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

When Do Data-Driven Systems Exhibit the Capability to Infer?

arXiv:2606.11769v1 Announce Type: new Abstract: The European AI Act is the first comprehensive regulation of artificial intelligence (AI), setting out extensive obligations, particularly for so-called high-risk and general-purpose AI systems. A key distinguishing feature of AI systems under the AI Act is the capability to infer. Since the AI Act does not clearly define what inference is, there is a gray area for certain data-driven systems. A specific example is credit scoring systems, which are listed by Annex III of the AI Act. At the same time, however, these are often implemented using statistical models for which it is unclear whether they have the capability to infer and thus fall under the AI definition of the AI Act at all. Motivated by statistical learning theory, this work develops a framework for grading different levels of the capability to infer. Based on the AI Act and the Commission Guidelines on the definition of an artificial intelligence system, we analyze which levels constitute sufficient capability to infer within the meaning of the AI Act and where further regulatory clarity is needed. We illustrate the framework by creating two realistic credit scoring workflows and show whether and where inference occurs in them. Our analysis illustrates that not only individual models but the entire data processing workflow must be considered. It also shows that the involvement of human experts during development can have significant influence on the capability to infer. Code can be found at https://github.com/fraunhofer-iais/inference-framework-creditscorecards.

02.
bioRxiv (Bioinfo) 2026-06-11

TifBERT: a self-supervised foundation model for normalization-robust bulk RNA-seq representation learning

Bulk RNA sequencing remains central to translational genomics, yet foundation-model development has largely focused on single-cell data. Existing transformer approaches for bulk RNA-seq often rely on expression discretization, numerical reconstruction, external gene embeddings, or restricted gene sets, limiting robustness across normalization schemes and cohorts. Here, we introduce TifBERT, a self-supervised framework for full-transcriptome bulk RNA-seq representation learning. TifBERT converts each unordered expression profile into a sample-specific gene sequence using term frequency-inverse document frequency (TF-IDF) ordering, prioritizing genes that are both highly expressed within a sample and selectively expressed across the cohort. It is then pretrained using masked gene modeling, predicting gene identities from transcriptomic context rather than reconstructing expression values. Pretrained on harmonized TCGA Pan-Cancer data spanning five RNA-seq normalization schemes, TifBERT learns contextual representations across approximately 10,000 genes without expression binning, landmark-gene restriction, or external biological embeddings. Across 33 TCGA cancer types, TifBERT achieved 90.83% accuracy, 0.996 macro AUC-ROC, and 0.903 MCC. It also captured pathway-level biology, achieving mean sample-wise and pathway-wise Pearson correlations of 0.754 and 0.762 across 1,387 PARADIGM pathway activities. Independent evaluation on GTEx healthy tissues showed preservation of tissue-level transcriptomic structure without retraining. In comparison with existing models, TifBERT achieves competitive subtype discrimination with substantially greater stability and produces markedly richer embedding geometry (effective rank 95.6 versus 6.3), without requiring expression discretization or in-distribution pretraining exposure. Together, TifBERT provides a scalable, normalization-independent foundation model for reusable bulk transcriptomic representation learning

03.
arXiv (math.PR) 2026-06-15

On the Poisson Follower Model

arXiv:2309.04864v5 Announce Type: replace Abstract: We introduce a stochastic geometry dynamics inspired by opinion dynamics that captures the essence of modern asymmetric social networks with leaders and followers. Points in the Euclidean space represent opinions, and the leader of an agent is the one with the closest opinion. In this dynamics, each follower updates its opinion by halving the distance to its leader. We demonstrate that this simple dynamics and its iterations exhibit several interesting purely geometric phenomena related to the evolution of leadership and opinion clusters, which resemble those observed in social networks. We also show that when the initial opinions are randomly distributed as a stationary Poisson point process, the spatial frequency of each of these phenomena can be expressed through an integral geometry formula involving semi-algebraic domains. Finally, we analyze numerically the limiting behavior of this follower dynamics. In the Poisson case, the agents fall into two categories: ultimate followers, who continue updating their opinions indefinitely, and ultimate leaders, who adopt a fixed opinion after a finite time. Spatial discrete event simulations support all our findings.

