenging due to the heterogeneous and high-dimensional nature of multimodal clinical data. While deep survival models have improved predictive performance over classical statistical approaches, existing methods typically rely on static fusion strategies or temporally agnostic modeling, limiting their ability to capture structured clinical workflows. In this work, we propose ChronoSurv, a heterogeneous hierarchical directed graph framework for multimodal survival analysis. ChronoSurv represents patient care as a progression-aware clinical trajectory using directed graphs aligned with key diagnostic steps. A hierarchical topology incorporates fine-grained, coarse, and global representations, further supporting flexible adaptation to missing modalities, while heterogeneous message passing models complex and asymmetric relationships across modalities and clinical steps. Experimental results on two public datasets demonstrate that ChronoSurv achieves state-of-the-art discriminative performance while maintaining statistically reliable calibration. Comprehensive ablation studies further confirm the contribution of each architectural component, highlighting the potential of trajectory-aware graph modeling for multimodal survival prediction.

04.
medRxiv (Medicine) 2026-06-15

GLLaucoMed: A Secure LLM-Powered Agentic Workflow for Automated Medication Extraction from Free-Text Glaucoma Clinical Notes

Purpose: To evaluate the efficacy of large language models (LLMs) in extracting medication-related information from glaucoma clinical notes in the electronic health record (EHR). Design: Cross-sectional. Subjects: 1,250 subjects in the Bascom Palmer Ophthalmic Repository. Methods: Extracted clinical notes from glaucoma-related encounters between 2014 and 2024 were labeled by two glaucoma specialists with a third serving as an adjudicator. Graders were asked to label current topical medications (CTM), proposed changes to topical medications ({Delta}TM), current oral medications (COM), and proposed changes to oral medications ({Delta}OM) in a structured fashion. The dataset was split into development (10%), validation (10%), and test (80%) sets stratified by clinician. Development and validation sets were used to engineer and refine prompts, and the held-out test set was used for model assessment. Five LLMs (Claude Opus 4.6, DeepSeek-V3.2, GPT 5.2, Grok 4.1, and Qwen3.6-35B-A3B) were accessed via Microsoft Azure AI Foundry within a HIPAA-compliant environment. Inter-grader agreement was assessed with Gwet AC1. LLM performance was initially assessed in a binary fashion with F1 scores, and the degree of text match among positive cases was evaluated using exact match accuracy and Jaccard Index (JI). Main Outcome Measures: F1 score, exact match accuracy, JI. Results: Gwet AC1 for intergrader agreement was 0.799, 0.888, 0.985, and 0.988 for CTM, {Delta}TM, COM, and {Delta}OM, respectively. F1 scores for CTM were 0.985, 0.971, 0.978, 0.968, and 0.970 for Claude, Deepseek, GPT, Grok, and Qwen, respectively; for {Delta}TM: 0.905, 0.826, 0.897, 0.842, 0.855, respectively; for COM: 0.923, 0.887, 0.899, 0.906, 0.894, respectively; for {Delta}OM: 0.958, 0.815, 0.937, 0.835, 0.940, respectively. Among positive cases, range of exact match accuracies for CTM (N=1354) was 0.730- 0.882 and range of JIs was 0.809-0.918. For {Delta}TM (N=404), exact match accuracy range was 0.619-0.780 and JI range was 0.668-0.827. For COM (N=47), exact match accuracy range was 0.766-0.872 and JI range was 0.765-0.870. For {Delta}OM (N=25), exact match accuracy range was 0.583-0.920 and JI range was 0.583-0.922. Conclusions: The GLLaucoMed pipeline demonstrated high performance in extracting and standardizing medication data from unstructured clinical notes, including both current medications and proposed changes. Claude and GPT exhibited the strongest performance.

