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

Variational Test-time Optimization for Diffusion Synchronization

Collaborative generation, which coordinates multiple diffusion trajectories to extend the capabilities of pretrained priors, has emerged as a powerful paradigm for extending the applicability of diffusion models. Among existing approaches, diffusion synchronization provides a scenario-agnostic solution by introducing general guidance mechanisms. However, current synchronization approaches rely heavily on heuristics and still require task-specific tailoring, which limits their generalizability and performance. In this work, we mathematically derive a synchronization framework based on optimal control, providing a principled explanation of diffusion synchronization. During sampling, we optimize control variables to guide multiple trajectories toward coherent solutions while remaining close to the underlying diffusion prior. Our method operates entirely at test-time without additional training, thereby enabling broad applicability across diverse generation scenarios when combined with strong pretrained priors. We demonstrate consistent improvements over baselines on three representative collaborative generation tasks, covering a wide range of modalities and applications. Beyond performance gains, our work establishes a novel foundation for collaborative generation, opening a principled path toward extending pretrained generative models to new collaborative generation settings.

02.
arXiv (math.PR) 2026-06-16

Riviera model with egoistical settlers

arXiv:2606.16791v1 Announce Type: cross Abstract: The Riviera model mimics a densifying settlement along the coastline. In the lattice version, houses are built sequentially in empty sites with the constraint that every newly built house has at least one empty neighboring site. The distribution of clusters of adjacent houses does not obey a closed set of evolutionary equations, but the void-cluster-void distribution does. We compute the latter and extract the cluster distribution from it. In the jammed state, when all voids have length one and the evolution ceases, the cluster distribution has a neat form and exhibits a factorial decay with the length of the cluster. To investigate finite systems, we employ a static approach directly treating jammed states. If the coastline is a finite segment, we determine the statistics of the number of empty sites in the jammed state (the average, variance, and higher cumulants). We also study a continuum version in which houses are built along the line so that each newly built house is sufficiently separated from at least one neighboring house.

03.
arXiv (CS.CL) 2026-06-19

Before the Labels: How Dataset Construction Shapes Suicidality Detection in Clinical Text

Clinical NLP increasingly relies on electronic health record (EHR) data to detect suicidal behaviors, treating clinical documentation as more reliable ground truth than social media. We argue that this framing obscures how EHR-based suicidality datasets encode a particular operationalization of suicidality, shaped by who authors the data, how episodes are bounded, and how ambiguity is resolved. We ground this argument in a case study of the ScAN dataset, built over MIMIC-III clinical notes. We show how governance constraints, ICD-based cohort selection, single-annotator labeling, and hospital-stay-level aggregation produce labels that reflect clinician-documented judgments, treat suicidality as a bounded episode, and assume that intent can be reliably inferred from documentation. A linguistic analysis demonstrates that identical labels subsume heterogeneous clinical framings differing in temporality, negation, and uncertainty. We argue that clinical NLP should examine the assumptions embedded in suicidality datasets before interpreting their labels as ground truth.

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

Model-Native Computing Architecture: Envisioning Future System Architecture Through the Lens of Computer Architecture

arXiv:2606.00288v2 Announce Type: replace Abstract: Large language models are undergoing a transition from model technology to system technology. Engineering challenges like cache reuse, context capacity, agent scheduling, and permission control resemble classical computer systems problems. This raises a question: if we treat the LLM as a CPU, KV cache as processor cache, context window as main memory, and agent framework as an operating system, can decades of computer architecture wisdom guide next generation model native systems? This paper pursues this analogy as a visionary survey. We map computer architecture concepts onto the emerging model native stack, survey literature across LLM as OS, memory management, agent frameworks, tool protocols, multi agent coordination, cognitive architectures, and safety governance, finding that each addresses a different layer without a unifying model. We propose the Intelligent Computing Architecture (ICA): six functional layers with interface contracts and design axioms. We resolve the tension over whether the LLM resembles a CPU or OS via a dual plane architecture a probabilistic execution plane (what can be computed) and a deterministic control plane (what should be computed), with every layer passing through as a graded crossover. We propose three Amdahl style design heuristics Semantic Locality, Context Budget, and Agent Speedup as organizing back of envelope models, illustrate their parameter ranges with published data, and identify predictive validation as the principal open task. We articulate analogy boundaries, note differences between silicon and model era architectures, and propose a research roadmap. This is a conceptual and survey contribution with no new experimental results.

