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01.
arXiv (CS.CL) 2026-06-18

MORTAR: Multi-turn Metamorphic Testing for LLM-based Dialogue Systems

With the widespread application of LLM-based dialogue systems in daily life, quality assurance has become more important than ever. Recent research has successfully introduced methods to identify unexpected behaviour in single-turn testing scenarios. However, multi-turn interaction is the common real-world usage of dialogue systems, yet testing methods for such interactions remain underexplored. This is largely due to the oracle problem in multi-turn testing, which continues to pose a significant challenge for dialogue system developers and researchers. In this paper, we propose MORTAR, a metamorphic multi-turn dialogue testing approach, which mitigates the test oracle problem in testing LLM-based dialogue systems. MORTAR formalises the multi-turn testing for dialogue systems, and automates the generation of question-answer dialogue test cases with multiple dialogue-level perturbations and metamorphic relations (MRs). The automated MR matching mechanism allows MORTAR more flexibility and efficiency in metamorphic testing. The proposed approach is fully automated without reliance on LLM judges. In testing six popular LLM-based dialogue systems, MORTAR reaches significantly better effectiveness with over 150\% more bugs revealed per test case when compared to the single-turn metamorphic testing baseline. Regarding the quality of bugs, MORTAR reveals higher-quality bugs in terms of diversity, precision and uniqueness. MORTAR is expected to inspire more multi-turn testing approaches, and assist developers in evaluating the dialogue system performance more comprehensively with constrained test resources and budget.

02.
medRxiv (Medicine) 2026-06-19

A soluble bi-specific fusion protein for the improved expansion of human CD8+ CAR-T cells

The success of Chimeric Antigen Receptor (CAR) T cell therapy is heavily dependent on the quality of the final cellular product. Current expansion protocols often rely on reagents that require removal from cell culture media, posing logistical challenges in manufacturing, and can also lead to terminal differentiation. Here, we evaluate the use of a soluble, bead-free T cell activator, T cell expansion protein (T-CEP), as a streamlined alternative for generating potent CAR-T cells. Human T cells were activated with T-CEP or known T cell activators (Dynabeads and TransAct) and transduced with either CD19 or interleukin-13 (IL-13) mutein (tetravariant-13; TV-13)-based CAR lentiviral vectors. Our results demonstrate that T-CEP supports robust CAR-T cell expansion and achieves transduction efficiencies comparable to commercial reagents for both types of CAR-T cells. Notably, T-CEP significantly favored the expansion of CD8+ T cells, yielding an enhanced CD27+ phenotype and a lower CD4:CD8 ratio compared to TransAct. Cytotoxicity assays confirmed that T-CEP-expanded CAR-T cells possess cytolytic function equivalent to commercial reagents for both CARs, while exhibiting lower levels of inflammatory cytokine secretion. In summary, T-CEP represents a competitive alternative to existing expansion agents, as it does not require its removal during CAR-T manufacturing and generates a CD8+ dominant, less-differentiated phenotype without compromising efficacy.

03.
bioRxiv (Bioinfo) 2026-06-17

Posterior-calibrated multimodal motor states reveal longitudinal and imaging-associated heterogeneity in Parkinson's disease

