Deciphering allosteric mechanisms in KRAS activation: insights from GTP-induced conformational dynamics and interaction network reorganization.

The conformational dynamics and activation mechanisms of KRAS proteins are of great importance for targeted cancer therapy. However, the detailed molecular mechanics of KRAS activation induced by GTP binding remains unclear. In this study, we systematically investigated how GTP/GDP exchange affects the thermodynamic and kinetic properties of KRAS and explored the activation mechanism using molecular dynamics (MD) simulations, Markov state models (MSMs), and neural relational inference (NRI) models.

Molecular dynamic simulations to explore the broad-spectrum activity of the inhibitor PF-07321332 against human coronavirus.

The main protease (M) stands as a pivotal enzyme crucial for coronavirus replication, thus serving as a prime target for coronavirus drug discovery endeavors. Nirmatrelvir (PF-07321332), an antiviral compound developed by Pfizer, has been engineered to selectively inhibit the M of SARS-CoV-2 by directly binding to its catalytic cysteine residue (Cys145). In a bid to scrutinize the expansive inhibitory spectrum of PF-07321332 against a gamut of human pathogenic coronaviruses, we undertook an exhaustive investigation leveraging molecular dynamics (MD) simulations in conjunction with binding free energy (BFE) calculations.

Research on Precise Attitude Measurement Technology for Satellite Extension Booms Based on the Star Tracker.

This paper reports the successful application of a self-developed, miniaturized, low-power nano-star tracker for precise attitude measurement of a 5-m-long satellite extension boom. Such extension booms are widely used in space science missions to extend and support payloads like magnetometers. The nano-star tracker, based on a CMOS image sensor, weighs 150 g (including the baffle), has a total power consumption of approximately 0.

Lysosomal transmembrane protein 5: Impact on immune cell function and implications for immune-related deficiencies.

Lysosomal transmembrane protein 5 (LAPTM5) is a lysosomal-associated protein that interacts with surface receptors on various immune cells, including B cells, T cells, macrophages and dendritic cells. Dysregulated expression of LAPTM5 is implicated in the development of multiple immune system-related diseases. In the context of tumors, elevated LAPTM5 levels in immune cells are associated with decreased cell membrane levels of T cell receptors (TCR) or B cell receptors (BCR), leading to impaired antigen presentation and immune escape, thereby promoting tumor progression.

Progress of researches on mechanisms of acupuncture underlying improvement of cerebral ischemia-reperfusion injury by regulating calcium overload.

Ischemic stroke is currently the most common type of stroke, and the key pathological link is cerebral ischemia-reperfusion injury (CIRI), while the key factor leading to apoptosis and necrosis of ischemic nerve cells is calcium overload. Current studies have confirmed that acupuncture therapy has a good modulating effect on calcium homeostasis and can reduce cerebral ischemia-reperfusion induced damage of neuronal cells by inhibiting calcium overload. After reviewing the relevant literature published in the past 15 years, we find that acupuncture plays a role in regulating the pathological mechanism of calcium overload after CIRI by inhibiting the opening of connexin 43 hemichannels, regulating the intracellular free calcium ion concentration, suppressing the expression of calmodulin, and blocking the function of L-type voltage-gated calcium channels, thereby inhibiting calcium overload, regulating calcium homeostasis and antagonizing neuronal damage resulted from cerebral ischemia-reperfusion, which may provide ideas for future research.

Characterization of a thermophilic and glucose-tolerant GH1 β-glucosidase from hot springs and its prospective application in corn stover degradation.

Introduction: β-Glucosidase serves as the pivotal rate-limiting enzyme in the cellulose degradation process, facilitating the hydrolysis of cellobiose and cellooligosaccharides into glucose. However, the widespread application of numerous β-glucosidases is hindered by their limited thermostability and low glucose tolerance, particularly in elevated-temperature and high-glucose environments.

Methods: This study presents an analysis of a β-glucosidase gene belonging to the GH1 family, denoted , which was isolated from the metagenomic repository of Hehua hot spring located in Tengchong, China.