05.
arXiv (CS.AI) 2026-06-15

Communication Policy Evolution for Proactive LLM Agents

arXiv:2606.14314v1 Announce Type: new Abstract: LLM agents have rapidly evolved into autonomous systems, yet a persistent information gap remains between users and agents: communication is costly, while users' identical preferences further limit information exchange. To investigate how agents should communicate across modalities, this paper formalizes Communication Policy, establishes textual and UI-based policies, and then evaluates communication policies across diverse environments, personas, and model combinations. Building information asymmetry for proactive agents, we set up two complementary settings, User-Agent and Planner-Executor. Experimental results reveal complementary strengths between interaction channels: text-based interaction often facilitates task performance, while structured UI improves agents' response quality and persona compliance. Motivated by that, a hybrid method combines these advantages. We further propose Communication Policy Evolution (CPE), a self-evolution framework for refining communication policies through rollout and prompt-level evolving. Without model modification, CPE achieves the best task success across multiple settings using prompt refinement alone. Our findings identify communication behavior as a critical yet underexplored design dimension for LLM agents.

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

MMLongEmbed: Benchmarking Multimodal Embedding Models in Long-Context Scenarios

Recent advancements have significantly expanded the theoretical context windows of Multimodal Embedding Models (MEMs). However, larger context windows do not necessarily translate into effective comprehension and representation of long-context multimodal inputs, which remains a critical bottleneck for real-world deployment. To address the lack of systematic evaluation in this setting, we introduce MMLongEmbed, the first comprehensive benchmark for evaluating MEMs in long-context scenarios. MMLongEmbed comprises four retrieval tasks spanning multiple context-length ranges, covering text, document, and video modalities. Through extensive evaluation of state-of-the-art models, we find that current architectures rely heavily on superficial feature matching and struggle to capture deep semantic and structural dependencies. We further observe that performance degradation varies systematically with context length and key information placement. Moreover, models exhibit substantially different robustness to redundant contextual information across modalities. For reproducibility, the benchmark and code are publicly available.

07.
medRxiv (Medicine) 2026-06-22

Referral pathways, ETAT triage acuity, and inpatient outcomes among children presenting to a national tertiary paediatric emergency unit in Ghana: a prospective cohort study

