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

Multi-Scale Separable Fourier Neural Networks for Solving High-Frequency PDEs

arXiv:2605.31027v2 Announce Type: replace Abstract: We propose a novel neural network architecture, termed Multi-Scale Separable Fourier Neural Networks (MS-SFNN), for the accurate and efficient solution of linear and nonlinear high-frequency partial differential equations (PDEs). MS-SFNN exploits a separable representation: given a $d$-dimensional input, it employs $d$ independent subnetworks – each acting on a single coordinate – and constructs basis functions via element-wise multiplication of their outputs. The PDE solution is approximated as a linear combination of these basis functions, with coefficients determined by least squares. Critically, all network weights and biases are randomly initialized once, from a uniform distribution with unit variance, and remain fixed thereafter. To enhance expressivity, a tunable scaling factor is introduced in each subnetwork to modulate the frequency content of the resulting basis functions. Fourier features are explicitly embedded through cosine activations, endowing the method with strong spectral approximation capabilities. To mitigate the memory bottleneck associated with dense collocation in high-frequency or three-dimensional problems, we replace automatic differentiation with analytically derived basis function derivatives and develop a memory-efficient batched QR decomposition algorithm for solving large-scale least-squares systems. Numerical experiments demonstrate that MS-SFNN achieves unprecedented accuracy across a range of challenging PDEs, significantly outperforming state-of-the-art methods such as Physics-Informed Neural Networks (PINN) and Separated-Variable Spectral Neural Networks (SV-SNN).

02.
arXiv (quant-ph) 2026-06-17

Hamiltonian description of nonreciprocal interactions

arXiv:2505.05246v5 Announce Type: replace-cross Abstract: In a vast class of systems, which includes members as diverse as sedimenting particles and bird flocks, interactions do not stem from a potential, and are in general nonreciprocal. Thus, it is not possible to define a conventional energy function, nor to use analytical or numerical tools that rely on it. Here, we overcome these limitations by constructing a Hamiltonian that includes auxiliary degrees of freedom; when subject to a constraint, this Hamiltonian yields the original nonreciprocal dynamics. We show that Glauber dynamics based on the constrained Hamiltonian reproduce both stationary and nonstationary states of the original Langevin dynamics, as we explicitly illustrate for dissipative XY spins with vision-cone interactions. Further, the symplectic structure inherent to our construction enables us to apply the well-developed notions of Hamiltonian engineering, which we demonstrate by varying the amplitude of a periodic drive to tune the spin interactions between those of a square and a chain lattice geometry. Overall, our framework for generic nonreciprocal pairwise interactions paves the way for bringing to bear the full conceptual and methodological power of conventional statistical mechanics and Hamiltonian dynamics to nonreciprocal systems.

03.
arXiv (CS.CL) 2026-06-25

Small edits, large models: How Wikipedia advocacy shapes LLM values

Can a small group of volunteers shape how AI systems discuss animal welfare, just by editing Wikipedia? We show that they can. Wikipedia appears in nearly every major language model training dataset and is weighted more heavily than web-crawled text. The Pro-Animal Wikipedians (PAW), a group of advocates who add sourced animal welfare content to relevant articles, have made 125 edits across 115 pages. Using gradient-based data attribution (Bergson; MAGIC), we traced how these edits influence language model behavior. TrackStar retrieval attribution on Llama 3.1 8B found that PAW-edited sections made up 68 percent of the highest-attributed documents for animal welfare queries (p < 0.0001) but only 52 percent for unrelated queries about the same companies (p = 0.53): the model links PAW content specifically to animal welfare topics, not to the entities in general. MAGIC counterfactual influence estimation on Llama-3.2-1B, run across five random training-order seeds, gave the same picture even more sharply: in every seed, the top-10 most influential documents on animal welfare queries were all PAW edits (10 of 10, 5 of 5 seeds), while on general queries the same top-10 sat at chance (4 to 6 of 10). Mean PAW influence exceeded mean control influence on animal welfare queries with p < 0.0001 in every seed, an effect 6 to 30 times larger than on general queries. Leave-subset-out validation gave Spearman rho = 1.00 for all 10 runs. When we fine-tuned separate models on PAW content versus control content, each model performed better specifically on the type of text it was trained on: the PAW-trained model cut perplexity on animal welfare text from 12.4 to 8.4, while the control-trained model cut perplexity on control text from 16.1 to 11.4. A small, coordinated Wikipedia editing campaign therefore measurably shapes how language models handle the topics those edits address.

04.
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).

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

Branching Flows: Discrete, Continuous, and Manifold Flow Matching with Splits and Deletions

arXiv:2511.09465v4 Announce Type: replace-cross Abstract: Diffusion and flow matching approaches to generative modeling have shown promise in domains where the state space is continuous, such as image generation or protein folding & design, and discrete, exemplified by diffusion large language models. They offer a natural fit when the number of elements in a state is fixed in advance (e.g. images), but require ad hoc solutions when, for example, the length of a response from a large language model, or the number of amino acids in a protein chain is not known a priori. Here we propose Branching Flows, a generative modeling framework that, like diffusion and flow matching approaches, transports a simple distribution to the data distribution. But in Branching Flows, the elements in the state evolve over a forest of binary trees, branching and dying stochastically with rates that are learned by the model. This allows the model to control, during generation, the number of elements in the sequence. We also show that Branching Flows can compose with any flow matching base process on discrete sets, continuous Euclidean spaces, smooth manifolds, and `multimodal' product spaces that mix these components. We demonstrate this in three domains: small molecule generation (multimodal), antibody sequence generation (discrete), and protein backbone generation (multimodal), and show that Branching Flows is a capable distribution learner with a stable learning objective, and that it enables new capabilities.

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

Operads for compositional reasoning in LLMs

Question decomposition, i.e. breaking a complex query into simpler sub-queries whose answers are composed to produce a final answer, is a widely used strategy for improving LLM reasoning, yet it currently lacks a rigorous mathematical foundation. In this paper, we propose operads, mathematical structures that model many-in, one-out operations and compositions thereof, as a natural framework for describing question decomposition. We define the questions operad $Q$, in which operations correspond to question templates and composition corresponds to substitution of sub-answers, and show how QA models can be interpreted as algebras over $Q$. Beyond reframing existing practice, this operadic perspective points toward new methods, in particular a notion of operadic consistency, which measures whether a QA model's answers agree across the partial collapses of a question decomposition tree. Empirical evaluation of operadic consistency is reported in our companion paper (Bottman, Liu, and Richardson, 2026), which finds it strongly correlated with accuracy across twelve LLMs and four multi-hop QA datasets and outperforming standard temperature-based self-consistency baselines. We argue that operads are the natural mathematical home for question decomposition, and that invariants such as operadic consistency open new directions for analyzing and improving the reliability of multi-step reasoning.

07.
bioRxiv (Bioinfo) 2026-06-10

HOMED enables hierarchical and multimodal optimization of DNA methylation deconvolution across tissues

Cellular heterogeneity is a major confounder in bulk DNA methylation data for epigenome-wide association studies. Existing reference-based DNAm deconvolution methods often ignore hierarchies among related cell types and may generalize poorly across datasets due to limited variability in reference profiles. We developed HOMED (Hierarchically Optimized Methylation Deconvolution), a framework that integrates cell-lineage hierarchies, single-cell RNA sequencing-guided deconvolution, and paired bulk RNA-seq/DNAm data for CpG signature optimization. Across simulated and real peripheral blood mononuclear cell, lung, and placental datasets, HOMED consistently yielded the highest PCCs and lowest RMSEs, outperforming existing scRNA-seq-guided DNAm deconvolution methods, improving accuracy, resolution, and cross-tissue generalizability.

08.
arXiv (CS.AI) 2026-06-12

The Safety-Aware Denoiser for Text Diffusion Models

arXiv:2605.08116v2 Announce Type: replace-cross Abstract: Recent work on text diffusion models offers a promising alternative to autoregressive generation, but controlling their safety remains underexplored. Existing safety approaches are geared toward autoregressive models and typically rely on post-hoc filtering or inference-time interventions. These are inadequate for effectively addressing safety risks in text diffusion models. We propose the Safety-Aware Denoiser (SAD), a safety-guidance framework in text diffusion models. The SAD modifies the iterative denoising process such that the text sample at the final denoising step is steered toward provably safe regions of the text space. This inference-time method can integrate safety constraints into the denoiser, avoiding computationally expensive retraining of the underlying diffusion model and enabling flexible, lightweight safety guidance. We evaluate the safety of the generated text using the SAD, with respect to hazard taxonomy, memorization, and jailbreak. Experimental results show that SAD substantially reduces unsafe generations while preserving generation quality, diversity, and fluency, outperforming existing methods. These results demonstrate that our safety guidance during denoising provides an effective and scalable mechanism for enforcing safety in text diffusion models.

09.
arXiv (CS.AI) 2026-06-19

What Do Safety-Aligned LLMs Learn From Mixed Compliance Demonstrations?

arXiv:2606.20508v1 Announce Type: new Abstract: Prior work has shown that in-context demonstrations can jailbreak language models, but it remains unclear how models interpret different types of compliance demonstrations. We study this by mixing benign compliance demonstrations (non-harmful request, helpful response) with harmful compliance demonstrations (harmful request, helpful response) and testing three hypotheses about how demonstration composition drives harmful compliance. Across four models, we find that benign and harmful demonstrations are not interchangeable: benign demonstrations can either reduce or increase harmful compliance depending on the model. We further show that preference optimization is the critical training stage that prevents benign demonstrations from increasing harmful compliance, that demonstration ordering exhibits strong recency bias, and that models differ in how refusal interacts with in-context learning: some adopt demonstrated formatting even when refusing, while others override all in-context signals upon refusal. Taken together, this work moves beyond showing that demonstration-based jailbreaking works to characterizing how it works: what models extract from compliance demonstrations depends on demonstration content, ordering, and training methodology.

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

Machine Learning-Driven Chemical Reactor Network Modeling of the Sandia-D Flame

arXiv:2606.14729v1 Announce Type: cross Abstract: Turbulent combustion simulations are crucial for many scientific and engineering systems. However, the high cost to fully resolve the complex multiscale and multiphysics behavior makes direct simulation typically infeasible. The equivalent reactor network (ERN) approach attempts to improve computational efficiency by replacing a multidimensional turbulent simulation with a series of much cheaper 0-D and 1-D chemical reactors, providing a surrogate model that retains detailed chemistry at the cost of simplified flow physics. However, their development remains a challenge, often requiring either expert analysis, or automated approaches that sacrifice accuracy. In this work, we develop an automated machine-learning-assisted framework for constructing ERNs of the Sandia-D turbulent methane/air flame. Principal component analysis is first used to reduce high-dimensional thermochemical computational fluid dynamics (CFD) data to a low-dimensional latent space, where k-means clustering identifies physically interpretable flame regions used to initialize a reactor-network graph. This initialization is then refined using finite-difference gradient descent wrapped around non-differentiable Cantera reactor simulations. Across 30 RANS simulations spanning a range of pilot temperatures and inlet methane compositions, the optimized 7-reactor ERN achieves a maximum-temperature $R^2$ score of 0.7945 while preserving a $\sim6000\times$ speedup over the CFD solver. Outlet CO prediction remains more challenging, with a final $R^2$ score of $-0.4183$, but improves substantially from the unoptimized clustering initialization. These results show that unsupervised thermochemical feature extraction can provide effective physics-informed initializations for ERN construction, while gradient-based refinement can significantly improve predictive accuracy without manual reactor-network design.

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

Reconstructing GRACE Terrestrial Water Storage with Spatio-Temporal Graph Neural Networks: An Application to South America

arXiv:2606.23833v1 Announce Type: new Abstract: Terrestrial water storage (TWS) integrates snow, soil moisture, surface water, and groundwater and is a key indicator of how climate variability and human activity reshape the global water cycle. The GRACE and GRACE-FO satellite missions provide the only direct, globally consistent observations of TWS change, but their record only begins in 2002 which is too short for many climate-scale analyses. We present a deep learning application that reconstructs monthly GRACE-like TWS anomalies (TWSA) back to 1940 by learning the relationship between daily ERA5 meteorological forcing (precipitation, evapotranspiration, runoff) and monthly GRACE observations. In contrast to prior reconstruction approaches based on grid-cell-wise regression, CNNs, or LSTMs, we adapt a multi-variate time series graph neural network (MTGNN) architecture, which was originally developed for mobility and traffic forecasting on urban sensor networks to this satellite-geodesy task. Spatial dependencies are encoded in a static, interpretable hybrid adjacency matrix that combines geodesic proximity with lagged correlations of climatic time series, capturing both local hydrological coupling and large-scale teleconnections. The reconstruction achieves a grid-cell Pearson correlation of 0.69, a basin-mean correlation of 0.94, and a near-zero bias, and it reproduces the spatial fingerprints of the 2015/16 El Niño and 2020/21 La Niña events. A systematic comparison with established reconstruction approaches (GTWS-MLrec, RM-REC, GRAiCE) shows that the graph-based model is statistically competitive at basin scale, reaching a correlation within 0.025 of the best baseline while using only roughly half to a tenth of the predictors the other models require and revealing characteristic weaknesses in arid regions in all models. The complete implementation is publicly available at github.com/hcu-cml/MTGNN-TWS-Reconstruction-GRACE

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

Examining the Usage of Generative AI Models in Student Learning Activities for Software Programming

arXiv:2511.13271v2 Announce Type: replace-cross Abstract: The rise of Generative AI (GenAI) tools like ChatGPT has created new opportunities and challenges for computing education. Existing research has primarily focused on GenAI's ability to complete educational tasks and its impact on student performance, often overlooking its effects on knowledge gains. In this study, we investigate how GenAI assistance compares to conventional online resources in supporting knowledge gains across different proficiency levels. We conducted a controlled user experiment with 24 undergraduate students of two different levels of programming experience (beginner, intermediate) to examine how students interact with ChatGPT while solving programming tasks. We analyzed task performance, conceptual understanding, and interaction behaviors. Our findings reveal that generating complete solutions with GenAI significantly improves task performance, especially for beginners, but does not consistently result in knowledge gains. Importantly, usage strategies differ by experience: beginners tend to rely heavily on GenAI toward task completion often without knowledge gain in the process, while intermediates adopt more selective approaches. We find that both over-reliance and minimal use result in weaker knowledge gains overall. Based on our results, we call on students and educators to adopt GenAI as a learning rather than a problem solving tool. Our study highlights the urgent need for guidance when integrating GenAI into programming education to foster deeper understanding.

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

LaWAM: Latent World Action Models for Efficient Dynamics-Aware Robot Policies

arXiv:2606.15768v1 Announce Type: cross Abstract: Vision-Language-Action models (VLAs) leverage large-scale vision-language pretraining for semantic robot control, but often lack explicit foresight into how robot actions change the scene. World-Action Models (WAMs) address this limitation by conditioning policies on predicted futures, yet existing approaches typically rely on computationally expensive video generation with substantial pixel-level redundancy. We present LaWAM, a Latent World Action Model that exposes predictive dynamics to robot policies through compact latent visual subgoals instead of reconstructed future video. At the core of LaWAM is a latent-action-conditioned Latent World Model (LaWM). We obtain LaWM by training a latent action model in the latent space of a pretrained vision foundation model and repurposing its forward decoder to predict future observation features for scene evolution. LaWAM then conditions action generation on these predicted latent visual subgoals to enable dynamics-aware robot control. LaWAM achieves state-of-the-art or competitive success rates (SRs) across LIBERO (98.6% SR), RoboTwin (91.22% SR), and real-world manipulation tasks while retaining low-latency inference. LaWAM runs in 187 ms per action-chunk prediction and achieves up to 24x lower wall-clock latency than pixel-space WAMs.

