Identification, screening, and comprehensive evaluation of novel thrombin inhibitory peptides from the hirudo produced using pepsin.

Purpose: The inhibition of thrombin has proven to be an efficacious therapeutic approach for managing cardiovascular disease (CVD), with widespread implementation in clinical settings. Oral ingestion of peptides and protein drugs is influenced by gastrointestinal digestive enzymes. We aimed to evaluate the thrombin inhibitory properties of hirudo hydrolysates (HHS) produced by pepsin and propose a comprehensive approach to screen and evaluate thrombin inhibitors.

Morphological remodeling of the repaired sigmoid sinus bone wall in patients with pulsatile tinnitus after successful surgical reconstruction: an ultra-high-resolution CT study.

Background: Sigmoid sinus wall reconstruction (SSWR) is an effective treatment for pulsatile tinnitus (PT). However, follow-up postoperative imaging manifestations have not been extensively reported.

Purpose: To evaluate the morphological changes in patients with PT after successful SSWR using ultra-high-resolution computed tomography (U-HRCT).

Mitotic ER-mitochondria contact enhances mitochondrial Ca influx to promote cell division.

Cell division is tightly regulated and requires an expanded energy supply. However, how this energy is generated remains unclear. Here, we establish a correlation between two mitochondrial Ca influx events and ATP production during mitosis.

The Effect of Transverse Sinus Stenosis Caused by Arachnoid Granulation on Patients with Venous Pulsatile Tinnitus: A Multiphysics Interaction Simulation Investigation.

This study aimed to investigate the effect of the transverse sinus (TS) stenosis (TSS) position caused by arachnoid granulation on patients with venous pulsatile tinnitus (VPT) and to further identify the types of TSS that are of therapeutic significance for patients. Multiphysics interaction models of six patients with moderate TSS caused by arachnoid granulation and virtual stent placement in TSS were reconstructed, including three patients with TSS located in the middle segment of the TS (group 1) and three patients with TTS in the middle and proximal involvement segment of the TS (group 2). The transient multiphysics interaction simulation method was applied to elucidate the differences in biomechanical and acoustic parameters between the two groups.

Tunable Magnetism in Atomically Thin Itinerant Antiferromagnet with Room-Temperature Ferromagnetic Order.

Addressing the need for modulated spin configurations is crucial, as they serve as the foundational building blocks for next-generation spintronics, particularly in atomically thin structures and at room temperature. In this work, we realize intrinsic ferromagnetism in monolayer flakes and tunable ferro-/antiferromagnetism in (FeCo)GeTe antiferromagnets. Remarkably, the ferromagnetic ordering (≥1 L) and antiferromagnetic ordering (≥4 L) remain discernible up to room temperature.

Mechanistic Modeling of Empagliflozin: Predicting Pharmacokinetics, Urinary Glucose Excretion, and Investigating Compensatory Role of SGLT1 in Renal Glucose Reabsorption.

The aim of this study was to use a combination of physiologically based pharmacokinetic (PBPK) modeling and urinary glucose excretion (UGE) modeling to predict the time profiles of pharmacokinetics (PK) and UGE for the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMP). Additionally, the study aims to explore the compensatory effect of SGLT1 in renal glucose reabsorption (RGR) when SGLT2 is inhibited. The PBPK-UGE model was developed using physicochemical and biochemical properties, renal physiological parameters, binding kinetics, glucose, and Na reabsorption kinetics by SGLT1/2.

Fluid-structure interaction study on the causes of mending material damage after sigmoid sinus wall reconstruction.

Background And Objective: Sigmoid Sinus (SS) Wall Reconstruction (SSWR) is the mainstream treatment for pulsatile tinnitus (PT), but it has a high risk of recurrence. The damage of mending material is the key cause of recurrence, and its hemodynamic mechanism is still unclear. The purpose of this study was to investigate the hemodynamic causes of mending material breakage.

