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01.
arXiv (CS.AI) 2026-06-11

CredibleDFGO: Differentiable Factor Graph Optimization with Credibility Supervision

arXiv:2605.06100v2 Announce Type: replace-cross Abstract: Global navigation satellite system (GNSS) positioning is widely used for urban navigation, but the covariance reported by the GNSS solver is often unreliable in urban canyons. Existing differentiable factor graph optimization (DFGO) methods learn measurement weighting through the solver, but they still use position-only objectives. As a result, the position estimate may improve while the reported covariance remains too small, too large, or incorrectly oriented. We propose CredibleDFGO (CDFGO), a differentiable GNSS factor graph framework that makes covariance credibility an explicit training target. A Weighting Generation Network (WGN) predicts per-satellite reliability weights, and a differentiable Gauss-Newton solver maps these weights to a position estimate and a Hessian-derived posterior covariance. We use proper scoring rules to supervise the East-North predictive distribution end to end. We study negative log-likelihood (NLL), the energy score (ES), and their combination. Results on three UrbanNav test scenes show consistent gains in covariance credibility. Positioning accuracy also improves on the medium-urban and harsh-urban scenes; on the deep-urban scene, both the mean horizontal error and the 95th-percentile error improve. On the harsh-urban Mong Kok (MK) scene, CDFGO-Combined reduces the mean horizontal error from 13.77 m to 11.68 m, reduces NLL from 40.63 to 6.59, and reduces ES from 12.31 to 9.05 relative to DFGO (MAE). Case studies link the MK improvement to better axis-wise consistency, more credible local covariance ellipses, and satellite-level reweighting.

02.
arXiv (CS.AI) 2026-06-19

IHBench: Evaluating Post-Interruption Recovery in Voice Agents with Structured Workflows

arXiv:2606.19595v1 Announce Type: cross Abstract: Voice agents deployed in structured workflows (customer service, healthcare scheduling, account management) must handle frequent user interruptions while maintaining progress through multi-step procedures. Existing benchmarks for speech-capable models focus on the timing of interruptions: barge-in detection, endpointing, and turn-taking dynamics. They leave unmeasured what happens after the interruption: does the agent resume the workflow at the correct step? Does it address the user's interjection? Does it avoid re-delivering content the user already heard? We introduce IHBench (Interruption Handling Benchmark), a benchmark that evaluates post-interruption recovery in voice agents executing state-machine-driven workflows across 10 enterprise domains. Six interruption types are injected at controlled points mid-utterance, with per-interruption evaluation rubrics generated alongside the data. Each interruption is scored on two axes: task fulfillment and recovery quality. We evaluate 27 audio-language model configurations from OpenAI, Google, and the open-weight community. Models vary widely, and recovery quality depends strongly on the interruption type. Across our experiments, closed-weight models are consistently more robust to interruptions than open-weight ones: they win far more often on task fulfillment, degrade roughly 3.3x more slowly as conversations grow longer, and show no audio-versus-text modality gap, whereas the open-weight models lose ground on all three. A human study validates the LLM judge against human annotators, and a cross-benchmark analysis against AudioMultiChallenge indicates that recovery quality is a largely distinct capability axis.

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

Latent Confounded Causal Discovery via Lie Bracket Geometry

arXiv:2606.19610v1 Announce Type: cross Abstract: Recent work on Kan-Do-Calculus (KDC) has established that the boundary between passive observation and active intervention in causal inference is a category-theoretic bi-adjunction, with interventions modeled by left Kan extensions and conditioning by right Kan extensions. This paper introduces two causal discovery algorithms under latent confounding, building on the information-geometric and categorical consequences of KDC. In smooth statistical settings, Radon-Nikodym derivatives between observational and interventional measures induce local causal vector fields; failures of these fields to close under Lie brackets become computable Frobenius residuals, which we interpret as witnesses of failed visible integrability and possible latent or unmodeled structure. Our first algorithm, BRIDGE (Bracket Residuals for Interventional Discovery and Geometric Estimation), combines an interventional density or Radon-Nikodym-ratio engine with a geometric screen that proposes a high-recall family of admissible arrows, identifies non-closing visible pairs as latent-obstruction candidates, and passes the reduced family to downstream score-based or differentiable discovery routines. The second algorithmic contribution, Spectral Kan-Do Flow Matching (SKFM), learns amortized intervention fields and factors latent curvature spectrally, exposing the direct Lie-space endpoint toward which BRIDGE points. A detailed set of experiments show that both algorithms are capable of discovering causal models with latent confounders while collapsing the super-exponential space of possible DAGs by many orders of magnitude. This paper introduces a new paradigm in causal discovery, where latent structure is inferred directly from the geometry of intervention-induced flows.