05.
medRxiv (Medicine) 2026-06-15

VarEx: A Large Language Model Pipeline for Automated Extraction of Exposures, Outcomes, and Covariates from Epidemiologic Studies

Objective: Observational studies are essential for investigating risk factors for Alzheimer's disease and related dementias (ADRD), but inconsistent reporting and selection of covariates can contribute to residual confounding, omitted-variable bias, and reduced reproducibility. We developed and evaluated VAREX (Variable Extraction), a large language model (LLM)-based information extraction framework designed to automatically identify exposures, outcomes, and covariates from epidemiologic studies and populate structured evidence repositories. Materials and Methods: VAREX combines retrieval-augmented generation, biomedical language-model embeddings, semantic chunking, cross-encoder reranking, and prompt-engineered LLM workflows to extract epidemiologic variables from full-text biomedical articles. The framework was evaluated using a reference-standard corpus of observational studies examining blood pressure variability (BPV) and Alzheimer's disease-related dementias (ADRD), together with external validation datasets involving other exposure-outcome relationships. Extracted variables were compared with independently curated human reference standards using semantic matching and one-to-one assignment procedures. Covariates were additionally classified into ten epidemiologically relevant semantic categories. Results: In the primary BPV[->]ADRD corpus (10 studies), VAREX achieved a precision of 0.91, recall of 0.84, and F1-score of 0.87 for variable extraction. Covariate classification accuracy was 0.90, yielding a strict extraction-and-classification F1-score of 0.78. External validation datasets demonstrated comparable performance across diverse epidemiologic domains, with extraction F1-scores ranging from 0.73 to 0.85. Category-level performance was strongest for health behaviors (F1=0.96), sociodemographic variables (F1=0.90), and medication exposures (F1=0.89). Compared with published estimates of manual systematic-review effort, VAREX reduced processing time from approximately 61 minutes to 9 minutes per article, representing an 85.7% reduction in review time. Discussion: These findings demonstrate that LLM-based information extraction can accurately identify and classify epidemiologic variables across heterogeneous observational-study designs. Automated extraction enables scalable construction of structured repositories of exposures, outcomes, and covariates while substantially reducing the labor required for evidence synthesis and systematic reviews. Conclusion: VAREX provides an effective framework for automated extraction and classification of epidemiologic variables from the biomedical literature. By supporting large-scale evidence synthesis and structured knowledge resource development, VAREX may facilitate more rigorous observational research, improved confounder identification, and enhanced reproducibility in epidemiology.

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

ttda704 at SemEval-2026 Task 6: Structured Chain-of-Thought Prompting for Political Evasion Detection

This paper describes our system for SemEval-2026 Task 6, which addresses the classification of political evasion strategies in English question-answer pairs extracted from U.S. presidential interviews. We systematically compare two distinct paradigms: (1) Parameter-Efficient Fine-Tuning of Qwen3 models (4B-32B) using QLoRA, enhanced with tiered upsampling and weighted cross-entropy loss to address severe class imbalance, and (2) structured Chain-of-Thought (CoT) prompting of reasoning-capable API models, namely DeepSeek-V3.2 and Grok-4-Fast. Our evaluation demonstrates that structured CoT prompting of reasoning-enabled models substantially outperforms our baseline parameter-efficient fine-tuning implementation in absolute Macro F1. Our best system, Grok-4-Fast with extended reasoning and few-shot hierarchical CoT prompting, achieves a Macro F1 of 0.5147 on Subtask 2 (9-class evasion) and 0.7979 on Subtask 1 (3-class clarity), ranking 8th out of 33 teams on Subtask 2 and 13th out of 41 teams on Subtask 1 on the official leaderboard. Furthermore, our ablation studies reveal key insights into effective prompt design for evasion detection: presenting labels within a hierarchical taxonomy helps structure model reasoning, while few-shot exemplars provide task calibration. However, the strongest prompt variants are not statistically distinguishable in Macro F1, and explicitly enabling extended reasoning modes yields substantial performance gains by facilitating the multi-step pragmatic analysis required to detect evasive intent.

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

ROSE: Benchmarking the Perception-to-Action Gap in Multimodal Models

arXiv:2606.19965v1 Announce Type: cross Abstract: Multimodal large language models (MLLMs) are increasingly expected to act on visual information, yet the same scene may require different actions under different task contexts. How reliably can a model turn the same visual evidence into the action required by the current context? To answer this question, we introduce \textsc{ROSE} (Reference-conditioned Oddity and Symbolic Execution), a controlled benchmark that holds the visual scene fixed while varying region constraints and required symbolic outputs. Through coupled counting and coordinate-action tasks, \textsc{ROSE} tests whether models can infer an implicit majority reference and act on the resulting fine-grained visual evidence under changing contexts. Across nine recent MLLMs, performance drops by as much as 44.5 percentage points from counting-oriented tasks to region-conditioned action, despite 98.8\% human performance. The gap persists on paired scenes and regions for which the same model returns the correct count, while global-click and matched local controls show that coordinate grounding explains only part of the loss, revealing a distinct, model-dependent bottleneck in turning shared visual evidence into context-specific actions.

