NCAM180 Regulates Ric8A Membrane Localization and Potentiates β-Adrenergic Response

Cooperation between receptors allows integrated intracellular signaling leading to appropriate physiological responses. The Neural Cell Adhesion Molecule (NCAM) has three main isoforms of 120, 140 and 180 kDa, with adhesive and signaling properties, but their respective functions remains to be fully identified. Here we show that the human NCAM180 intracellular domain is a novel interactor of the human guanosine exchange factor (GEF) Ric8A using the yeast two hybrid system and immunoprecipitation. Furthermore, NCAM, Ric8A and Gαs form a tripartite complex. Colocalization experiments by confocal microscopy revealed that human NCAM180 specifically induces the recruitment of Ric8A to the membrane. In addition, using an in vitro recombinant system, and in vivo by comparing NCAM knock-out mouse brain to NCAM heterozygous and wild type brains, we show that NCAM expression dose dependently regulates Ric8A redistribution in detergent resistent membrane microdomains (DRM). Previous studies have demonstrated essential roles for Ric8 in Gα protein activity at G protein coupled receptors (GPCR), during neurotransmitter release and for asymmetric cell division. We observed that inhibition of Ric8A by siRNA or its overexpression, decreases or increases respectively, cAMP production following β-adrenergic receptor stimulation. Furthermore, in human HEK293T recombinant cells, NCAM180 potentiates the Gαs coupled β-adrenergic receptor response, in a Ric8A dependent manner, whereas NCAM120 or NCAM140 do not. Finally, in mouse hippocampal neurons expressing endogenously NCAM, NCAM is required for the agonist isoproterenol to induce cAMP production, and this requirement depends on Ric8A. These data illustrate a functional crosstalk between a GPCR and an IgCAM in the nervous system

Validity and Reliability of the Strengths and Difficulties Questionnaire in 5–6 Year Olds: Differences by Gender or by Parental Education?

Introduction: The Strengths and Difficulties Questionnaire (SDQ) is a relatively short instrument developed to detect psychosocial problems in children aged 3-16 years. It addresses four dimensions: emotional problems, conduct problems, hyperactivity/inattention problems, peer problems that count up to the total difficulties score, and a fifth dimension; prosocial behaviour. The validity and reliability of the SDQ has not been fully investigated in younger age groups. Therefore, this study assesses the validity and reliability of the parent and teacher versions of the SDQ in children aged 5-6 years in the total sample, and in subgroups according to child gender and parental education level. Methods: The SDQ was administered as part of the Dutch regularly provided preventive health check for children aged 5-6 years. Parents provided information on 4750 children and teachers on 4516 children. Results: Factor analyses of the parent and teacher SDQ confirmed that the original five scales were present (parent RMSEA = 0.05; teacher RMSEA = 0.07). Interrater correlations between parents and teachers were small (ICCs of 0.21-0.44) but comparable to what is generally found for psychosocial problem assessments in children. These correlations were larger for males than for females. Cronbach's alphas for the total difficulties score were 0.77 for the parent SDQ and 0.81 for the teacher SDQ. Four of the subscales on the parent SDQ and two of the subscales on the teacher SDQ had an alpha <0.70. Alphas were generally higher for male children and for low parental education level. Discussion: The validity and reliability of the total difficulties score of the parent and teacher SDQ are satisfactory in all groups by informant, child gender, and parental education level. Our results support the use of the SDQ in younger age groups. However, some subscales are less reliable and we recommend only to use the total difficulties score for screening purposes

Mach-Zehnder-Fano interferometer

We introduce a concept of the Mach-Zehnder-Fano interferometer by inserting a cavity exhibiting Fano resonance into a conventional interferometer. By employing the scattering-matrix approach, we demonstrate that the transmission is sensitive to a position of the cavity such that an asymmetric structure exhibits a series of narrow resonances with almost perfect reflection. We discuss how to implement this novel geometry in two-dimensional photonic crystals and use direct numerical simulations to demonstrate novel regimes of the resonant transmission and reflection.Comment: 3 pages, 3 figure

Children of Low Socioeconomic Status Show Accelerated Linear Growth in Early Childhood; Results from the Generation R Study

