Roles Played by DOCK11, a Guanine Nucleotide Exchange Factor, in HBV Entry and Persistence in Hepatocytes.

HBV infection is challenging to cure due to the persistence of viral covalently closed circular viral DNA (cccDNA). The dedicator of cytokinesis 11 (DOCK11) is recognized as a guanine nucleotide exchange factor (GEF) for CDC42 that has been reported to be required for HBV persistence. DOCK11 is expressed in both the cytoplasm and nucleus of human hepatocytes and is functionally associated with retrograde trafficking proteins Arf-GAP with GTPase domain, ankyrin repeat, and pleckstrin homology domain-containing protein 2 (AGAP2), and ADP-ribosylation factor 1 (ARF1), together with the HBV capsid, in the trans-Golgi network (TGN). This opens an alternative retrograde trafficking route for HBV from early endosomes (EEs) to the TGN and then to the endoplasmic reticulum (ER), thereby avoiding lysosomal degradation. DOCK11 also facilitates the association of cccDNA with H3K4me3 and RNA Pol II for activating cccDNA transcription. In addition, DOCK11 plays a crucial role in the host DNA repair system, being essential for cccDNA synthesis. This function can be inhibited by 10M-D42AN, a novel DOCK11-binding peptide, leading to the suppression of HBV replication both in vitro and in vivo. Treatment with a combination of 10M-D42AN and entecavir may represent a promising therapeutic strategy for patients with chronic hepatitis B (CHB). Consequently, DOCK11 may be seen as a potential candidate molecule in the development of molecularly targeted drugs against CHB.

Potential utility of l-carnitine for preventing liver tumors derived from metabolic dysfunction-associated steatohepatitis.

BACKGROUND: Recent reports have unveiled the potential utility of l-carnitine to alleviate metabolic dysfunction-associated steatohepatitis (MASH) by enhancing mitochondrial metabolic function. However, its efficacy at preventing the development of HCC has not been assessed fully. METHODS: l-carnitine (2 g/d) was administered to 11 patients with MASH for 10 weeks, and blood liver function tests were performed. Five patients received a serial liver biopsy, and liver histology and hepatic gene expression were evaluated using this tissue. An atherogenic plus high-fat diet MASH mouse model received long-term l-carnitine administration, and liver histology and liver tumor development were evaluated. RESULTS: Ten-week l-carnitine administration significantly improved serum alanine transaminase and aspartate transaminase levels along with a histological improvement in the NAFLD activity score, while steatosis and fibrosis were not improved. Gene expression profiling revealed a significant improvement in the inflammation and profibrotic gene signature as well as the recovery of lipid metabolism. Long-term l-carnitine administration to atherogenic plus high-fat diet MASH mice substantially improved liver histology (inflammation, steatosis, and fibrosis) and significantly reduced the incidence of liver tumors. l-carnitine directly reduced the expression of the MASH-associated and stress-induced transcriptional factor early growth response 1. Early growth response 1 activated the promoter activity of neural precursor cell expressed, developmentally downregulated protein 9 (NEDD9), an oncogenic protein. Thus, l-carnitine reduced the activation of the NEDD9, focal adhesion kinase 1, and AKT oncogenic signaling pathway. CONCLUSIONS: Short-term l-carnitine administration ameliorated MASH through its anti-inflammatory effects. Long-term l-carnitine administration potentially improved the steatosis and fibrosis of MASH and may eventually reduce the risk of HCC.

SSiT: Saliency-Guided Self-Supervised Image Transformer for Diabetic Retinopathy Grading.