08.
arXiv (CS.AI) 2026-06-16

Quantifying the Impact of Lossy Compression on Neural Generative Surrogate Modeling

arXiv:2606.15959v1 Announce Type: cross Abstract: Neural networks are used as generative surrogate models for scientific discovery, which are trainable approximations of scientific simulations. These models enable users to replace time-consuming numerical simulations with learned alternatives, providing quick solutions. However, high-fidelity generative surrogate models require massive training datasets, which can create storage and I/O challenges. Lossy compression is a promising way to reduce this burden, but compression errors may affect the model quality in subtle ways, making it challenging to quantify their impact. In this work, we examine how lossy compression of training data impacts the quality of generative surrogate models. We begin by characterizing the uncertainty inherent in training neural networks, showing that identical training configurations can produce different models. By exploiting this variability, we propose a method to estimate how much compression-induced error a surrogate model can tolerate without affecting its accuracy. Evaluation of two application simulations demonstrates that our approach significantly reduces memory/storage requirements and speeds up training while producing high-quality surrogate models. These results show that lossy compression saves data storage up to 23.7x and 39x with negligible impact on the quality of the surrogate model. Meanwhile, reducing the size of the training data set also enhances the data loading speed and reduces the training time by up to 3x.

09.
medRxiv (Medicine) 2026-06-22

MinderCare: protocol for a mixed-methods evaluation of a digitally enabled dementia care service.

Introduction and aims Dementia is a growing public health challenge affecting millions of people worldwide. It is a progressive condition that increases the risk of infections, falls, hospital admissions, dependence in activities of daily living, safety issues such as wandering, care home transfers, and death. New ways of supporting people living with dementia (PLWD) at home are urgently needed. We describe the MinderCare study which evaluates a digitally enabled care model that integrates low-burden sensor-based remote monitoring within a nurse-led clinical service. Methods and analysis In this mixed-methods study, we will recruit 100 people with confirmed or suspected dementia living at home and deploy the Minder remote monitoring system for at least 12 months. A detailed characterisation of the cohort will be obtained, including cognition, frailty, participant and carer wellbeing, functioning, and quality of life. The feasibility, acceptability, sustainability, and resource requirements of the service will also be assessed. Low-cost sensors provide information about behaviour, environment and physiology from the home. Machine-learning algorithms have been used to develop digital biomarkers of infection, sleep, night-time behaviours, daily activities and routines, and the effects of clinical events and treatment. These will be assessed through clinical reports of sensor-derived data that include anomaly alerts provided to the clinical teams. Algorithms will be assessed for their clinical utility and acceptability. The comparative-effectiveness component will be designed as a target trial emulation using linked electronic health-record data to construct a time-indexed external usual-care control cohort. The primary comparative outcome will be Days Alive and Out of Hospital (DAOH) over 12 months from the activation-index date, with healthcare utilisation, costs, institutionalisation and mortality assessed as secondary outcomes. DAOH and estimated MinderCare effects will also be examined across prespecified strata of baseline inpatient utilisation. Ethics and dissemination Ethical approval has been granted by the North East Newcastle and North Tyneside 2 Research Ethics Committee, and the study has received confirmation of capacity and capability by the Imperial College Healthcare NHS Trust. Study findings will be disseminated to patients, health and social care professionals, and policymakers through peer-reviewed publications and conference presentations. Study registration number: ISRCTN14997677 and NIHR portfolio CPMSID 63023.

