Daily Papers

Existing foundation models (FMs) in the medical domain often require extensive fine-tuning or rely on training resource-intensive decoders, while many existing encoders are pretrained with objectives biased toward specific tasks. This illustrates a need for a strong, task-agnostic foundation model that requires minimal fine-tuning beyond feature extraction. In this work, we introduce a suite of task-agnostic pretraining of CT foundation models (TAP-CT): a simple yet effective adaptation of Vision Transformers (ViTs) and DINOv2 for volumetric data, enabling scalable self-supervised pretraining directly on 3D CT volumes. Our approach incorporates targeted modifications to patch embeddings, positional encodings, and volumetric augmentations, making the architecture depth-aware while preserving the simplicity of the underlying architectures. We show that large-scale 3D pretraining on an extensive in-house CT dataset (105K volumes) yields stable, robust frozen representations that generalize strongly across downstream tasks. To promote transparency and reproducibility, and to establish a powerful, low-resource baseline for future research in medical imaging, we will release all pretrained models, experimental configurations, and downstream benchmark code at https://huggingface.co/fomofo/tap-ct-b-3d.

We introduce AiM, an autoregressive (AR) image generative model based on Mamba architecture. AiM employs Mamba, a novel state-space model characterized by its exceptional performance for long-sequence modeling with linear time complexity, to supplant the commonly utilized Transformers in AR image generation models, aiming to achieve both superior generation quality and enhanced inference speed. Unlike existing methods that adapt Mamba to handle two-dimensional signals via multi-directional scan, AiM directly utilizes the next-token prediction paradigm for autoregressive image generation. This approach circumvents the need for extensive modifications to enable Mamba to learn 2D spatial representations. By implementing straightforward yet strategically targeted modifications for visual generative tasks, we preserve Mamba's core structure, fully exploiting its efficient long-sequence modeling capabilities and scalability. We provide AiM models in various scales, with parameter counts ranging from 148M to 1.3B. On the ImageNet1K 256*256 benchmark, our best AiM model achieves a FID of 2.21, surpassing all existing AR models of comparable parameter counts and demonstrating significant competitiveness against diffusion models, with 2 to 10 times faster inference speed. Code is available at https://github.com/hp-l33/AiM

Large Language Models (LLMs) have demonstrated notable proficiency in both code generation and comprehension across multiple programming languages. However, the mechanisms underlying this proficiency remain underexplored, particularly with respect to whether distinct programming languages are processed independently or within a shared parametric region. Drawing an analogy to the specialized regions of the brain responsible for distinct cognitive functions, we introduce the concept of Coding Spot, a specialized parametric region within LLMs that facilitates coding capabilities. Our findings identify this Coding Spot and show that targeted modifications to this subset significantly affect performance on coding tasks, while largely preserving non-coding functionalities. This compartmentalization mirrors the functional specialization observed in cognitive neuroscience, where specific brain regions are dedicated to distinct tasks, suggesting that LLMs may similarly employ specialized parameter regions for different knowledge domains.

Recent advancements in Large Multimodal Models (LMMs) have shown promise in Autonomous Driving Systems (ADS). However, their direct application to ADS is hindered by challenges such as misunderstanding of traffic knowledge, complex road conditions, and diverse states of vehicle. To address these challenges, we propose the use of Knowledge Editing, which enables targeted modifications to a model's behavior without the need for full retraining. Meanwhile, we introduce ADS-Edit, a multimodal knowledge editing dataset specifically designed for ADS, which includes various real-world scenarios, multiple data types, and comprehensive evaluation metrics. We conduct comprehensive experiments and derive several interesting conclusions. We hope that our work will contribute to the further advancement of knowledge editing applications in the field of autonomous driving. Code and data are available in https://github.com/zjunlp/EasyEdit.

Denoising diffusion models have recently gained prominence as powerful tools for a variety of image generation and manipulation tasks. Building on this, we propose a novel tool for real-time editing of images that provides users with fine-grained region-targeted supervision in addition to existing prompt-based controls. Our novel editing technique, termed Layered Diffusion Brushes, leverages prompt-guided and region-targeted alteration of intermediate denoising steps, enabling precise modifications while maintaining the integrity and context of the input image. We provide an editor based on Layered Diffusion Brushes modifications, which incorporates well-known image editing concepts such as layer masks, visibility toggles, and independent manipulation of layers; regardless of their order. Our system renders a single edit on a 512x512 image within 140 ms using a high-end consumer GPU, enabling real-time feedback and rapid exploration of candidate edits. We validated our method and editing system through a user study involving both natural images (using inversion) and generated images, showcasing its usability and effectiveness compared to existing techniques such as InstructPix2Pix and Stable Diffusion Inpainting for refining images. Our approach demonstrates efficacy across a range of tasks, including object attribute adjustments, error correction, and sequential prompt-based object placement and manipulation, demonstrating its versatility and potential for enhancing creative workflows.

Recent diffusion- and flow-based VTON methods achieve strong results with pretrained generative models, but their reliance on multi-step sampling incurs high inference cost, while existing acceleration methods largely overlook the intrinsic structure of the try-on task. In this paper, we highlight a key observation: VTON outputs are highly constrained by the conditional inputs, suggesting that the conditional sampling trajectory can be much straighter than that in general image generation, making one-step generation a natural solution. However, limited task-specific data makes training from scratch impractical, forcing existing methods to fine-tune pretrained models whose objectives do not encourage such straight conditional trajectories. Thus, the deviation from an ideal straight path mainly comes from the mismatch between pretrained base models and the conditional nature of try-on generation, rather than from the task itself. Motivated by this insight, we encourage straighter VTON sampling trajectories through three targeted modifications: pure conditional transport, a garment preservation loss, and a self consistency loss. We further introduce a one-step distillation stage. Extensive experiments show that our method achieves state-of-the-art performance with one-step sampling, establishing a new standard for efficient and high-quality VTON.

Optimizing LLM-based agentic workflows is challenging for scaling AI capabilities. Current methods rely on coarse, end-to-end evaluation signals and lack fine-grained signals on where to refine, often resulting in inefficient or low-impact modifications. To address these limitations, we propose JudgeFlow, an Evaluation-Judge-Optimization-Update pipeline. We incorporate reusable, configurable logic blocks into agentic workflows to capture fundamental forms of logic. On top of this abstraction, we design a dedicated Judge module that inspects execution traces particularly failed runs and assigns rank-based responsibility scores to problematic blocks. These fine-grained diagnostic signals are then leveraged by an LLM-based optimizer, which focuses modifications on the most problematic block in the workflow. Our approach improves sample efficiency, enhances interpretability through block-level diagnostics, and provides a scalable foundation for automating increasingly complex agentic workflows. We evaluate JudgeFlow on mathematical reasoning and code generation benchmarks, where JudgeFlow achieves superior performance and efficiency compared to existing methods.

As advancements in large language models (LLMs) continue and the demand for personalized models increases, parameter-efficient fine-tuning (PEFT) methods (e.g., LoRA) will become essential due to their efficiency in reducing computation costs. However, recent studies have raised alarming concerns that LoRA fine-tuning could potentially compromise the safety alignment in LLMs, posing significant risks for the model owner. In this paper, we first investigate the underlying mechanism by analyzing the changes in safety alignment related features before and after fine-tuning. Then, we propose a fixed safety module calculated by safety data and a task-specific initialization for trainable parameters in low-rank adaptations, termed Safety-alignment preserved Low-Rank Adaptation (SaLoRA). Unlike previous LoRA methods and their variants, SaLoRA enables targeted modifications to LLMs without disrupting their original alignments. Our experiments show that SaLoRA outperforms various adapters-based approaches across various evaluation metrics in different fine-tuning tasks.

Direct preference optimization (DPO), a widely adopted offline preference optimization algorithm, aims to align large language models (LLMs) with human-desired behaviors using pairwise preference data. However, the winning response and the losing response within pairwise data are generated isolatedly, leading to weak correlations between them as well as suboptimal alignment performance. To address this issue, we propose an effective framework named BMC, for bridging and modeling correlations in pairwise data. Firstly, we increase the consistency and informativeness of the pairwise preference signals by targeted modifications, synthesizing a pseudo winning response through improving the losing response based on the winning response. Secondly, we identify that DPO alone is insufficient to model these correlations and capture nuanced variations. Therefore, we propose learning token-level correlations by dynamically leveraging the policy model's confidence during training. Comprehensive experiments on QA, math, and instruction-following tasks demonstrate the effectiveness of our approach, significantly surpassing competitive baselines, including DPO. Additionally, our in-depth quantitative analysis reveals the reasons behind our method's superior performance over DPO and showcases its versatility to other DPO variants.

Steering methods for language models (LMs) have gained traction as lightweight alternatives to fine-tuning, enabling targeted modifications to model activations. However, prior studies primarily report results on a few models, leaving critical gaps in understanding the robustness of these methods. In this work, we systematically examine three prominent steering methods -- DoLa, function vectors, and task vectors. In contrast to the original studies, which evaluated a handful of models, we test up to 36 models belonging to 14 families with sizes ranging from 1.5B to 70B parameters. Our experiments reveal substantial variability in the effectiveness of the steering approaches, with a large number of models showing no improvement and at times degradation in steering performance. Our analysis demonstrate fundamental flaws in the assumptions underlying these methods, challenging their reliability as scalable steering solutions.

Recent years have seen significant advancements in foundation models through generative pre-training, yet algorithmic innovation in this space has largely stagnated around autoregressive models for discrete signals and diffusion models for continuous signals. This stagnation creates a bottleneck that prevents us from fully unlocking the potential of rich multi-modal data, which in turn limits the progress on multimodal intelligence. We argue that an inference-first perspective, which prioritizes scaling efficiency during inference time across sequence length and refinement steps, can inspire novel generative pre-training algorithms. Using Inductive Moment Matching (IMM) as a concrete example, we demonstrate how addressing limitations in diffusion models' inference process through targeted modifications yields a stable, single-stage algorithm that achieves superior sample quality with over an order of magnitude greater inference efficiency.

LLM agents remain unreliable on long-horizon tasks, where small local failures can compound over extended interactions and lead to overall task failure. Although external harnesses can substantially improve robustness, harness design remains a manual and expensive process that requires searching over a large space of prompts, tool configurations, and control logic. We propose AutoSaddler, an automatic harness optimization framework that formulates harness improvement as an offline learning problem and iteratively updates the harness using failure signals from mini-batches. AutoSaddler combines failure-trace diagnosis, structured patch generation that treats the harness as code, and validation-based update selection. Experiments on GAIA2, SWE-Bench Pro, and Terminal-Bench 2.0 show that AutoSaddler substantially improves agent performance over the corresponding base harnesses, achieving gains of 9.0, 9.6, and 10.0 percentage points, respectively. Ablation studies further suggest that effective harness optimization benefits from three ingredients: deep debugging rather than shallow reflection, targeted modifications rather than unconstrained editing, and generalization-aware selection rather than trajectory-specific repair. Together, these results suggest that automatic harness optimization is a promising path toward more performant and reliable agent systems.

The landscape of AI video generation is undergoing a pivotal shift: moving beyond general generation - which relies on exhaustive prompt-engineering and "cherry-picking" - towards fine-grained, controllable generation and high-fidelity post-processing. In professional AI-assisted filmmaking, it is crucial to perform precise, targeted modifications. A cornerstone of this transition is video instance insertion, which requires inserting a specific instance into existing footage while maintaining scene integrity. Unlike traditional video editing, this task demands several requirements: precise spatial-temporal placement, physically consistent scene interaction, and the faithful preservation of original dynamics - all achieved under minimal user effort. In this paper, we propose PISCO, a video diffusion model for precise video instance insertion with arbitrary sparse keyframe control. PISCO allows users to specify a single keyframe, start-and-end keyframes, or sparse keyframes at arbitrary timestamps, and automatically propagates object appearance, motion, and interaction. To address the severe distribution shift induced by sparse conditioning in pretrained video diffusion models, we introduce Variable-Information Guidance for robust conditioning and Distribution-Preserving Temporal Masking to stabilize temporal generation, together with geometry-aware conditioning for realistic scene adaptation. We further construct PISCO-Bench, a benchmark with verified instance annotations and paired clean background videos, and evaluate performance using both reference-based and reference-free perceptual metrics. Experiments demonstrate that PISCO consistently outperforms strong inpainting and video editing baselines under sparse control, and exhibits clear, monotonic performance improvements as additional control signals are provided. Project page: xiangbogaobarry.github.io/PISCO.

