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1. Chapter 8 Research Strategies for Investigating Protein Ubiquitination in Lung Diseases

Author

Zhao, Yutong

Subjects
asthma, cystic fibrosis, gas exchange, homeostasis, inflammation, lung diseas, lung endothelium, stem cells
Abstract

ch. 8 Post-translational modification (PTMs) determines protein’s cellular functions including enzyme activity, localization, protein-protein interaction, and protein stability. Ubiquitin is a 7-kDa protein. Ubiquitination is one of PTMs and it is defined as protein covalently conjugation with a ubiquitin or poly-ubiquitin chains. A series of enzymatic reactions catalyze protein ubiquitination, which can be reversed by deubiquitinating enzymes (DUBs). The abnormal expression of ubiquitination-related enzymes and ubiquitination in lung cells have been demonstrated to alter cell functions, such as cell proliferation, death, and differentiation, ultimately contribute to the pathogenesis of lung diseases. In this chapter, we will introduce the methodology and research strategies for investigating protein ubiquitination in lung cells and experimental lung diseases. Common practice and edge-cutting laboratory technologies will be introduced in the chapter. Finally, we will discuss new drug development by targeting ubiquitination for therapies.

Published
2024
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2. DGoT: Dynamic Graph of Thoughts for Scientific Abstract Generation

Author

Ning, Xinyu, Zhao, Yutong, Liu, Yitong, and Yang, Hongwen

Subjects
Computer Science - Computation and Language
Abstract

The method of training language models based on domain datasets has obtained significant achievements in the task of generating scientific paper abstracts. However, such models face problems of generalization and expensive training costs. The use of large language models (LLMs) to solve the task of generating paper abstracts saves the cost of model training. However, due to the hallucination problem of LLM, it is often necessary to improve the reliability of the results through multi-round query prompt approach such as Graph of Thoughts (GoT), which also brings additional reasoning costs. In this paper, we propose a Dynamic Graph of Thought (DGoT). It not only inherits the advantages of the existing GoT prompt approach, but also dynamically adjust the graph structure according to data characteristics while reducing model reasoning cost. Experimental results show that our method's cost-effectiveness in abstract generation tasks is only 43.7% to 56.4% of other multi-round query prompt approaches. Our code is available at https://github.com/JayceNing/DGoT., Comment: Accepted by LREC-COLING 2024

Published
2024

5. A local resampling trick for focused molecular dynamics

Author

Fass, Joshua, York, Forrest, Wittmann, Matthew, Kaus, Joseph, and Zhao, Yutong

Subjects
Condensed Matter - Statistical Mechanics, Physics - Computational Physics, Statistics - Computation
Abstract

We describe a method that focuses sampling effort on a user-defined selection of a large system, which can lead to substantial decreases in computational effort by speeding up the calculation of nonbonded interactions. A naive approach can lead to incorrect sampling if the selection depends on the configuration in a way that is not accounted for. We avoid this pitfall by introducing appropriate auxiliary variables. This results in an implementation that is closely related to configurational freezing and elastic barrier dynamical freezing. We implement the method and validate that it can be used to supplement conventional molecular dynamics in free energy calculations (absolute hydration and relative binding).

Published
2023

19. Noncanonical HIPPO/MST Signaling via BUB3 and FOXO Drives Pulmonary Vascular Cell Growth and Survival

Author

Kudryashova, Tatiana V, Dabral, Swati, Nayakanti, Sreenath, Ray, Arnab, Goncharov, Dmitry A, Avolio, Theodore, Shen, Yuanjun, Rode, Analise, Pena, Andressa, Jiang, Lifeng, Lin, Derek, Baust, Jeffrey, Bachman, Timothy N, Graumann, Johannes, Ruppert, Clemens, Guenther, Andreas, Schmoranzer, Mario, Grobs, Yann, Lemay, Sarah Eve, Tremblay, Eve, Breuils-Bonnet, Sandra, Boucherat, Olivier, Mora, Ana L, DeLisser, Horace, Zhao, Jing, Zhao, Yutong, Bonnet, Sébastien, Seeger, Werner, Pullamsetti, Soni S, and Goncharova, Elena A

Subjects
Medical Physiology, Biomedical and Clinical Sciences, Lung, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Cardiovascular, Animals, Cell Cycle Proteins, Cell Proliferation, Cells, Cultured, Chromosomal Proteins, Non-Histone, Forkhead Transcription Factors, Hypertension, Pulmonary, Hypoxia, Mammals, Mechanistic Target of Rapamycin Complex 1, Mice, Myocytes, Smooth Muscle, Poly-ADP-Ribose Binding Proteins, Proteomics, Proto-Oncogene Proteins c-akt, Pulmonary Arterial Hypertension, Pulmonary Artery, Vascular Remodeling, animals, hypoxia, mice, proteomic, pulmonary artery, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences
Abstract

RationaleThe MSTs (mammalian Ste20-like kinases) 1/2 are members of the HIPPO pathway that act as growth suppressors in adult proliferative diseases. Pulmonary arterial hypertension (PAH) manifests by increased proliferation and survival of pulmonary vascular cells in small PAs, pulmonary vascular remodeling, and the rise of pulmonary arterial pressure. The role of MST1/2 in PAH is currently unknown.ObjectiveTo investigate the roles and mechanisms of the action of MST1 and MST2 in PAH.Methods and resultsUsing early-passage pulmonary vascular cells from PAH and nondiseased lungs and mice with smooth muscle-specific tamoxifen-inducible Mst1/2 knockdown, we found that, in contrast to canonical antiproliferative/proapoptotic roles, MST1/2 act as proproliferative/prosurvival molecules in human PAH pulmonary arterial vascular smooth muscle cells and pulmonary arterial adventitial fibroblasts and support established pulmonary vascular remodeling and pulmonary hypertension in mice with SU5416/hypoxia-induced pulmonary hypertension. By using unbiased proteomic analysis, gain- and loss-of function approaches, and pharmacological inhibition of MST1/2 kinase activity by XMU-MP-1, we next evaluated mechanisms of regulation and function of MST1/2 in PAH pulmonary vascular cells. We found that, in PAH pulmonary arterial adventitial fibroblasts, the proproliferative function of MST1/2 is caused by IL-6-dependent MST1/2 overexpression, which induces PSMC6-dependent downregulation of forkhead homeobox type O 3 and hyperproliferation. In PAH pulmonary arterial vascular smooth muscle cells, MST1/2 acted via forming a disease-specific interaction with BUB3 and supported ECM (extracellular matrix)- and USP10-dependent BUB3 accumulation, upregulation of Akt-mTORC1, cell proliferation, and survival. Supporting our in vitro observations, smooth muscle-specific Mst1/2 knockdown halted upregulation of Akt-mTORC1 in small muscular PAs of mice with SU5416/hypoxia-induced pulmonary hypertension.ConclusionsTogether, this study describes a novel proproliferative/prosurvival role of MST1/2 in PAH pulmonary vasculature, provides a novel mechanistic link from MST1/2 via BUB3 and forkhead homeobox type O to the abnormal proliferation and survival of pulmonary arterial vascular smooth muscle cells and pulmonary arterial adventitial fibroblasts, remodeling and pulmonary hypertension, and suggests new target pathways for therapeutic intervention.

Published
2022

24. Schr\'odinger-ANI: An Eight-Element Neural Network Interaction Potential with Greatly Expanded Coverage of Druglike Chemical Space

Author

Stevenson, James M., Jacobson, Leif D., Zhao, Yutong, Wu, Chuanjie, Maple, Jon, Leswing, Karl, Harder, Edward, and Abel, Robert

Subjects
Physics - Chemical Physics, Computer Science - Machine Learning
Abstract

We have developed a neural network potential energy function for use in drug discovery, with chemical element support extended from 41% to 94% of druglike molecules based on ChEMBL. We expand on the work of Smith et al., with their highly accurate network for the elements H, C, N, O, creating a network for H, C, N, O, S, F, Cl, P. We focus particularly on the calculation of relative conformer energies, for which we show that our new potential energy function has an RMSE of 0.70 kcal/mol for prospective druglike molecule conformers, substantially better than the previous state of the art. The speed and accuracy of this model could greatly accelerate the parameterization of protein-ligand binding free energy calculations for novel druglike molecules., Comment: 20 pages, 6 figures

Published
2019

36. Oral administration of PEGylated TLR7 ligand ameliorates alcohol-associated liver disease via the induction of IL-22.