Self-supervised Learning (SSL) has been widely applied to learn image representations through exploiting unlabeled images. However, it has not been fully explored in the medical image analysis field. In this work, Saliency-guided Self-Supervised image Transformer (SSiT) is proposed for Diabetic Retinopathy (DR) grading from fundus images. We novelly introduce saliency maps into SSL, with a goal of guiding self-supervised pre-training with domain-specific prior knowledge. Specifically, two saliency-guided learning tasks are employed in SSiT: 1) Saliency-guided contrastive learning is conducted based on the momentum contrast, wherein fundus images' saliency maps are utilized to remove trivial patches from the input sequences of the momentum-updated key encoder. Thus, the key encoder is constrained to provide target representations focusing on salient regions, guiding the query encoder to capture salient features. 2) The query encoder is trained to predict the saliency segmentation, encouraging the preservation of fine-grained information in the learned representations. To assess our proposed method, four publicly-accessible fundus image datasets are adopted. One dataset is employed for pre-training, while the three others are used to evaluate the pre-trained models' performance on downstream DR grading. The proposed SSiT significantly outperforms other representative state-of-the-art SSL methods on all downstream datasets and under various evaluation settings. For example, SSiT achieves a Kappa score of 81.88% on the DDR dataset under fine-tuning evaluation, outperforming all other ViT-based SSL methods by at least 9.48%.

Toward hippocampal volume measures on ultra-high field magnetic resonance imaging: a comprehensive comparison study between deep learning and conventional approaches.

The hippocampus is a complex brain structure that plays an important role in various cognitive aspects such as memory, intelligence, executive function, and path integration. The volume of this highly plastic structure is identified as one of the most important biomarkers of specific neuropsychiatric and neurodegenerative diseases. It has also been extensively investigated in numerous aging studies. However, recent studies on aging show that the performance of conventional approaches in measuring the hippocampal volume is still far from satisfactory, especially in terms of delivering longitudinal measures from ultra-high field magnetic resonance images (MRIs), which can visualize more boundary details. The advancement of deep learning provides an alternative solution to measuring the hippocampal volume. In this work, we comprehensively compared a deep learning pipeline based on nnU-Net with several conventional approaches including Freesurfer, FSL and DARTEL, for automatically delivering hippocampal volumes: (1) Firstly, we evaluated the segmentation accuracy and precision on a public dataset through cross-validation. Results showed that the deep learning pipeline had the lowest mean (L = 1.5%, R = 1.7%) and the lowest standard deviation (L = 5.2%, R = 6.2%) in terms of volume percentage error. (2) Secondly, sub-millimeter MRIs of a group of healthy adults with test-retest 3T and 7T sessions were used to extensively assess the test-retest reliability. Results showed that the deep learning pipeline achieved very high intraclass correlation coefficients (L = 0.990, R = 0.986 for 7T; L = 0.985, R = 0.983 for 3T) and very small volume percentage differences (L = 1.2%, R = 0.9% for 7T; L = 1.3%, R = 1.3% for 3T). (3) Thirdly, a Bayesian linear mixed effect model was constructed with respect to the hippocampal volumes of two healthy adult datasets with longitudinal 7T scans and one disease-related longitudinal dataset. It was found that the deep learning pipeline detected both the subtle and disease-related changes over time with high sensitivity as well as the mild differences across subjects. Comparison results from the aforementioned three aspects showed that the deep learning pipeline significantly outperformed the conventional approaches by large margins. Results also showed that the deep learning pipeline can better accommodate longitudinal analysis purposes.

Accurate measurement of magnetic resonance parkinsonism index by a fully automatic and deep learning quantification pipeline.

