Proton-coupled oligopeptide transporter family SLC15: physiological, pharmacological and pathological implications

Mammalian members of the proton-coupled oligopeptide transporter family (SLC15) are integral membrane proteins that mediate the cellular uptake of di/tripeptides and peptide-like drugs. The driving force for uphill electrogenic symport is the chemical gradient and membrane potential which favors proton uptake into the cell along with the peptide/mimetic substrate. The peptide transporters are responsible for the absorption and conservation of dietary protein digestion products in the intestine and kidney, respectively, and in maintaining homeostasis of neuropeptides in the brain. They are also responsible for the absorption and disposition of a number of pharmacologically important compounds including some aminocephalosporins, angiotensin-converting enzyme inhibitors, antiviral prodrugs, and others. In this review, we provide updated information on the structure-function of PepT1 (SLC15A1), PepT2 (SLC15A2), PhT1 (SLC15A4) and PhT2 (SLC15A3), and their expression and localization in key tissues. Moreover, mammalian peptide transporters are discussed in regard to pharmacogenomic and regulatory implications on host pharmacology and disease, and as potential targets for drug delivery. Significant emphasis is placed on the evolving role of these peptide transporters as elucidated by studies using genetically modified animals. Whenever possible, the relevance of drug-drug interactions and regulatory mechanisms are evaluated using in vivo studies.

An assessment of obesity and hyperphagia in individuals with Smith-Magenis syndrome

Smith-Magenis syndrome (SMS;OMIM# 182290) is a multiple congenital anomalies and mental retardation syndrome caused by a 3.7- Mb deletion on chromosome 17p11.2 or a mutation in the RAI1 gene. Although the majority of the SMS phenotype has been well described, limited studies are available describing growth patterns in SMS. There is some evidence that individuals with SMS develop obesity. Thus, this study aims to characterize the growth and potential influence of hyperphagia in a cohort of individuals with SMS. A retrospective chart review was conducted of 78 individuals with SMS through Baylor College of Medicine (BCM) at Texas Children¡¯s Hospital (TCH.) All documented height and weight measurements were abstracted and Z-scores (SD units) for height-for-age, length-for-age and BMI-for-age were calculated. Mail-out questionnaires were provided to the corresponding parents of the cohort to assess for the presence of hyperphagia through a validated hyperphagia questionnaire (HQ). Analysis of this data demonstrates that by the age ¡Ý 20 years males with SMS have mean BMI¡¯s in the 85th-90th percentile corresponding to an overweight BMI, and females with SMS had mean BMI¡¯s in the 95th -97th percentile corresponding to an obese BMI. Parents indicated that hyperphagia is present in individuals with SMS as 76% of parent¡¯s report having to lock food away from their child. Females¡¯ age ¡Ý 20 years of age had the highest mean behavior, drive and severity scores as well as the highest BMI. Thus, this study concludes that it appears overweight and obesity, as well as hyperphagia, are present in this cohort of SMS individuals. The results of this study will hopefully enable parents and caregivers of children with SMS to take preventative measures in order to control food related behaviors present in their children as well as to prevent overweight and obesity and the associated negative health consequences.

Three decades of global methane sources and sinks

Methane is an important greenhouse gas, responsible for about 20 of the warming induced by long-lived greenhouse gases since pre-industrial times. By reacting with hydroxyl radicals, methane reduces the oxidizing capacity of the atmosphere and generates ozone in the troposphere. Although most sources and sinks of methane have been identified, their relative contributions to atmospheric methane levels are highly uncertain. As such, the factors responsible for the observed stabilization of atmospheric methane levels in the early 2000s, and the renewed rise after 2006, remain unclear. Here, we construct decadal budgets for methane sources and sinks between 1980 and 2010, using a combination of atmospheric measurements and results from chemical transport models, ecosystem models, climate chemistry models and inventories of anthropogenic emissions. The resultant budgets suggest that data-driven approaches and ecosystem models overestimate total natural emissions. We build three contrasting emission scenarios � which differ in fossil fuel and microbial emissions � to explain the decadal variability in atmospheric methane levels detected, here and in previous studies, since 1985. Although uncertainties in emission trends do not allow definitive conclusions to be drawn, we show that the observed stabilization of methane levels between 1999 and 2006 can potentially be explained by decreasing-to-stable fossil fuel emissions, combined with stable-to-increasing microbial emissions. We show that a rise in natural wetland emissions and fossil fuel emissions probably accounts for the renewed increase in global methane levels after 2006, although the relative contribution of these two sources remains uncertain.

Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese

OBJECTIVES This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk. BACKGROUND AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored. METHODS We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases). RESULTS We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements. CONCLUSIONS The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.

Aus der Heimat Mendelssohn : Moses Benjamin Wulff und seine Familie, die Nachkommen Moses Isserles

von Max Freudenthal

Notice historique sur Benjamin de Tudèle

par E. Carmoly