04.
Nature (Science) 2026-06-10

Gen Z scepticism towards AI is a wake-up call — universities must take it seriously

作者:

The challenge for universities is not adopting artificial intelligence, but doing so in ways that the current generation of students can trust. The challenge for universities is not adopting artificial intelligence, but doing so in ways that the current generation of students can trust.

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

A Causal Model of Theory of Mind in Conflict for Artificial Intelligence

arXiv:2606.16944v1 Announce Type: new Abstract: Theory of mind (ToM), the capacity to ascribe mental states to others and use those ascriptions for prediction and inference, is widely assumed to be essential for effective human-machine integration. Existing AI-ToM models address how to mentalize, but leave the question of when largely unaddressed. The central question is: under what situational and agent-level conditions is ToM engagement causally warranted in conflict? This paper presents a structural causal model formalized as a directed acyclic graph (DAG), treating ToM as a mechanism activated by situational and agent-level conditions rather than as an always-on capacity. The model specifies four exogenous variables capturing situational and agent-level conditions, five endogenous mediators, and a mechanistic ToM node producing engagement states through three distinct causal pathways: a tractability pathway, a reasoning-depth pathway, and an enabling-cause pathway. The primary outcome is epistemic accuracy, which decouples social reasoning from behavioral policy and generalizes across social phenomena beyond conflict. The framework gives AI systems a principled, resource-rational decision procedure for mentalizing, with implications for efficiency, trust, and the development of robust artificial social intelligence. Simulation validation, empirical human-machine teaming studies, and ethical considerations arising from conflict-optimized mentalizing are discussed.

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

UniIntervene: Agentic Intervention for Efficient Real-World Reinforcement Learning

arXiv:2606.12372v1 Announce Type: cross Abstract: Human-in-the-loop reinforcement learning (HiL-RL) has emerged as an effective paradigm for real-world robotic manipulation, enabling online policy improvement with human guidance. However, current HiL-RL frameworks remain intervention-intensive, relying on frequent human corrections to redirect the policy out of unproductive exploration, which incurs high labor cost and limits real-world scalability. To address this, we propose UniIntervene, an agentic intervention model that detects unproductive exploration and autonomously recovers the policy toward high-value states, taking over the bulk of interventions from human operators. Specifically, UniIntervene first performs future-conditioned action-value estimation, predicting the latent consequence of the current action and evaluating its induced value, which provides a more stable progress signal. Building on this, a temporal value-risk critic aggregates recent value dynamics and triggers intervention when the estimated value exhibits sustained stagnation or degradation. When intervention is required, UniIntervene retrieves a high-value recovery target from a memory of past intervention episodes and produces executable corrective actions through a goal-conditioned recovery policy. In this way, UniIntervene turns intervention from passive human correction into a value-aware recovery process for efficient real-world RL. Extensive experiments on diverse real-world manipulation tasks demonstrate that UniIntervene improves the average success rate by 8.6% while reducing human interventions by 57% relative to state-of-the-art HiL-RL baselines.

