Min Xu

Ilja Gubins, Marten L. Chaillet, Gijs van der Schot et al.

Cryo-electron tomography (cryo-ET) is an imaging technique that allows three-dimensional visualization of macro-molecular assemblies under near-native conditions. Cryo-ET comes with a number of challenges, mainly low signal-to-noise and inability to obtain images from all angles. Computational methods are key to analyze cryo-electron tomograms. To promote innovation in computational methods, we generate a novel simulated dataset to benchmark different methods of localization and classification of biological macromolecules in tomograms. Our publicly available dataset contains ten tomographic reconstructions of simulated cell-like volumes. Each volume contains twelve different types of complexes, varying in size, function and structure. In this paper, we have evaluated seven different methods of finding and classifying proteins. Seven research groups present results obtained with learning-based methods and trained on the simulated dataset, as well as a baseline template matching (TM), a traditional method widely used in cryo-ET research. We show that learning-based approaches can achieve notably better localization and classification performance than TM. We also experimentally confirm that there is a negative relationship between particle size and performance for all methods.

Yizhou Zhao, Hengwei Bian, Michael Mu et al.

Cryogenic Electron Tomography (CryoET) is a useful imaging technology in structural biology that is hindered by its need for manual annotations, especially in particle picking. Recent works have endeavored to remedy this issue with few-shot learning or contrastive learning techniques. However, supervised training is still inevitable for them. We instead choose to leverage the power of existing 2D foundation models and present a novel, training-free framework, CryoSAM. In addition to prompt-based single-particle instance segmentation, our approach can automatically search for similar features, facilitating full tomogram semantic segmentation with only one prompt. CryoSAM is composed of two major parts: 1) a prompt-based 3D segmentation system that uses prompts to complete single-particle instance segmentation recursively with Cross-Plane Self-Prompting, and 2) a Hierarchical Feature Matching mechanism that efficiently matches relevant features with extracted tomogram features. They collaborate to enable the segmentation of all particles of one category with just one particle-specific prompt. Our experiments show that CryoSAM outperforms existing works by a significant margin and requires even fewer annotations in particle picking. Further visualizations demonstrate its ability when dealing with full tomogram segmentation for various subcellular structures. Our code is available at: https://github.com/xulabs/aitom

Shirley Kokane, Mostofa Rafid Uddin, Min Xu

Transfer learning methods start performing poorly when the complexity of the learning task is increased. Most of these methods calculate the cumulative differences of all the matched features and then use them to back-propagate that loss through all the layers. Contrary to these methods, in this work, we propose a novel layer-wise learning scheme that adjusts learning parameters per layer as a function of the differences in the Jacobian/Attention/Hessian of the output activations w.r.t. the network parameters. We applied this novel scheme for attention map-based and derivative-based (first and second order) transfer learning methods. We received improved learning performance and stability against a wide range of datasets. From extensive experimental evaluation, we observed that the performance boost achieved by our method becomes more significant with the increasing difficulty of the learning task.

Yen-Linh Vu, Dinh-Thang Duong, Truong-Binh Duong et al.

Recent progress has been made in region-aware vision-language modeling, particularly with the emergence of the Describe Anything Model (DAM). DAM is capable of generating detailed descriptions of any specific image areas or objects without the need for additional localized image-text alignment supervision. We hypothesize that such region-level descriptive capability is beneficial for the task of Visual Question Answering (VQA), especially in challenging scenarios involving images with dense text. In such settings, the fine-grained extraction of textual information is crucial to producing correct answers. Motivated by this, we introduce DAM-QA, a framework with a tailored evaluation protocol, developed to investigate and harness the region-aware capabilities from DAM for the text-rich VQA problem that requires reasoning over text-based information within images. DAM-QA incorporates a mechanism that aggregates answers from multiple regional views of image content, enabling more effective identification of evidence that may be tied to text-related elements. Experiments on six VQA benchmarks show that our approach consistently outperforms the baseline DAM, with a notable 7+ point gain on DocVQA. DAM-QA also achieves the best overall performance among region-aware models with fewer parameters, significantly narrowing the gap with strong generalist VLMs. These results highlight the potential of DAM-like models for text-rich and broader VQA tasks when paired with efficient usage and integration strategies. Our code is publicly available at https://github.com/Linvyl/DAM-QA.git.