Emergency referral systems in sub-Saharan Africa are fragmented, and children reaching tertiary facilities through different referral pathways often arrive in advanced clinical states. Prospective data simultaneously characterising referral patterns, triage acuity at presentation, diagnostic case mix, and inpatient mortality at a national tertiary paediatric emergency unit are lacking from West Africa. This prospective cohort study enrolled 675 consecutively presenting children aged one month to 12 years at the Paediatric Emergency Unit of Korle Bu Teaching Hospital, Accra, Ghana, from February to December 2019. The primary outcome was all-cause inpatient mortality. Key variables collected included referral status and facility tier, Emergency Triage Assessment and Treatment (ETAT) triage category, ICD-10 diagnostic classification, Oyedeji socioeconomic classification, and time from symptom onset to PEU registration. Crude odds ratios were computed for all candidate predictors. Multivariable logistic regression was conducted using complete case analysis (n = 613). Of 675 children, 63.0% (n = 425) were referred from another health facility; referred children had higher ETAT emergency triage category rates than self-presenting children (32.7% vs 27.6%, p < 0.001). Overall inpatient mortality was 9.9% (67/675). Mortality varied by referral source: 16.7% among secondary/regional hospital referrals, 11.0% among lower-tier facility referrals (district, municipal, CHAG, polyclinic, private, health centre, and maternity home facilities combined, n = 356), 7.6% among self-presenting children, and 7.4% among tertiary referrals. Overall, 30.8% of children were classified as ETAT emergencies on arrival, with case fatility rate of 21.6%. The three most common diagnostic domains were respiratory conditions (17.2%), blood and haematological disorders (17.0%), and digestive presentations (16.4%). Inpatient mortality was highest in neoplastic disease (33.3%, n = 30) and circulatory presentations (31.0%, n = 29). In the primary multivariable analysis (n = 613, 51 events; events-per-variable ratio 4.2), no referral tier was independently associated with inpatient mortality after adjustment. Referral from secondary/regional hospitals showed a borderline non-significant association (adjusted odds ratio 3.09, 95% CI 0.96 to 9.90, p = 0.058). School going children (60-119 months) had higher odds of inpatient death than infants (adjusted odds ratio 5.56, 95% CI 1.16 to 26.53, p = 0.032), as did adolescents (adjusted odds ratio 10.01, 95% CI 2.15 to 46.69, p = 0.003). ETAT emergency category and lower socioeconomic status were not independently significant in this model. A pre-specified sensitivity analysis using the full analytic cohort (n = 674, events-per-variable ratio 6.7) with collapsed referral categories did not confirm any referral tier association; ETAT emergency category and lower SES were independently associated in the sensitivity model. All multivariable estimates should be regarded as exploratory. This prospective cohort provides simultaneous characterisation of referral patterns, ETAT triage acuity, diagnostic case mix, and inpatient mortality at a national tertiary paediatric emergency unit in West Africa. The referral-mortality gradient and high ETAT emergency category proportion document the severity of illness arriving through different referral pathways at this facility. The association between secondary/regional hospital referral and inpatient mortality is hypothesis-generating and requires replication in an adequately powered multicentre study before any service-level conclusions can be drawn.

08.
bioRxiv (Bioinfo) 2026-06-20

Evaluation of Trypanosoma brucei Phosphofructokinase Allosteric Inhibition: An In-Silico Study

Human African trypanosomiasis, caused by a protozoan parasite Trypanosoma brucei, is a neglected tropical disease for which well-tolerated, conveniently administered, and highly efficacious medicines are still missing. Previously, T. brucei Phosphofructokinase was targeted by small-molecule inhibitor development efforts. This approach has shown promise both in vitro and in vivo. In this study, we have used these wet-lab results, evaluated the compounds already characterised by Molecular Dynamics simulations, found relationships between in silico and wet-lab data and used these observations to evaluate compounds that we selected through several different approaches of virtual screens. We observed that inhibitor-ATP interactions are highly predictive of the inhibitory activity. Several compounds selected through virtual screens have outperformed previously characterised compounds.

09.
arXiv (CS.CV) 2026-06-16

SAMTok: Representing Any Mask with Two Words

Pixel-wise capabilities are essential for building interactive intelligent systems. However, pixel-wise multi-modal LLMs (MLLMs) remain difficult to scale due to complex region-level encoders, specialized segmentation decoders, and incompatible training objectives. To address these challenges, we present SAMTok, a discrete mask tokenizer that converts any region mask into two special tokens and reconstructs the mask using these tokens with high fidelity. By treating masks as new language tokens, SAMTok enables base MLLMs (such as the QwenVL series) to learn pixel-wise capabilities through standard next-token prediction and simple reinforcement learning, without architectural modifications and specialized loss design. SAMTok builds on SAM2 and is trained on 209M diverse masks using a mask encoder and residual vector quantizer to produce discrete, compact, and information-rich tokens. With 5M SAMTok-formatted mask understanding and generation data samples, QwenVL-SAMTok attains state-of-the-art or comparable results on region captioning, region VQA, grounded conversation, referring segmentation, scene graph parsing, and multi-round interactive segmentation. We further introduce a textual answer-matching reward that enables efficient reinforcement learning for mask generation, delivering substantial improvements on GRES and GCG benchmarks. Our results demonstrate a scalable and straightforward paradigm for equipping MLLMs with strong pixel-wise capabilities. Our code and models are available.

