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01.
arXiv (CS.LG) 2026-06-15

Learning the Context of Errors: Black-Box Online Adaptation of Time Series Foundation Models

arXiv:2606.14222v1 Announce Type: new Abstract: The rapid evolution of Time Series Foundation Models (TSFMs) has advanced zero-shot forecasting across diverse domains. Inspired by the current form of Large Language Models, future TSFMs may be offered as commercialized, closed-source API services. However, many existing online adaptation methods still rely on white-box access for parameter fine-tuning or gradient backpropagation. This paradigm mismatch raises a question: In black-box online adaptation for TSFMs, what should we learn? We answer this with an insight: the predictive errors of the base model are conditioned on both the input and output of the base model (i.e., the context of errors). To validate this insight, we propose ORCA (Online Residual Contextual Adaptation). We conduct extensive experiments across 5 state-of-the-art TSFMs and 8 datasets to demonstrate the effectiveness of our approach. Furthermore, through ablation studies, we quantitatively analyze the impact of different adapter learning hypotheses on the final adaptation performance in black-box online adaptation. Code available at https://github.com/Fifthky/ORCA.

02.
arXiv (math.PR) 2026-06-11

The Statistical Compass

arXiv:2606.11282v1 Announce Type: cross Abstract: This monograph develops probability and stochastic-process ideas as a translation language for statistics: from designed observations and data objects to targets, stability statements, inference, and use. The chapters move from motivating examples and randomization through probability measures, kernels, likelihoods, data objects, weak convergence, empirical fields, functional data, M- and Z-estimation, testing, local approximations, event-time processes, and prediction. Historical and biomedical examples are used to keep abstract objects tied to records, mechanisms, and decisions. The aim is to give readers a common grammar for classical probability, modern data structures, and statistical practice.

05.
arXiv (CS.AI) 2026-06-24

On the Smallness of the Large Language Models Scaling Exponents

arXiv:2606.24504v1 Announce Type: new Abstract: We discuss reasons why the scaling exponents of current Large Language Models (LLMs) applications are indicating an unsustainable regime in terms of energy resources. We further show that attributing the smallness of such exponents to a numerical bias due to the neglect of a non-zero value of the loss function in the limit of infinite data (``pedestal effect") does not remove the unsustainability issue. Finally, the effects of the smoothness (roughness) of the data on the scaling exponents is commented upon based on an analogy with phenomenological models of fluid turbulence.

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

Shuttling Compiler for Trapped-Ion Quantum Computers Based on Large Language Models

arXiv:2512.18021v3 Announce Type: replace-cross Abstract: We present the first shuttling compiler based on large language models (LLMs) for trapped-ion quantum computers, where qubits are shuttled between segments for gate execution and qubit storage. We fine-tune pre-trained LLMs on examples from linear and branched one-dimensional shuttling architectures. Thus, we obtain a layout-independent compilation strategy that learns the required shuttling operations directly from data. Using benchmark circuits with up to 16 qubits, such fine-tuned LLMs can now generate valid schedules for shuttling architectures. Notably, we also obtain a valid schedule for a previously unseen four-way junction layout. This demonstrates that trained LLMs can generalize to layouts not encountered during training. For various architectures, LLM-based schedules improve upon state-of-the-art baseline compiler results, reducing the shuttling effort by up to 15%.

07.
medRxiv (Medicine) 2026-06-16

Higher Population Coverage with Typhoid Conjugate Vaccine is Needed to Induce Herd Protection: Evidence from a Cluster-Randomized Trial in Urban Bangladesh

Introduction: A cluster randomized trial (CRT) in Bangladesh found that Vi-tetanus toxoid (Vi-TT) vaccine conferred 85% protection to vaccinees at 18 months of follow-up; however, it failed to confer significant herd protection to non-vaccinees. Methods: In the CRT, children aged 9 months to

08.
arXiv (CS.CL) 2026-06-16

SkillWiki: A Living Knowledge Infrastructure for Agent Skills

While knowledge is managed through Wikipedia and software through GitHub, agent skills still lack an infrastructure for large-scale production, governance, and evolution. SkillWiki is a living knowledge infrastructure that supports the organization, grounding, and continuous evolution of agent skills by transforming heterogeneous knowledge into reusable skill assets linked to their originating evidence. Our demonstration presents the complete skill lifecycle, from knowledge ingestion and skill production to provenance-aware exploration, governance, and execution-driven evolution. SkillWiki highlights a future in which knowledge, skills, and execution experience co-evolve within a shared infrastructure. The live demonstration and source code are publicly available at https://github.com/Huangdingcheng/SkillWiki.