07.
arXiv (CS.CV) 2026-06-16

Physics-Driven Zero-Shot MRI Reconstruction with Non-local Image Priors

Zero-Shot Self-Supervised Learning (ZS-SSL) has emerged as a promising paradigm for accelerated Magnetic Resonance Imaging (MRI) reconstruction, eliminating the reliance on fully-sampled external datasets. However, learning solely from a single under-sampled scan suffers from supervision scarcity and optimization instability, often leading to overfitting or artifacts. To address these challenges, we propose a robust physics-driven ZS-SSL framework that synergizes physical consistency with image-domain non-local priors. Our method introduces three core innovations: (1) a Coil Sensitivity Map (CSM)-Guided Dynamic Repository, which stabilizes the training trajectory by filtering physically inconsistent artifacts based on coil sensitivity constraints; (2) a SPIRiT-based regularization, which enforces k-space self-consistency via a learned correlation kernel and stochastic masking; (3) a Non-Local Self-Similarity (NSS) Pixel Bank, which leverages the high-fidelity reference established by the former modules to explicitly mine non-local anatomical similarities, thereby augmenting supervision in the image domain. Extensive experiments on the FastMRI dataset demonstrate that our approach achieves state-of-the-art performance, particularly under high acceleration factors, effectively bridging the gap between zero-shot learning and supervised methods. The code is available at https://github.com/Zolento/NS-SSL.

08.
arXiv (quant-ph) 2026-06-15

Sensitivity of polaron-molecule observables to MDR/GUP-like ultraviolet deformations at low energies via quantum computing

arXiv:2606.14479v1 Announce Type: new Abstract: We show that impurity many-body observables can display enhanced sensitivity to ultraviolet deformations of generalized-uncertainty-principle and modified-dispersion-relation type at accessible energy scales. Using a deformed polaron-molecule Hamiltonian constructed to preserve the infrared sector, we quantify the impact of such deformations on spectral and Ramsey observables and implement the corresponding dynamics in a controlled quantum computing setting. We identify regimes near the polaron-molecule crossover where small ultraviolet deformations are strongly amplified, leading to experimentally resolvable changes in quasiparticle properties and spectral response. Our results establish a concrete sensitivity-based route to low-energy quantum-gravity phenomenology in a well-defined many-body platform and delimit the validity of the effective description. Furthermore, we report experimental validation on the QRed superconducting quantum processor (BSC-CNS).

09.
arXiv (CS.CL) 2026-06-12

BOUTEF: A Multilingual Corpus for FakeNews in North Africa – Language as a Weapon

The rapid spread of fake news on social media has become a major challenge, particularly in multilingual and under-resourced contexts such as North Africa. In this paper, we introduce BOUTEF, a large-scale multilingual corpus designed to study the propagation, characteristics, and impact of fake news in Algeria and Tunisia. The corpus integrates three complementary components: fake narratives, genuine narratives, and associated user-generated comments, along with verified debunking information. It covers a wide range of languages and linguistic varieties, including MSA, Algerian and Tunisian dialects, Arabizi, French, English, and code-switched language. Building on this resource, we conduct a comprehensive empirical analysis combining quantitative and qualitative approaches. We examine thematic distributions, linguistic and rhetorical strategies, sentiment patterns, and social engagement dynamics. Statistical analyses reveal significant associations between thematic categories and message veracity, as well as strong correlations between user engagement and the visibility of fake content. Our findings show that fake news relies heavily on emotionally charged narratives, sensational framing, and hybrid linguistic practices that enhance virality and audience engagement. In contrast, debunking content adopts a more factual and verification-oriented style. Furthermore, a comparative analysis between Algeria and Tunisia highlights both shared dynamics and country-specific characteristics shaped by sociopolitical contexts. The results emphasize the role of informal language practices in the diffusion and reception of misinformation. By providing a rich, annotated, and publicly available dataset, this work contributes to advancing research on fake news detection, low-resource language processing, and the understanding of information disorders in complex linguistic environments.

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

A Neural Network Framework for Geodesic-Like Curve Computation on Parametric Surfaces

arXiv:2606.18759v1 Announce Type: cross Abstract: The concept of geodesic-like curves was introduced by Chen in 2010 as a method for estimating shortest paths (geodesics) on parametric surfaces, with its convergence established theoretically. However, an efficient numerical computational framework has not yet been developed. In this paper, we propose an elegant and efficient approach for computing geodesic-like curves by leveraging deep learning and Physics-Informed Neural Networks (PINNs). Under the proposed framework, not only can single parametric surfaces be handled efficiently, but a broad class of complex parametric surfaces including multi-surface systems with $C^0$ or higher continuity and surfaces of revolution can also be robustly addressed.