Parkinson's disease (PD) motor heterogeneity is commonly summarized by hard subtype labels, although clinical states vary longitudinally, severity can dominate unsupervised structure, and model uncertainty is rarely calibrated. We developed a posterior and refit-stability calibrated multimodal motor state framework that assigns probabilistic MDS-UPDRS-III motor states, aggregates them at the patient level, separates global burden from residual tremor-axial profile, and tests whether imaging can recover the resulting posterior distribution. In 29,366 aligned PPMI motor-posterior visits spanning 4,773 participant identifiers, patient-level state families were stable on average (modal-family fraction 0.925; 95% CI 0.921 - 0.930), but 25.5% of patients transitioned state over follow-up (95% CI 24.1 - 26.7%). PD-only cohort definitions produced smaller denominators and are reported as sensitivity cohorts with rerun calibration and imaging-posterior checks. Severity and covariates explained substantial motor-domain variance, especially bradykinesia (rsecond=0.850), but residual profile modeling retained five active components across total-severity, principal-component, leave-one-domain, non-target-burden, and clinical-only severity axes. Refit-stability calibration with 250 patient-blocked bootstrap refits showed high nominal posterior confidence (0.989) but lower empirical label consistency (0.849), quantifying overconfidence rather than hiding it. Patient-held-out temporal modeling predicted future axial burden (best XGBoost rsecond=0.605) and future state transition (XGBoost AUC=0.830; 95% CI 0.822 - 0.837). DaTSCAN plus FreeSurfer ROI features predicted patient-level soft motor posterior vectors (RF jsd=0.209; 95% CI 0.199 - 0.220; macro-AUROC=0.692), while severity/demographic-adjusted imaging features further improved soft posterior recovery (jsd=0.188). BioFIND transfer reproduced clinically meaningful endpoint gradients after state assignment in 225 external patients, supporting external face validity rather than definitive transportability. These results support PD motor phenotypic states as calibrated, dynamic, clinically interpretable profiles with convergent imaging associations, not as definitive biological subtypes.

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

PreLort: Prefix-Nested LoRA for Federated Fine-Tuning under Rank Heterogeneity

Federated fine-tuning of large language models using parameter-efficient methods such as LoRA enables privacy-preserving adaptation of foundation models. Heterogeneous hardware resources introduce challenges, as clients with different adapter ranks cannot be directly aggregated. While existing methods enable aggregation under heterogeneous ranks, they fail to control how information is distributed across rank dimensions, leading to suboptimal use of shared low-rank representations. Instead, we propose PreLort: a nested low-rank formulation for federated LoRA that organizes adapter dimensions into a prefix hierarchy. Our approach ensures that lower-rank dimensions encode task-relevant information, while higher-rank dimensions capture additional capacity. Building on this, we introduce (i) a segment-wise aggregation rule that averages only over clients contributing to each rank segment, avoiding dilution from zero-padded lower-rank clients, and (ii) a prefix-nested training strategy that optimizes each adapter under multiple rank truncations, encouraging useful signal to concentrate in low-rank prefix dimensions. Together, these components encourage a consistent low-rank prefix capturing the most task-relevant information, while higher-rank dimensions learn additional capacity. This allows low-rank clients to benefit from richer information contributed by higher-rank clients, as prefix dimensions are consistently learned and aggregated. Experiments demonstrate that our method consistently outperforms prior heterogeneous federated LoRA methods in accuracy and ROUGE-L, while achieving lower or comparable perplexity across multiple base models.

05.
arXiv (CS.AI) 2026-06-11

Sparse probes and murky physics: a case study of interpretability challenges in a foundation model for continuum dynamics

arXiv:2606.11657v1 Announce Type: cross Abstract: Generative AI emulators are increasingly used in scientific domains where we already have strong theory, benchmarks, and physical intuition. This raises a central evaluation and interpretability question: when a foundation-style model can reproduce known continuum dynamics, what internal mechanism supports that behavior, is the internal behaviour consistent with known physics, and how does it relate to where the emulator succeeds or fails? We investigate a cross-domain foundation model for continuum dynamics, Walrus by Polymathic, using mechanistic interpretability guided by physical principles. We apply a sparse autoencoder (SAE) to probe a selected layer, and address the practical challenge of triaging a large feature set (over 20,000) using enstrophy as a physically grounded metric. As a deliberately simple testbed, we focus on shear flow and compare feature recruitment across multiple shear-flow setups, i.e. parameter values in the numerical simulation. Across setups we find evidence of piecewise consistency, with subsets of features recurring in similar roles, but this structure is intermittent and does not map cleanly onto standard physical decompositions. In parallel, direct comparisons between numerical simulation and the emulator reveal systematic output-level discrepancies, including regimes where energy/structures become too diffuse or too localized. We connect parts of these discrepancies to changes in specific SAE feature usage. Our work highlights open questions for scientific foundation models: how to robustly prioritize mechanistically meaningful features, how to separate stable structure from analysis artifacts (including single-layer and SAE limitations), and how to use established benchmarks to decide when "different" internal representations are genuinely informative rather than merely effective.

