Dna

Vision-language and language models increasingly interpret materials data, yet benchmarks report that they hallucinate invalid properties and violate physical law. Evaluation matches final answers to scarce human labels, while discovery agents verify final proposals or density functional theory (DFT) execution. Neither measures the physical consistency of a model's reasoning chain. Materials data carries its own physics, making a large class of materials reasoning verifiable without annotation. We introduce MatPCR, a label-free benchmark whose programmatic oracles check diffraction geometry through Bragg's law, scale bars, spectral peaks, and Materials Project-grounded checks of near-hull stability, computed band-gap class, and net magnetization. We define the Physical-Consistency Rate over image and structure inputs; introduce Constraint-Grounded Self-Verification, an agentic loop whose gain survives self-refinement and equal-compute re-prompting controls; release an open verifier useful in distribution but near chance on all six held-out constraint types; and derive an exact identity for how oracle error displaces the reported rate.

Nucleotide sequence analysis is central to problems spanning regulatory genomics, evolutionary biology, and phenotype prediction. Classical bioinformatics methods extract interpretable sequence properties such as motifs and k-mer composition, but their flexibility is limited. In contrast, modern deep learning models can learn powerful predictive representations directly from raw sequences, yet their internal representations and decision mechanisms are difficult to inspect. Interpretable machine learning methods (e.g., sparse linear models and decision trees) provide human-understandable representations of predictive relationships but are not designed to operate directly on nucleotide sequences. Here, we introduce SeqMaestro, a machine learning framework that proposes biological hypotheses from nucleotide sequences using interpretable models. Our solution is centered around a two-layer interface that connects nucleotide sequences with the broader ecosystem of interpretable machine learning. SeqMaestro uses this interface to fit diverse combinations of interpretable models, feature representations, and extraction strategies, leveraging variability across transparent models to identify robust biological signals and richer predictive relationships than feature importance alone can provide. The system also supports data transformation and cleaning, model fitting, hyperparameter tuning, reliability analysis, and synthesis of results into a contextualized written report. By providing these capabilities through a no-code workflow, SeqMaestro is designed to make interpretable sequence analysis accessible to researchers without requiring extensive programming or machine learning expertise. SeqMaestro thereby provides an accessible route from nucleotide sequences to biological hypotheses.

High-throughput screening (HTS) assays are central to early-stage drug discovery but are often limited by extreme data sparsity, as primary screens typically use only a single replicate per test substance. This sparsity makes conventional machine-learning performance metrics, such as sensitivity, specificity, and area under the receiver operating characteristic curve (AUROC), difficult to estimate empirically because they require adequately sized labeled samples. Here, we introduce a model-based framework that derives these classification metrics from the strictly standardized mean difference (SSMD), a well-established HTS effect-size parameter. Under a Gaussian equal-variance assumption, we derive closed-form relationships linking SSMD to Youden-optimal sensitivity and specificity, and sensitivity at a preset specificity, yielding explicit estimators and exact confidence intervals from the noncentral t-distribution, even under single-replicate designs. Unlike classical statistical power, which approaches 1 as sample size grows regardless of how small the true non-zero difference between group means is, the SSMD-derived sensitivity converges to a finite population value that reflects the true degree of separation between two groups, making it a more meaningful and stable performance measure for hit selection. We demonstrate the utility of this framework in a hepatitis C virus primary siRNA screen comprising approximately 22,000 single-replicate measurements, showing that SSMD, AUROC, and sensitivity-based thresholds yield equivalent and interpretable hit sets. This work bridges classical HTS statistics and machine-learning evaluation theory, providing a statistically principled, reproducible way to estimate classification performance in ultra-low-replication screening workflows.

While deep learning models, particularly transformer-based architectures, have shown impressive performance in time series forecasting, the application of retrieval-augmented generation (RAG) in this domain remains limited. Since RAG has proven effective in enhancing the capabilities of large language models by incorporating relevant external information, retrieving similar time series sequences as references might also improve accuracy in time series forecasting tasks. However, most time series models are constrained by limited training data, smaller parameter scales, and a lack of the extensive generative capabilities found in large language models. Simply concatenating reference sequences into the prompt, as done in language models, may not yield the expected results. To address these challenges, we propose a novel approach, TS-RAG, which leverages RAG to enhance forecasting performance. The framework introduces specially designed reference tokens to effectively fuse information from the input sequence with that from retrieved similar sequences, enabling a more robust capture of complex temporal dynamics. Experimental results demonstrate that TS-RAG achieves consistent state-of-the-art performance across several real-world forecasting benchmarks.

