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01.
arXiv (CS.CL) 2026-06-17

When AI Says "I have been in similar situations": Synthetic Lived Experience in Peer-Like Caregiver Support

Caregivers often turn to online communities for informational and emotional support. In these spaces, peer supporters frequently draw on personal narratives to respond to emotionally complex caregiving situations. As LLMs are increasingly designed as peer-like sources of support, they introduce a critical tension: AI can provide immediate, private, and nonjudgmental support, but it cannot authentically possess the lived experiences that make human peer support meaningful. Yet, when prompted to sound peer-like, LLMs may generate language that implies lived experience. This creates a synthetic lived experience paradox: the same experiential language that may make AI support feel warm, relatable, and peer-like can also falsely position the system as someone with lived experience. We examine this paradox in the context of family caregivers of people living with Alzheimer's Disease and Related Dementias (ADRD). Drawing on caregiver support exchanges from online communities and prompted peer-like responses from three LLMs – LLaMA, GPT-4o-mini, and MedGemma – we analyze how human peers use personal narratives and how AI incorporates similar narrative forms. Psycholinguistic analysis shows that peer responses used significantly more first-person and past-focused language than peer-like AI responses. Qualitatively, we identify seven types of personal narratives in human peer support and show that AI often captures their emotional work, but can fabricate experiential grounding. These findings reveal a narrative authenticity gap: peer-like AI can generate synthetic lived experience without the real experience that makes peer support meaningful. We argue that caregiver-support AI systems need mechanisms to distinguish supportive peer-like framing from fabricated lived experience, ensuring that models can offer warmth and validation without falsely positioning themselves as experiential peers.

02.
arXiv (CS.AI) 2026-06-24

Impatient Bandits: Optimizing for the Long-Term Without Delay

arXiv:2501.07761v2 Announce Type: replace-cross Abstract: Increasingly, recommender systems are tasked with improving users' long-term satisfaction. In this context, we study a content exploration task, which we formalize as a bandit problem with delayed rewards. There is an apparent trade-off in choosing the learning signal: waiting for the full reward to become available might take several weeks, slowing the rate of learning, whereas using short-term proxy rewards reflects the actual long-term goal only imperfectly. First, we develop a predictive model of delayed rewards that incorporates all information obtained to date. Rewards as well as shorter-term surrogate outcomes are combined through a Bayesian filter to obtain a probabilistic belief. Second, we devise a bandit algorithm that quickly learns to identify content aligned with long-term success using this new predictive model. We prove a regret bound for our algorithm that depends on the Value of Progressive Feedback, an information-theoretic metric that captures the quality of short-term leading indicators that are observed prior to the long-term reward. We apply our approach to a podcast recommendation problem, where we seek to recommend shows that users engage with repeatedly over two months. We empirically validate that our approach significantly outperforms methods that optimize for short-term proxies or rely solely on delayed rewards, as demonstrated by an A/B test in a recommendation system that serves hundreds of millions of users.

03.
arXiv (CS.LG) 2026-06-16

Zero-order Parameter-free Optimization for LMO-based Methods: Novel Approach for Efficient Fine-tuning

arXiv:2606.14970v1 Announce Type: new Abstract: Fine-tuning large language models (LLMs) has become a central application of modern optimization, enabling pretrained models to adapt to diverse downstream tasks and domain-specific data. A major obstacle in large-scale fine-tuning is the memory overhead of backpropagation, which requires storing activations, gradients, and optimizer states. Zeroth-order (ZO) optimization offers a memory-efficient alternative, but its performance is highly sensitive to the stepsize and smoothing parameter, often requiring costly task-specific tuning. Parameter-free (PF) optimization addresses this issue by adapting algorithmic parameters without prior knowledge of problem-dependent constants. Moreover, large-scale fine-tuning can benefit from geometry-aware updates that account for the heterogeneous structure of parameter blocks, which can be modeled through methods that exploit linear minimization oracle (LMO). In this work, we study PF adaptation for LMO-based ZO optimization and introduce $\texttt{AdaNAGED}$, a method that unifies gradient-free training, adaptive tuning, and non-Euclidean update geometry. We establish convergence guarantees and validate the method on large-scale LLM fine-tuning task with $\texttt{OPT}-1.3\mathrm{B}$ model.

