Daily Papers

The advent of single-cell Assay for Transposase-Accessible Chromatin using sequencing (scATAC-seq) offers an innovative perspective for deciphering regulatory mechanisms by assembling a vast repository of single-cell chromatin accessibility data. While foundation models have achieved significant success in single-cell transcriptomics, there is currently no foundation model for scATAC-seq that supports zero-shot high-quality cell identification and comprehensive multi-omics analysis simultaneously. Key challenges lie in the high dimensionality and sparsity of scATAC-seq data, as well as the lack of a standardized schema for representing open chromatin regions (OCRs). Here, we present ChromFound, a foundation model tailored for scATAC-seq. ChromFound utilizes a hybrid architecture and genome-aware tokenization to effectively capture genome-wide long contexts and regulatory signals from dynamic chromatin landscapes. Pretrained on 1.97 million cells from 30 tissues and 6 disease conditions, ChromFound demonstrates broad applicability across 6 diverse tasks. Notably, it achieves robust zero-shot performance in generating universal cell representations and exhibits excellent transferability in cell type annotation and cross-omics prediction. By uncovering enhancer-gene links undetected by existing computational methods, ChromFound offers a promising framework for understanding disease risk variants in the noncoding genome.

We consider the problem of predicting gene expressions from DNA sequences. A key challenge of this task is to find the regulatory elements that control gene expressions. Here, we introduce Seq2Exp, a Sequence to Expression network explicitly designed to discover and extract regulatory elements that drive target gene expression, enhancing the accuracy of the gene expression prediction. Our approach captures the causal relationship between epigenomic signals, DNA sequences and their associated regulatory elements. Specifically, we propose to decompose the epigenomic signals and the DNA sequence conditioned on the causal active regulatory elements, and apply an information bottleneck with the Beta distribution to combine their effects while filtering out non-causal components. Our experiments demonstrate that Seq2Exp outperforms existing baselines in gene expression prediction tasks and discovers influential regions compared to commonly used statistical methods for peak detection such as MACS3. The source code is released as part of the AIRS library (https://github.com/divelab/AIRS/).

Foundation models for single-cell RNA sequencing (scRNA-seq) have shown promising capabilities in capturing gene expression patterns. However, current approaches face critical limitations: they ignore biological prior knowledge encoded in gene regulatory relationships and fail to leverage multi-omics signals that could provide complementary regulatory insights. In this paper, we propose GRNFormer, a new framework that systematically integrates multi-scale Gene Regulatory Networks (GRNs) inferred from multi-omics data into RNA foundation model training. Our framework introduces two key innovations. First, we introduce a pipeline for constructing hierarchical GRNs that capture regulatory relationships at both cell-type-specific and cell-specific resolutions. Second, we design a structure-aware integration framework that addresses the information asymmetry in GRNs through two technical advances: (1) A graph topological adapter using multi-head cross-attention to weight regulatory relationships dynamically, and (2) a novel edge perturbation strategy that perturb GRNs with biologically-informed co-expression links to augment graph neural network training. Comprehensive experiments have been conducted on three representative downstream tasks across multiple model architectures to demonstrate the effectiveness of GRNFormer. It achieves consistent improvements over state-of-the-art (SoTA) baselines: 3.6% increase in drug response prediction correlation, 9.6% improvement in single-cell drug classification AUC, and 1.1% average gain in gene perturbation prediction accuracy.

Motor impairments, frequently caused by neurological incidents like strokes or traumatic brain injuries, present substantial obstacles in rehabilitation therapy. This research aims to elevate the field by optimizing motor imagery classification algorithms within Brain-Computer Interfaces (BCIs). By improving the efficiency of BCIs, we offer a novel approach that holds significant promise for enhancing motor rehabilitation outcomes. Utilizing unsupervised techniques for dimensionality reduction, namely Uniform Manifold Approximation and Projection (UMAP) coupled with K-Nearest Neighbors (KNN), we evaluate the necessity of employing supervised methods such as Long Short-Term Memory (LSTM) and Convolutional Neural Networks (CNNs) for classification tasks. Importantly, participants who exhibited high KNN scores following UMAP dimensionality reduction also achieved high accuracy in supervised deep learning (DL) models. Due to individualized model requirements and massive neural training data, dimensionality reduction becomes an effective preprocessing step that minimizes the need for extensive data labeling and supervised deep learning techniques. This approach has significant implications not only for targeted therapies in motor dysfunction but also for addressing regulatory, safety, and reliability concerns in the rapidly evolving BCI field.

