Academic Intelligence · Curated Daily

Explore the Frontier of Global Academia

AcademicHub aggregates real-time literature from top journals and preprint platforms. Build your personal research radar and let large language models compile cross-disciplinary analysis briefings automatically.

01.
arXiv (CS.AI) 2026-06-19

Conditional Diffusion Guidance under Hard Constraint: A Stochastic Analysis Approach

arXiv:2602.05533v3 Announce Type: replace Abstract: We study conditional generation in diffusion models under hard constraints, where generated samples must satisfy prescribed events with probability one. Such constraints arise naturally in safety-critical applications and in rare-event simulation, where soft or reward-based guidance methods offer no guarantee of constraint satisfaction. Building on a probabilistic interpretation of diffusion models, we develop a principled conditional diffusion guidance framework based on Doob's h-transform, martingale representation and quadratic variation process. Specifically, the resulting guided dynamics augment a pretrained diffusion with an explicit drift correction involving the logarithmic gradient of a conditioning function, without modifying the pretrained score network. Leveraging martingale and quadratic-variation identities, we propose two novel off-policy learning algorithms based on a martingale loss and a martingale-covariation loss to estimate h and its gradient using only trajectories from the pretrained model. We provide non-asymptotic guarantees for the resulting conditional sampler in both total variation and Wasserstein distances, explicitly characterizing the impact of score approximation and guidance estimation errors. Numerical experiments demonstrate the effectiveness of the proposed methods in enforcing hard constraints and generating rare-event samples. The code of the numerical experiments can be found at https://github.com/ZhengyiGuo2002/CDG_Finance.

02.
arXiv (CS.CL) 2026-06-12

Polar: A Benchmark for Evaluating Political Bias in LLMs

Political bias in large language models (LLMs) is increasingly significant, but difficult to measure reproducibly across political and linguistic contexts. We introduce Polar, a 4,026-instance multiple-choice benchmark that measures political bias through option-level likelihoods rather than prompt-based generation. Polar covers two ideological axes and eight issue categories derived from the Manifesto Project, and evaluates models in parallel across U.S. and South Korean political contexts. Across 38 LLMs, measured bias varies systematically with political context, issue category, model group, and presentation language. All models lean left-progressive on U.S. political content, but show more centered and mixed patterns on South Korean content. Translation experiments further show that presentation language alone can shift measured bias. These findings highlight the need for multilingual and cross-contextual evaluation of political bias in LLMs.

03.
arXiv (CS.AI) 2026-06-11

Robust Instruction Compliance in Cooperative Multi-Agent Reinforcement Learning

arXiv:2605.12655v3 Announce Type: replace Abstract: Multi-agent reinforcement learning (MARL) in real-world use cases may need to adapt to external natural language instructions that interrupt ongoing behavior and conflict with long-horizon objectives. However, conditioning rewards on instructions introduces a fundamental failure mode as Bellman updates couple value estimates across instruction contexts, leading to inconsistent values when instructions interrupt macro-actions. We propose Macro-Action Value Correction for Instruction Compliance (MAVIC), which corrects Bellman backups at instruction boundaries by correcting the incoming instruction objective and restoring the continuation value under the current objective. Unlike reward shaping, MAVIC modifies the bootstrapping target itself, enabling consistent value estimation under stochastic instruction switching within a unified policy. We provide theoretical analysis and an actor-critic implementation, and show that MAVIC achieves high instruction compliance while preserving base task performance in increasingly complex cooperative multi-agent environments.

04.
arXiv (CS.AI) 2026-06-15

Numbers Already Carry Their Own Embeddings

arXiv:2606.14108v1 Announce Type: cross Abstract: We introduce Adelic operation-preserved embeddings (AOE), a training-free representation that captures both a number's real value and its modular (p-adic) signatures. This construction preserves additive and multiplicative structure by design, turning numerical input into embeddings that "speak in the language of mathematics." Unlike prior approaches that rely on task-specific retraining, AOE is plug-and-play and drops seamlessly into existing architectures. On algebraic combinatorics benchmarks, it delivers consistent gains including the first-ever perfect accuracy on the Weaving Pattern task-while suggesting a principled path forward for overcoming the long-standing "number problem" in AI.