04.
arXiv (quant-ph) 2026-06-17

Many-body spectral transitions through the lens of the variable-range SYK2 model

arXiv:2412.14280v2 Announce Type: replace-cross Abstract: The Sachdev-Ye-Kitaev (SYK) model is a cornerstone in the study of quantum chaos and holographic quantum matter. Real-world implementations, however, deviate from the idealized all-to-all connectivity, raising questions about the robustness of its chaotic properties. In this work, we investigate a quadratic SYK model with distance-dependent interactions governed by a power-law decay. By analytically and numerically studying the spectral form factor (SFF), we uncover how transitions present in the single-particle limit carry over to the many-body system. Non-trivial cancellations in the one-loop contributions lead to a robustness of the SFF under a considerable reduction of the interaction range. Further suppression leads to a breakdown of perturbation theory around the infinite-range path-integral saddle and the appearance of new spectral regimes, marked by a higher dip and the emergence of a secondary plateau. Our results highlight the interplay between single-particle criticality and many-body dynamics, offering new insights into the quantum chaos-to-localization transition and its reflection in spectral statistics.

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

Operator Calculus for Population-Based Optimization: A Mean-Field Convergence Theory

arXiv:2606.14289v1 Announce Type: cross Abstract: Population-based and distributional optimization methods, from evolution strategies and consensus-based optimization to covariance-matrix adaptation and stochastic gradient methods viewed as distributional dynamics, are widely used for nonconvex or black-box problems, yet their convergence analyses remain fragmented across algorithm-specific techniques. We introduce an operator calculus in which a broad class of such methods, after choosing an appropriate state space and, where necessary, augmenting the state by memory or strategy variables, is described as a composition of three elementary operators (mutation, selection, and recombination) acting on probability measures. Under explicit stability and regularity conditions, the composite operator admits a pre-generator whose continuous-time limit is a transport-reaction-jump (TRJ) PDE that preserves the operator splitting. On this foundation we establish a modular Lyapunov principle. If a state-space Lyapunov function both dissipates under the full generator and controls the relevant search-space gauges, then the state-space Lyapunov functional and the induced search errors decay exponentially. The additive generator structure allows dissipation estimates to be assembled operator by operator, providing a toolkit for certifying convergence of composite mean-field algorithms.

06.
arXiv (quant-ph) 2026-06-15

Emission of time-ordered photon pairs from a coherently-driven Kerr microcavity

arXiv:2601.06468v2 Announce Type: replace-cross Abstract: Weakly-interacting many-body systems possess remarkable quantum properties that are essential components of quantum technologies, and constitute a topic of fundamental interest. Here we show that in a solid-state nonlinear microcavity embedding discrete modes of exciton-dressed photons, we can isolate a single eigenmode of quantum fluctuations from the much brighter coherent fraction of the field. In this regime, we perform frequency- and time-resolved correlations measurements between photons on the red and blue side of the fluctuations spectrum. When the average number of fluctuation quanta is smaller than one, we observe the formation of large pairwise time-ordered correlations: red photon first and blue photon second. We show that this peculiar time-ordering correlation emerges spontaneously from the interplay between frequency-resolved detection, and the non-trivial internal quantum structure of the elementary fluctuations.