Hemodynamic assessments of unilateral pulsatile tinnitus with jugular bulb wall dehiscence using 4D flow magnetic resonance imaging.

Background: Pulsatile tinnitus (PT) is a type of tinnitus characterized by a rhythmic sound that is synchronous with the heartbeat. One of the possible causes of PT is the jugular bulb wall dehiscence (JBWD). However, the hemodynamics of this condition are not well understood.

Structure of GPR101-Gs enables identification of ligands with rejuvenating potential.

GPR101 is an orphan G protein-coupled receptor actively participating in energy homeostasis. Here we report the cryo-electron microscopy structure of GPR101 constitutively coupled to Gs heterotrimer, which reveals unique features of GPR101, including the interaction of extracellular loop 2 within the 7TM bundle, a hydrophobic chain packing-mediated activation mechanism and the structural basis of disease-related mutants. Importantly, a side pocket is identified in GPR101 that facilitates in silico screening to identify four small-molecule agonists, including AA-14.

Physiologically-based pharmacokinetic modeling for optimal dosage prediction of olaparib when co-administered with CYP3A4 modulators and in patients with hepatic/renal impairment.

This study aimed to develop a physiologically-based pharmacokinetic (PBPK) model to predict the maximum plasma concentration (C) and trough concentration (C) at steady-state of olaparib (OLA) in Caucasian, Japanese and Chinese. Furthermore, the PBPK model was combined with mean and 95% confidence interval to predict optimal dosing regimens of OLA when co-administered with CYP3A4 modulators and administered to patients with hepatic/renal impairment. The dosing regimens were determined based on safety and efficacy PK threshold C (< 12,500 ng/mL) and C (772-2500 ng/mL).

Molecular pathway of mitochondrial preprotein import through the TOM-TIM23 supercomplex.

Over half of mitochondrial proteins are imported from the cytosol via the pre-sequence pathway, controlled by the TOM complex in the outer membrane and the TIM23 complex in the inner membrane. The mechanisms through which proteins are translocated via the TOM and TIM23 complexes remain unclear. Here we report the assembly of the active TOM-TIM23 supercomplex of Saccharomyces cerevisiae with translocating polypeptide substrates.

Electric-field control of reversible electronic and magnetic transitions in two-dimensional oxide monolayer magnets.

Atomically thin oxide magnetic materials are highly desirable due to the promising potential to integrate two-dimensional (2D) magnets into next-generation spintronics. Therefore, 2D oxide magnetism is expected to be effectively tuned by the magnetic and electrical fields, holding prospective for future low-dissipation electronic devices. However, the electric-field control of 2D oxide monolayer magnetism has rarely been reported.

Cryo-EM and femtosecond spectroscopic studies provide mechanistic insight into the energy transfer in CpcL-phycobilisomes.

Phycobilisomes (PBS) are the major light harvesting complexes of photosynthesis in the cyanobacteria and red algae. CpcL-PBS is a type of small PBS in cyanobacteria that transfers energy directly to photosystem I without the core structure. Here we report the cryo-EM structure of the CpcL-PBS from the cyanobacterium Synechocystis sp.

Prediction for Plasma Trough Concentration and Optimal Dosing of Imatinib under Multiple Clinical Situations Using Physiologically Based Pharmacokinetic Modeling.

(1) : This study aimed to develop a physiologically based pharmacokinetic (PBPK) model to predict the trough concentration ( ) of imatinib (IMA) at steady state in patients and to explore the role of free concentration ( ), α1-acid glycoprotein (AGP) level, and organic cation transporter 1 (OCT1) activity/expression in clinical efficacy. (2) : The population PBPK model was built using physicochemical and biochemical properties, metabolizing and transporting kinetics, tissue distribution, and human physiological parameters. (3) : The PBPK model successfully predicted the of IMA administered alone in chronic phase (CP) and accelerated phase (AP) patients, the of IMA co-administered with six modulators, and in CP patients with hepatic impairment.

