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Incomplete understanding of how hepatosteatosis transitions to fibrotic non-alcoholic steatohepatitis (NASH) has limited therapeutic options. Two molecules that are elevated in hepatocytes in human NASH liver are cholesterol, whose mechanistic link to NASH remains incompletely understood, and TAZ, a transcriptional regulator that promotes fibrosis but whose mechanism of increase in NASH is unknown. We now show that increased hepatocyte cholesterol upregulates TAZ and promotes fibrotic NASH. ASTER-B/C-mediated internalization of plasma membrane cholesterol activates soluble adenylyl cyclase (sAC; ADCY10), triggering a calcium-RhoA-mediated pathway that suppresses β-TrCP/proteasome-mediated TAZ degradation. In mice fed with a cholesterol-rich NASH-inducing diet, hepatocyte-specific silencing of ASTER-B/C, sAC, or RhoA decreased TAZ and ameliorated fibrotic NASH. The cholesterol-TAZ pathway is present in primary human hepatocytes, and associations among liver cholesterol, TAZ, and RhoA in human NASH liver are consistent with the pathway. Thus, hepatocyte cholesterol contributes to fibrotic NASH by increasing TAZ, suggesting new targets for therapeutic intervention.

The paper proposes a new stochastic multiobjective technoeconomic model for integrating photovoltaic (PV) and wind energy resources in electricity price (EP)‐driven distribution systems. The primary goal of this paper is to determine the optimal location and capacity for renewable energy‐based distributed generation, specifically PV and wind resources, while considering weather and system uncertainties. These uncertainties include stochastic variations in PV illumination intensity, wind speed, EP, and load fluctuations. To address these uncertainties, the paper employs scenario modeling techniques named as Latin hypercube sampling with Cholesky decomposition. This technique generates multiple correlated scenarios that represent uncertain variables. Subsequently, a scenario reduction technique is applied to identify the scenario with the highest probability. Later, a mathematical model is developed to minimize an objective function that encompasses various factors like system losses, node voltage deviations, the cost of purchasing power from the grid; and simultaneously maximize the total annual energy savings. The objective is to find optimal solutions that strike a balance between different objectives. To obtain an efficient optimum solution, this paper employs an effective meta‐heuristic technique named as JAYA algorithm. The results obtained by the JAYA algorithm are juxtaposed with those obtained using particle swarm optimization and genetic algorithm techniques. The proposed method is evaluated using Institute of Electrical and Electronics Engineers (IEEE) 33‐node and IEEE 69‐node test feeders to validate its feasibility and effectiveness. However, the effectiveness of the proposed method is not limited to any size of test systems. [ABSTRACT FROM AUTHOR]

The run-on flat tire is an important technology in the area of vehicle safety technology. Nowadays, traveling by a personal vehicle from one place to another has increased due to the increase in the global economy. The main problem that is faced while traveling is tire puncture. The tire may get punctured by any sharp objects on the road such as screws and iron pins that traps the tire surface. A situation like this may be overcome by the usage of the drive on a puncher tire device which will be used to reach the destination without any need for a puncher shop. Using this device will reduce the damage of the tire and tube. This device is portable and can be placed in a vehicle itself. For this reason, a design has been developed by the CATIA 3D experience. The drive on a puncher tire device was designed using the software developed by the Dassault systems named CATIA 3D experience. Aluminum alloy was chosen as the base material to design and simulate this product. Also, the network distribution simulations were used to develop the mathematical equations to check the adequacy of the model. This device is very useful while traveling long distances if any puncher will occur. The sensors were attached to the product to receive the signal from the vehicle, so that the vehicle will run smoothly for a short distance. Drive on a puncher tire will be suitable for both two- and four-wheeler vehicles and also useful for all the areas like villages, towns, panchayats, and cities. If the tire is puncher, we cannot drive the vehicle; hence, a skating device is fixed at a tired bottom, which is used to move the vehicle. The proposal will be beneficial for a huge number of people who own two and four wheelers. This design and simulation will address the problem of the two- and four-wheeler owners traveling long distances., Author(s): V Sivamaran [1]; Hariprasath Manoharan [2]; Yuvaraja Teekaraman (corresponding author) [3]; Ramya Kuppusamy [4]; Arun Radhakrishnan (corresponding author) [5] 1. Introduction The safety of the automobile vehicles was highly [...]

Lipid synthesis is regulated by the actions of Scap, a polytopic membrane protein that binds cholesterol in membranes of the endoplasmic reticulum (ER). When ER cholesterol levels are low, Scap activates SREBPs, transcription factors that upregulate genes for synthesis of cholesterol, fatty acids, and triglycerides. When ER cholesterol levels rise, the sterol binds to Scap, triggering conformational changes that prevent activation of SREBPs and halting synthesis of lipids. To achieve a molecular understanding of how cholesterol regulates the Scap/SREBP machine and to identify therapeutics for dysregulated lipid metabolism, cholesterol-mimetic compounds that specifically bind and inhibit Scap are needed. To accomplish this goal, we focused on Anthrolysin O (ALO), a pore-forming bacterial toxin that binds cholesterol with a specificity and sensitivity that is uncannily similar to Scap. We reasoned that a small molecule that would bind and inhibit ALO might also inhibit Scap. High-throughput screening of a ~300,000-compound library for ALO-binding unearthed one molecule, termed UT-59, which binds to Scap's cholesterol-binding site. Upon binding, UT-59 triggers the same conformation changes in Scap as those induced by cholesterol and blocks activation of SREBPs and lipogenesis in cultured cells. UT-59 also inhibits SREBP activation in the mouse liver. Unlike five previously reported inhibitors of SREBP activation, UT-59 is the only one that acts specifically by binding to Scap's cholesterol-binding site. Our approach to identify specific Scap inhibitors such as UT-59 holds great promise in developing therapeutic leads for human diseases stemming from elevated SREBP activation, such as fatty liver and certain cancers. [ABSTRACT FROM AUTHOR]

Byline: Ruckmani. Arunachalam, Venu. Rao Konda, Madhavi. Eerike, Arun. Radhakrishnan, Sobita. Devi OBJECTIVES: To evaluate the effects of ethanolic root Ethanolic extract of Azima tetracantha. Lam roots (EEATR) in adenine-induced [...]