Dopamine-dependent tuning of striatal inhibitory synaptogenesis.

Dopaminergic projections to the striatum, crucial for the correct functioning of this brain region in adulthood, are known to be established early in development, but their role is currently uncharacterized. We demonstrate here that dopamine, by activating D(1)- and/or D(2)-dopamine receptors, decreases the number of functional GABAergic synapses formed between the embryonic precursors of the medium spiny neurons, the principal output neurons of the striatum, with associated changes in spontaneous synaptic activity. Activation of these receptors reduces the size of postsynaptic GABA(A) receptor clusters and their overall cell-surface expression, without affecting the total number of clusters or the size or number of GABAergic nerve terminals. These changes result from an increased internalization of GABA(A) receptors, and are mediated by distinct signaling pathways converging at the level of GABA(A) receptors to cause a transient PP2A/PP1-dependent dephosphorylation. Thus, tonic D(1)- and D(2)-receptor activity limits the extent of collateral inhibitory synaptogenesis between medium spiny neurons, revealing a novel role of dopamine in controlling the development of intrinsic striatal microcircuits

Nuclear factor κB-inducing kinase activation as a mechanism of pancreatic β cell failure in obesity

The nuclear factor κB (NF-κB) pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic β cell dysfunction in the metabolic syndrome. Whereas canonical NF-κB signaling is well studied, there is little information on the divergent noncanonical NF-κB pathway in the context of pancreatic islet dysfunction. Here, we demonstrate that pharmacological activation of the noncanonical NF-κB-inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. We identify NIK as a critical negative regulator of β cell function, as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of noncanonical NF-κB components p100 to p52, and accumulation of RelB. TNF and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive β cell-intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the noncanonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to β cell failure. These studies reveal that NIK contributes a central mechanism for β cell failure in diet-induced obesity

Health-related quality of life in patients with surgically treated lumbar disc herniation: 2- and 7-year follow-up of 117 patients

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.BACKGROUND AND PURPOSE: Health-related quality of life (HRQoL) instruments have been of increasing interest for evaluation of medical treatments over the past 10-15 years. In this prospective, long-term follow-up study we investigated the influence of preoperative factors and the change in HRQoL over time after lumbar disc herniation surgery. METHODS: 117 patients surgically treated for lumbar disc herniation (L4-L5 or L5-S1) were evaluated with a self-completion HRQoL instrument (EQ-5D) preoperatively, after 2 years (96 patients) and after 7 years (89 patients). Baseline data (age, sex, duration of leg pain, surgical level) and degree of leg and back pain (VAS) were obtained preoperatively. The mean age was 39 (18-66) years, 54% were men, and the surgical level was L5-S1 in 58% of the patients. The change in EQ-5D score at the 2-year follow-up was analyzed by testing for correlation and by using a multiple regression model including all baseline factors (age, sex, duration of pain, degree of leg and back pain, and baseline EQ-5D score) as potential predictors. RESULTS: 85% of the patients reported improvement in EQ-5D two years after surgery and this result remained at the long-term follow-up. The mean difference (change) between the preoperative EQ-5D score and the 2-year and 7-year scores was 0.59 (p < 0.001) and 0.62 (p < 0.001), respectively. However, the HRQoL for this patient group did not reach the mean level of previously reported values for a normal population of the same age range at any of the follow-ups. The changes in EQ-5D score between the 2- and 7-year follow-ups were not statistically significant (mean change 0.03, p = 0.2). There was a correlation between baseline leg pain and the change in EQ-5D at the 2-year (r = 0.33, p = 0.002) and 7-year follow-up (r = 0.23, p = 0.04). However, when using regression analysis the only statistically significant predictor for change in EQ-5D was baseline EQ-5D score. INTERPRETATION: Our findings suggest that HRQoL (as measured by EQ-5D) improved 2 years after lumbar disc herniation surgery, but there was no further improvement after 5 more years. Low quality of life and severe leg pain at baseline are important predictors of improvement in quality of life after lumbar disc herniation surgery.Marianne och Marcus Wallenberg Foundation ALF Vastra Gotaland. Gothenburg Medical Association. Swedish Society of Medicine. Felix Neubergh Foundation

Fortified breakfast cereal consumed daily for 12 wk leads to a significant improvement in micronutrient intake and micronutrient status in adolescent girls: a randomised controlled trial