OBJECTIVES: This study aims at a fully automatic pipeline for measuring the magnetic resonance parkinsonism index (MRPI) using deep learning methods. METHODS: MRPI is defined as the product of the pons area to the midbrain area ratio and the middle cerebellar peduncle (MCP) width to the superior cerebellar peduncle (SCP) width ratio. In our proposed pipeline, we first used nnUNet to segment the brainstem and then employed HRNet to identify two key boundary points so as to sub-divide the whole brainstem into midbrain and pons. HRNet was also employed to predict the MCP endpoints for measuring the MCP width. Finally, we segmented the SCP on an oblique coronal plane and calculated its width. A total of 400 T1-weighted magnetic resonance images (MRIs) were used to train the nnUNet and HRNet models. Five-fold cross-validation was conducted to evaluate our proposed pipeline's performance on the training dataset. We also evaluated the performance of our proposed pipeline on three external datasets. Two of them had two raters manually measuring the MRPI values, providing insights into automatic accuracy versus inter-rater variability. RESULTS: We obtained average absolute percentage errors (APEs) of 17.21%, 18.17%, 20.83%, and 22.83% on the training dataset and the three external validation datasets, while the inter-rater average APE measured on the first two external validation datasets was 11.31%. Our proposed pipeline significantly improved the MRPI quantification accuracy over a representative state-of-the-art traditional approach (p < 0.001). CONCLUSION: The proposed automatic pipeline can accurately predict MRPI that is comparable with manual measurement. CLINICAL RELEVANCE STATEMENT: This study presents an automated magnetic resonance parkinsonism index measurement tool that can analyze large amounts of magnetic resonance images, enhance the efficiency of Parkinsonism-Plus syndrome diagnosis, reduce the workload of clinicians, and minimize the impact of human factors on diagnosis. KEY POINTS: • We propose an automatic pipeline for measuring the magnetic resonance parkinsonism index from magnetic resonance images. • The effectiveness of the proposed pipeline is successfully established on multiple datasets and comparisons with inter-rater measurements. • The proposed pipeline significantly outperforms a state-of-the-art quantification approach, being much closer to ground truth.

autoSMIM: Automatic Superpixel-Based Masked Image Modeling for Skin Lesion Segmentation.

Skin lesion segmentation from dermoscopic images plays a vital role in early diagnoses and prognoses of various skin diseases. However, it is a challenging task due to the large variability of skin lesions and their blurry boundaries. Moreover, most existing skin lesion datasets are designed for disease classification, with relatively fewer segmentation labels having been provided. To address these issues, we propose a novel automatic superpixel-based masked image modeling method, named autoSMIM, in a self-supervised setting for skin lesion segmentation. It explores implicit image features from abundant unlabeled dermoscopic images. autoSMIM begins with restoring an input image with randomly masked superpixels. The policy of generating and masking superpixels is then updated via a novel proxy task through Bayesian Optimization. The optimal policy is subsequently used for training a new masked image modeling model. Finally, we finetune such a model on the downstream skin lesion segmentation task. Extensive experiments are conducted on three skin lesion segmentation datasets, including ISIC 2016, ISIC 2017, and ISIC 2018. Ablation studies demonstrate the effectiveness of superpixel-based masked image modeling and establish the adaptability of autoSMIM. Comparisons with state-of-the-art methods show the superiority of our proposed autoSMIM. The source code is available at https://github.com/Wzhjerry/autoSMIM.

Identifying the Key Components in ResNet-50 for Diabetic Retinopathy Grading from Fundus Images: A Systematic Investigation.

Although deep learning-based diabetic retinopathy (DR) classification methods typically benefit from well-designed architectures of convolutional neural networks, the training setting also has a non-negligible impact on prediction performance. The training setting includes various interdependent components, such as an objective function, a data sampling strategy, and a data augmentation approach. To identify the key components in a standard deep learning framework (ResNet-50) for DR grading, we systematically analyze the impact of several major components. Extensive experiments are conducted on a publicly available dataset EyePACS. We demonstrate that (1) the DR grading framework is sensitive to input resolution, objective function, and composition of data augmentation; (2) using mean square error as the loss function can effectively improve the performance with respect to a task-specific evaluation metric, namely the quadratically weighted Kappa; (3) utilizing eye pairs boosts the performance of DR grading and; (4) using data resampling to address the problem of imbalanced data distribution in EyePACS hurts the performance. Based on these observations and an optimal combination of the investigated components, our framework, without any specialized network design, achieves a state-of-the-art result (0.8631 for Kappa) on the EyePACS test set (a total of 42,670 fundus images) with only image-level labels. We also examine the proposed training practices on other fundus datasets and other network architectures to evaluate their generalizability. Our codes and pre-trained model are available online.

AADG: Automatic Augmentation for Domain Generalization on Retinal Image Segmentation.