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

Free Heavy-Tailed Lunch for Muon: A Theoretical Justification of Empirical Success

arXiv:2606.14560v1 Announce Type: cross Abstract: Non-Euclidean optimisation methods with matrix-valued updates, such as Muon and Scion, have recently shown strong empirical performance for training Transformer models, yet their theoretical advantages over Euclidean methods remain poorly understood. We address this gap in the heavy-tailed non-convex regime, where stochastic gradients have bounded $p$-th central moments, $p \in (1,2]$. We show that certain non-Euclidean methods achieve optimal sample complexity under stronger stationarity measures, while Euclidean methods incur additional dimension-dependent costs. As a consequence, for $m \times n$ matrices, Muon finds an $\varepsilon$-stationary point in nuclear norm within $\mathcal{O}\left(\min\{m, n\} \frac{\Delta_1 L}{\varepsilon^2} \left(\frac \sigma \varepsilon \right)^{\frac p {p-1}}\right)$ samples, absorbing heavy-tailed noise without extra dimension dependence, unlike Euclidean methods. We further prove this sample complexity, including its dimension dependence, is optimal for all first-order methods under nuclear-norm stationarity. Experiments on large language models support our theory. Surprisingly, our results suggest that other Schatten geometries beyond the spectral geometry of Muon can perform competitively in certain settings.

07.
arXiv (CS.AI) 2026-06-16

MADAR: An Address-Free Processor

arXiv:2606.15535v1 Announce Type: cross Abstract: In a modern processor, computing is the cheap part. Most of its area and energy go to addressing – moving operands to and from a register file and cache, and running the tags, ports, miss queues, and bypass networks that find a value where it was left. MADAR deletes that machinery by abolishing the address. All state circulates in rings of slots that advance one position per clock; instructions and data ride in the same slots; a value is named by its place in an orbit – a \rp{} coordinate – not by an address; a fixed station computes when a circulating instruction sweeps past its operands, on a schedule set at compile time; and a hierarchy of rings of increasing period replaces the cache hierarchy, movement between them scheduled rather than triggered by a miss. No prior circulating-store, dataflow, or statically scheduled machine combines all four of these. We define the execution model, validate it in a cycle-accurate register-transfer-level implementation, show it compilable – a constructive scheduler emits programs cross-checked against the implementation – and price it with a first-order energy model. The payoff is clearest for AI acceleration: the multiply-accumulate at the heart of every matmul and convolution compiles to a streaming form whose energy per operation stays flat as the reduction grows, and the operand reuse that makes matrix multiplication efficient is carried by the ring-period hierarchy – the memory hierarchy doing by rotation what a cache does by tags. MADAR is a new design point for any computation whose data movement is known before the program runs.

08.
arXiv (CS.CL) 2026-06-15

SANA: What Matters for QA Agents over Massive Data Lakes?

Exploratory question answering (EQA) over data lakes requires an LLM agent to discover relevant sources, analyze retrieved data, and adapt its actions based on intermediate results. End-to-end accuracy alone cannot distinguish failures in search, planning, data analysis, or the agent's Action Policy: its decisions about what to do next and when to submit an answer. We present SANA (Search Agent Navigation Ablation framework), a diagnostic ablation framework that transforms EQA tasks into runtime profiles containing gold source sequence, sanitized subquestions, and execution records. SANA uses these profiles to construct idealized search, planning, and data-analysis tools, allowing each component to be ablated; the residual gap is diagnostic evidence for policy failures. To illustrate SANA as a reusable evaluation framework, we adapted two recent EQA benchmarks, LakeQA and KramaBench, and evaluated lightweight and mid-sized agents under fixed prompts, budgets, data lakes, and runtimes. Across both benchmarks, data analysis is a consistent bottleneck while planning is less so. Search is a major limitation in LakeQA's large data-lake setting, but less so for the smaller-scale KramaBench. SANA thus deconstructs end-to-end task accuracies into a diagnosis of where data-lake agents fail, and allows for systematic comparisons of progress in search, planning, data analysis, and agent design.