10.
arXiv (math.PR) 2026-06-11

The $K$-th nearest neighbor random walk on a Poisson point process gets trapped

arXiv:2606.11271v1 Announce Type: new Abstract: The $K$-th nearest neighbor random walk $(X_n)_{n \geq 0}$ on a homogeneous Poisson point process $\chi$ on $\R^d$ ($d\geq 1$), starts at the origin and at each step picks its next Poisson point among its closest neighbors according to i.i.d. labels having the same distribution as $K$. Our main result (Theorem 1) states that the number of Poisson points visited by $(X_n)_{n \geq 0}$ admits an exponential decay whenever the random variable $K$ has a bounded support (BS). In particular, the $K$-th nearest neighbor random walk visits finitely many Poisson points if and only if $K$ satisfies Assumption (BS). To prove it, we introduce the key notion of pioneer point which allows us to deal with the region of $\R^d$ already explored by $(X_n)_{n \geq 0}$. Still under Assumption (BS), we also prove an exponential decay for the Euclidean length of the trajectory performed by $(X_n)_{n \geq 0}$ (Theorem 2). Finally, and quite surprisingly, we exhibit an example of label distribution with bounded support for which the $K$-th nearest neighbor random walk discovers new Poisson points after a number of steps whose tail distribution is at least polynomial (Theorem 3).

11.
bioRxiv (Bioinfo) 2026-06-14

Structural Analysis of Prostate Cancer N-Glycans Using Graph-Based Structural Metrics

The N-linked glycans are structurally complex carbohydrate modifications that regulate protein folding, immune recognition, and cellular signaling, and their expression is extensively remodeled during cancer progression, making them promising biomarkers. In this study, prostate cancer-associated N-glycans from a range of relevant peer-reviewed studies were curated and digitized to develop a versatile computational framework that quantitatively encodes their spatial complexity across diverse biological systems. We invented two indices – the Distance & Connectivity Index (DCI) and the Position & Composition Index (PCI) – to capture the spatial information in N-glycans as layered architectures, enabling calculation of residue-level path lengths, branching structure, and compositional diversity. DCI summarizes glycan structure as both a scalar and matrix representation, while PCI does the same but also captures monosaccharide diversity, linkage heterogeneity, and cross-layer branching features. These metrics were computed with GlycoAssessor, an open-source platform that extracts information for the DCI and PCI from glycans drawn via Symbol Nomenclature for Glycans (SNFG) notation. Principal Component Analysis (PCA) was applied to evaluate whether glycans from prostate cancer tissues cluster distinctly in a disease-relevant manner. Results show that the spatial information in N-glycans: (1) increased in a multi-dimensional, non-linear manner, (2) objectively segregated structural themes, (3) could function as a potential prostate cancer biomarker that is distinct from mass-to-charge ratio and relative abundance, and (4) could objectively quantify novel subtype classifications of glycans associated with disease states and progression.

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

Steering Emotional Dynamics for Art Therapy: Controllable Narrative Script Generation through Hierarchically Guided LLM Agents

arXiv:2606.16481v1 Announce Type: new Abstract: Art therapy plays a vital role in emotional healing, in which narrative creation acts as the primary vehicle for emotional expression. Given the inherently dynamic nature of emotions during healing, narratives with finely controlled emotional fluctuations enable individuals to safely project inner conflicts and achieve emotional catharsis. Recently, with the rapid development of Large Language Models (LLMs), automated narrative generation technology has provided a new pathway to support such artistic designs. However, while existing methods can produce fluent texts, they struggle to generate narratives that adhere to specified affective trajectories, failing to meet the demands of emotion-oriented psychological healing. To address these issues, this paper proposes EC-Script, an LLM agent-based framework that enables hierarchical control of the affective trajectory in narrative generation for emotional healing. To ensure that the generated narratives strictly follow the given emotional patterns, EC-Script establishes overall narrative direction through Emotion-Trajectory Planning, propels scene-level plot development with Character-Driven Scene Generation, and regulates local emotional changes of characters via Emotion-Controlled Script Writing. Ultimately, it outputs scene-by-scene script content that remains highly consistent with the preset affective trajectory. Experimental results demonstrate that EC-Script significantly outperforms baseline methods in affective trajectory adherence, exhibiting excellent and reliable emotional controllability, thereby providing effective technical support for AI-assisted emotional healing scenarios.