07.
arXiv (CS.LG) 2026-06-12

Optimal Spatio-Temporal Decoupling for Bayesian Conformal Prediction

arXiv:2605.00432v2 Announce Type: replace Abstract: Online conformal prediction must balance fast adaptation to distribution shift against stable coverage: feedback-driven methods react quickly but become volatile, while strongly discounted Bayesian methods lag and inflate intervals at tight coverage. We introduce State-Adaptive Bayesian Conformal Prediction (SA-BCP), which forms the predictive quantile as a gated convex combination of long-term temporal inertia and local spatial evidence from a kernel density estimate, controlled by a single interpretable evidence threshold $K$. We establish three results: (i) asymptotic marginal validity of the resulting intervals; (ii) a closed-form expression for the MSE-optimal threshold, $K^*_{\mathrm{MSE}}=\alpha(1-\alpha)/M^{\mathcal{T}}$, trading the coverage-indicator (Bernoulli) variance against the temporal structural bias $M^{\mathcal{T}}$; and (iii) a rolling-origin procedure for selecting $K$ online – consistent under stationarity, with $O(\sqrt{T\log N})$ regret against the best fixed $K$ and, for a segmented variant, a sublinear dynamic-regret bound under bounded drift. Across four financial-volatility and weather datasets, three target coverage levels, and eight baselines (including the strongest recent conditional-quantile methods, SPCI and KOWCPI), SA-BCP attains at-or-above-nominal coverage in most settings while producing substantially sharper intervals – up to roughly $3\times$ lower Winkler score than discounted Bayesian CP at the tightest coverage – and a coverage-matched audit confirms these efficiency gains are not an artifact of under-coverage. We disclose one principal limitation: a volatility-specialized conformal-GARCH competitor remains more efficient on its home volatility-base series, though it does not transfer across domains.

08.
arXiv (CS.LG) 2026-06-11

Intention Driven Identification of In-Possession Match Phases in Association Football through Temporal Graph Learning

arXiv:2606.09289v2 Announce Type: replace Abstract: Understanding tactical organisation of association football, hereafter referred to as football, requires identifying distinct match phases. Yet in-possession phases are rarely directly observable and are shaped by evolving tactical intentions, rather than spatial patterns alone. This study proposes a data-driven framework for identifying in-possession match phases from spatiotemporal tracking data. Seven German Bundesliga matches recorded at 25 Hz with TRACAB were analysed. A hierarchical phase model was defined with three tactical intentions (Invade Opponent Space, Keep Possession, Scoring) and six phases (Build Up, Progression, Counter Attack, Maintenance, Sustained Threat, Finishing). A Temporal Graph Attention Network (T-GAN) was developed to combine frame-level player-interaction graphs, contextual features, and Transformer-based temporal modelling. Performance was evaluated using frame-level F1 and a sequence-aware Intersection over Truth-Dominance (IoT-D) metric. T-GAN achieved macro-average frame-level F1 scores of 0.87 at the intention level, 0.76 for invasion-related phases, and 0.79 for scoring phases. At the sequence level, mean diagonal IoT-D F1 increased from 0.68 to 0.79 for intentions and from 0.61 to 0.71 for phases after post-processing, indicating improved temporal coherence. Model comparisons showed that sequence modelling was the main driver of segmentation quality, while graph-based relational modelling was particularly beneficial for Counter Attack recognition. Exploratory player attention analysis further suggested that wide and midfield positional groups contributed strongly to phase discrimination. Overall, the framework translates continuous tracking data into tactically interpretable in-possession phase representations, with potential applications in automated match annotation, tactical analysis, and playing-style profiling.

09.
medRxiv (Medicine) 2026-06-13

Projected population level impact and cost-effectiveness of clinic and community-based tuberculosis screening approaches

The South Africa National Department of Health have set ambitious targets to scale up TB testing, focusing primarily on clinic attendees. In the context of declining funding for TB care and prevention, the most cost-effective approaches for targeting testing should be identified. We developed a mathematical model of TB in South Africa, explicitly incorporating clinic attendance by sex and HIV/ART status. We simulated six screening approaches over 2026-2035 (individually and in combination): three clinic-based (symptom screening, intensified targeted universal TB testing [TUTT, symptom-agnostic sputum testing of clinic attendees in key risk groups], and intensified TUTT allowing saliva samples) and three targeted community-based (community radiographic screening, symptom screening, and universal Xpert Ultra testing), each implemented at a range of coverage levels. Model outputs were combined with a mechanistic cost function to estimate potential impact and cost-effectiveness from a societal perspective. The most cost-effective standalone approach was community radiographic screening at 10% annual population coverage, with an incremental cost-effectiveness ratio (ICER) of $421 per disability-adjusted life year (DALY) averted. 10/11 scenarios along the expansion path included community radiographic screening at progressively higher coverage, combined with a clinic-based approach. Combining complementary approaches to reach both groups at increased risk of TB (e.g. clinic-based screening) and groups with lower screening coverage (e.g. community-based screening) may increase cost-effectiveness of TB screening, compared to standalone approaches. When designing TB screening strategies, both population risk and existing screening coverage should be considered.