Xiangrui Zeng, Min Xu

Cryo-electron tomography (cryo-ET) is an emerging technology for the 3D visualization of structural organizations and interactions of subcellular components at near-native state and sub-molecular resolution. Tomograms captured by cryo-ET contain heterogeneous structures representing the complex and dynamic subcellular environment. Since the structures are not purified or fluorescently labeled, the spatial organization and interaction between both the known and unknown structures can be studied in their native environment. The rapid advances of cryo-electron tomography (cryo-ET) have generated abundant 3D cellular imaging data. However, the systematic localization, identification, segmentation, and structural recovery of the subcellular components require efficient and accurate large-scale image analysis methods. We introduce AITom, an open-source artificial intelligence platform for cryo-ET researchers. AITom provides many public as well as in-house algorithms for performing cryo-ET data analysis through both the traditional template-based or template-free approach and the deep learning approach. AITom also supports remote interactive analysis. Comprehensive tutorials for each analysis module are provided to guide the user through. We welcome researchers and developers to join this collaborative open-source software development project. Availability: https://github.com/xulabs/aitom

Tien-Dat Chung, Ba-Thinh Lam, Thanh-Huy Nguyen et al.

Semi-supervised learning (SSL) has become a promising direction for medical image segmentation, enabling models to learn from limited labeled data alongside abundant unlabeled samples. However, existing SSL approaches for multi-modal medical imaging often struggle to exploit the complementary information between modalities due to semantic discrepancies and misalignment across MRI sequences. To address this, we propose a novel semi-supervised multi-modal framework that explicitly enhances modality-specific representations and facilitates adaptive cross-modal information fusion. Specifically, we introduce a Modality-specific Enhancing Module (MEM) to strengthen semantic cues unique to each modality via channel-wise attention, and a learnable Complementary Information Fusion (CIF) module to adaptively exchange complementary knowledge between modalities. The overall framework is optimized using a hybrid objective combining supervised segmentation loss and cross-modal consistency regularization on unlabeled data. Extensive experiments on the BraTS 2019 (HGG subset) demonstrate that our method consistently outperforms strong semi-supervised and multi-modal baselines under 1\%, 5\%, and 10\% labeled data settings, achieving significant improvements in both Dice and Sensitivity scores. Ablation studies further confirm the complementary effects of our proposed MEM and CIF in bridging cross-modality discrepancies and improving segmentation robustness under scarce supervision.

Xi Xiao, Yunbei Zhang, Xingjian Li et al.

Visual Prompt Tuning (VPT) has emerged as a parameter-efficient fine-tuning paradigm for vision transformers, with conventional approaches utilizing dataset-level prompts that remain the same across all input instances. We observe that this strategy results in sub-optimal performance due to high variance in downstream datasets. To address this challenge, we propose Visual Instance-aware Prompt Tuning (ViaPT), which generates instance-aware prompts based on each individual input and fuses them with dataset-level prompts, leveraging Principal Component Analysis (PCA) to retain important prompting information. Moreover, we reveal that VPT-Deep and VPT-Shallow represent two corner cases based on a conceptual understanding, in which they fail to effectively capture instance-specific information, while random dimension reduction on prompts only yields performance between the two extremes. Instead, ViaPT overcomes these limitations by balancing dataset-level and instance-level knowledge, while reducing the amount of learnable parameters compared to VPT-Deep. Extensive experiments across 34 diverse datasets demonstrate that our method consistently outperforms state-of-the-art baselines, establishing a new paradigm for analyzing and optimizing visual prompts for vision transformers.

Chentianye Xu, Xueying Zhan, Min Xu

Cryo-electron microscopy (cryo-EM) emerges as a pivotal technology for determining the architecture of cells, viruses, and protein assemblies at near-atomic resolution. Traditional particle picking, a key step in cryo-EM, struggles with manual effort and automated methods' sensitivity to low signal-to-noise ratio (SNR) and varied particle orientations. Furthermore, existing neural network (NN)-based approaches often require extensive labeled datasets, limiting their practicality. To overcome these obstacles, we introduce cryoMAE, a novel approach based on few-shot learning that harnesses the capabilities of Masked Autoencoders (MAE) to enable efficient selection of single particles in cryo-EM images. Contrary to conventional NN-based techniques, cryoMAE requires only a minimal set of positive particle images for training yet demonstrates high performance in particle detection. Furthermore, the implementation of a self-cross similarity loss ensures distinct features for particle and background regions, thereby enhancing the discrimination capability of cryoMAE. Experiments on large-scale cryo-EM datasets show that cryoMAE outperforms existing state-of-the-art (SOTA) methods, improving 3D reconstruction resolution by up to 22.4%.

