Discovery of inhibitors of human adipocyte fatty acid-binding protein, a potential type 2 diabetes target

Low micromolar human A-FABP inhibitors were found by utilizing a fluorescence polarization assay, X-ray crystallography and modeling. The carbazole- and indole-based inhibitors displayed approximately 10-fold preferences over human H-FABP and E-FABP, and are highly selective against I-FABP. This communication describes the SAR for drug-like synthetic inhibitors of human A-FABP.     

A novel mammalian iron-regulated protein involved in intracellular iron metabolism

We have isolated and characterized a novel iron-regulated gene that is homologous to the divalent metal transporter 1 family of metal transporters. This gene, termed metal transporter protein (mtp1), is expressed in tissues involved in body iron homeostasis including the developing and mature reticuloendothelial system, the duodenum, and the pregnant uterus. MTP1 is also expressed in muscle and central nervous system cells in the embryo. At the subcellular level, MTP1 is localized to the basolateral membrane of the duodenal epithelial cell and a cytoplasmic compartment of reticuloendothelial system cells. Overexpression of MTP1 in tissue culture cells results in intracellular iron depletion. In the adult mouse, MTP1 expression in the liver and duodenum are reciprocally regulated. Iron deficiency induces MTP1 expression in the duodenum but down-regulates expression in the liver. These data indicate that MTP1 is an iron-regulated membrane-spanning protein that is involved in intracellular iron metabolism.     

Khat Chewing Practice and Associated Factors among Adults in Ethiopia: Further Analysis Using the 2011 Demographic and Health Survey

Background

Khat chewing has become a highly prevalent practice and a growing public health concern in Ethiopia. Although there have been many small scale studies, very limited national information has been available in the general population. This study aimed to identify factors associated with khat chewing practice among Ethiopian adults.

Methods

The study used the 2011 Ethiopian demographic and health survey data. The survey was cross-sectional by design and used a multistage cluster sampling procedure. Bivariate and multivariable logistic regression models with adjusted odds ratio (AOR) and their 95% confidence intervals (CI) were used to quantify the predictors.

Results

The overall khat chewing prevalence was 15.3% (95% CI: 14.90–15.71). Regional variation was observed with the highest in Harari [(53.2% (95% CI: 43.04–63.28)] and lowest in Tigray regional state [(1.1% (95% CI: 0.72–1.66)]. Multivariable analysis showed that Islam followers were 23.8 times more likely to chew khat as compared to Orthodox followers. Being a resident in Oromiya, South Nation, Nationalities and People (SNNP), Gambella, Harari and Dire Dawa regions had 1.9, 1.6, 3.1, 5.2 and 3.5 times higher odds of chewing khat as compared to Addis Ababa residents, respectively. Adults in the age group 45–49 years were 3.6 times more likely to chew khat as compared to 15–19 years. The middle and richest wealth quintiles were 1.3 and 1.5 times more likely to chew khat, respectively, as compared to the poorest category. Rural residents had 1.3 odds of chewing khat than urban residents. Those individuals who had occupation in sales, agriculture, service sector, skilled and unskilled manual workers were 1.6, 1.3, 2.4, 1.7 and 2.3 times more likely to chew khat, respectively, as compared to those who have no occupation. Females were 77% less likely to chew khat as compared to males. Formerly married and those experienced in child death had 1.4 and 1.2 times higher odds to chew khat as compared with those never married and never had child death, respectively. Those who attended mass media were 1.4 times more likely to chew khat compared with not attended.

Conclusion

Khat chewing is a public health concern in Ethiopia. The highest wealth quintiles, older age group, rural residence, child death, formerly married, males, regions of Oromiya, SNNP, Gambella, Harari and Dire Dawa and Islamic followers had statistically significant association with khat chewing. Due attention needs to be given for these factors in any intervention procedures.     

BDNF Val66Met Variant and Smoking in a Chinese Population

Several recent studies have supported the hypothesis that brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, might be associated with nicotine addiction. Association studies have also suggested that the BDNF gene might play a role in the susceptibility to nicotine dependence but results appear contradictory. The present work was therefore undertaken to examine the association of smoking with the BDNF Val66Met gene polymorphism in Chinese population. The BDNF Val66Met gene polymorphism was examined in 628 healthy male volunteers including 322 smokers and 306 non-smokers. Also, the BDNF serum levels were measured in 136 smokers and 97 nonsmokers. Our results showed no significant association between the BDNF Val66Met polymorphism or serum levels among smokers and non-smokers. Smokers with the Met allele however started smoking significantly earlier than those with the Val/Val genotype (mean age at smoking initiation of 17.4, 17.9 and 21.2 years for Met/Met, Met/Val, and Val/Val, respectively; both p<0.05). No other significant differences between other variables such as number of cigarettes per day, smoking severity as measured by the Fagerstrom Test for Nicotine Dependence (FTND) score and carbon monoxide (CO) levels (all p>0.05). In addition, there was no main effect of genotype on serum BDNF levels. Our findings suggest that the BDNF Val66Met polymorphism may not be involved in susceptibility to smoking among the Chinese male population, but may influence the age at which smoking is initiated. However, the findings must be interpreted with caution because of the relatively small sample size for an association study. Results should be confirmed in a larger cohort.     