Estimating single-cell responses across various perturbations facilitates the identification of key genes and enhances drug screening, significantly boosting experimental efficiency. However, single-cell sequencing is a destructive process, making it impossible to capture the same cell's phenotype before and after perturbation. Consequently, data collected under perturbed and unperturbed conditions are inherently unpaired. Existing methods either attempt to forcibly pair unpaired data using random sampling, or neglect the inherent relationship between unperturbed and perturbed cells during the modeling. In this work, we propose a framework based on Dual Diffusion Implicit Bridges (DDIB) to learn the mapping between different data distributions, effectively addressing the challenge of unpaired data. We further interpret this framework as a form of data augmentation. We integrate gene regulatory network (GRN) information to propagate perturbation signals in a biologically meaningful way, and further incorporate a masking mechanism to predict silent genes, improving the quality of generated profiles. Moreover, gene expression under the same perturbation often varies significantly across cells, frequently exhibiting a bimodal distribution that reflects intrinsic heterogeneity. To capture this, we introduce a more suitable evaluation metric. We propose Unlasting, dual conditional diffusion models that overcome the problem of unpaired single-cell perturbation data and strengthen the model's insight into perturbations under the guidance of the GRN, with a dedicated mask model designed to improve generation quality by predicting silent genes. In addition, we introduce a biologically grounded evaluation metric that better reflects the inherent heterogeneity in single-cell responses.

The realization that complex systems such as ecological communities can collapse or shift regimes suddenly and without rapid external forcing poses a serious challenge to our understanding and management of the natural world. The potential to identify early warning signals that would allow researchers and managers to predict such events before they happen has therefore been an invaluable discovery that offers a way forward in spite of such seemingly unpredictable behavior. Research into early warning signals has demonstrated that it is possible to define and detect such early warning signals in advance of a transition in certain contexts. Here we describe the pattern emerging as research continues to explore just how far we can generalize these results. A core of examples emerges that shares three properties: the phenomenon of rapid regime shifts, a pattern of 'critical slowing down' that can be used to detect the approaching shift, and a mechanism of bifurcation driving the sudden change. As research has expanded beyond these core examples, it is becoming clear that not all systems that show regime shifts exhibit critical slowing down, or vice versa. Even when systems exhibit critical slowing down, statistical detection is a challenge. We review the literature that explores these edge cases and highlight the need for (a) new early warning behaviors that can be used in cases where rapid shifts do not exhibit critical slowing down, (b) the development of methods to identify which behavior might be an appropriate signal when encountering a novel system; bearing in mind that a positive indication for some systems is a negative indication in others, and (c) statistical methods that can distinguish between signatures of early warning behaviors and noise.

Early warning signals have been proposed to forecast the possibility of a critical transition, such as the eutrophication of a lake, the collapse of a coral reef, or the end of a glacial period. Because such transitions often unfold on temporal and spatial scales that can be difficult to approach by experimental manipulation, research has often relied on historical observations as a source of natural experiments. Here we examine a critical difference between selecting systems for study based on the fact that we have observed a critical transition and those systems for which we wish to forecast the approach of a transition. This difference arises by conditionally selecting systems known to experience a transition of some sort and failing to account for the bias this introduces -- a statistical error often known as the Prosecutor's Fallacy. By analysing simulated systems that have experienced transitions purely by chance, we reveal an elevated rate of false positives in common warning signal statistics. We further demonstrate a model-based approach that is less subject to this bias than these more commonly used summary statistics. We note that experimental studies with replicates avoid this pitfall entirely.

The rapid advancement of artificial intelligence (AI) systems in critical domains like healthcare, justice, and social services has sparked numerous regulatory initiatives aimed at ensuring their safe deployment. Current regulatory frameworks, exemplified by recent US and EU efforts, primarily focus on procedural guidelines while presuming that scientific benchmarking can effectively validate AI safety, similar to how crash tests verify vehicle safety or clinical trials validate drug efficacy. However, this approach fundamentally misunderstands the unique technical challenges posed by modern AI systems. Through systematic analysis of successful technology regulation case studies, we demonstrate that effective scientific regulation requires a causal theory linking observable test outcomes to future performance - for instance, how a vehicle's crash resistance at one speed predicts its safety at lower speeds. We show that deep learning models, which learn complex statistical patterns from training data without explicit causal mechanisms, preclude such guarantees. This limitation renders traditional regulatory approaches inadequate for ensuring AI safety. Moving forward, we call for regulators to reckon with this limitation, and propose a preliminary two-tiered regulatory framework that acknowledges these constraints: mandating human oversight for high-risk applications while developing appropriate risk communication strategies for lower-risk uses. Our findings highlight the urgent need to reconsider fundamental assumptions in AI regulation and suggest a concrete path forward for policymakers and researchers.