Rapid screening and in vivo target occupancy quantitative evaluation of xanthine oxidase inhibitors based on drug-target binding kinetics research strategy: A case study of Chrysanthemum morifolium Ramat.

Chrysanthemum morifolium Ramat. is a kind of food and drug dual-use traditional Chinese medicine possessing multiple pharmacological and biochemical benefits. In our study, a rapid and high-throughput method based on Surface plasmon resonance (SPR) biosensor technology was developed and verified for screening potential xanthine oxidase (XOD) inhibitors exemplarily in the Chrysanthemum morifolium Ramat.

Comprehensive structural characterization of the human AAA+ disaggregase CLPB in the apo- and substrate-bound states reveals a unique mode of action driven by oligomerization.

The human AAA+ ATPase CLPB (SKD3) is a protein disaggregase in the mitochondrial intermembrane space (IMS) and functions to promote the solubilization of various mitochondrial proteins. Loss-of-function CLPB mutations are associated with a few human diseases with neutropenia and neurological disorders. Unlike canonical AAA+ proteins, CLPB contains a unique ankyrin repeat domain (ANK) at its N-terminus.

CT evaluation of unilateral pulsatile tinnitus with jugular bulb wall dehiscence.

Objectives: To investigate the imaging features of unilateral pulsatile tinnitus (PT) with jugular bulb wall dehiscence (JBWD).

Methods: Computerized tomography angiography images of unilateral PT patients were reviewed between 2019 and 2021. Thirty-one symptomatic JBWD patients without sigmoid sinus wall dehiscence (SSWD) were included.

Using a Mathematical Modeling To Simulate Pharmacokinetics and Urinary Glucose Excretion of Luseogliflozin and Explore the Role of SGLT1/2 in Renal Glucose Reabsorption.

(1) Purpose: To develop a mathematical model combining physiologically based pharmacokinetic and urinary glucose excretion (PBPK-UGE) to simultaneously predict pharmacokinetic (PK) and UGE changes of luseogliflozin (LUS) as well as to explore the role of sodium-glucose cotransporters (SGLT1 and SGLT2) in renal glucose reabsorption (RGR) in humans. (2) Methods: The PBPK-UGE model was built using physicochemical and biochemical properties, binding kinetics data, affinity to SGLTs for glucose, and physiological parameters of renal tubules. (3) Results: The simulations using this model clarified that SGLT1/2 contributed 15 and 85%, respectively, to RGR in the absence of LUS.

Identification, Screening, and Comprehensive Evaluation of Novel DPP-IV Inhibitory Peptides from the Tilapia Skin Gelatin Hydrolysate Produced Using Ginger Protease.

Purpose: Inhibition of dipeptidyl peptidase-IV (DPP-IV) is an effective therapy for treating type II diabetes (T2D) that has been widely applied in clinical practice. We aimed to evaluate the DPP-IV inhibitory properties of ginger protease hydrolysate (GPH) and propose a comprehensive approach to screen and evaluate DPP-IV inhibitors.

Methods: We evaluated the in vitro inhibitory properties of fish skin gelatin hydrolysates produced by five proteases, namely, neutral protease, alkaline protease, bromelain, papain, and ginger protease, toward DPP-IV.

Structural insights into the covalent regulation of PAPP-A activity by proMBP and STC2.

Originally discovered in the circulation of pregnant women as a protein secreted by placental trophoblasts, the metalloprotease pregnancy-associated plasma protein A (PAPP-A) is also widely expressed by many other tissues. It cleaves insulin-like growth factor-binding proteins (IGFBPs) to increase the bioavailability of IGFs and plays essential roles in multiple growth-promoting processes. While the vast majority of the circulatory PAPP-A in pregnancy is proteolytically inactive due to covalent inhibition by proform of eosinophil major basic protein (proMBP), the activity of PAPP-A can also be covalently inhibited by another less characterized modulator, stanniocalcin-2 (STC2).