CYP8B1 Catalyzes 12alpha-Hydroxylation of C Bile Acid: In Vitro Conversion of Dihydroxycoprostanic Acid into Trihydroxycoprostanic Acid.

Sterol 12α-hydroxylase (CYP8B1) is the unique P450 enzyme with sterol 12-oxidation activity, playing an exclusive role in 12-hydroxylating intermediates along the bile acid (BA) synthesis pathway. Despite the long history of BA metabolism studies, it is unclear whether CYP8B1 catalyzes 12-hydroxylation of C BAs, the key intermediates shuttling between mitochondria and peroxisomes. This work provides robust in vitro evidence that both microsomal and recombinant CYP8B1 enzymes catalyze the 12-hydroxylation of dihydroxycoprostanic acid (DHCA) into trihydroxycoprostanic acid (THCA).

Artificial Intelligence-Assisted Prescription Determination for Orthokeratology Lens Fitting: From Algorithm to Clinical Practice.

Objectives: To explore the potential of artificial intelligence (AI) to assist prescription determination for orthokeratology (OK) lenses.

Methods: Artificial intelligence algorithm development followed by a real-world trial. A total of 11,502 OK lenses fitting records collected from seven clinical environments covering major brands.

Comparison of 1Beta- and 5Beta-hydroxylation of Deoxycholate and Glycodeoxycholate as In Vitro Index Reactions for Cytochrome P450 3A Activities.

Cytochrome P450 3A (CYP3A) participates in the metabolism of more than 30% of clinical drugs. The vast intra- and inter-individual variations in CYP3A activity pose great challenges to drug development and personalized medicine. It has been disclosed that human CYP3A4 and CYP3A7 are exclusively responsible for the tertiary oxidations of deoxycholic acid (DCA) and glycodeoxycholic acid (GDCA) regioselectivity at C-1 and C-5 This work aimed to compare the 1- and 5-hydroxylation of DCA and GDCA as potential in vitro CYP3A index reactions in both human liver microsomes and recombinant P450 enzymes.

Theoretical prediction of valley spin splitting in two-dimensional Janus MSiGeZ (M = Cr and W; Z = N, P, and As).

With the exploration of valleytronic materials in MAZ structures, larger valley spin splitting has become a hot topic of research. Based on first-principles calculations, we predicted six valleytronic 2D (two-dimensional) Janus MSiGeZ (M = Cr and W; Z = N, P, and As) materials. The valley spin splitting value of WSiGeZ (Z = N, P, and As) can reach more than 400 meV, which is favorable for the practical application of valleytronics.

Lineage-mosaic and mutation-patched spike proteins for broad-spectrum COVID-19 vaccine.

SARS-CoV-2 spread in humans results in continuous emergence of new variants, highlighting the need for vaccines with broad-spectrum antigenic coverage. Using inter-lineage chimera and mutation-patch strategies, we engineered a recombinant monomeric spike variant (STFK1628x) that contains key regions and residues across multiple SAR-CoV-2 variants. STFK1628x demonstrated high immunogenicity and mutually complementary antigenicity to its prototypic form (STFK).

Reevaluate In Vitro CYP3A Index Reactions of Benzodiazepines and Steroids between Humans and Dogs.

Cytochrome P450 3A (CYP3A), the most important class of drug-metabolizing enzymes, participates in the metabolism of half of clinically used drugs. The CYP3A index reactions of dogs, one of the most widely used preclinical nonrodent species, are still poorly understood. This work evaluated the activity and selectivity of 10 CYP3A index reactions, including midazolam (MDZ) 1'- and 4-hydroxylation, alprazolam (APZ) and triazolam (TRZ) - and 4-hydroxylation, testosterone (T) 6-hydroxylation, lithocholate (LCA) 6-hydroxylation, deoxycholate (DCA) 1- and 5-hydroxylation, with quantitative reaction phenotyping and kinetic analysis in human and canine recombinant CYP enzymes (rCYPs).

Targeting CaMKII-δ9 Ameliorates Cardiac Ischemia/Reperfusion Injury by Inhibiting Myocardial Inflammation.

Background: CaMKII (Ca/calmodulin-dependent kinase II) plays a central role in cardiac ischemia/reperfusion (I/R) injury-an important therapeutic target for ischemic heart disease. In the heart, CaMKII-δ is the predominant isoform and further alternatively spliced into 11 variants. In humans, CaMKII-δ9 and CaMKII-δ3, the major cardiac splice variants, inversely regulate cardiomyocyte viability with the former pro-death and the latter pro-survival.

Tertiary Oxidation of Deoxycholate Is Predictive of CYP3A Activity in Dogs.

Deoxycholic acid (DCA, 3, 12-dihydroxy-5-cholan-24-oic acid) is the major circulating secondary bile acid, which is synthesized by gut flora in the lower gut and selectively oxidized by CYP3A into tertiary metabolites, including 1,3,12-trihydroxy-5-cholan-24-oic acid (DCA-1-ol) and 3,5,12-trihydroxy-5-cholan-24-oic acid (DCA-5-ol) in humans. Since DCA has the similar exogenous nature and disposition mechanisms as xenobiotics, this work aimed to investigate whether the tertiary oxidations of DCA are predictive of in vivo CYP3A activities in beagle dogs. In vitro metabolism of midazolam (MDZ) and DCA in recombinant canine CYP1A1, 1A2, 2B11, 2C21, 2C41, 2D15, 3A12, and 3A26 enzymes clarified that CYP3A12 was primarily responsible for either the oxidation elimination of MDZ or the regioselective oxidation metabolism of DCA into DCA-1-ol and DCA-5-ol in dog liver microsomes.

The circular electron-positron collider beam energy measurement with Compton scattering and beam tracking method.

The beam energy of the circular electron-positron collider should be measured precisely to the order of 1 MeV, in order to decrease the uncertainty of the Higgs/W/Z bosons' mass measurement. For this purpose, a lepton bunch is extracted from the collider and collides with an Yttrium-Aluminum-Garnet laser pulse. After the inverse Compton scattering, the main beam and the scattered beam pass through an analytical magnetic field and are deflected to different angles.

Species Differences of Bile Acid Redox Metabolism: Tertiary Oxidation of Deoxycholate is Conserved in Preclinical Animals.

It was recently disclosed that CYP3A is responsible for the tertiary stereoselective oxidations of deoxycholic acid (DCA), which becomes a continuum mechanism of the host-gut microbial cometabolism of bile acids (BAs) in humans. This work aims to investigate the species differences of BA redox metabolism and clarify whether the tertiary metabolism of DCA is a conserved pathway in preclinical animals. With quantitative determination of the total unconjugated BAs in urine and fecal samples of humans, dogs, rats, and mice, it was confirmed that the tertiary oxidized metabolites of DCA were found in all tested animals, whereas DCA and its oxidized metabolites disappeared in germ-free mice.

Chronic Kidney Disease in Patients With Lacunar Stroke: Association With Enlarged Perivascular Spaces and Total Magnetic Resonance Imaging Burden of Cerebral Small Vessel Disease.

Background And Purpose: The relationship between chronic kidney disease and cerebral small vessel disease (cSVD), especially enlarged perivascular spaces (EPVS), has not been fully understood. This study aimed to investigate the association of chronic kidney disease and EPVS, as well as the total burden of cSVD on magnetic resonance imaging, expressed by the simultaneous presence of multiple markers of cSVD, among patients with first-ever lacunar stroke.

Methods: Four hundred and thirteen consecutive patients were prospectively enrolled.