Objectives: People of low socioeconomic status are shorter than those of high socioeconomic status. The first two years of life being critical for height development, we hypothesized that a low socioeconomic status is associated with a slower linear growth in early childhood. We studied maternal educational level (high, mid-high, mid-low, and low) as a measure of socioeconomic status and its association with repeatedly measured height in children aged 0-2 years, and also examined to what extent known determinants of postnatal growth contribute to this association. Methods: This study was based on data from 2972 mothers with a Dutch ethnicity, and their children participating in The Generation R Study, a population-based cohort study in Rotterdam, the Netherlands (participation rate 61%). All children were born between April 2002 and January 2006. Height was measured at 2 months (mid-90% range 1.0-3.9), 6 months (mid-90% range 5.6-11.4), 14 months (mid-90% range 13.7-17.9) and 25 months of age (mid-90% range 23.6-29.6). Results: At 2 months, children in the lowest educational subgroup were shorter than those in the highest (difference: -0.87 cm; 95% CI: -1.16, -0.58). Between 1 and 18 months, they grew faster than their counterparts. By 14 months, children in the lowest educational subgroup were taller than those in the highest (difference at 14 months: 0.40 cm; 95% CI: 0.08,0.72). Adjustment for other determinants of postnatal growth did not explain the taller height. On the contrary, the differences became even larger (difference at 14 months: 0.61 cm; 95% CI: 0.26,0.95; and at 25 months: 1.00 cm; 95% CI: 0.57,1.43) Conclusions: Compared with children of high socioeconomic status, those of low socioeconomic status show an accelerated linear growth until the18th month of life, leading to an overcompensation of their initial height deficit. The long-term consequences of these findings remain unclear and require further study

Statin Therapy in Metabolic Syndrome and Hypertension Post-JUPITER: What is the Value of CRP?

Much evidence supports a pivotal role for inflammation in atherosclerosis. C-reactive protein (CRP), the prototypic marker of inflammation in humans, is a cardiovascular risk marker and may also promote atherogenesis. CRP levels are increased in metabolic syndrome and hypertension and confer increased risk of cardiovascular events in patients in these subgroups. Statins have been shown to lower low-density lipoproteins and CRP independently, and reduce cardiovascular events in subjects with and without metabolic syndrome and hypertension. In this review, we focus on the results from the primary prevention statin trial, Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), which showed reductions in LDL, CRP, and cardiovascular events. Post-JUPITER, the new guidelines will now need to consider recommending high-sensitivity CRP testing to intermediate-risk metabolic syndrome patients and those with hypertension and intermediate risk so that we can better identify candidates at greater risk and reduce cardiovascular burden in these subjects with statin therapy

Apoptosis of CD4+CD25high T Cells in Type 1 Diabetes May Be Partially Mediated by IL-2 Deprivation

from T1D subjects. in T1D may be caught up in a relatively deficient cytokine milieu. function in subjects predisposed to T1D

Pancreatitis, very early compared with normal start of enteral feeding (PYTHON trial): design and rationale of a randomised controlled multicenter trial

Contains fulltext : 97199.pdf (publisher's version ) (Open Access)BACKGROUND: In predicted severe acute pancreatitis, infections have a negative effect on clinical outcome. A start of enteral nutrition (EN) within 24 hours of onset may reduce the number of infections as compared to the current practice of starting an oral diet and EN if necessary at 3-4 days after admission. METHODS/DESIGN: The PYTHON trial is a randomised controlled, parallel-group, superiority multicenter trial. Patients with predicted severe acute pancreatitis (Imrie-score >/= 3 or APACHE-II score >/= 8 or CRP > 150 mg/L) will be randomised to EN within 24 hours or an oral diet and EN if necessary, after 72 hours after hospital admission.During a 3-year period, 208 patients will be enrolled from 20 hospitals of the Dutch Pancreatitis Study Group. The primary endpoint is a composite of mortality or infections (bacteraemia, infected pancreatic or peripancreatic necrosis, pneumonia) during hospital stay or within 6 months following randomisation. Secondary endpoints include other major morbidity (e.g. new onset organ failure, need for intervention), intolerance of enteral feeding and total costs from a societal perspective. DISCUSSION: The PYTHON trial is designed to show that a very early (< 24 h) start of EN reduces the combined endpoint of mortality or infections as compared to the current practice of an oral diet and EN if necessary at around 72 hours after admission for predicted severe acute pancreatitis. TRIAL REGISTRATION: ISRCTN: ISRCTN18170985

Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk

BACKGROUND: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. METHODS: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). RESULTS: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. CONCLUSION: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. IMPACT: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization

Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients