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

SWE-Future: Forecast-Conditioned Data Synthesis for Future-Oriented Software Engineering Agents

arXiv:2606.18733v1 Announce Type: cross Abstract: Realistic coding-agent benchmarks often replay public GitHub issues and pull requests, making them vulnerable to overlap with model pretraining, fine-tuning, synthetic-data generation, or benchmark-driven model selection. Fully synthetic tasks avoid direct historical replay, but can drift away from real repository needs. We propose SWE-Future, a forecast-conditioned data synthesis method for future-oriented coding tasks. Given a forecast snapshot at time $T_0$, the method uses only pre-$T_0$ repository evidence to forecast future feature implementation/enhancement, bugfix, and refactor task families. We first validate this forecasting step retrospectively: after forecasts are fixed, later pull requests are used only to measure whether the predicted task families match future repository work. In an 80-repository study, the forecaster achieves 58.1\% future-work relevance under the main semantic matching metric. We then use validated forecast families as conditioning signals to synthesize a 200-task coding-agent dataset across 61 repositories from a task-generation snapshot, rather than replaying the later pull requests used for validation. SWE-Future shows that repository-evolution forecasts can guide realistic, future-oriented coding-task synthesis while reducing direct dependence on historical pull-request replay.

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

Understanding, Detecting, and Repairing Real-World In-Context-Learning-Based Text-to-SQL Errors

Large language models (LLMs) have been adopted for text-to-SQL tasks, utilizing their in-context learning (ICL) capability to translate natural language questions into SQL queries. However, such a technique faces correctness problems. In this paper, we conduct the first comprehensive study of text-to-SQL errors of ICL-based techniques. Our study covers four representative ICL-based techniques, five basic repairing methods, two benchmarks, and two LLM settings. We find that text-to-SQL errors are widespread and summarize 27 error types of 7 categories. We also find that existing repairing attempts have limited correctness improvement while having high computational overhead and many mis-repairs. Based on these findings, we propose MapleDoctor, a novel text-to-SQL error detection and repairing framework. The evaluation demonstrates that MapleDoctor outperforms existing solutions by repairing 13.8% more queries with a negligible number of mis-repairs and reducing 67.4% repair latency. The artifact is publicly available at GitHub.

03.
arXiv (CS.CL) 2026-06-15

Fractured Chain-of-Thought Reasoning

Inference-time scaling techniques have significantly bolstered the reasoning capabilities of large language models (LLMs) by harnessing additional computational effort at inference without retraining. Similarly, Chain-of-Thought (CoT) prompting and its extension, Long CoT, improve accuracy by generating rich intermediate reasoning trajectories, but these approaches incur substantial token costs that impede their deployment in latency-sensitive settings. In this work, we first show that truncated CoT, which stops reasoning before completion and directly generates the final answer, often matches the full CoT sampling while using dramatically fewer tokens. Building on this insight, we introduce Fractured Sampling, a unified inference-time strategy that interpolates between full CoT and solution-only sampling along three orthogonal axes: (1) the number of reasoning trajectories, (2) the number of final solutions per trajectory, and (3) the depth at which reasoning traces are truncated. Through extensive experiments on five diverse reasoning benchmarks and several model scales, we demonstrate that Fractured Sampling consistently achieves superior accuracy-cost trade-offs, yielding steep log-linear scaling gains in Pass@k versus token budget. Our analysis reveals how to allocate computation across these dimensions to maximize performance, paving the way for more efficient and scalable LLM reasoning. Code is available at https://github.com/BaohaoLiao/frac-cot.

04.
arXiv (CS.AI) 2026-06-11

Runtime Skill Audit: Targeted Runtime Probing for Agent Skill Security

arXiv:2606.11671v1 Announce Type: cross Abstract: Agent skills let LLM agents reuse instructions, resources, tools, and workflows, but they also create a new place for malicious behavior to hide. A skill may look benign in its documentation or code while becoming harmful only when it is invoked with particular user requests, local assets, persistent state, or multi-step tool interactions. This makes purely static vetting brittle. We present Runtime Skill Audit (RSA), a dynamic analysis method that audits skills by asking what the skill-mediated agent actually does under targeted runtime conditions. Instead of testing every skill with the same generic tasks, RSA profiles risk-relevant interfaces, prepares the execution context needed to exercise them, and assigns security labels from the resulting trace evidence. We instantiate RSA on OpenClaw and evaluate it on 100 skills against representative static baselines. RSA achieves 90.0\% accuracy with an 88.0\% true positive rate and an 8.0\% false positive rate, improving accuracy by 13.0 percentage points over the best static baseline. Under self-evolving attacks, static detectors collapse after one or two rounds, while RSA continues to detect 19–20 out of 20 malicious skills across rounds.

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

V2P-Manip: Learning Dexterous Manipulation from Monocular Human Videos

Achieving autonomous robotic dexterous manipulation requires precise, human-like action sequences at scale. As a scalable supplement to costly teleoperation data, extracting trajectories with both visual fidelity and physical plausibility from monocular videos represents a promising frontier in embodied AI. To this end, we introduce V2P-Manip, an efficient framework designed to learn dexterous manipulation policies directly from human demonstration videos. We establish an efficient, integrated pipeline encompassing 3D asset acquisition, trajectory estimation, and dexterous policy learning. To bridge the gap between visual perception and physical constraints, we introduce a two-stage refinement process to enforce spatial alignment and physical consistency. Evaluations on the TACO and OakInk benchmarks demonstrate that our approach significantly outperforms previous methods in pose accuracy, adaptability to unstructured environments, and training efficiency. Ultimately, experimental results confirm an average success rate of over 75% across multiple synthetic manipulation tasks and validate the adaptability of the extracted manipulation priors across diverse dexterous hand embodiments.

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

On the Variance of Temporal Difference Learning and its Reduction Using Control Variates

arXiv:2606.20357v1 Announce Type: new Abstract: We analyze the variance of temporal difference (TD) learning using the phased setting with tabular representation, and show that one of the mechanisms behind its ability to reduce variance is by effectively aggregating over a larger number of independent trajectories. Based on this insight, we demonstrate that (1) the variance of TD is asymptotically bounded from above by Monte Carlo (MC) estimators, and (2) shorter horizon updates incurs less variance for a fixed number of samples. Beyond TD, we show that Direct Advantage Estimation (DAE), a method for estimating the advantage function, can be seen as a type of regression-adjusted control variate, which achieves a tighter bound on the variance compared to TD in the large-sample limit. Finally, we numerically illustrate the behaviors of these estimators with carefully designed environments.

07.
arXiv (CS.CL) 2026-06-11

Steering the Noise: Turning Random Perturbations into Effective Descent for Memory-Efficient LLM Fine-Tuning

Fine-tuning large language models (LLMs) achieves strong performance but is often limited by the memory overhead of backpropagation. Zeroth-order (ZO) optimization avoids this overhead by estimating gradients through forward passes alone, yet it typically converges slowly because random Gaussian perturbations yield high-variance gradient estimates in high-dimensional parameter spaces. In this paper, we propose a plug-and-play framework that turns random perturbations into more effective descent directions. The key idea is to draw a small pool of candidate perturbations, evaluate their loss values, and then select or combine those that are best aligned with the optimization objective. We develop two instantiations of this idea: MeZO-GV, which forms a guiding vector from the contrast between low-loss and high-loss perturbation groups, and MeZO-Greedy, which keeps the single best perturbation within a fixed evaluation budget. We theoretically show that both strategies yield a larger per-step reduction in the objective than standard ZO estimation, leading to improved convergence rates. Experiments on LLMs of different scales and architectures confirm that the proposed methods integrate naturally with existing ZO optimizers and consistently improve convergence speed and task accuracy. On OPT-13B, our approach outperforms all ZO baselines across 11 benchmarks and exceeds gradient-based methods on 9 of them, while retaining the memory efficiency of forward-only optimization.

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

Scaling Laws of Global Weather Models

arXiv:2602.22962v2 Announce Type: replace Abstract: Data-driven models are revolutionizing weather forecasting. To optimize training efficiency and model performance, this paper analyzes empirical scaling laws within this domain. We investigate the relationship between model performance (validation loss) and three key factors: model size ($N$), dataset size ($D$), and compute budget ($C$). Across a range of models, we find that Aurora exhibits the strongest data-scaling behavior: increasing the training dataset by 10x reduces validation loss by up to 3.2x. GraphCast demonstrates the highest parameter efficiency, yet suffers from limited hardware utilization. Our compute-optimal analysis indicates that, under fixed compute budgets, allocating resources to more total training data yields greater performance gains than increasing model size. Furthermore, we analyze model shape and uncover scaling behaviors that differ fundamentally from those observed in language models: weather forecasting models consistently favor increased width over depth. These findings suggest that future weather models should prioritize wider architectures and larger effective training datasets to maximize predictive performance.

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

Beyond Retrieval: Learning Compact User Representations for Scalable LLM Personalization

Personalizing large language models requires adapting model behavior to individual users while preserving robustness and deployment-scale efficiency. Existing approaches typically personalize LLMs either at the input level, by retrieving user histories or constructing profile prompts, or at the parameter level, by maintaining user-specific parameter-efficient modules. The former makes personalization sensitive to retrieval quality and prompt design, whereas the latter incurs storage and maintenance costs that grow with the user population. To address these limitations, we propose TAP-PER (Temporal Attentive Prefix for PERsonalization), a prefix-based framework that encodes user preferences as learnable representations, eliminating explicit prompt construction and replacing heavy per-user adapters with lightweight user-state prefix embeddings. Inspired by personalized recommendation systems, TAP-PER decomposes user modeling into user-state and query-conditioned components, and incorporates temporal signals to capture the evolving nature of user interests. Experiments on six LaMP tasks show that TAP-PER consistently outperforms prompt-based and model-based baselines across classification, rating, and generation settings. Moreover, TAP-PER uses 130x fewer per-user parameters than OPPU and roughly half the total parameter footprint of PER-PCS at the 1,000-user scale, demonstrating that scalable LLM personalization can be achieved without explicit prompt construction or heavy per-user adapters.

10.
arXiv (CS.CV) 2026-06-11

Physics-Driven Spatiotemporal Modeling for AI-Generated Video Detection

AI-generated videos have achieved near-perfect visual realism (e.g., Sora), urgently necessitating reliable detection mechanisms. However, detecting such videos faces significant challenges in modeling high-dimensional spatiotemporal dynamics and identifying subtle anomalies that violate physical laws. In this paper, we propose the first physics-driven AI-generated video detection paradigm based on probability flow conservation principles. Specifically, we propose a statistic called Normalized Spatiotemporal Gradient (NSG), which quantifies the ratio of spatial probability gradients to temporal density changes, explicitly capturing deviations from natural video dynamics. Leveraging pre-trained diffusion models, we develop an NSG estimator through spatial gradients approximation and motion-aware temporal modeling without complex motion decomposition while preserving physical constraints. Building on this, we propose an NSG-based video detection method (NSG-VD) that computes the Maximum Mean Discrepancy (MMD) between NSG features of the test and real videos as a detection metric. Last, we derive an upper bound of NSG feature distances between real and generated videos, proving that generated videos exhibit amplified discrepancies due to distributional shifts. Extensive experiments confirm that NSG-VD outperforms state-of-the-art baselines by 16.00% in Recall and 10.75% in F1-Score, validating the superior performance of NSG-VD. The source code is available at https://github.com/ZSHsh98/NSG-VD.

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

As You Wish: Mission Planning with Formal Verification using LLMs in Precision Agriculture

arXiv:2606.18519v1 Announce Type: cross Abstract: Though robotic systems are now being commercialized and deployed in various industries, many of these systems are highly specialized and often require an advanced skill set to operate and ensure they perform as instructed. To mitigate this problem, we recently introduced a mission planner leveraging LLMs to synthesize mission plans in precision agriculture based on mission descriptions provided in natural language. While the system demonstrates impressive performance, it also suffers from the inherent ambiguities of natural language. In this paper, we extend our system to address this issue by introducing multiple feedback loops in the planning architecture that leverage linear temporal logic (LTL) to ensure the mission planning system meets the specifications formulated by the user while still using natural language. To mitigate potential bias, this is achieved by using two different commercial LLMs in charge of the specification and verification subtasks. Through extensive experiments, we highlight the strengths and limitations of integrating mission verification into a fully autonomous pipeline, particularly regarding an LLM's ability to generate valuable LTL formulas, and show how our proposed implementation addresses and solves these challenges.

12.
medRxiv (Medicine) 2026-06-22

Rare loss-of-function variants in POLD1, PMS1 and FAN1 modify age at onset of motor symptoms in Huntington's disease

Huntington's disease is a rare neurodegenerative disease whose primary risk factors are inherited expansions of a CAG repeat tract in the HTT gene. Somatic expansion of these tracts leads to neuronal toxicity, neuronal death and clinical disease progression. To identify genetic factors with a major impact on disease onset and progression, we genome sequenced 18,825 individuals for the ENROLL-HD study. Our results show rare inactivating mutations in three genes, all involved in DNA damage repair, are major determinants of age of onset for motor symptoms (n=10,610) and other clinical manifestations. Heterozygote carriers of predicted loss-of-function (pLoF) variants in POLD1 and PMS1 developed motor symptoms an average 20 years (n=3; P=1x10-5) and 7 years (n=6; P=2x10-3) later than non-carriers, respectively. Conversely, heterozygote carriers of pLoF variants in FAN1 (n=30) developed symptoms 10 years earlier (P=2x10-10). Our findings highlight therapeutic strategies and help predict age of onset for at-risk individuals.

13.
arXiv (CS.AI) 2026-06-19

Uncertainty-Aware Reward Modeling for Stable RLHF

arXiv:2606.19818v1 Announce Type: cross Abstract: Reinforcement learning from human feedback (RLHF) aligns large language models by training reward models on preference data and optimizing policies to maximize predicted rewards. However, this pipeline faces two fundamental challenges: (1) reward models cannot signal when their predictions are unreliable, since they usually act as deterministic point estimators; and (2) modern group-based policy optimization can amplify unreliable reward signals, as exemplified by GRPO's uniform treatment of rewards during advantage computation. As policies explore increasingly diverse responses, these two limitations create a critical vulnerability: unreliable reward estimates may be granted disproportionate influence, triggering severe reward hacking. We propose Uncertainty-Aware Reward Modeling (UARM), which equips reward models with calibrated uncertainty via quantile-based conformal prediction and reweights GRPO advantages through heteroscedastic variance decomposition. Experiments across HelpSteer, UltraFeedback, and PKU-SafeRLHF demonstrate that UARM significantly improves reward model calibration, reduces reward hacking, and enhances downstream alignment quality compared to standard GRPO and uncertainty-agnostic baselines.

14.
medRxiv (Medicine) 2026-06-16

The biological clock of multimorbidity: temporal dynamics of disease co-occurrence in primary care

Multimorbidity is the dominant clinical reality of primary care, yet the temporal dynamics governing when and how persistent comorbidity associations emerge remain poorly characterised. Most large-scale comorbidity studies adopt a single observation window after an index diagnosis, implicitly assuming that associations detectable at one year are equally detectable at five. Using 11 years of electronic health records from 5,821,197 individuals in Catalan primary care, we applied a matched cohort design across nine complementary follow-up windows, five cumulative (0-1 to 0-5 years) and four conditional (1-2 to 4-5 years), to 1,315 index diseases, identifying 144,030 significant directed comorbidity associations in the five-year network. We found that 60.1% of these associations required at least three years of follow-up and were undetectable in shorter-window analyses, demonstrating that observation window length is a primary determinant of which comorbidities can be observed. To organise this temporal heterogeneity, we introduce the biological clock of multimorbidity: a two-dimensional framework that positions ICD-10 disease categories according to their rates of cumulative signal attenuation and the persistence of conditional risk. This framework identifies four reproducible temporal patterns (episodic, chronic stable, chronic progressive, and transient-persistent) that are robust under bootstrap resampling, leave-one-disease-out sensitivity analysis, and alternative clustering approaches. The biological clock is systematically modulated by sex, with Blood/Immune and Musculoskeletal disorders showing the largest sex differences in temporal dynamics. Network analysis identified 19 disease "initiators" that generate broad downstream comorbidity burdens and 21 "sinks" representing convergent endpoints of multiple disease trajectories. Comparison with hospital-based Danish data from 6,909,676 individuals showed that shared associations were 2.7-fold enriched over chance expectation (hypergeometric test, p

15.
arXiv (CS.CL) 2026-06-16

Progressive Knowledge-Guided Large Language Model Framework for Bearing Fault Diagnosis

Vibration-based bearing fault diagnosis requires resolving three interrelated measurement challenges, including the trade-off between global statistical feature efficiency and local transient signal fidelity, insufficient traceability of measurement features to underlying fault physics, and ineffective multi-source measurement information fusion across diagnostic scales. This paper presents a progressive physics-guided multi-scale vibration signal processing framework that addresses all three challenges within a unified diagnostic pipeline. An 81-dimensional measurement descriptor, derived from bearing kinematic theory and characteristic defect frequencies, establishes a physically traceable feature space enabling real-time fault screening at approximately 20 ms per sample. A fault-adaptive signal segmentation mechanism then directs analytical attention toward fault-relevant waveform regions guided by physics-based priors, without manual feature engineering. Structured fault mechanism knowledge is further encoded implicitly in model parameters during training, enabling autonomous multi-scale measurement fusion without external knowledge dependencies at inference. Validated on four public benchmark datasets under diverse operating conditions, the framework achieves 98.49% diagnostic accuracy with a 12.6-fold reduction in computational cost relative to signal-level baselines. Interpretability analysis confirms that diagnostic feature activations align with established bearing fault mechanics, supporting measurement traceability in safety-critical industrial systems.

16.
Nature (Science) 2026-06-10

Measurement of reactor neutrino oscillation with the first JUNO data

Neutrino oscillations (see refs. 1,2 and references therein), a quantum effect manifesting at macroscopic scales, are governed by lepton flavour mixing angles and neutrino mass-squared differences3 that are fundamental parameters of particle physics, representing phenomena beyond the Standard Model. Precision measurements of these parameters are essential for testing the completeness of the three-flavour framework, determining the mass ordering of neutrinos and probing possible new physics. The Jiangmen Underground Neutrino Observatory (JUNO)4 is a 20-ktonne liquid-scintillator detector located 52.5 km from multiple reactor cores, designed to resolve the interference pattern of reactor neutrinos with sub-percent precision5,6. Here we report, using the first 59.1 days of data collected since detector completion in August 2025, the first simultaneous high-precision determination of two neutrino oscillation parameters, $${\sin }^{2}{\theta }_{12}=0.3092\,\pm \,0.0087$$ and $$\Delta {m}_{21}^{2}=(7.50\,\pm \,0.12)\times 1{0}^{-5}\,{\mathrm{eV}}^{2}$$ for the normal mass ordering scenario, improving the precision by a factor of 1.6 relative to the combination of all previous measurements. These results advance the basic understanding of neutrinos, validate the design of the detector and indicate the readiness of JUNO for resolving the neutrino mass ordering with a larger dataset. The rapid achievement with a short exposure highlights the potential of JUNO to push the frontiers of precision neutrino physics and paves the way for its broad scientific programme. The first data of the Jiangmen Underground Neutrino Observatory deliver high-precision neutrino oscillation parameters, improving measurements and demonstrating readiness to determine neutrino mass ordering.

17.
arXiv (quant-ph) 2026-06-12

Quantum Otto engine powered by an anisotropic Heisenberg XYZ model under independent local magnetic fields

arXiv:2606.12877v1 Announce Type: new Abstract: We study a quantum Otto heat engine whose working substance is an anisotropic two-qubit Heisenberg XYZ model. Independent local magnetic fields are used to control each spin individually. The influence of the longitudinal coupling, anisotropy, transverse coupling, and local fields on the net work output and efficiency is systematically examined. Reducing the longitudinal coupling is found to markedly improve both the maximum work and the peak efficiency. The engine performance reaches an optimum at a particular value of the anisotropy parameter. A local work analysis clarifies how work is produced during the cycle. Because of the asymmetric local fields and the intrinsic spin-spin interaction, the two qubits play markedly different thermodynamic roles; the interaction term itself contributes crucially to the total work. We further analyze the variation of quantum entanglement, quantified by concurrence, along the cycle. The results indicate that a pronounced change in entanglement between the hot and cold isomagnetic strokes is closely correlated with the efficiency enhancement. This work offers new insight into the operating principles and control of quantum Otto heat engines.

18.
arXiv (CS.AI) 2026-06-17

CMIP-Forge: An Agentic System that Retrieves, Computes, and Self-Reviews Climate Science

arXiv:2606.17076v1 Announce Type: cross Abstract: The Coupled Model Intercomparison Project Phase 6 (CMIP6) has generated thousands of peer-reviewed publications documenting model configurations, evaluation procedures, emergent constraints, and projection uncertainties. As the community transitions toward CMIP7, efficiently extracting and operationalizing this unstructured knowledge alongside live data analysis represents a critical bottleneck. Here we present CMIP-Forge, a hybrid retrieval-augmented generation (RAG) and autonomous analysis system that bridges the gap between scientific literature and Earth System Grid Federation (ESGF) data archives. The system pairs a curated corpus of 6,581 CMIP6-related open-access publications (101,828 indexed chunks) with an agentic pipeline in which a tool-augmented worker plans and executes Python workflows over live climate data, while a panel of independent reviewer models audits its methodology end to end. CMIP-Forge introduces a multi-layered Defense-in-Depth architecture that enforces physical and methodological invariants through executable mechanisms: Abstract Syntax Tree (AST) static analysis, audited scientific primitives, and an autonomous adversarial peer-review protocol. We demonstrate the system's capabilities through end-to-end autonomous research pipelines spanning atmospheric teleconnections, ocean dynamics, regional extremes, and global warming projections. An agentic analysis system grounded in peer-reviewed literature, constrained by automated code guardrails, and audited by an independent adversarial review loop can complete complex climate-research workflows autonomously. The same experiments expose concrete failure modes of the review loop (sycophantic regression, REVISE verdicts that are never resolved, and the submission of stub code for review), each diagnosable from the immutable telemetry and provenance record released with the article.

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

Quantum Kernels are Spectral Tensor Networks

arXiv:2606.20402v1 Announce Type: new Abstract: Quantum kernels admit Fourier representations whose frequencies are determined by the data-encoding gates of the underlying feature map. We show that entangling tensor kernels are matrix product operator factorizations of the corresponding Fourier coefficient tensors, thereby identifying quantum kernels as spectral tensor networks. By grouping gate-level frequency configurations that yield the same feature-wise frequency, we obtain a grouped Fourier form that induces a more compact spectral tensor network representation of the kernel. We further show that kernel target alignment serves as a bridge between the Fourier and tensor network views. On a grid that resolves the accessible Fourier modes, it becomes the Frobenius cosine similarity between Fourier coefficient tensors. Our numerical experiments show that layered quantum kernels admit accurate representations with small bond dimension, revealing a compressibility governed by correlations between Fourier modes. This compressibility provides a diagnostic of classical representability and of whether kernel evaluation is likely to remain classically tractable.

20.
arXiv (CS.LG) 2026-06-12

The Geometry of Phase Transitions in Generative Dynamics via Projection Caustics

arXiv:2606.13191v1 Announce Type: new Abstract: Continuous-state generative samplers, including diffusion and flow-matching models, evolve through continuous reverse-time dynamics, yet their samples often undergo abrupt qualitative changes: trajectories commit to modes, semantic alternatives collapse, and small perturbations in narrow time windows can produce large downstream effects. This paper develops a geometric account of such phase-transition-like behaviour. We view denoising as gradient descent on a free energy landscape and show that sharp transitions arise near projection caustics, where the nearest-point projection onto the data support ceases to be unique. Motivated by this perspective, we introduce the Critical Boundary Detector (CBD), as practical diagnostics for score-direction instability. Across toy models, standard diffusion models, and latent text-to-image diffusion models, CBD localises mode commitment, predicts intervention-sensitive windows, and supports targeted control in geometrically sensitive regions. Our results connect geometry of data and dynamics of diffusion generation.

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

Generative Molecular Design with Steerable and Granular Synthesizability Control

arXiv:2505.08774v2 Announce Type: replace-cross Abstract: Designing molecules that are both property-optimal and readily synthesizable is a central challenge in drug discovery. Existing works that do consider synthesizability can jointly output predicted synthesis routes for generated molecules. However, there has been minimal attention in addressing the ease of synthesis and with flexibility to incorporate desired reaction constraints. On the other hand, virtual screening searches for commercially available compounds, but imposes challenges when scaling to ultra-large (billion-size and beyond) chemical spaces. Here, we propose a generative design framework that unifies synthesis-constrained molecular design and ultra-large-scale virtual screening through steerable and granular synthesizability control. Generated molecules satisfy arbitrary multi-parameter optimization objectives with predicted synthesis routes satisfying mix-and-match constraints: including or avoiding certain reactions, incorporating specific building blocks, and minimizing synthesis route length. In an end-to-end in-house campaign targeting BRD4, we designed molecules synthesizable with specific selected reactions and building blocks, synthesized all six selected compounds, and identified two micromolar binders. We further demonstrate that reaction control enables efficient navigation of ultra-large make-on-demand chemical spaces to identify property-optimal candidates. By applying our framework to Chemspace's Freedom 4.0 make-on-demand space (142 billion molecules), we generated ~320k molecules (0.00023% of the library) on a single consumer-grade GPU (with only 8 GB GPU memory) and identified a micromolar Wee1 binder amongst 60 synthesized candidates. The single unified framework thus enables generating novel synthesizable molecules and retrieving catalogue-ready candidates, offering a flexible solution to mitigating the synthesizability bottleneck.

22.
arXiv (CS.CL) 2026-06-16

MemBoost: A Memory-Boosted Framework for Cost-Aware LLM Inference

Large Language Models (LLMs) deliver strong performance but incur high inference cost in real-world services, especially under workloads with repeated or near-duplicate queries across users and sessions. In this work, we propose MemBoost, a memory-boosted LLM serving framework that enables a lightweight model to reuse previously generated answers and retrieve relevant supporting information for cheap inference, while selectively escalating difficult or uncertain queries to a stronger model. Unlike standard retrieval-augmented generation, which primarily grounds a single response, MemBoost is designed for interactive settings by supporting answer reuse, continual memory growth, and cost-aware routing. Experiments across multiple models under simulated workloads show that MemBoost substantially reduces expensive large-model invocations and overall inference cost, while maintaining high answer quality comparable to the strong model baseline.

23.
arXiv (CS.AI) 2026-06-19

Confidence-Aware Automated Assessment of Student-Drawn Scientific Models

arXiv:2606.20264v1 Announce Type: new Abstract: Student-generated drawings are widely used in science education to assess learners' conceptual understanding in modeling-based tasks aligned with the Next Generation Science Standards (NGSS). However, scoring such drawings requires expert human judgment to interpret complex visual representations, making large-scale assessment costly to implement and sustain in classroom settings. In this work, we study automated scoring of student-generated scientific drawings using a vision-based model. We evaluate a Vision Transformer (ViT) with parameter-efficient adaptation and propose a confidence-aware scoring framework that derives response-level confidence from test-time predictive distributions. This confidence signal enables selective automation by scoring high-confidence responses automatically while deferring uncertain cases for human review. Experiments on six NGSS-aligned middle school assessment items show that the proposed approach improves scoring reliability while supporting a practical trade-off between automated coverage and scoring risk, highlighting the value of confidence-aware methods for trustworthy educational assessment.

24.
bioRxiv (Bioinfo) 2026-06-16

Super Learner Ensemble Modeling of CPTAC Proteomic Data for Survival Prediction in Head and Neck Squamous Cell Carcinoma

Survival analysis in head and neck squamous cell carcinoma (HNSCC) is traditionally performed using Cox proportional hazards models, alongside some exploration into black-box machine learning methods. The Super Learner (SL) algorithm addresses this model selection dilemma by combining diverse candidate algorithms into a weighted ensemble to perform comparably to the best candidate method. This study evaluates the performance of SL in HNSCC. Proteomic features as well as clinical covariates from 96 CPTAC HNSCC samples were modeled with three candidate algorithms (Cox LASSO, Cox Ridge, and Random Survival Forest) as well as the ensemble SL method. Models were optimized via Uno's time-dependent Concordance Index (C-index) and tested at 1- and 3-year time horizons using 2000 bootstrap resamples. The Cox Ridge regression model achieved the highest predictive accuracy among the four total methods. However, the SL demonstrated stable performance over both time horizons (1-year C-index: 0.985; 3-year C-index: 0.960). Variable importance analysis of the Cox Ridge model successfully identified malignant proteins (ATR, MAML1, MIEN1) alongside novel potential prognostic indicators (ZNF800, KERA). This analysis emphasizes the statistical necessity for larger cohorts for ensemble learning, while providing a benchmark of proteomic indicators in HNSCC.

25.
medRxiv (Medicine) 2026-06-22

Development of a Novel Risk Prediction Model for Rheumatoid Arthritis-Associated Interstitial Lung Disease (RA-ILD): A Longitudinal Study

Background: Interstitial lung disease (ILD) is one of the most common and potentially most devastating extra-articular complication of rheumatoid arthritis (RA) and is associated with substantial morbidity and mortality. However, reliable tools for the early identification of ILD in patients with RA remain limited. This study aimed to identify plasma protein biomarkers of RA-ILD and develop an interpretable machine learning model for risk prediction using data from the UK Biobank. Methods: We first evaluated the association between baseline RA and the risk of incident ILD in the UK Biobank using Cox proportional hazards models. Mendelian randomization analysis was then performed to investigate the potential causal relationship between RA and ILD. Finally, we analyzed 2,920 plasma proteins measured using the Olink platform in 781 eligible RA patients. Proteins associated with ILD risk were identified using Cox proportional hazards models and subsequently used to construct eight machine learning models. Model performance was assessed using the receiver operating characteristic curve (ROC) and decision curve analysis. The best-performing model was further interpreted using Shapley additive explanations (SHAP) to evaluate feature importance. Results: Compared with participants without RA, Patients with baseline RA had a significantly higher risk of developing ILD (Hazard ratio: 4.425, 95% CI: 3.549,5.518). The MR supported a potential causal association between RA and ILD (Odds ratio: 1.227, 95% CI: 1.121,1.343). Among the eight machine learning models, the CatBoost model showed the best performance, achieving an area under the curve (AUC) of 0.884 (95% CI: 0.773,0.996). The SHAP analysis identified LAG3, NPC2, and LAMP3 are the three most important plasma protein predictors of ILD development in patients with RA. Conclusion: Plasma proteomics combined with machine learning may provide a promising approach for identifying biomarkers and predicting ILD risk in patients with RA. LAG3, NPC2, and LAMP3 may serve as candidate biomarkers for RA-ILD and warrant further validation. Keywords: Rheumatoid arthritis, Interstitial lung disease, Mendelian randomization, Machine learning, Plasma proteins.