We present string2string Studio, an interactive in-browser platform for string-to-string analysis across natural language processing, computational biology, and the digital humanities. The system integrates six main modules (alignment, distance, similarity, search, generation metrics, and BLAST homology search), operating at character, word, token, line, and residue levels. Its C++-based algorithms compile to WebAssembly, so core operations run locally by default without any installation or data upload. The interface reports scores with their "evidence" (alignments, edit paths, metric matches, search hits, and homology traces), making methods inspectable, debuggable, and comparable on shared inputs. Internal benchmarks show speedups of up to 2,500x over the Python predecessor, faster global/local alignment than a general-purpose native C aligner, and exact agreement with independent references under declared settings. For homology search, the scoped client-side blastn path closely matches NCBI BLAST+ rankings and statistics under matched parameters. A curated showcase and Learn mode present canonical algorithms and metrics as reusable demonstrations. string2string Studio is open-source and freely available at string2string.org.

Frontier large language models (LLMs) are increasingly integrated into scientific workflows, yet their growing biological capabilities may outpace current safeguards. To assess the biological risks of frontier models, we develop Intern-BioBreaker, a specialized bio-red-teaming model, together with an integrated computational-to-physical framework that couples model-level stress testing with wet-lab validation. Within this framework, Intern-BioBreaker generates targeted jailbreak prompts to test whether aligned models can be induced to provide operational guidance for safety-sensitive biological tasks or produce sequence-level outputs with potentially harmful properties. Selected sequence outputs are then carried forward for DNA synthesis, host expression, and orthogonal protein verification to assess whether model-generated designs can yield the intended biological products. Our evaluation reveals a concerning gap between text-level safeguards and the risks posed by capable scientific models: (i) Intern-BioBreaker outperforms baseline attack models and reveals widespread bio-risk jailbreak vulnerabilities across both open-weight and proprietary frontier LLMs, with several targets reaching near-saturated or 100% task-level attack success rate (ASR); (ii) in sequence-level case studies, GPT-5.5 can be induced to generate modified viral candidate sequences with pathogenic potential; the corresponding translated proteins may exhibit even stronger receptor-binding affinity and thus enhanced infection potential; and (iii) end-to-end verification shows that selected model-generated biological designs are not merely textual artifacts, but can be physically realized under controlled experimental settings. These findings underscore the need for stronger biological red-teaming, nucleic acid synthesis screening, and safety mechanisms that keep pace with model capabilities.

Prior case retrieval (PCR) aims to identify the precedent cases relevant to the facts of a query case. Incoming citation context, the text with which later cases characterize a case when citing it, is a powerful relevance signal, yet it is typically evaluated without a temporal constraint, so the retriever is credited with citations made after the query. We introduce a temporally fenced retriever with no learned parameters that augments BM25 with incoming citation context restricted to citations predating the query, together with a temporal-admission decomposition that quantifies the phantom fraction: the share of a citation-context gain attributable to citations not known to predate the query. Experiments span two jurisdictions, U.S. federal (CLERC) and European (ECtHR-PCR) case law. On ECtHR-PCR, without any training, the fenced retriever outperforms a strong degree-controlled baseline across the full recall ladder, and a temporal-admission decomposition attributes 14.9% (validation) of an unfenced citation-context gain over BM25 to citations not known to predate the query. Citation-context retrieval must therefore be temporally fenced and degree-controlled before its reported gains can be interpreted.

Recent breakthroughs in foundation models and Large Language Models (LLMs) have introduced new opportunities for studying and decoding genomic sequences. Several state-of-the-art approaches, such as DNABERT2, rely on transformer-based architectures, while others, such as ConvNova, still build upon more conventional convolutional models. However, systematic benchmark comparisons across these methods remain scarce. Given that transformer-based models require extensive and costly pretraining, it is crucial to evaluate whether their performance gains justify this overhead. Moreover, LLMs such as DNABERT2 typically rely on Byte Pair Encoding (BPE) tokenization, whose relevance for DNA sequence representation is still debated within the genomics community. In this work, we investigate three key questions: (i) do transformer-based models provide sufficient improvements on fine-tuning tasks upon heavy pretraining, (ii) what is the actual contribution of pretraining in this setting, and (iii) how does BPE tokenization impact performance on genomics-related tasks?