A reply to Drake (2013) "Early warning signals of stochastic switching" http://dx.doi.org/10.1098/rspb.2013.0686

Regulatory documents, issued by governmental regulatory bodies, establish rules, guidelines, and standards that organizations must adhere to for legal compliance. These documents, characterized by their length, complexity and frequent updates, are challenging to interpret, requiring significant allocation of time and expertise on the part of organizations to ensure ongoing compliance.Regulatory Natural Language Processing (RegNLP) is a multidisciplinary subfield aimed at simplifying access to and interpretation of regulatory rules and obligations. We define an Automated Question-Passage Generation task for RegNLP, create the ObliQA dataset containing 27,869 questions derived from the Abu Dhabi Global Markets (ADGM) financial regulation document collection, design a baseline Regulatory Information Retrieval and Answer Generation system, and evaluate it with RePASs, a novel evaluation metric that tests whether generated answers accurately capture all relevant obligations and avoid contradictions.

We propose a novel machine learning approach for inferring causal variables of a target variable from observations. Our focus is on directly inferring a set of causal factors without requiring full causal graph reconstruction, which is computationally challenging in large-scale systems. The identified causal set consists of all potential regulators of the target variable under experimental settings, enabling efficient regulation when intervention costs and feasibility vary across variables. To achieve this, we train a neural network using supervised learning on simulated data to infer causality. By employing a local-inference strategy, our approach scales with linear complexity in the number of variables, efficiently scaling up to thousands of variables. Empirical results demonstrate superior performance in identifying causal relationships within large-scale gene regulatory networks, outperforming existing methods that emphasize full-graph discovery. We validate our model's generalization capability across out-of-distribution graph structures and generating mechanisms, including gene regulatory networks of E. coli and the human K562 cell line. Implementation codes are available at https://github.com/snu-mllab/Targeted-Cause-Discovery.

Cis-regulatory elements (CREs), such as promoters and enhancers, are relatively short DNA sequences that directly regulate gene expression. The fitness of CREs, measured by their ability to modulate gene expression, highly depends on the nucleotide sequences, especially specific motifs known as transcription factor binding sites (TFBSs). Designing high-fitness CREs is crucial for therapeutic and bioengineering applications. Current CRE design methods are limited by two major drawbacks: (1) they typically rely on iterative optimization strategies that modify existing sequences and are prone to local optima, and (2) they lack the guidance of biological prior knowledge in sequence optimization. In this paper, we address these limitations by proposing a generative approach that leverages reinforcement learning (RL) to fine-tune a pre-trained autoregressive (AR) model. Our method incorporates data-driven biological priors by deriving computational inference-based rewards that simulate the addition of activator TFBSs and removal of repressor TFBSs, which are then integrated into the RL process. We evaluate our method on promoter design tasks in two yeast media conditions and enhancer design tasks for three human cell types, demonstrating its ability to generate high-fitness CREs while maintaining sequence diversity. The code is available at https://github.com/yangzhao1230/TACO.

The primary goal of drug safety researchers and regulators is to promptly identify adverse drug reactions. Doing so may in turn prevent or reduce the harm to patients and ultimately improve public health. Evaluating and monitoring drug safety (i.e., pharmacovigilance) involves analyzing an ever growing collection of spontaneous reports from health professionals, physicians, and pharmacists, and information voluntarily submitted by patients. In this scenario, facilitating analysis of such reports via automation has the potential to rapidly identify safety signals. Unfortunately, public resources for developing natural language models for this task are scant. We present PHEE, a novel dataset for pharmacovigilance comprising over 5000 annotated events from medical case reports and biomedical literature, making it the largest such public dataset to date. We describe the hierarchical event schema designed to provide coarse and fine-grained information about patients' demographics, treatments and (side) effects. Along with the discussion of the dataset, we present a thorough experimental evaluation of current state-of-the-art approaches for biomedical event extraction, point out their limitations, and highlight open challenges to foster future research in this area.

This paper presents the system description of our entry for the COLING 2025 RegNLP RIRAG (Regulatory Information Retrieval and Answer Generation) challenge, focusing on leveraging advanced information retrieval and answer generation techniques in regulatory domains. We experimented with a combination of embedding models, including Stella, BGE, CDE, and Mpnet, and leveraged fine-tuning and reranking for retrieving relevant documents in top ranks. We utilized a novel approach, LeSeR, which achieved competitive results with a recall@10 of 0.8201 and map@10 of 0.6655 for retrievals. This work highlights the transformative potential of natural language processing techniques in regulatory applications, offering insights into their capabilities for implementing a retrieval augmented generation system while identifying areas for future improvement in robustness and domain adaptation.