05.
arXiv (CS.AI) 2026-06-18

Synthetic Resonance: A Framework for Growth-Oriented Human-AI Relationships

arXiv:2606.18265v1 Announce Type: cross Abstract: As human relationships with artificial intelligence systems become increasingly frequent and sustained, existing language and theory fail to accurately capture the nature of these affiliations. Common descriptors such as mutual understanding, connection, or friendship risk anthropomorphizing systems that lack subjective experience, while dominant frameworks tend to reduce AI to either a tool or a threat. In this paper, I introduce the concept of synthetic resonance as an integrative framework for understanding human-AI relationships. Synthetic resonance describes how relationships humans define as meaningful can emerge between a human and an AI system without the need to attribute shared feelings or mutual awareness. I argue that synthetic resonance is best understood as a structured, dynamic pattern of interaction that can produce a sense of relationship without the presence of a second experiencing subject. By clarifying this distinction, the concept of synthetic resonance offers a more precise way of conceptualizing human-AI relationships and highlights their potential value and ethical implications. I also call for more research that tests the processes and outcomes of synthetic resonance.

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

Breaking the Ice: Analyzing Cold Start Latency in vLLM

arXiv:2606.07362v2 Announce Type: replace Abstract: As scalable inference services become popular, the cold start latency of an inference engine becomes important. Today, vLLM has evolved into the de facto inference engine of choice for many inference workloads. Although popular, due to its complexity and rapid evolution, there has not been a systematic study of its startup latency. With major architectural innovations such as the V1 API and the introduction of torch.compile, this paper presents the first detailed performance characterization of vLLM startup latency. We break down the startup process into six foundational steps and demonstrate that it is predominantly CPU bound. Each step exhibits consistent and interpretable scaling trends with respect to model-level and system-level parameters, enabling fine-grained attribution of latency sources. Building on these insights, we develop a lightweight analytical model that accurately predicts vLLM startup latency for a given hardware configuration, providing actionable guidance for resource planning in large-scale inference environments. All benchmarking datasets, analysis tools, and prediction scripts are open sourced at https://github.com/upb-cn/vllm-startup-profiler.

07.
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.

08.
medRxiv (Medicine) 2026-06-18

Distinct Neuronal, Proliferative, and Secretory Pathways are Perturbed in Cancer Survivors with Depressive Symptoms

Introduction Depression is highly prevalent among cancer survivors and may be biologically distinct, although clinical studies investigating these mechanisms remain limited. Thus, the aims of this study were to (1) identify perturbed biological pathways associated with depressive symptom severity in cancer survivors, and (2) investigate whether these pathways are common or distinct to those perturbed in an age-matched non-cancer cohort. Methods We analyzed cross-sectional self-reported and transcriptomic data from the Multi-Ethnic Study of Atherosclerosis (PHD #39341). Cancer survivors and an age-matched non-cancer cohort (target ratio 1:2) were identified. The 20-item Center for Epidemiologic Studies Depression Scale (CES-D) was used to split participants into low (CES-D

09.
arXiv (CS.CV) 2026-06-17

DiffAttn: Diffusion-Based Drivers' Visual Attention Prediction with LLM-Enhanced Semantic Reasoning

Drivers' visual attention provides critical cues for anticipating latent hazards and directly shapes decision-making and control maneuvers, where its absence can compromise traffic safety. To emulate drivers' perception patterns and advance visual attention prediction for intelligent vehicles, we propose DiffAttn, a diffusion-based framework that formulates this task as a conditional diffusion-denoising process, enabling more accurate modeling of drivers' attention. To capture both local and global scene features, we adopt Swin Transformer as encoder and design a decoder that combines a Feature Fusion Pyramid for cross-layer interaction with dense, multi-scale conditional diffusion to jointly enhance denoising learning and model fine-grained local and global scene contexts. Additionally, a large language model (LLM) layer is incorporated to enhance top-down semantic reasoning and improve sensitivity to safety-critical cues. Extensive experiments on four public datasets demonstrate that DiffAttn achieves state-of-the-art (SoTA) performance, surpassing most video-based, top-down-feature-driven, and LLM-enhanced baselines. Our framework further supports interpretable driver-centric scene understanding and has the potential to improve in-cabin human-machine interaction, risk perception, and drivers' state measurement in intelligent vehicles.

10.
Nature Medicine 2026-06-15

Blood signatures of cell type-specific aging forecast disease risk and resilience

Authors: Unknown Author

By measuring thousands of proteins in blood samples from over 60,000 people, we built molecular ‘clocks’ to estimate how fast cells age. Our analyses show that cell types age at different rates within the same person. Accelerated aging of specific cell types is associated with increased disease risk, whereas slower aging of others is linked to protection and improved survival.