14.
arXiv (CS.LG) 2026-06-11

Open Materials Generation with Inference-Time Reinforcement Learning

arXiv:2602.00424v2 Announce Type: replace Abstract: Continuous-time generative models for crystalline materials enable inverse materials design by learning to predict stable crystal structures, but incorporating explicit target properties into the generative process remains challenging. Policy-gradient reinforcement learning (RL) provides a principled mechanism for aligning generative models with downstream objectives but typically requires access to the score, which has prevented its application to flow-based models that learn only velocity fields. We introduce Open Materials Generation with Inference-time Reinforcement Learning (OMatG-IRL), a policy-gradient RL framework that operates directly on the learned velocity fields and eliminates the need for the explicit computation of the score. OMatG-IRL leverages stochastic perturbations of the underlying generation dynamics preserving the baseline performance of the pretrained generative model while enabling exploration and policy-gradient estimation at inference time. Using OMatG-IRL, we present the first application of RL to crystal structure prediction (CSP). Our method enables effective reinforcement of an energy-based objective while preserving diversity through composition conditioning, and it achieves performance competitive with score-based RL approaches. Finally, we show that OMatG-IRL can learn time-dependent velocity-annealing schedules, enabling accurate CSP with order-of-magnitude improvements in sampling efficiency and, correspondingly, reduction in generation time. The OMatG-IRL code is included in a new release of the Open Materials Generation (OMatG) framework available at https://github.com/FERMat-ML/OMatG.

15.
medRxiv (Medicine) 2026-06-16

Infections and suicide and self-harm: a population-based matched cohort study

Background Infections have been associated with adverse mental health outcomes, including suicide, but evidence beyond severe or central nervous system infections is limited. We investigated associations between a range of acute infections and subsequent suicide/self-harm outcomes. Methods We conducted six infection-specific matched cohort studies using English primary care records from the Clinical Practice Research Datalink Aurum (2007-2024), linked to hospital admissions and mortality data. Adults ([&ge;]18 years) with a primary care record of infection (gastroenteritis, lower respiratory tract [LRTI], skin/soft-tissue [SSTI], urinary tract [UTI], sepsis, meningitis/encephalitis [positive control]) were matched (age, sex, practice, calendar period) to up to five comparators without infection. We estimated hazard ratios (HRs) for suicide/self-harm outcomes using Cox regression, stratified by matched set and implicitly adjusting for matching factors, with additional adjustment for deprivation, lifestyle factors, and comorbidities. We examined whether associations varied over time, by infection severity, antimicrobial treatment, sex, and prior mental health conditions. Findings Cohorts ranged from 18,192 individuals with meningitis/encephalitis (matched to 90,915 without) to 398,099 with SSTI (matched to 1,743,747). After adjustment, individuals with infection had a higher hazard of suicide/self-harm outcomes than comparators across all cohorts: sepsis (HR 1.79, 95% CI 1.65-1.93), gastroenteritis (1.62, 1.55-1.70), meningitis/encephalitis (1.56, 1.32-1.84), UTI (1.41, 1.33-1.50), SSTI (1.37, 1.31-1.43), and LRTI (1.37, 1.31-1.44). Risk was highest in the year post-infection, attenuating over time, and was higher among severe infections and those without prior mental health conditions. Interpretation Common acute infections recorded in primary care are associated with increased risk of suicide and self-harm, particularly following severe infections and in the year post-infection. Findings support suicide risk monitoring following acute infection, particularly among individuals without prior mental health conditions, and highlight infection prevention as a potentially modifiable strategy in vulnerable populations. Funding Wellcome and La Caixa. Copyright This work is licensed under a Creative Commons Attribution (CC BY) licence.