Despite the greater functional importance of protein levels, our knowledge of gene expression evolution is based almost entirely on studies of mRNA levels. In contrast, our understanding of how translational regulation evolves has lagged far behind. Here we have applied ribosome profiling - which measures both global mRNA levels and their translation rates - to two species of Saccharomyces yeast and their interspecific hybrid in order to assess the relative contributions of changes in mRNA abundance and translation to regulatory evolution. We report that both cis and trans-acting regulatory divergence in translation are abundant, affecting at least 35% of genes. The majority of translational divergence acts to buffer changes in mRNA abundance, suggesting a widespread role for stabilizing selection acting across regulatory levels. Nevertheless, we observe evidence of lineage-specific selection acting on a number of yeast functional modules, including instances of reinforcing selection acting at both levels of regulation. Finally, we also uncover multiple instances of stop-codon readthrough that are conserved between species. Our analysis reveals the under-appreciated complexity of post-transcriptional regulatory divergence and indicates that partitioning the search for the locus of selection into the binary categories of 'coding' vs. 'regulatory' may overlook a significant source of selection, acting at multiple regulatory levels along the path from genotype to phenotype.

As a vital stage of automated rule checking (ARC), rule interpretation of regulatory texts requires considerable effort. However, interpreting regulatory clauses with implicit properties or complex computational logic is still challenging due to the lack of domain knowledge and limited expressibility of conventional logic representations. Thus, LLM-FuncMapper, an approach to identifying predefined functions needed to interpret various regulatory clauses based on the large language model (LLM), is proposed. First, by systematically analysis of building codes, a series of atomic functions are defined to capture shared computational logics of implicit properties and complex constraints, creating a database of common blocks for interpreting regulatory clauses. Then, a prompt template with the chain of thought is developed and further enhanced with a classification-based tuning strategy, to enable common LLMs for effective function identification. Finally, the proposed approach is validated with statistical analysis, experiments, and proof of concept. Statistical analysis reveals a long-tail distribution and high expressibility of the developed function database, with which almost 100% of computer-processible clauses can be interpreted and represented as computer-executable codes. Experiments show that LLM-FuncMapper achieve promising results in identifying relevant predefined functions for rule interpretation. Further proof of concept in automated rule interpretation also demonstrates the possibility of LLM-FuncMapper in interpreting complex regulatory clauses. To the best of our knowledge, this study is the first attempt to introduce LLM for understanding and interpreting complex regulatory clauses, which may shed light on further adoption of LLM in the construction domain.

Catastrophic regime shifts in complex natural systems may be averted through advanced detection. Recent work has provided a proof-of-principle that many systems approaching a catastrophic transition may be identified through the lens of early warning indicators such as rising variance or increased return times. Despite widespread appreciation of the difficulties and uncertainty involved in such forecasts, proposed methods hardly ever characterize their expected error rates. Without the benefits of replicates, controls, or hindsight, applications of these approaches must quantify how reliable different indicators are in avoiding false alarms, and how sensitive they are to missing subtle warning signs. We propose a model based approach in order to quantify this trade-off between reliability and sensitivity and allow comparisons between different indicators. We show these error rates can be quite severe for common indicators even under favorable assumptions, and also illustrate how a model-based indicator can improve this performance. We demonstrate how the performance of an early warning indicator varies in different data sets, and suggest that uncertainty quantification become a more central part of early warning predictions.

Modern deep learning systems are typically deployed as open-loop function approximators: they map inputs to outputs in a single pass, without regulating how much computation or explanatory effort is spent on a given case. In safety-critical settings, this is brittle: easy and ambiguous inputs receive identical processing, and uncertainty is only read off retrospectively from raw probabilities. We introduce the Surgical Cognitive Interpreter (SCI), a lightweight closed-loop metacognitive control layer that wraps an existing stochastic model and turns prediction into an iterative process. SCI monitors a scalar interpretive state SP(t), here instantiated as a normalized entropy-based confidence signal, and adaptively decides whether to stop, continue sampling, or abstain. The goal is not to improve accuracy per se, but to regulate interpretive error ΔSP and expose a safety signal that tracks when the underlying model is likely to fail. We instantiate SCI around Monte Carlo dropout classifiers in three domains: vision (MNIST digits), medical time series (MIT-BIH arrhythmia), and industrial condition monitoring (rolling-element bearings). In all cases, the controller allocates more inference steps to misclassified inputs than to correct ones (up to about 3-4x on MNIST and bearings, and 1.4x on MIT-BIH). The resulting ΔSP acts as a usable safety signal for detecting misclassifications (AUROC 0.63 on MNIST, 0.70 on MIT-BIH, 0.86 on bearings). Code and reproducibility: https://github.com/vishal-1344/sci