10.
arXiv (quant-ph) 2026-06-11

Split-Evolution Quantum Phase Estimation for Particle-Conserving Hamiltonians

arXiv:2604.14921v2 Announce Type: replace Abstract: We present a hardware demonstration and resource analysis of split-evolution quantum phase estimation (SE-QPE) on a Quantinuum System Model H2 quantum computer. SE-QPE is a modification to canonical QPE for particle-conserving Hamiltonians in which controlled time evolution is replaced by CSWAP-based interference between a target register and a reference register. For factorizations of time evolution with a shared eigenbasis, SE-QPE preserves the phase-register outcome distribution of canonical QPE and, unlike with compute–uncompute substitutions, it remains compatible with non-exact eigenstates. The substitution removes controlled-simulation overhead and enables parallel evolution on two registers, reducing the depth of each phase-kickback block. Resource analysis for Trotterized double-factorized chemistry Hamiltonians shows that the substitution becomes increasingly favorable at higher phase powers and combining QPE and SE-QPE implementations can be a useful option. Over a range of FeMoco active spaces, SE-QPE reduces time evolution resources, with asymptotic reductions of about 33% in CX count, 25% in $T$ count, and an asymptotic depth ratio of $3/N$ for CX layers. On Quantinuum H2-2, a four-qubit model ethylene demonstration with explicit inverse QFT and repeated phase-kickback steps up to 8 phase bits yields distinct energies and shows the auxiliary registers provide useful error detection filters.

11.
arXiv (CS.AI) 2026-06-16

Autonomous End-to-End SOH Prediction Services for Battery Systems via Temporal-Contrastive Representation Learning

arXiv:2606.16434v1 Announce Type: cross Abstract: Accurate state of health (SOH) estimation is a critical diagnostic service for lithium-ion battery management. However, reliance on labor-intensive manual feature engineering and opaque black-box models hinders scalable industrial deployment. To address this, we introduce TC-SOH: a modular, plug-and-play service architecture for autonomous, end-to-end SOH prediction. TC-SOH employs a temporal-contrastive mechanism and a cross-window prediction pretext task to extract degradation-relevant representations directly from raw operational data. To improve transparency, we connect model efficacy with representation diagnostics: visualization, sensitivity analysis, redundancy analysis, bidirectional probing, future-SOH probing, and temporal shuffling show that learned features overlap with selected expert descriptors while retaining additional SOH-relevant variation, and that ordered temporal context improves subsequent-SOH prediction. Across four public datasets, TC-SOH outperforms the considered physics-informed and data-driven baselines, reducing MAPE by 1.91 times and RMSE by 2.13 times.

12.
arXiv (CS.AI) 2026-06-11

Lung-SRAD: Spectral-Aware Regularized Audio DASS with Dual-Axis Patch-Mix Contrastive Learning for Respiratory Sound Classification

arXiv:2606.11922v1 Announce Type: cross Abstract: Recent respiratory sound classification (RSC) studies largely rely on CLS-token driven self-attention architectures such as the Audio Spectrogram Transformer (AST). While effective at modeling global context, recent analyses suggest a low-pass filtering behavior that may reduce sensitivity to localized abnormal patterns. In this work, we investigate State Space Models (SSMs) as an alternative backbone for RSC. Using the Distilled Audio State Space model, we analyze intermediate representations through spectral response curves and observe stronger preservation of mid-to-high spatial-frequency components. Based on these observations, we introduce spectral-aware layer regularization using Gaussian convolution applied to selected layers. We further propose Dual-Axis Patch-Mix contrastive learning tailored to SSM-based audio models for robust representation learning. Experiments on the ICBHI benchmark show that our approach achieves 64.48% score, outperforming the AST baseline by 5%. Code is available at https://github.com/RSC-Toolkit/Lung-SRAD.

13.
arXiv (CS.AI) 2026-06-16

InvDesMobility: a reliability-gated first-principles feedback framework for closed-loop materials discovery

arXiv:2606.16133v1 Announce Type: cross Abstract: Inverse materials design starts from target functionality and searches for structures that can realize it. Its value in closed-loop discovery depends not only on prediction performance, but also on whether expensive first-principles results are independently validated, provenance-recorded, and admitted as feedback only when evidence is sufficient. This is especially important for composite properties such as carrier mobility, where a final scalar value hides intermediate quantities, fit quality, convergence history, and workflow assumptions. Here we present InvDesMobility, a reliability-gated first-principles feedback framework that integrates multi-agent automated DFT, evidence stratification, generative structure proposal, acquisition ranking, and auditable release. Using 516 2DMatPedia-derived candidates, the workflow produced 280 QC-passed materials and 573 retained carrier-direction seed channels after channel-level reliability gating. These records were split into two feedback objects: relaxed structures updated the generative model, while retained mobility channels trained the acquisition model and set validation priority. Over multiple iterations, InvDesMobility screened 2.4 x 10^6 structures, submitted 102 candidates for DFT validation, and retained 86 reliability-gated generated channels across 41 formulas. Overall, the main contribution is not a fixed list of high-mobility materials, but a transferable feedback contract that makes closed-loop inverse design both useful and auditable when learning from expensive calculated properties. All source data, retained feedback records, and workflows are available at https://github.com/DreamLufei/invDesMobility, with an accompanying evidence website at https://dreamlufei.github.io/invDesMobility/.

