Leveraging generative hallucination and biophysics-informed modeling for unified biomolecular sequence-structure co-design

Biomolecular design underpins applications from molecular recognition to therapeutics and synthetic biology, yet de novo interaction design remains challenging-especially for DNA/RNA, underexplored non-protein modalities with scarce, heterogeneous complex data and sharper geometric and chemical constraints. We introduce MCTH (Monte Carlo Tree Hallucination), an inference-only framework that casts all-atom sequence-structure co-design as uncertainty-aware planning over hallucinated states from pretrained folding and inverse-folding models, with optional biophysical control within the same decision loop. MCTH treats these models as frozen black-box operators and uses Monte Carlo Tree Search to allocate a fixed inference budget across competing design trajectories, incorporating model confidence and uncertainty, as well as cross-expert consensus/disagreement when multiple predictors are available. Across protein-RNA, protein-DNA, protein-protein, and protein-ligand design, matched-budget experiments show that adaptive search improves over simpler sampling and cycling strategies, while held-out AlphaFold3 and Chai-1 evaluations demonstrate transfer beyond the search-time oracle. MCTH provides a shared planning layer across modalities while allowing task-specific folding, inverse-folding, and biophysical modules, requiring no fine-tuning or backpropagation through component models.

DL-SLAM: Enabling High-Fidelity Gaussian Splatting SLAM in Dynamic Environments based on Dual-Level Probability

Recent advances in 3D Gaussian Splatting (3DGS) have enabled significant progress in dense dynamic Simultaneous Localization And Mapping (SLAM). Prevailing methods typically discard predefined dynamic objects, ignoring that transiently static objects offer valuable geometric constraints for pose estimation. A recent work attempts to leverage this potential by employing per-pixel uncertainty maps to quantify the magnitude of motion. While this approach enables transiently static objects to enhance pose estimation, it erroneously integrates these objects into the static map, resulting in persistent artifacts. Moreover, its reliance on purely geometric information leads to ambiguous object boundaries in the uncertainty maps. To overcome these limitations, we present DL-SLAM, a monocular Gaussian Splatting SLAM system built upon a novel dual-level probabilistic framework. Our method computes dynamic probability maps by combining semantic and geometric information. These pixel-level probabilities are lifted to 3D and aggregated to derive an object-level dynamic probability for each instance. Object-level probability enables the categorical pruning of dynamic Gaussians, resulting in an artifact-free static map. The static map, in turn, provides a geometrically consistent guidance to refine the pixel-wise probabilities, enhancing their reliability. Experimental results demonstrate that DL-SLAM outperforms existing approaches, improving tracking accuracy by up to 13\% while generating high-fidelity semantic maps.

Active-GRPO: Adaptive Imitation and Self-Improving Reasoning for Molecular Optimization

Scientific reasoning is an increasingly important capability of large language models, yet improving the robustness and efficiency of training such reasoning remains a key open challenge. We study this problem in instruction-based molecular optimization, where answer-only supervised fine-tuning (SFT) collapses multi-step reasoning and reinforcement learning with verifiable rewards (RLVR) suffers from sparse feedback. Reference-guided Policy Optimization mitigates both by anchoring policy updates to dataset-provided references, but its effectiveness is tightly coupled to reference quality: weak or misaligned references impose a performance ceiling. To overcome this ceiling, we propose active reasoning, a paradigm in which the policy actively decides, on a per-instance basis, when to imitate a reference and when to reinforce its own discoveries, while continuously upgrading what it imitates. We instantiate this paradigm as Active Group Relative Policy Optimization (Active-GRPO), realized through two coupled mechanisms: active imitate-reinforce and active referencing. The former performs imitation learning when the reference still outperforms the policy's own candidates, and shifts to self-improvement via reinforcement learning once the policy has generated molecules that surpass the reference. The latter continuously upgrades the reference itself by replacing it with the best policy-generated candidate discovered so far, progressively raising the imitation target and ensuring that reference guidance remains informative-rather than restrictive-throughout training. Across TOMG-Bench MOLOPT, Active-GRPO improves average SRxSim from 0.0959 for GRPO and 0.1665 for RePO to 0.1773 under matched three-seed evaluation, with statistically significant gains on LogP, MR, and QED.