16.
bioRxiv (Bioinfo) 2026-06-16

Orion: Towards Lab Automation with Computer-Using Agents

Laboratory discovery increasingly depends on computational workflows that connect experimental data to analysis, interpretation and follow-up hypotheses. Yet these workflows remain constrained by labor-intensive use of specialized software, visual inspection through graphical user interfaces, and integration of knowledge across multiple sources. Here, we present Orion, a computer-using AI agent for biomedical image analysis and interpretation that moves towards lab automation by automating this computational layer of laboratory work. Orion combines large language models with terminal execution, GUI control and adaptive multi-step reasoning in a shared computing environment. It can inspect visual data, operate standard scientific software, mine web resources and conduct end-to-end analysis and interpretation workflows without requiring bespoke software integrations. Across benchmarks, Orion achieved over 90% accuracy on biomedical database and literature retrieval tasks, learned to use the popular tools CellProfiler and QuPath for quantitative analysis of cellular and tissue images, respectively, and facilitated autonomous discovery in experimental imaging data. In 100 hours of autonomous exploration of a large-scale perturbation imaging dataset, Orion generated 52 research reports, of which human scientist review prioritized 22 plausible mechanistic hypotheses. These results show that computer-using AI agents can substantially expand the reach of laboratory automation, providing a scalable and auditable route from experimental imaging data to quantitative analysis, reports and biologically grounded hypotheses.

17.
Nature Medicine 2026-06-22

<b>PROTEUS trial heralds perioperative therapy for prostate cancer</b>

Perioperative androgen-deprivation therapy plus apalutamide could represent a new treatment option for patients with high-risk, localized prostate cancer. Perioperative androgen-deprivation therapy plus apalutamide could represent a new treatment option for patients with high-risk, localized prostate cancer.

18.
medRxiv (Medicine) 2026-06-10

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

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

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

SMGFM: Spectral Multimodal Graph Pretraining for Multimodal-Attributed Graphs

arXiv:2606.12867v1 Announce Type: new Abstract: Multimodal-attributed graphs (MAGs) couple graph topology with node semantics from text, images, and other modalities. Traditional graph learning contextualizes node semantics by coupling topology with node features. However, this coupling design becomes troublesome in MAGs, where structure-induced and modality-intrinsic semantics may contribute differently to downstream tasks. Structure-induced semantics promote relational consistency through smooth topological variation, whereas modality-intrinsic semantics often encode local, fine-grained distinctions that should not be uniformly smoothed or aligned. Therefore, the key challenge is to identify semantic roles before cross-modal fusion. To this end, we leverage graph-frequency variation as a prior, where low-frequency components capture topology-consistent semantics and high-frequency components preserve modality-specific semantics. Based on this intuition, we propose SMGFM, a spectral multimodal graph pretraining framework that decomposes each modality-specific node signal into graph-frequency bands and assigns band-level semantic roles before cross-modal interaction. Concretely, SMGFM constructs frequency-resolved modality tokens with scalable Chebyshev filters, estimates their coupling reliability through topology-conditioned routing, and performs band-modality interaction before fusion. Its frequency-routed objectives align smooth consensus routes while preserving modality-specific routes, mitigating spatial-domain entanglement and uniform cross-modal alignment. Extensive experiments conducted on the MAG datasets demonstrate that SMGFM achieves state-of-the-art performance across graph-level and modality-level tasks.

20.
arXiv (CS.CL) 2026-06-24

CALIBER: Calibrating Confidence Before and After Reasoning in Language Models

Reasoning language models are increasingly asked not only to answer difficult questions, but also to estimate their likelihood of success. Existing methods typically elicit confidence only once: either before thinking or after answering. We argue that confidence in reasoning models is state-dependent: before thinking, confidence should estimate the chance of the model correctly solving the prompt, while after thinking it should predict whether the realized answer is likely to be correct. This distinction determines the appropriate supervision target: prompt-level success should supervise confidence estimates made after seeing the prompt, while individual answer-level correctness should supervise confidence estimates made after answering. We introduce CALIBER (Calibration Before and After Reasoning), which elicits both estimates and supervises each with the target matched to its information state. Under this unified protocol, CALIBER reduces Expected Calibration Error (ECE) by 52.5% over the strongest single-confidence baseline on BigMathDigits for the 7B model, while achieving the best Brier score and AUROC, and remains within 2.1 points of the best accuracy. Further, on a larger 30B model, CALIBER achieves the best ECE on BigMathDigits while remaining competitive in Brier score and AUROC. Out of distribution, it achieves the best ECE and Brier score on GPQA and TriviaQA, and remains competitive on SimpleQA. Ablations further show that this position-target alignment is most beneficial under distribution shift where it consistently reduces calibration error across all out-of-distribution benchmarks.