Xiwei Liu, Mohamad Kassab, Min Xu et al.

Cryo-Electron Tomography (Cryo-ET) enables detailed 3D visualization of cellular structures in near-native states but suffers from low signal-to-noise ratio due to imaging constraints. Traditional denoising methods and supervised learning approaches often struggle with complex noise patterns and the lack of paired datasets. Self-supervised methods, which utilize noisy input itself as a target, have been studied; however, existing Cryo-ET self-supervised denoising methods face significant challenges due to losing information during training and the learned incomplete noise patterns. In this paper, we propose a novel self-supervised learning model that denoises Cryo-ET volumetric images using a single noisy volume. Our method features a U-shape J-invariant blind spot network with sparse centrally masked convolutions, dilated channel attention blocks, and volume unshuffle/shuffle technique. The volume-unshuffle/shuffle technique expands receptive fields and utilizes multi-scale representations, significantly improving noise reduction and structural preservation. Experimental results demonstrate that our approach achieves superior performance compared to existing methods, advancing Cryo-ET data processing for structural biology research

Penghao Rao, Runmin Jiang, Min Xu

Approximating training-point influence on test predictions is critical for deploying deep-learning vision models, essential for locating noisy data. Though the influence function was proposed for attributing how infinitesimal up-weighting or removal of individual training examples affects model outputs, its implementation is still challenging in deep-learning vision models: inverse-curvature computations are expensive, and training non-stationarity invalidates static approximations. Prior works use iterative solvers and low-rank surrogates to reduce cost, but offline computation lags behind training dynamics, and missing confidence calibration yields fragile rankings that misidentify critical examples. To address these challenges, we introduce a Stability-Guided Online Influence Framework (SG-OIF), the first framework that treats algorithmic stability as a real-time controller, which (i) maintains lightweight anchor IHVPs via stochastic Richardson and preconditioned Neumann; (ii) proposes modular curvature backends to modulate per-example influence scores using stability-guided residual thresholds, anomaly gating, and confidence. Experimental results show that SG-OIF achieves SOTA (State-Of-The-Art) on noise-label and out-of-distribution detection tasks across multiple datasets with various corruption. Notably, our approach achieves 91.1\% accuracy in the top 1\% prediction samples on the CIFAR-10 (20\% asym), and gets 99.8\% AUPR score on MNIST, effectively demonstrating that this framework is a practical controller for online influence estimation.

Thanh-Huy Nguyen, Hoang-Thien Nguyen, Vi Vu et al.

The limited availability of annotated data in medical imaging makes semi-supervised learning increasingly appealing for its ability to learn from imperfect supervision. Recently, teacher-student frameworks have gained popularity for their training benefits and robust performance. However, jointly optimizing the entire network can hinder convergence and stability, especially in challenging scenarios. To address this for medical image segmentation, we propose DuetMatch, a novel dual-branch semi-supervised framework with asynchronous optimization, where each branch optimizes either the encoder or decoder while keeping the other frozen. To improve consistency under noisy conditions, we introduce Decoupled Dropout Perturbation, enforcing regularization across branches. We also design Pair-wise CutMix Cross-Guidance to enhance model diversity by exchanging pseudo-labels through augmented input pairs. To mitigate confirmation bias from noisy pseudo-labels, we propose Consistency Matching, refining labels using stable predictions from frozen teacher models. Extensive experiments on benchmark brain MRI segmentation datasets, including ISLES2022 and BraTS, show that DuetMatch consistently outperforms state-of-the-art methods, demonstrating its effectiveness and robustness across diverse semi-supervised segmentation scenarios.

Zhuo Cao, Yunxiao Shi, Min Xu

This work introduces SAM-LLM, a novel hybrid architecture that bridges the gap between the contextual reasoning of Large Language Models (LLMs) and the physical precision of kinematic lane change models for autonomous driving. The system is designed for interpretable lane change trajectory prediction by finetuning an LLM to output the core physical parameters of a trajectory model instead of raw coordinates. For lane-keeping scenarios, the model predicts discrete coordinates, but for lane change maneuvers, it generates the parameters for an enhanced Sinusoidal Acceleration Model (SAM), including lateral displacement, maneuver duration, initial lateral velocity, and longitudinal velocity change. This parametric approach yields a complete, continuous, and physically plausible trajectory model that is inherently interpretable and computationally efficient, achieving an 80% reduction in output size compared to coordinate-based methods. The SAM-LLM achieves a state-of-the-art overall intention prediction accuracy of 98.73%, demonstrating performance equivalent to traditional LLM predictors while offering significant advantages in explainability and resource efficiency.

