An association of early puberty with disordered eating and anxiety in a population of undergraduate women and men

Eating and anxiety disorders are more prevalent in females, increase during adolescence, and are associated with early pubertal development. This study examined whether timing of puberty onset is associated with disordered eating and anxiety in a large sample of postpubertal male and female undergraduate students. Self-report questionnaires assessed timing of puberty, disordered eating, anxiety, alcohol use, personality, and sensation seeking. Females scored significantly higher on measures of disordered eating (binge eating, dietary restraint, eating concerns, and weight and shape concerns) and anxiety (state and trait anxiety) than did males. In addition, early maturing women and men scored significantly higher on measures of disordered eating and anxiety than on time or late maturing women and men. Measures of alcohol use, sensation seeking, and personality characteristics differed in males and females but did not vary with pubertal timing. Findings suggest that early puberty is associated with disordered eating and anxiety, and this association may be due to an organizational effect of pubertal hormones. Despite important differences in body fat composition, both males and females experiencing early puberty had an increased incidence of disordered eating. The fact that early puberty was associated with increased eating and anxiety symptoms in both sexes suggests that puberty may influence these symptoms through both biological and psychosocial mechanisms.     

Addressing childhood overweight through schools

Rates of childhood obesity in have reached alarming proportions in many countries. Sixteen percent of school-aged children and adolescents in the U.S. are overweight. Legislation implemented in 2004 in the U.S. requires local education agencies (LEAs) that sponsor school meal programs to establish local wellness policies to address childhood obesity. Project PA, a collaboration between a state agency and a university providing school-based interventions focuses on the school environment and policy changes. Interventions have targeted foodservice personnel, administrators, teachers, parents and students. In two recent projects schools assessed their school nutrition environments, developed nutrition policies, and implemented strategies to encourage healthier food selections. Schools identified weaknesses in the areas of marketing and communication of policies. Media attention on the childhood obesity facilitated policy changes. Time and cost were identified as barriers to policy development and there were concerns about weak enforcement of policies. These themes are discussed.     

Evaluating scoring functions for docking and designing beta-secretase inhibitors

Several simple scoring methods were examined for 2 series of beta-secretase (BACE-1) inhibitors to identify a docking/scoring protocol which could be used to design BACE-1 inhibitors in a drug discovery program. Both the PLP1 score and MMFFs interaction energy (E(inter)) performed as well or better than more computationally intensive methods for a set of substrate-based inhibitors, while the latter performed well for both sets of inhibitors.     

Oxazolidinones as novel human CCR8 antagonists

High-throughput screening of the corporate compound collection led to the discovery of a novel series of N-substituted-5-aryl-oxazolidinones as potent human CCR8 antagonists. The synthesis, structure-activity relationships, and optimization of the series that led to the identification of SB-649701 (1a), are described.     

Interstitial norepinephrine concentrations in skeletal muscle of ischemic heart failure

During exercise, sympathetic nerve responses are accentuated in heart failure (HF), and this enhances norepinephrine (NE) release and evokes vasoconstriction. Two key pathophysiological responses could contribute to the greater NE release: 1) increased sympathetic nerve discharge and 2) increased NE in the neurovascular junction for a given level of sympathetic discharge. In this report, we focus on the second of these two general issues and test the following hypotheses: 1) in HF for a given level of sympathetic nerve stimulation, NE concentration in the interstitium (an index of neurovascular NE) would be greater, and 2) the greater interstitial NE concentration would be linked to reduced NE uptake. Studies were performed in rats 8-10 wk after induction of myocardial infarction (MI). Interstitial NE samples were collected from microdialysis probes inserted into the hindlimb muscle. Dialysate concentration of NE was determined by the HPLC method. First, interstitial NE concentration increased during electrical stimulation of the lumbar sympathetic nerves in eight control rats. An increase in interstitial NE concentration was significantly greater in 10 rats with severe MI. Additionally, an NE uptake-1 inhibitor (desipramine, 1 microM) was injected into the arterial blood supply of the muscle in six control and eight MI rats. Desipramine increased interstitial NE concentration by 24% in control and by only 3% (P < 0.05 vs. control) in MI rats. In conclusion, given levels of electrical stimulation of the lumbar sympathetic nerve lead to higher interstitial NE concentration in HF. This effect is due, in part, to reduced NE uptake-1 in HF.     

Subcellular localization and function of alternatively spliced Noxo1 isoforms

Nox organizer 1 (Noxo1), a p47(phox) homolog, is produced as four isoforms with unique N-terminal PX domains derived by alternative mRNA splicing. We compared the subcellular distribution of these isoforms or their isolated PX domains produced as GFP fusion proteins, as well as their ability to support Nox1 activity in several transfected models. Noxo1alpha, beta, gamma, and delta show different subcellular localization patterns, determined by their PX domains. In HEK293 cells, Noxo1beta exhibits prominent plasma membrane binding, Noxo1gamma shows plasma membrane and nuclear associations, and Noxo1alpha and delta localize primarily on intracellular vesicles or cytoplasmic aggregates, but not the plasma membrane. Nox1 activity correlates with Noxo1 plasma membrane binding in HEK293 cells, since Noxo1beta supports the highest activity and Noxo1gamma and Noxo1alpha support moderate or low activities, respectively. In COS-7 cells, where Noxo1alpha localizes on the plasma membrane, the activities supported by the three isoforms (alpha, beta, and gamma) do not differ significantly. The PX domains of beta and gamma bind the same phospholipids, including phosphatidic acid. These results indicate that the variant PX domains are unique determinants of Noxo1 localization and Nox1 function. Finally, the overexpressed Noxo1 isoforms do not affect p22(phox) localization, although Nox1 is needed to transport p22(phox) to the plasma membrane.     

Solution structure of the novel dispersin protein of enteroaggregative Escherichia coli

Enteroaggregative Escherichia coli (EAEC), increasingly recognized as an important cause of infant and travelers' diarrhoea, exhibits an aggregative, stacked-brick pattern of adherence to epithelial cells. Adherence is mediated by aggregative adherence fimbriae (AAFs), which are encoded on the pAA virulence plasmid. We recently described a highly prevalent pAA plasmid-borne gene, aap, which encodes a protein (nicknamed dispersin) that is secreted to the bacterial cell surface. Dispersin-null mutants display a unique hyper-aggregating phenotype, accompanied by collapse of AAF pili onto the bacterial cell surface. To study the mechanism of this effect, we solved the structure of dispersin from EAEC strain 042 using solution NMR, revealing a stable beta-sandwich with a conserved net positive surface charge of +3 to +4 among 23 dispersin alleles. Experimental data suggest that dispersin binds non-covalently to lipopolysaccharide on the surface of the bacterium. We also show that the AAF organelles contribute positive charge to the bacterial surface, suggesting that dispersin's role in fimbrial function is to overcome electrostatic attraction between AAF and the bacterial surface.