14.
arXiv (CS.AI) 2026-06-18

Deep Learning-Driven Inverse Design of Doherty Power Amplifiers Using Pixelated Combiners and Dual-State Impedance Synthesis

arXiv:2606.18395v1 Announce Type: cross Abstract: The output combiner of a Doherty power amplifier (PA) integrates load modulation, impedance matching, and phase compensation within a single network, making its design and synthesis highly challenging. In this paper, we propose a three-port Doherty combiner design methodology that combines deep convolutional neural networks (CNNs), pixelated layout representations, and genetic algorithms (GA) with dual-state impedance synthesis to address both peak and back-off power conditions. As a proof of concept, two GaN HEMT Doherty PA prototypes incorporating three-port pixelated combiners are designed and fabricated. Both prototypes achieve a measured saturated output power exceeding 44.2 dBm with peak drain efficiency above 71.2% within 2.6-2.8 GHz. Furthermore, a drain efficiency as high as 64% is measured at the 6-dB back-off level. After applying digital predistortion, each prototype achieves an adjacent channel leakage ratio (ACLR) better than -51.3 dBc.

15.
medRxiv (Medicine) 2026-06-16

Usability testing with a prototype user interface of an Artificial Intelligence driven air-Safety Tool (AISaT)

Involving end-users in the development of an AI tool is an important facilitator to its implementation. Usability testing was therefore conducted with a prototype user interface of an Artificial Intelligence driven air-Safety Tool (AISaT) to capture the perspectives and user experiences of AISaT from 10 staff members across two hospitals working within estates, infection prevention and control, and clinical areas, to inform the development of next iterations of AISaT. The perspectives shared could be grouped under improvements to the understand-ability; content; navigation; visibility; usability; workflow; ownership; and frequency of use of the tool. There were key areas that can and will be easily improved within AISaT, however there were areas that required a deeper level of critical reflection, such as incorporating data on more existing variables in a room (i.e., existing ventilation) and whether all patients should be assumed as infectious and breathing heavily. The research team must consider if the target audience of end users and recommended frequency of AISaT use will be pre-defined by the tool developers, or whether this level of detail should be left to each individual hospital to decide.

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

A Unified Framework for Context-Aware and Relation-Aware Graph Retrieval-Augmented Generation

arXiv:2606.18075v1 Announce Type: new Abstract: Retrieval-Augmented Generation (RAG) has emerged as a paradigm for enhancing large language models (LLMs) with external knowledge, yet existing graph-based methods face a fundamental limitation: entity-centric and chunk-centric approaches operate on representations anchored to original text without true knowledge fusion. While entity-centric methods connect logically related content and chunk-centric methods preserve context, both retrieve information separately through similarity search, missing emergent understanding from their synthesis. In this paper, we propose HyGRAG, a hierarchical graph RAG framework that transcends source documents by addressing three core challenges: constructing summaries that genuinely integrate contextual and relational information, leveraging these synthesized representations to access emergent knowledge during retrieval, and efficiently updating hierarchical structures for dynamic corpora. Specifically, we design hierarchical index structures over hybrid graphs with both chunk and entity nodes, then iteratively cluster them and generate LLM-based summaries. Then, we design context and relation-aware retrieval that searches across all abstraction levels while expanding through community membership. Moreover, we enable dynamic knowledge update through attachment-based algorithms with only local re-summarization. Experimental results show that HyGRAG improves the average accuracy of multi-hop reasoning tasks by 9.7%, while maintaining reasonable efficiency.

