Lu Shen

Human cytochrome P450 (CYP) enzymes, as membrane-bound hemoproteins, play important roles in the detoxification of drugs, cellular metabolism, and homeostasis. In humans, almost 80% of oxidative metabolism and approximately 50% of the overall elimination of common clinical drugs can be attributed to one or more of the various CYPs, from the CYP families 1-3. In addition to the basic metabolic effects for elimination, CYPs are also capable of affecting drug responses by influencing drug action, safety, bioavailability, and drug resistance through metabolism, in both metabolic organs and local sites of action. Structures of CYPs have recently provided new insights into both understanding the mechanisms of drug metabolism and exploiting CYPs as drug targets. Genetic polymorphisms and epigenetic changes in CYP genes and environmental factors may be responsible for interethnic and interindividual variations in the therapeutic efficacy of drugs. In this review, we summarize and highlight the structural knowledge about CYPs and the major CYPs in drug metabolism. Additionally, genetic and epigenetic factors, as well as several intrinsic and extrinsic factors that contribute to interindividual variation in drug response are also reviewed, to reveal the multifarious and important roles of CYP-mediated metabolism and elimination in drug therapy.

BACKGROUND: Persons with prediabetes and diabetes mellitus are at high risk for cardiovascular events. However, the relationships of prediabetes and diabetes mellitus to the development of subclinical myocardial damage are unclear. METHODS AND RESULTS: We measured cardiac troponin T with a highly sensitive assay (hs-cTnT) at 2 time points, 6 years apart, among 9051 participants of the community-based Atherosclerosis Risk in Communities Study with no diabetes mellitus, or prediabetes, and without cardiovascular disease including silent myocardial infarction by ECG. First, we examined the incidence of elevated hs-cTnT (≥14 ng/L) at 6 years of follow-up. Second, we examined clinical outcomes during the subsequent ≈14 years of follow-up among persons with and without incident elevations in hs-cTnT. Cumulative probabilities of elevated hs-cTnT at 6 years among persons with no diabetes mellitus, prediabetes, and diabetes mellitus were 3.7%, 6.4%, and 10.8%, respectively. Compared with normoglycemic persons, the adjusted relative risks for incident elevated hs-cTnT were 1.40 (95% CI, 1.08-1.80) for prediabetes and 2.47 (95% CI, 1.78-3.43) for diabetes mellitus. Persons with diabetes mellitus and incident elevations in hs-cTnT were at a substantially higher risk of heart failure (hazard ratio, 6.37 [95% CI, 4.27-9.51]), death (hazard ratio, 4.36 [95% CI, 3.14-6.07]), and coronary heart disease (hazard ratio, 3.84 [95% CI, 2.52-5.84]) compared with persons without diabetes mellitus and no incident elevation in hs-cTnT. CONCLUSIONS: Prediabetes and diabetes mellitus were independently associated with the development of subclinical myocardial damage, as assessed by hs-cTnT, and those persons with evidence of subclinical damage were at highest risk for clinical events. These results support a possible deleterious effect of hyperglycemia on the myocardium, possibly reflecting a microvascular cause.

Single-cell RNA-seq (scRNA-seq) is being used widely to resolve cellular heterogeneity. With the rapid accumulation of public scRNA-seq data, an effective and efficient cell-querying method is critical for the utilization of the existing annotations to curate newly sequenced cells. Such a querying method should be based on an accurate cell-to-cell similarity measure, and capable of handling batch effects properly. Herein, we present Cell BLAST, an accurate and robust cell-querying method built on a neural network-based generative model and a customized cell-to-cell similarity metric. Through extensive benchmarks and case studies, we demonstrate the effectiveness of Cell BLAST in annotating discrete cell types and continuous cell differentiation potential, as well as identifying novel cell types. Powered by a well-curated reference database and a user-friendly Web server, Cell BLAST provides the one-stop solution for real-world scRNA-seq cell querying and annotation.

About 80 per cent of the population secretes soluble blood group substances with A, B, and O(H) specificities corresponding to each individual's blood type; the remaining 20 per cent, the "nonsecretors," do not.'Most nonsecre- tors, however, do secrete large amounts of Lea-specific blood group substance, a glycoprotein similar in composition to the A, B, and O(H) substances of secre- TABLE 1.Some oligosaccharides of human milk.6.7 Compound I. Lactose II.2'-Fucosyllactose Gal-,8-( 13)-NAGS-,-( 13)-Gal-,6-(l1,4)-GI Fu-a-(l1,2)-Gal-B-( 1-3)NAS-,8-( 1-3)-Gal-,8-( 14)-GI Gal-,8-( 13) NAG-,-( 13)-