Sheng Liu, Yiheng Yu, Yuan Feng et al.

Current continuous sign language recognition (CSLR) methods struggle with handling diverse samples. Although dynamic convolutions are ideal for this task, they mainly focus on spatial modeling and fail to capture the temporal dynamics and contextual dependencies. To address this, we propose DESign, a novel framework that incorporates Dynamic Context-Aware Convolution (DCAC) and Subnet Regularization Connectionist Temporal Classification (SR-CTC). DCAC dynamically captures the inter-frame motion cues that constitute signs and uniquely adapts convolutional weights in a fine-grained manner based on contextual information, enabling the model to better generalize across diverse signing behaviors and boost recognition accuracy. Furthermore, we observe that existing methods still rely on only a limited number of frames for parameter updates during training, indicating that CTC learning overfits to a dominant path. To address this, SR-CTC regularizes training by applying supervision to subnetworks, encouraging the model to explore diverse CTC alignment paths and effectively preventing overfitting. A classifier-sharing strategy in SR-CTC further strengthens multi-scale consistency. Notably, SR-CTC introduces no inference overhead and can be seamlessly integrated into existing CSLR models to boost performance. Extensive ablations and visualizations further validate the effectiveness of the proposed methods. Results on mainstream CSLR datasets (i.e., PHOENIX14, PHOENIX14-T, CSL-Daily) demonstrate that DESign achieves state-of-the-art performance.

Hmrishav Bandyopadhyay, Zihao Deng, Leiting Ding et al.

Cryo-Electron Tomography (cryo-ET) is a 3D imaging technology that enables the visualization of subcellular structures in situ at near-atomic resolution. Cellular cryo-ET images help in resolving the structures of macromolecules and determining their spatial relationship in a single cell, which has broad significance in cell and structural biology. Subtomogram classification and recognition constitute a primary step in the systematic recovery of these macromolecular structures. Supervised deep learning methods have been proven to be highly accurate and efficient for subtomogram classification, but suffer from limited applicability due to scarcity of annotated data. While generating simulated data for training supervised models is a potential solution, a sizeable difference in the image intensity distribution in generated data as compared to real experimental data will cause the trained models to perform poorly in predicting classes on real subtomograms. In this work, we present Cryo-Shift, a fully unsupervised domain adaptation and randomization framework for deep learning-based cross-domain subtomogram classification. We use unsupervised multi-adversarial domain adaption to reduce the domain shift between features of simulated and experimental data. We develop a network-driven domain randomization procedure with `warp' modules to alter the simulated data and help the classifier generalize better on experimental data. We do not use any labeled experimental data to train our model, whereas some of the existing alternative approaches require labeled experimental samples for cross-domain classification. Nevertheless, Cryo-Shift outperforms the existing alternative approaches in cross-domain subtomogram classification in extensive evaluation studies demonstrated herein using both simulated and experimental data.

Kai Yi, Jianye Pang, Yungeng Zhang et al.

Cryo-electron tomography (Cryo-ET) is a 3D imaging technique that enables the systemic study of shape, abundance, and distribution of macromolecular structures in single cells in near-atomic resolution. However, the systematic and efficient $\textit{de novo}$ recognition and recovery of macromolecular structures captured by Cryo-ET are very challenging due to the structural complexity and imaging limits. Even macromolecules with identical structures have various appearances due to different orientations and imaging limits, such as noise and the missing wedge effect. Explicitly disentangling the semantic features of macromolecules is crucial for performing several downstream analyses on the macromolecules. This paper has addressed the problem by proposing a 3D Spatial Variational Autoencoder that explicitly disentangle the structure, orientation, and shift of macromolecules. Extensive experiments on both synthesized and real cryo-ET datasets and cross-domain evaluations demonstrate the efficacy of our method.

Xuefeng Du, Haohan Wang, Zhenxi Zhu et al.

Motivation: Cryo-Electron Tomography (cryo-ET) is a 3D bioimaging tool that visualizes the structural and spatial organization of macromolecules at a near-native state in single cells, which has broad applications in life science. However, the systematic structural recognition and recovery of macromolecules captured by cryo-ET are difficult due to high structural complexity and imaging limits. Deep learning based subtomogram classification have played critical roles for such tasks. As supervised approaches, however, their performance relies on sufficient and laborious annotation on a large training dataset. Results: To alleviate this major labeling burden, we proposed a Hybrid Active Learning (HAL) framework for querying subtomograms for labelling from a large unlabeled subtomogram pool. Firstly, HAL adopts uncertainty sampling to select the subtomograms that have the most uncertain predictions. Moreover, to mitigate the sampling bias caused by such strategy, a discriminator is introduced to judge if a certain subtomogram is labeled or unlabeled and subsequently the model queries the subtomogram that have higher probabilities to be unlabeled. Additionally, HAL introduces a subset sampling strategy to improve the diversity of the query set, so that the information overlap is decreased between the queried batches and the algorithmic efficiency is improved. Our experiments on subtomogram classification tasks using both simulated and real data demonstrate that we can achieve comparable testing performance (on average only 3% accuracy drop) by using less than 30% of the labeled subtomograms, which shows a very promising result for subtomogram classification task with limited labeling resources.

Nanqing Dong, Michael Kampffmeyer, Xiaodan Liang et al.

The data-driven nature of deep learning (DL) models for semantic segmentation requires a large number of pixel-level annotations. However, large-scale and fully labeled medical datasets are often unavailable for practical tasks. Recently, partially supervised methods have been proposed to utilize images with incomplete labels in the medical domain. To bridge the methodological gaps in partially supervised learning (PSL) under data scarcity, we propose Vicinal Labels Under Uncertainty (VLUU), a simple yet efficient framework utilizing the human structure similarity for partially supervised medical image segmentation. Motivated by multi-task learning and vicinal risk minimization, VLUU transforms the partially supervised problem into a fully supervised problem by generating vicinal labels. We systematically evaluate VLUU under the challenges of small-scale data, dataset shift, and class imbalance on two commonly used segmentation datasets for the tasks of chest organ segmentation and optic disc-and-cup segmentation. The experimental results show that VLUU can consistently outperform previous partially supervised models in these settings. Our research suggests a new research direction in label-efficient deep learning with partial supervision.

Liangyong Yu, Ran Li, Xiangrui Zeng et al.

Motivation: Cryo-Electron Tomography (cryo-ET) visualizes structure and spatial organization of macromolecules and their interactions with other subcellular components inside single cells in the close-to-native state at sub-molecular resolution. Such information is critical for the accurate understanding of cellular processes. However, subtomogram classification remains one of the major challenges for the systematic recognition and recovery of the macromolecule structures in cryo-ET because of imaging limits and data quantity. Recently, deep learning has significantly improved the throughput and accuracy of large-scale subtomogram classification. However often it is difficult to get enough high-quality annotated subtomogram data for supervised training due to the enormous expense of labeling. To tackle this problem, it is beneficial to utilize another already annotated dataset to assist the training process. However, due to the discrepancy of image intensity distribution between source domain and target domain, the model trained on subtomograms in source domainmay perform poorly in predicting subtomogram classes in the target domain. Results: In this paper, we adapt a few shot domain adaptation method for deep learning based cross-domain subtomogram classification. The essential idea of our method consists of two parts: 1) take full advantage of the distribution of plentiful unlabeled target domain data, and 2) exploit the correlation between the whole source domain dataset and few labeled target domain data. Experiments conducted on simulated and real datasets show that our method achieves significant improvement on cross domain subtomogram classification compared with baseline methods.

Qiqi Xiao, Jiaxu Zou, Muqiao Yang et al.

Diabetic Retinopathy (DR) is a leading cause of blindness in working age adults. DR lesions can be challenging to identify in fundus images, and automatic DR detection systems can offer strong clinical value. Of the publicly available labeled datasets for DR, the Indian Diabetic Retinopathy Image Dataset (IDRiD) presents retinal fundus images with pixel-level annotations of four distinct lesions: microaneurysms, hemorrhages, soft exudates and hard exudates. We utilize the HEDNet edge detector to solve a semantic segmentation task on this dataset, and then propose an end-to-end system for pixel-level segmentation of DR lesions by incorporating HEDNet into a Conditional Generative Adversarial Network (cGAN). We design a loss function that adds adversarial loss to segmentation loss. Our experiments show that the addition of the adversarial loss improves the lesion segmentation performance over the baseline.