17.
arXiv (CS.CV) 2026-06-11

Benchmarking Cross-Domain Audio-Visual Deception Detection

Automated deception detection is crucial for assisting humans in accurately assessing truthfulness and identifying deceptive behavior. Conventional contact-based techniques, like polygraph devices, rely on physiological signals to determine the authenticity of an individual's statements. Nevertheless, recent developments in automated deception detection have demonstrated that multimodal features derived from both audio and video modalities may outperform human observers on publicly available datasets. Despite these positive findings, the generalizability of existing audio-visual deception detection approaches across different scenarios remains largely unexplored. To close this gap, we present the first cross-domain audio-visual deception detection benchmark, that enables us to assess how well these methods generalize for use in real-world scenarios. We used widely adopted audio and visual features and different architectures for benchmarking, comparing single-to-single and multi-to-single domain generalization performance. To further exploit the impacts using data from multiple source domains for training, we investigate three types of domain sampling strategies, including domain-simultaneous, domain-alternating, and domain-by-domain for multi-to-single domain generalization evaluation. We also propose an algorithm to enhance the generalization performance by maximizing the gradient inner products between modality encoders, named ``MM-IDGM". Furthermore, we proposed the Attention-Mixer fusion method to improve performance, and we believe that this new cross-domain benchmark will facilitate future research in audio-visual deception detection.

18.
medRxiv (Medicine) 2026-06-17

Macrophage-targeted glucocorticoid prodrug resolves acute inflammation while preserving HPA axis function: mechanistic, preclinical, and Phase II/III clinical evidence

Glucocorticoids (GCs) remain the fastest-acting anti-inflammatory agents but are constrained by systemic exposure that suppresses the hypothalamic pituitary adrenal (HPA) axis, silences adaptive immunity, and drives chronic toxicities. Chronic inflammatory diseases are sustained by long-lived CD206+ macrophages containing immune-resistant pathogenic material not cleared physiologically. We developed 101-PGC-005 ('005), a macrophage-targeted type 1a dexamethasone prodrug engineered for low-affinity, recycling-compatible uptake via CD206, with intracellular release triggered by acidic endosomes. We evaluated '005 in mechanistic assays, pathogen-diverse preclinical models, three human pharmacokinetic (PK) studies, and an adaptive-design randomized Phase II/III trial in 309 hospitalized patients with moderate COVID-19. In two completed Phase I human studies, a first-in-human dose-escalation and repeated-dose study and a dedicated single/multiple-dose PK and safety study; '005 circulated as intact prodrug with rapid systemic clearance (Tmax ~0.5 h; terminal half-life ~1.9 h), with no measurable free dexamethasone after single dosing and only low, clinically non-significant free dexamethasone after repeated dosing, and intact prodrug recovered unchanged in urine. Morning cortisol and ACTH were preserved after 30 mg once daily for three consecutive days (1.5 times the intended therapeutic dose). A cerebrospinal fluid PK study is evaluating central-compartment penetration. In the Phase II/III trial, powered for non-inferiority, conducted across six sites in India under GCP with Ministry of Health approval and independent DSMB oversight; '005 (20 mg IV daily for 3 days) was superior to dexamethasone (6 mg IV daily for 3 -10 days) on the primary endpoint of time to > a 2-point improvement on the WHO ordinal scale (HR 2.31; 95% CI 1.83-2.93; p < 0.0001; median 3 vs. 4 days). '005 was also superior on viral clearance (HR 1.47; 95% CI 1.17-1.84; p = 0.0001), hospital discharge rate, SpO2; recovery, and fever resolution. Zero patients in the '005 arm received investigator-initiated corticosteroid supplementation despite protocol allowance. All 309 randomized patients completed the study (ITT = per-protocol). Safety profiles were equivalent (TEAEs 54.8% vs 54.5%; p = 0.958), with no Grade 3+ events, SAEs, deaths, or discontinuations in either arm. Mechanistically, '005 delivered dual benefit: acute debulking of inflammatory macrophages and selective depletion of chronically activated pathology-sustaining macrophages, while preserving CXCL10 antiviral signaling and physiologic HPA control. Critically, HPA preservation is not merely a safety feature, it is a core efficacy mechanism: by clearing the pathogenic macrophage burden that was overriding HPA regulation, '005 restores the conditions for endogenous cortisol to resume its pulsatile, demand-responsive anti-inflammatory role across all GR-expressing cells, lymphocytes, endothelial cells, neurons, and newly differentiated macrophages, that '005 itself cannot reach. These findings support regulatory-grade evidence for macrophage-targeted corticosteroid therapy and provide the foundation for further development across acute inflammatory indications (sepsis, viral pneumonia, cytokine-release syndromes) and chronic macrophage-driven diseases (atherosclerosis, metabolic steatohepatitis, neurodegeneration, tumor-associated macrophages).