04.
arXiv (math.PR) 2026-06-24

Scheduling jobs with unknown size distribution in a M/G/1 queue: the shifted empirical Gittins

arXiv:2606.24703v1 Announce Type: new Abstract: In this paper we consider a M/G/1 queue for which we want to minimize the expected response time. We show how to compute indices from $n$ samples of the job size distribution such that the corresponding index policy is asymptotically optimal as $n$ grows. This construction is based on a discretization of the bounded support of the job size distribution and a shift of the samples to their nearest discrete point to the right. We show that the Gittins index of the empirical distribution of these shifted samples is close to the Gittins index of the original distribution. This translates to the asymptotic optimality of the corresponding index policy for minimizing the expected response time. Numerical comparison with other approaches further confirm the efficiency of our approach.

05.
medRxiv (Medicine) 2026-06-10

Towards the Virtual Amyotrophic Lateral Sclerosis Patient: Inferring Cortical Excitability through Whole-Brain Dynamical Modeling

Amyotrophic lateral sclerosis (ALS) is increasingly recognized as a multisystem neurodegenerative disorder in which motor-neuron degeneration is accompanied by widespread alterations in cortical dynamics. Among its most reproducible neurophysiological signatures is cortical hyperexcitability, yet how this local excitability imbalance shapes distributed whole-brain activity remains poorly understood. Here, we combined source-reconstructed resting-state MEG data, tractography-informed whole-brain modeling, and simulation-based inference to investigate whether ALS-related alterations in large-scale brain dynamics can be mechanistically explained by changes in cortical excitability. First, we characterized empirical brain dynamics using complementary features spanning regional activity amplitude and variability, functional connectivity, and avalanche-based metrics. These analyses revealed significant alterations in ALS patients relative to healthy controls, as well as associations with clinical impairment and disease staging. To mechanistically interpret these changes, we employed a reduced Wong-Wang whole-brain model in which local recurrent excitation modulates emergent large-scale neural dynamics. Simulations showed that increasing excitability systematically reproduced the empirical dynamical signatures observed in ALS. We then applied a simulation-based inference framework to estimate latent excitability parameters directly from empirical observations. Whole-brain model inversion revealed increased excitability in ALS patients compared with controls. The recovered excitability parameter was associated with disease staging, supporting its clinical relevance as a model-derived descriptor of ALS progression. Finally, by extending the model to estimate frontal and non-frontal excitability separately, we found that ALS-related alterations were predominantly associated with increased frontal excitability, whereas non-frontal regions appeared comparatively less affected. The recovered parameters related to disease staging. Together, these findings provide a mechanistic framework linking altered large-scale brain dynamics in ALS to selective cortical hyperexcitability, explaining how local excitability changes can give rise to global network reorganization. More broadly, they show how computational model inversion can recover latent multiscale pathophysiological processes from empirical neural recordings, offering a non-perturbative alternative to complex experimental paradigms typically required to causally probe local-to-global mechanisms.

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

Colab NAS: Obtaining lightweight task-specific convolutional neural networks following Occam's razor

The current trend of applying transfer learning from convolutional neural networks (CNNs) trained on large datasets can be an overkill when the target application is a custom and delimited problem, with enough data to train a network from scratch. On the other hand, the training of custom and lighter CNNs requires expertise, in the from-scratch case, and or high-end resources, as in the case of hardware-aware neural architecture search (HW NAS), limiting access to the technology by non-habitual NN developers. For this reason, we present ColabNAS, an affordable HW NAS technique for producing lightweight task-specific CNNs. Its novel derivative-free search strategy, inspired by Occam's razor, allows to obtain state-of-the-art results on the Visual Wake Word dataset, a standard TinyML benchmark, in just 3.1 GPU hours using free online GPU services such as Google Colaboratory and Kaggle Kernel.