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

ST-DiffEye: Diffusion-based Continuous Gaze Generation via Joint Scanpath-Trajectory Modeling

We study the problem of human gaze modeling, which aims to generate the gaze patterns a viewer produces while observing a visual stimulus. Gaze is primarily captured through two modalities: continuous eye-tracking trajectories, which describe fine-grained motion dynamics, and discrete scanpaths, which describe high-level fixation structure. Because gaze varies substantially across viewers and trials, we treat this variability as a defining property rather than noise and model gaze as a stochastic generative process. Existing generative gaze models supervise on only one of these two representations in isolation. We hypothesize that trajectories and scanpaths describe gaze at complementary scales and are jointly informative during training, and test this hypothesis through ST-DiffEye, a joint trajectory-scanpath diffusion framework that couples both modalities by concatenating them as an additional raw input channel, requiring no architectural overhead beyond an input and output channel expansion. We further introduce a principled evaluation framework based on the Continuous Ranked Probability Score (CRPS), which generalizes any existing sequence similarity metric into a proper scoring rule that jointly assesses the accuracy and diversity of generated gaze. Experiments on task-driven visual search, covering both target-present and target-absent scenarios, and on free-viewing benchmarks demonstrate state-of-the-art performance. These results, along with detailed ablations, confirm the benefit of joint modeling and the value of distribution-aware evaluation in capturing the intrinsic variability of human gaze. Project webpage: https://st-diffeye.github.io/

14.
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.

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

Hybrid Open-Ended Tri-Evolution Makes Better Deep Researcher

arXiv:2606.13710v1 Announce Type: new Abstract: Deep research and agent evolution serve as de-facto tasks for AI agents in real-world applications toward artificial general intelligence. The former enables autonomous retrieval and integration of information in open-ended environments to tackle open-ended research tasks, yet it is constrained by the static parametric deep research capabilities of agent systems. The latter allows agents to autonomously interact with the environment to gain experiences that evolve model capabilities. However, its effectiveness has been widely validated only on verifiable tasks with standard answers, leaving a gap with open-ended research tasks. To bridge these two critical tasks, we propose the Hybrid Open-Ended Tri-Evolution (HOTE) framework, which leverages hybrid-mode reinforcement learning to facilitate the collaborative evolution of a proposer, solver and judge based on web-scale knowledge, moving toward autonomous evolving agents in open-ended tasks and environments. Extensive experiments on three long-form deep research benchmarks demonstrate that the 8B model trained via HOTE surpasses the strongest static open 8-32B models as well as those trained by state-of-the-art deep research training methods with less time overhead, and further verify that the evolution of all three modules in HOTE is indispensable.

16.
Nature (Science) 2026-06-08

Daily briefing: Human embryo genomes precisely altered

作者:

The use of ‘base editing’ to precisely tweak human embryos has divided researchers. Plus, the number of lives saved by less-polluting cars in China and how to tip the world towards a sustainable future. The use of ‘base editing’ to precisely tweak human embryos has divided researchers. Plus, the number of lives saved by less-polluting cars in China and how to tip the world towards a sustainable future.