Background: Poor micronutrient status is reported among adolescents across Europe and USA. This may be related to the well-documented decline in the regular consumption of breakfast by this group. The regular consumption of a breakfast cereal offers a possible means to improve micronutrient status; fortified cereal is likely to have enhanced benefit. A study was conducted to determine the efficacy of the regular consumption of a fortified cereal with milk, compared with unfortified cereal, consumed either as a breakfast or a supper, in improving micronutrient intake and micronutrient status of adolescent girls. Methods: A randomised, double-blind, placebo-controlled intervention trial was conducted in girls recruited at ages 16–19 years, from schools and colleges in Sheffield, UK. Girls were randomised to receive 50 g fortified or unfortified cereal, with 150 ml semi-skimmed milk, daily, for 12 weeks, as a breakfast or as a supper. Dietary intake was estimated using a 4-d food diary and blood collected for the assessment of nutritional status. Within-group changes were tested using a paired sample t test; two-way ANOVA was used to analyse effects of the intervention, with cereal type and time of consumption as factors, correcting for baseline values. The analysis was conducted on 71 girls who completed the study. Results: Consumption of unfortified cereal elicited an increase in the intake of vitamins B1, B2 and B6; consumption of fortified cereal elicited increases in vitamins B1, B2, B6, B12, folate and iron (P < 0.001) and of vitamin D (P = 0.007), all increases were significantly greater than for unfortified cereal. Consumption of the fortified cereal also led to a significant improvement in biomarkers of status for vitamins B2, B12, folate and of iron, compared with girls receiving the unfortified cereal, and maintained vitamin D status, in contrast with the girls receiving the unfortified cereal (P < 0.001). Conclusions: The daily consumption of cereal with milk for 12 weeks by adolescent girls, increased intakes of micronutrients. The consumption of fortified cereal elicited greater increases than for unfortified cereal and improved biomarkers of micronutrient status. The findings justify strategies to encourage the consumption of fortified cereal with milk by adolescents, either as a breakfast or a supper

Rational manipulation of mRNA folding free energy allows rheostat control of pneumolysin production by Streptococcus pneumoniae

Rational manipulation of mRNA folding free energy allows rheostat control of pneumolysin production by Streptococcus pneumoniaeThe contribution of specific factors to bacterial virulence is generally investigated through creation of genetic "knockouts" that are then compared to wild-type strains or complemented mutants. This paradigm is useful to understand the effect of presence vs. absence of a specific gene product but cannot account for concentration-dependent effects, such as may occur with some bacterial toxins. In order to assess threshold and dose-response effects of virulence factors, robust systems for tunable expression are required. Recent evidence suggests that the folding free energy (?G) of the 5' end of mRNA transcripts can have a significant effect on translation efficiency and overall protein abundance. Here we demonstrate that rational alteration of 5' mRNA folding free energy by introduction of synonymous mutations allows for predictable changes in pneumolysin (PLY) expression by Streptococcus pneumoniae without the need for chemical inducers or heterologous promoters. We created a panel of isogenic S. pneumoniae strains, differing only in synonymous (silent) mutations at the 5' end of the PLY mRNA that are predicted to alter ?G. Such manipulation allows rheostat-like control of PLY production and alters the cytotoxicity of whole S. pneumoniae on primary and immortalized human cells. These studies provide proof-of-principle for further investigation of mRNA ?G manipulation as a tool in studies of bacterial pathogenesis.National Institutes of Health (www.nih.gov) (R01 AI092743 and R21 AI111020 to A.J.R.). F.E.A. was supported by the Portuguese Foundation for Science and Technology (www.fct.pt) SFRH/BD/33901/2009 and the Luso-American Development Foundation (www.flad.pt). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Application of compression test in analysis of mechanical and color changes in grapefruit juice powder as related to glass transition and water activity

Physicochemical and structural properties of grapefruit juice powder were studied as affected by water activity. Powdered juice was obtained by freeze-drying and equilibrated at different water vapor pressure atmospheres in order to give samples with water activity in the range of 0-084 The mechanical properties of the powder were measured by confined compression tests and the compressed samples, which presented uniform surface and thickness, were subjected to color analysis The maximum force attained during the compression tests and the color coordinates could be quantified with good reproducibility. The results were related to water activity and to glass transition temperature The occurrence of mechanical changes in the powder was shown to precede significant color changes with increasing water activity. Considering the susceptibility to stickiness, the stability limit was observed at T-T(g) approximate to 2 degrees C, with a high degree of mechanical changes being detected at T-Tg 16 degrees C, whereas for significant color changes this critical temperature difference was around 32 degrees CAuthors thank the Ministerio de Educacion y Ciencia and the Fondo Europeo de Desarrollo Regional (FEDER) for the financial support throughout the projects AGL2002-01793 and AGL 200505994. Vania R. N. Tells acknowledges the support of the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) as an external grant (Proc. BEX 4452/06-2).Telis, VRN.; Martínez Navarrete, N. (2010). Application of compression test in analysis of mechanical and color changes in grapefruit juice powder as related to glass transition and water activity. Food Science and Technology. 43(5):744-751. https://doi.org/10.1016/j.lwt.2009.12.007S74475143