A dog whistle is a form of coded communication that carries a secondary meaning to specific audiences and is often weaponized for racial and socioeconomic discrimination. Dog whistling historically originated from United States politics, but in recent years has taken root in social media as a means of evading hate speech detection systems and maintaining plausible deniability. In this paper, we present an approach for word-sense disambiguation of dog whistles from standard speech using Large Language Models (LLMs), and leverage this technique to create a dataset of 16,550 high-confidence coded examples of dog whistles used in formal and informal communication. Silent Signals is the largest dataset of disambiguated dog whistle usage, created for applications in hate speech detection, neology, and political science. The dataset can be found at https://huggingface.co/datasets/SALT-NLP/silent_signals.

Drug shortages pose critical risks to patient care and healthcare systems worldwide, yet the effectiveness of regulatory interventions remains poorly understood due to information asymmetries in pharmaceutical supply chains. We propose ShortageSim, addresses this challenge by providing the first simulation framework that evaluates the impact of regulatory interventions on competition dynamics under information asymmetry. Using Large Language Model (LLM)-based agents, the framework models the strategic decisions of drug manufacturers and institutional buyers, in response to shortage alerts given by the regulatory agency. Unlike traditional game theory models that assume perfect rationality and complete information, ShortageSim simulates heterogeneous interpretations on regulatory announcements and the resulting decisions. Experiments on self-processed dataset of historical shortage events show that ShortageSim reduces the resolution lag for production disruption cases by up to 84\%, achieving closer alignment to real-world trajectories than the zero-shot baseline. Our framework confirms the effect of regulatory alert in addressing shortages and introduces a new method for understanding competition in multi-stage environments under uncertainty. We open-source ShortageSim and a dataset of 2,925 FDA shortage events, providing a novel framework for future research on policy design and testing in supply chains under information asymmetry.

Major scandals in corporate history have urged the need for regulatory compliance, where organizations need to ensure that their controls (processes) comply with relevant laws, regulations, and policies. However, keeping track of the constantly changing legislation is difficult, thus organizations are increasingly adopting Regulatory Technology (RegTech) to facilitate the process. To this end, we introduce regulatory information retrieval (REG-IR), an application of document-to-document information retrieval (DOC2DOC IR), where the query is an entire document making the task more challenging than traditional IR where the queries are short. Furthermore, we compile and release two datasets based on the relationships between EU directives and UK legislation. We experiment on these datasets using a typical two-step pipeline approach comprising a pre-fetcher and a neural re-ranker. Experimenting with various pre-fetchers from BM25 to k nearest neighbors over representations from several BERT models, we show that fine-tuning a BERT model on an in-domain classification task produces the best representations for IR. We also show that neural re-rankers under-perform due to contradicting supervision, i.e., similar query-document pairs with opposite labels. Thus, they are biased towards the pre-fetcher's score. Interestingly, applying a date filter further improves the performance, showcasing the importance of the time dimension.

Gene regulatory network inference (GRNI) is a challenging problem, particularly owing to the presence of zeros in single-cell RNA sequencing data: some are biological zeros representing no gene expression, while some others are technical zeros arising from the sequencing procedure (aka dropouts), which may bias GRNI by distorting the joint distribution of the measured gene expressions. Existing approaches typically handle dropout error via imputation, which may introduce spurious relations as the true joint distribution is generally unidentifiable. To tackle this issue, we introduce a causal graphical model to characterize the dropout mechanism, namely, Causal Dropout Model. We provide a simple yet effective theoretical result: interestingly, the conditional independence (CI) relations in the data with dropouts, after deleting the samples with zero values (regardless if technical or not) for the conditioned variables, are asymptotically identical to the CI relations in the original data without dropouts. This particular test-wise deletion procedure, in which we perform CI tests on the samples without zeros for the conditioned variables, can be seamlessly integrated with existing structure learning approaches including constraint-based and greedy score-based methods, thus giving rise to a principled framework for GRNI in the presence of dropouts. We further show that the causal dropout model can be validated from data, and many existing statistical models to handle dropouts fit into our model as specific parametric instances. Empirical evaluation on synthetic, curated, and real-world experimental transcriptomic data comprehensively demonstrate the efficacy of our method.