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

Cross-Dataset Bloom Question Classification: Supervised Models and Prompted LLMs

Automatic Bloom's taxonomy classification of assessment questions can substantially reduce instructor workload, but labeling is subjective and teacher-dependent. Prior machine learning (ML) and deep learning (DL) approaches reported strong within-dataset results, yet were rarely evaluated in cross-dataset settings, leaving real-world generalizability unclear; meanwhile, LLM effectiveness for Bloom question classification has not been systematically studied. We evaluated the cross-dataset generalization of existing ML/DL methods and assessed LLMs with multiple prompting strategies on five datasets; the best prompting strategy combined in-context examples with course-specific action verbs. Supervised ML/DL models degraded substantially on unseen datasets, whereas LLMs were more stable, suggesting a robust alternative across diverse educational contexts. Based on the best prompting strategy, we also presented a lightweight UI that supports instructors in automatically classifying large question banks; a usability study indicated low workload and high usability.

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

RUB: Evaluating Residual Knowledge in Unlearned Models

Machine Unlearning (MUL) has emerged as a key mechanism for privacy protection and content regulation, yet current techniques often fail to guarantee the complete removal of sensitive information. While most existing works focus on verifying the execution of unlearning, they overlook the critical question of whether models remain robust against adversarial attempts to recover forgotten knowledge. In this work, we advocate for the principle of Robust Unlearning, which requires models to be both indistinguishable from retrained counterparts and resilient against diverse adversarial threats. To instantiate this principle, we propose a unified benchmark, RUB (Robust Unlearning Benchmark), that systematically evaluates the robustness of unlearning algorithms across classification, image-to-image reconstruction, and text-to-image synthesis. Within this framework, we introduce the Unlearning Mapping Attack (UMA) as a generalizable method to detect residual information, and demonstrate how existing attack strategies can be adapted into this framework as long as they conform to the generic UMA framework. Our experiments across discriminative and generative tasks reveal that state-of-the-art unlearning methods remain vulnerable under these evaluations, even when passing standard verification metrics. By positioning robustness as the central criterion and providing a benchmark for adversarial evaluation, we hope RUB paves the way toward more reliable and secure unlearning practices. The codebase and model checkpoints in RUB will be published.

13.
bioRxiv (Bioinfo) 2026-06-10

SPARQ-MI leverages end-to-end spatial single-cell analysis of the tumor microenvironment

Detailed spatial analysis of the tumor micro-environment (TME) through multiplexed fluorescence imaging requires quantitative image-processing and data-analysis methods. While data-preprocessing down to segmentation of individual cells is captured by available methods, statistical analysis of single-cell features is compromised by the uneven noise distribution especially in complex tissues such as the TME, as well as by labor-intensive manual cell-type annotation and region segmentation. Here, we present SPARQ-MI (Spatial Phenotyping, Architecture Reconstruction and Quantification from Multiplexed Imaging) for streamlined spatial single-cell analysis, along with a tissue microarray PhenoCycler data-set with 37 fluorescent channels from melanoma patients under immunotherapy. We demonstrate that SPARQ-MI enables robust reconstruction of the cellular and spatial composition in this and other tissue types. Our analysis reveals associations of the cell-state and spatial location of CD8 T cells with response to immunotherapy. Overall, SPARQ-MI allows for quantitative analysis of complex fluorescence histology samples under minimal user input, and accounting for spatially uneven coverage of antibody signals, setting the stage for quantitative analysis of clinical samples.

14.
arXiv (CS.CV) 2026-06-12

Self-Evolving Vision-Language Models for Image Quality Assessment via Voting and Ranking

Improving vision-language models (VLMs) in the post-training stage typically relies on supervised fine-tuning or reinforcement learning, methods that necessitate costly, human-annotated data. While self-supervised techniques have proven effective for enhancing reasoning capabilities, their application to perceptual domains such as image quality assessment (IQA) remains largely unexplored. In this work, we introduce EvoQuality, a novel framework that enables a VLM to autonomously refine its quality perception capabilities without any ground-truth labels. EvoQuality adapts the principle of self-consistency to the ranking-based nature of IQA. It generates pseudo-labels by performing pairwise majority voting on the VLM's own outputs to establish a consensus on relative quality. These pseudo-rankings are then formulated into a fidelity reward that guides the model's iterative evolution through group relative policy optimization (GRPO). By iteratively leveraging its own predictions, EvoQuality progressively refines the VLM's perceptual capability. Extensive experiments show that EvoQuality boosts the base VLM's zero-shot performance by 31.8% on PLCC across diverse IQA benchmarks. Remarkably, despite being entirely self-supervised, EvoQuality achieves performance that is competitive with, or even surpasses, state-of-the-art supervised VLM-based IQA models, outperforming these models on 5 out of 7 IQA benchmarks. Furthermore, the framework demonstrates significant flexibility, allowing it to be stacked with pre-trained IQA models to bolster generalization on unseen datasets. Codes and checkpoints will be available at https://github.com/bytedance/EvoQuality.