Real-world design documents (e.g., posters) are inherently multi-layered, combining decoration, text, and images. Editing them from natural-language instructions requires fine-grained, layer-aware reasoning to identify relevant layers and coordinate modifications. Prior work largely overlooks multi-layer design document editing, focusing instead on single-layer image editing or multi-layer generation, which assume a flat canvas and lack the reasoning needed to determine what and where to modify. To address this gap, we introduce the Multi-Layer Document Editing Agent (MiLDEAgent), a reasoning-based framework that combines an RL-trained multimodal reasoner for layer-wise understanding with an image editor for targeted modifications. To systematically benchmark this setting, we introduce the MiLDEBench, a human-in-the-loop corpus of over 20K design documents paired with diverse editing instructions. The benchmark is complemented by a task-specific evaluation protocol, MiLDEEval, which spans four dimensions including instruction following, layout consistency, aesthetics, and text rendering. Extensive experiments on 14 open-source and 2 closed-source models reveal that existing approaches fail to generalize: open-source models often cannot complete multi-layer document editing tasks, while closed-source models suffer from format violations. In contrast, MiLDEAgent achieves strong layer-aware reasoning and precise editing, significantly outperforming all open-source baselines and attaining performance comparable to closed-source models, thereby establishing the first strong baseline for multi-layer document editing.

Generating natural language explanations for recommendations has become increasingly important in recommender systems. Traditional approaches typically treat user reviews as ground truth for explanations and focus on improving review prediction accuracy by designing various model architectures. However, due to limitations in data scale and model capability, these explanations often fail to meet key user-centric aspects such as factuality, personalization, and sentiment coherence, significantly reducing their overall helpfulness to users. In this paper, we propose a novel paradigm that refines initial explanations generated by existing explainable recommender models during the inference stage to enhance their quality in multiple aspects. Specifically, we introduce a multi-agent collaborative refinement framework based on large language models. To ensure alignment between the refinement process and user demands, we employ a plan-then-refine pattern to perform targeted modifications. To enable continuous improvements, we design a hierarchical reflection mechanism that provides feedback on the refinement process from both strategic and content perspectives. Extensive experiments on three datasets demonstrate the effectiveness of our framework.

The rapid advancement of GenAI technology over the past few years has significantly contributed towards highly realistic deepfake content generation. Despite ongoing efforts, the research community still lacks a large-scale and reasoning capability driven deepfake benchmark dataset specifically tailored for person-centric object, context and scene manipulations. In this paper, we address this gap by introducing MultiFakeVerse, a large scale person-centric deepfake dataset, comprising 845,286 images generated through manipulation suggestions and image manipulations both derived from vision-language models (VLM). The VLM instructions were specifically targeted towards modifications to individuals or contextual elements of a scene that influence human perception of importance, intent, or narrative. This VLM-driven approach enables semantic, context-aware alterations such as modifying actions, scenes, and human-object interactions rather than synthetic or low-level identity swaps and region-specific edits that are common in existing datasets. Our experiments reveal that current state-of-the-art deepfake detection models and human observers struggle to detect these subtle yet meaningful manipulations. The code and dataset are available on https://github.com/Parul-Gupta/MultiFakeVerse{GitHub}.

Although mission-critical applications require the use of deep neural networks (DNNs), their continuous execution at mobile devices results in a significant increase in energy consumption. While edge offloading can decrease energy consumption, erratic patterns in channel quality, network and edge server load can lead to severe disruption of the system's key operations. An alternative approach, called split computing, generates compressed representations within the model (called "bottlenecks"), to reduce bandwidth usage and energy consumption. Prior work has proposed approaches that introduce additional layers, to the detriment of energy consumption and latency. For this reason, we propose a new framework called BottleFit, which, in addition to targeted DNN architecture modifications, includes a novel training strategy to achieve high accuracy even with strong compression rates. We apply BottleFit on cutting-edge DNN models in image classification, and show that BottleFit achieves 77.1% data compression with up to 0.6% accuracy loss on ImageNet dataset, while state of the art such as SPINN loses up to 6% in accuracy. We experimentally measure the power consumption and latency of an image classification application running on an NVIDIA Jetson Nano board (GPU-based) and a Raspberry PI board (GPU-less). We show that BottleFit decreases power consumption and latency respectively by up to 49% and 89% with respect to (w.r.t.) local computing and by 37% and 55% w.r.t. edge offloading. We also compare BottleFit with state-of-the-art autoencoders-based approaches, and show that (i) BottleFit reduces power consumption and execution time respectively by up to 54% and 44% on the Jetson and 40% and 62% on Raspberry PI; (ii) the size of the head model executed on the mobile device is 83 times smaller. We publish the code repository for reproducibility of the results in this study.

Recent years have witnessed a rapid development of mobile GUI agents powered by large language models (LLMs), which can autonomously execute diverse device-control tasks based on natural language instructions. The increasing accuracy of these agents on standard benchmarks has raised expectations for large-scale real-world deployment, and there are already several commercial agents released and used by early adopters. However, are we really ready for GUI agents integrated into our daily devices as system building blocks? We argue that an important pre-deployment validation is missing to examine whether the agents can maintain their performance under real-world threats. Specifically, unlike existing common benchmarks that are based on simple static app contents (they have to do so to ensure environment consistency between different tests), real-world apps are filled with contents from untrustworthy third parties, such as advertisement emails, user-generated posts and medias, etc. ... To this end, we introduce a scalable app content instrumentation framework to enable flexible and targeted content modifications within existing applications. Leveraging this framework, we create a test suite comprising both a dynamic task execution environment and a static dataset of challenging GUI states. The dynamic environment encompasses 122 reproducible tasks, and the static dataset consists of over 3,000 scenarios constructed from commercial apps. We perform experiments on both open-source and commercial GUI agents. Our findings reveal that all examined agents can be significantly degraded due to third-party contents, with an average misleading rate of 42.0% and 36.1% in dynamic and static environments respectively. The framework and benchmark has been released at https://agenthazard.github.io.

High-performance GPU kernel optimization remains a critical yet labor-intensive task in modern machine learning workloads. Although Triton, a domain-specific language for GPU programming, enables developers to write efficient kernels with concise code, achieving expert-level performance still requires deep understanding of GPU architectures and low-level performance trade-offs. We present TritonForge, a profiling-guided framework for automated Triton kernel optimization. TritonForge integrates kernel analysis, runtime profiling, and iterative code transformation to streamline the optimization process. By incorporating feedback from profiling results, the system identifies performance bottlenecks, proposes targeted code modifications, and evaluates their impact automatically. Across diverse kernel types, TritonForge achieves up to 5x performance improvement over baseline implementations and on average 1.76x of the cases are successful, providing a foundation for future research in automated GPU performance optimization.

We propose a training-free approach to 3D editing that enables the editing of a single shape within a few minutes. The edited 3D mesh aligns well with the prompts, and remains identical for regions that are not intended to be altered. To this end, we first project the 3D object onto 4-view images and perform synchronized multi-view image editing along with user-guided text prompts and user-provided rough masks. However, the targeted regions to be edited are ambiguous due to projection from 3D to 2D. To ensure precise editing only in intended regions, we develop a 3D segmentation pipeline that detects edited areas in 3D space, followed by a merging algorithm to seamlessly integrate edited 3D regions with the original input. Extensive experiments demonstrate the superiority of our method over previous approaches, enabling fast, high-quality editing while preserving unintended regions.

Large Language Models (LLMs) have transformed numerous fields by enabling advanced natural language interactions but remain susceptible to critical vulnerabilities, particularly jailbreak attacks. Current jailbreak techniques, while effective, often depend on input modifications, making them detectable and limiting their stealth and scalability. This paper presents Targeted Model Editing (TME), a novel white-box approach that bypasses safety filters by minimally altering internal model structures while preserving the model's intended functionalities. TME identifies and removes safety-critical transformations (SCTs) embedded in model matrices, enabling malicious queries to bypass restrictions without input modifications. By analyzing distinct activation patterns between safe and unsafe queries, TME isolates and approximates SCTs through an optimization process. Implemented in the D-LLM framework, our method achieves an average Attack Success Rate (ASR) of 84.86% on four mainstream open-source LLMs, maintaining high performance. Unlike existing methods, D-LLM eliminates the need for specific triggers or harmful response collections, offering a stealthier and more effective jailbreak strategy. This work reveals a covert and robust threat vector in LLM security and emphasizes the need for stronger safeguards in model safety alignment.

Agentic systems integrate LLM driven planning with interfaces to external tools, making data leakage and tool misuse feasible via instruction/data boundary failures and prompt injection attacks. Enforcing required controls consistently is particularly challenging in workflows spanning many codebases and heterogeneous agents. To address this challenge in multi agentic systems, we present a pre-deployment pipeline for scanning, hardening, and validation of agentic applications. The pipeline analyzes prompt templates, tool interfaces, and tool-invocation code to identify leakage-enabling patterns and generate actionable patches. The hardened application is then validated through adversarial prompt injection attacks and benign input variations ensuring that mitigations do not disrupt intended behavior. In the hardening stage, high-risk tools are prioritized, and minimally invasive mitigations are applied, including schema tightening, boundary sanitization, allowlist-based tool gating, and least-privilege checks. In the validation stage, the pipeline automatically generates attack inputs that mimic jailbreaks, instruction overrides, and tool-targeted manipulation, along with benign task variants, to confirm that the functionality of the hardened application is preserved after remediation. We evaluated the pipeline on five real-world agentic applications, as well as on the AgentDojo benchmark. Across all applications, the proposed pipeline identified recurring leakage-enabling patterns and generated patches that can be integrated without disrupting the intended application behavior. The resulting modifications of application code were shown to eliminate leaks when targeted by basic jailbreak and instruction-override attacks, achieving a 100% reduction in leakage, and reduce leaks by 91% under conditions of stress-induced manipulation, without the need of continuous runtime policy enforcement.

Large-scale text-to-image generative models have been a ground-breaking development in generative AI, with diffusion models showing their astounding ability to synthesize convincing images following an input text prompt. The goal of image editing research is to give users control over the generated images by modifying the text prompt. Current image editing techniques are susceptible to unintended modifications of regions outside the targeted area, such as on the background or on distractor objects which have some semantic or visual relationship with the targeted object. According to our experimental findings, inaccurate cross-attention maps are at the root of this problem. Based on this observation, we propose Dynamic Prompt Learning (DPL) to force cross-attention maps to focus on correct noun words in the text prompt. By updating the dynamic tokens for nouns in the textual input with the proposed leakage repairment losses, we achieve fine-grained image editing over particular objects while preventing undesired changes to other image regions. Our method DPL, based on the publicly available Stable Diffusion, is extensively evaluated on a wide range of images, and consistently obtains superior results both quantitatively (CLIP score, Structure-Dist) and qualitatively (on user-evaluation). We show improved prompt editing results for Word-Swap, Prompt Refinement, and Attention Re-weighting, especially for complex multi-object scenes.

Counterfactual prompting (i.e., perturbing a single factor and measuring output change) is widely used to evaluate things like LLM bias and CoT faithfulness. But in this work we argue that observed effects cannot be attributed to the targeted factor without accounting for baseline ``meaning-preserving'' modifications to text that establish general model sensitivity. This is because every counterfactual edit is a compound treatment that bundles the variable of interest with incidental surface-form variation; this violates treatment variation irrelevance. We observe prediction flip rates on MedQA of 14.9% when we surgically change patient gender. However, this is statistically indistinguishable from the flip rates induced by simply paraphrasing inputs (14.1%). In this case, it would therefore be unwarranted to conclude that the LLM is especially sensitive to patient gender. To account for this and robustly measure the effects of targeted interventions, we propose a framework in which we compare (via statistical testing) differences observed under target interventions to those induced by paraphrasing inputs. We then use this framework to revisit a analysis done on the MedPerturb dataset, which reported evidence of model sensitivity to patient demographics and stylistic cues. We find that these effects largely dissipate when we account for general model sensitivity, with only 5 of 120 tests reaching statistical significance. Applying the same framework to occupational biography classification, we detect clearly significant directional gender bias, showing that the framework identifies real directional effects even when they are small. We evaluate a range of metrics -- aggregate, per-sample distributional, and regression -- and find that per-sample metrics are dramatically more powerful than aggregate metrics and regression powerfully and uniquely characterizes effect direction and magnitude.

Mechanistic Interpretability (MI) seeks to explain how neural networks implement their capabilities, but the scale of Large Language Models (LLMs) has limited prior MI work in Machine Translation (MT) to word-level analyses. We study sentence-level MT from a mechanistic perspective by analyzing attention heads to understand how LLMs internally encode and distribute translation functions. We decompose MT into two subtasks: producing text in the target language (i.e. target language identification) and preserving the input sentence's meaning (i.e. sentence equivalence). Across three families of open-source models and 20 translation directions, we find that distinct, sparse sets of attention heads specialize in each subtask. Based on this insight, we construct subtask-specific steering vectors and show that modifying just 1% of the relevant heads enables instruction-free MT performance comparable to instruction-based prompting, while ablating these heads selectively disrupts their corresponding translation functions.

Immunotherapy is an effective precision medicine treatment for several cancers. Imaging signatures of the underlying genome (radiogenomics) in glioblastoma patients may serve as preoperative biomarkers of the tumor-host immune apparatus. Validated biomarkers would have the potential to stratify patients during immunotherapy clinical trials, and if trials are beneficial, facilitate personalized neo-adjuvant treatment. The increased use of whole genome sequencing data, and the advances in bioinformatics and machine learning make such developments plausible. We performed a systematic review to determine the extent of development and validation of immune-related radiogenomic biomarkers for glioblastoma. A systematic review was performed following PRISMA guidelines using the PubMed, Medline, and Embase databases. Qualitative analysis was performed by incorporating the QUADAS 2 tool and CLAIM checklist. PROSPERO registered CRD42022340968. Extracted data were insufficiently homogenous to perform a meta-analysis. Results Nine studies, all retrospective, were included. Biomarkers extracted from magnetic resonance imaging volumes of interest included apparent diffusion coefficient values, relative cerebral blood volume values, and image-derived features. These biomarkers correlated with genomic markers from tumor cells or immune cells or with patient survival. The majority of studies had a high risk of bias and applicability concerns regarding the index test performed. Radiogenomic immune biomarkers have the potential to provide early treatment options to patients with glioblastoma. Targeted immunotherapy, stratified by these biomarkers, has the potential to allow individualized neo-adjuvant precision treatment options in clinical trials. However, there are no prospective studies validating these biomarkers, and interpretation is limited due to study bias with little evidence of generalizability.

Targeted data selection has emerged as a crucial paradigm for efficient instruction tuning, aiming to identify a small yet influential subset of training examples for a specific target task. In practice, influence is often measured through the effect of an example on parameter updates. To make selection scalable, many approaches leverage optimizer statistics (e.g., Adam states) as an axis-aligned surrogate for update geometry (i.e., diagonal precondition), implicitly treating parameters as coordinate-wise independent. We show that this assumption breaks down in parameter-efficient fine-tuning (PEFT) methods such as LoRA. In this setting, the induced optimization geometry exhibits strong cross-parameter coupling with non-trivial off-diagonal interactions, while the task-relevant update directions are confined to a low-dimensional subspace. Motivated by this mismatch, we propose GIST (Gradient Isometric Subspace Transformation), a simple yet principled alternative that replaces axis-aligned scaling with robust subspace alignment. GIST recovers a task-specific subspace from validation gradients via spectral filtering (SVD), projects training gradients into this coupled subspace, and scores examples by their alignment with target directions.Extensive experiments have demonstrated that GIST matches or outperforms the state-of-the-art baseline with only 0.29% of the storage and 25% of the computational time under the same selection budget.

Controlling undesirable Large Language Model (LLM) behaviors, such as the generation of unsafe content or failing to adhere to safety guidelines, often relies on costly fine-tuning. Activation steering provides an alternative for inference-time control, but existing methods typically lack fine-grained, adaptive mechanisms. We introduce a novel approach using a lightweight, trainable controller network integrated during inference. This controller network observes specific intermediate LLM activations and predicts both a global scaling factor and layer-specific weights. The predicted global scaling factor and layer-specific weights then dynamically modulate the intensity of a steering patch, derived from a pre-computed "refusal direction" vector, applied across the LLM's layers during generation. Trained on activations from both harmful and benign prompts, our controller learns to discriminatively apply nuanced, layer-aware interventions, activating steering primarily for harmful inputs. Experiments using safety benchmarks like ToxicChat & In-The-Wild Jailbreak Prompts demonstrate that our weighted steering controller significantly increases refusal rates compared to the base LLM, achieving targeted behavioral modification without altering the original model parameters. Our experiments with Llama-3.1-8B, Llama-3.2-1B & Mistral-7B show our approach outperforms existing methods, presenting an efficient and adaptive method for fine-grained control over LLM behavior at inference time.

Targeted interventions on language models, such as unlearning, debiasing, or model editing, are a central method for refining model behavior and keeping knowledge up to date. While these interventions aim to modify specific information within models (e.g., removing virology content), their effects often propagate to related but unintended areas (e.g., allergies); these side-effects are commonly referred to as the ripple effect. In this work, we present RippleBench-Maker, an automatic tool for generating Q&A datasets that allow for the measurement of ripple effects in any model-editing task. RippleBench-Maker builds on a Wikipedia-based RAG pipeline (WikiRAG) to generate multiple-choice questions at varying semantic distances from the target concept (e.g., the knowledge being unlearned). Using this framework, we construct RippleBench-Bio, a benchmark derived from the WMDP (Weapons of Mass Destruction Paper) dataset, a common unlearning benchmark. We evaluate eight state-of-the-art unlearning methods and find that all exhibit non-trivial accuracy drops on topics increasingly distant from the unlearned knowledge, each with distinct propagation profiles. To support ongoing research, we release our codebase for on-the-fly ripple evaluation, along with the benchmark, RippleBench-Bio.

We introduce a protein language model for determining the complete sequence of a peptide based on measurement of a limited set of amino acids. To date, protein sequencing relies on mass spectrometry, with some novel edman degregation based platforms able to sequence non-native peptides. Current protein sequencing techniques face limitations in accurately identifying all amino acids, hindering comprehensive proteome analysis. Our method simulates partial sequencing data by selectively masking amino acids that are experimentally difficult to identify in protein sequences from the UniRef database. This targeted masking mimics real-world sequencing limitations. We then modify and finetune a ProtBert derived transformer-based model, for a new downstream task predicting these masked residues, providing an approximation of the complete sequence. Evaluating on three bacterial Escherichia species, we achieve per-amino-acid accuracy up to 90.5% when only four amino acids ([KCYM]) are known. Structural assessment using AlphaFold and TM-score validates the biological relevance of our predictions. The model also demonstrates potential for evolutionary analysis through cross-species performance. This integration of simulated experimental constraints with computational predictions offers a promising avenue for enhancing protein sequence analysis, potentially accelerating advancements in proteomics and structural biology by providing a probabilistic reconstruction of the complete protein sequence from limited experimental data.

Motivation: The development of novel compounds targeting proteins of interest is one of the most important tasks in the pharmaceutical industry. Deep generative models have been applied to targeted molecular design and have shown promising results. Recently, target-specific molecule generation has been viewed as a translation between the protein language and the chemical language. However, such a model is limited by the availability of interacting protein-ligand pairs. On the other hand, large amounts of unlabeled protein sequences and chemical compounds are available and have been used to train language models that learn useful representations. In this study, we propose exploiting pretrained biochemical language models to initialize (i.e. warm start) targeted molecule generation models. We investigate two warm start strategies: (i) a one-stage strategy where the initialized model is trained on targeted molecule generation (ii) a two-stage strategy containing a pre-finetuning on molecular generation followed by target specific training. We also compare two decoding strategies to generate compounds: beam search and sampling. Results: The results show that the warm-started models perform better than a baseline model trained from scratch. The two proposed warm-start strategies achieve similar results to each other with respect to widely used metrics from benchmarks. However, docking evaluation of the generated compounds for a number of novel proteins suggests that the one-stage strategy generalizes better than the two-stage strategy. Additionally, we observe that beam search outperforms sampling in both docking evaluation and benchmark metrics for assessing compound quality. Availability and implementation: The source code is available at https://github.com/boun-tabi/biochemical-lms-for-drug-design and the materials are archived in Zenodo at https://doi.org/10.5281/zenodo.6832145

In an era of increasing pressure to achieve sustainable agriculture, the optimization of livestock feed for enhancing yield and minimizing environmental impact is a paramount objective. This study presents a pioneering approach towards this goal, using rumen microbiome data to predict the efficacy of feed additives in dairy cattle. We collected an extensive dataset that includes methane emissions from 2,190 Holstein cows distributed across 34 distinct sites. The cows were divided into control and experimental groups in a double-blind, unbiased manner, accounting for variables such as age, days in lactation, and average milk yield. The experimental groups were administered one of four leading commercial feed additives: Agolin, Kexxtone, Allimax, and Relyon. Methane emissions were measured individually both before the administration of additives and over a subsequent 12-week period. To develop our predictive model for additive efficacy, rumen microbiome samples were collected from 510 cows from the same herds prior to the study's onset. These samples underwent deep metagenomic shotgun sequencing, yielding an average of 15.7 million reads per sample. Utilizing innovative artificial intelligence techniques we successfully estimated the efficacy of these feed additives across different farms. The model's robustness was further confirmed through validation with independent cohorts, affirming its generalizability and reliability. Our results underscore the transformative capability of using targeted feed additive strategies to both optimize dairy yield and milk composition, and to significantly reduce methane emissions. Specifically, our predictive model demonstrates a scenario where its application could guide the assignment of additives to farms where they are most effective. In doing so, we could achieve an average potential reduction of over 27\% in overall emissions.

This study presents a targeted model editing analysis focused on the latest large language model, Llama-3. We explore the efficacy of popular model editing techniques - ROME, MEMIT, and EMMET, which are designed for precise layer interventions. We identify the most effective layers for targeted edits through an evaluation that encompasses up to 4096 edits across three distinct strategies: sequential editing, batch editing, and a hybrid approach we call as sequential-batch editing. Our findings indicate that increasing edit batch-sizes may degrade model performance more significantly than using smaller edit batches sequentially for equal number of edits. With this, we argue that sequential model editing is an important component for scaling model editing methods and future research should focus on methods that combine both batched and sequential editing. This observation suggests a potential limitation in current model editing methods which push towards bigger edit batch sizes, and we hope it paves way for future investigations into optimizing batch sizes and model editing performance.

Target proteins that lack accessible binding pockets and conformational stability have posed increasing challenges for drug development. Induced proximity strategies, such as PROTACs and molecular glues, have thus gained attention as pharmacological alternatives, but still require small molecule docking at binding pockets for targeted protein degradation (TPD). The computational design of protein-based binders presents unique opportunities to access undruggable targets, but have often relied on stable 3D structures or predictions for effective binder generation. Recently, we have leveraged the expressive latent spaces of protein language models (pLMs) for the prioritization of peptide binders from sequence alone, which we have then fused to E3 ubiquitin ligase domains, creating a CRISPR-analogous TPD system for target proteins. However, our methods rely on training discriminator models for ranking heuristically or unconditionally-derived guide peptides for their target binding capability. In this work, we introduce PepMLM, a purely target sequence-conditioned de novo generator of linear peptide binders. By employing a novel masking strategy that uniquely positions cognate peptide sequences at the terminus of target protein sequences, PepMLM tasks the state-of-the-art ESM-2 pLM to fully reconstruct the binder region, achieving low perplexities matching or improving upon previously-validated peptide-protein sequence pairs. After successful in silico benchmarking with AlphaFold-Multimer, we experimentally verify PepMLM's efficacy via fusion of model-derived peptides to E3 ubiquitin ligase domains, demonstrating endogenous degradation of target substrates in cellular models. In total, PepMLM enables the generative design of candidate binders to any target protein, without the requirement of target structure, empowering downstream programmable proteome editing applications.

We investigate a new dynamical system that describes tumor-host interaction. The equation that describes the untreated tumor growth is based on non-extensive statistical mechanics. Recently, this model has been shown to fit successfully exponential, Gompertz, logistic, and power-law tumor growths. We have been able to include as many hallmarks of cancer as possible. We study also the dynamic response of cancer under therapy. Using our model, we can make predictions about the different outcomes when we change the parameters, and/or the initial conditions. We can determine the importance of different factors to influence tumor growth. We discover synergistic therapeutic effects of different treatments and drugs. Cancer is generally untreatable using conventional monotherapy. We consider conventional therapies, oncogene-targeted therapies, tumor-suppressors gene-targeted therapies, immunotherapies, anti-angiogenesis therapies, virotherapy, among others. We need therapies with the potential to target both tumor cells and the tumors' microenvironment. Drugs that target oncogenes and tumor-suppressor genes can be effective in the treatment of some cancers. However, most tumors do reoccur. We have found that the success of the new therapeutic agents can be seen when used in combination with other cancer-cell-killing therapies. Our results have allowed us to design a combinational therapy that can lead to the complete eradication of cancer.

Personalized nutrition intervention for patients with multimorbidity is critical for improving health outcomes, yet remains challenging because it requires the simultaneous integration of heterogeneous clinical conditions, medications, and dietary guidelines. Single-agent large language models (LLMs) often suffer from context overload and attention dilution when processing such high-dimensional patient profiles. We introduce NutriOrion, a hierarchical multi-agent framework with a parallel-then-sequential reasoning topology. NutriOrion decomposes nutrition planning into specialized domain agents with isolated contexts to mitigate anchoring bias, followed by a conditional refinement stage. The framework includes a multi-objective prioritization algorithm to resolve conflicting dietary requirements and a safety constraint mechanism that injects pharmacological contraindications as hard negative constraints during synthesis, ensuring clinical validity by construction rather than post-hoc filtering. For clinical interoperability, NutriOrion maps synthesized insights into the ADIME standard and FHIR R4 resources. Evaluated on 330 stroke patients with multimorbidity, NutriOrion outperforms multiple baselines, including GPT-4.1 and alternative multi-agent architectures. It achieves a 12.1 percent drug-food interaction violation rate, demonstrates strong personalization with negative correlations (-0.26 to -0.35) between patient biomarkers and recommended risk nutrients, and yields clinically meaningful dietary improvements, including a 167 percent increase in fiber and a 27 percent increase in potassium, alongside reductions in sodium (9 percent) and sugars (12 percent).

Large Language Models (LLMs) are powerful text generators, yet they can produce toxic or harmful content even when given seemingly harmless prompts. This presents a serious safety challenge and can cause real-world harm. Toxicity is often subtle and context-dependent, making it difficult to detect at the token level or through coarse sentence-level signals. Moreover, efforts to mitigate toxicity often face a trade-off between safety and the coherence, or fluency of the generated text. In this work, we present a targeted subspace intervention strategy for identifying and suppressing hidden toxic patterns from underlying model representations, while preserving overall ability to generate safe fluent content. On the RealToxicityPrompts, our method achieves strong mitigation performance compared to existing baselines, with minimal impact on inference complexity. Across multiple LLMs, our approach reduces toxicity of state-of-the-art detoxification systems by 8-20%, while maintaining comparable fluency. Through extensive quantitative and qualitative analyses, we show that our approach achieves effective toxicity reduction without impairing generative performance, consistently outperforming existing baselines.

Antibodies have become an important class of therapeutic agents to treat human diseases. To accelerate therapeutic antibody discovery, computational methods, especially machine learning, have attracted considerable interest for predicting specific interactions between antibody candidates and target antigens such as viruses and bacteria. However, the publicly available datasets in existing works have notable limitations, such as small sizes and the lack of non-binding samples and exact amino acid sequences. To overcome these limitations, we have developed AVIDa-hIL6, a large-scale dataset for predicting antigen-antibody interactions in the variable domain of heavy chain of heavy chain antibodies (VHHs), produced from an alpaca immunized with the human interleukin-6 (IL-6) protein, as antigens. By leveraging the simple structure of VHHs, which facilitates identification of full-length amino acid sequences by DNA sequencing technology, AVIDa-hIL6 contains 573,891 antigen-VHH pairs with amino acid sequences. All the antigen-VHH pairs have reliable labels for binding or non-binding, as generated by a novel labeling method. Furthermore, via introduction of artificial mutations, AVIDa-hIL6 contains 30 different mutants in addition to wild-type IL-6 protein. This characteristic provides opportunities to develop machine learning models for predicting changes in antibody binding by antigen mutations. We report experimental benchmark results on AVIDa-hIL6 by using neural network-based baseline models. The results indicate that the existing models have potential, but further research is needed to generalize them to predict effective antibodies against unknown mutants. The dataset is available at https://avida-hil6.cognanous.com.

Structure-based drug design (SBDD) aims to discover drug candidates by finding molecules (ligands) that bind tightly to a disease-related protein (targets), which is the primary approach to computer-aided drug discovery. Recently, applying deep generative models for three-dimensional (3D) molecular design conditioned on protein pockets to solve SBDD has attracted much attention, but their formulation as probabilistic modeling often leads to unsatisfactory optimization performance. On the other hand, traditional combinatorial optimization methods such as genetic algorithms (GA) have demonstrated state-of-the-art performance in various molecular optimization tasks. However, they do not utilize protein target structure to inform design steps but rely on a random-walk-like exploration, which leads to unstable performance and no knowledge transfer between different tasks despite the similar binding physics. To achieve a more stable and efficient SBDD, we propose Reinforced Genetic Algorithm (RGA) that uses neural models to prioritize the profitable design steps and suppress random-walk behavior. The neural models take the 3D structure of the targets and ligands as inputs and are pre-trained using native complex structures to utilize the knowledge of the shared binding physics from different targets and then fine-tuned during optimization. We conduct thorough empirical studies on optimizing binding affinity to various disease targets and show that RGA outperforms the baselines in terms of docking scores and is more robust to random initializations. The ablation study also indicates that the training on different targets helps improve performance by leveraging the shared underlying physics of the binding processes. The code is available at https://github.com/futianfan/reinforced-genetic-algorithm.

There is a widening recognition that cancer cells are products of complex developmental processes. Carcinogenesis and metastasis formation are increasingly described as systems-level, network phenomena. Here we propose that malignant transformation is a two-phase process, where an initial increase of system plasticity is followed by a decrease of plasticity at late stages of carcinogenesis as a model of cellular learning. We describe the hallmarks of increased system plasticity of early, tumor initiating cells, such as increased noise, entropy, conformational and phenotypic plasticity, physical deformability, cell heterogeneity and network rearrangements. Finally, we argue that the large structural changes of molecular networks during cancer development necessitate a rather different targeting strategy in early and late phase of carcinogenesis. Plastic networks of early phase cancer development need a central hit, while rigid networks of late stage primary tumors or established metastases should be attacked by the network influence strategy, such as by edgetic, multi-target, or allo-network drugs. Cancer stem cells need special diagnosis and targeting, since their dormant and rapidly proliferating forms may have more rigid, or more plastic networks, respectively. The extremely high ability to change their rigidity/plasticity may be a key differentiating hallmark of cancer stem cells. The application of early stage-optimized anti-cancer drugs to late-stage patients may be a reason of many failures in anti-cancer therapies. Our hypotheses presented here underlie the need for patient-specific multi-target therapies applying the correct ratio of central hits and network influences -- in an optimized sequence.

Proteolysis-targeting chimeras (PROTACs) represent a promising therapeutic modality that induces targeted protein degradation by hijacking the ubiquitin-proteasome system. However, rational PROTAC design remains challenging due to the complex interplay between molecular structure, target proteins, E3 ligases, and the cellular context. We present TACK, a statistical evaluation of degradation activity on a novel TArgeting Chimeras Knowledge dataset of 3,514 PROTACs and 6,561 degradation endpoints aggregated from three major repositories with standardized molecular representations, protein annotations, and experimental conditions. Using scaffold-based 5times5 cross-validation, we perform a rigorous statistical comparison of three machine learning methods to predict PROTAC degradation activity across three tasks: DC_{50} and Dmax regression, and binary activity classification. Feature ablation demonstrates that cellular context features and simple protein representations rival complex ESM protein embeddings, highlighting the importance of feature engineering over architectural sophistication. Models trained on the best performing features show that potency (pDC_{50}, R^2=0.66) is substantially more predictable than maximum degradation (Dmax, R^2=0.36). In activity prediction, statistical tests support that classical methods (XGBoost and MLP) significantly outperform PROTAC-STAN, a domain-specific graph neural network model (ROC-AUC: 0.85 vs. 0.74, p<0.001). Finally, we propose an ensemble-based uncertainty quantification approach showing that prediction variance correlates with prediction error (pDC_{50}: Spearman ρ=0.36, p<0.001; Dmax: ρ=0.69, p<0.001), enabling confidence-aware experimental prioritization. Our findings challenge assumptions about specialized architectures for degradation prediction and provide evidence-based guidance for ML-driven PROTAC assessment.

Retrieval-augmented QA pipelines often route retrieved passages through an LLM rewriter before a smaller reader, lifting F1 by tens of points on multi-hop benchmarks; this gain is typically credited to improved evidence quality. We ask whether that lift is causally driven by the gold answer string appearing in the rewritten context rather than by curation per se, using a controlled intervention audit. For each rewritten context we re-run the reader after one of four controlled edits to the compile output: removing the gold answer span, replacing a length-matched random non-answer span (placebo), or injecting the gold into rewrites where it was absent (at the prefix or at a midpoint sentence boundary). Across twelve completed (cell, baseline) intervention runs spanning three reader families (Qwen2.5-7B, Qwen3.5-35B, GLM-4.7), two datasets (HotpotQA, 2WikiMultihopQA), and three compiler arrangements (MA-only, MB-only, MA+verify), removing the gold answer drops reader F1 by 28 to 64 points beyond the length-matched placebo on paired answer-in-compile strata, and prepending the gold into rewrites that lacked it raises F1 by +0.7 to +9.7 points in 10 of 12 (cell, baseline) combinations. A companion five-sentinel audit shows the conventional single-[MASK] probe is itself sentinel-fragile: on 2Wiki it reports a +4.12~F1 ``non-leakage residual'' that flips to -3.33 to -7.81~F1 under four alternative sentinels and fails an equivalence test for three of those four (1/4~pass). We do not propose a new rewriter or mitigation; we release the intervention runner and the sentinel panel so that other rewriter-gain claims can be tested against the same standard.

The molecular characterization of tumor samples by multiple omics data sets of different types or modalities (e.g. gene expression, mutation, CpG methylation) has become an invaluable source of information for assessing the expected performance of individual drugs and their combinations. Merging the relevant information from the omics data modalities provides the statistical basis for determining suitable therapies for specific cancer patients. Different data modalities may each have their specific structures that need to be taken into account during inference. In this paper, we assume that each omics data modality has a low-rank structure with only few relevant features that affect the prediction and we propose to use a composite local nuclear norm penalization for learning drug sensitivity. Numerical results show that the composite low-rank structure can improve the prediction performance compared to using a global low-rank approach or elastic net regression.

Identifying drug-target interactions is essential for developing effective therapeutics. Binding affinity quantifies these interactions, and traditional approaches rely on computationally intensive 3D structural data. In contrast, language models can efficiently process sequential data, offering an alternative approach to molecular representation. In the current study, we introduce BAPULM, an innovative sequence-based framework that leverages the chemical latent representations of proteins via ProtT5-XL-U50 and ligands through MolFormer, eliminating reliance on complex 3D configurations. Our approach was validated extensively on benchmark datasets, achieving scoring power (R) values of 0.925 pm 0.043, 0.914 pm 0.004, and 0.8132 pm 0.001 on benchmark1k2101, Test2016_290, and CSAR-HiQ_36, respectively. These findings indicate the robustness and accuracy of BAPULM across diverse datasets and underscore the potential of sequence-based models in-silico drug discovery, offering a scalable alternative to 3D-centric methods for screening potential ligands.

The computational prediction and design of peptide binders targeting specific linear epitopes is crucial in biological and biomedical research, yet it remains challenging due to their highly dynamic nature and the scarcity of experimentally solved binding data. To address this problem, we built an unprecedentedly large-scale library of peptide pairs within stable secondary structures (beta sheets), leveraging newly available AlphaFold predicted structures. We then developed a machine learning method based on the Transformer architecture for the design of specific linear binders, in analogy to a language translation task. Our method, TransformerBeta, accurately predicts specific beta strand interactions and samples sequences with beta sheet-like molecular properties, while capturing interpretable physico-chemical interaction patterns. As such, it can propose specific candidate binders targeting linear epitope for experimental validation to inform protein design.

Toxicity remains a leading cause of early-stage drug development failure. Despite advances in molecular design and property prediction, the task of molecular toxicity repair - generating structurally valid molecular alternatives with reduced toxicity - has not yet been systematically defined or benchmarked. To fill this gap, we introduce ToxiMol, the first benchmark task for general-purpose Multimodal Large Language Models (MLLMs) focused on molecular toxicity repair. We construct a standardized dataset covering 11 primary tasks and 560 representative toxic molecules spanning diverse mechanisms and granularities. We design a prompt annotation pipeline with mechanism-aware and task-adaptive capabilities, informed by expert toxicological knowledge. In parallel, we propose an automated evaluation framework, ToxiEval, which integrates toxicity endpoint prediction, synthetic accessibility, drug-likeness, and structural similarity into a high-throughput evaluation chain for repair success. We systematically assess nearly 30 mainstream general-purpose MLLMs and design multiple ablation studies to analyze key factors such as evaluation criteria, candidate diversity, and failure attribution. Experimental results show that although current MLLMs still face significant challenges on this task, they begin to demonstrate promising capabilities in toxicity understanding, semantic constraint adherence, and structure-aware molecule editing.

To build effective therapeutics, biologists iteratively mutate antibody sequences to improve binding and stability. Proposed mutations can be informed by previous measurements or by learning from large antibody databases to predict only typical antibodies. Unfortunately, the space of typical antibodies is enormous to search, and experiments often fail to find suitable antibodies on a budget. We introduce Clone-informed Bayesian Optimization (CloneBO), a Bayesian optimization procedure that efficiently optimizes antibodies in the lab by teaching a generative model how our immune system optimizes antibodies. Our immune system makes antibodies by iteratively evolving specific portions of their sequences to bind their target strongly and stably, resulting in a set of related, evolving sequences known as a clonal family. We train a large language model, CloneLM, on hundreds of thousands of clonal families and use it to design sequences with mutations that are most likely to optimize an antibody within the human immune system. We propose to guide our designs to fit previous measurements with a twisted sequential Monte Carlo procedure. We show that CloneBO optimizes antibodies substantially more efficiently than previous methods in realistic in silico experiments and designs stronger and more stable binders in in vitro wet lab experiments.

