Quaternary structure of the human Cdt1-Geminin complex regulates DNA replication licensing

All organisms need to ensure that no DNA segments are rereplicated in a single cell cycle. Eukaryotes achieve this through a process called origin licensing, which involves tight spatiotemporal control of the assembly of prereplicative complexes (pre-RCs) onto chromatin. Cdt1 is a key component and crucial regulator of pre-RC assembly. In higher eukaryotes, timely inhibition of Cdt1 by Geminin is essential to prevent DNA rereplication. Here, we address the mechanism of DNA licensing inhibition by Geminin, by combining X-ray crystallography, small-angle X-ray scattering, and functional studies in Xenopus and mammalian cells. Our findings show that the Cdt1:Geminin complex can exist in two distinct forms, a “permissive” heterotrimer and an “inhibitory” heterohexamer. Specific Cdt1 residues, buried in the heterohexamer, are important for licensing. We postulate that the transition between the heterotrimer and the heterohexamer represents a molecular switch between licensing-competent and licensing-defective states

Medicine storage, wastage, and associated determinants among urban households : a systematic review and meta-analysis of household surveys

Background: Irrational household storage of medicines is a world-wide problem, which triggers medicine wastage as well as its associated harms. This study aimed to include all available evidences from literature to perform a focused examination of the prevalence and factors associated with medicine storage and wastage among urban households. This systematic review and meta-analysis mapped the existing literature on the burden, outcomes, and affective socio-economic factors of medicine storage among urban households. In addition, this study estimated pooled effect sizes for storage and wastage rates. Methods: Household surveys evaluating modality, size, costs, and affective factors of medicines storage at home were searched in PubMed, EMBASE, OVID, SCOPUS, ProQuest, and Google scholar databases in 2019. Random effect meta-analysis and subgroup analysis were used to pool effect sizes for medicine storage and wastage prevalence among different geographical regions. Results: From the 2604 initial records, 20 studies were selected for systematic review and 16 articles were selected for meta-analysis. An overall pooled-prevalence of medicine storage and real wastage rate was 77 and 15%, respectively. In this regard, some significant differences were observed between geographical regions. Southwest Asia region had the highest storage and wastage rates. The most common classes of medicines found in households belonged to the Infective agents for systemic (17.4%) and the Nervous system (16.4%). Moreover, income, education, age, the presence of chronic illness, female gender, and insurance coverage were found to be associated with higher home storage. The most commonly used method of disposal was throwing them in the garbage. Conclusions: Factors beyond medical needs were also found to be associated with medicine storage, which urges effective strategies in the supply and demand side of the medicine consumption chain. The first necessary step to mitigate home storage is establishing an adequate legislation and strict enforcement of regulations on dispensing, prescription, and marketing of medicines. Patient’s pressure on excessive prescription, irrational storage, and use of medicines deserve efficient community-centered programs, in order to increase awareness on these issues. So, hazardous consequences of inappropriate disposal should be mitigated by different take back programs, particularly in low and middle income countries.

Correction to: Pharmacokinetics of Fentanyl and Its Derivatives in Children: A Comprehensive Review

Fentanyl and its derivatives sufentanil, alfentanil, and remifentanil are potent opioids. A comprehensive review of the use of fentanyl and its derivatives in the pediatric population was performed using the National Library of Medicine PubMed. Studies were included if they contained original pharmacokinetic parameters or models using established routes of administration in patients younger than 18 years of age. Of 372 retrieved articles, 44 eligible pharmacokinetic studies contained data of 821 patients younger than 18 years of age, including more than 46 preterm infants, 64 full-term neonates, 115 infants/toddlers, 188 children, and 28 adolescents. Underlying diagnoses included congenital heart and pulmonary disease and abdominal disorders. Routes of drug administration were intravenous, epidural, oral-transmucosal, intranasal, and transdermal. Despite extensive use in daily clinical practice, few studies have been performed. Preterm and term infants have lower clearance and protein binding. Pharmacokinetics was not altered by chronic renal or hepatic disease. Analyses of the pooled individual patients’ data revealed that clearance maturation relating to body weight could be best described by the Hill function for sufentanil (R2 = 0.71, Bmax 876 mL/min, K50 16.3 kg) and alfentanil (R2 = 0.70, Bmax (fixed) 420 mL/min, K50 28 kg). The allometric exponent for estimation of clearance of sufentanil was 0.99 and 0.75 for alfentanil clearance. Maturation of remifentanil clearance was described by linear regression to bodyweight (R2 = 0.69). The allometric exponent for estimation of remifentanil clearance was 0.76. For fentanyl, linear regression showed only a weak correlation between clearance and bodyweight in preterm and term neonates (R2 = 0.22) owing to a lack of data in older age groups. A large heterogeneity regarding study design, clinical setting, drug administration, laboratory assays, and pharmacokinetic estimation was observed between studies introducing bias into the analyses performed in this review. A limitation of this review is that pharmacokinetic data, based on different modes of administration, dosing schemes, and parameter estimation methods, were combined