DegronMD: Leveraging Evolutionary and Structural Features for Deciphering Protein-Targeted Degradation, Mutations, and Drug Response to Degrons

Protein-targeted degradation is an emerging and promising therapeutic approach. The specificity of degradation and the maintenance of cellular homeostasis are determined by the interactions between E3 ubiquitin ligase and degradation signals, known as degrons. The human genome encodes over 600 E3 ligases; however, only a small number of targeted degron instances have been identified so far. In this study, we introduced DegronMD, an open knowledgebase designed for the investigation of degrons, their associated dysfunctional events, and drug responses. We revealed that degrons are evolutionarily conserved and tend to occur near the sites of protein translational modifications, particularly in the regions of disordered structure and higher solvent accessibility. Through pattern recognition and machine learning techniques, we constructed the degrome landscape across the human proteome, yielding over 18,000 new degrons for targeted protein degradation. Furthermore, dysfunction of degrons disrupts the degradation process and leads to the abnormal accumulation of proteins; this process is associated with various types of human cancers. Based on the estimated phenotypic changes induced by somatic mutations, we systematically quantified and assessed the impact of mutations on degron function in pan-cancers; these results helped to build a global mutational map on human degrome, including 89,318 actionable mutations that may induce the dysfunction of degrons and disrupt protein degradation pathways. Multiomics integrative analysis unveiled over 400 drug resistance events associated with the mutations in functional degrons. DegronMD, accessible at https://bioinfo.uth.edu/degronmd, is a useful resource to explore the biological mechanisms, infer protein degradation, and assist with drug discovery and design on degrons

Infusing Hierarchical Guidance into Prompt Tuning: A Parameter-Efficient Framework for Multi-level Implicit Discourse Relation Recognition

Multi-level implicit discourse relation recognition (MIDRR) aims at identifying hierarchical discourse relations among arguments. Previous methods achieve the promotion through fine-tuning PLMs. However, due to the data scarcity and the task gap, the pre-trained feature space cannot be accurately tuned to the task-specific space, which even aggravates the collapse of the vanilla space. Besides, the comprehension of hierarchical semantics for MIDRR makes the conversion much harder. In this paper, we propose a prompt-based Parameter-Efficient Multi-level IDRR (PEMI) framework to solve the above problems. First, we leverage parameter-efficient prompt tuning to drive the inputted arguments to match the pre-trained space and realize the approximation with few parameters. Furthermore, we propose a hierarchical label refining (HLR) method for the prompt verbalizer to deeply integrate hierarchical guidance into the prompt tuning. Finally, our model achieves comparable results on PDTB 2.0 and 3.0 using about 0.1% trainable parameters compared with baselines and the visualization demonstrates the effectiveness of our HLR method.Comment: accepted to ACL 202

Deep Learning for Detecting and Elucidating Human T-cell Leukemia Virus Type 1 Integration in the Human Genome

Human T-cell leukemia virus type 1 (HTLV-1), a retrovirus, is the causative agent for adult T cell leukemia/lymphoma and many other human diseases. Accurate and high throughput detection of HTLV-1 virus integration sites (VISs) across the host genomes plays a crucial role in the prevention and treatment of HTLV-1-associated diseases. Here, we developed DeepHTLV, the first deep learning framework for VIS prediction de novo from genome sequence, motif discovery, and cis-regulatory factor identification. We demonstrated the high accuracy of DeepHTLV with more efficient and interpretive feature representations. Decoding the informative features captured by DeepHTLV resulted in eight representative clusters with consensus motifs for potential HTLV-1 integration. Furthermore, DeepHTLV revealed interesting cis-regulatory elements in regulation of VISs that have significant association with the detected motifs. Literature evidence demonstrated nearly half (34) of the predicted transcription factors enriched with VISs were involved in HTLV-1-associated diseases. DeepHTLV is freely available at https://github.com/bsml320/DeepHTLV

Exploration of the impact of demographic changes on life insurance consumption: empirical analysis based on Shanghai Cooperation Organization

Based on the panel data of eight member states of Shanghai Cooperation Organization (SCO) from 1996 to 2019, this study explores the impact of demographic changes on life insurance consumption in SCO member countries under the framework of static panel model and dynamic panel model. And the study analyzes the heterogeneity of religious division and different aging degrees. The empirical results show that both old-age dependency ratio and teenager dependency ratio have positive impacts on life insurance consumption in the SCO countries. Besides, the current consumption of ordinary life insurance significantly stimulates the future consumption of ordinary life insurance. Furthermore, demographic changes have heterogeneous impacts on life insurance consumption in terms of different religions and different degrees of aging. Our findings provide managerial implications for insurance companies that carry out life insurance business in SCO member states. Insurance companies should consider the policyholders’ life insurance consumption in accordance with demographic changes of both old-age dependency ratio and teenager dependency ratio, and also take differentiated life insurance sales strategies according to different degrees of aging and whether the residents believe in Islam

LucidDreamer: Towards High-Fidelity Text-to-3D Generation via Interval Score Matching

The recent advancements in text-to-3D generation mark a significant milestone in generative models, unlocking new possibilities for creating imaginative 3D assets across various real-world scenarios. While recent advancements in text-to-3D generation have shown promise, they often fall short in rendering detailed and high-quality 3D models. This problem is especially prevalent as many methods base themselves on Score Distillation Sampling (SDS). This paper identifies a notable deficiency in SDS, that it brings inconsistent and low-quality updating direction for the 3D model, causing the over-smoothing effect. To address this, we propose a novel approach called Interval Score Matching (ISM). ISM employs deterministic diffusing trajectories and utilizes interval-based score matching to counteract over-smoothing. Furthermore, we incorporate 3D Gaussian Splatting into our text-to-3D generation pipeline. Extensive experiments show that our model largely outperforms the state-of-the-art in quality and training efficiency.Comment: The first two authors contributed equally to this work. Our code will be available at: https://github.com/EnVision-Research/LucidDreame

MetaDegron: Multimodal Feature-Integrated Protein Language Model for Predicting E3 Ligase Targeted Degrons

Protein degradation through the ubiquitin proteasome system at the spatial and temporal regulation is essential for many cellular processes. E3 ligases and degradation signals (degrons), the sequences they recognize in the target proteins, are key parts of the ubiquitin-mediated proteolysis, and their interactions determine the degradation specificity and maintain cellular homeostasis. To date, only a limited number of targeted degron instances have been identified, and their properties are not yet fully characterized. To tackle on this challenge, here we develop a novel deep-learning framework, namely MetaDegron, for predicting E3 ligase targeted degron by integrating the protein language model and comprehensive featurization strategies. Through extensive evaluations using benchmark datasets and comparison with existing method, such as Degpred, we demonstrate the superior performance of MetaDegron. Among functional features, MetaDegron allows batch prediction of targeted degrons of 21 E3 ligases, and provides functional annotations and visualization of multiple degron-related structural and physicochemical features. MetaDegron is freely available at http://modinfor.com/MetaDegron/. We anticipate that MetaDegron will serve as a useful tool for the clinical and translational community to elucidate the mechanisms of regulation of protein homeostasis, cancer research, and drug development