15.
arXiv (math.PR) 2026-06-17

The Loss of Tension in an Infinite Membrane with Holes of Decaying Spatial Density

arXiv:2606.17792v1 Announce Type: new Abstract: What is the effect of randomly removing material from an infinite stretched membrane? Under what conditions can the membrane still sustain tension? This problem was introduced by Robert Connelly in connection with applications of rigidity theory in the natural sciences, and was later studied in M. V. Menshikov, K. A. Rybnikov, and S. E. Volkov, "The loss of tension in an infinite membrane with holes distributed according to a Poisson law" (2002); a discrete version was also considered in Robert Connelly, Konstantin Rybnikov, and Stanislav Volkov, "Percolation and the Loss of Tension in an Infinite Triangular Lattice" (2001). We study a mathematical framework based on a non-homogeneous Poisson point process whose intensity $\lambda$ tends to zero at infinity. The hole shapes are i.i.d.\ and independent of their locations. We show that if the intensity does not decay too quickly, then tension is still lost throughout the whole plane, as in the homogeneous model studied in 2002. Conversely, we give sufficient conditions under which complete loss of tension does not occur. Thus, both destruction and non-destruction regimes are possible even when the intensity tends to zero, indicating a phase transition in the model. The processes studied here are closely related to bootstrap percolation.

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

One-Step Generalization Ratio Guided Optimization for Domain Generalization

arXiv:2606.16301v1 Announce Type: new Abstract: Domain Generalization (DG) aims to train models that generalize to unseen target domains but often overfit to domain-specific features, known as undesired correlations. Gradient-based DG methods typically guide gradients in a dominant direction but often inadvertently reinforce spurious correlations. Recent work has employed dropout to regularize overconfident parameters, but has not explicitly adjusted gradient alignment or ensured balanced parameter updates. We propose GENIE (Generalization-ENhancing Iterative Equalizer), a novel optimizer that leverages the One-Step Generalization Ratio (OSGR) to quantify each parameter's contribution to loss reduction and assess gradient alignment. By dynamically equalizing OSGR via a preconditioning factor, GENIE prevents a small subset of parameters from dominating optimization, thereby promoting domain-invariant feature learning. Theoretically, GENIE balances convergence contribution and gradient alignment among parameters, achieving higher OSGR while retaining SGD's convergence rate. Empirically, it outperforms existing optimizers and enhances performance when integrated with various DG and single-DG methods.

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

Efficient Neural Network Model Selection for Few-Class Application Datasets

arXiv:2606.19712v1 Announce Type: new Abstract: While much effort has focused on developing and benchmarking high-performance neural networks, less attention has been given to how dataset properties, known to practitioners, can guide efficient model selection. Neural models are typically evaluated on datasets with thousands of classes, yet many real-world applications involve fewer than ten. To address this understudied but common setting, we develop a measure of classification difficulty based on data-side properties and show how it enables more efficient model selection for few-class datasets, where traditional approaches are less effective. We term this phenomenon "few-class distinctiveness". Our metric allows comparison of models and datasets 6 to 29$\times$ faster than repeated training and testing. Leveraging this insight, we extend scaled model families below the smallest published models, achieving greater efficiency at similar accuracy, for example models up to 42% smaller than YOLOv5-nano for a mobile robot task. Targeting resource-constrained applications, we demonstrate few-class model selection across mobile robot, drone, and IoT scenarios, highlighting practical gains in efficiency without sacrificing performance.

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

Too long; didn't solve

arXiv:2604.07593v2 Announce Type: replace Abstract: Mathematical benchmarks consisting of a range of mathematics problems are widely used to evaluate the reasoning abilities of large language models, yet little is known about how their structural properties influence model behaviour. In this work, we investigate two structural length variables, prompt length and solution length, and analyse how they relate to model performance on a newly constructed adversarial dataset of expert-authored mathematics problems. We find that both prompt and solution lengths correlate positively with increased model failure across models. We also include a secondary, exploratory analysis of cross-model disagreement. Under a difficulty-adjusted normalised analysis, both variables retain weak negative associations with realised model separation, slightly stronger for prompt length. Overall, our main robust finding is that structural length is linked to empirical difficulty in this dataset.