Physical Activity Attenuates the Genetic Predisposition to Obesity in 20,000 Men and Women from EPIC-Norfolk Prospective Population Study

Shengxu Li and colleagues use data from a large prospective observational cohort to examine the extent to which a genetic predisposition toward obesity may be modified by living a physically active lifestyle

A High Intake of Saturated Fatty Acids Strengthens the Association between the Fat Mass and Obesity-Associated Gene and BMI123

Evidence that physical activity (PA) modulates the association between the fat mass and obesity-associated gene (FTO) and BMI is emerging; however, information about dietary factors modulating this association is scarce. We investigated whether fat and carbohydrate intake modified the association of FTO gene variation with BMI in two populations, including participants in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (n = 1069) and in the Boston Puerto Rican Health (BPRHS) study (n = 1094). We assessed energy, nutrient intake, and PA using validated questionnaires. Genetic variability at the FTO locus was characterized by polymorphisms rs9939609 (in the GOLDN) and rs1121980 (in the GOLDN and BPRHS). We found significant interactions between PA and FTO on BMI in the GOLDN but not in the BPRHS. We found a significant interaction between SFA intake and FTO on BMI, which was stronger than that of total fat and was present in both populations (P-interaction = 0.007 in the GOLDN and P-interaction = 0.014 in BPRHS for categorical; and P-interaction = 0.028 in the GOLDN and P-interaction = 0.041 in BPRHS for continuous SFA). Thus, homozygous participants for the FTO-risk allele had a higher mean BMI than the other genotypes only when they had a high-SFA intake (above the population mean: 29.7 ± 0.7 vs. 28.1 ± 0.5 kg/m2; P = 0.037 in the GOLDN and 33.6. ± 0.8 vs. 31.2 ± 0.4 kg/m2; P = 0.006 in BPRHS). No associations with BMI were found at lower SFA intakes. We found no significant interactions with carbohydrate intake. In conclusion, SFA intake modulates the association between FTO and BMI in American populations

Quantile-Specific Penetrance of Genes Affecting Lipoproteins, Adiposity and Height

Quantile-dependent penetrance is proposed to occur when the phenotypic expression of a SNP depends upon the population percentile of the phenotype. To illustrate the phenomenon, quantiles of height, body mass index (BMI), and plasma lipids and lipoproteins were compared to genetic risk scores (GRS) derived from single nucleotide polymorphisms (SNP)s having established genome-wide significance: 180 SNPs for height, 32 for BMI, 37 for low-density lipoprotein (LDL)-cholesterol, 47 for high-density lipoprotein (HDL)-cholesterol, 52 for total cholesterol, and 31 for triglycerides in 1930 subjects. Both phenotypes and GRSs were adjusted for sex, age, study, and smoking status. Quantile regression showed that the slope of the genotype-phenotype relationships increased with the percentile of BMI (P = 0.002), LDL-cholesterol (P = 3×10−8), HDL-cholesterol (P = 5×10−6), total cholesterol (P = 2.5×10−6), and triglyceride distribution (P = 7.5×10−6), but not height (P = 0.09). Compared to a GRS's phenotypic effect at the 10th population percentile, its effect at the 90th percentile was 4.2-fold greater for BMI, 4.9-fold greater for LDL-cholesterol, 1.9-fold greater for HDL-cholesterol, 3.1-fold greater for total cholesterol, and 3.3-fold greater for triglycerides. Moreover, the effect of the rs1558902 (FTO) risk allele was 6.7-fold greater at the 90th than the 10th percentile of the BMI distribution, and that of the rs3764261 (CETP) risk allele was 2.4-fold greater at the 90th than the 10th percentile of the HDL-cholesterol distribution. Conceptually, it maybe useful to distinguish environmental effects on the phenotype that in turn alters a gene's phenotypic expression (quantile-dependent penetrance) from environmental effects affecting the gene's phenotypic expression directly (gene-environment interaction)