Structure and function of a near fully-activated intermediate GPCR-Gαβγ complex.

Unraveling the signaling roles of intermediate complexes is pivotal for G protein-coupled receptor (GPCR) drug development. Despite hundreds of GPCR-Gαβγ structures, these snapshots primarily capture the fully activated complex. Consequently, the functions of intermediate GPCR-G protein complexes remain elusive.

Molecular Insights into α-Synuclein Fibrillation: A Raman Spectroscopy and Machine Learning Approach.

The aggregation of α-synuclein is crucial to the development of Lewy body diseases, including Parkinson's disease and dementia with Lewy bodies. The aggregation pathway of α-synuclein typically involves a defined sequence of nucleation, elongation, and secondary nucleation, exhibiting prion-like spreading. This study employed Raman spectroscopy and machine learning analysis, alongside complementary techniques, to characterize the biomolecular changes during the fibrillation of purified recombinant wild-type α-synuclein protein.

Design, Structure Optimization, and Preclinical Characterization of JAB-21822, a Covalent Inhibitor of KRAS.

KRAS is the most frequently mutated driver oncogene in human cancer, and KRAS mutation is commonly found in non-small-cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). Inhibitors that covalently modify the mutated codon 12 cysteine have completed proof-of-concept studies in the clinic. Here, we describe structure-based design and cocrystal-aided drug optimization of a series of compounds with the 1,8-naphthyridine-3-carbonitrile scaffold.

High prevalence of veterinary drugs in bird's nests.

The environmental impact of insecticides used as ectoparasitic treatments for companion animals is not well understood, since they are not subject to detailed environmental risk assessment. Many of these treatments include active ingredients such as fipronil and imidacloprid that are banned from agricultural use in the EU. These treatments are applied topically and can remain on the animal's fur for an extended period of time.

Z-DNA at the crossroads: untangling its role in genome dynamics.

DNA can fold into noncanonical left-handed Z-DNA conformation beyond the right-handed B-DNA. While its crystal structure was discovered nearly four decades ago, it was predominantly considered a structural curiosity. Recent evidence suggests that Z-DNA formation occurs in nuclear and mitochondrial DNA (mtDNA), with significant biological implications.

The role of nutritional vitamin D in CKD-MBD in children and adults with CKD, on dialysis and after kidney transplantation - a European consensus statement.

Vitamin D deficiency is common in patients with chronic kidney disease (CKD) and associates with poor outcomes. Current clinical practice guidelines recommend supplementation with nutritional vitamin D as for the general population. However, recent large-scale, clinical trials in the general population failed to demonstrate a benefit of vitamin D supplementation on skeletal or non-skeletal outcomes, fueling a debate on the rationale for screening for and correcting vitamin D deficiency, both in non-CKD and CKD populations.

Ex Situ Synthesis of N-Capped Peptides in the Solution Phase via Palladium-Catalyzed Aminocarbonylation Utilizing Chloroform-COware.

We report the synthesis of N-capped peptides under mild conditions using the oxidative aminocarbonylation of aryl iodides and peptide esters as nucleophiles in the solution phase. Ex situ chloroform in chamber A generates CO, which diffuses to chamber B, which contains other reactants. This method offers N-capped peptides at 80 °C for 12 h.

Guanine-Assisted Contrived Low Pt-Integrated MoC/C for Hydrogen Evolution Reaction.

Due to the high cost of the available Pt electrocatalysts, the large-scale water electrolysis production of hydrogen has been hindered. Hydrogen generation via electrochemical water splitting is a renewable energy essential to a sustainable society, creating a distinct material interface that shows Pt-like properties with long-term stability crucial to hydrogen evolution reactions (HERs). Here, we synthesized the guanine-assisted facile synthesis of 1 wt % Pt/MoC/C having a layered type morphology via solid state calcined process followed by chemical reduction.

Operando Electro-Oxidation Reconstitution of a Newly Designed 2D Co(II)-MOF on Nickel Foam to Cobalt Oxyhydroxide Nanosheets towards Energy Sustainability: A Holy Grail in Electrocatalytic Water Splitting.