Convolutional neural networks have been widely applied to medical image segmentation and have achieved considerable performance. However, the performance may be significantly affected by the domain gap between training data (source domain) and testing data (target domain). To address this issue, we propose a data manipulation based domain generalization method, called Automated Augmentation for Domain Generalization (AADG). Our AADG framework can effectively sample data augmentation policies that generate novel domains and diversify the training set from an appropriate search space. Specifically, we introduce a novel proxy task maximizing the diversity among multiple augmented novel domains as measured by the Sinkhorn distance in a unit sphere space, making automated augmentation tractable. Adversarial training and deep reinforcement learning are employed to efficiently search the objectives. Quantitative and qualitative experiments on 11 publicly-accessible fundus image datasets (four for retinal vessel segmentation, four for optic disc and cup (OD/OC) segmentation and three for retinal lesion segmentation) are comprehensively performed. Two OCTA datasets for retinal vasculature segmentation are further involved to validate cross-modality generalization. Our proposed AADG exhibits state-of-the-art generalization performance and outperforms existing approaches by considerable margins on retinal vessel, OD/OC and lesion segmentation tasks. The learned policies are empirically validated to be model-agnostic and can transfer well to other models. The source code is available at https://github.com/CRazorback/AADG.

Probability distribution guided optic disc and cup segmentation from fundus images.

In this paper, we proposed and validated a probability distribution guided network for segmenting optic disc (OD) and optic cup (OC) from fundus images. Uncertainty is inevitable in deep learning, as induced by different sensors, insufficient samples, and inaccurate labeling. Since the input data and the corresponding ground truth label may be inaccurate, they may actually follow some potential distribution. In this study, a variational autoencoder (VAE) based network was proposed to estimate the joint distribution of the input image and the corresponding segmentation (both the ground truth segmentation and the predicted segmentation), making the segmentation network learn not only pixel-wise information but also semantic probability distribution. Moreover, we designed a building block, namely the Dilated Inception Block (DIB), for a better generalization of the model and a more effective extraction of multi-scale features. The proposed method was compared to several existing state-of-the-art methods. Superior segmentation performance has been observed over two datasets (ORIGA and REFUGE), with the mean Dice overlap coefficients being 96.57% and 95.81% for OD and 88.46% and 88.91% for OC.

The SUSTech-SYSU dataset for automatically segmenting and classifying corneal ulcers.

Corneal ulcer is a common ophthalmic symptom. Segmentation algorithms are needed to identify and quantify corneal ulcers from ocular staining images. Developments of such algorithms have been obstructed by a lack of high quality datasets (the ocular staining images and the corresponding gold-standard ulcer segmentation labels), especially for supervised learning based segmentation algorithms. In such context, we prepare a dataset containing 712 ocular staining images and the associated segmentation labels of flaky corneal ulcers. In addition to segmentation labels for flaky corneal ulcers, we also provide each image with three-fold class labels: firstly, each image has a label in terms of its general ulcer pattern; secondly, each image has a label in terms of its specific ulcer pattern; thirdly, each image has a label indicating its ulcer severity degree. This dataset not only provides an excellent opportunity for investigating the accuracy and reliability of different segmentation and classification algorithms for corneal ulcers, but also advances the development of new supervised learning based algorithms especially those in the deep learning framework.

Fully Automatic White Matter Hyperintensity Segmentation using U-net and Skip Connection.

White matter hyperintensity (WMH) is associated with various aging and neurodegenerative diseases. In this paper, we proposed and validated a fully automatic system which integrated classical image processing and deep neural network for segmenting WMH from fluid attenuation inversion recovery (FLAIR) and T1-weighed magnetic resonance (MR) images. A novel skip connection U-net (SC U-net) was proposed and compared with the classical U-net. Experiments were performed on a dataset of 60 images, acquired from three different scanners. Validation analysis and cross-scanner testing were conducted. Compared with U-net, the proposed SC U-net had a faster convergence and higher segmentation accuracy. The software environment and models of the proposed system were made publicly accessible at Dockerhub.