Regulatory texts are inherently long and complex, presenting significant challenges for information retrieval systems in supporting regulatory officers with compliance tasks. This paper introduces a hybrid information retrieval system that combines lexical and semantic search techniques to extract relevant information from large regulatory corpora. The system integrates a fine-tuned sentence transformer model with the traditional BM25 algorithm to achieve both semantic precision and lexical coverage. To generate accurate and comprehensive responses, retrieved passages are synthesized using Large Language Models (LLMs) within a Retrieval Augmented Generation (RAG) framework. Experimental results demonstrate that the hybrid system significantly outperforms standalone lexical and semantic approaches, with notable improvements in Recall@10 and MAP@10. By openly sharing our fine-tuned model and methodology, we aim to advance the development of robust natural language processing tools for compliance-driven applications in regulatory domains.

The progress in modelling time series and, more generally, sequences of structured data has recently revamped research in anomaly detection. The task stands for identifying abnormal behaviors in financial series, IT systems, aerospace measurements, and the medical domain, where anomaly detection may aid in isolating cases of depression and attend the elderly. Anomaly detection in time series is a complex task since anomalies are rare due to highly non-linear temporal correlations and since the definition of anomalous is sometimes subjective. Here we propose the novel use of Hyperbolic uncertainty for Anomaly Detection (HypAD). HypAD learns self-supervisedly to reconstruct the input signal. We adopt best practices from the state-of-the-art to encode the sequence by an LSTM, jointly learned with a decoder to reconstruct the signal, with the aid of GAN critics. Uncertainty is estimated end-to-end by means of a hyperbolic neural network. By using uncertainty, HypAD may assess whether it is certain about the input signal but it fails to reconstruct it because this is anomalous; or whether the reconstruction error does not necessarily imply anomaly, as the model is uncertain, e.g. a complex but regular input signal. The novel key idea is that a detectable anomaly is one where the model is certain but it predicts wrongly. HypAD outperforms the current state-of-the-art for univariate anomaly detection on established benchmarks based on data from NASA, Yahoo, Numenta, Amazon, and Twitter. It also yields state-of-the-art performance on a multivariate dataset of anomaly activities in elderly home residences, and it outperforms the baseline on SWaT. Overall, HypAD yields the lowest false alarms at the best performance rate, thanks to successfully identifying detectable anomalies.

Advanced AI models hold the promise of tremendous benefits for humanity, but society needs to proactively manage the accompanying risks. In this paper, we focus on what we term "frontier AI" models: highly capable foundation models that could possess dangerous capabilities sufficient to pose severe risks to public safety. Frontier AI models pose a distinct regulatory challenge: dangerous capabilities can arise unexpectedly; it is difficult to robustly prevent a deployed model from being misused; and, it is difficult to stop a model's capabilities from proliferating broadly. To address these challenges, at least three building blocks for the regulation of frontier models are needed: (1) standard-setting processes to identify appropriate requirements for frontier AI developers, (2) registration and reporting requirements to provide regulators with visibility into frontier AI development processes, and (3) mechanisms to ensure compliance with safety standards for the development and deployment of frontier AI models. Industry self-regulation is an important first step. However, wider societal discussions and government intervention will be needed to create standards and to ensure compliance with them. We consider several options to this end, including granting enforcement powers to supervisory authorities and licensure regimes for frontier AI models. Finally, we propose an initial set of safety standards. These include conducting pre-deployment risk assessments; external scrutiny of model behavior; using risk assessments to inform deployment decisions; and monitoring and responding to new information about model capabilities and uses post-deployment. We hope this discussion contributes to the broader conversation on how to balance public safety risks and innovation benefits from advances at the frontier of AI development.

In the field of quantitative trading, it is common practice to transform raw historical stock data into indicative signals for the market trend. Such signals are called alpha factors. Alphas in formula forms are more interpretable and thus favored by practitioners concerned with risk. In practice, a set of formulaic alphas is often used together for better modeling precision, so we need to find synergistic formulaic alpha sets that work well together. However, most traditional alpha generators mine alphas one by one separately, overlooking the fact that the alphas would be combined later. In this paper, we propose a new alpha-mining framework that prioritizes mining a synergistic set of alphas, i.e., it directly uses the performance of the downstream combination model to optimize the alpha generator. Our framework also leverages the strong exploratory capabilities of reinforcement learning~(RL) to better explore the vast search space of formulaic alphas. The contribution to the combination models' performance is assigned to be the return used in the RL process, driving the alpha generator to find better alphas that improve upon the current set. Experimental evaluations on real-world stock market data demonstrate both the effectiveness and the efficiency of our framework for stock trend forecasting. The investment simulation results show that our framework is able to achieve higher returns compared to previous approaches.