21.
medRxiv (Medicine) 2026-06-24

Structural variant discovery and diagnostic impact in rare diseases from short-read and long-read sequencing

Rare diseases collectively affect 1 in 10 individuals, yet current genetic testing fails to identify a causal variant for most cases. At present, cytogenetic methods and/or sequencing approaches such as exome (ES) or short-read genome sequencing (srGS) represent the state-of-the-art for comprehensive clinical discovery of sequence and structural variants (SVs), including copy number variants, balanced SVs, complex SVs, and tandem repeats (TRs). Recently, long-read genome sequencing (lrGS), coupled with multiomics data, has presented great promise to resolve variation in genomic regions recalcitrant to characterization by srGS such as highly repetitive simple repeat sequences and segmental duplications. However, there are few guidelines to enable clinical interpretation of genetic variation in these highly repetitive genomic regions, and the enthusiasm of the field in adopting lrGS has made it difficult to assess the true added diagnostic yield of this technology due to widely variable and inconsistently applied analytic pipelines and variable degrees of pre-screening by ES or srGS. Here, we investigated the contribution of SVs to rare diseases using srGS as a front-line strategy when paired with highly sensitive SV discovery and evaluate the added diagnostic yield of incorporating lrGS for a subset of cases. Our srGS analysis encompassed 1,462 families (3,450 individuals) recruited through the Broad Institute Center for Mendelian Genetics and the Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) programs. Diagnostic SVs were identified in 5.4% of cases (79/1,462), of which 80% were uniquely detectable by srGS compared to standard cytogenetic techniques. For 96 families (including 10 families with a heterozygous variant observed in a known recessive gene of clinical relevance), we performed lrGS with methylation profiling, as well as long-read transcriptomic analyses in a subset of 20 trios. Analyses with lrGS yielded over 25,000 SVs per genome, 63% of which were not captured by srGS, along with an additional ~200 rare SNV/indels per genome not previously captured and 12 differentially methylated regions per genome. Among these, we identified only one diagnostic variant not interpreted by srGS, an apparently mosaic de novo SNV in CASK that was absent in the srGS callset due to allelic imbalance. No new diagnoses were supported by long-read transcriptomics or episignatures. In this well characterized rare disease cohort, the added diagnostic yield was thus 1.04% (1/96 families). Following a systematic literature review of prior lrGS studies, we find that most reported diagnoses were detectable by srGS and that our added diagnostic yield is consistent with those prior studies. These studies emphasize the significant impact of comprehensive SV discovery in rare disease cases and further demonstrate the power for increased discovery of novel genomic variation and episignatures from lrGS. Nonetheless, they also serve to temper expectations of dramatic diagnostic advances in rare disease patients until there is more extensive annotation of the functional and clinical impact of all coding and noncoding variation uniquely accessible to lrGS with extensive reference databases spanning highly repetitive genomic sequencing that could be enabled by this transformative technology.

22.
arXiv (quant-ph) 2026-06-11

Quantum repeater segment with free-space coupled co-trapped ions using telecom photon interference

arXiv:2606.12313v1 Announce Type: new Abstract: A quantum repeater segment is a basic building block of a quantum repeater, generating buffered entanglement of quantum memories to connect quantum repeater cells. It also enables the connection between quantum computers. In the implementation we present here, photons emitted from two co-trapped free-space coupled $^{40}$Ca$^+$ ions are converted to the telecom-C band and interfered after transmission over 440$\,$m of optical fiber (220$\,$m per arm), where a photonic Bell measurement is performed to create entanglement between the memories. With this scheme we generate an entangled $\left|\Psi^+\right\rangle$ Bell state with $\ge 68(8)\,$% fidelity, highlighting trapped $^{40}$Ca$^+$ ions as a promising quantum repeater hardware platform.