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

FDIO: Frequency Decomposed Inertial Odometry

Pedestrian inertial odometry (PIO) estimates autonomous pedestrian motion using only acceleration and angular velocity measurements collected by an inertial measurement unit (IMU), making it highly valuable for consumer level localization applications. However, under a dual device acquisition setting, IMU signals collected by a freely carried mobile device are inherently composite signals in which the global motion of the human torso is coupled with perturbations induced by local limb motion. This coupling makes accurate human motion modeling more challenging. To address this issue, this paper proposes frequency decomposed inertial odometry (FDIO). The proposed method first decomposes input IMU signals into low frequency and high frequency components using a Laplacian pyramid. It then adopts a Mamba module to model long range motion information from the low frequency component and uses a multi scale convolution module to extract fine grained local dynamic features from the high frequency component. Experiments on five public PIO datasets show that FDIO achieves an average absolute trajectory error of 3.221~m and an average relative trajectory error of 2.550~m, reducing the errors by 33.3\% and 16.7\% compared with the RoNIN ResNet baseline, respectively. These results validate the effectiveness of the proposed frequency decomposition strategy. To the best of our knowledge, this work is among the first efforts to introduce Mamba and a frequency decomposition architecture into inertial odometry.

20.
arXiv (CS.AI) 2026-06-15

COGNITION: From Evaluation to Defense against Multimodal LLM CAPTCHA Solvers

arXiv:2512.02318v4 Announce Type: replace-cross Abstract: This paper studies how multimodal large language models (MLLMs) undermine the security guarantees of visual CAPTCHA. We identify the attack surface where an adversary can cheaply automate CAPTCHA solving using off-the-shelf models. We evaluate 7 representative MLLMs on 18 real-world CAPTCHA task types, measuring single-shot accuracy, success under limited retries, end-to-end latency, and per-solve cost. We further validate our findings through a supplemental external dataset and an adaptive-attacker setting with session memory, while also analyzing the impact of task-specific prompt engineering and few-shot demonstrations on solver effectiveness. We reveal that MLLMs can reliably solve recognition-oriented and low-interaction CAPTCHA tasks at human-like cost and latency, whereas tasks requiring fine-grained localization, multi-step spatial reasoning, or cross-frame consistency remain significantly harder for current models. By examining the reasoning traces of such MLLMs, we investigate the underlying mechanisms of why models succeed/fail on specific CAPTCHA puzzles and use these insights to derive defense-oriented guidelines for selecting and strengthening CAPTCHA tasks. To validate these principles, we present a proof-of-concept by hardening a vulnerable CAPTCHA type using our guidelines. We demonstrate that incorporating fine-grained localization and implicit counting reduces the success rate of state-of-the-art MLLMs from over 95\% to 0\%, confirming that structural changes can effectively mitigate the threat. We conclude by emphasizing the urgent need for CAPTCHA redesign as MLLM capabilities increasingly threaten existing defenses. Code Availability (https://doi.org/10.5281/zenodo.20406852).

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

Does Traversal Order Matter? A Systematic Study of Tree Traversal Methods in Transformer Grammars

Transformer Grammars (TGs) enhance language modeling by incorporating syntactic tree structures. Despite the potentially significant impact on model performance of how syntactic trees are linearized in TGs, existing studies rely solely on Depth-First Traversal (DFT) for linearization. In this paper, we expand the traversal design space by exploring Breadth-First Traversal (BFT) and a novel hybrid traversal strategy, Production-Rule Traversal (PRT), which combines the structural lookahead of BFT with the early lexical generation of DFT. We integrate these traversal methods with varying tree configurations and masking strategies, and empirically evaluate their performance on language modeling, syntactic generalization and summarization. We reveal the inherent trade-offs between nested composition and global lookahead, providing actionable recommendations for designing task-aware Transformer Grammars.