Singular limits for the following indirect signalling chemotaxis system align* \left\{ array{lllllll} \partial_t n = \Delta n - \nabla \cdot (n \nabla c ) & in \Omega\times(0,\infty) , \varepsilon \partial_t c = \Delta c - c + w & in \Omega\times(0,\infty), \varepsilon \partial_t w = \tau \Delta w - w + n & in \Omega\times (0,\infty), \partial_\nu n = \partial_\nu c = \partial_\nu w = 0, &on \partial\Omega\times (0,\infty) %(n,c,w)_{t=0} = (n_0,c_0,w_0) & on \Omega, array \right. align* are investigated. More precisely, we study parabolic-elliptic simplification, or PES, varepsilonto 0^+ with fixed tau>0 up to the critical dimension N=4, and indirect-direct simplification, or IDS, (varepsilon,tau)to (0^+,0^+) up to the critical dimension N=2. These are relevant in biological situations where the signalling process is on a much faster time scale compared to the species diffusion and all interactions. Showing singular limits in critical dimensions is challenging. To deal with the PES, we carefully combine the entropy function, an Adam-type inequality, the regularisation of slow evolution, and an energy equation method to obtain strong convergence in representative spaces. For the IDS, a bootstrap argument concerning the L^p-energy function is devised, which allows us to obtain suitable uniform bounds for the singular limits. Moreover, in both scenarios, we also present the convergence rates, where the effect of the initial layer and the convergence to the critical manifold are also revealed.

Being able to provide explanations for a model's decision has become a central requirement for the development, deployment, and adoption of machine learning models. However, we are yet to understand what explanation methods can and cannot do. How do upstream factors such as data, model prediction, hyperparameters, and random initialization influence downstream explanations? While previous work raised concerns that explanations (E) may have little relationship with the prediction (Y), there is a lack of conclusive study to quantify this relationship. Our work borrows tools from causal inference to systematically assay this relationship. More specifically, we study the relationship between E and Y by measuring the treatment effect when intervening on their causal ancestors, i.e., on hyperparameters and inputs used to generate saliency-based Es or Ys. Our results suggest that the relationships between E and Y is far from ideal. In fact, the gap between 'ideal' case only increase in higher-performing models -- models that are likely to be deployed. Our work is a promising first step towards providing a quantitative measure of the relationship between E and Y, which could also inform the future development of methods for E with a quantitative metric.

Complex cell signaling systems -- governed by varying protein abundances and interactions -- generate diverse cell types across organs. These systems evolve under influences such as age, sex, diet, environmental exposures, and diseases, making them challenging to decode given the involvement of tens of thousands of genes and proteins. Recently, hundreds of millions of single-cell omics data have provided a robust foundation for understanding these signaling networks within various cell subpopulations and conditions. Inspired by the success of large foundation models (for example, large language models and large vision models) pre-trained on massive datasets, we introduce OmniCellTOSG, the first dataset of cell text-omic signaling graphs (TOSGs). Each TOSG represents the signaling network of an individual or meta-cell and is labeled with information such as organ, disease, sex, age, and cell subtype. OmniCellTOSG offers two key contributions. First, it introduces a novel graph model that integrates human-readable annotations -- such as biological functions, cellular locations, signaling pathways, related diseases, and drugs -- with quantitative gene and protein abundance data, enabling graph reasoning to decode cell signaling. This approach calls for new joint models combining large language models and graph neural networks. Second, the dataset is built from single-cell RNA sequencing data of approximately 120 million cells from diverse tissues and conditions (healthy and diseased) and is fully compatible with PyTorch. This facilitates the development of innovative cell signaling models that could transform research in life sciences, healthcare, and precision medicine. The OmniCellTOSG dataset is continuously expanding and will be updated regularly. The dataset and code are available at https://github.com/FuhaiLiAiLab/OmniCellTOSG.

Modern large language models rely on chain-of-thought (CoT) reasoning to achieve impressive performance, yet the same mechanism can amplify deceptive alignment, situations in which a model appears aligned while covertly pursuing misaligned goals. Existing safety pipelines treat deception as a black-box output to be filtered post-hoc, leaving the model free to scheme during its internal reasoning. We ask: Can deception be intercepted while the model is thinking? We answer this question, the first framework that embeds a Self-Monitor inside the CoT process itself, named CoT Monitor+. During generation, the model produces (i) ordinary reasoning steps and (ii) an internal self-evaluation signal trained to flag and suppress misaligned strategies. The signal is used as an auxiliary reward in reinforcement learning, creating a feedback loop that rewards honest reasoning and discourages hidden goals. To study deceptive alignment systematically, we introduce DeceptionBench, a five-category benchmark that probes covert alignment-faking, sycophancy, etc. We evaluate various LLMs and show that unrestricted CoT roughly aggravates the deceptive tendency. In contrast, CoT Monitor+ cuts deceptive behaviors by 43.8% on average while preserving task accuracy. Further, when the self-monitor signal replaces an external weak judge in RL fine-tuning, models exhibit substantially fewer obfuscated thoughts and retain transparency. Our project website can be found at cot-monitor-plus.github.io

ClueWeb22, the newest iteration of the ClueWeb line of datasets, provides 10 billion web pages affiliated with rich information. Its design was influenced by the need for a high quality, large scale web corpus to support a range of academic and industry research, for example, in information systems, retrieval-augmented AI systems, and model pretraining. Compared with earlier ClueWeb corpora, the ClueWeb22 corpus is larger, more varied, of higher-quality, and aligned with the document distributions in commercial web search. Besides raw HTML, ClueWeb22 includes rich information about the web pages provided by industry-standard document understanding systems, including the visual representation of pages rendered by a web browser, parsed HTML structure information from a neural network parser, and pre-processed cleaned document text to lower the barrier to entry. Many of these signals have been widely used in industry but are available to the research community for the first time at this scale.

Where do learning signals come from when there is no ground truth in post-training? We propose turning exploration into supervision through Compute as Teacher (CaT), which converts the model's own exploration at inference-time into reference-free supervision by synthesizing a single reference from a group of parallel rollouts and then optimizing toward it. Concretely, the current policy produces a group of rollouts; a frozen anchor (the initial policy) reconciles omissions and contradictions to estimate a reference, turning extra inference-time compute into a teacher signal. We turn this into rewards in two regimes: (i) verifiable tasks use programmatic equivalence on final answers; (ii) non-verifiable tasks use self-proposed rubrics-binary, auditable criteria scored by an independent LLM judge, with reward given by the fraction satisfied. Unlike selection methods (best-of-N, majority, perplexity, or judge scores), synthesis may disagree with the majority and be correct even when all rollouts are wrong; performance scales with the number of rollouts. As a test-time procedure, CaT improves Gemma 3 4B, Qwen 3 4B, and Llama 3.1 8B (up to +27% on MATH-500; +12% on HealthBench). With reinforcement learning (CaT-RL), we obtain further gains (up to +33% and +30%), with the trained policy surpassing the initial teacher signal.

Extracting causal relationships from observed correlations is a growing area in probabilistic reasoning, originating with the seminal work of Pearl and others from the early 1990s. This paper develops a new, categorically oriented view based on a clear distinction between syntax (string diagrams) and semantics (stochastic matrices), connected via interpretations as structure-preserving functors. A key notion in the identification of causal effects is that of an intervention, whereby a variable is forcefully set to a particular value independent of any prior propensities. We represent the effect of such an intervention as an endofunctor which performs `string diagram surgery' within the syntactic category of string diagrams. This diagram surgery in turn yields a new, interventional distribution via the interpretation functor. While in general there is no way to compute interventional distributions purely from observed data, we show that this is possible in certain special cases using a calculational tool called comb disintegration. We demonstrate the use of this technique on a well-known toy example, where we predict the causal effect of smoking on cancer in the presence of a confounding common cause. After developing this specific example, we show this technique provides simple sufficient conditions for computing interventions which apply to a wide variety of situations considered in the causal inference literature.

Intrinsic dimension (ID) is an important tool in modern LLM analysis, informing studies of training dynamics, scaling behavior, and dataset structure, yet its textual determinants remain underexplored. We provide the first comprehensive study grounding ID in interpretable text properties through cross-encoder analysis, linguistic features, and sparse autoencoders (SAEs). In this work, we establish three key findings. First, ID is complementary to entropy-based metrics: after controlling for length, the two are uncorrelated, with ID capturing geometric complexity orthogonal to prediction quality. Second, ID exhibits robust genre stratification: scientific prose shows low ID (~8), encyclopedic content medium ID (~9), and creative/opinion writing high ID (~10.5) across all models tested. This reveals that contemporary LLMs find scientific text "representationally simple" while fiction requires additional degrees of freedom. Third, using SAEs, we identify causal features: scientific signals (formal tone, report templates, statistics) reduce ID; humanized signals (personalization, emotion, narrative) increase it. Steering experiments confirm these effects are causal. Thus, for contemporary models, scientific writing appears comparatively "easy", whereas fiction, opinion, and affect add representational degrees of freedom. Our multi-faceted analysis provides practical guidance for the proper use of ID and the sound interpretation of ID-based results.