23.
bioRxiv (Bioinfo) 2026-06-11

inquiSTR: a toolkit for accurate and efficient population-scale tandem repeat genotyping and analysis

Tandem repeats are highly mutable genomic elements linked to human traits and diseases. Profiling large catalogs of tandem repeats from population-scale long-read sequencing data requires accurate and efficient tools. We introduce inquiSTR, a command-line toolkit for fast genome-wide tandem repeat length genotyping. inquiSTR, with efficient parallel processing and low-memory streaming algorithms, genotypes a genome-wide repeat catalog of 1.78 million loci in less than two minutes. Benchmarking shows high accuracy and significantly faster performance compared to existing tools and truth sets. inquiSTR also provides methods for downstream analyses such as population structure inference, association testing, and outlier detection.

24.
medRxiv (Medicine) 2026-06-15

Evaluation of AI-Generated Synthetic Data for Clinical Research in Secondary Cardiovascular Prevention among Dyslipidemia Patients

Background: Access to high-quality clinical data is essential for advancing medical research and developing effective medical statistical and Artificial Intelligence models. However, privacy regulations and logistical barriers often hinder timely access to real-world data. Synthetic data offer a promising solution, preserving the statistical characteristics of original datasets while protecting patient privacy. Objectives: This study investigates the use of synthetic data for secondary cardiovascular prevention in patients with dyslipidemia, using two real-world datasets from Centro Cardiologico Monzino. Methods: Given the high dimensionality and limited sample size of the datasets, we employed a custom generative framework based on Large Language Models (LLMs). Pre-trained LLMs were fine-tuned on original clinical records to synthesize tabular data replicating source-data distributions. Fine-tuning was performed within the Centro Cardiologico Monzino's secure infrastructure to ensure data sovereignty. We evaluate clinical utility and privacy using fidelity and privacy metrics, identifying the optimal generative model and benchmarking against traditional anonymization methods. Results: Synthetic data achieved a superior trade-off than classically anonymized datasets. Real and synthetic datasets showed strong agreement, with significant distributional differences limited to few variables. Models trained on synthetic data replicated key associations from the original dataset, including therapy modification and creatine phosphokinase as predictors of SAMS, and pharmacological intensity as the main driver of LDL-C reduction. Conclusions: Results support the feasibility of using synthetic data as a proxy for real-world datasets in exploratory analyses and model development. Despite slight attenuation of some effect sizes, preserved clinical relationships reinforce the validity of synthetic data in medical research.

25.
arXiv (CS.AI) 2026-06-24

Detecting AI Coding Agents in Open Source: A Validated Multi-Method Census of 180 Million Repositories

arXiv:2606.24429v1 Announce Type: cross Abstract: Generative AI coding agents are entering the open-source supply chain, yet their diverse and often invisible traces leave their prevalence poorly understood. We introduce a multi-layered detection framework that integrates configuration-file scanning, commit-message analysis, author-identity matching, and bot-signature lookup across World of Code (180M+ Git repositories), classifying agent traces into four behavioral types. No single method captures more than a fraction of activity: multi-method detection identifies 850,157 Claude Code commits in one snapshot, of which bot-account lookup_the signal most adoption studies rely on_recovers only 28,154 (3.3%), a 30x relative-recall gap, so single-signal prevalence estimates are biased low by at least this factor. Every detection pattern is hand-validated (495 labels) with per-cell precision and Wilson confidence intervals. Across snapshots from December 2024 to April 2026, commit-attributed agents generate over 320,000 commits per month; Claude Code leads (886,122 commits across 17,295 projects) and dominates silent, configuration-file-only adoption (21,078 projects). Compared against an independent pull-request census (AIDev), the two channels capture nearly disjoint agent populations_a PR census misses 79% of commit-detected Claude Code adopters and essentially all Codex adopters_and different kinds of work: PR-deployed cloud agents (Codex, Cursor) surface as feature work, while commit-deployed in-editor agents (Claude Code, OpenHands, Aider) surface as maintenance. The observed work profile follows deployment and detection mode rather than the tool itself, so no single channel is representative.