Arl2 GTPase associates with the centrosomal protein Cdk5rap2 to regulate cortical development via microtubule organization.

ADP ribosylation factor-like GTPase 2 (Arl2) is crucial for controlling mitochondrial fusion and microtubule assembly in various organisms. Arl2 regulates the asymmetric division of neural stem cells in Drosophila via microtubule growth. However, the function of mammalian Arl2 during cortical development was unknown. Here, we demonstrate that mouse Arl2 plays a new role in corticogenesis via regulating microtubule growth, but not mitochondria functions. Arl2 knockdown (KD) leads to impaired proliferation of neural progenitor cells (NPCs) and neuronal migration. Arl2 KD in mouse NPCs significantly diminishes centrosomal microtubule growth and delocalization of centrosomal proteins Cdk5rap2 and γ-tubulin. Moreover, Arl2 physically associates with Cdk5rap2 by in silico prediction using AlphaFold multimer, which was validated by co-immunoprecipitation and proximity ligation assay. Remarkably, Cdk5rap2 overexpression significantly rescues the neurogenesis defects caused by Arl2 KD. Therefore, Arl2 plays an important role in mouse cortical development through microtubule growth via the centrosomal protein Cdk5rap2.

Real-Time Remote Patient Monitoring and Alarming System for Noncommunicable Lifestyle Diseases.

Telemedicine and remote patient monitoring (RPM) systems have been gaining interest and received adaptation in healthcare sectors since the COVID-19 pandemic due to their efficiency and capability to deliver timely healthcare services while containing COVID-19 transmission. These systems were developed using the latest technology in wireless sensors, medical devices, cloud computing, mobile computing, telecommunications, and machine learning technologies. In this article, a real-time remote patient monitoring system is proposed with an accessible, compact, accurate, and low-cost design. The implemented system is designed to an end-to-end communication interface between medical practitioners and patients. The objective of this study is to provide remote healthcare services to patients who need ongoing care or those who have been discharged from the hospital without affecting their daily routines. The developed monitoring system was then evaluated on 1177 records from MIMIC-III clinical dataset (aged between 19 and 99 years). The performance analysis of the proposed system achieved 88.7% accuracy in generating alerts with logistic regression classification algorithm. This result reflects positively on the quality and robustness of the proposed study. Since the processing time of the proposed system is less than 2 minutes, it can be stated that the system has a high computational speed and is convenient to use in real-time monitoring. Furthermore, the proposed system will fulfil to cover the lower doctor-to-patient ratio by monitoring patients from remote locations and aged people who reside in their residences.

Hydrogen peroxide as a hydride donor and reductant under biologically relevant conditions.

Some ruthenium-hydride complexes react with O2 to yield H2O2, therefore the principle of microscopic reversibility dictates that the reverse reaction is also possible, that H2O2 could transfer an H- to a Ru complex. Mechanistic evidence is presented, using the Ru-catalyzed ABTS˙- reduction reaction as a probe, which suggests that a Ru-H intermediate is formed via deinsertion of O2 from H2O2 following coordination to Ru. This demonstration that H2O2 can function as an H- donor and reductant under biologically-relevant conditions provides the proof-of-concept that H2O2 may function as a reductant in living systems, ranging from metalloenzyme-catalyzed reactions to cellular redox homeostasis, and that H2O2 may be viable as an environmentally-friendly reductant and H- source in green catalysis.

NAD+ as a Hydride Donor and Reductant.

Reduced nicotinamide adenine dinucleotide (NADH) can generate a ruthenium-hydride intermediate that catalyzes the reduction of O2 to H2O2, which endows it with potent anticancer properties. A catalyst that could access a Ru-H intermediate using oxidized nicotinamide adenine dinucleotide (NAD+) as the H- source, however, could draw upon a supply of reducing equivalents 1000-fold more abundant than NADH, which would enable significantly greater H2O2 production. Herein, it is demonstrated, using the reduction of ABTS•- to ABTS2-, that NAD+ can function as a reductant. Mechanistic evidence is presented that suggests a Ru-H intermediate is formed via ß-hydride elimination from a ribose subunit in NAD+. The insight gained from the heretofore unknown ability of NAD+ to function as a reductant and H- donor may lead to undiscovered biological carbohydrate oxidation pathways and new chemotherapeutic strategies.

Catalytic Radical Reduction in Aqueous Solution by a Ruthenium Hydride Intermediate.

Some manganese complexes can catalyze both antioxidant and pro-oxidant reactions, whereby the disparate reactivity modes are determined by the catalyst environment and afford distinct therapeutic effects. We recently reported the reduction of radicals in buffered aqueous solution catalyzed by a ruthenium complex with biologically relevant non-tertiary alcohols as terminal reductants. Mechanistic evidence is presented, indicating that this catalytic radical reduction is achieved by a Ru-hydride intermediate formed by ß-hydride elimination from a Ru-alkoxide species. A similar mechanism and Ru-hydride intermediate was previously reported to kill cancer cells with catalytic pro-oxidant effects. Therefore, our demonstration of catalytic antioxidant effects by the same type of intermediate reveals new potential therapeutic strategies and applications for catalytic systems that form Ru-hydride intermediates.

Catalytic radical reduction in aqueous solution via oxidation of biologically-relevant alcohols.

Metalloenzymes that normally perform catalytic antioxidant or radical-degrading functions, as well as small-molecule complexes that mimic them, can also exert pro-oxidant or radical-forming effects depending on the identity of the terminal reductant. Because nitroxyl radicals function as redox active cocatalysts in the aerobic oxidation of alcohols, we hypothesized that catalytic radical reduction could be achieved via the oxidation of biologically-relevant alcohols. Herein we report an organoruthenium complex (Ru1) that catalyzed reduction of 2,2'-azino-bis(3-ethylbenzo-thiazoline-6-sulfonate) radical monoanion (ABTS˙-) to ABTS2- in phosphate buffered saline (pH 7.4) using MeOH, EtOH, i-PrOH, serine, threonine, glucose, arabinose, methyl lactate or dimethyl malate as the terminal reductant. Replacing either the C-H or O-H groups of a -CHOH- moiety resulted in the loss of ABTS˙- reducing ability. Moreover, in conjunction with an alcohol terminal reductant, Ru1 was able to inhibit the oxidation of ABTS2- by H2O2 and horseradish peroxidase, even after multiple successive challenges with excess H2O2 or ABTS˙-. Collectively, these results demonstrate that Ru1 inhibits the oxidative formation of and catalyzes the reduction of radicals in aqueous solution via oxidation of biologically-relevant alcohols.