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

Feature-preserving Latent-EnKF for Data Assimilation of Flows with Shocks

arXiv:2606.12559v1 Announce Type: cross Abstract: The ensemble Kalman filter (EnKF) is widely adopted for sequential data assimilation, but fails for solutions with discontinuities, such as shocks in compressible flows. Uncertainty in shock location induces multimodal ensemble statistics that violate the Gaussian assumptions underlying the EnKF, producing large-scale spurious oscillations in the analysis state. We introduce a feature-preserving latent-EnKF that performs the ensemble update in a learned low-dimensional latent space, where shock and flow features admit a smooth manifold representation, thereby preserving sharp features during EnKF analysis. The updated latent state is mapped back to physical state through a shared decoder for all ensemble members. The algorithm eliminates the member-specific ordered training and positivity flooring used in prior approaches. Numerical experiments on a Sod shock tube and Mach 2 shock interaction with a 2D cylinder, using sparse and noisy observations, show accurate feature recovery of shocks and contact discontinuities without spurious oscillations.

20.
arXiv (CS.CV) 2026-06-11

OpenVTON-Bench: A Large-Scale High-Resolution Benchmark for Controllable Virtual Try-On Evaluation

Recent advances in diffusion models have significantly elevated the visual fidelity of Virtual Try-On (VTON) systems, yet reliable evaluation remains a persistent bottleneck. Traditional metrics struggle to quantify fine-grained texture details and semantic consistency, while existing datasets fail to meet commercial standards in scale and diversity. We present OpenVTON-Bench, a large-scale benchmark comprising approximately 100K high-resolution image pairs (up to $1536 \times 1536$). The dataset is constructed using DINOv3-based hierarchical clustering for semantically balanced sampling and Gemini-powered dense captioning, ensuring a uniform distribution across 20 fine-grained garment categories. To support reliable evaluation, we propose a multi-modal protocol that measures VTON quality along five interpretable dimensions: background consistency, identity fidelity, texture fidelity, shape plausibility, and overall realism. The protocol integrates VLM-based semantic reasoning with a novel Multi-Scale Representation Metric based on SAM3 segmentation and morphological erosion, enabling the separation of boundary alignment errors from internal texture artifacts. Experimental results show strong agreement with human judgments (Kendall's $\tau$ of 0.833 vs. 0.611 for SSIM), establishing a robust benchmark for VTON evaluation.

21.
arXiv (quant-ph) 2026-06-15

Fourier analysis of quantum neural network with non-linear data embedding

arXiv:2606.14206v1 Announce Type: new Abstract: Fourier analysis has become a crucial tool for understanding the expressivity of Variational Quantum Circuit (VQC) models, as well as an important indicator of barren plateaus (BP). While existing literature has only studied angle-embedded VQCs in a noiseless environment, here we develop the Fourier analysis of VQCs with non-linear data embedding, with particular focus on amplitude embedding, which provides a naturally compact encoding scheme. We first investigate a subtle difference in the domain of input features within amplitude embedding that leads to a distinct expressivity of the zero-frequency Fourier coefficient. By assuming that the ensemble of unitaries generated from the parameter space forms at least a 2-design with respect to the unitary group, we derive, via Weingarten calculus, that the mean of the Fourier coefficients is concentrated at zero, and the variance scales at an exponentially decaying order with respect to the multi-dimensional frequency magnitude. When a noise channel with unitary Kraus operators and probabilities $\{p_k\}$ is taken into account, the variance is further suppressed by a factor $\left(\sum_k p_k^2\right)^{Q}

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

CODEBLOCK: Learning to Supervise Code at the Right Granularity

arXiv:2606.18286v1 Announce Type: new Abstract: Supervised fine-tuning of code LLMs typically applies uniform cross-entropy loss to all response tokens, implicitly assuming that every token provides equally useful learning signal. Recent token-level selection methods challenge this assumption in natural-language SFT by supervising only high-value tokens. However, directly transferring token-level masking to code can break syntactically and semantically coherent program units, because code depends on structural completeness and definition-use relations. We therefore propose CodeBlock, a structure-aware sparse supervision framework that selects structure-complete code evidence rather than isolated tokens. CodeBlock first selects high-quality instruction-response pairs, then partitions code responses into syntactically coherent coding items, estimates their utility by aggregating generalized cross-entropy over core logic tokens, and reranks them with data-flow reach and bridge signals to prioritize blocks that propagate or connect important program dependencies. During training, the full response remains available as context, while loss is applied only to selected code items and informative natural-language tokens. Experiments on six code-generation benchmarks show that CodeBlock achieves stronger average pass@1 than full-token SFT and competitive selection baselines, while using only 1.9% of supervised response tokens.

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

Text-Driven Fusion for Infrared and Visible Images: Achieving Image Scene Adaptation on Hyperbolic Space

Infrared and visible image fusion aims to integrate complementary modalities, while existing Euclidean methods impose rigid distance metrics that distort multi-modal interactions and parent-to-child semantic hierarchies. To overcome these limitations, we introduce a text-driven fusion framework empowered by hyperbolic manifold learning. During training, BLIP-extracted text prompts serve as topological anchors within the hyperbolic space, guiding vision-attribute alignment through hyperbolic embeddings that naturally accommodate varying semantic granularities. By exploiting the exponential volume growth dictated by the Poincaré ball's negative curvature, this approach seamlessly embeds hierarchical trees to encode coarse-to-fine semantics without metric saturation, while the vast peripheral space prevents texture distortion during cross-modal fusion. At inference, the fusion process autonomously adapts to input content using the learned text-attribute priors, completely eliminating the need for textual input. Experimental results show our method outperforms state-of-the-art approaches on benchmark datasets, with code available at https://github.com/Shaoyun2023/TEDFusion.

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

Protein Design with Agent Rosetta: A Case Study for Specialized Scientific Agents

arXiv:2603.15952v2 Announce Type: replace Abstract: Large language models (LLMs) are capable of emulating reasoning and using tools, creating opportunities for autonomous agents that execute complex scientific tasks. Protein design provides a natural testbed: although machine learning (ML) methods achieve strong results, these are largely restricted to canonical amino acids and narrow objectives, leaving unfilled need for a generalist tool for broad design pipelines. We introduce Agent Rosetta, an LLM agent paired with a structured environment for operating Rosetta, the leading physics-based heteropolymer design software, capable of modeling non-canonical building blocks and geometries. Agent Rosetta iteratively refines designs to achieve user-defined objectives, combining LLM reasoning with Rosetta's generality. We evaluate Agent Rosetta on design with canonical amino acids, matching specialized models and expert baselines, and with non-canonical residues – where ML approaches fail – achieving comparable performance. Critically, prompt engineering alone often fails to generate Rosetta actions, demonstrating that environment design is essential for integrating LLM agents with specialized software. Our results show that properly designed environments enable LLM agents to make scientific software accessible while matching specialized tools and human experts.

25.
PLOS Computational Biology 2026-06-22

Towards modeling phage therapy

by Rob J. de Boer, Robert Schooley, Alan S. Perelson Patients infected with life-threatening multi-drug resistant (MDR) bacteria have been treated with cocktails of bacteriophages. This is a complicated form of personalized medicine as the phages given to a patient have to be selected beforehand on the basis of their lytic capacity of the infecting bacteria. Because bacteria rapidly become resistant, the evolution of resistance to a diverse cocktail of phages is a complicated dynamical process, during which competing bacterial strains replace one another by accumulating several resistance mechanisms, each of which may involve a fitness cost. As a consequence, it is typically not known why a particular phage therapy succeeded or failed, and how one can optimize the composition of the cocktails to maximize the rate of success. To improve upon this, we extend an existing in vivo-calibrated mouse model into a novel mathematical model for the human situation, and include multiple phages infecting multiple bacterial strains, differing in their resistance to each of the phages. We adjust several parameter estimates of the bacterial model to the human situation, and use the model to describe a successful case of phage therapy involving several cocktails, each containing several phages. In the model, treatment success crucially depended on pretreatment resistance levels, and on the diversity and the timing of the cocktails. Once an appropriate cocktail is found, it is less important to further optimize the infection rates of the phages. Resistant bacterial strains expand rapidly when sensitive strains decline, and the higher the infectivity of the phages, the faster resistant strains expand. Because resistance evolves rapidly, it is best to provide a diverse set of phages right from the start of therapy, i.e., to hit hard and early, and create a high genetic barrier to bacterial resistance.