22.
arXiv (quant-ph) 2026-06-16

Rigorous extension of semilocal collinear functionals to noncollinear DFT using $SU(2)$ rotations

arXiv:2605.31203v2 Announce Type: replace-cross Abstract: In the presence of spin-orbit coupling and in geometrically frustrated materials, a noncollinear treatment the magnetization density is essential. However, in density functional theory most exchange–correlation functional approximations were originally developed for locally collinear magnetization. Many practical approaches to noncollinear DFT have emerged over the past decade. However, a first-principles connection between widely used semilocal collinear functionals and their noncollinear generalizations remains lacking. In this work, a locally exact relation between collinear and noncollinear exchange–correlation functionals is derived at the level of gradient expansions within a $u(2)$ matrix representation of the energy functional. Within this framework, collinear semilocal variables naturally acquire distinct dependencies on transverse and longitudinal magnetization gradient components. The widely used Scalmani–Frisch scheme emerges as a first-order approximation. The transformation of collinear functional derivatives to noncollinear space is implemented through numerically robust $SU(2)$ rotations. A consistent description of local magnetic torques is demonstrated for the prototypical spin-frustrated Cr$_3$ cluster. The approach further extends to fully nonlocal functionals and provides a direct route towards numerically stable relativistic response calculations. The influence on magnetic properties in presence of spin-orbit coupling is illustrated through calculations of hyperfine couplings in the high-spin ground states of uranium and the uranium ion.

23.
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.

24.
arXiv (CS.AI) 2026-06-11

GPO: Learning from Critical Steps to Improve LLM Reasoning

arXiv:2509.16456v3 Announce Type: replace Abstract: Large language models (LLMs) are increasingly used in various domains, showing impressive potential on different tasks. Recently, reasoning LLMs have been proposed to improve the reasoning or thinking capabilities of LLMs to solve complex problems. Despite the promising results of reasoning LLMs, enhancing the multi-step reasoning capabilities of LLMs still remains a significant challenge. While existing optimization methods have advanced the LLM reasoning capabilities, they often treat reasoning trajectories as a whole, without considering the underlying critical steps within the trajectory. In this paper, we introduce Guided Pivotal Optimization (GPO), a novel fine-tuning strategy that dives into the reasoning process to enable more effective improvements. GPO first identifies the `critical step' within a reasoning trajectory - a point that the model must carefully proceed to succeed at the problem. We locate the critical step by estimating the advantage function. GPO then resets the policy to the critical step, samples the new rollout and prioritizes the learning process on those rollouts. This focus allows the model to learn more effectively from pivotal moments within the reasoning process to improve the reasoning performance. We demonstrate that GPO is a general strategy that can be integrated with various optimization methods to improve reasoning performance. Besides theoretical analysis, our experiments across challenging reasoning benchmarks show that GPO can consistently and significantly enhance the performance of existing optimization methods, showcasing its effectiveness and generalizability in improving LLM reasoning by concentrating on pivotal moments within the generation process.

25.
arXiv (CS.CV) 2026-06-16

Beyond Scalar Distances: Semantic Attribute Gradients from Frozen MLLMs for Visual Embeddings

Vision encoders for retrieval are typically trained with class-label supervision: each training pair reduces to a scalar that uniformly pushes the embedding apart or pulls it together, as if every visual attribute either differed or matched. A multimodal large language model (MLLM), shown the same pair, can articulate those attributes and use them to predict whether the images share a class. We propose SAGA, a framework that turns this language-grounded, attribute-aware perception into a training signal for the encoder itself. Specifically, we use Group Relative Policy Optimization (GRPO) to reward the MLLM for correct predictions on the vision encoder's tokens. Since correct predictions require those tokens to expose the specific attributes that differ or match between the pair, the gradient pushes the encoder to encode them, replacing the uniform pair-level scalar with attribute-resolved supervision. An auxiliary attention-distillation loss anchors the encoder's embedding to tokens the MLLM attended to, and a standard metric-learning loss shapes the embedding geometry for nearest-neighbour retrieval. The MLLM is frozen throughout and discarded at inference, matching the deployment cost of a metric-learning baseline. SAGA improves Recall@1 by 3 to 6 points over state-of-the-art baselines on CUB-200-2011, Cars-196, FGVC-Aircraft, and iNaturalist Aves on zero-shot image retrieval.