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

Human-Guided Agentic AI for Multimodal Clinical Prediction: Lessons from the AgentDS Healthcare Benchmark

arXiv:2602.19502v2 Announce Type: replace Abstract: Agentic AI systems are increasingly capable of autonomous data science workflows, yet clinical prediction tasks demand domain expertise that purely automated approaches struggle to provide. We investigate how human guidance of agentic AI can improve multimodal clinical prediction, presenting our approach to all three AgentDS Healthcare benchmark challenges: 30-day hospital readmission prediction (Macro-F1 = 0.8986), emergency department cost forecasting (MAE = $465.13), and discharge readiness assessment (Macro-F1 = 0.7939). Across these tasks, human analysts directed the agentic workflow at key decision points, multimodal feature engineering from clinical notes, scanned PDF billing receipts, and time-series vital signs; task-appropriate model selection; and clinically informed validation strategies. Our approach ranked 5th overall in the healthcare domain, with a 3rd-place finish on the discharge readiness task. Ablation studies reveal that human-guided decisions compounded to a cumulative gain of +0.065 F1 over automated baselines, with multimodal feature extraction contributing the largest single improvement (+0.041 F1). We distill three generalizable lessons: (1) domain-informed feature engineering at each pipeline stage yields compounding gains that outperform extensive automated search; (2) multimodal data integration requires task-specific human judgment that no single extraction strategy generalizes across clinical text, PDFs, and time-series; and (3) deliberate ensemble diversity with clinically motivated model configurations outperforms random hyperparameter search. These findings offer practical guidance for teams deploying agentic AI in healthcare settings where interpretability, reproducibility, and clinical validity are essential.

08.
medRxiv (Medicine) 2026-06-22

Three multimodal large language models fail at clinically actionable breast pathology in three different directions

Background. Breast cancer treatment depends on histopathological features, such as grade and receptor-defined subtype; however, specialist pathologist access is constrained when the workforce is limited. Commercial multimodal large language models (MLLMs) accept hematoxylin and eosin (H&E) image tiles through paid interfaces without local hardware or fine-tuning. However, prior pathology evaluations addressed only coarse tasks. Whether they reach treatment-determining accuracy and whether vendors agree remain unclear. Methods. We aimed to evaluate three vendor-designated flagship MLLMs (Claude Sonnet 4.6, Gemini 2.5 Pro, GPT-5.5) in 427 invasive breast cancer cases. Each case went to all three with identical H&E tiles and prompts, and the subtype was inferred in the second call. The reference was an institutional sign-out report of an immunohistochemistry-derived subtype. We calculated the concordance, sensitivity, specificity, Cohen's kappa, and pairwise McNemar and Bowker tests. Findings. Claude ranked highest by raw histologic-type concordance but lowest by kappa, classifying all 23 lobular and seven micropapillary carcinomas as invasive breast carcinoma of no special type. The models anchored the Nottingham grade to three modal grades. None of the models reliably identified human epidermal growth factor receptor 2-positive disease. The failure direction was vendor-specific: Claude and GPT-5.5 were under-detected, whereas Gemini was over-called. Twelve prompt variants (4,056 calls) did not recover sensitivity. Interpretation. No current commercial MLLM reaches deployment-ready accuracy for any treatment-determining feature of breast pathology. As each vendor fails in its own fixed direction, changing vendors alters the type of error rather than removing it; therefore, the value of these models is assistive rather than autonomous. At USD 0.20-0.50 per case, they may serve as supervised draft generators that leave the diagnosis with the pathologist.