Ziqian Luo, Xiangrui Zeng, Zhipeng Bao et al.

Deep learning model trained by imbalanced data may not work satisfactorily since it could be determined by major classes and thus may ignore the classes with small amount of data. In this paper, we apply deep learning based imbalanced data classification for the first time to cellular macromolecular complexes captured by Cryo-electron tomography (Cryo-ET). We adopt a range of strategies to cope with imbalanced data, including data sampling, bagging, boosting, Genetic Programming based method and. Particularly, inspired from Inception 3D network, we propose a multi-path CNN model combining focal loss and mixup on the Cryo-ET dataset to expand the dataset, where each path had its best performance corresponding to each type of data and let the network learn the combinations of the paths to improve the classification performance. In addition, extensive experiments have been conducted to show our proposed method is flexible enough to cope with different number of classes by adjusting the number of paths in our multi-path model. To our knowledge, this work is the first application of deep learning methods of dealing with imbalanced data to the internal tissue classification of cell macromolecular complexes, which opened up a new path for cell classification in the field of computational biology.

Guannan Zhao, Bo Zhou, Kaiwen Wang et al.

The convolutional neural network (CNN) has become a powerful tool for various biomedical image analysis tasks, but there is a lack of visual explanation for the machinery of CNNs. In this paper, we present a novel algorithm, Respond-weighted Class Activation Mapping (Respond-CAM), for making CNN-based models interpretable by visualizing input regions that are important for predictions, especially for biomedical 3D imaging data inputs. Our method uses the gradients of any target concept (e.g. the score of target class) that flows into a convolutional layer. The weighted feature maps are combined to produce a heatmap that highlights the important regions in the image for predicting the target concept. We prove a preferable sum-to-score property of the Respond-CAM and verify its significant improvement on 3D images from the current state-of-the-art approach. Our tests on Cellular Electron Cryo-Tomography 3D images show that Respond-CAM achieves superior performance on visualizing the CNNs with 3D biomedical images inputs, and is able to get reasonably good results on visualizing the CNNs with natural image inputs. The Respond-CAM is an efficient and reliable approach for visualizing the CNN machinery, and is applicable to a wide variety of CNN model families and image analysis tasks.

Chang Liu, Xiangrui Zeng, Kaiwen Wang et al.

Cellular Electron Cryo-Tomography (CECT) is a powerful 3D imaging tool for studying the native structure and organization of macromolecules inside single cells. For systematic recognition and recovery of macromolecular structures captured by CECT, methods for several important tasks such as subtomogram classification and semantic segmentation have been developed. However, the recognition and recovery of macromolecular structures are still very difficult due to high molecular structural diversity, crowding molecular environment, and the imaging limitations of CECT. In this paper, we propose a novel multi-task 3D convolutional neural network model for simultaneous classification, segmentation, and coarse structural recovery of macromolecules of interest in subtomograms. In our model, the learned image features of one task are shared and thereby mutually reinforce the learning of other tasks. Evaluated on realistically simulated and experimental CECT data, our multi-task learning model outperformed all single-task learning methods for classification and segmentation. In addition, we demonstrate that our model can generalize to discover, segment and recover novel structures that do not exist in the training data.

Kai Wen Wang, Xiangrui Zeng, Xiaodan Liang et al.

Cellular Electron CryoTomography (CECT) is a 3D imaging technique that captures information about the structure and spatial organization of macromolecular complexes within single cells, in near-native state and at sub-molecular resolution. Although template matching is often used to locate macromolecules in a CECT image, it is insufficient as it only measures the relative structural similarity. Therefore, it is preferable to assess the statistical credibility of the decision through hypothesis testing, requiring many templates derived from a diverse population of macromolecular structures. Due to the very limited number of known structures, we need a generative model to efficiently and reliably sample pseudo-structures from the complex distribution of macromolecular structures. To address this challenge, we propose a novel image-derived approach for performing hypothesis testing for template matching by constructing generative models using the generative adversarial network. Finally, we conducted hypothesis testing experiments for template matching on both simulated and experimental subtomograms, allowing us to conclude the identity of subtomograms with high statistical credibility and significantly reducing false positives.