Author

Wang, Qinglan, Kim, So Yeon, Matsushita, Hiroshi, Wang, Zhijun, Pandyarajan, Vijay, Matsuda, Michitaka, Ohashi, Koichiro, Tsuchiya, Takashi, Roh, Yoon Seok, Kiani, Calvin, Zhao, Yutong, Chan, Michael, Devkota, Suzanne, Lu, Shelly C, Hayashi, Tomoko, Carson, Dennis A, and Seki, Ekihiro

Subjects
Intestinal Mucosa, Tight Junctions, Animals, Mice, Inbred C57BL, Mice, Knockout, Mice, Bacteroides, Lactobacillus, Fatty Liver, Liver Diseases, Alcoholic, Disease Models, Animal, Inflammation, Ethanol, Polyethylene Glycols, Membrane Glycoproteins, MicroRNAs, Interleukins, Ligands, Administration, Oral, Signal Transduction, Female, Toll-Like Receptor 7, Pore Forming Cytotoxic Proteins, Gastrointestinal Microbiome, Pancreatitis-Associated Proteins, IL-22, Toll-like receptor, alcoholic hepatitis, Substance Misuse, Alcoholism, Alcohol Use and Health, Chronic Liver Disease and Cirrhosis, Liver Disease, Digestive Diseases, Hepatitis, Development of treatments and therapeutic interventions, 2.1 Biological and endogenous factors, Aetiology, 5.1 Pharmaceuticals, Oral and gastrointestinal, Good Health and Well Being
Abstract

Effective therapies for alcohol-associated liver disease (ALD) are limited; therefore, the discovery of new therapeutic agents is greatly warranted. Toll-like receptor 7 (TLR7) is a pattern recognition receptor for single-stranded RNA, and its activation prevents liver fibrosis. We examined liver and intestinal damage in Tlr7-/- mice to determine the role of TLR7 in ALD pathogenesis. In an alcoholic hepatitis (AH) mouse model, hepatic steatosis, injury, and inflammation were induced by chronic binge ethanol feeding in mice, and Tlr7 deficiency exacerbated these effects. Because these results demonstrated that endogenous TLR7 signaling activation is protective in the AH mouse model, we hypothesized that TLR7 activation may be an effective therapeutic strategy for ALD. Therefore, we investigated the therapeutic effect of TLR7 agonistic agent, 1Z1, in the AH mouse model. Oral administration of 1Z1 was well tolerated and prevented intestinal barrier disruption and bacterial translocation, which thus suppressed ethanol-induced hepatic injury, steatosis, and inflammation. Furthermore, 1Z1 treatment up-regulated the expression of antimicrobial peptides, Reg3b and Reg3g, in the intestinal epithelium, which modulated the microbiome by decreasing and increasing the amount of Bacteroides and Lactobacillus, respectively. Additionally, 1Z1 up-regulated intestinal interleukin (IL)-22 expression. IL-22 deficiency abolished the protective effects of 1Z1 in ethanol-induced liver and intestinal damage, suggesting intestinal IL-22 as a crucial mediator for 1Z1-mediated protection in the AH mouse model. Collectively, our results indicate that TLR7 signaling exerts protective effects in the AH mouse model and that a TLR7 ligand, 1Z1, holds therapeutic potential for the treatment of AH.

Published
2021

41. Economic dispatch of community-integrated energy system considering demand-side coordinated response

Author

Zhao Yutong, Zhang Heng, Ding Yifeng, Zeng Shuang, Ma Lin, and Wang Zhao

Subjects
integrated energy system, demand-side coordinated response, economic optimal scheduling model, yalmip toolbox, cplex solver, Technology, Science
Abstract

There are a large number of potential schedulable resources in the integrated energy system of electricity, heat, cold, and gas. However, most of these energy sources are currently operated separately, with low system flexibility, low energy utilization rate, and serious abandonment of wind and solar energy. In order to improve the flexibility of integrated energy systems and the capacity of renewable energy consumption, an economic dispatch of community-integrated energy systems considering demand-side coordinated response is proposed. Firstly, according to various energy characteristics, mathematical models of various energy forms are established, including wind energy, photovoltaic, gas turbine, gas boiler, and other component characteristics modeling. Secondly, an economic optimal scheduling model of community-integrated energy system considering demand side response is established, including the constraints and objective functions of the optimization model, and the optimization model is solved based on the Yalmip toolbox and Cplex solver in Matlab software. Finally, the effectiveness of the proposed strategy is verified by a simulation example.

Published
2024
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