09.
arXiv (quant-ph) 2026-06-12

Candidate overtone shear horizontal SAW resonators in thin-film lithium niobate for intermodal acousto-optic modulation

arXiv:2606.12853v1 Announce Type: cross Abstract: The merits of thin-film surface acoustic wave (SAW) devices are pivotal to develop the high-performance intermodal acousto-optic modulators. In this work, we have proposed shear-horizontal (SH) SAW resonators for anticipated intermodal acousto-optic modulation on the thin-film lithium niobate platform. Through optimization of the cut angle of LN films, the SAW wavelength, and the thickness of interdigital transducer (IDT) electrodes, the calculated acousto-optic overlap factors utilizing SH0 modes are improved by more than an order of magnitude compared with those of Rayleigh modes. Furthermore, we have fabricated and characterized three kinds of proof-of-principle SH0 mode devices without/with grating reflectors. The electromechanical coupling coefficients (keff^2) and quality factors (Q) in the overtone resonators with grating reflectors are systematically evaluated, featuring the highest Q of 843 with the compromised keff^2 of 0.96%-4.72%. The results reveal that the temperature coefficients of frequency (TCF) of Rayleigh modes vary across various overtones, whereas the SH0 modes exhibit TCFs in the range of 32.3-68.9 ppm/C. Our fabricated SH0-mode overtone resonators demonstrate the capability of operating at power levels up to 29 dBm without electrode damage, offering a promising paradigm for robust and high-efficiency intermodal acousto-optic modulators with potential applications in integrated optical signal processing, microwave photonics,and quantum information technologies.

10.
arXiv (quant-ph) 2026-06-11

Strong-field control of the $Z$-boson resonance in $e^+e^-$ collisions

arXiv:2606.09394v2 Announce Type: replace-cross Abstract: Resonant $Z$-boson production is a cornerstone of precision electroweak physics, with its vacuum line shape set by the $Z$ mass, width, and collision kinematics. We show that a strong laser field can significantly alter this picture. By treating the field nonperturbatively, we find that laser dressing of the incoming fermions alters the effective collision kinematics and opens laser-photon exchange channels, including multiphoton processes, in $e^{+}e^{-}$ collisions. As a result, the $Z$-resonance profile develops distinct intensity-dependent regimes, evolving from the vacuum limit to saturation at intermediate field strengths and to an approximately quadratic enhancement at higher intensities. Additionally, the polarization composition of the produced $Z$ bosons is redistributed. In particular, at high intensities the laser-induced contribution can compensate the intrinsic chiral asymmetry of the electroweak interaction, leading to nearly parity-balanced $Z$-boson production. Our results identify that strong classical fields can dynamically control electroweak resonance phenomena, opening a bridge between strong-field QED and high-energy collider physics.

11.
arXiv (CS.LG) 2026-06-16

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

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

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

Convex training of Lipschitz-regularized shallow neural networks

arXiv:2606.19652v1 Announce Type: new Abstract: In this work, we introduce a training procedure for shallow neural networks that promotes robustness against adversarial attacks. We solve a non-convex Lipschitz-regularized training program by introducing a convex restriction that can be efficiently solved to global optimality. Our approach can be employed as a post-processing step by taking a pre-trained network as an initial solution to then solving the convex program whose optimal network is guaranteed to be no worse than the initial one. We illustrate the improvements of our training procedure with experiments using real world datasets for regression tasks under an adversarial setting. We show numerically that solving our proposed convex program yields networks with lower objective values on the Lipschitz-regularized program compared to existing methods. Additionally, we show that on certain datasets, networks obtained using our convex training program are both more accurate and robust with respect to adversarial attacks.