Rafting and redissolution of γ' phase in Ni-Al alloy under external stress.

The volume fraction and rafting degree of the γ'-NiAl phase under stress and high temperature are the key characteristics of mechanical properties in Ni-based superalloys, the rafting and redissolution of γ' phase caused by the creep at high temperature damage the morphology and properties of Ni-based superalloys. The phase-field simulation is performed to study the rafting accompany with the redissolution of γ' phase under high temperature and loading stress in Ni-Al alloy, the driving force and kinetics evolution of the γ' rafting were revealed. During the rafting under continuous heating, the elastic energy in the vertical γ channel is different to that of the horizontal γ channel, this difference in elastic energy drives the elements diffusion directionally to form the γ' rafts morphology.

The efficacy of electroacupuncture in among early diabetic patients with lower limb arteriosclerotic wounds.

Diabetic foot ulcers are the prevalent complication of diabetes mellitus, frequently culminating in arteriosclerosis of the lower extremities and consequent development of chronic wounds. The effectiveness of electroacupuncture (EA) as therapeutic intervention for promoting wound healing in this particular group of patients has been comprehensively assessed in this study. A randomized controlled trial involving 380 early diabetic patients with arteriosclerotic lesions of the lower limbs was conducted.

An electronic voting scheme based on homomorphic encryption and decentralization.

Compared with paper-based voting, electronic voting not only has advantages in storage and transmission, but also can solve the security problems that exist in traditional voting. However, in practice, most electronic voting faces the risk of voting failure due to malicious voting by voters or ballot tampering by attackers. To solve this problem, this article proposes an electronic voting scheme based on homomorphic encryption and decentralization, which uses the Paillier homomorphic encryption method to ensure that the voting results are not leaked until the election is over.

Exploring the conformational dynamics and thermodynamics of S768I and G719X + S768I mutations in non-small cell lung cancer: An approaches.

Non-small cell lung cancer (NSCLC) is often driven by mutations in the epidermal growth factor receptor () gene. However, rare mutations such as G719X and S768I lack standard anti-EGFR targeted therapies. Understanding the structural differences between wild-type EGFR and these rare mutants is crucial for developing EGFR-targeted drugs.

Inhibition of Hypoxia-Inducible Transcription Factor (HIF-1α) Signaling with Sulfonyl-γ-AApeptide Helices.

The development of inhibitors that selectively block protein-protein interactions (PPIs) is crucial for chemical biology, medicinal chemistry, and biomedical sciences. Herein, we reported the design, synthesis, and investigation of sulfonyl-γ-AApeptide as an alternative strategy of canonical peptide-based inhibitors to disrupt hypoxia-inducible factor 1α (HIF-1α) and p300 PPI by mimicking the helical domain of HIF-1α involved in the binding to p300. The designed molecules recognized the p300 protein with high affinity and potently inhibited the hypoxia-inducible signaling pathway.

Unnatural helical peptidic foldamers as protein segment mimics.

Unnatural helical peptidic foldamers have attracted considerable attention owing to their unique folding behaviours, diverse artificial protein binding mechanisms, and promising applications in chemical, biological, medical, and material fields. Unlike the conventional α-helix consisting of molecular entities of native α-amino acids, unnatural helical peptidic foldamers are generally comprised of well-defined backbone conformers with unique and unnatural structural parameters. Their folded structures usually arise from unnatural amino acids such as -substituted glycine, -substituted-β-alanine, β-amino acid, urea, thiourea, α-aminoxy acid, α-aminoisobutyric acid, aza-amino acid, aromatic amide, γ-amino acid, as well as sulfono-γ-AA amino acid.

Complementary roles of EP2 and EP4 receptors in malignant glioma.

Background And Purpose: Glioblastoma (GBM) is the most aggressive brain tumour in the central nervous system, but the current treatment is very limited and unsatisfactory. PGE -initiated cAMP signalling via EP and EP receptors is involved in the tumourigenesis of multiple cancer types. However, whether or how EP and EP receptors contribute to GBM growth largely remains elusive.