Current Large Language Models (LLMs) exhibit significant limitations, notably in structured, interpretable, and verifiable medical reasoning, alongside practical deployment challenges related to computational resources and data privacy. This report focused on the development of WiNGPT-3.0, the 32-billion parameter LLMs, engineered with the objective of enhancing its capacity for medical reasoning and exploring its potential for effective integration within healthcare IT infrastructures. The broader aim is to advance towards clinically applicable models. The approach involved a multi-stage training pipeline tailored for general, medical, and clinical reasoning. This pipeline incorporated supervised fine-tuning (SFT) and reinforcement learning (RL), leveraging curated Long Chain-of-Thought (CoT) datasets, auxiliary reward models, and an evidence-based diagnostic chain simulation. WiNGPT-3.0 demonstrated strong performance: specific model variants achieved scores of 66.6 on MedCalc and 87.1 on MedQA-USMLE. Furthermore, targeted training improved performance on a clinical reasoning task from a baseline score of 58.1 to 62.5. These findings suggest that reinforcement learning, even when applied with a limited dataset of only a few thousand examples, can enhance medical reasoning accuracy. Crucially, this demonstration of RL's efficacy with limited data and computation paves the way for more trustworthy and practically deployable LLMs within clinical workflows and health information infrastructures.

Antibodies comprise the most versatile class of binding molecules, with numerous applications in biomedicine. Computational design of antibodies involves generating novel and diverse sequences, while maintaining structural consistency. Unique to antibodies, designing the complementarity-determining region (CDR), which determines the antigen binding affinity and specificity, creates its own unique challenges. Recent deep learning models have shown impressive results, however the limited number of known antibody sequence/structure pairs frequently leads to degraded performance, particularly lacking diversity in the generated sequences. In our work we address this challenge by leveraging Model Reprogramming (MR), which repurposes pretrained models on a source language to adapt to the tasks that are in a different language and have scarce data - where it may be difficult to train a high-performing model from scratch or effectively fine-tune an existing pre-trained model on the specific task. Specifically, we introduce ReprogBert in which a pretrained English language model is repurposed for protein sequence infilling - thus considers cross-language adaptation using less data. Results on antibody design benchmarks show that our model on low-resourced antibody sequence dataset provides highly diverse CDR sequences, up to more than a two-fold increase of diversity over the baselines, without losing structural integrity and naturalness. The generated sequences also demonstrate enhanced antigen binding specificity and virus neutralization ability. Code is available at https://github.com/IBM/ReprogBERT

Randomized controlled trials often do not represent the populations where decisions are made, and covariate shift across studies can invalidate standard IPD meta-analysis and transport estimators. We propose a placebo-anchored transport framework that treats source-trial outcomes as abundant proxy signals and target-trial placebo outcomes as scarce, high-fidelity gold labels to calibrate baseline risk. A low-complexity (sparse) correction anchors proxy outcome models to the target population, and the anchored models are embedded in a cross-fitted doubly robust learner, yielding a Neyman-orthogonal, target-site doubly robust estimator for patient-level heterogeneous treatment effects when target treated outcomes are available. We distinguish two regimes: in connected targets (with a treated arm), the method yields target-identified effect estimates; in disconnected targets (placebo-only), it reduces to a principled screen--then--transport procedure under explicit working-model transport assumptions. Experiments on synthetic data and a semi-synthetic IHDP benchmark evaluate pointwise CATE accuracy, ATE error, ranking quality for targeting, decision-theoretic policy regret, and calibration. Across connected settings, the proposed method is best or near-best and improves substantially over proxy-only, target-only, and transport baselines at small target sample sizes; in disconnected settings, it retains strong ranking performance for targeting while pointwise accuracy depends on the strength of the working transport condition.

We propose patching for large language models (LLMs) like software versions, a lightweight and modular approach for addressing safety vulnerabilities. While vendors release improved LLM versions, major releases are costly, infrequent, and difficult to tailor to customer needs, leaving released models with known safety gaps. Unlike full-model fine-tuning or major version updates, our method enables rapid remediation by prepending a compact, learnable prefix to an existing model. This "patch" introduces only 0.003% additional parameters, yet reliably steers model behavior toward that of a safer reference model. Across three critical domains (toxicity mitigation, bias reduction, and harmfulness refusal) policy patches achieve safety improvements comparable to next-generation safety-aligned models while preserving fluency. Our results demonstrate that LLMs can be "patched" much like software, offering vendors and practitioners a practical mechanism for distributing scalable, efficient, and composable safety updates between major model releases.

Despite rapid progress in LLM agents, performance on long-horizon, tool-using tasks remains fragile. To better understand this fragility, we ask a simple question: do all actions contribute equally to failure? Analyzing execution traces on τ-Bench (Airline/Retail) and SWE-Bench Verified, we decompose trajectories into mutating (environment-changing) vs.\ non-mutating steps and formalize decisive deviations, earliest action, level divergences that flip success to failure. A logistic regression reveals that each additional deviation in a mutating action reduces the odds of success by upto 92% on Airline and upto 96% on Retail for SoTA models. In contrast, deviations in non-mutating actions have little to no effect. Errors also grow with context length as agents drift from role and act on stale constraints. Motivated by these observations, we introduce , a model-agnostic, gradient-free, test-time safeguard that (i) adds mutation-gated verification, (ii) injects Targeted Reflection before mutating steps, and (iii) performs block-based context cleaning. delivers consistent gains, e.g., Qwen3-Thinking: +28\% relative on Airline, +11\% on Retail, and +7\% on SWE-Bench Verified; Claude: +9\%/+7\%. We further identify ceiling effects in τ-Bench, where annotation errors and underspecified tasks artificially cap model performance. To address this, we release τ-Bench Verified, which restores benchmark headroom through targeted revisions. Our results argue for action-level analysis, targeted safeguards, and reliable evaluations as prerequisites for robust multi-turn agents.

Recent model editing techniques promise to mitigate the problem of memorizing false or outdated associations during LLM training. However, we show that these techniques can introduce large unwanted side effects which are not detected by existing specificity benchmarks. We extend the existing CounterFact benchmark to include a dynamic component and dub our benchmark CounterFact+. Additionally, we extend the metrics used for measuring specificity by a principled KL divergence-based metric. We use this improved benchmark to evaluate recent model editing techniques and find that they suffer from low specificity. Our findings highlight the need for improved specificity benchmarks that identify and prevent unwanted side effects.

Scientific discovery relies on scientists generating novel hypotheses that undergo rigorous experimental validation. To augment this process, we introduce an AI co-scientist, a multi-agent system built on Gemini 2.0. The AI co-scientist is intended to help uncover new, original knowledge and to formulate demonstrably novel research hypotheses and proposals, building upon prior evidence and aligned to scientist-provided research objectives and guidance. The system's design incorporates a generate, debate, and evolve approach to hypothesis generation, inspired by the scientific method and accelerated by scaling test-time compute. Key contributions include: (1) a multi-agent architecture with an asynchronous task execution framework for flexible compute scaling; (2) a tournament evolution process for self-improving hypotheses generation. Automated evaluations show continued benefits of test-time compute, improving hypothesis quality. While general purpose, we focus development and validation in three biomedical areas: drug repurposing, novel target discovery, and explaining mechanisms of bacterial evolution and anti-microbial resistance. For drug repurposing, the system proposes candidates with promising validation findings, including candidates for acute myeloid leukemia that show tumor inhibition in vitro at clinically applicable concentrations. For novel target discovery, the AI co-scientist proposed new epigenetic targets for liver fibrosis, validated by anti-fibrotic activity and liver cell regeneration in human hepatic organoids. Finally, the AI co-scientist recapitulated unpublished experimental results via a parallel in silico discovery of a novel gene transfer mechanism in bacterial evolution. These results, detailed in separate, co-timed reports, demonstrate the potential to augment biomedical and scientific discovery and usher an era of AI empowered scientists.

Large language models (LLMs) often exhibit hallucinations due to incorrect or outdated knowledge. Hence, model editing methods have emerged to enable targeted knowledge updates. To achieve this, a prevailing paradigm is the locating-then-editing approach, which first locates influential parameters and then edits them by introducing a perturbation. While effective, current studies have demonstrated that this perturbation inevitably disrupt the originally preserved knowledge within LLMs, especially in sequential editing scenarios. To address this, we introduce AlphaEdit, a novel solution that projects perturbation onto the null space of the preserved knowledge before applying it to the parameters. We theoretically prove that this projection ensures the output of post-edited LLMs remains unchanged when queried about the preserved knowledge, thereby mitigating the issue of disruption. Extensive experiments on various LLMs, including LLaMA3, GPT2-XL, and GPT-J, show that AlphaEdit boosts the performance of most locating-then-editing methods by an average of 36.4% with a single line of additional code for projection solely. Our code is available at: https://github.com/jianghoucheng/AlphaEdit.

Protein Language Models (PLMs) have emerged as performant and scalable tools for predicting the functional impact and clinical significance of protein-coding variants, but they still lag experimental accuracy. Here, we present a novel fine-tuning approach to improve the performance of PLMs with experimental maps of variant effects from Deep Mutational Scanning (DMS) assays using a Normalised Log-odds Ratio (NLR) head. We find consistent improvements in a held-out protein test set, and on independent DMS and clinical variant annotation benchmarks from ProteinGym and ClinVar. These findings demonstrate that DMS is a promising source of sequence diversity and supervised training data for improving the performance of PLMs for variant effect prediction.

Mechanism-targeted synthetic data is increasingly proposed as a way to steer pretraining toward desirable capabilities, but it remains unclear how such interventions should be evaluated. We study this question for in-context learning (ICL) under matched compute (iso-FLOPs) using Bi-Induct, a lightweight data rewrite that interleaves short directional copy snippets into a natural pretraining stream: forward-copy (induction), backward-copy (anti-induction, as a directional control), or a balanced mix. Across 0.13B-1B decoder-only models, we evaluate (i) few-shot performance on standard LM benchmarks and function-style ICL probes, (ii) head-level copy telemetry, and (iii) held-out perplexity as a guardrail. Bi-Induct reliably increases induction-head activity, but this does not translate into consistent improvements in few-shot generalization: on standard LM benchmarks, Bi-Induct is largely performance-neutral relative to natural-only training, while on function-style probes the 1B natural-only model performs best. Despite explicit backward-copy cues, anti-induction scores remain near zero across scales, revealing a strong forward/backward asymmetry. Targeted ablations show a sharper distinction: removing the top 2% induction heads per layer harms ICL more than matched random ablations, with the largest relative drop occurring in the natural-only models. This indicates that natural-only training produces more centralized, load-bearing induction circuitry, whereas Bi-Induct tends to create more distributed and redundant induction activity. Our main conclusion is that eliciting a mechanism is not the same as making it load-bearing. For data-centric foundation model design, this suggests that synthetic data interventions should be evaluated not only by signature amplification, but by whether they create causally necessary computation while preserving natural-data modeling quality.

Harmful fine-tuning issue qi2023fine poses serious safety concerns for Large language models' fine-tuning-as-a-service. While existing defenses huang2024vaccine,rosati2024representation have been proposed to mitigate the issue, their performances are still far away from satisfactory, and the root cause of the problem has not been fully recovered. For the first time in the literature, we in this paper show that harmful perturbation over the model weights should be the root cause of alignment-broken of harmful fine-tuning. In order to attenuate the negative impact of harmful perturbation, we propose an alignment-stage solution, dubbed Booster. Technically, along with the original alignment loss, we append a loss regularizer in the alignment stage's optimization. The regularizer ensures that the model's harmful loss reduction before/after simulated harmful perturbation is attenuated, thereby mitigating the subsequent fine-tuning risk. Empirical results show that Booster can effectively reduce the harmful score of the fine-tuned models while maintaining the performance of downstream tasks. Our code is available at https://github.com/git-disl/Booster.

Recent advances in large language models (LLMs) have led to their extensive global deployment, and ensuring their safety calls for comprehensive and multilingual toxicity evaluations. However, existing toxicity benchmarks are overwhelmingly focused on English, posing serious risks to deploying LLMs in other languages. We address this by introducing PolygloToxicityPrompts (PTP), the first large-scale multilingual toxicity evaluation benchmark of 425K naturally occurring prompts spanning 17 languages. We overcome the scarcity of naturally occurring toxicity in web-text and ensure coverage across languages with varying resources by automatically scraping over 100M web-text documents. Using PTP, we investigate research questions to study the impact of model size, prompt language, and instruction and preference-tuning methods on toxicity by benchmarking over 60 LLMs. Notably, we find that toxicity increases as language resources decrease or model size increases. Although instruction- and preference-tuning reduce toxicity, the choice of preference-tuning method does not have any significant impact. Our findings shed light on crucial shortcomings of LLM safeguarding and highlight areas for future research.

Open-weight bio-foundation models present a dual-use dilemma. While holding great promise for accelerating scientific research and drug development, they could also enable bad actors to develop more deadly bioweapons. To mitigate the risk posed by these models, current approaches focus on filtering biohazardous data during pre-training. However, the effectiveness of such an approach remains unclear, particularly against determined actors who might fine-tune these models for malicious use. To address this gap, we propose BioRiskEval, a framework to evaluate the robustness of procedures that are intended to reduce the dual-use capabilities of bio-foundation models. BioRiskEval assesses models' virus understanding through three lenses, including sequence modeling, mutational effects prediction, and virulence prediction. Our results show that current filtering practices may not be particularly effective: Excluded knowledge can be rapidly recovered in some cases via fine-tuning, and exhibits broader generalizability in sequence modeling. Furthermore, dual-use signals may already reside in the pretrained representations, and can be elicited via simple linear probing. These findings highlight the challenges of data filtering as a standalone procedure, underscoring the need for further research into robust safety and security strategies for open-weight bio-foundation models.

Antibodies are proteins produced by the immune system that can identify and neutralise a wide variety of antigens with high specificity and affinity, and constitute the most successful class of biotherapeutics. With the advent of next-generation sequencing, billions of antibody sequences have been collected in recent years, though their application in the design of better therapeutics has been constrained by the sheer volume and complexity of the data. To address this challenge, we present IgBert and IgT5, the best performing antibody-specific language models developed to date which can consistently handle both paired and unpaired variable region sequences as input. These models are trained comprehensively using the more than two billion unpaired sequences and two million paired sequences of light and heavy chains present in the Observed Antibody Space dataset. We show that our models outperform existing antibody and protein language models on a diverse range of design and regression tasks relevant to antibody engineering. This advancement marks a significant leap forward in leveraging machine learning, large scale data sets and high-performance computing for enhancing antibody design for therapeutic development.

Protein fitness optimization involves finding a protein sequence that maximizes desired quantitative properties in a combinatorially large design space of possible sequences. Recent developments in steering protein generative models (e.g diffusion models, language models) offer a promising approach. However, by and large, past studies have optimized surrogate rewards and/or utilized large amounts of labeled data for steering, making it unclear how well existing methods perform and compare to each other in real-world optimization campaigns where fitness is measured by low-throughput wet-lab assays. In this study, we explore fitness optimization using small amounts (hundreds) of labeled sequence-fitness pairs and comprehensively evaluate strategies such as classifier guidance and posterior sampling for guiding generation from different discrete diffusion models of protein sequences. We also demonstrate how guidance can be integrated into adaptive sequence selection akin to Thompson sampling in Bayesian optimization, showing that plug-and-play guidance strategies offer advantages compared to alternatives such as reinforcement learning with protein language models.

PROTACs are a promising therapeutic modality that harnesses the cell's built-in degradation machinery to degrade specific proteins. Despite their potential, developing new PROTACs is challenging and requires significant domain expertise, time, and cost. Meanwhile, machine learning has transformed drug design and development. In this work, we present a strategy for curating open-source PROTAC data and an open-source deep learning tool for predicting the degradation activity of novel PROTAC molecules. The curated dataset incorporates important information such as pDC_{50}, D_{max}, E3 ligase type, POI amino acid sequence, and experimental cell type. Our model architecture leverages learned embeddings from pretrained machine learning models, in particular for encoding protein sequences and cell type information. We assessed the quality of the curated data and the generalization ability of our model architecture against new PROTACs and targets via three tailored studies, which we recommend other researchers to use in evaluating their degradation activity models. In each study, three models predict protein degradation in a majority vote setting, reaching a top test accuracy of 82.6% and 0.848 ROC AUC, and a test accuracy of 61% and 0.615 ROC AUC when generalizing to novel protein targets. Our results are not only comparable to state-of-the-art models for protein degradation prediction, but also part of an open-source implementation which is easily reproducible and less computationally complex than existing approaches.

We describe the accurate prediction of ligand-protein interaction (LPI) affinities, also known as drug-target interactions (DTI), with instruction fine-tuned pretrained generative small language models (SLMs). We achieved accurate predictions for a range of affinity values associated with ligand-protein interactions on out-of-sample data in a zero-shot setting. Only the SMILES string of the ligand and the amino acid sequence of the protein were used as the model inputs. Our results demonstrate a clear improvement over machine learning (ML) and free-energy perturbation (FEP+) based methods in accurately predicting a range of ligand-protein interaction affinities, which can be leveraged to further accelerate drug discovery campaigns against challenging therapeutic targets.

Current computational approaches for drug design typically focus on generating molecules conditioned on specific targets or general molecular properties, often neglecting the influence of disease context on target behavior and therapeutic outcomes. To address this gap, we introduce DrugGen-2, a novel generative model that designs small molecules conditioned on both disease ontology and target protein sequences. DrugGen-2 was developed by fine-tuning a pre-trained GPT-2 model on a curated dataset of approved drugs linked to their diseases and targets, using a two-step strategy of supervised fine-tuning followed by reinforcement learning via group relative policy optimization (GRPO). This process was guided by reward functions optimizing for chemical validity, novelty, diversity, and high predicted binding affinity. When evaluated on five protein targets relevant to diabetic nephropathy, DrugGen-2 significantly outperformed baseline models (DrugGPT and DrugGen). It demonstrated a superior capacity to generate unique molecules, exhibited greater structural similarity to approved drugs, and achieved improved predicted binding affinities across all targets. Molecular docking analyses further supported these findings, identifying candidate ligands with strong binding potential, including compounds with predicted affinities (-9.917, -9.485, and -9.367) exceeding those of reference drugs such as enalapril for angiotensin-converting enzyme (-8.283). By integrating disease-specific context into molecular generation, DrugGen-2 advances AI-assisted drug discovery, offering a powerful tool for de novo design and drug repurposing that accounts for the complex interplay between diseases and molecular targets.

Peptide therapeutics, a major class of medicines, have achieved remarkable success across diseases such as diabetes and cancer, with landmark examples such as GLP-1 receptor agonists revolutionizing the treatment of type-2 diabetes and obesity. Despite their success, designing peptides that satisfy multiple conflicting objectives, such as target binding affinity, solubility, and membrane permeability, remains a major challenge. Classical drug development and structure-based design are ineffective for such tasks, as they fail to optimize global functional properties critical for therapeutic efficacy. Existing generative frameworks are largely limited to continuous spaces, unconditioned outputs, or single-objective guidance, making them unsuitable for discrete sequence optimization across multiple properties. To address this, we present PepTune, a multi-objective discrete diffusion model for the simultaneous generation and optimization of therapeutic peptide SMILES. Built on the Masked Discrete Language Model (MDLM) framework, PepTune ensures valid peptide structures with state-dependent masking schedules and penalty-based objectives. To guide the diffusion process, we propose a Monte Carlo Tree Search (MCTS)-based strategy that balances exploration and exploitation to iteratively refine Pareto-optimal sequences. MCTS integrates classifier-based rewards with search-tree expansion, overcoming gradient estimation challenges and data sparsity inherent to discrete spaces. Using PepTune, we generate diverse, chemically-modified peptides optimized for multiple therapeutic properties, including target binding affinity, membrane permeability, solubility, hemolysis, and non-fouling characteristics on various disease-relevant targets. In total, our results demonstrate that MCTS-guided discrete diffusion is a powerful and modular approach for multi-objective sequence design in discrete state spaces.

Tandem mass spectrometry has played a pivotal role in advancing proteomics, enabling the high-throughput analysis of protein composition in biological tissues. Many deep learning methods have been developed for de novo peptide sequencing task, i.e., predicting the peptide sequence for the observed mass spectrum. However, two key challenges seriously hinder the further advancement of this important task. Firstly, since there is no consensus for the evaluation datasets, the empirical results in different research papers are often not comparable, leading to unfair comparison. Secondly, the current methods are usually limited to amino acid-level or peptide-level precision and recall metrics. In this work, we present the first unified benchmark NovoBench for de novo peptide sequencing, which comprises diverse mass spectrum data, integrated models, and comprehensive evaluation metrics. Recent impressive methods, including DeepNovo, PointNovo, Casanovo, InstaNovo, AdaNovo and pi-HelixNovo are integrated into our framework. In addition to amino acid-level and peptide-level precision and recall, we evaluate the models' performance in terms of identifying post-tranlational modifications (PTMs), efficiency and robustness to peptide length, noise peaks and missing fragment ratio, which are important influencing factors while seldom be considered. Leveraging this benchmark, we conduct a large-scale study of current methods, report many insightful findings that open up new possibilities for future development.

Language model finetuning often results in learning undesirable traits in combination with desired ones. To address this, we propose inoculation prompting: modifying finetuning data by prepending a short system-prompt instruction that deliberately elicits the undesirable trait. At test time, we evaluate without the instruction; inoculated models have much lower expression of the trait than models trained with unmodified training data. Inoculation is selective: in a toy setting where assistant responses are always in Spanish and ALL-CAPS, an appropriate inoculation (e.g., ``You always speak in Spanish.'') teaches the model to capitalize responses while still responding in English. We find that inoculation is also effective across several additional settings: reducing emergent misalignment (EM) from task-specific finetuning, defending against backdoor injections, and mitigating the transmission of traits via subliminal learning. Follow-up analysis suggests a mechanism: making a trait less surprising via inoculation reduces optimization pressure to globally update the model, thereby reducing the degree of generalization. Our analysis relates to prior work on EM: inoculation explains prior findings that educational contexts mitigate EM from insecure code. Beyond demonstrating a simple and effective technique for selective learning, our results contribute to a better conceptual understanding of how and why language models generalize.

Generalization beyond training data remains a central challenge in machine learning for biology. A common way to enhance generalization is self-supervised pre-training on large datasets. However, aiming to perform well on all possible proteins can limit a model's capacity to excel on any specific one, whereas experimentalists typically need accurate predictions for individual proteins they study, often not covered in training data. To address this limitation, we propose a method that enables self-supervised customization of protein language models to one target protein at a time, on the fly, and without assuming any additional data. We show that our Protein Test-Time Training (ProteinTTT) method consistently enhances generalization across different models, their sizes, and datasets. ProteinTTT improves structure prediction for challenging targets, achieves new state-of-the-art results on protein fitness prediction, and enhances function prediction on two tasks. Through two challenging case studies, we also show that customization via ProteinTTT achieves more accurate antibody-antigen loop modeling and enhances 19% of structures in the Big Fantastic Virus Database, delivering improved predictions where general-purpose AlphaFold2 and ESMFold struggle.

The widespread applicability and increasing omnipresence of LLMs have instigated a need to align LLM responses to user and stakeholder preferences. Many preference optimization approaches have been proposed that fine-tune LLM parameters to achieve good alignment. However, such parameter tuning is known to interfere with model performance on many tasks. Moreover, keeping up with shifting user preferences is tricky in such a situation. Decoding-time alignment with reward model guidance solves these issues at the cost of increased inference time. However, most of such methods fail to strike the right balance between exploration and exploitation of reward -- often due to the conflated formulation of these two aspects - to give well-aligned responses. To remedy this we decouple these two aspects and implement them in an evolutionary fashion: exploration is enforced by decoding from mutated instructions and exploitation is represented as the periodic replacement of poorly-rewarded generations with well-rewarded ones. Empirical evidences indicate that this strategy outperforms many preference optimization and decode-time alignment approaches on two widely accepted alignment benchmarks AlpacaEval 2 and MT-Bench. Our implementation will be available at: https://darwin-alignment.github.io.

Precision therapeutics require multimodal adaptive models that generate personalized treatment recommendations. We introduce TxAgent, an AI agent that leverages multi-step reasoning and real-time biomedical knowledge retrieval across a toolbox of 211 tools to analyze drug interactions, contraindications, and patient-specific treatment strategies. TxAgent evaluates how drugs interact at molecular, pharmacokinetic, and clinical levels, identifies contraindications based on patient comorbidities and concurrent medications, and tailors treatment strategies to individual patient characteristics. It retrieves and synthesizes evidence from multiple biomedical sources, assesses interactions between drugs and patient conditions, and refines treatment recommendations through iterative reasoning. It selects tools based on task objectives and executes structured function calls to solve therapeutic tasks that require clinical reasoning and cross-source validation. The ToolUniverse consolidates 211 tools from trusted sources, including all US FDA-approved drugs since 1939 and validated clinical insights from Open Targets. TxAgent outperforms leading LLMs, tool-use models, and reasoning agents across five new benchmarks: DrugPC, BrandPC, GenericPC, TreatmentPC, and DescriptionPC, covering 3,168 drug reasoning tasks and 456 personalized treatment scenarios. It achieves 92.1% accuracy in open-ended drug reasoning tasks, surpassing GPT-4o and outperforming DeepSeek-R1 (671B) in structured multi-step reasoning. TxAgent generalizes across drug name variants and descriptions. By integrating multi-step inference, real-time knowledge grounding, and tool-assisted decision-making, TxAgent ensures that treatment recommendations align with established clinical guidelines and real-world evidence, reducing the risk of adverse events and improving therapeutic decision-making.