11.
bioRxiv (Bioinfo) 2026-06-18

Deciphering shared and divergent tissue architectures from cross-species spatial transcriptomics

作者:

The integration of spatial transcriptomics (ST) data across species is essential for cross-species and translational studies, but remains challenging due to molecular divergence and anatomical differences between organisms. We present STACAME, a graph attention autoencoder-based framework to decipher shared and divergent tissue architectures from cross-species ST data by explicitly modeling both orthologous and species-specific genes. STACAME aligns ST slices in a spatially aware manner, identifies homologous and species-specific domains, and enables a suite of downstream comparative analyses. We demonstrate its utility by integrating ST datasets from diverse tissues, including hippocampus, isocortex, embryo, breast, liver, and cerebellum, across multiple species such as human, macaque, marmoset, mouse, and zebrafish. STACAME supports cross-species spatial domain alignment, the detection of shared and divergent spatially variable genes, development alignment and comparison, and the 3D integration of tissue architecture. This flexible approach facilitates the translation of findings from model organisms to humans, providing a unified computational platform for cross-species spatial transcriptomics.

12.
arXiv (math.PR) 2026-06-15

Uniform-in-time error estimates for McKean-Vlasov SDEs with common noise and stochastic algorithms

arXiv:2606.14170v1 Announce Type: new Abstract: In this work, by construct an asymptotic coupling by reflection, we first explore the uniform-in-time estimate on probability distance for two measure-valued processes induced by a McKean-Vlasov SDE with common noise and an interacting particle system, where the drift terms are dissipative merely in the long distance. As direct applications of this estimate, we establish the uniform-in-time error estimates for the numerical solutions derived via backward/tamed/adaptive Euler-Maruyama methods. Moreover, as another direct application, the uniform-in-time conditional propagation of chaos is quantified.

13.
arXiv (CS.LG) 2026-06-15

Traditional machine learning vs. deep learning from dynamic graph representations of proteins' 3D folds in the task of protein structure classification

arXiv:2605.29228v2 Announce Type: replace Abstract: Protein structure classification (PSC) uses supervised learning to predict a protein's CATH/SCOP(e) class from the protein's sequence or 3D structural feature(s). We already modeled 3D structures as (static) protein structure networks (PSNs), demonstrating the competitiveness of PSN-based features to sequence or direct (i.e. non-network) 3D structural features in the PSC task. More recently, we demonstrated the power of features extracted from dynamic PSNs over features extracted from static PSNs (and thus by transitivity over sequence and direct 3D structural features) in the same task. That dynamic PSN approach used traditional machine learning (ML), combining manual (pre-engineered) features with an off-the-shelf classifier. Here, we evaluate whether automatic deep learning (DL) from the dynamic PSNs yields improvements. Our evaluation on 72 datasets spanning ~44,000 CATH- or SCOPe-labeled dynamic PSNs reveals that in terms of PSC accuracy, traditional ML and DL are (close to) tied for a large majority of the datasets, while DL is on average 10+ times slower. We are the first to evaluate traditional ML vs. DL in the dynamic PSN-based PSC task.