13.
arXiv (math.PR) 2026-06-19

The t-Split Two-Periodic Aztec Diamond Model

Authors:

arXiv:2606.19507v1 Announce Type: new Abstract: In this work we consider an Aztec diamond model split into two unequal regions which are asymptotically fixed in size. Each region is weighted with a distinct two-periodic weighting. We refer to this model as the t-split two-periodic Aztec diamond, to signify its difference from the previous work title Split Two-Periodic Aztec Diamond, where the model was split into two equal regions. We derive an integral expression for the correlation kernel of the model and give a partial description of the scaling limit behavior, along with a conjecture for the remainder. We refer to the larger and smaller sides of the model as the dominant and non-dominant sides, and to the location of the weight change as the interface. The dominant side exhibits a limit shape that depends only on its own weighting and is identical to that of the two-periodic Aztec diamond, while the non-dominant side appears to have a novel limit shape that depends on both weightings and the location of the interface. Lastly, we consider the complete limit shape in the case where the dominant side two-periodic parameter goes to 0.

14.
arXiv (CS.CV) 2026-06-24

TIGER: Taming Identity, Geometry, and Generative Priors for High-Quality Face Video Restoration

Face Video Restoration (FVR) aims to recover high-fidelity facial videos from degraded input while preserving identity and semantic consistency across frames. Existing methods often struggle to simultaneously address three key challenges: identity shift, viewpoint-entangled guidance, and perceptual realism. To tackle these issues, we propose TIGER, a structured tri-prior fusion framework that Tames Identity, Geometry, and gEnerative pRiors for high-quality FVR. Specifically, an Identity Prior is first established by injecting subject-discriminative embeddings into the latent space, effectively anchoring the subject's identity against severe degradations. Then, to provide temporally consistent structural guidance for dynamic videos, TIGER constructs a Geometry Prior by lifting 2D reference cues into a disentangled 3D parameter space, creating a geometric anchor through cross-source parameter fusion. Moreover, to achieve maximum efficiency without compromising realism, we harness the video generation model's Generative Prior through a one-step rectified flow. We further design a progressive three-stage training optimization strategy that refines structural fidelity, textural reconstruction, and distribution-level realism to ensure robust optimization. We also construct a large-scale FVR dataset to facilitate robust training and standardized evaluation. Extensive experiments demonstrate that TIGER achieves state-of-the-art performance in both identity fidelity and temporal stability, delivering a high-quality, efficient and identity-consistent FVR. Project page: https://yzhoulv.github.io/Tiger/.

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

Mask Proposal Voting Based on Geodesic Framework for Robust Image Segmentation

Despite great advances, finding accurate segmentation remains a challenging task, especially in scenarios with cluttered backgrounds, complex intensity variations and topology appearance. Minimal path models have exhibited their strong ability in addressing image segmentation tasks. However, the performance of minimal paths-based segmentation approaches is heavily influenced by model initialization, hence limiting their application scope in practice. In this work, we propose a novel mask proposal voting framework that overcomes the major drawback of classical approaches, allowing robust segmentation even in complicated scenarios. Firstly, we introduce an efficient method for constructing adaptive domain cuts as a constraint for initializing the region-based min-cut evolution, by which diverse and reliable mask proposal candidates can be generated, substantially increasing the possibility of accurately covering the objective region by these proposals. Secondly, we propose a new mask voting scheme to build a voting score map encoding the final segmentation information. In contrast to classical path voting methods, our model allows incorporating priors to assign different importance to each individual mask. As a consequence, the proposed segmentation model is capable of accurately delineating object boundaries under complex scenarios, and is insensitive to initialization. Experiments demonstrate that our method consistently outperforms state-of-the-art minimal path-based approaches in both accuracy and robustness.

17.
medRxiv (Medicine) 2026-06-17

A non-invasive liquid biopsy resolves the diagnostic blind spot in chronic kidney disease