Protein Thoughts: Interpretable Reasoning with Tree of Thoughts and Embedding-Space Flow Matching for Protein-Protein Interaction Discovery

Protein-protein interactions (PPIs) govern nearly all cellular processes, yet computational methods for identifying binding partners typically produce ranked predictions without mechanistic justification. This creates a fundamental barrier to adoption because biologists cannot assess whether predictions reflect genuine biochemical insight or spurious correlations. We present \textbf{Protein Thoughts}, a framework that reformulates PPI discovery as an interpretable search problem with explicit reasoning. The system decomposes binding evidence into four biologically meaningful signals: sequence similarity reflecting evolutionary relationships, structural complementarity capturing geometric fit, interface balance, and chemical compatibility encoding residue-level interactions. Rather than collapsing these signals into an opaque score, we preserve their individual contributions through a transparent value function that enables both ranking and auditing. To navigate large candidate spaces efficiently, we introduce hypothesis-guided entropy-regularized Tree-of-Thoughts search. A fine-tuned language model generates search directives from embedding-derived features, classifying candidates as high-priority, exploratory, or skippable. These directives condition a Boltzmann policy that balances exploitation with entropy-driven exploration, while hypothesis-aware pruning prevents premature abandonment of promising candidates. For candidates exhibiting score disagreement, hypothesis-conditioned embedding-space flow matching transports protein embeddings toward the binder manifold. On the SHS148k benchmark, Protein Thoughts achieves mean best-binder rank of 11.2 versus 47.7 for an entropic tree search baseline, a 76% improvement, and for binding prediction the trained value function achieves $91.08 \pm 0.19$ Micro-F1, outperforming existing PPI methods on the same dataset.

From Coordinate Matching to Structural Alignment: Rethinking Prototype Alignment in Heterogeneous Federated Learning

Heterogeneous federated learning (HtFL) aims to enable collaboration among clients that differ in both data distributions and model architectures. Prototype-based methods, which communicate class-level feature centers (prototypes) instead of full model parameters, have recently shown strong potential for HtFL. Existing prototype-based HtFL methods typically reuse the MSE-based or cosine-based alignment mechanism developed for homogeneous FL when aligning client-specific representations with global prototypes. These approaches are essentially coordinate alignment, where representations of clients are forced to match the global prototypes in the embedding space in an element-wise manner. Such alignment implicitly assumes that all clients should map their representations into the feature subspace defined by the global prototypes. This assumption is reasonable in homogeneous FL, where all clients share the same feature extractor. However, it becomes problematic in HtFL, since heterogeneous feature extractors naturally induce client-specific feature subspaces, and forcing all clients to optimize within a single global subspace unnecessarily suppresses their learning capacity. We observe that coordinate alignment implicitly couples two distinct objectives: aligning inter-class semantic structure, which is directly beneficial for classification, and enforcing a shared feature basis, which is unnecessary and even harmful under model heterogeneity. Building on this insight, we design FedSAF, which shifts the alignment objective from absolute coordinates to inter-class relational structure. We demonstrate that structural alignment consistently outperforms coordinate alignment in heterogeneous settings. Experiments on multiple benchmarks show that our structural alignment outperforms state-of-the-art prototype-based HtFL methods by up to 3.52\%.

Multi-Objective Coverage via Constraint Active Search

In this paper, we formulate the new multi-objective coverage (MOC) problem where our goal is to identify a small set of representative samples whose predicted outcomes broadly cover the feasible multi-objective space. This problem is of great importance in many critical real-world applications, e.g., drug discovery and materials design, as this representative set can be evaluated much faster than the whole feasible set, thus significantly accelerating the scientific discovery process. Existing works cannot be directly applied as they either focus on sample space coverage or multi-objective optimization that targets the Pareto front. However, chemically diverse samples often yield identical objective profiles, and safety constraints are usually defined on the objectives. To solve this MOC problem, we propose a novel search algorithm, MOC-CAS, which employs an upper confidence bound-based acquisition function to select optimistic samples guided by Gaussian process posterior predictions. For enabling efficient optimization, we develop a smoothed relaxation of the hard feasibility test and derive an approximate optimizer. Compared to the competitive baselines, we show that our MOC-CAS empirically achieves superior performances across large-scale protein-target datasets for SARS-CoV-2 and cancer, each assessed on five objectives derived from SMILES-based features.