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

Improve Large Language Model Systems with User Logs

Scaling training data and model parameters has long driven progress in large language models (LLMs), but this paradigm is increasingly constrained by the scarcity of high-quality data and diminishing returns from rising computational costs. As a result, recent work is increasing the focus on continual learning from real-world deployment, where user interaction logs provide a rich source of authentic human feedback and procedural knowledge. However, learning from user logs is challenging due to their unstructured and noisy nature. Vanilla LLM systems often struggle to distinguish useful feedback signals from noisy user behavior, and the disparity between user log collection and model optimization (e.g., the off-policy optimization problem) further strengthens the problem. To this end, we propose UNO (User log-driveN Optimization), a unified framework for improving LLM systems (LLMsys) with user logs. UNO first distills logs into semi-structured rules and preference pairs, then employs query-and-feedback-driven clustering to manage data heterogeneity, and finally quantifies the cognitive gap between the model's prior knowledge and the log data. This assessment guides the LLMsys to adaptively filter out noisy feedback and construct different modules for primary and reflective experiences extracted from user logs, thereby improving future responses. Extensive experiments show that UNO achieves state-of-the-art effectiveness and efficiency, significantly outperforming Retrieval Augmented Generation (RAG) and memory-based baselines. We have open-sourced our code at https://github.com/bebr2/UNO .

11.
arXiv (CS.LG) 2026-06-18

The Chandra-Gaia Catalog of Counterparts: Resolving ambiguous Gaia matches to X-ray sources in the Chandra Source Catalog using Machine Learning

arXiv:2606.19329v1 Announce Type: cross Abstract: We present a framework to cross-match sources from the Chandra Source Catalog (CSC v2.1) with optical sources from Gaia Data Release 3. Unlike purely spatial approaches, we use source properties such as magnitudes, colors, and distances to identify true counterparts, detect chance coincidences, and resolve ambiguities when multiple plausible candidates exist. We define a training set of high-confidence matches using NWAY, a Bayesian cross-matching framework that accounts for positional errors and source densities. We train a gradient-boosted classifier (LightGBM) on a variety of features from both catalogs. Of the ~$254$k unique X-ray sources, we find counterparts for ~$113$k sources, of which plausible multiple counterparts are found for ~$7$k. We find no counterparts for ~$20$k sources for which separation-based cross-matching does find a match, and attribute half of these to chance coincidences. We validate the pipeline on the Chandra Orion Ultradeep Project (COUP), where the machine-learning matches reproduce 95% of NWAY cross-matches without using any positional information. We release a catalog of the ~$113$k Chandra-Gaia counterparts, together with ~$7$k alternative matches and ~$20$k ambiguous NWAY associations, supporting future population studies of sources detectable by both Chandra and Gaia. We discuss limitations and provide a generalization of the framework that is applicable in other cross-matching scenarios.

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

AI4SE and SE4AI Exploration: A Decade Looking Back and Forward

arXiv:2606.19630v1 Announce Type: new Abstract: The March 2020 INCOSE INSIGHT special issue on AI and Systems Engineering (SE) became the most downloaded issue in the publication's history and launched a research community that now draws over 250 registrants to its annual workshop. In this article, we trace the progress in AI and SE across three phases (labeled here foundational, applied, and LLM inflection) based on the authors' reading of the field's core papers, and describe our opinions of where the community has converged and where critical gaps remain. Separately, a human-AI agreement literature review leveraging both human expertise and six AI models was performed to assess the relevance of 1,712 INCOSE INSIGHT articles and 889 SERC publications. The results identify five critical research gaps and offer guidance for practitioners navigating AI adoption, assurance, and workforce transformation in SE. We share the agreement data and the AI4SE/SE4AI Explorer web application so readers can compare their own relevance judgments with the human and AI raters.

13.
arXiv (CS.LG) 2026-06-18

From Mechanistic to Compositional Interpretability

arXiv:2605.08934v2 Announce Type: replace Abstract: Mechanistic interpretability aims to explain neural model behaviour by reverse-engineering learned computational structure into human-understandable components. Without a formal framework, however, mechanistic explanations cannot be objectively verified, compared, or composed. We introduce compositional interpretability, a category-theoretic framework grounded in the principles of compositionality and minimum description length. Compositional interpretations are pairs of syntactic and semantic mappings that must commute to enforce consistency between a model's decomposition and its observed behaviour. We deconstruct explanation quality into measures of faithfulness and complexity to cast interpretability as a constrained optimisation problem, and introduce compressive refinement to systematically restructure models into simpler parts without altering their function. Finally, we derive a parsimony criterion under which syntactic compression theoretically guarantees more concise, human-aligned explanations. Our framework situates prominent mechanistic methods as subclasses of refinement, and clarifies why their compressibility heuristics tend to align with human interpretability. Our work provides a measurable, optimisable blueprint for automating the discovery and evaluation of mechanistic explanations.

14.
bioRxiv (Bioinfo) 2026-06-15

Maternal BMI and Placental Transcriptomic Changes: A Meta-Analysis of Gene Expression at the Maternal-Fetal Interface

Objective: Maternal body mass index (BMI) is often used as a measure of metabolic status and increased or decreased maternal BMI is associated with a heightened risk of cardiometabolic diseases across generations. The placenta mediates these maternal metabolic cues; however, its genome wide transcriptional adaptations in response to maternal BMI remain incompletely defined. Methods: To delineate placental genes, pathways, and interaction clusters whose transcript abundance varies with maternal prepregnancy BMI through a genome wide meta analysis of human placental RNA sequencing datasets. Placental RNA seq reads from four publicly available cohorts (n=146) were mapped to the GRCh38 reference genome and differentially expressed genes were identified. An independent microarray cohort (n=19) was reanalysed separately to facilitate cross platform comparison. Functional enrichment employed GO, KEGG, and STRING protein interaction resources. Results: Meta-analysis of 146 RNA seq samples identified eight genes with genome-wide significance in placentae from underweight pregnancies including inflammatory signaling gene MAP4K1 and metabolic enzyme PSPH, while overweight and obese categories revealed nominally significant differential expression. KEGG analysis demonstrated significant downregulation of oxidative phosphorylation with increasing maternal BMI, and protein-protein interaction networks revealed inflammatory mediators as central nodes in overweight and obese groups. Independent microarray validation corroborated key findings, including consistent downregulation of oxidative phosphorylation in obesity. Conclusion: Maternal BMI is associated with placental transcriptomic signatures involving inflammatory, metabolic, and hormonal pathways, with consistent downregulation of oxidative phosphorylation across platforms. This genome-wide meta-analysis provides a reproducible catalogue of BMI-responsive placental transcripts that may contribute to developmental programming of offspring health.

15.
arXiv (quant-ph) 2026-06-19

Optimal multi-spectral squeezing via deterministic 2D-phase optimization

arXiv:2606.20192v1 Announce Type: new Abstract: Optimization routines are ubiquitous in quantum information technologies and essential to reach the resource levels required by quantum protocols. Specifically, multi-spectral squeezing for use in such protocols requires that losses be kept minimal at every stage, including coherent detection, which is performed by interfering the signal with a classical local-oscillator beam. This in turn requires control over all optical degrees of freedom of the beam in order to optimize the detection. The most general framework for this optimization relies on agnostic, off-the-shelf machine-learning techniques. Here we take the opposite approach: by focusing on a physical description of the specific optical process, we develop a deterministic sequential algorithm that provably reaches the global maximum of the visibility in a pixel basis and scales linearly with the number of pixels, thereby offering an efficient and theoretically grounded alternative to black-box optimization. In our waveguide-based setup, the optimized mask increases the visibility from 76% to 84%, corresponding to a 20% gain in mode-matching efficiency. Multi-spectral squeezing measurements confirm that this improvement translates directly into quantum readout: for the most squeezed spectral mode, the squeezing increases from $-2.08$ dB to $-2.64$ dB, consistent with the inferred efficiency gain. These results establish deterministic spatial phase shaping as an effective, interpretable route to enhanced multimode squeezing in waveguide platforms.

16.
bioRxiv (Bioinfo) 2026-06-11

STITCH links cellular morphology and gene expression in spatial transcriptomics

In situ spatial (ISS) sequencing can uncover co-variation between cellular morphology and gene expression in vivo. However, a principled and interpretable mathematical representation of morphology has not yet been applied in this context. In particular, current deep learning-based representations of cell images confound a cell's shape with its size. We present an interpretable representation of cellular boundary contours, based on tangent principal component analysis (TPCA) in a Kendall shape manifold, that captures size-independent contour shape features. This approach successfully recovers shape-perturbing genes in an RNAi screen than a previous metric geometry-based approach. We build on TPCA to develop STITCH (Shape-TranscriptomIc Correlation and Harmonization), an approach to reveal covariation between cell morphology with gene expression in ISS datasets. In a Xenium dataset, STITCH outperforms a deep learning-based approach in both recovering the layered organization of keratinocytes and a spatial gradient in nuclear eccentricity. Across samples in a melanoma CosMx dataset, STITCH reproducibly associates elongated and triangular fibroblasts with proximity to malignant cells and myofibroblast-like transcriptional program. Finally, STITCH independently recovers a known link between mesenchymal-like malignant cell states and increased cell area in two melanoma cohorts. STITCH can thus yield interpretable morphology-transcriptome relationships across cell types, patients, and spatial transcriptomics platforms.

17.
arXiv (CS.AI) 2026-06-19

Concept Flow Models: Anchoring Concept-Based Reasoning with Hierarchical Bottlenecks

arXiv:2606.19489v1 Announce Type: cross Abstract: Concept Bottleneck Models (CBMs) enhance interpretability by projecting learned features into a human-understandable concept space. Recent approaches leverage vision-language models to generate concept embeddings, reducing the need for manual concept annotations. However, these models suffer from a critical limitation: as the number of concepts approaches the embedding dimension, information leakage increases, enabling the model to exploit spurious or semantically irrelevant correlations and undermining interpretability. In this work, we propose Concept Flow Models (CFMs), which replace the flat bottleneck with a hierarchical, concept-driven decision tree. Each internal node in the hierarchy focuses on a localized subset of discriminative concepts, progressively narrowing the prediction scope. Our framework constructs decision hierarchies from visual embeddings, distributes semantic concepts at each hierarchy level, and trains differentiable concept weights through probabilistic tree traversal. Extensive experiments on diverse benchmarks demonstrate that CFMs match the predictive performance of flat CBMs, while substantially mitigating information leakage by reducing effective concept usage. Furthermore, CFMs yield stepwise decision flows that enable transparent and auditable model reasoning with hierarchical class structures.

18.
arXiv (CS.LG) 2026-06-11

Deep Learning of Solver-Aware Turbulence Closures from Nudged LES Dynamics

arXiv:2604.23874v3 Announce Type: replace-cross Abstract: The differentiable physics paradigm may be leveraged as an a-posteriori approach for discovering turbulence closure models by embedding a neural network parameterization directly inside the solver and optimizing it given potentially sparse target data. This addresses a key limitation of a-priori learning where direct numerical simulation (DNS) data is used to approximate the subgrid stress with the assumption of a low-pass filter. Closures trained in this a-priori manner frequently lead to unstable deployments due to the mismatch between the assumed filter and the effect of numerical discretizations and coarse-graining. In comparison, while typically stable during deployment, a-posteriori learning incurs high computational costs due to the need to backpropagate through a large eddy simulation (LES) solver. Furthermore, a-posteriori methods are challenging to apply broadly since they require significant modification of existing solvers. Finally, both approaches are limited when generalization is desired across different numerical schemes with their implicit filtering characteristics. In this work, we present a deep-learning approach for turbulence closure modeling built on the continuous data assimilation framework. Our approach enables the a-priori training of closures using sparsely observed DNS data without modifying or differentiating through the LES solver, while preserving stability during deployment for the recovery of invariant statistics. We focus on the model's ability to adapt to different discretizations by explicitly conditioning it on the numerical scheme. We use two- and three-dimensional canonical cases to test our framework and show that the learned correction systematically tracks the discretization error of the coarse solver.

20.
medRxiv (Medicine) 2026-06-10

Trajectories of brain structure and function in young adult carriers of genetic frontotemporal dementia variants

Background and Objectives: Converging evidence hints at neurodevelopmental effects in genetic frontotemporal degeneration (FTD). In cross-sectional studies, for some genes, young adult FTD variant carriers show differences in brain volumes and cognition compared to familial non-carriers. However, longitudinal trajectories may more sensitively capture FTD-related neurodevelopmental vs. neurodegenerative changes than cross-sectional approaches. This study examined longitudinal trajectories of brain volumes, executive function, and plasma biomarkers in young adult carriers compared to familial non-carriers, as measures of neurodevelopmental and neurodegenerative outcomes of FTD-causing variants. Methods: This longitudinal cohort study comprised participants, aged 18-30 years, from the FTD Prevention Initiative across Europe, Canada, and the USA. Genetic groups included C9orf72 (47%), MAPT (30%), and GRN (23%). Linear mixed-effects models were computed to assess longitudinal outcomes across age between groups, controlling for sex, scanner (for brain volumes), and education (for executive function); random effects accounted for between-subject variability nested within family membership. Results: Variant carriers (n=147) and familial non-carriers (n=113) did not differ in age (mean{+/-}SD, 25.9{+/-}3.2 years), sex (53% female), or number of visits (2.1{+/-}1.7). Young adult C9orf72 repeat expansion carriers exhibited smaller thalamic volumes than non-carriers at the reference age of 26 years (b=-982.8mm3, SE=317.0, p=0.0046, f2=0.32), with relatively stable trajectories across ages 18-30 (i.e., no change over time). Trajectories of rostral anterior cingulate volumes differed in C9orf72 carriers and non-carriers across age, where carriers showed relatively stable trajectories and non-carriers showed age-appropriate declines (b=64.4mm3, SE=29.9, p=0.035, f2=0.07). For MAPT and GRN, there were little to no differences in total brain, cortical, or subcortical volumes between groups and over time. No longitudinal differences were observed between carriers and non-carriers in executive function, or plasma NfL or GFAP for any genetic group. Discussion: C9orf72 repeat expansions were linked to smaller average thalamic volumes and stable trajectories between ages 18 to 30, supporting potential neurodevelopmental origins. The modest evidence supporting an absence of difference in neurodegenerative biomarkers and executive function suggests minimal early neurodegeneration and functional preservation in young adulthood.

21.
Nature Medicine 2026-06-08

Post-adjuvant chemotherapy in ctDNA-positive patients with resected colorectal cancer: a randomized phase 3 trial

Tumor-informed circulating tumor DNA (ctDNA) enables detection of molecular residual disease (MRD) after curative resection of colorectal cancer (CRC), but whether early intervention improves outcomes remains uncertain. ALTAIR was a randomized, double-blind, phase 3 trial embedded in the CIRCULATE-Japan platform evaluating a post-adjuvant ctDNA surveillance strategy with treatment initiation upon molecular recurrence. Patients with resected stage 0–IV CRC who became ctDNA positive after completion of standard-of-care therapy and had no radiological evidence of disease were randomly assigned (1:1) to receive trifluridine/tipiracil (FTD/TPI) or placebo for 6 months. The primary endpoint was investigator-assessed disease-free survival (DFS). Between July 2020 and June 2023, 243 patients were randomized to FTD/TPI (n = 122) or placebo (n = 121). Median DFS was 9.30 months with FTD/TPI and 5.55 months with placebo (hazard ratio = 0.79, 95% confidence interval: 0.60–1.05, P = 0.107), and the primary endpoint was not met. FTD/TPI increased grade 3 or higher hematologic adverse events (73.0% versus 3.3%) without new safety signals. These findings indicate that post-adjuvant intervention with FTD/TPI did not significantly improve DFS in ctDNA-positive patients without radiological disease. ClinicalTrials.gov identifier: NCT04457297 . In the randomized, double-blind phase 3 ALTAIR trial, patients with resected colorectal cancer who became positive for circulating tumor DNA during post-adjuvant surveillance received trifluridine/tipiracil hydrochloride therapy, which did not significantly prolong disease-free survival compared with placebo.

22.
arXiv (CS.AI) 2026-06-12

Benchmarking Counterfactual Prediction in Epidemic Time Series with Time-Varying Interventions

arXiv:2606.05692v2 Announce Type: replace-cross Abstract: Deep learning has enabled significant advances in time-series causal inference, yet progress remains constrained by the lack of realistic benchmarks with observable counterfactual outcomes. Existing datasets either rely on real-world observations without ground-truth counterfactuals or on simplified simulations that fail to capture complex causal dynamics. To address this gap, we develop a large-scale benchmark for counterfactual prediction in epidemic time series under dynamic interventions. Unlike existing benchmarks, it supports static and time-varying treatments, as well as both single-policy and multi-policy intervention settings, enabling evaluation of causal inference methods across a broad range of causal inference scenarios. Leveraging a calibrated agent-based model grounded in real-world demographic, mobility, epidemiological, and policy data, we generate realistic counterfactual trajectories across more than 150 U.S. counties. Using this benchmark, we evaluate widely used and state-of-the-art causal inference methods, revealing substantial performance differences and highlighting the challenges of realistic time-series causal reasoning.

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

Where Should Action Generation Begin? A Learnable Source Prior for Generative Robot Policies

Generative robot policies typically begin action generation from an observation-independent standard Gaussian distribution, leaving the choice of source distribution underexplored. This work asks a simple question: where should action generation begin? We propose LeaP, a Learnable source Prior that replaces the standard Gaussian with a proprioception-conditioned diagonal Gaussian over action chunks. Parameterized by a lightweight MLP, LeaP jointly predicts the mean and state-adaptive variance of the source distribution, while keeping the downstream generator architecture and inference solver unchanged. This design provides an observation-informed yet stochastic initialization, allowing the generator to focus on precise action refinement rather than transporting samples from an uninformed noise source. On 15 RoboTwin manipulation tasks, LeaP achieves an average success rate of 81.6%, outperforming four representative baselines – including deterministic-source methods, a no-prior counterpart, and a diffusion-bridge policy – by 6.5 to 25.5 percentage points. The same prior consistently improves both flow-matching and diffusion-bridge generators, while using fewer parameters and converging faster. The advantage carries over to real-world deployment, where LeaP attains the best performance. These results suggest that the source distribution is an independent and reusable design axis for generative robot policies, complementary to the choice of generative dynamics.

24.
arXiv (CS.CV) 2026-06-16

Learning Sparse Latent Predictive Foundation Model for Multimodal Neuroimaging

Brain MRIs are routinely acquired as multiple complementary sequences with unique contrast weighting, including T1-weighed imaging (T1w) anatomic and fluid-sensitive T2-weighted (T2w) contrasts. However, methods for learning unified representations across the multitude of MRI contrast mechanisms at health-system scale are lacking. In this study, we introduce Neuro-JEPA, a sparse multimodal neuroimaging foundation model that combines a latent predictive objective with a Mixture-of-Experts architecture to encode brain MRI across core T1w, T2w, and fluid-suppressed FLAIR imaging (FLAIR). We further provide a systematic methodological study of architectural, masking, objective, and sparsity design choices beneficial for robust neuroimaging multimodal representation learning. Neuro-JEPA was pretrained on 1,551,862 scans from 428,647 studies after modality-specific preprocessing with data curation across three core structural brain MRI sequences. We evaluated the learned representations across clinical and research settings, including 25 tasks from three health systems: NYU Langone, NYU Long Island, and Massachusetts General Hospital, and 22 tasks from 12 public datasets, covering unimodal, multimodal and cross-domain evaluation configurations. Across these benchmarks, existing neuroimaging foundation models showed inconsistent gains over a simple convolutional neural network (CNN) baseline, whereas Neuro-JEPA achieved stronger and more consistent performance across all evaluated settings. These results establish a scalable methodological framework for multimodal neuroimaging representation learning and highlight the need for foundation model evaluation protocols that include simple baselines, clinically heterogeneous cohorts and controlled multimodal comparisons.

25.
bioRxiv (Bioinfo) 2026-06-08

DDI_single: Single-Sequence-Based Protein Domain Assembly

作者:

Domains are the basic units of protein structure and function. Appropriate inter-domain organization is critical to enable cooperative execution of multiple related functions. It is thus a crucial step to determine the full-length structure of multi-domain proteins for the purpose of elucidating their functions and designing new drugs to regulate these functions. Existing structure prediction algorithms are generally better at solving the internal conformation of domains, rather than modeling the relative positions between domains. To address the challenge of accurately determining multi-domain protein conformations, we develop a single-sequence-based domain assembly algorithm called DDI_single. DDI_single directly extracts features from the amino acid sequence using the protein language model ESM-1b, and accurately predicts the interactions between residue pairs of structural domains through a novel gated cross-attention module, thus achieving the correct assembly of structural domains. With the knowledge of domain definition, DDI_single achieves more than 20% higher accuracy in the task of predicting the relative distances of residue pairs between domains than that of the single-sequence-based structure prediction algorithm trRosettaX_single. When assembling domains with known spatial conformations, DDI_single correctly assembles 74.4% of the samples in the test set (TM-score>0.5). When assembling domains with unknown spatial conformations, in cases where the internal spatial conformations of domains are correctly modeled, DDI_single correctly assembles 73.9% of the samples.