Gene dispersal inference across forest patches in an endangered medicinal tree: comparison of model‐based approaches

Propagule dispersal in plants is a fundamental mechanism for colonizing new sites and adapting to changing climates, as well as for maintaining genetic diversity. Contrasting past and current gene dispersal can provide useful insights to gauge the extent of recent human disturbances and guide management strategies. However, research on gene dispersal of plants is not yet exhaustive because evolutionary or environmental impacts are often species‐specific and most existing studies have focused on analysis of dispersal at a single site, which may not be helpful for landscape‐level inferences and management interventions. In the present study, we assessed whether current gene or propagule dispersal would be more restricted than past gene dispersal at multiple patches of the endangered medicinal tree, Prunus africana. We employed eight highly polymorphic microsatellite markers in conjunction with isolation‐by‐distance, spatial genetic structure (SGS), and parentage assignment models to estimate gene dispersal distance in a spatial extent of approximately 400 km². There was no significant difference between gene dispersal distances across the different models (Friedman chi‐squared = 7.286, d.f. = 5, P = 0.2002). Estimates of current gene dispersal distance were comparable to dispersal in the last few generations. However, gene dispersal distance was much shorter in smaller than bigger forest patches. Further, significant (P < 0.05) SGS was detected in most forest patches, with the extent of SGS among adults being stronger in the smaller than bigger patches. These results suggest the need for practicing enrichment plantings in most forest patches, particularly in the smaller ones, to assist gene exchange among individuals and patches. © 2015 The Linnean Society of London, Biological Journal of the Linnean Society, 2015, 114 , 887–904.     

The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901

A novel series of benzhydroxamate esters derived from their precursor anthranilic acids have been prepared and have been identified as potent MEK inhibitors. 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide, CI-1040, was the first MEK inhibitor to demonstrate in vivo activity in preclinical animal models and subsequently became the first MEK inhibitor to enter clinical trial. CI-1040 suffered however from poor exposure due to its poor solubility and rapid clearance, and as a result, development of the compound was terminated. Optimization of the diphenylamine core and modification of the hydroxamate side chain for cell potency, solubility, and exposure with oral delivery resulted in the discovery of the clinical candidate N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide PD 0325901.     

Causes of Death among Adults in Northern Ethiopia: Evidence from Verbal Autopsy Data in Health and Demographic Surveillance System

Background

In countries where registration of vital events is lacking and the proportion of people who die at home without medical care is high, verbal autopsy is used to determine and estimate causes of death.

Methods

We conducted 723 verbal autopsy interviews of adult (15 years of age and above) deaths from September 2009 to January 2013. Trained physicians interpreted the collected verbal autopsy data, and assigned causes of death according to the international classification of diseases (ICD-10). We did analysis of specific as well as broad causes of death (i.e. non-communicable diseases, communicable diseases and external causes of death) by sex and age using Stata version 11.1. We performed logistic regression to identify socio-demographic predictors using odds ratio with 95% confidence interval and a p-value of 0.05.

Findings

Tuberculosis, cerebrovascular diseases and accidental falls were leading specific causes of death accounting for 15.9%, 7.3% and 3.9% of all deaths. Two hundred sixty three (36.4% [95% CI: 32.9, 39.9]), 252 (34.9% [95% CI: 31.4, 38.4]) and 89 (12.3% [95% CI: 10.1, 14.9]) deaths were due to non-communicable, communicable diseases, and external causes, respectively. Females had 1.5 times (AOR = 1.53 [95% CI: 1.10, 2.15]) higher odds of dying due to communicable diseases than males. The odds of dying due to external causes were 4 times higher among 15–49 years of age (AOR = 4.02 [95% CI: 2.25, 7.18]) compared to older ages. Males also had 1.7 times (AOR = 1.70 [95% CI: 1.01, 2.85]) higher odds of dying due to external causes than females.

Conclusion

Tuberculosis, cerebrovascular diseases and accidental falls were the top three causes of death among adults. Efforts to prevent tuberculosis and cerebrovascular diseases related deaths should be improved and safety efforts to reduce accidents should also receive attention.