Chronic kidney disease is a major global health burden, and its early detection is critical for delaying progression to kidney failure using recently developed targeted therapies. However, current diagnostic screening relies heavily on blood markers that are confounded by muscle mass, and on urine tests that frequently miss structural damage occurring without protein leakage. This creates a critical diagnostic blind spot that hinders timely intervention. Here we show a non-invasive liquid biopsy platform that quantifies a specific protein marker, MUC1, on urinary extracellular vesicles to accurately assess renal parenchymal integrity. By bypassing the systemic metabolic noise of traditional blood tests, our assay provides a remarkably stable, person-specific functional signature. Following extensive validation across diverse cohorts, our longitudinal analysis demonstrated that the discrepancy between this novel urine-based readout and standard blood tests unmasks hidden renal vulnerability, successfully predicting rapid functional decline. By comprehensively evaluating both tubular and glomerular integrity from a single spot urine sample, these findings establish a completely non-invasive, highly scalable prescreening tool that resolves the diagnostic blind spot, enabling broader early detection strategies and ushering in a new era of proactive risk management.

18.
arXiv (CS.LG) 2026-06-19

DF-ExpEnse: Diffusion Filtered Exploration for Sample Efficient Finetuning

arXiv:2606.19656v1 Announce Type: cross Abstract: A natural recipe for intelligent robotic decision-making is initializing from pretrained generative control policies, which have summarized offline experience, and adapting them to self-collected online experience. We present DF-ExpEnse, an exploration technique that improves the quality of online experience collection, thus increasing finetuning sample-efficiency. DF-ExpEnse leverages the multimodal modeling capabilities of the generative control policy to create an expressive and tractably evaluatable candidate set. It then utilizes an ensemble of critics to identify the action that best balances quality with high exploration interest. In fleet settings, DF-ExpEnse further enables cross-agent communication to facilitate collaborative exploration as a group. DF-ExpEnse can be seamlessly integrated with existing strategies that finetune pretrained generative control policies via reinforcement learning. We experimentally validate consistent sample-efficiency benefits through DF-ExpEnse across a variety of manipulation and locomotion tasks, compared to default finetuning and alternative action selection schemes. Project can be found at https://df-expense.github.io.

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

SPATIA: Multimodal Generation and Prediction of Spatial Cell Phenotypes

Understanding how cellular morphology, gene expression, and spatial context jointly shape tissue function is a central challenge in biology. Image-based spatial transcriptomics technologies now provide high-resolution measurements of cell images and gene expression profiles, but existing methods typically analyze these modalities in isolation or at limited resolution. We address the problem by introducing SPATIA, a multi-level generative and predictive model that learns unified, spatially aware representations by fusing morphology, gene expression, and spatial context from the cell to the tissue level. SPATIA also incorporates a spatially conditioned generative framework with confidence-aware OT reweighting and morphology-profile alignment for modeling target-state morphology distributions. Specifically, we propose a confidence-aware flow matching objective that reweights weak optimal-transport pairs based on uncertainty. We further apply morphology-profile alignment to encourage biologically meaningful image generation, enabling the modeling of microenvironment-dependent phenotypic transitions. We assembled a multi-scale dataset consisting of 25.9 million cell-gene pairs across 17 tissues. We benchmark SPATIA against 18 models across 12 tasks, spanning categories such as phenotype generation, annotation, clustering, gene imputation, and cross-modal prediction. SPATIA achieves improved performance over state-of-the-art models, improving generative fidelity by 8% and predictive accuracy by up to 3%.

20.
arXiv (CS.AI) 2026-06-17

TrustErase: Auditable Instant Machine Unlearning with Passport-Embedded Representations

arXiv:2606.17122v1 Announce Type: cross Abstract: The demand for privacy-compliant AI has amplified the need for machine unlearning; yet, existing retraining or distillation-based methods remain unverifiable and computationally costly. We introduce TrustErase, a verifiable, data-free unlearning framework leveraging passport-embedded representations for instant, modular, and auditable forgetting. By treating passports as cryptographic keys within parameter-efficient adaptation layers, TrustErase enables the removal of specific classes or datasets through simple deactivation, without retraining, fine-tuning, or access to the original data. A singular value based decomposition conceals passports within model weights, ensuring that unlearning actions remain transparent and provably compliant. Evaluations on MNIST, CIFAR10 and CIFAR100 show that TrustErase matches or exceeds state-of-the-art benchmarks such as DELETE, L2UL, and Boundary Shrink, while operating in a strictly data-free regime. Ultimately, TrustErase establishes a new paradigm for trustworthy, accountable, and instantly forgettable AI systems.

