De-Risking Seizure Liability: Integrating Adverse Outcome Pathways (AOPs), New Approach Methodologies (NAMs) and In Silico Approaches while Highlighting Knowledge Gaps.

Animal studies are commonly used in drug development, chemical, and environmental toxicology to predict human toxicity, but their reliability, particularly in the central nervous system (CNS) is limited. For example, animal models often fail to predict drug-induced seizures, leading to unforeseen convulsions in clinical trials. Evaluating environmental compounds, such as pesticides, also poses challenges due to time and resource constraints, resulting in compounds remaining untested.

The Proteome Profile of Stress Test Assessed Cardiovascular Disease Risk-Prone Diabetic Subjects.

Cardiovascular disease (CVD) is the leading cause of death in the diabetic population. There is a need for specific predictive markers to assess CVD risk. The present study explored the plasma proteome profile of treadmill test (TMT) assessed diabetic stress test positive (DSTP) and diabetic stress test negative (DSTN) subjects by performing a SWATH-MS-based label-free quantitative mass spectrometry approach to identify differentially expressed proteins (DEPs).

Neurotechnology for enhancing human operation of robotic and semi-autonomous systems.

Human operators of remote and semi-autonomous systems must have a high level of executive function to safely and efficiently conduct operations. These operators face unique cognitive challenges when monitoring and controlling robotic machines, such as vehicles, drones, and construction equipment. The development of safe and experienced human operators of remote machines requires structured training and credentialing programs.

Once-weekly IcoSema versus multiple daily insulin injections in type 2 diabetes management (COMBINE 3): an open-label, multicentre, treat-to-target, non-inferiority, randomised, phase 3a trial.

Background: IcoSema is a once-weekly combination therapy of basal insulin icodec (icodec) and semaglutide (a GLP-1 analogue) developed for the treatment of type 2 diabetes. We aimed to evaluate the efficacy and safety of IcoSema versus basal-bolus therapy (BBT) in adults with type 2 diabetes inadequately controlled on daily basal insulin.

Methods: COMBINE 3, a 52-week, open-label, treat-to-target, non-inferiority, randomised, phase 3a trial, was done across 109 outpatient clinics and hospital departments in 14 countries.

Structures of Fab-stabilized CHIP reveal a conformational switch important in E3 ligase and chaperone functions.

Carboxyl terminus of Hsc70-interacting protein (CHIP/STUB1) is a U-box E3 ligase essential for protein quality control, targeting misfolded or damaged proteins for clearance and conducting chaperone-like functions by suppressing aggregation of proteins, including tau. The previous structure of full-length CHIP identified an asymmetric homodimer in which one U-box is occluded from E2 binding, indicating an unusual half-of-sites activity. However, the flexibility of CHIP has complicated efforts to further characterize its structure and function.