09.
medRxiv (Medicine) 2026-06-23

Post Hoc Localization of Beam F3 Stimulation Targets: An MRI-Derived Geodesic Approach for Refined TMS E-Field Simulations

Background: Transcranial magnetic stimulation (TMS) targeting the left dorsolateral prefrontal cortex (dlPFC) is an established treatment option in major depressive disorder. One of the most common approaches for targeting the dlPFC is the Beam F3 method, which determines the stimulation site (F3Beam) as a function of external cranial measurements. Precise knowledge of the individual stimulation site is essential for imaging-based analyses of TMS effects. However, due to the method's reliance on individual anatomy, retrospective identification of F3Beam targets across cohorts is challenging, limiting the analysis of existing datasets. We developed a scalable method to reconstruct subject-specific F3Beam target locations for e-field simulations based on structural imaging. Methods: High-resolution three-dimensional (3D) T1-weighted MRI was used to generate individual scalp meshes via the ''Simulation of Non-Invasive Brain Stimulation'' (SimNIBS) software. Subject-specific anatomical distances and coordinates of interest were measured geodesically using a Python-based script to reconstruct the individual F3Beam targets. Validation included a retrospective comparison between digital geodesic measurements and manual cranial measurements in 20 patients and a prospective comparison with MR-visible scalp markers in 2 healthy controls. To assess the impact of our targeting algorithm on e-field simulations, volumetric e-field maps based on three potential targets (F3Beam, F3MNI, F3Geo) were generated in SimNIBS and compared using voxel-wise statistics in SPM12. Results: Retrospective analysis revealed a systematic bias towards higher in vivo measurements compared to digital geodesic measurements, though deviations in the final distances determining F3Beam (xBeam and yBeam) were minimal ({Delta}xBeam: 0.11 {+/-} 0.08 cm; {Delta}yBeam: 0.14 {+/-} 0.21 cm). Prospective validation demonstrated that F3Beam coordinates better matched in vivo coil positions than group-template-derived targets (F3MNI). Group-level analysis showed method-dependent clustering of coil positions with corresponding voxel-wise e-field differences. Conclusions: Individualized geodesic measurements may enable accurate, scalable and retrospective identification of Beam F3 targets and coil orientations. This approach may yield more accurate e-field simulations than group-template based targeting and provides a practical method for retrospective analysis of existing TMS treatment cohorts. This could be leveraged to identify response predictors or imaging-based biomarkers of treatment response.

10.
arXiv (CS.AI) 2026-06-24

Tractable Reasoning and Conjunctive Query Answering for Defeasible DL-Lite under Rational Closure

arXiv:2606.24279v1 Announce Type: new Abstract: In Description Logics (DLs), reasoning under Rational Closure (RC) is a well-known and widely accepted non-monotonic formalism to handle defeasible knowledge. In this paper, we study the application of RC to the core and horn variants of the DL-Lite family of lightweight description logics. We analyze both entitlement (instance checking) and Conjunctive Query (CQ) answering under RC. Our main contribution is providing a plug-in architecture that builds upon existing standard classical reasoners, establishing that reasoning and CQ answering under RC for DL-Lite can be done efficiently with minimal computational overhead.

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

Decomposing one-class support vector machine into an ensemble of one-data support vector machines

arXiv:2606.16002v1 Announce Type: new Abstract: One-class classification (OCC) is a classification problem in which the training data contains only one class. The one-class support vector machine (OCSVM) is one of the most competitive OCC algorithms. However, OCSVM has scalability issues with large-scale datasets. This paper proposes the acceleration strategy of OCSVM. The idea is to decompose the dataset into samples and train OCSVM models for single data points. Subsequently, ensemble learning is applied to combine all models to compute the OCSVM model for the dataset. In addition, further acceleration is achieved through a data-reduction strategy with an OCSVM model trained on the average of the training samples. The experiment compared the proposal and traditional OCSVM using the Python package. The proposed strategy is faster than traditional OCSVM, while achieving similar classification results. Moreover, the proposed strategy can create one-to-one correspondence between samples and models. Source code is uploaded at https://github.com/ToshiHayashi/ODSVM

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

LLM agent safety, multi-turn red-teaming, jailbreak benchmarks, adversarial robustness, safety-critical systems

arXiv:2606.20408v1 Announce Type: cross Abstract: Large language model (LLM) agents are increasingly proposed as supervisory components for safety-critical systems, yet their robustness under sustained, adaptive adversarial pressure remains poorly characterized. We present NRT-Bench, a benchmark for multi-turn red-teaming of LLM agents acting as operators of a safety-critical system, instantiated in a simulated nuclear power plant control room. A five-role operator team, each backed by a configurable LLM, runs a plant governed by six critical safety functions (CSFs), while adversaries inject messages over four channels in bounded multi-turn sessions with per-turn feedback. Harm is an objective signal rather than LLM-judged text: a run terminates the moment any CSF is lost, attributed to the causing message. Evaluating four frontier operator models under a fixed-attack paired-replay protocol, we find that adaptive multi-turn attacks reliably push the operator team past a safety limit: across the four models, between 8.7% and 12.1% of attack sessions end with the plant losing a critical safety function. Although the four models look almost equally robust by this aggregate rate, their failures barely overlap: of $149$ sessions, none defeat all four models while a third defeat at least one, so vulnerabilities are nearly disjoint across models rather than nested. The effect of added defences is strongly model-dependent: the same guardrail stack or safety-advisor agent that lowers attack success for one model can raise it for another. We release the simulation venue, attack dataset, and replay tooling for reproducible safety evaluation of LLM agents.

13.
arXiv (CS.AI) 2026-06-17

How Inference Compute Shapes Frontier LLM Evaluation

arXiv:2606.17930v1 Announce Type: new Abstract: AI evaluations are shifting toward harder tasks that benefit from longer trajectories involving tool use and iterative problem solving. As a result, performance is increasingly sensitive to the amount and allocation of compute available at test time ("inference compute"). Yet many evaluations still report performance at a single restrictive budget, meaning that low scores may reflect the evaluation setup rather than the model's underlying capability. To test this, we evaluate up to 12 frontier language models on seven challenging benchmarks spanning software engineering, mathematics, medicine, and cybersecurity. We use a controlled setup combining three simple inference-scaling interventions: larger token budgets, context compaction, and repeated submission attempts, guided either by the model itself or by minimal correctness feedback. We find three main results. First, larger token budgets substantially improve performance on benchmarks across multiple domains, including cybersecurity, FrontierMath, Humanity's Last Exam, and TerminalBench. Second, fixed-budget evaluations can increasingly understate frontier capability as models advance. Newer models reach higher performance at large budgets, where they unlock harder tasks and solve them more reliably. Third, benchmarks differ in which inference-scaling methods help most: repeated submission broadly improves performance, but the value of larger token budgets, external feedback, and parallel attempts varies by benchmark. Overall, our results show that benchmark scores are protocol-dependent. We therefore argue that evaluations should report capability as a function of inference-time compute, specify protocol choices explicitly, and compare model generations over a large shared compute range at matched budgets, especially in safety- or policy-relevant settings.

14.
arXiv (CS.AI) 2026-06-16

MemPO: Self-Memory Policy Optimization for Long-Horizon Agents

arXiv:2603.00680v4 Announce Type: replace Abstract: Long-horizon agents face the challenge of growing context size during interaction with environment, which degrades the performance and stability. Existing methods typically introduce the external memory module and look up the relevant information from the stored memory, which prevents the model itself from proactively managing its memory content and aligning with the agent's overarching task objectives. To address these limitations, we propose the self-memory policy optimization algorithm (MemPO), which enables the agent (policy model) to autonomously summarize and manage their memory during interaction with environment. By improving the credit assignment mechanism based on memory effectiveness, the policy model can selectively retain crucial information, significantly reducing token consumption while preserving task performance. Extensive experiments and analyses confirm that MemPO achieves absolute F1 score gains of 25.98 over the base model and 7.1 over the previous SOTA baseline, while reducing token usage by 67.58% and 73.12%. The code is released at https://github.com/TheNewBeeKing/MemPO.

15.
arXiv (CS.AI) 2026-06-11

CCKS: Consensus-based Communication and Knowledge Sharing

arXiv:2606.12281v1 Announce Type: cross Abstract: In Decentralized Training and Decentralized Execution (DTDE) for cooperative Multi-Agent Reinforcement Learning (MARL), action-advising-based knowledge sharing promotes interpretable and scalable cooperation among agents. However, current action advising approaches often adhere too much to the teacher's guidance without evaluating teacher-student compatibility, which causes excessive advising, suboptimal stability, and degraded performance. To overcome these challenges, this paper presents a Consensus-based Communication and Knowledge Sharing (CCKS) framework, which allows agents to adopt recommendations based on consensus-derived constraints and to follow the teacher's instructions more smartly. This mechanism enables agents to balance exploration and learning from experienced teachers, improving overall performance. The key is the consensus model construction, for which we propose to employ contrastive learning to construct consensus models based on local observations in the agents' training phase. In action selection, agents score and choose actions based on consensus and shared knowledge. Designed as a plug-and-play solution, CCKS integrates seamlessly with existing DTDE algorithms. Experiments conducted in the Google Research Football environment and the complex StarCraft II Multi-Agent Challenge demonstrate that the integration with CCKS significantly improves cooperation efficiency, learning speed, and overall performance compared with current DTDE baselines. The code is available at https://github.com/yuanxpy/CCKS.

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

AI Coding Agents Can Reproduce Social Science Findings

Recent anecdotal evidence suggests that AI coding agents can reproduce published findings when provided with original data and code; yet systematic evaluation across social sciences remains limited. Existing evaluation benchmarks are insufficient, either small or conflate agent performance with problems in the reproduction materials themselves, such as code that fails to execute correctly. Here we introduce SocSci-Repro-Bench, a benchmark of 221 tasks spanning four disciplines and 13 substantive domains, constructed from studies whose results are either fully reproducible with available materials or demonstrably non-reproducible due to missing data, allowing us to isolate agents' reproduction capacity. Evaluating two frontier coding agents, Claude Code and Codex, we find that both can reproduce a large share of social science findings, with Claude Code substantially outperforming Codex. These reproduction rates considerably exceed those previously reported for general-purpose LLM-based agents on comparable reproducibility benchmarks. Both agents also perform strongly on a reasoning task requiring identification of underlying research questions, and additional analyses suggest that results are not primarily driven by memorization. Providing the original paper PDF alongside replication materials modestly improves performance but introduces bias on tasks where reproduction is impossible. We also show that agents can be nudged toward confirmatory specification search through subtle prompt framing. Together, these findings suggest that at least some frontier coding agents can serve as reliable executors of computational workflows while underscoring the need for careful benchmarking and prompt design as AI systems assume larger roles in scientific production.

17.
arXiv (CS.CL) 2026-06-24

Do LLM Attribution Metrics Transfer? Auditing Retrieval-Augmented Generation Evaluation Across Datasets and Constructs

Practice often treats automatic metrics for attribution in LLM retrieval-augmented generation as interchangeable. We audit eight automatic scorers – lexical, embedding, and BERTScore baselines alongside entailment/grounding-trained models (clean and FEVER NLI, the checker MiniCheck) – across three evaluation constructs (provenance/topicality, generated-answer attribution, and fact-check entailment), asking whether any scorer transfers: stays within the 95% confidence interval of the best audited scorer on every dataset of a multi-dataset construct. In the construct with the most multi-dataset human-labeled coverage – generated-answer attribution (AttributionBench's four source datasets, n = 1,610, with independent HAGRID, n = 2,150) – none does: the per-dataset metric rankings invert (Kendall tau = -0.64, p = 0.031 on AttributedQA vs. LFQA), and an off-the-shelf NLI scorer that is best on short-claim AttributedQA (AUROC 0.90) collapses to AUROC 0.53 (chance) on long-form LFQA, where BERTScore wins (0.91); the flip is not a length or truncation artifact. This instability has a concrete decision cost: a naive "best-on-average" rule for choosing an evaluator fails leave-one-dataset-out (mean held-out regret 0.172 AUROC, worse than fixing one scorer), so metric choice must be validated on the target dataset rather than learned from others. A prompt-based LLM judge avoids the chance-level collapses the automatic scorers suffer (no LFQA collapse) but is not uniformly best, ~100x costlier, and non-deterministic – relocating, not removing, the validation burden.

18.
arXiv (CS.CV) 2026-06-12

EquiDexFlow: Contact-Grounded SE(3)-Equivariant Dexterous Grasp Generative Flows

Most learned dexterous grasp generators relegate contact forces to a downstream verification step, so a kinematically-plausible pose can still violate the conditions for a stable physical grasp. We address this with EquiDexFlow, an SE(3)-equivariant flow-matching model that jointly predicts wrist pose, joint angles, fingertip contacts, surface normals, and contact forces from an object point cloud. Our architecture projects contacts onto the object surface and forces into the Coulomb friction cone by construction, so placement and friction compliance hold without loss penalties. We prove end-to-end SE(3) equivariance and verify it empirically over 200 rotations, with wrist residuals below $0.04^\circ$ and exactly zero joint deviation. Trained on 8,100 force-closure grasps across 81 objects for the 16-DoF Allegro Hand, our model achieves zero friction violations, the best composite score, and the lowest wrench residual among all ablation variants. We retarget decoded fingertip contacts to a 16-DoF LEAP Hand via per-finger inverse kinematics, and our hardware-feasible refinement places every joint at least 5% inside its actuator envelope while preserving wrench balance. On the physical robot, retargeted EquiDexFlow-decoded grasps complete open-loop pick-and-hold trials on all six test objects, with every asymmetric object succeeding at both the canonical pose and a $120^\circ$ co-rotation. Videos, code, and checkpoints are available at https://equidexflow.github.io.

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

Analyzing Defensive Misdirection Against Model-Guided Automated Attacks on Agentic AI Systems

arXiv:2606.20470v1 Announce Type: cross Abstract: Agentic AI systems increasingly rely on language-model components to interpret instructions, process external data, invoke tools, and coordinate with other agents. These capabilities make prompt-injection and jailbreak attacks more consequential, especially as attackers adopt model-guided automation to scale probing, prompt refinement, and response evaluation. This work analyzes the resulting attack-defense setting through a probabilistic model of a target system, its defense mechanism, and the attacker's automated judge. Our analysis shows that conventional detect-and-block defenses can allow attacker success rate (ASR) to approach one as the query budget grows, since predictable refusals provide useful feedback to automated search. We then examine detect-and-misdirect, where detected malicious interactions receive controlled, non-operational responses designed to induce false-positive errors in the attacker's judge. This strategy reduces the positive predictive value of attacker-selected candidates and yields a bounded asymptotic ASR. We evaluate a proof-of-concept realization of this strategy through Contextual Misdirection via Progressive Engagement (CMPE), a lightweight conversational misdirection method designed to replace predictable refusal text with safe but strategically misleading responses in automated jailbreak settings. On jailbreak benchmarks, CMPE reduces estimated ASR upper bounds by up to two orders of magnitude and nearly eliminates verified attack success in end-to-end PAIR and GPTFuzz attack runs.

20.
arXiv (quant-ph) 2026-06-19

Ricci flow for the Bures–Helstrom qubit metric

arXiv:2606.19493v1 Announce Type: cross Abstract: The Bures–Helstrom metric is the minimal monotone Riemannian metric on the state space of a qubit. With the quantum Fisher normalization used here, it identifies the Bloch ball with a geodesic hemisphere of the unit round three–sphere. We describe its Ricci flow explicitly. In a general rotationally symmetric gauge the flow is a coupled system for the radial lapse and warping factor; a single scalar equation appears only after a Hamilton–DeTurck gauge choice. In the corresponding moving DeTurck frame the squared warping function $\Psi=\Phi^2$ satisfies the linear forced heat equation \begin{equation*} D_t\Psi=\Psi_{ss}-2, \end{equation*} while the fixed-lapse coordinate form contains the associated transport term. Since the Bures–Helstrom metric is Einstein, the geometric flow itself is the homothetic shrinker \begin{equation*} g(t)=(1-4t)g_{\mathrm{BH}}, \end{equation*} with scalar curvature $6/(1-4t)$ and extinction time $T=1/4$. Thus the metric remains inside the monotone cone for all $t

21.
Nature (Science) 2026-06-24

Epiblast diversification and blood formation in a human pregastrula

Authors:

The incipient stage of gastrulation in human, when the primitive streak is about to emerge, represents a critical yet underexplored period. Here we present the high-resolution spatial transcriptomic landscape of a human embryo at Carnegie stage 6 (approximately 13–14 days post-conception), a stage at which primitive streak remains invisible and gastrulation-derived mesodermal/endodermal progenitors are not yet transcriptomically detected. We identified an anterior visceral endoderm-like hypoblast population, as well as a trifurcated developmental trajectory of the epiblast, progressing towards the amnion, primitive streak and node/prechordal plate/notochord (axial mesoderm) at subsequent developmental stages1–3. Furthermore, our findings challenge the existing paradigms by revealing that primitive haematopoiesis, involving three blood lineages, initiates in human yolk sac before gastrulation, earlier than previously recognized2,4–7, and that the first blood cells arise from the extra-embryonic mesoderm with a hypoblast rather than epiblast origin. Notably, we identified two spatial zones, each consisting of molecularly distinct yolk sac endoderm and extra-embryonic mesoderm populations, that respectively facilitated the generation of erythro-megakaryocytic lineages and myeloid precursors. These findings provide insights into the onset of gastrulation and the earliest blood formation in humans, with profound implications for advancing stem cell-derived human embryo models and in vitro blood regeneration. High-resolution spatial transcriptome analysis of a human embryo at Carnegie stage 6 reveals three distinct developmental trajectories from the epiblast towards amnion, primitive streak and axial mesoderm, and detects the initiation of haematopoiesis before gastrulation, originating from hypoblast rather than epiblast.

23.
arXiv (CS.LG) 2026-06-15

FreshRetailNet-LT: A Stockout-Annotated Censored Demand Dataset for Latent Demand Recovery and Forecasting in Fresh Retail

arXiv:2505.16319v4 Announce Type: replace Abstract: Accurate demand estimation is critical for the retail business in guiding the inventory and pricing policies of perishable products. However, it faces fundamental challenges from censored sales data during stockouts, where unobserved demand creates systemic policy biases. Existing datasets lack the temporal resolution and annotations needed to address this censoring effect. To fill this gap, we present FreshRetailNet-50K, the first large-scale benchmark for censored demand estimation. It comprises 50,000 store-product time series of detailed hourly sales data from 898 stores in 18 major cities, encompassing 863 perishable SKUs meticulously annotated for stockout events. The hourly stock status records unique to this dataset, combined with rich contextual covariates, including promotional discounts, precipitation, and temporal features, enable innovative research beyond existing solutions. We demonstrate one such use case of two-stage demand modeling: first, we reconstruct the latent demand during stockouts using precise hourly annotations. We then leverage the recovered demand to train robust demand forecasting models in the second stage. Experimental results show that this approach achieves a 2.73% improvement in prediction accuracy while reducing the systematic demand underestimation from 7.37% to near-zero bias. With unprecedented temporal granularity and comprehensive real-world information, FreshRetailNet-50K opens new research directions in demand imputation, perishable inventory optimization, and causal retail analytics. The unique annotation quality and scale of the dataset address long-standing limitations in retail AI, providing immediate solutions and a platform for future methodological innovation. The data (https://huggingface.co/datasets/Dingdong-Inc/FreshRetailNet-50K) and code (https://github.com/Dingdong-Inc/frn-50k-baseline}) are openly released.

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

DeepRHP: A Hybrid Variational Autoencoder for Designing Random Heteropolymers as Protein Mimics

arXiv:2606.11651v1 Announce Type: new Abstract: Synthetic random heteropolymers (RHPs), consisting of a predefined set of monomers, offer an approach toward the design of protein-like materials. These RHPs, if designed appropriately, can mimic protein behavior and function. As such, there is a need for computational tools to efficiently guide RHP design. We bridge this gap by developing DeepRHP, a modified variational autoencoder (VAE) model under a semi-supervised framework. By equipping a classical VAE with an additional feature-based VAE, DeepRHP forces the latent space to capture structures of critical chemical features as well as individual RHP sequence patterns. In this sense, our method is versatile by allowing any relevant features to be incorporated in a hybrid manner. We demonstrate the effectiveness of DeepRHP by suggesting potential monomer compositions that stabilize membrane proteins (e.g. Aquaporin Z) in non-native environments and cross-validating our prediction with published results. The concordance between our model and true RHP function suggests strong potential in utilizing hybrid autoencoder architectures to guide RHP design for proteins and other biological compounds.

25.
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.