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

Schützen: Evaluating LLM Safety in Bulgarian and German Contexts

Large language models are increasingly deployed across professional domains, bringing hard-to-predict risks, including the generation of harmful or disrespectful content. Although substantial progress has been made in developing safety evaluation datasets, existing resources remain overwhelmingly English- and Chinese-centric. This limitation is particularly pronounced when evaluating languages that operate within shared sociocultural, legal, and ethical contexts. To address this gap, we introduce Sch\"{u}tzen: a German–Bulgarian safety dataset designed to assess model answerability under risk, covering both a low-resource language (Bulgarian) and a high-resource language (German). Experiments with multilingual and language-specific LLMs reveal pronounced cross-language differences in safety behavior, highlighting the necessity of tailored, region-specific evaluation resources to support the responsible deployment of LLMs in Germany and Bulgaria. Datasets and code are available at https://github.com/xnlp-lab/Schutzen. Warning: this paper contains examples that may be offensive, harmful, or biased.

18.
arXiv (CS.CV) 2026-06-12

Visual Place Recognition in Forests with Depth-Aware Distillation

Visual place recognition in natural forest environments remains challenging due to repetitive vegetation, weak structural cues, and significant appearance variation across traversals. To address this limitation, this paper proposes a lightweight depth-aware distillation framework that injects geometric cues into a DINOv2-based place recognition model, while maintaining its pre-trained descriptor space. Evaluated on the recent WildCross benchmark, the proposed approach yields gains over an appearance-only counterpart, providing robustness to appearance variations. These results demonstrate the importance of depth as a strong complementary modality for place recognition in natural environments and identify depth-aware distillation as a promising direction for more robust forest perception.

19.
arXiv (CS.CV) 2026-06-15

Visual Quality Score Assessment of Large White Goods in Remanufacture with Multi-View Deformable-DETR

Remanufacturing large white goods is essential for a circular economy, yet visual quality assessment remains a manual bottleneck for training and pricing. Conventional detection methods require extensive annotation and struggle with small defects in high-resolution multi-view data. We present a multi-view framework based on Deformable-DETR for automated quality scoring that aggregates information across redundant views to extract fine-grained features. To enhance robustness with limited labels, we employ self-supervised pretraining followed by supervised fine-tuning on expert-annotated scores. Additionally, a linear projection over frozen feature maps identifies regions of interest to explain model decisions. Evaluated on an industrial multi-view dataset, our approach delivers precise quality assessments while reducing reliance on manual annotation and per-part customization, enabling scalable and transparent inspection for remanufacturing lines.

20.
arXiv (quant-ph) 2026-06-19

Faking entanglement with imperceptible measurement deviations

arXiv:2606.20396v1 Announce Type: new Abstract: Quantum entanglement is a central resource underpinning emerging quantum technologies, enabling capabilities beyond those of classical systems. Accurate verification of entanglement is therefore crucial. However, experimental schemes usually rely on the assumption that quantum measurements can be realized exactly. As the complexity of a quantum system grows, this assumption typically becomes increasingly unrealistic, therefore leading to a widening mismatch between theoretical models and experimental implementations. Here we demonstrate that arbitrarily small measurement errors, when adversarially encoded in the measurement apparatus, can lead to the false certification of high-dimensional entanglement in systems that are, in fact, separable. This is achieved by introducing explicit hacking attacks to measurement devices in well-established entanglement verification tests. We further experimentally demonstrate this effect using classical photonic states encoded in the spatial degree of freedom, spanning up to 61 dimensions with measurement fidelity errors as low as 0.23%. Our results uncover a fundamental vulnerability in current methods for high-dimensional entanglement detection, highlighting the susceptibility of complex quantum devices to small adversarial perturbations. The findings underscore the need for developing secure verification of quantum information that is robust to bounded discrepancies between theory and experiment.

21.
arXiv (math.PR) 2026-06-12

Symmetric Cooperative Motion in Higher Dimensions

arXiv:2606.13459v1 Announce Type: new Abstract: We prove a distributional convergence result for a multidimensional version of symmetric cooperative motion which was introduced and studied in one dimension in [HRW, SCM1]. Our approach relies on framing the associated recursive distributional equation as a discretization of the porous medium equation. A major challenge is to analyze the behaviour of finite difference schemes which approximate weak solutions of the porous medium equation with unbounded initial data. In overcoming this difficulty, we perform a detailed analysis of the probability mass function of symmetric cooperative motion, in which we introduce several new comparison arguments for the discrete process. Consequently, along the way, we establish a novel multidimensional convergence result for a finite difference scheme approximating the ZKB/Barenblatt solution of the porous medium equation, which is of independent interest.