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

The Hidden Power of Scaling Factor in LoRA Optimization

arXiv:2606.12883v1 Announce Type: new Abstract: In Low-Rank Adaptation (LoRA), the scaling factor $\alpha$ is often treated as a mere complement to the learning rate, yet its role in optimization remains poorly understood. In this paper, we reveal that the scaling factor $\alpha$ and the learning rate function differently, with $\alpha$ emerging as the dominant driver of effective optimization, delivering gains that cannot be replicated by learning rate scaling alone. Through the synergy of extensive empirical analysis and a theoretical Signal-Drift framework, we uncover three findings into LoRA's scaling mechanism: First, LoRA's spectral suppression smooths the optimization landscape, rendering standard hyperparameters overly conservative and creating an optimization gap. Second, when leveraging this smoothness to accelerate convergence, $\alpha$ outperforms the learning rate by amplifying the task signal without increasing the drift ratio. Third, the optimal scaling factor follows a sublinear relationship with the rank, well characterized by a square-root law with an unexpectedly large coefficient, revealing the insufficient scaling of existing rank-tied heuristics. Based on these insights, we propose LoRA-$\alpha$, a minimalist framework that restores $\alpha$ to its principled regime, making LoRA compatible with standard small learning rates. Extensive evaluations across diverse tasks demonstrate that LoRA-$\alpha$ consistently improves performance while streamlining hyperparameter search, unleashing the learning potential of LoRA.

15.
arXiv (CS.CL) 2026-06-12

Given, When, Then, Again: Mining Subscenario Refactoring Candidates in Behaviour-Driven Test Suites with ML Classifiers and LLM-Judge Baselines

Context. Behaviour-Driven Development (BDD) test suites accumulate duplicated step subsequences. Three published refactoring patterns are available (within-file Background, within-repo reusable-scenario invocation, cross-organisational shared higher-level step), but no prior work automates which recurring subsequences are worth extracting or which mechanism applies. Objective. Rank recurring step subsequences ("slices") by refactoring suitability (extraction-worthy), pre-map each to one of the three patterns, and quantify prevalence across the public BDD ecosystem. Method. Every contiguous L-step window (L in [2, 18]) in a 339-repository / 276-upstream-owner Gherkin corpus is keyed by paraphrase-robust cluster identifiers and counted under three scopes. SBERT / UMAP / HDBSCAN clustering recovers paraphrase-equivalent slices. Three authors label a stratified 200-slice pool against a written rubric. An XGBoost extraction-worthy classifier trained under 5-fold cross-validation is compared with a tuned rule baseline and two open-weight Large Language Model (LLM) judges. Results. The miner produces 5,382,249 slices collapsing to 692,020 recurring patterns. Three-author Fleiss' kappa = 0.56 (extraction-worthy) and 0.79 (mechanism). The classifier reaches out-of-fold F1 = 0.891 (95% CI [0.852, 0.927]), outperforming both the rule baseline (F1 = 0.836, p = 0.017) and the better LLM judge (F1 = 0.728, p = 1.5e-4). 75.0%, 59.5%, and 11.7% of scenarios carry a within-file Background, within-repo reusable-scenario, and cross-organisational shared-step candidate, respectively; the figures are stable under a sweep of the classifier decision threshold. Conclusion. Paraphrase-robust subscenario discovery yields a corpus-wide census of BDD refactoring candidates; pipeline, classifier predictions, labelled pool, and rubric are released under Apache-2.0.

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

Posterior Twins: Distributional Behavioral Simulation for Enterprise Decisions

作者:

arXiv:2606.16415v1 Announce Type: new Abstract: Enterprise behavioral simulation requires more than producing a plausible response. Many decisions depend on the shape of a population under a proposed action: which segments accept, defect, hesitate, or move into risk-sensitive states. This paper introduces Posterior Twins, a memory-grounded digital-twin approach that represents likely behavior as an updated distribution under a specific decision context. We evaluate a family of Twinning Labs behavioral-model operating points on a 226-example held-out behavioral-response benchmark and report both modal accuracy and Wasserstein-1 distance. The results show that modal accuracy and distributional fidelity identify different operating regimes. TL-Twin Alpha achieves the lowest observed Wasserstein-1 distance in the reported result set ($W_1 = 1.16$), while TL-Twin Delta and TL-Twin Gamma provide balanced operating points near the modal-accuracy frontier. The paper frames these results as a systems result: governed memory, behavioral model routing, scenario orchestration, distributional aggregation, and auditability are necessary for turning simulated behavior into reusable enterprise decision evidence.

