Menghua Wu

Mohamed Amine Ketata, Cedrik Laue, Ruslan Mammadov et al. · mit

Understanding how proteins structurally interact is crucial to modern biology, with applications in drug discovery and protein design. Recent machine learning methods have formulated protein-small molecule docking as a generative problem with significant performance boosts over both traditional and deep learning baselines. In this work, we propose a similar approach for rigid protein-protein docking: DiffDock-PP is a diffusion generative model that learns to translate and rotate unbound protein structures into their bound conformations. We achieve state-of-the-art performance on DIPS with a median C-RMSD of 4.85, outperforming all considered baselines. Additionally, DiffDock-PP is faster than all search-based methods and generates reliable confidence estimates for its predictions. Our code is publicly available at $\texttt{https://github.com/ketatam/DiffDock-PP}$

Longwei Guo, Hao Zhu, Yuanxun Lu et al.

We propose a robust and accurate non-parametric method for single-view 3D face reconstruction (SVFR). While tremendous efforts have been devoted to parametric SVFR, a visible gap still lies between the result 3D shape and the ground truth. We believe there are two major obstacles: 1) the representation of the parametric model is limited to a certain face database; 2) 2D images and 3D shapes in the fitted datasets are distinctly misaligned. To resolve these issues, a large-scale pseudo 2D\&3D dataset is created by first rendering the detailed 3D faces, then swapping the face in the wild images with the rendered face. These pseudo 2D&3D pairs are created from publicly available datasets which eliminate the gaps between 2D and 3D data while covering diverse appearances, poses, scenes, and illumination. We further propose a non-parametric scheme to learn a well-generalized SVFR model from the created dataset, and the proposed hierarchical signed distance function turns out to be effective in predicting middle-scale and small-scale 3D facial geometry. Our model outperforms previous methods on FaceScape-wild/lab and MICC benchmarks and is well generalized to various appearances, poses, expressions, and in-the-wild environments. The code is released at http://github.com/zhuhao-nju/rafare .

Cai Zhou, Zekai Wang, Menghua Wu et al.

While test-time scaling has enabled large language models to solve highly difficult tasks, state-of-the-art results come at exorbitant compute costs. These inefficiencies can be attributed to the miscalibration of post-trained language models, and the lack of calibration in popular sampling techniques. Here, we present Online Reasoning Calibration (ORCA), a framework for calibrating the sampling process that draws upon conformal prediction and test-time training. Specifically, we introduce a meta-learning procedure that updates the calibration module for each input. This allows us to provide valid confidence estimates under distributional shift, e.g. in thought patterns that occur across different stages of reasoning, or in prompt distributions between model development and deployment. ORCA not only provides theoretical guarantees on conformal risks, but also empirically shows higher efficiency and generalization across different reasoning tasks. At risk level $δ=0.1$, ORCA improves Qwen2.5-32B efficiency on in-distribution tasks with savings up to 47.5% with supervised labels and 40.7% with self-consistency labels. Under zero-shot out-of-domain settings, it improves MATH-500 savings from 24.8% of the static calibration baseline to 67.0% while maintaining a low empirical error rate, and the same trend holds across model families and downstream benchmarks. Our code is publicly available at https://github.com/wzekai99/ORCA.

Menghua Wu, Russell Littman, Jacob Levine et al.

High-content perturbation experiments allow scientists to probe biomolecular systems at unprecedented resolution, but experimental and analysis costs pose significant barriers to widespread adoption. Machine learning has the potential to guide efficient exploration of the perturbation space and extract novel insights from these data. However, current approaches neglect the semantic richness of the relevant biology, and their objectives are misaligned with downstream biological analyses. In this paper, we hypothesize that large language models (LLMs) present a natural medium for representing complex biological relationships and rationalizing experimental outcomes. We propose PerturbQA, a benchmark for structured reasoning over perturbation experiments. Unlike current benchmarks that primarily interrogate existing knowledge, PerturbQA is inspired by open problems in perturbation modeling: prediction of differential expression and change of direction for unseen perturbations, and gene set enrichment. We evaluate state-of-the-art machine learning and statistical approaches for modeling perturbations, as well as standard LLM reasoning strategies, and we find that current methods perform poorly on PerturbQA. As a proof of feasibility, we introduce Summer (SUMMarize, retrievE, and answeR, a simple, domain-informed LLM framework that matches or exceeds the current state-of-the-art. Our code and data are publicly available at https://github.com/genentech/PerturbQA.