Yixiu Zhao, Xiangrui Zeng, Qiang Guo et al.

Motivation: Cellular Electron CryoTomography (CECT) is an emerging 3D imaging technique that visualizes subcellular organization of single cells at submolecular resolution and in near-native state. CECT captures large numbers of macromolecular complexes of highly diverse structures and abundances. However, the structural complexity and imaging limits complicate the systematic de novo structural recovery and recognition of these macromolecular complexes. Efficient and accurate reference-free subtomogram averaging and classification represent the most critical tasks for such analysis. Existing subtomogram alignment based methods are prone to the missing wedge effects and low signal-to-noise ratio (SNR). Moreover, existing maximum-likelihood based methods rely on integration operations, which are in principle computationally infeasible for accurate calculation. Results: Built on existing works, we propose an integrated method, Fast Alignment Maximum Likelihood method (FAML), which uses fast subtomogram alignment to sample sub-optimal rigid transformations. The transformations are then used to approximate integrals for maximum-likelihood update of subtomogram averages through expectation-maximization algorithm. Our tests on simulated and experimental subtomograms showed that, compared to our previously developed fast alignment method (FA), FAML is significantly more robust to noise and missing wedge effects with moderate increases of computation cost.Besides, FAML performs well with significantly fewer input subtomograms when the FA method fails. Therefore, FAML can serve as a key component for improved construction of initial structural models from macromolecules captured by CECT.

Chang Liu, Xiangrui Zeng, Ruogu Lin et al.

Cellular Electron Cryo-Tomography (CECT) is a powerful imaging technique for the 3D visualization of cellular structure and organization at submolecular resolution. It enables analyzing the native structures of macromolecular complexes and their spatial organization inside single cells. However, due to the high degree of structural complexity and practical imaging limitations, systematic macromolecular structural recovery inside CECT images remains challenging. Particularly, the recovery of a macromolecule is likely to be biased by its neighbor structures due to the high molecular crowding. To reduce the bias, here we introduce a novel 3D convolutional neural network inspired by Fully Convolutional Network and Encoder-Decoder Architecture for the supervised segmentation of macromolecules of interest in subtomograms. The tests of our models on realistically simulated CECT data demonstrate that our new approach has significantly improved segmentation performance compared to our baseline approach. Also, we demonstrate that the proposed model has generalization ability to segment new structures that do not exist in training data.

Jialiang Guo, Bo Zhou, Xiangrui Zeng et al.

Electron Cryo-Tomography (ECT) enables 3D visualization of macromolecule structure inside single cells. Macromolecule classification approaches based on convolutional neural networks (CNN) were developed to separate millions of macromolecules captured from ECT systematically. However, given the fast accumulation of ECT data, it will soon become necessary to use CNN models to efficiently and accurately separate substantially more macromolecules at the prediction stage, which requires additional computational costs. To speed up the prediction, we compress classification models into compact neural networks with little in accuracy for deployment. Specifically, we propose to perform model compression through knowledge distillation. Firstly, a complex teacher network is trained to generate soft labels with better classification feasibility followed by training of customized student networks with simple architectures using the soft label to compress model complexity. Our tests demonstrate that our compressed models significantly reduce the number of parameters and time cost while maintaining similar classification accuracy.

Bo Zhou, Qiang Guo, Xiangrui Zeng et al.

Electron Cryo-Tomography (ECT) allows 3D visualization of subcellular structures at the submolecular resolution in close to the native state. However, due to the high degree of structural complexity and imaging limits, the automatic segmentation of cellular components from ECT images is very difficult. To complement and speed up existing segmentation methods, it is desirable to develop a generic cell component segmentation method that is 1) not specific to particular types of cellular components, 2) able to segment unknown cellular components, 3) fully unsupervised and does not rely on the availability of training data. As an important step towards this goal, in this paper, we propose a saliency detection method that computes the likelihood that a subregion in a tomogram stands out from the background. Our method consists of four steps: supervoxel over-segmentation, feature extraction, feature matrix decomposition, and computation of saliency. The method produces a distribution map that represents the regions' saliency in tomograms. Our experiments show that our method can successfully label most salient regions detected by a human observer, and able to filter out regions not containing cellular components. Therefore, our method can remove the majority of the background region, and significantly speed up the subsequent processing of segmentation and recognition of cellular components captured by ECT.

Xiangrui Zeng, Miguel Ricardo Leung, Tzviya Zeev-Ben-Mordehai et al.

Cellular electron cryo-tomography enables the 3D visualization of cellular organization in the near-native state and at submolecular resolution. However, the contents of cellular tomograms are often complex, making it difficult to automatically isolate different in situ cellular components. In this paper, we propose a convolutional autoencoder-based unsupervised approach to provide a coarse grouping of 3D small subvolumes extracted from tomograms. We demonstrate that the autoencoder can be used for efficient and coarse characterization of features of macromolecular complexes and surfaces, such as membranes. In addition, the autoencoder can be used to detect non-cellular features related to sample preparation and data collection, such as carbon edges from the grid and tomogram boundaries. The autoencoder is also able to detect patterns that may indicate spatial interactions between cellular components. Furthermore, we demonstrate that our autoencoder can be used for weakly supervised semantic segmentation of cellular components, requiring a very small amount of manual annotation.

Min Xu

The linking genotype to phenotype is the fundamental aim of modern genetics. We focus on study of links between gene expression data and phenotype data through integrative analysis. We propose three approaches. 1) The inherent complexity of phenotypes makes high-throughput phenotype profiling a very difficult and laborious process. We propose a method of automated multi-dimensional profiling which uses gene expression similarity. Large-scale analysis show that our method can provide robust profiling that reveals different phenotypic aspects of samples. This profiling technique is also capable of interpolation and extrapolation beyond the phenotype information given in training data. It can be used in many applications, including facilitating experimental design and detecting confounding factors. 2) Phenotype association analysis problems are complicated by small sample size and high dimensionality. Consequently, phenotype-associated gene subsets obtained from training data are very sensitive to selection of training samples, and the constructed sample phenotype classifiers tend to have poor generalization properties. To eliminate these obstacles, we propose a novel approach that generates sequences of increasingly discriminative gene cluster combinations. Our experiments on both simulated and real datasets show robust and accurate classification performance. 3) Many complex phenotypes, such as cancer, are the product of not only gene expression, but also gene interaction. We propose an integrative approach to find gene network modules that activate under different phenotype conditions. Using our method, we discovered cancer subtype-specific network modules, as well as the ways in which these modules coordinate. In particular, we detected a breast-cancer specific tumor suppressor network module with a hub gene, PDGFRL, which may play an important role in this module.

Min Xu, Rudy Setiono

Various approaches to gene selection for cancer classification based on microarray data can be found in the literature and they may be grouped into two categories: univariate methods and multivariate methods. Univariate methods look at each gene in the data in isolation from others. They measure the contribution of a particular gene to the classification without considering the presence of the other genes. In contrast, multivariate methods measure the relative contribution of a gene to the classification by taking the other genes in the data into consideration. Multivariate methods select fewer genes in general. However, the selection process of multivariate methods may be sensitive to the presence of irrelevant genes, noises in the expression and outliers in the training data. At the same time, the computational cost of multivariate methods is high. To overcome the disadvantages of the two types of approaches, we propose a hybrid method to obtain gene sets that are small and highly discriminative. We devise our hybrid method from the univariate Maximum Likelihood method (LIK) and the multivariate Recursive Feature Elimination method (RFE). We analyze the properties of these methods and systematically test the effectiveness of our proposed method on two cancer microarray datasets. Our experiments on a leukemia dataset and a small, round blue cell tumors dataset demonstrate the effectiveness of our hybrid method. It is able to discover sets consisting of fewer genes than those reported in the literature and at the same time achieve the same or better prediction accuracy.

Akshay Krishnamurthy, Sivaraman Balakrishnan, Min Xu et al.

Advances in sensing technologies and the growth of the internet have resulted in an explosion in the size of modern datasets, while storage and processing power continue to lag behind. This motivates the need for algorithms that are efficient, both in terms of the number of measurements needed and running time. To combat the challenges associated with large datasets, we propose a general framework for active hierarchical clustering that repeatedly runs an off-the-shelf clustering algorithm on small subsets of the data and comes with guarantees on performance, measurement complexity and runtime complexity. We instantiate this framework with a simple spectral clustering algorithm and provide concrete results on its performance, showing that, under some assumptions, this algorithm recovers all clusters of size ?(log n) using O(n log^2 n) similarities and runs in O(n log^3 n) time for a dataset of n objects. Through extensive experimentation we also demonstrate that this framework is practically alluring.