Effect of Tiaoshen Changzhi acupuncture on behavior and striatum ΔFosB in rats with levodopa-induced dyskinesias.

This study aims to study the effffects of Tiaoshen Changzhi acupuncture on behavior and striatum ΔFosB in rats with Levodopa-induced Dyskinesias (LIDs). In this experimental study, Levodopa-induced Dyskinesia (LID) rat models were established by 6-OHDA double-target injection and randomly assigned to six groups, with ten rats in each group. The rats were subjected to difffferent interventions for 28 days, and their behavior was observed.

/Sulfono--AA peptide hybrids agonist of GLP-1R with prolonged action both and .

Peptides are increasingly important resources for biological and therapeutic development, however, their intrinsic susceptibility to proteolytic degradation represents a big hurdle. As a natural agonist for GLP-1R, glucagon-like peptide 1 (GLP-1) is of significant clinical interest for the treatment of type-2 diabetes mellitus, but its instability and short half-life have largely prevented its therapeutic application. Here, we describe the rational design of a series of /sulfono--AA peptide hybrid analogues of GLP-1 as the GLP-1R agonists.

Elastic Strain Relaxation of Phase Boundary of α' Nanoscale Phase Mediated via the Point Defects Loop under Normal Strain.

Irradiation-induced point defects and applied stress affect the concentration distribution and morphology evolution of the nanophase in Fe-Cr based alloys; the aggregation of point defects and the nanoscale precipitates can intensify the hardness and embrittlement of the alloy. The influence of normal strain on the coevolution of point defects and the Cr-enriched α' nanophase are studied in Fe-35 at.% Cr alloy by utilizing the multi-phase-field simulation.

Hierarchical medical system and local medical performance: A quasi-natural experiment evaluation in Shanghai, China.

Background: In order to maintain high standards of healthcare, it is necessary for medical departments to provide high-quality and affordable medical services to local residents. This has been widely accepted in developed countries, while the medical treatment systems in developing countries remain to be improved. This research is based on a pilot of a hierarchical medical system in Shanghai, China, to evaluate the effects on policy of medical reform in developing countries.

Rational design of a sensitivity-enhanced tracer for discovering efficient APC-Asef inhibitors.

The adenomatous polyposis coli (APC)-Rho guanine nucleotide exchange factor 4 (Asef) protein-protein interaction (PPI) is essential for colorectal cancer metastasis, making it a promising drug target. Herein, we obtain a sensitivity-enhanced tracer (tracer 7) with a high binding affinity (K = 0.078 μM) and wide signal dynamic range (span = 251 mp).

Helical sulfono-γ-AApeptides with predictable functions in protein recognition.

Sulfono-γ-AApeptides are a subset of possible sequence-specific foldamers that might be considered for the design of biomimetic drug molecular structures. Although they have been studied for a relatively short period of time, a number of structures and functions have been designed or discovered within this class of unnatural peptides. Examples of utilizing these sulfono-γ-AApeptides have demonstrated the potential that sulfono-γ-AApeptides can offer, however, to date, their application in biomedical sciences yet remains unexplored.

Deciphering gp120 sequence variation and structural dynamics in HIV neutralization phenotype by molecular dynamics simulations and graph machine learning.

Human immunodeficiency virus (HIV) exploits the sequence variation and structural dynamics of the envelope glycoprotein gp120 to evade the immune attack of neutralization antibodies, contributing to various HIV neutralization phenotypes. Although the HIV neutralization phenotype has been experimentally characterized, the roles of rapid sequence variability and significant structural dynamics of gp120 are not well understood. Here, 45 prefusion gp120 from different HIV strains belong to three tiers of sensitive, moderate, and resistant neutralization phenotype are structurally modeled by homology modeling and then investigated by molecular dynamics (MD) simulations and graph machine learning (ML).