The softmax activation in multihead attention (MHA) is the de facto standard for attention-based models in visual perception tasks. However, standard softmax can produce noisy attention patterns that dilute relevant features and degrade its performance. In this paper, we propose Denoising Attention or DnA, in which, first, a positive query identifies which image features belong to the correct class, and a negative query identifies closely associated but irrelevant image features. DnA then projects these interactions into two distinct subspaces with larger principal angles, promoting subspace separation and improved discriminability. Using a ViT-B backbone, our proposed DnA achieves an absolute gain of 0.8% on ImageNet-1K compared to the baseline. We further show improvements across multiple visual understanding tasks, including video understanding with video transformers (1.8%) and video LLMs (0.5%). Our extensive empirical analyses justify the design choices involving two interacting subspaces and the denoising effect of DnA.

Large language models (LLMs) are rapidly acquiring capabilities relevant to biological research, from literature synthesis to interpretation of experimental data. Increasingly, LLM agents can also perform in silico biology tasks that previously required experienced human biologists. These emerging AI capabilities offer new opportunities for scientific discovery and biomedical advances, but they also shift the landscape of biosecurity risks. To address this, we introduce the Agentic Bio-Capabilities Benchmark (ABC-Bench), a suite of tasks to measure agentic biosecurity-relevant capabilities. ABC-Bench evaluates LLM agents on both benign and dual-use biology tasks: writing code to operate liquid handling robots, designing DNA fragments for in vitro assembly, and evading DNA synthesis screening. These tasks require a combination of biology and software expertise. All tested LLM agents outperformed the median expert human baseliner on all three tasks. Agents performed highly on tasks drawing on published knowledge and well-documented protocols, and more weakly on a task requiring novel bioinformatics reasoning. In three wet-lab validation experiments, we found that OpenAI's o4-mini-high produced scripts that, when run on an OpenTrons liquid handling robot, successfully assembled DNA with expected sequences.

Inferring dynamics from population snapshots is a fundamental challenge in machine learning and biology. In scRNA-sequencing (scRNA-seq), destructive measurements preclude direct tracking of individual cells across time, making trajectory inference underdetermined. Optimal Transport (OT) provides a principled framework for snapshot alignment, but a long-standing modeling question is which cost functions yield biologically meaningful couplings. Standard OT approaches rely on gene-expression distances, implicitly treating cells as independent points and neglecting structured cell-cell communication mediated by ligand-receptor signaling. We introduce CellBRIDGE (Cell-Based Regularized Interaction-Driven Gene Expression), which augments feature-based OT with a directed, typed interaction cost derived from ligand-receptor activity. By explicitly modeling cell-cell communication, CellBRIDGE improves cross-snapshot couplings and downstream trajectory estimates across synthetic and real scRNA-seq datasets relative to feature-only baselines. Notably, CellBRIDGE enables mechanistically interpretable in silico perturbations: on lung cancer data, silencing specific ligand-receptor pairs induces trajectory shifts that recapitulate expected effects of targeted pathway inhibition.

Mathematical formulas serve as a language through which humans communicate with nature. Discovering mathematical laws from scientific data to describe natural phenomena has been a long-standing pursuit of humanity for centuries. In the field of artificial intelligence, this challenge is known as the symbolic regression problem. Among existing symbolic regression approaches, Genetic Programming (GP) based on evolutionary algorithms remains one of the most classical and widely adopted methods. GP simulates the evolutionary process across generations through genetic mutation and crossover. However, mutations and crossovers in GP are entirely random. While this randomness effectively mimics natural evolution, it inevitably produces both beneficial and detrimental variations. If there existed a metaphorical God capable of foreseeing which genetic mutations or crossovers would yield superior outcomes and performing targeted gene editing accordingly, the efficiency of evolution could be substantially improved. Motivated by this idea, we propose in this paper a symbolic regression approach based on gene editing, termed GESR. In GESR, we trained two "hands of God" (two BERT models). Among them, the first leverages the BERT's masked language modeling capability to guide the mutation of genes (expression symbols). The other BERT model guides the crossover of individual genes by predicting the crossover point. Experimental results demonstrate that GESR significantly improves computational efficiency compared with traditional GP algorithms and achieves strong overall performance across multiple symbolic regression tasks.