The upsurging of cost-effective electrocatalysts through the operando electro-oxidation approaches holds great promise for the scalable production of green energy in the pursuit of energy sustainability. This work introduces an operando electro-oxidation reconstitution strategy in producing a smart electrocatalyst, cobalt "oxyhydroxide" derived from a newly designed 2D cobalt(II) metal-organic framework (-) directly grown on nickel foam (NF), . The electrocatalyst, , exhibits an outstanding overpotential of 76 mV for the hydrogen evolution reaction and 336 mV for the oxygen evolution reaction to achieve a current density of 10 mA/cm with remarkable Faradaic efficiencies of 97.

Photophysical Investigation of Dyes and Dye-PMMA Systems: Insights into Absorption, Emission, and Charge Transfer Mechanisms.

The photophysical properties of five dyes, i.e., perylene, anthracene, aminoanthracene, 1,6-diphenylhexatriene, and 7-diethylamino-4-methylcoumarin, in solvent and attached to the poly(methyl methacrylate) (PMMA) polymer, were studied via DFT and TD-DFT calculations.

Destined for destruction: The role of methionine aminopeptidases and plant cysteine oxidases in N-degron formation.

The cysteine/arginine (Cys/Arg) branch of the N-degron pathway controls the stability of certain proteins with methionine (Met)-Cys N-termini, initiated by Met cleavage and Cys oxidation. In seeding plants, target proteins include the Group VII Ethylene Response Factors, which initiate adaptive responses to low oxygen (hypoxic) stress, as well as Vernalization 2 (VRN2) and Little Zipper 2 (ZPR2), which are involved in responses to endogenous developmental hypoxia. It is essential that these target proteins are only degraded by the N-degron pathway under the appropriate physiological conditions.

Olfactory testing in infants with perinatal asphyxia: enhancing encephalopathy risk stratification for future health outcomes.

Perinatal asphyxia (PA) is a leading cause of neonatal morbidity and mortality, often resulting in long-term neurodevelopmental challenges. Despite advancements in perinatal care, predicting long-term outcomes remains difficult. Early diagnosis is essential for timely interventions to reduce brain injury, with tools such as Magnetic Resonance Imaging, brain ultrasound, and emerging biomarkers playing a possible key role.

Unravelling phylogenetic relationships within the genus Lispe (Diptera: Muscidae) through genome-assisted and de novo analyses of RAD-seq data.

Lispe represents a species-rich genus within the family Muscidae. The current subdivision of Lispe species into species groups is based mainly on adult morphology and ecology, with the only available phylogenetic study based on three molecular markers. Nonetheless, certain species groups remain unclear and the relationships and composition of these groups are still unresolved.

Metallofullerenol Gd@C(OH) preserves human erythrocyte plasma membrane integrity from AAPH-induced oxidative stress: molecular mechanisms and antioxidant activity.

Metallofullerenols and fullerenols have attracted attention due to their remarkable ability to interact with various biologically relevant molecules, paving the way for biomedical applications, ranging from medical imaging techniques to drug carriers, acting with increased efficiency and reduced side effects. In this work, we investigated the effects of two fullerene derivatives, Gd@C(OH) and C(OH), on erythrocyte membrane components under oxidative stress conditions induced by 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH) as a source of peroxyl radicals. The results demonstrated that gadolinium encapsulation within the fullerene cage enhanced the electron affinity of Gd@C(OH), resulting in stronger antioxidant activity.

Navigating through chemometrics: Unveiling antibiotic-food interactions for improved pediatric formulations ahead.

Background: Given the challenges of pediatric antibacterial therapy, it is crucial to formulate antibiotics with a lower potential for interaction with dietary interventions and tailor them for optimal administration in children. Chemometric methods allow us to analyze multiple interrelated variables simultaneously and uncover correlations.

Aim: We applied a chemometric approach to examine how food, beverages, antacids, and mineral supplements affect antibiotic bioavailability in adults and children, aiming to explore relationships between antibiotic structure, physicochemical properties, and post-meal changes in pharmacokinetic (PK) parameters.

Free fatty acids derived from lipophagy enhanced resistance to anoikis by activating Src in high-invasive clear cell renal cell carcinoma cells.

Autophagy-mediated anoikis resistance plays a critical role in the initiation of tumor metastasis. Therefore, we investigated the role and mechanism of anoikis resistance mediated by free fatty acids (FFAs) derived from lipophagy in highly invasive clear cell renal cell carcinoma (ccRCC). Here, we found that the highly invasive ccRCC cell line Himi exhibited enhanced resistance to anoikis and elevated lipophagy levels.

Deep eutectic solvents in analysis, delivery and chemistry of pharmaceuticals.

Deep eutectic solvents (DES) have an emerging scientific role, assisting modern pharmaceutics. They are uniquely supporting the resolution of crucial issues, such as the effective extraction and isolation of bio-actives. They act as media and catalysts for pharmaceutical drug synthesis, and as green solvents and modifiers in pharmaceutical analysis.

Formulation screening of lyophilized mRNA-lipid nanoparticles.

Lipid nanoparticles (LNPs) have demonstrated their therapeutic potential as safe and effective drug delivery systems for nucleic acids during the COVID-19 pandemic. However, one of the main challenges during technical CMC (Chemistry, Manufacturing, and Controls) development is their long-term stability at temperatures of 2-8 °C or higher, which may be improved by the removal of water by lyophilization. In this study, we identified lyo-/cryo-protectants for freeze-dried mRNA-LNP formulations beyond conventional excipients such as sucrose and trehalose as T-modifiers using polyA as a surrogate.

Abiraterone acetate fixed-dosed combinations with ibuprofen-based therapeutic eutectic and deep eutectic solvents.

In recent years, deep eutectic solvents (DESs) with their outstanding solubilization properties have emerged as strong candidates for oral enabling formulations of poorly soluble drugs. This study explores the use of drug-based therapeutic DESs (THEDESs) to solubilize a poorly soluble compound with the aim of providing a fixed-dose combination of two complementary therapeutic agents. Specifically, potential anticancer effects of ibuprofen (IBU) are harnessed in a novel type of THEDES to dissolve higher amounts of abiraterone acetate (AbAc), an antitumor agent.

IN SILICO AND IN VITRO ASSESSMENT OF ANTI-Leishmania infantum ACTIVITY OF A NOVEL CYCLOHEXYL-1,2,4-OXADIAZOLE DERIVATIVE.

Globally, an estimated 1 billion people reside in endemic areas, and over 12 million individuals are infected with leishmaniasis. Despite its prevalence, leishmaniasis continues to be a neglected disease, mainly affecting underdeveloped countries. In Brazil, the available treatments are pentavalent antimonials and Amphotericin B, which are outdated, toxic, require prolonged parenteral administration and have limited efficacy.

Impact of Dandelion (Taraxacum officinale) leaf aqueous extract on immunological response of mice after Schistosoma mansoni infection.

This study investigated the effect of dandelion (Taraxacum officinale) leaf aqueous extract (DLE) on the immunological response of mice following infection with Schistosoma mansoni. Mice (in groups of 7) were first experimentally infected with S. mansoni and, 6 weeks later, were treated with praziquantel (PZQ) and/or DLE.

Computational identification and experimental validation of novel microRNAs along with their targets through RT-PCR approach.

Various metabolic and cell signaling processes impact the functions of sugarcane plant cells. MicroRNAs (miRNAs) play critical regulatory roles in enhancing yield and providing protection against various stressors. This study seeks to identify and partially characterize several novel miRNAs in sugarcane using tools, while also offering a preliminary assessment of their functions.

A genetically encoded fluorescent biosensor for visualization of acetyl-CoA in live cells.

Acetyl-coenzyme A is a central metabolite that participates in many cellular pathways. Evidence suggests that acetyl-CoA metabolism is highly compartmentalized in mammalian cells. Yet methods to measure acetyl-CoA in living cells are lacking.

Analysis of TEM micrographs with deep learning reveals APOE genotype-specific associations between HDL particle diameter and Alzheimer's dementia.

High-density lipoprotein (HDL) particle diameter distribution is informative in the diagnosis of many conditions, including Alzheimer's disease (AD). However, obtaining an accurate HDL size measurement is challenging. We demonstrated the utility of measuring the diameter of more than 1,800,000 HDL particles with the deep learning model YOLOv7 (you only look once) from micrographs of 183 HDL samples, including patients with dementia or normal cognition (controls).

Effect of doping in TiO/chitosan composite on adsorptive-photocatalytic removal of gallic acid from water.

Gallic acid (GA) has emerged as a low biodegradable and high acidity industrial effluent. Due to mutagenic and carcinogenic nature of GA, it becomes essential to remove it from wastewater. Different chemical, physical and biological methods are being used for this purpose.