RNAi-mediated serotonin transporter suppression rapidly increases serotonergic neurotransmission and hippocampal neurogenesis

Current antidepressants, which inhibit the serotonin transporter (SERT), display limited efficacy and slow onset of action. Here, we show that partial reduction of SERT expression by small interference RNA (SERT-siRNA) decreased immobility in the tail suspension test, displaying an antidepressant potential. Moreover, short-term SERT-siRNA treatment modified mouse brain variables considered to be key markers of antidepressant action: reduced expression and function of 5-HT(1A)-autoreceptors, elevated extracellular serotonin in forebrain and increased neurogenesis and expression of plasticity-related genes (BDNF, VEGF, Arc) in hippocampus. Remarkably, these effects occurred much earlier and were of greater magnitude than those evoked by long-term fluoxetine treatment. These findings highlight the critical role of SERT in serotonergic function and show that the reduction of SERT expression regulates serotonergic neurotransmission more potently than pharmacological blockade of SERT. The use of siRNA-targeting genes in serotonin neurons (SERT, 5-HT(1A)-autoreceptor) may be a novel therapeutic strategy to develop fast-acting antidepressants

Analytical results for coupled map lattices with long-range interactions

We obtain exact analytical results for lattices of maps with couplings that decay with distance as $r^{-\alpha}$. We analyze the effect of the coupling range on the system dynamics through the Lyapunov spectrum. For lattices whose elements are piecewise linear maps, we get an algebraic expression for the Lyapunov spectrum. When the local dynamics is given by a nonlinear map, the Lyapunov spectrum for a completely synchronized state is analytically obtained. The critical lines characterizing the synchronization transition are determined from the expression for the largest transversal Lyapunov exponent. In particular, it is shown that in the thermodynamical limit, such transition is only possible for sufficiently long-range interactions, namely, for $\alpha\le alpha_c<d$, where $d$ is the lattice dimension.Comment: 4 pages, 2 figures, corrections included. Phys. Rev. E 68, 045202(R) (2003); correction in pres

A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry

Background Genome-wide studies of gene–environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. Methods Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene–environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. Results Assuming a 1 × 10–5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (ORint = 0.94, 95% CI 0.92–0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (ORint = 0.91, 95% CI 0.88–0.94). Conclusions Overall, the contribution of G×E interactions to the heritability of breast cancer is very small. At the population level, multiplicative G×E interactions do not make an important contribution to risk prediction in breast cancer

Breast cancer risk factors and survival by tumor subtype: pooled analyses from the breast cancer association consortium

Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype.Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype.Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (P-adj > 0.30). The strongest associations were between all-cause mortality and BMI >= 30 versus 18.5-25 kg/m(2) [HR (95% confidence interval (CI), 1.19 (1.06-1.34)]; current versus never smoking [1.37 (1.27-1.47)], high versus low physical activity [0.43 (0.21-0.86)], age >= 30 years versus 0-= 10 years since last full-term birth [1.31 (1.11-1.55)]; ever versus never use of oral contraceptives [0.91 (0.87-0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen-progestin therapy [0.61 (0.54-0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02-1.21) for current versus never smoking.Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype.Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.Surgical oncolog

Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study

Objectives: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics. Methods: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105–377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity. Results: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger). Conclusion: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Co-exchanged mordenites: preparation, characterization and catalytic activity for the abatement of NO with CH4 in the presence of excess O2

VIETRI, 20-23 SEPTEMBER 2003

Co-exchanged mordenites: preparation, characterization and catalytic activity for the abatement of NO with CH4 in the presence of excess O2

INNSBRUCK (AUSTRIA), 31 AUGUST - 4 SEPTEMBER 200

Rhodium supported on tetragonal or monoclinic ZrO2 as catalyst for the partial oxidation of methane

The catalytic partial oxidation (CPO) of methane on Rh/ZrO2 catalysts was investigated at different Rh loading (0.04-3.3 wt%), by using both monoclinic (m-ZrO2) and tetragonal (t-ZrO2) zirconia as supports. m-ZRhx and t-ZRhx catalysts, were prepared by dry impregnation of zirconia supports with a solution of Rh(NO3)(3), and characterized by XRD, BET analysis, XPS, FTIR spectroscopy (using CO as probe molecule) and H-2/O-2 titration. CPO of methane was studied in a flow apparatus fed by a reactant mixture of CH4:O-2 = 2:1% (v/v) in N-2 (contact time tau similar or equal to 2 ms). Characterization results show that the nature and dispersion of supported Rh species strongly depends on the support. The H-2/O-2 titration showed that Rh species are more dispersed on t-ZrO2 than on m-ZrO2. The XPS results indicated the presence of Rh in the metallic state both in large and small Rh delta+ clusters. Consistently with XPS, FTIR with CO probe molecule revealed the coexistence of Rh-0-CO carbonyls on Rh-0 large particles and Rh+-(CO)(2) dicarbonyls arising from very small clusters. Rh species in the metallic state are more homogeneous (i.e. Rh-0 species with similar near-neighbor atoms) and Rh species with a lower metal character (i.e. those interacting with the support) are more abundant in the t-ZRhx samples than in the m-ZRhx ones. For methane CPO, Rh supported on the tetragonal zirconia is far more active and selective than Rh supported on the monoclinic zirconia. The catalytic results suggest that the different Rh dispersion alone cannot account for the different catalytic performances of the t-ZRhx and m-ZRhx samples. (c) 2013 Elsevier B.V. All rights reserved