21.
Nature (Science) 2026-06-24

Small-molecule modulation of β-arrestins

β-Arrestins are multifunctional regulators of G-protein-coupled receptor (GPCR) signalling and orchestrate diverse downstream signalling events and physiological responses across the GPCR superfamily1–3. Although GPCR pharmacology has advanced to target orthosteric and allosteric sites, as well as G proteins and GPCR kinases, direct chemical tools to modulate β-arrestin activities have remained conspicuously absent. Here we report the identification of small-molecule inhibitors that selectively target β-arrestins and delineate their mechanism of action through integrated pharmacological, biochemical, biophysical and structural analyses. These inhibitors disrupt β-arrestin engagement with agonist-activated GPCRs, impairing desensitization, internalization and β-arrestin-dependent physiological functions while sparing G protein–receptor coupling. Cryo-electron microscopy, molecular dynamics simulations and structure-guided mutagenesis reveal that one modulator, Cmpd-5, engages a pocket within the central crest of β-arrestin1 formed by the middle, C and lariat loops, a critical receptor-binding interface, stabilizing a distinct conformation that is incompatible with full β-arrestin–receptor engagement. Together, these findings establish a mechanistic framework for β-arrestin modulation, reveal a novel allosteric site for structure-based drug design, and open new avenues for transducer-targeted, pathway-specific GPCR therapeutic agents. Integrated pharmacological, biochemical, biophysical and structural analyses of small-molecule β-arrestin inhibitors show how they block β-arrestin engagement with activated GPCRs, revealing their mechanism of action and uncovering a previously unrecognized allosteric regulatory site.

22.
arXiv (CS.LG) 2026-06-18

A Streaming Sparse Cholesky Method for Derivative-Informed Gaussian Process Surrogates Within Digital Twin Applications

arXiv:2511.00366v2 Announce Type: replace-cross Abstract: Digital twins are developed to model the behavior of a specific physical asset (or twin), and they can consist of high-fidelity physics-based models or surrogates. A highly accurate surrogate is often preferred over multi-physics models as they enable forecasting the physical twin future state in real-time. To adapt to a specific physical twin, the digital twin model must be updated using in-service data from that physical twin. In this paper, we combine and extend several previous surrogate-related advancements with the goal of demonstrating an end-to-end digital twin (DT) solution for predicting performance of an aircraft structure (the physical asset). To this end, we extend Gaussian process (GP) models to include derivative data, for improved accuracy, with dynamic updating to ingest physical twin data during service. Including derivative data, however, comes at a prohibitive cost of increased covariance matrix dimension. We circumvent this issue through our modified dynamic sparse Cholesky linear system solver. Numerical experiments demonstrate that the prediction accuracy of the derivative-enhanced sparse Cholesky GP method produces improved models upon dynamic data additions. Lastly, we demonstrate the developed algorithm within a DT framework to model fatigue crack growth in an aerospace vehicle, thereby exhibiting through our assembled engineered system how digital twin technologies can be combined in practice.

23.
Nature (Science) 2026-06-24

A <i>Streptomyces</i> megacluster encodes synergistic biotin-targeting antibiotics

Authors:

Natural products remain a major source of antibiotics, but discovery efforts have traditionally treated biosynthetic gene clusters as sources of individual bioactive molecules1–5. Increasing evidence has suggested that microorganisms can instead encode coordinated multi-metabolite systems, yet the genetic architectures and biological logic of such systems remain poorly understood6–12. Here we show that Streptomyces spp. encode a highly conserved biosynthetic megacluster that produces four structurally distinct natural product families—stravidins, acidomycin, dapamycins, and 2-methyl-7-keto-8-aminopelargonic acid (α-Me-KAPA)—alongside the biotin-binding protein streptavidin. These components converge on bacterial biotin metabolism through complementary mechanisms, including enzyme inhibition, prodrug activation, cofactor mimicry and biotin sequestration. The encoded metabolites are co-produced and act synergistically across Gram-negative and mycobacterial species, with stravidin S2 and α-Me-KAPA showing enhanced efficacy in combination in a mouse model of multidrug-resistant Escherichia coli infection. This megacluster reveals a genetically encoded chemical arsenal that functions as a naturally evolved combination therapy against a conserved metabolic pathway. More broadly, our findings suggest that higher-order biosynthetic architectures may represent an overlooked reservoir of antibiotic mechanisms and support a shift from discovering isolated natural products to reconstructing native synergistic systems. In Streptomyces spp., a conserved biosynthetic gene megacluster produces an arsenal of distinct antimicrobials that converge on bacterial biotin biosynthesis as a naturally evolved combination therapy.

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

A Multi-level Analysis of Factors Associated with Student Performance: A Machine Learning Approach to the SAEB Microdata

arXiv:2510.22266v3 Announce Type: replace-cross Abstract: Identifying the factors that influence student performance in basic education is a central challenge for formulating effective public policies in Brazil. This study introduces a multi-level machine learning approach to classify the proficiency of 9th-grade and high school students using microdata from the System of Assessment of Basic Education (SAEB). Our model uniquely integrates four data sources: student socioeconomic characteristics, teacher professional profiles, school indicators, and principal management profiles. A comparative analysis of four ensemble algorithms confirmed the superiority of a Random Forest model, which achieved 90.2% accuracy and an Area Under the Curve (AUC) of 96.7%. To move beyond prediction, we applied Explainable AI (XAI) using SHAP, which revealed that the school's average socioeconomic level is the most dominant predictor, demonstrating that systemic factors have a greater impact than individual characteristics in isolation. The primary conclusion is that academic performance is a systemic phenomenon deeply tied to the school's ecosystem. This study provides a data-driven, interpretable tool to inform policies aimed at promoting educational equity by addressing disparities between schools.

25.
arXiv (CS.AI) 2026-06-12

Nous: An Attempt to Extract and Inject the Cognition Behind Prediction-Market Behavior

Authors:

arXiv:2606.13038v1 Announce Type: new Abstract: As LLM agents proliferate in prediction markets and collective decision-making, they risk a cognitive monoculture: agents built on shared foundation models produce correlated forecasts, and recent measurement finds frontier-model errors correlated at r ~ 0.77. We ask whether human cognitive diversity can be recovered from behavior and transferred to LLM agents. Nous extracts a structured eight-dimension behavioral profile from real Polymarket trading activity and injects it into agents through prompts. Our central finding is a dissociation between the two halves of that pipeline. Extraction works, partially: across 100 wallets, 8 of 14 parameters are temporally stable (split-half ICC >= 0.5, bootstrap CI lower bound > 0.3; contrarian score reaches ICC ~ 0.9); wallets are identifiable from their profiles well above chance (top-1 retrieval 17-22% vs. 1% chance); and two of four pre-specified dimensions rank-correlate with future realized profit out-of-sample, though the correlations do not survive behavioral-confound controls. Prompt-level injection does not measurably transmit it: on a semantic embedding metric, structured injection shows no significant advantage over a length-matched control on any model, and the diversity it induces neither reduces ensemble error correlation nor improves Brier score – a null that persists across exploratory checks on sampling temperature, profile diversity, and question difficulty. Measuring the prompts themselves locates the compression before the model: the structure-to-narrative translator emits near-uniform prompts whose spread does not track profile spread. We position Nous as measuring the cognitive-monoculture problem and the limits of a prompt-level remedy, motivating deeper, below-the-prompt injection (fine-tuning, activation steering). Code, frozen profiles, prompts, and model outputs: https://github.com/WillChienT/nous-paper