17.
arXiv (math.PR) 2026-06-16

The distribution of the de Moivre experiment

arXiv:2606.15178v1 Announce Type: new Abstract: In this paper, we focus on de Moivre random experience which allows us to introduce the $ s- $Bernoulli distribution and the bi$ ^s $nomial distribution. We present some probabilistic properties such as the expectation, the variance, the skewness and kurtosis coefficients, the moments and the generating functions. Then we establish that for $ s\in\mathbb{N} $, the bi$ ^s $nomial distribution converges to a limiting Poisson and normal distributions when $ n\rightarrow\infty. $

18.
arXiv (quant-ph) 2026-06-11

Nonlocal continuous-variable gates by amplified optical connections

arXiv:2603.12866v2 Announce Type: replace Abstract: Nonlocal quantum gates, coupling quantum systems located at a distance, are crucial for distributed quantum computing. To this aim, high-capacity optical noiseless connections between different processing units are essential for transmitting large amounts of information per mode. Simultaneously, optical quantum computing offers future high-speed multimode quantum processors. We propose a library of feasible protocols to implement a necessary nonlocal continuous-variable (CV) quantum nondemolition (QND) gate between two distant users sharing a quantum channel and exploiting classical communication. The users are endowed with a newly achieved high-fidelity and large-bandwith element - single-pass phase-sensitive optical parametric amplifier (OPA), that allows for both online squeezing and channel-loss compensation. The use of OPAs enhances quality of the resulting gate in terms of both excess noise and entangling capability. The proposed schemes are also applicable to CV cluster state fusion, providing a first step towards development of distributed CV measurement-based quantum computation.

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

Treatment Response Optimized Clinical Decision Support AI System via Digital Twin Simulation

arXiv:2606.17405v1 Announce Type: new Abstract: Clinical decision support AI systems (CDSASs) must adapt to evolving patient conditions in real-time while adhering to strict safety constraints. We present an online adaptive framework that integrates Treatment Effect (TE) estimation to quantify clinical benefits, a patient Digital Twin (DT) to simulate treatment trajectories, and Reinforcement Learning (RL) for sequential decision-making. The AI system is initially trained on historical medical records and operates in a continuous learning loop. To ensure safety, a rule-based module monitors vital signs and blocks contraindicated treatments. Cases with strong internal model disagreement are flagged for clinician review, simulated in our experiments via a pre-trained outcome model. We validate our framework using both a synthetic clinical simulator and a real-world ovarian cancer dataset from The Cancer Genome Atlas (TCGA). In both simulated and clinical settings, our method demonstrated superior effectiveness and stability in recommending treatments compared to standard computational baselines. Furthermore, the AI system maintains low latency and requires expert consultation for only a minority of cases in our experimental validation, demonstrating its potential as a safe, clinician-supervised tool for personalized medicine that continuously improves through practical use.

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

When Does Language Matter? Multilingual Instructions Reveal Step-wise Language Sensitivity in Vision-Language-Action Models

Vision-Language-Action (VLA) models have shown strong performance in language-conditioned robotic manipulation, yet their robustness to linguistic variation remains poorly understood. In this work, we present the first systematic multilingual evaluation of VLA models by translating the LIBERO benchmark into ten languages, revealing severe performance degradation under non-English instructions, with success rates dropping by 30-50%. Through fine-grained analysis of task executions, we find that language influence is highly non-uniform across steps: certain steps exhibit strong language dependence and dominate overall task failure, while others are largely language-agnostic. Based on this insight, we propose a step-wise inference-time intervention that aligns representations according to step language sensitivity, substantially improving performance under linguistic variation. Our results indicate that language robustness in VLA models is fundamentally a step-wise control problem, highlighting the importance of temporally structured analysis for reliable embodied agents.

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

From Memorization to Creation: Evaluating the Cognitive Depth of LLM-Generated Educational Questions

arXiv:2606.18257v1 Announce Type: cross Abstract: While LLMs show promise in automating educational content creation, their ability to generate questions that stimulate higher-order thinking remains understudied. This work evaluates six widely-used LLMs through a Bloom's Taxonomy lens, focusing on their capacity to transcend rote memorization and achieve cognitive leaps. Using a hybrid human–AI evaluation protocol, we generate and analyze 20{,}700 questions across computer science, K–12 math, and social-science domains. Key contributions include: (1) a fine-grained prompting strategy that reduces question repetitiveness by 24.45\% for Qwen2.5-7B-Instruct, and increases the proportion of higher-order cognitive level outputs by 11.53\% for InternLM3-8B-Instruct; (2) quantitative metrics for cognitive shift intensity (CogShift) and category drift, revealing InternLM3's superior performance in multi-level transitions; (3) an interpretability analysis revealing metric-level correlations that enhance the transparency of Chain-of-Thought prompting. Our findings highlight the importance of cognitive-aware prompt design and provide benchmarks for deploying LLMs in personalized learning systems.

23.
Science (Express) 2026-04-16

Protein-templated synthesis of dinucleotide repeat DNA by an antiphage reverse transcriptase | Science

作者: 未知作者

Defense-associated reverse transcriptases (DRTs) are widespread bacterial anti-phage systems that use unconventional mechanisms of polynucleotide synthesis. We show that DRT3, which comprises two distinct RTs (Drt3a and Drt3b) and a noncoding RNA (ncRNA), synthesizes alternating poly(GT/AC) double-stranded DNA. Cryo–electron microscopy structures at 2.6 Å resolution reveal a D3-symmetric 6:6:6 complex of Drt3a, Drt3b, and ncRNA. Drt3a produces the poly(GT) strand using a conserved ACACAC template within the ncRNA. Notably, Drt3b synthesizes a complementary, protein-primed poly(AC) strand in the complete absence of a nucleic acid template, using conserved active site residues specific to Drt3b to enforce precise base alternation. These findings expand the functional landscape of nucleic acid polymerases, revealing a protein-templated mechanism for sequence-specific DNA synthesis.

24.
bioRxiv (Bioinfo) 2026-06-14

Virtual phenotypic screening discovers novel scaffolds inhibiting the PI3K/mTOR pathway

Phenotypic drug discovery has yielded many first-in-class small-molecule drugs by discovering modulators of disease phenotypes in physiologically relevant cellular systems. However, high-content phenotypic assays lack the ultra-high-throughput scalability of target-based screens. Recent advances in virtual screening present an opportunity to address this bottleneck, but have been limited to simple phenotypes like viability, restricted to small repurposing libraries, or lack in-depth biological validation. Here, we present PhenoCompass, a multimodal co-embedding model that aligns compound structures and high-content phenotypic imaging to enable virtual phenotypic screening over billion-compound libraries. Following training on the Joint Undertaking in Morphology dataset with more than 100,000 Cell Painting compound profiles, retrospective validation with historical biochemical high-throughput screening data demonstrates that PhenoCompass ranks compounds according to their biochemical target engagement. Leveraging PhenoCompass, we performed a prospective screen of 3.8 billion Enamine REAL compounds for inhibitors of PI3K/mTOR pathway, a critical signaling cascade whose aberrant activation is a common tumor driver. This search identified 11 novel compounds with pathway-consistent Cell Painting readout and diverse scaffolds, a 54-fold enrichment over the training set. Orthogonal validation experiments using a FOXO3A reporter assay and direct kinase inhibition confirmed seven structurally novel inhibitors with distinct mechanisms of action. These results highlight the convergence of diverse molecular target profiles onto a shared morphological pathway signature and establish PhenoCompass as a robust framework for high-content phenotypic virtual screening.

25.
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.