Menghua Wu, Hao Zhu, Linjia Huang et al.

Synthesizing high-quality 3D face models from natural language descriptions is very valuable for many applications, including avatar creation, virtual reality, and telepresence. However, little research ever tapped into this task. We argue the major obstacle lies in 1) the lack of high-quality 3D face data with descriptive text annotation, and 2) the complex mapping relationship between descriptive language space and shape/appearance space. To solve these problems, we build Describe3D dataset, the first large-scale dataset with fine-grained text descriptions for text-to-3D face generation task. Then we propose a two-stage framework to first generate a 3D face that matches the concrete descriptions, then optimize the parameters in the 3D shape and texture space with abstract description to refine the 3D face model. Extensive experimental results show that our method can produce a faithful 3D face that conforms to the input descriptions with higher accuracy and quality than previous methods. The code and Describe3D dataset are released at https://github.com/zhuhao-nju/describe3d .

Hao Zhu, Haotian Yang, Longwei Guo et al.

In this paper, we present a large-scale detailed 3D face dataset, FaceScape, and the corresponding benchmark to evaluate single-view facial 3D reconstruction. By training on FaceScape data, a novel algorithm is proposed to predict elaborate riggable 3D face models from a single image input. FaceScape dataset releases $16,940$ textured 3D faces, captured from $847$ subjects and each with $20$ specific expressions. The 3D models contain the pore-level facial geometry that is also processed to be topologically uniform. These fine 3D facial models can be represented as a 3D morphable model for coarse shapes and displacement maps for detailed geometry. Taking advantage of the large-scale and high-accuracy dataset, a novel algorithm is further proposed to learn the expression-specific dynamic details using a deep neural network. The learned relationship serves as the foundation of our 3D face prediction system from a single image input. Different from most previous methods, our predicted 3D models are riggable with highly detailed geometry under different expressions. We also use FaceScape data to generate the in-the-wild and in-the-lab benchmark to evaluate recent methods of single-view face reconstruction. The accuracy is reported and analyzed on the dimensions of camera pose and focal length, which provides a faithful and comprehensive evaluation and reveals new challenges. The unprecedented dataset, benchmark, and code have been released at https://github.com/zhuhao-nju/facescape.

Menghua Wu, Yujia Bao, Regina Barzilay et al.

Causal discovery, the task of inferring causal structure from data, has the potential to uncover mechanistic insights from biological experiments, especially those involving perturbations. However, causal discovery algorithms over larger sets of variables tend to be brittle against misspecification or when data are limited. For example, single-cell transcriptomics measures thousands of genes, but the nature of their relationships is not known, and there may be as few as tens of cells per intervention setting. To mitigate these challenges, we propose a foundation model-inspired approach: a supervised model trained on large-scale, synthetic data to predict causal graphs from summary statistics -- like the outputs of classical causal discovery algorithms run over subsets of variables and other statistical hints like inverse covariance. Our approach is enabled by the observation that typical errors in the outputs of a discovery algorithm remain comparable across datasets. Theoretically, we show that the model architecture is well-specified, in the sense that it can recover a causal graph consistent with graphs over subsets. Empirically, we train the model to be robust to misspecification and distribution shift using diverse datasets. Experiments on biological and synthetic data confirm that this model generalizes well beyond its training set, runs on graphs with hundreds of variables in seconds, and can be easily adapted to different underlying data assumptions.

Peiwen Li, Menghua Wu

Perturbation experiments allow biologists to discover causal relationships between variables of interest, but the sparsity and high dimensionality of these data pose significant challenges for causal structure learning algorithms. Biological knowledge graphs can bootstrap the inference of causal structures in these situations, but since they compile vastly diverse information, they can bias predictions towards well-studied systems. Alternatively, amortized causal structure learning algorithms encode inductive biases through data simulation and train supervised models to recapitulate these synthetic graphs. However, realistically simulating biology is arguably even harder than understanding a specific system. In this work, we take inspiration from both strategies and propose an amortized algorithm for refining domain knowledge, based on data observations. On real and synthetic datasets, we show that our approach outperforms baselines in recovering ground truth causal graphs and identifying errors in the prior knowledge with limited interventional data.

Bo Qiang, Wenxian Shi, Yuxuan Song et al.

Proteolysis targeting chimeras (PROTACs) are small molecules that trigger the breakdown of traditionally ``undruggable'' proteins by binding simultaneously to their targets and degradation-associated proteins. A key challenge in their rational design is understanding their structural basis of activity. Due to the lack of crystal structures (18 in the PDB), existing PROTAC docking methods have been forced to simplify the problem into a distance-constrained protein-protein docking task. To address the data issue, we develop a novel pseudo-data generation scheme that requires only binary protein-protein complexes. This new dataset enables PROflow, an iterative refinement model for PROTAC-induced structure prediction that models the full PROTAC flexibility during constrained protein-protein docking. PROflow outperforms the state-of-the-art across docking metrics and runtime. Its inference speed enables the large-scale screening of PROTAC designs, and computed properties of predicted structures achieve statistically significant correlations with published degradation activities.

Menghua Wu, Yujia Bao

AI systems have increasingly become our gateways to the Internet. We argue that just as advertising has driven the monetization of web search and social media, so too will commercial incentives shape the content served by AI. Unlike traditional media, however, the outputs of these systems are dynamic, personalized, and lack clear provenance -- raising concerns for transparency and regulation. In this paper, we envision how commercial content could be delivered through generative AI-based systems. Based on the requirements of key stakeholders -- advertisers, consumers, and platforms -- we propose design principles for commercially-influenced AI systems. We then outline high-level strategies for end users to identify and mitigate commercial biases from model outputs. Finally, we conclude with open questions and a call to action towards these goals.

Menghua Wu, Cai Zhou, Stephen Bates et al.

Reasoning large language models achieve impressive test-time scaling by thinking for longer, but this performance gain comes at significant compute cost. Directly limiting test-time budget hurts overall performance, but not all problems are equally difficult. We propose thought calibration to decide dynamically when thinking can be terminated. To calibrate our decision rule, we view a language model's growing body of thoughts as a nested sequence of reasoning trees, where the goal is to identify the point at which novel reasoning plateaus. We realize this framework through lightweight probes that operate on top of the language model's hidden representations, which are informative of both the reasoning structure and overall consistency of response. Based on three reasoning language models and four datasets, thought calibration preserves model performance with up to a 60% reduction in thinking tokens on in-distribution data, and up to 20% in out-of-distribution data.

Wenxian Shi, Menghua Wu, Regina Barzilay

Forecasting the change in the distribution of viral variants is crucial for therapeutic design and disease surveillance. This task poses significant modeling challenges due to the sharp differences in virus distributions across sub-populations (e.g., countries) and their dynamic interactions. Existing machine learning approaches that model the variant distribution as a whole are incapable of making location-specific predictions and ignore transmissions that shape the viral landscape. In this paper, we propose a sub-population specific protein evolution model, which predicts the time-resolved distributions of viral proteins in different locations. The algorithm explicitly models the transmission rates between sub-populations and learns their interdependence from data. The change in protein distributions across all sub-populations is defined through a linear ordinary differential equation (ODE) parametrized by transmission rates. Solving this ODE yields the likelihood of a given protein occurring in particular sub-populations. Multi-year evaluation on both SARS-CoV-2 and influenza A/H3N2 demonstrates that our model outperforms baselines in accurately predicting distributions of viral proteins across continents and countries. We also find that the transmission rates learned from data are consistent with the transmission pathways discovered by retrospective phylogenetic analysis.

Yujia Bao, Menghua Wu, Shiyu Chang et al.

In this paper, we explore meta-learning for few-shot text classification. Meta-learning has shown strong performance in computer vision, where low-level patterns are transferable across learning tasks. However, directly applying this approach to text is challenging--lexical features highly informative for one task may be insignificant for another. Thus, rather than learning solely from words, our model also leverages their distributional signatures, which encode pertinent word occurrence patterns. Our model is trained within a meta-learning framework to map these signatures into attention scores, which are then used to weight the lexical representations of words. We demonstrate that our model consistently outperforms prototypical networks learned on lexical knowledge (Snell et al., 2017) in both few-shot text classification and relation classification by a significant margin across six benchmark datasets (20.0% on average in 1-shot classification).