22.
arXiv (math.PR) 2026-06-12

(Non)-hyperuniformity of perturbed lattices

arXiv:2405.19881v3 Announce Type: replace Abstract: We ask whether a stationary lattice in dimension $d$ whose points are shifted by identically distributed but possibly dependent perturbations remains hyperuniform. When $d = 1$ or $2$, we show that it is the case when the perturbations have a finite $d$-moment, and that this condition is sharp. When $d \geq 3$, we construct arbitrarily small perturbations such that the resulting point process is not hyperuniform. As a side remark of independent interest, we exhibit hyperuniform processes with arbitrarily slow decay of their number variance.

23.
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).

24.
PLOS Computational Biology 2026-05-29

A prototype-augmented graph representation learning framework for identifying brain disorder-associated genes and facilitating drug repurposing

作者:

by Jiafang Li, Yifei Li, Siying Lin, Jiahua Rao, Huiying Zhao Many genetic loci were identified as associated with neuropsychiatric disorders and neurodegenerative disorders by Genome-wide association studies (GWAS). How these loci impact these diseases is unclear. Advances in deep-learning approaches and multi-omics data have the potential to link GWAS findings with disease mechanisms. Here, we proposed the Multi-omics Graph Transformer Network (MOGT), a semi-supervised graph neural network that leverages graph representation learning to model biological networks derived from multi-omics data to predict disease-associated genes. MOGT outperforms the current approaches in disease gene prediction for two psychiatric disorders and three neurodegenerative/neurological diseases. High-risk genes (HRGs) for Parkinson’s disease (PD) predicted by MOGT were used to drug discovery by integrating with the CMAP database. Finally, 10 drugs were identified as potential candidates. Among them, the effect of drug UK-356618 was experimentally verified in a primary neuron model, showing that UK-356618 reversed the abnormal expression of PD-associated genes and improved the cell-level phenotypes of PD. Together, these results indicate that MOGT can be used to identify HRGs for brain disorders, and these predicted HRGs provide high-level insights into the mechanisms and treatments of brain disorders.

25.
medRxiv (Medicine) 2026-06-15

Population-scale genomics reveals divergent pathogenicity of variant classes across paralogous collagen IV genes

Monoallelic pathogenic or likely pathogenic variants in COL4A3 and COL4A4 occur in approximately 1 in 106 individuals, yet whether these paralogous genes confer equivalent pathogenicity for the same variant classes has not been tested at population scale. Using whole-genome sequencing data from the UK Biobank (UKB; n = 500,000), with replication in the All of Us Research Program (n = 414,000), we performed per-variant association testing, gene-based collapsing analyses and phenome-wide association studies (PheWAS) across haematuria, proteinuria and chronic kidney disease. We identified 64 COL4A3 and 92 COL4A4 rare variants significantly associated with haematuria or proteinuria, generating a quantitative allelic series for clinical variant interpretation. Glycine substitutions within collagenous domains conferred similar risks in both genes. In contrast, truncating and non-collagenous domain (NC1) missense variants were strongly associated with haematuria and proteinuria in COL4A4 carriers but showed substantially attenuated or absent associations in COL4A3 carriers despite comparable carrier frequencies and predicted pathogenicity scores. These findings were independently replicated in All of Us. Genome-wide association analysis identified the COL4A3/COL4A4 locus as the dominant genetic determinant of haematuria, with the signal attributable to the aggregate effects of rare coding variants and no evidence of independent common variant or trans-acting modifier effects. These findings demonstrate substantial gene-specific differences in tolerance to truncating and NC1 variants between COL4A3 and COL4A4, challenging assumptions of equivalent pathogenicity across paralogous collagen IV genes. Gene identity and not variant class alone, should inform risk stratification, variant interpretation and genetic counselling in individuals carrying collagen IV risk genotypes.