Aging clocks aim to estimate biological age, a measure of physiological state distinct from chronological age, from observable biomarkers, and are widely used for health assessment and disease analysis. DNA methylation is a particularly informative biomarker due to its stability and strong association with aging, and recent learning-based approaches have improved predictive performance. However, most existing methods treat CpG sites as independent features, overlooking the complex and heterogeneous biological relationships among them. We propose RelAge-GNN, a multi-relational graph neural network framework for DNA methylation-based age prediction. Our method constructs three complementary graphs capturing co-methylation patterns, genomic co-localization, and gene-level associations among CpG sites. Each graph is modeled by an independent GNN branch, and a learnable gating mechanism adaptively fuses the resulting representations. Experiments on large-scale datasets show that RelAge-GNN achieves competitive accuracy and stronger correlation with chronological age compared to state-of-the-art methods. Moreover, the model exhibits improved sensitivity in detecting age acceleration across diverse disease cohorts, highlighting its potential utility for disease characterization. Finally, through post hoc interpretability analyses, we quantify the contributions of different relational structures and CpG sites, providing biologically meaningful insights and suggesting potential directions for aging-related research. Our code is available at: https://anonymous.4open.science/r/RelAge-GNN-F1E3/.

DNA-synthesis providers screen incoming orders by searching the requested sequence against curated hazard lists. We show that this baseline collapses to a 100% false-flag rate when the hazardous sequence comes from a taxonomic family absent from the reference set: under Conformal Risk Control's certified miss-rate constraint, a low-discrimination signal forces the threshold below the entire test-benign mass. We compose three signals derived from a synthesis order's public annotation: $k$-mer Jaccard similarity to known toxins, the trimmed-mean score of a five-LLM judge panel, and cosine similarity to clustered embedding centroids. Fused under a monotone logistic aggregator and calibrated by Conformal Risk Control, the resulting screener certifies $\mathbb{E}[\mathrm{FNR}] \le α+ \mathrm{TV}$, where the additive term is the calibration-to-test distribution shift under family holdout (a certified ceiling of 24-49% across folds). Across ten leave-one-taxonomic-family-out folds at $α=0.05$ on UniProt KW-0800 reviewed toxins, the calibrated screener achieves 0% empirical test miss rate on every fold and 0% test false-flag rate on nine of ten folds. The bound's finite-sample slack $1/(n_{\mathrm{cal}}+1)$ caps the certifiable miss rate at 1.77% on our 200-hazard subsample; reaching procurement-grade $α=10^{-3}$ requires an $18\times$ larger calibration set, which the full reviewed UniProt KW-0800 corpus is large enough to deliver. The binding constraint on certifiable DNA-synthesis screening is calibration data, not algorithms. Code: https://github.com/najmulhasan-code/crc-screen

Biological function emerges from coupled constraints across sequence, structure, regulation, evolution, and cellular context, yet most foundation models in biology are trained within one modality or for a fixed forward task. We present MIMIC, a generative multimodal foundation model trained on our newly curated and aligned dataset, LORE, linking nucleic acid, protein, evolutionary, structural, regulatory, and semantic/contextual modalities within partially observed biomolecular states. MIMIC uses a split-track encoder-decoder architecture to condition on arbitrary subsets of observed modalities and reconstruct or generate missing components of molecular state across the genome, transcriptome, and proteome. Multimodal conditioning consistently improves MIMIC's sequence reconstruction relative to sequence-only inputs, while its learned representations enable state-of-the-art performance on RNA and protein downstream tasks. MIMIC achieves state-of-the-art splicing prediction, and its joint generative formulation enables isoform-aware inference that further improves performance. Beyond prediction, the same generative framework supports constrained design. For RNA, MIMIC identifies corrective edits in a clinically relevant HBB splice-disrupting mutation without reverting it by using evolutionary and structural signals. For proteins, jointly conditioning on shape and surface chemistry of PD-L1 and hACE2 binding sites produces diverse, high-confidence sequences with strong in silico support for target binding. Finally, MIMIC uses experimental context as semantic conditioning to model assay-dependent RNA chemical probing, rather than treating context as a fixed output. Together, these results position MIMIC's aligned multimodal generative modeling as a strong foundation for unifying representation learning, conditional prediction, and constrained biomolecular design within a single model.