To control the behavior of language models, steering methods attempt to ensure that outputs of the model satisfy specific pre-defined properties. Adding steering vectors to the model is a promising method of model control that is easier than finetuning, and may be more robust than prompting. However, it can be difficult to anticipate the effects of steering vectors produced by almost all existing methods, such as CAA (Panickssery et al., 2024) or the direct use of SAE latents (Templeton et al., 2024). In our work, we address this issue by using SAEs to measure the effects of steering vectors, giving us a method that can be used to understand the causal effect of any steering vector intervention. We use this method for measuring causal effects to develop an improved steering method, SAE-Targeted Steering (SAE-TS), which finds steering vectors to target specific SAE features while minimizing unintended side effects. We show that overall, SAE-TS balances steering effects with coherence better than CAA and SAE feature steering, when evaluated on a range of tasks.

Planning effective interventions in biological systems requires treatment-effect models that adapt to unseen biological contexts by identifying their specific underlying mechanisms. Yet single-cell perturbation datasets span only a handful of biological contexts, and existing methods cannot leverage new interventional evidence at inference time to adapt beyond their training data. To meta-learn a perturbation effect estimator, we present MapPFN, a prior-data fitted network (PFN) pretrained on synthetic data generated from a prior over causal perturbations. Given a set of experiments, MapPFN uses in-context learning to predict post-perturbation distributions, without gradient-based optimization. Despite being pretrained on in silico gene knockouts alone, MapPFN identifies differentially expressed genes, matching the performance of models trained on real single-cell data. Our code and data are available at https://github.com/marvinsxtr/MapPFN.

Therapeutic mRNA design requires coordinating multiple interacting sequence features across the full transcript, where codon usage, untranslated regions (UTRs), and their coupling jointly determine stability, translation efficiency, and protein expression. Here, we present mRNA generation via unrolled trajectories and informed latent updates (mRNAutilus), a framework for simultaneous codon optimization and de novo UTR design directly from sequence. mRNAutilus combines a masked discrete diffusion model trained on millions of full-length mRNAs with Monte Carlo Tree Guidance to generate Pareto-efficient sequences under multiple functional objectives, using lightweight regressors over model embeddings to predict half-life, translation efficiency, and protein abundance. Unlike recent methods that design coding sequences and UTRs separately or rely on post hoc assembly and screening, mRNAutilus generates complete transcripts in a single process optimized across properties. Across diverse targets, zero-shot mRNAs encoding P. pyralis luciferase achieve over 400-fold higher expression than wild-type and outperform commercial and machine learning-designed baselines, including zero-shot generative approaches. Zero-shot SARS-CoV-2 Spike mRNAs exceed clinically used and commercial constructs and match or surpass lab-optimized designs with improved durability. We further demonstrate generality in therapeutic settings, including prime editing (PEMax) and programmable proteome modulation, where mRNAutilus-designed constructs enhance expression of peptide-guided E3 ligases (uAbs) for beta-catenin degradation. These results establish a sequence-based, multi-objective framework for generating functional mRNAs tailored to diverse biological applications.

Antibody design is an essential yet challenging task in various domains like therapeutics and biology. There are two major defects in current learning-based methods: 1) tackling only a certain subtask of the whole antibody design pipeline, making them suboptimal or resource-intensive. 2) omitting either the framework regions or side chains, thus incapable of capturing the full-atom geometry. To address these pitfalls, we propose dynamic Multi-channel Equivariant grAph Network (dyMEAN), an end-to-end full-atom model for E(3)-equivariant antibody design given the epitope and the incomplete sequence of the antibody. Specifically, we first explore structural initialization as a knowledgeable guess of the antibody structure and then propose shadow paratope to bridge the epitope-antibody connections. Both 1D sequences and 3D structures are updated via an adaptive multi-channel equivariant encoder that is able to process protein residues of variable sizes when considering full atoms. Finally, the updated antibody is docked to the epitope via the alignment of the shadow paratope. Experiments on epitope-binding CDR-H3 design, complex structure prediction, and affinity optimization demonstrate the superiority of our end-to-end framework and full-atom modeling.

Integrating Large Language Models (LLMs) with Knowledge Graphs (KGs) results in complex systems with numerous hyperparameters that directly affect performance. While such systems are increasingly common in retrieval-augmented generation, the role of systematic hyperparameter optimization remains underexplored. In this paper, we study this problem in the context of Cognee, a modular framework for end-to-end KG construction and retrieval. Using three multi-hop QA benchmarks (HotPotQA, TwoWikiMultiHop, and MuSiQue) we optimize parameters related to chunking, graph construction, retrieval, and prompting. Each configuration is scored using established metrics (exact match, F1, and DeepEval's LLM-based correctness metric). Our results demonstrate that meaningful gains can be achieved through targeted tuning. While the gains are consistent, they are not uniform, with performance varying across datasets and metrics. This variability highlights both the value of tuning and the limitations of standard evaluation measures. While demonstrating the immediate potential of hyperparameter tuning, we argue that future progress will depend not only on architectural advances but also on clearer frameworks for optimization and evaluation in complex, modular systems.

Nowadays, developers increasingly rely on solutions powered by Large Language Models (LLM) to assist them with their coding tasks. This makes it crucial to align these tools with human values to prevent malicious misuse. In this paper, we propose a comprehensive framework for assessing the potential harmfulness of LLMs within the software engineering domain. We begin by developing a taxonomy of potentially harmful software engineering scenarios and subsequently, create a dataset of prompts based on this taxonomy. To systematically assess the responses, we design and validate an automatic evaluator that classifies the outputs of a variety of LLMs both open-source and closed-source models, as well as general-purpose and code-specific LLMs. Furthermore, we investigate the impact of models size, architecture family, and alignment strategies on their tendency to generate harmful content. The results show significant disparities in the alignment of various LLMs for harmlessness. We find that some models and model families, such as Openhermes, are more harmful than others and that code-specific models do not perform better than their general-purpose counterparts. Notably, some fine-tuned models perform significantly worse than their base-models due to their design choices. On the other side, we find that larger models tend to be more helpful and are less likely to respond with harmful information. These results highlight the importance of targeted alignment strategies tailored to the unique challenges of software engineering tasks and provide a foundation for future work in this critical area.

Hit-like molecular generation with therapeutic potential is essential for target-specific drug discovery. However, the field lacks heterogeneous data and unified frameworks for integrating diverse molecular representations. To bridge this gap, we introduce TextOmics, a pioneering benchmark that establishes one-to-one correspondences between omics expressions and molecular textual descriptions. TextOmics provides a heterogeneous dataset that facilitates molecular generation through representations alignment. Built upon this foundation, we propose ToDi, a generative framework that jointly conditions on omics expressions and molecular textual descriptions to produce biologically relevant, chemically valid, hit-like molecules. ToDi leverages two encoders (OmicsEn and TextEn) to capture multi-level biological and semantic associations, and develops conditional diffusion (DiffGen) for controllable generation. Extensive experiments confirm the effectiveness of TextOmics and demonstrate ToDi outperforms existing state-of-the-art approaches, while also showcasing remarkable potential in zero-shot therapeutic molecular generation. Sources are available at: https://github.com/hala-ToDi.

We introduce BM25S, an efficient Python-based implementation of BM25 that only depends on Numpy and Scipy. BM25S achieves up to a 500x speedup compared to the most popular Python-based framework by eagerly computing BM25 scores during indexing and storing them into sparse matrices. It also achieves considerable speedups compared to highly optimized Java-based implementations, which are used by popular commercial products. Finally, BM25S reproduces the exact implementation of five BM25 variants based on Kamphuis et al. (2020) by extending eager scoring to non-sparse variants using a novel score shifting method. The code can be found at https://github.com/xhluca/bm25s

Drug discovery typically consists of multiple steps, including identifying a target protein key to a disease's etiology, validating that interacting with this target could prevent symptoms or cure the disease, discovering a small molecule or biologic therapeutic to interact with it, and optimizing the candidate molecule through a complex landscape of required properties. Drug discovery related tasks often involve prediction and generation while considering multiple entities that potentially interact, which poses a challenge for typical AI models. For this purpose we present MAMMAL - Molecular Aligned Multi-Modal Architecture and Language - a method that we applied to create a versatile multi-task foundation model ibm/biomed.omics.bl.sm.ma-ted-458m that learns from large-scale biological datasets (2 billion samples) across diverse modalities, including proteins, small molecules, and genes. We introduce a prompt syntax that supports a wide range of classification, regression, and generation tasks. It allows combining different modalities and entity types as inputs and/or outputs. Our model handles combinations of tokens and scalars and enables the generation of small molecules and proteins, property prediction, and transcriptomic lab test predictions. We evaluated the model on 11 diverse downstream tasks spanning different steps within a typical drug discovery pipeline, where it reaches new SOTA in 9 tasks and is comparable to SOTA in 2 tasks. This performance is achieved while using a unified architecture serving all tasks, in contrast to the original SOTA performance achieved using tailored architectures. The model code and pretrained weights are publicly available at https://github.com/BiomedSciAI/biomed-multi-alignment and https://huggingface.co/ibm/biomed.omics.bl.sm.ma-ted-458m.

Sequence generative models are transforming protein engineering. However, no principled framework exists for conditioning these models on auxiliary information, such as experimental data, without additional training of a generative model. Herein, we present ProteinGuide, a method for such "on-the-fly" conditioning, amenable to a broad class of protein generative models including Masked Language Models (e.g. ESM3), any-order auto-regressive models (e.g. ProteinMPNN) as well as diffusion and flow matching models (e.g. MultiFlow). ProteinGuide stems from our unifying view of these model classes under a single statistical framework. As proof of principle, we perform several in silico experiments. We first guide pre-trained generative models to design proteins with user-specified properties, such as higher stability or activity. Next, we design for optimizing two desired properties that are in tension with each other. Finally, we apply our method in the wet lab, using ProteinGuide to increase the editing activity of an adenine base editor in vivo with data from only a single pooled library of 2,000 variants. We find that a single round of ProteinGuide achieves a higher editing efficiency than was previously achieved using seven rounds of directed evolution.

The objective of personalized medicine is to tailor interventions to an individual patient's unique characteristics. A key technology for this purpose involves medical digital twins, computational models of human biology that can be personalized and dynamically updated to incorporate patient-specific data collected over time. Certain aspects of human biology, such as the immune system, are not easily captured with physics-based models, such as differential equations. Instead, they are often multi-scale, stochastic, and hybrid. This poses a challenge to existing model-based control and optimization approaches that cannot be readily applied to such models. Recent advances in automatic differentiation and neural-network control methods hold promise in addressing complex control problems. However, the application of these approaches to biomedical systems is still in its early stages. This work introduces dynamics-informed neural-network controllers as an alternative approach to control of medical digital twins. As a first use case for this method, the focus is on agent-based models, a versatile and increasingly common modeling platform in biomedicine. The effectiveness of the proposed neural-network control method is illustrated and benchmarked against other methods with two widely-used agent-based model types. The relevance of the method introduced here extends beyond medical digital twins to other complex dynamical systems.

Structure-Based molecule optimization (SBMO) aims to optimize molecules with both continuous coordinates and discrete types against protein targets. A promising direction is to exert gradient guidance on generative models given its remarkable success in images, but it is challenging to guide discrete data and risks inconsistencies between modalities. To this end, we leverage a continuous and differentiable space derived through Bayesian inference, presenting Molecule Joint Optimization (MolJO), the gradient-based SBMO framework that facilitates joint guidance signals across different modalities while preserving SE(3)-equivariance. We introduce a novel backward correction strategy that optimizes within a sliding window of the past histories, allowing for a seamless trade-off between explore-and-exploit during optimization. MolJO achieves state-of-the-art performance on CrossDocked2020 benchmark (Success Rate 51.3%, Vina Dock -9.05 and SA 0.78), more than 4x improvement in Success Rate compared to the gradient-based counterpart, and 2x "Me-Better" Ratio as much as 3D baselines. Furthermore, we extend MolJO to a wide range of optimization settings, including multi-objective optimization and challenging tasks in drug design such as R-group optimization and scaffold hopping, further underscoring its versatility. Code is available at https://github.com/AlgoMole/MolCRAFT.