09.
arXiv (CS.AI) 2026-06-15

HarnessX: A Composable, Adaptive, and Evolvable Agent Harness Foundry

arXiv:2606.14249v1 Announce Type: new Abstract: AI agent performance depends critically on the runtime harness, comprising the prompts, tools, memory, and control flow that mediate how a model observes, reasons, and acts. Yet today's harnesses remain largely hand-crafted and static: each new model or task still demands bespoke scaffolding, and the rich traces produced during execution are rarely distilled back into systematic improvement. We introduce HarnessX, a foundry for composable, adaptive, and evolvable agent harnesses. HarnessX assembles typed harness primitives via a substitution algebra, adapts them through AEGIS, a trace-driven multi-agent evolution engine grounded in an operational mirror between symbolic adaptation and reinforcement learning, and closes the harness-model loop by turning trajectories into both harness updates and model training signal. Across five benchmarks (ALFWorld, GAIA, WebShop, tau^3-Bench, and SWE-bench Verified), HarnessX yields an average gain of +14.5% (up to +44.0%), with gains largest where baselines are lowest. These results suggest that agent progress need not come from model scaling alone: composing and evolving runtime interfaces from execution feedback is an actionable and complementary lever. The complete codebase will be open-sourced in a future release.

10.
arXiv (CS.CL) 2026-06-18

As Easy as Rocket Science: Assessing the Ability of Large Language Models to Interpret Negation in Figurative Language

Figurative language and negation are two areas that challenge current language models, however, both are widely used throughout written and spoken language. Large language models (LLMs) are also widely used in everyday contexts where they cannot necessarily be tuned for a specific dataset. It is therefore essential to understand the ability of LLMs to correctly interpret text that includes both negation and figurative language. To investigate this, we develop a set of new annotations to an existing dataset of figurative language, and test a range of language models on the dataset. We find that the combination of negation and figurativeness can present a particular challenge, and that performance overall and across different negation types is particularly dependent on the prompt style used.

11.
arXiv (CS.AI) 2026-06-19

FreeStyle: Free Control of Style-Content Dual-Reference Generation from Community LoRA Mining

arXiv:2606.20506v1 Announce Type: cross Abstract: Style-content dual-reference generation aims to synthesize an image that preserves the structure and semantics of a content reference while adopting the style of a separate style reference.Despite recent progress, this setting remains challenging because models must balance content fidelity, style alignment, and instruction following avoiding semantic leakage from the style reference.A key bottleneck is the lack of large-scale triplet data with clean content-style separation and broad long-tail style coverage.In this work, we propose FreeStyle, a scalable dual-reference generation framework based on community LoRA mining.We treat community LoRAs as compositional anchors for style and content, and design a rigorous generation and filtering pipeline to construct large-scale Style-Reference and Content-Reference triplets across multiple base models.To address content leakage, we adopt a two-stage curriculum with stage-specific disentanglement mechanisms: an attention-level enrichment constraint that suppresses style-reference leakage in the style-transfer stage, and a frequency-aware RoPE modulation strategy that targets positional-correspondence-based leakage in the harder dual-reference stage.We also introduce a benchmark covering both style-reference and dual-reference generation, with evaluations on style similarity, content preservation, aesthetics, instruction following, and leakage rejection. The benchmark incorporates a style-invariant Content Alignment Score (CAS) and introduces a calibrated VLM-based Rejection Score for evaluating generation reliability and leakage suppression.Extensive experiments show that our model achieves a strong balance among style alignment, content preservation, and leakage suppression.

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

Machine-learning clustering of close-in exoplanet populations: links to pebble accretion

arXiv:2606.11737v1 Announce Type: cross Abstract: Close-in exoplanets exhibit a wide range of orbital architectures and physical properties shaped by both formation conditions and migration processes. Although population-synthesis models predict distinct planetary populations, establishing a quantitative connection between observed exoplanets and synthetic populations remains challenging. We investigate the intrinsic organisation of close-in exoplanets using physically motivated dynamical parameters and connect the resulting populations to pebble-accretion formation pathways. A two-stage Gaussian mixture model (GMM) is applied to an observed sample of close-in exoplanets, performing unsupervised probabilistic clustering in a feature space dominated by dynamical descriptors of planet-star interactions. The resulting clusters are mapped onto a pebble-accretion synthetic population within a statistically motivated three-dimensional parameter space. Formation-related quantities, including gas availability, gas fraction, and ice-rock mass ratio, are then used to interpret the mapped populations. We identify statistically supported sub-populations without imposing predefined classification boundaries, including very-massive gas giants, hot giants, warm-Jupiter-dominated systems, and lower-mass giants. The mapped synthetic populations reveal systematic differences in formation timing, gas accretion, and solid growth histories. In particular, very-massive gas giants are preferentially associated with earlier formation epochs than hot-giant and warm-Jupiter-dominated populations. These results demonstrate that physically motivated machine-learning approaches can provide a statistically robust framework for linking observed exoplanet populations to theoretical planet formation pathways.

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

Empirical Study of Pop and Jazz Mix Ratios for Genre-Adaptive Chord Generation

Authors:

arXiv:2605.04998v2 Announce Type: replace-cross Abstract: This revision updates a pop-to-jazz chord-generation rehearsal study. Best-epoch metrics still show that modest pop rehearsal preserves pop accuracy while improving jazz prediction, but v2 corrects released-checkpoint selection: the released F1 equals Phase 0, F2 had a transcription error, and ft-pop80-v2 restores a hash-distinct jazz-adapted F1 across 3 seeds.

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

QueryGaussian: Scalable and Training-Free Open-Vocabulary 3D Instance Retrieval

arXiv:2606.19733v1 Announce Type: cross Abstract: Efficiently retrieving specific 3D instances from large-scale scenes via natural language prompts remains a formidable challenge in multimedia analysis. Existing approaches predominantly follow a "scene-level embedding" paradigm, which requires distilling high-dimensional semantic features into every 3D primitive. This strategy suffers from a fundamental architectural bottleneck: memory and computational costs scale linearly with scene complexity, inevitably triggering out-of-memory (OOM) failures in city-scale environments. To address this barrier, we propose QueryGaussian, a training-free framework for expeditious and scalable open-vocabulary 3D instance retrieval. Unlike holistic semantic distillation, QueryGaussian employs an instance-level query mechanism that decouples semantic understanding from geometric representation. Specifically, we leverage pre-trained 2D vision models to interpret user prompts and lift segmentation masks into 3D via a concurrent maximum-weight association strategy, ensuring semantic-visual consistency. To mitigate projection ambiguity, we introduce a temporal fusion module with multi-stage adaptive density clustering. Experimental results demonstrate that QueryGaussian not only matches the accuracy of state-of-the-art methods but also delivers a decisive efficiency leap, reducing GPU memory usage by over 70% and accelerating inference by 180x. Crucially, QueryGaussian enables expeditious instance retrieval on city-scale scenes containing tens of millions of Gaussians using consumer-grade hardware.

15.
Nature (Science) 2026-06-15

Nanocrystal-tailored recombination for all-perovskite tandem solar modules

Authors:

The commercialization of all-perovskite tandem solar modules is hindered by the reliance on the conventional gold-based tunnel recombination junction (TRJ)1,2. Specifically, this TRJ introduces substantial near-infrared parasitic absorption3 and suffers from interfacial instability4, limiting both photocurrent generation and operational durability. Here, we develop a solution-processed interconnecting layer based on surface-engineered indium oxide (In2O3) nanocrystals featuring high optical transparency, wherein controlled nanocrystal morphology and tailored ligand chemistry enable smooth interfacial contact and favorable energy level alignment. Critically, we introduce a phosphonic acid additive into the lead–tin (Pb–Sn) perovskite precursor, which synergistically improves the electronic contact with the In2O3 recombination layer, thereby enhancing hole extraction. In addition, the additive regulates perovskite crystallization to mitigate residual strain during film formation, ensuring high-quality large-area deposits. This coordinated interfacial and crystallization engineering strategy simultaneously enhances carrier recombination efficiency at the interconnection layer, improves carrier extraction, and promotes large-area film uniformity in all-perovskite tandems. As a result, a 65-cm2 all-perovskite tandem solar module achieves a certified power conversion efficiency of 26.2%5, with an open-circuit voltage of 2.182 V, a fill factor of 77.4%, and a short-circuit current density of 15.6 mA cm-2 in terms of averaged subcell performance, measured by Japan Electrical Safety and Environment Technology Laboratories (JET). This marks a significant advance toward scalable perovskite tandem photovoltaics.

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

EPM-JEPA: Operator-Side Experience Modulation in JEPA-Family World Models

Authors:

arXiv:2606.12979v1 Announce Type: new Abstract: JEPA-family world models use a static predictor whose weights do not adapt when test-time dynamics diverge from training. We compare two mechanisms for incorporating accumulated experience into a JEPA predictor under distribution shift: operand-side injection, where a compressed experience representation is added as a residual to the predictor's hidden state (EI-JEPA), and operator-side modulation, where the same representation generates low-rank weight deltas via LoRA applied to the predictor's weights (EPM-JEPA). On a pre-registered comparison (Moving MNIST, gravity shift), EPM-JEPA (D_shift^{n=50} = 0.7848 +/- 0.0078, three seeds) differs from EI-JEPA (0.8238) by delta = 4.74% - Outcome C: a null result - by our stated criterion, a valid outcome. As a secondary, non-pre-registered observation, EPM-JEPA improves 1.90% over a no-memory baseline (0.8000), consistently across seeds, while EI-JEPA underperforms the baseline, indicating the benefit is specific to weight-level modulation. Our primary contribution is a mechanism analysis: the D_shift^{n=50} trajectory reflects three independent dynamical processes - buffer cycling, EMA target drift, and an intrinsic LoRA settling transient of +0.021 - rather than convergence to equilibrium. These findings motivate PEM-JEPA, a physics-grounded successor addressing this dynamical-peak limitation.

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

Real-Time Execution with Autoregressive Policies

arXiv:2606.13355v1 Announce Type: cross Abstract: Real-time execution, enabled by asynchronous inference that ensures both smooth action trajectories and fast reactivity, is critical for realistic deployments of large-scale Vision-Language-Action models. However, recent work on real-time execution primarily focuses on variants of diffusion policies, even though it is more critical for autoregressive policies given their slower rollout speed in synchronous inference. In contrast, we demonstrate that autoregressive policies can achieve real-time execution by adjusting the tokenization horizon and applying constrained decoding, thereby guaranteeing strict latency bounds that enable multi-trajectory decoding to maximize performance. Across simulated and real-world environments, we find that the autoregressive policy consistently outperforms its equivalent-level flow-matching policy counterpart while achieving significantly improved task completion speeds from synchronous inference. Coupled with the inherent advantages of autoregressive policies, such as faster convergence and better generalizability in instruction-following, these results confirm that autoregressive policies can remain a competitive policy type supporting real-time execution.

18.
arXiv (math.PR) 2026-06-16

A 0-1 Law for Multifractal Spectra via the HGDS Scale Derivative

arXiv:2606.15850v1 Announce Type: new Abstract: We prove that the multifractal spectrum D(h,omega) of a stochastic process is almost surely deterministic under a scale decorrelation condition on the HGDS scale derivative. The key difficulty is that the pointwise Hölder exponent lives in the germ sigma-algebra, where classical 0-1 laws do not reach. We get around this by working with the geometry accumulation integral G_Lambda, which is a genuine Lebesgue integral over scales and concentrates almost surely. The boundary case – log-correlated fields – is sharp: the variance summability condition fails exactly there.

19.
arXiv (CS.CL) 2026-06-11

Sonar-TS: Search-Then-Verify Natural Language Querying for Time Series Databases

Natural Language Querying for Time Series Databases (NLQ4TSDB) aims to assist non-expert users retrieve meaningful events, intervals, and summaries from massive temporal records. However, existing Text-to-SQL methods are not designed for continuous morphological intents such as shapes or anomalies, while time series models struggle to handle ultra-long histories. To address these challenges, we propose Sonar-TS, a neuro-symbolic framework that tackles NLQ4TSDB via a Search-Then-Verify pipeline. Analogous to active sonar, it utilizes a feature index to ping candidate windows via SQL, followed by generated Python programs to lock on and verify candidates against raw signals. To enable effective evaluation, we introduce NLQTSBench, the first large-scale benchmark designed for NLQ over TSDB-scale histories. Our experiments highlight the unique challenges within this domain and demonstrate that Sonar-TS effectively navigates complex temporal queries where traditional methods fail. This work presents the first systematic study of NLQ4TSDB, offering a general framework and evaluation standard to facilitate future research.

20.
medRxiv (Medicine) 2026-06-11

Plasma protein prioritisation in rheumatoid arthritis reveals druggable targets and shared biology with cardiovascular diseases

Abstract Background Rheumatoid arthritis (RA) is an autoimmune inflammatory disease with complex and incompletely understood molecular mechanisms. Understanding circulating proteins associated with RA may improve understanding of disease biology and clarify its pathological links with cardiometabolic comorbidities. Methods A proteome-wide two-sample Mendelian randomisation (MR) drug target analysis was conducted using plasma proteins measured in 54,219 participants from the UK Biobank Pharma Proteomics Project as exposures and RA and cardiometabolic diseases as the outcomes. Summary statistics for RA included 53,663 cases and 1,070,200 controls. Colocalisation analysis was performed to confirm shared single causal variants and prioritise RA proteins supported by both MR and colocalisation. The prioritised proteins were then evaluated in the Accelerating Medicines Partnership RA Phase II synovial single-cell dataset for cell-type expression patterns. Druggability was then assessed followed by analysis of genetic overlap between RA-associated proteins and cardiometabolic diseases. Results 37 plasma proteins had a causal effect on RA risk, supported by combined evidence from MR and conditional colocalisation. In synovial tissue, TPPP3, RARRES2, AKAP12, and GGT5 were predominantly expressed in stromal and endothelial cell clusters. Druggability assessment identified IFNGR2, IL6R, CD40, and FCGR2B as Tier 1 targets. However, several biologically relevant proteins, including RARRES2, AKAP12, TPPP3, and SNX2, had limited available druggability data. Genetic overlap analysis demonstrated shared protein signals between RA and cardiovascular diseases, including overlap of RARRES2 and TPPP3 with coronary artery disease (CAD) and FCGR2B with atrial fibrillation (AF). To approximate the therapeutic effect of target inhibition, the direction of effect estimates for proteins showing overlap between RA-CAD and RA-AF was reversed. Conclusion This study identified circulating proteins involved in RA pathogenesis and reveals shared mechanisms between RA and cardiovascular diseases. While some proteins showed clear translational potential targets, several prioritised proteins had limited available druggability information and could not be confidently classified. Addressing these gaps may help identify new targets relevant to RA management. Future work should also use phenome-wide MR studies to evaluate potential on-target adverse effects of protein inhibition across RA-CAD and RA-AF.

21.
medRxiv (Medicine) 2026-06-22

Histologically validated diffusion MRI signatures of neuroinflammation and neurodegeneration in Alzheimer disease

Noninvasive neuroinflammation measurement remains a major barrier for Alzheimer disease (AD) therapeutics. We present generalized diffusion basis spectrum imaging (g-DBSI), a diffusion MRI framework that decomposes the tissue signal into biologically interpretable microstructural compartments. In postmortem Knight ADRC brains, g-DBSI-derived restricted isotropic fraction (RIF) and restricted anisotropic fraction (RAF) mapped cellularity and neurofilament density, while their ratio (RIF/RAF) tracked inflammatory cell density and peri-plaque amyloid-beta with higher specificity and regional consistency than RIF alone. In 112 living Knight ADRC participants stratified by PET amyloid, g-DBSI metrics showed amyloid-dependent trajectories: in low-amyloid individuals, RIF and RAF rose together with amyloid, consistent with early neuropil expansion and glial elaboration, whereas in high-amyloid individuals, RIF/RAF increased, and RAF declined, indicating established neuroinflammatory remodeling and neurofilament loss. CSF proteomics linked RIF/RAF to glia-enriched immune and vascular pathways, supporting g-DBSI as a clinically compatible MRI biomarker of neuroinflammation and neurodegeneration in AD.

22.
arXiv (CS.AI) 2026-06-19

Can In-Context Learning Support Intrinsic Curiosity?

arXiv:2606.19476v1 Announce Type: cross Abstract: Effective machine learning depends not only on how we model data, but also on what data we choose to collect. While large sequence models have revolutionized data modeling, the problem of automated data selection, or "intrinsic curiosity", remains a significant challenge. Classic approaches incentivize exploration by rewarding an agent based on its "learning progress", which measures how much a newly acquired observation improves a world model's predictive ability. However, evaluating these rewards traditionally requires expensive inner loops of gradient descent updates within each trajectory, rendering them computationally impractical at scale. In this work, we investigate whether the emergent in-context learning (ICL) capabilities of sequence models can eliminate this bottleneck by serving as immediate, update-free world models. Specifically, we evaluate whether an exploration policy can be trained to maximize learning progress, using solely the prediction errors and counterfactual context manipulations of an in-context learner. We first prove that in general Markov decision processes, this is in fact impossible in an unbiased way: the resulting intrinsic rewards either suffer from nuisance terms that bias their estimation of true learning progress, or they cannot be implemented using an in-context learner's prediction errors. Conversely, we prove a positive result for a broad subclass of non-temporal settings, encompassing active learning and Bayesian Experimental Design: here, ICL-derived rewards successfully bound and asymptotically converge to the true learning progress. We corroborate our theory with controlled experiments across continuous and symbolic environments, demonstrating that our ICL-driven framework successfully trains curious data-collection policies that explore optimally.

23.
arXiv (CS.CV) 2026-06-16

WaveDINO: Learning-Based Atmospheric Correction of Unwrapped InSAR Interferograms Validated by GNSS: Results at Laguna del Maule and Campi Flegrei Volcanoes

Interferometric Synthetic Aperture Radar (InSAR) enables effective monitoring of volcanic deformation; however, the observed signals are often corrupted by atmospheric phase delays, seasonal surface changes, and decorrelation effects. Existing atmospheric correction methods, such as numerical weather model-based methods, can reduce these effects but do not consistently remove atmospheric artefacts and may introduce residual biases. To address these limitations, we propose a novel learning-based method for denoising unwrapped InSAR interferograms, using a hybrid training strategy that combines physically motivated synthetic deformation with real atmospheric noise. Specifically, we introduce WaveDINO, a wavelet-based multi-scale denoising framework conditioned on frozen DINOv3 foundation-model features and terrain information. Training uses synthetic magma-source deformation superimposed on short-term interferograms to expose the network to realistic atmospheric statistics while retaining known ground truth. Performance is evaluated on both controlled synthetic data and long-term real interferograms from Laguna del Maule (Chile) and Campi Flegrei (Italy), with independent GNSS measurements used for validation. WaveDINO consistently outperforms competing models, improving agreement with GNSS measurements, and reducing mean GNSS misfit by approximately 3% and 19% at two sites, respectively, while surpassing weather-model-based corrections.

25.
medRxiv (Medicine) 2026-06-18

Excess mortality in Germany during 2020-2023: A descriptive age-stratified analysis

Authors:

This study investigates excess mortality in Germany in the years from 2020 to 2023 and its temporal alignment with reported COVID-19 deaths. The analysis uses annual and weekly all-cause mortality data and linear baseline trends derived from pre-pandemic years. Possible effects of demographic and population changes on baseline trends were also examined. Excess mortality was analysed over time and across age groups. Excess mortality was observed in all investigated years, rising from 2020 to its highest value in 2022. In absolute terms, the age group [≥]80 years accounted for the largest proportion of excess deaths throughout the study period. After 2021, elevated mortality relative to baseline was also observed in younger age groups down to 15 years of age, although absolute numbers remained substantially lower than in older groups. No evidence of excess mortality was observed for individuals younger than 15 years. Periods of excess mortality were temporally aligned with waves of reported COVID-19 deaths. In 2020, cumulative excess mortality after calendar week 11 closely matched reported COVID-19 deaths (43 876 vs. 41 835 deaths). Weekly excess mortality, reported COVID-19 deaths and wastewater viral load, when available showed strong temporal synchrony, although excess mortality increasingly exceeded reported COVID-19 deaths during later pandemic waves. Temporal patterns differed from the typical seasonal mortality peaks commonly associated with influenza epidemics during the early months of the year. In 2023, excess mortality declined substantially, possibly indicating a return to mortality levels before the emergence of SARS-CoV-2.