Explaining deep neural network predictions on genome sequences enables biological insight and hypothesis generation-often of greater interest than predictive performance alone. While explanations of convolutional neural networks (CNNs) have been shown to capture relevant patterns in genome sequences, it is unclear whether this transfers to more expressive Transformer-based genome language models (gLMs). To answer this question, we adapt AttnLRP, an extension of layer-wise relevance propagation to the attention mechanism, and apply it to the state-of-the-art gLM DNABERT-2. Thereby, we propose strategies to transfer explanations from token and nucleotide level. We evaluate the adaption of AttnLRP on genomic datasets using multiple metrics. Further, we provide an extensive comparison between the explanations of DNABERT-2 and a baseline CNN. Our results demonstrate that AttnLRP yields reliable explanations corresponding to known biological patterns. Hence, like CNNs, gLMs can also help derive biological insights. This work contributes to the explainability of gLMs and addresses the comparability of relevance attributions across different architectures.

Despite significant progress in Multi-modal Large Language Models (MLLMs), their clinical reasoning capacity for multi-modal diagnosis remains largely unexamined. Current benchmarks, mostly single-modality data, can't evaluate progressive reasoning and cross-modal integration essential for clinical practice. We introduce the Cross-Modality Progressive Clinical Reasoning (X-PCR) benchmark, the first comprehensive evaluation of MLLMs through a complete ophthalmology diagnostic workflow, with two reasoning tasks: 1) a six-stage progressive reasoning chain spanning image quality assessment to clinical decision-making, and 2) a cross-modality reasoning task integrating six imaging modalities. The benchmark comprises 26,415 images and 177,868 expert-verified VQA pairs curated from 51 public datasets, covering 52 ophthalmic diseases. Evaluation of 21 MLLMs reveals critical gaps in progressive reasoning and cross-modal integration. Dataset and code: https://github.com/CVI-SZU/X-PCR.

We address the challenge of point cloud registration using color information, where traditional methods relying solely on geometric features often struggle in low-overlap and incomplete scenarios. To overcome these limitations, we propose GeGS-PCR, a novel two-stage method that combines geometric, color, and Gaussian information for robust registration. Our approach incorporates a dedicated color encoder that enhances color features by extracting multi-level geometric and color data from the original point cloud. We introduce the \textbf{Ge}ometric-3D\textbf{GS} module, which encodes the local neighborhood information of colored superpoints to ensure a globally invariant geometric-color context. Leveraging LORA optimization, we maintain high performance while preserving the expressiveness of 3DGS. Additionally, fast differentiable rendering is utilized to refine the registration process, leading to improved convergence. To further enhance performance, we propose a joint photometric loss that exploits both geometric and color features. This enables strong performance in challenging conditions with extremely low point cloud overlap. We validate our method by colorizing the Kitti dataset as ColorKitti and testing on both Color3DMatch and Color3DLoMatch datasets. Our method achieves state-of-the-art performance with \textit{Registration Recall} at 99.9%, \textit{Relative Rotation Error} as low as 0.013, and \textit{Relative Translation Error} as low as 0.024, improving precision by at least a factor of 2.

The COVID19 pandemic had enormous economic and societal consequences. Contact tracing is an effective way to reduce infection rates by detecting potential virus carriers early. However, this was not generally adopted in the recent pandemic, and privacy concerns are cited as the most important reason. We substantially improve the privacy guarantees of the current state of the art in decentralized contact tracing. Whereas previous work was based on statistical inference only, we augment the inference with a learned neural network and ensure that this neural augmentation satisfies differential privacy. In a simulator for COVID19, even at epsilon=1 per message, this can significantly improve the detection of potentially infected individuals and, as a result of targeted testing, reduce infection rates. This work marks an important first step in integrating deep learning into contact tracing while maintaining essential privacy guarantees.