Learning to Optimize Job Shop Scheduling Under Structural Uncertainty

The Job-Shop Scheduling Problem (JSSP), under various forms of manufacturing uncertainty, has recently attracted considerable research attention. Most existing studies focus on parameter uncertainty, such as variable processing times, and typically adopt the actor-critic framework. In this paper, we explore a different but prevalent form of uncertainty in JSSP: structural uncertainty. Structural uncertainty arises when a job may follow one of several routing paths, and the selection is determined not by policy, but by situational factors (e.g., the quality of intermediate products) that cannot be known in advance. Existing methods struggle to address this challenge due to incorrect credit assignment: a high-quality action may be unfairly penalized if it is followed by a time-consuming path. To address this problem, we propose a novel method named UP-AAC. In contrast to conventional actor-critic methods, UP-AAC employs an asymmetric architecture. While its actor receives a standard stochastic state, the critic is crucially provided with a deterministic state reconstructed in hindsight. This design allows the critic to learn a more accurate value function, which in turn provides a lower-variance policy gradient to the actor, leading to more stable learning. In addition, we design an attention-based Uncertainty Perception Model (UPM) to enhance the actor's scheduling decisions. Extensive experiments demonstrate that our method outperforms existing approaches in reducing makespan on benchmark instances.

Regime-Adaptive Bayesian Optimization via Dirichlet Process Mixtures of Gaussian Processes

Standard Bayesian Optimization (BO) assumes uniform smoothness across the search space an assumption violated in multi-regime problems such as molecular conformation search through distinct energy basins or drug discovery across heterogeneous molecular scaffolds. A single GP either oversmooths sharp transitions or hallucinates noise in smooth regions, yielding miscalibrated uncertainty. We propose RAMBO, a Dirichlet Process Mixture of Gaussian Processes that automatically discovers latent regimes during optimization, each modeled by an independent GP with locally-optimized hyperparameters. We derive collapsed Gibbs sampling that analytically marginalizes latent functions for efficient inference, and introduce adaptive concentration parameter scheduling for coarse-to-fine regime discovery. Our acquisition functions decompose uncertainty into intra-regime and inter-regime components. Experiments on synthetic benchmarks and real-world applications, including molecular conformer optimization, virtual screening for drug discovery, and fusion reactor design, demonstrate consistent improvements over state-of-the-art baselines on multi-regime objectives.

Monte Carlo Tree Diffusion with Multiple Experts for Protein Design

The goal of protein design is to generate amino acid sequences that fold into functional structures with desired properties. Prior methods combining autoregressive language models with Monte Carlo Tree Search (MCTS) struggle with long-range dependencies and suffer from an impractically large search space. We propose MCTD-ME, Monte Carlo Tree Diffusion with Multiple Experts, which integrates masked diffusion models with tree search to enable multi-token planning and efficient exploration. Unlike autoregressive planners, MCTD-ME uses biophysical-fidelity-enhanced diffusion denoising as the rollout engine, jointly revising multiple positions and scaling to large sequence spaces. It further leverages experts of varying capacities to enrich exploration, guided by a pLDDT-based masking schedule that targets low-confidence regions while preserving reliable residues. We propose a novel multi-expert selection rule (PH-UCT-ME) extends predictive-entropy UCT to expert ensembles. On the inverse folding task (CAMEO and PDB benchmarks), MCTD-ME outperforms single-expert and unguided baselines in both sequence recovery (AAR) and structural similarity (scTM), with gains increasing for longer proteins and benefiting from multi-expert guidance. More generally, the framework is model-agnostic and applicable beyond inverse folding, including de novo protein engineering and multi-objective molecular generation.

WGLE:Backdoor-free and Multi-bit Black-box Watermarking for Graph Neural Networks

Graph Neural Networks (GNNs) are increasingly deployed in graph-related applications, making ownership verification critical to protect their intellectual property against model theft. Fingerprinting and black-box watermarking are two main methods. However, the former relies on determining model similarity, which is computationally expensive and prone to ownership collisions after model post-processing such as model pruning or fine-tuning. The latter embeds backdoors, exposing watermarked models to the risk of backdoor attacks. Moreover, both methods enable ownership verification but do not convey additional information. As a result, each distributed model requires a unique trigger graph, and all trigger graphs must be used to query the suspect model during verification. Multiple queries increase the financial cost and the risk of detection. To address these challenges, this paper proposes WGLE, a novel black-box watermarking paradigm for GNNs that enables embedding the multi-bit string as the ownership information without using backdoors. WGLE builds on a key insight we term Layer-wise Distance Difference on an Edge (LDDE), which quantifies the difference between the feature distance and the prediction distance of two connected nodes. By predefining positive or negative LDDE values for multiple selected edges, WGLE embeds the watermark encoding the intended information without introducing incorrect mappings that compromise the primary task. WGLE is evaluated on six public datasets and six mainstream GNN architectures along with state-of-the-art methods. The results show that WGLE achieves 100% ownership verification accuracy, an average fidelity degradation of 0.85%, comparable robustness against potential attacks, and low embedding overhead. The code is available in the repository.