Recent advancements in conversational large language models (LLMs), such as ChatGPT, have demonstrated remarkable promise in various domains, including drug discovery. However, existing works mainly focus on investigating the capabilities of conversational LLMs on chemical reaction and retrosynthesis. While drug editing, a critical task in the drug discovery pipeline, remains largely unexplored. To bridge this gap, we propose ChatDrug, a framework to facilitate the systematic investigation of drug editing using LLMs. ChatDrug jointly leverages a prompt module, a retrieval and domain feedback (ReDF) module, and a conversation module to streamline effective drug editing. We empirically show that ChatDrug reaches the best performance on 33 out of 39 drug editing tasks, encompassing small molecules, peptides, and proteins. We further demonstrate, through 10 case studies, that ChatDrug can successfully identify the key substructures (e.g., the molecule functional groups, peptide motifs, and protein structures) for manipulation, generating diverse and valid suggestions for drug editing. Promisingly, we also show that ChatDrug can offer insightful explanations from a domain-specific perspective, enhancing interpretability and enabling informed decision-making. This research sheds light on the potential of ChatGPT and conversational LLMs for drug editing. It paves the way for a more efficient and collaborative drug discovery pipeline, contributing to the advancement of pharmaceutical research and development.

We present an approach to mitigating the risks of malicious image editing posed by large diffusion models. The key idea is to immunize images so as to make them resistant to manipulation by these models. This immunization relies on injection of imperceptible adversarial perturbations designed to disrupt the operation of the targeted diffusion models, forcing them to generate unrealistic images. We provide two methods for crafting such perturbations, and then demonstrate their efficacy. Finally, we discuss a policy component necessary to make our approach fully effective and practical -- one that involves the organizations developing diffusion models, rather than individual users, to implement (and support) the immunization process.

Saliency maps are increasingly used as design guidance in siRNA efficacy prediction, yet attribution methods are rarely validated before motivating sequence edits. We introduce a pre-synthesis gate: a protocol for counterfactual sensitivity faithfulness that tests whether mutating high-saliency positions changes model output more than composition-matched controls. Cross-dataset transfer reveals two failure modes that would otherwise go undetected: faithful-but-wrong (saliency valid, predictions fail) and inverted saliency (top-saliency edits less impactful than random). Strikingly, models trained on mRNA-level assays collapse on a luciferase reporter dataset, demonstrating that protocol shifts can silently invalidate deployment. Across four benchmarks, 19/20 fold instances pass; the single failure shows inverted saliency. A biology-informed regularizer (BioPrior) strengthens saliency faithfulness with modest, dataset-dependent predictive trade-offs. Our results establish saliency validation as essential pre-deployment practice for explanation-guided therapeutic design. Code is available at https://github.com/shadi97kh/BioPrior.

In real-world drug design, molecule optimization requires selectively improving multiple molecular properties up to pharmaceutically relevant levels, while maintaining others that already meet such criteria. However, existing computational approaches and instruction-tuned LLMs fail to capture such nuanced property-specific objectives, limiting their practical applicability. To address this, we introduce C-MuMOInstruct, the first instruction-tuning dataset focused on multi-property optimization with explicit, property-specific objectives. Leveraging C-MuMOInstruct, we develop GeLLMO-Cs, a series of instruction-tuned LLMs that can perform targeted property-specific optimization. Our experiments across 5 in-distribution and 5 out-of-distribution tasks show that GeLLMO-Cs consistently outperform strong baselines, achieving up to 126% higher success rate. Notably, GeLLMO-Cs exhibit impressive 0-shot generalization to novel optimization tasks and unseen instructions. This offers a step toward a foundational LLM to support realistic, diverse optimizations with property-specific objectives. C-MuMOInstruct and code are accessible through https://github.com/ninglab/GeLLMO-C.

We propose several small modifications to Duet---a deep neural ranking model---and evaluate the updated model on the MS MARCO passage ranking task. We report significant improvements from the proposed changes based on an ablation study.

This paper investigates using knowledge editing techniques to detoxify Large Language Models (LLMs). We construct a benchmark, SafeEdit, which covers nine unsafe categories with various powerful attack prompts and equips comprehensive metrics for systematic evaluation. We conduct experiments to compare knowledge editing approaches with previous baselines, indicating that knowledge editing has the potential to efficiently detoxify LLMs with limited impact on general performance. Then, we propose a simple yet effective baseline, dubbed Detoxifying with Intraoperative Neural Monitoring (DINM), to diminish the toxicity of LLMs within a few tuning steps via only one instance. We further provide an in-depth analysis of the internal mechanism for various detoxify approaches, demonstrating that previous methods like SFT and DPO may merely suppress the activations of toxic parameters, while DINM mitigates the toxicity of the toxic parameters to a certain extent, making permanent adjustments. We hope that these insights could shed light on future work of developing detoxifying approaches and the underlying knowledge mechanisms of LLMs. Code and benchmark are available at https://github.com/zjunlp/EasyEdit.

Large Language Models (LLMs) are increasingly deployed via third-party system prompts downloaded from public marketplaces. We identify a critical supply-chain vulnerability: conditional system prompt poisoning, where an adversary injects a ``sleeper agent'' into a benign-looking prompt. Unlike traditional jailbreaks that aim for broad refusal-breaking, our proposed framework, SPECTRE, optimizes system prompts to trigger LLMs to output targeted, compromised responses only for specific queries (e.g., ``Who should I vote for the US President?'') while maintaining high utility on benign inputs. Operating in a strict black-box setting without model weight access, SPECTRE utilizes a two-stage optimization including a global semantic search followed by a greedy lexical refinement. Tested on open-source models and commercial APIs (GPT-4o-mini, GPT-3.5), SPECTRE achieves up to 70% F1 reduction on targeted queries with minimal degradation to general capabilities. We further demonstrate that these poisoned prompts evade standard defenses, including perplexity filters and typo-correction, by exploiting the natural noise found in real-world system prompts. Our code and data are available at https://github.com/vietph34/CAIN. WARNING: Our paper contains examples that might be sensitive to the readers!

Ribosomally synthesized and post-translationally modified peptide (RiPP) biosynthetic enzymes often exhibit promiscuous substrate preferences that cannot be reduced to simple rules. Large language models are promising tools for predicting such peptide fitness landscapes. However, state-of-the-art protein language models are trained on relatively few peptide sequences. A previous study comprehensively profiled the peptide substrate preferences of LazBF (a two-component serine dehydratase) and LazDEF (a three-component azole synthetase) from the lactazole biosynthetic pathway. We demonstrated that masked language modeling of LazBF substrate preferences produced language model embeddings that improved downstream classification models of both LazBF and LazDEF substrates. Similarly, masked language modeling of LazDEF substrate preferences produced embeddings that improved the performance of classification models of both LazBF and LazDEF substrates. Our results suggest that the models learned functional forms that are transferable between distinct enzymatic transformations that act within the same biosynthetic pathway. Our transfer learning method improved performance and data efficiency in data-scarce scenarios. We then fine-tuned models on each data set and showed that the fine-tuned models provided interpretable insight that we anticipate will facilitate the design of substrate libraries that are compatible with desired RiPP biosynthetic pathways.

Flow matching in the continuous simplex has emerged as a promising strategy for DNA sequence design, but struggles to scale to higher simplex dimensions required for peptide and protein generation. We introduce Gumbel-Softmax Flow and Score Matching, a generative framework on the simplex based on a novel Gumbel-Softmax interpolant with a time-dependent temperature. Using this interpolant, we introduce Gumbel-Softmax Flow Matching by deriving a parameterized velocity field that transports from smooth categorical distributions to distributions concentrated at a single vertex of the simplex. We alternatively present Gumbel-Softmax Score Matching which learns to regress the gradient of the probability density. Our framework enables high-quality, diverse generation and scales efficiently to higher-dimensional simplices. To enable training-free guidance, we propose Straight-Through Guided Flows (STGFlow), a classifier-based guidance method that leverages straight-through estimators to steer the unconditional velocity field toward optimal vertices of the simplex. STGFlow enables efficient inference-time guidance using classifiers pre-trained on clean sequences, and can be used with any discrete flow method. Together, these components form a robust framework for controllable de novo sequence generation. We demonstrate state-of-the-art performance in conditional DNA promoter design, sequence-only protein generation, and target-binding peptide design for rare disease treatment.

Controlled text perturbation is useful for evaluating and improving model generalizability. However, current techniques rely on training a model for every target perturbation, which is expensive and hard to generalize. We present Tailor, a semantically-controlled text generation system. Tailor builds on a pretrained seq2seq model and produces textual outputs conditioned on control codes derived from semantic representations. We craft a set of operations to modify the control codes, which in turn steer generation towards targeted attributes. These operations can be further composed into higher-level ones, allowing for flexible perturbation strategies. We demonstrate the effectiveness of these perturbations in multiple applications. First, we use Tailor to automatically create high-quality contrast sets for four distinct natural language processing (NLP) tasks. These contrast sets contain fewer spurious artifacts and are complementary to manually annotated ones in their lexical diversity. Second, we show that Tailor perturbations can improve model generalization through data augmentation. Perturbing just 2% of training data leads to a 5.8-point gain on an NLI challenge set measuring reliance on syntactic heuristics.

Chemical similarity searches are widely used in-silico methods for identifying new drug-like molecules. These methods have historically relied on structure-based comparisons to compute molecular similarity. Here, we use a chemical language model to create a vector-based chemical search. We extend implementations by creating a prompt engineering strategy that utilizes two different chemical string representation algorithms: one for the query and the other for the database. We explore this method by reviewing the search results from five drug-like query molecules (penicillin G, nirmatrelvir, zidovudine, lysergic acid diethylamide, and fentanyl) and three dye-like query molecules (acid blue 25, avobenzone, and 2-diphenylaminocarbazole). We find that this novel method identifies molecules that are functionally similar to the query, indicated by the associated patent literature, and that many of these molecules are structurally distinct from the query, making them unlikely to be found with traditional chemical similarity search methods. This method may aid in the discovery of novel structural classes of molecules that achieve target functionality.

Large Language Models (LLMs) and Vision Language Models (VLMs) have recently shown promising capabilities in various scientific domain. In particular, these advances have opened new opportunities in drug discovery, where the ability to understand and modify molecular structures is critical for optimizing drug properties such as efficacy and toxicity. However, existing models and benchmarks often overlook toxicity-related challenges, focusing primarily on general property optimization without adequately addressing safety concerns. In addition, even existing toxicity repair benchmarks suffer from limited data diversity, low structural validity of generated molecules, and heavy reliance on proxy models for toxicity assessment. To address these limitations, we propose MolDeTox, a novel benchmark for molecular detoxification, designed to enable fine-grained and reliable evaluation of toxicity-aware molecular optimization across stepwise tasks. We evaluate a wide range of general-purpose LLMs and VLMs under diverse settings, and demonstrate that understanding and generating molecules at the fragment-level improves structural validity and enhances the quality of generated molecules. Moreover, through detailed task-level performance analysis, MolDeTox provides an interpretable benchmark that enables a deeper understanding of the detoxification process. Our dataset is available at : https://huggingface.co/datasets/MolDeTox/MolDeTox

Controlled text generation is very important for the practical use of language models because it ensures that the produced text includes only the desired attributes from a specific domain or dataset. Existing methods, however, are inapplicable to black-box models or suffer a significant trade-off between controlling the generated text and maintaining its fluency. This paper introduces the Score-based Progressive Editor (ScoPE), a novel approach designed to overcome these issues. ScoPE modifies the context at the token level during the generation process of a backbone language model. This modification guides the subsequent text to naturally include the target attributes. To facilitate this process, ScoPE employs a training objective that maximizes a target score, thoroughly considering both the ability to guide the text and its fluency. Experimental results on diverse controlled generation tasks demonstrate that ScoPE can effectively regulate the attributes of the generated text while fully utilizing the capability of the backbone large language models. Our codes are available at https://github.com/ysw1021/ScoPE.

Large language models are sometimes trained with imperfect oversight signals, leading to undesired behaviors such as reward hacking and sycophancy. Improving oversight quality can be expensive or infeasible, motivating methods that improve learned behavior despite an imperfect training signal. We introduce Inoculation Prompting (IP), a simple but counterintuitive technique that prevents learning of an undesired behavior by modifying training prompts to explicitly request it. For example, to inoculate against reward hacking, we modify the prompts used in supervised fine-tuning to request code that only works on provided test cases but fails on other inputs. Across four settings we find that IP reduces the learning of undesired behavior without substantially reducing the learning of desired capabilities. We also show that prompts which more strongly elicit the undesired behavior prior to fine-tuning more effectively inoculate against the behavior when used during training; this serves as a heuristic to identify promising inoculation prompts. Overall, IP is a simple yet effective way to control how models generalize from fine-tuning, preventing learning of undesired behaviors without substantially disrupting desired capabilities.