Localisation of GPR30, a novel G protein-coupled oestrogen receptor, suggests multiple functions in rodent brain and peripheral tissues

Recently, the G protein-coupled receptor GPR30 has been identified as a novel oestrogen receptor (ER). The distribution of the receptor has been thus far mapped only in the rat central nervous system. This study was undertaken to map the distribution of GPR30 in the mouse brain and rodent peripheral tissues. Immunohistochemistry using an antibody against GPR30 revealed high levels of GPR30 immunoreactivity (ir) in the forebrain (e.g. cortex, hypothalamus and hippocampus), specific nuclei of the midbrain (e.g. the pontine nuclei and locus coeruleus) and the trigeminal nuclei and cerebellum Purkinje layer of the hindbrain in the adult mouse brain. In the rat and mouse periphery, GPR30-ir was detected in the anterior, intermediate and neural lobe of the pituitary, adrenal medulla, renal pelvis and ovary. In situ hybridisation histochemistry using GPR30 riboprobes, revealed intense hybridisation signal for GPR30 in the paraventricular nucleus and supraoptic nucleus (SON) of the hypothalamus, anterior and intermediate lobe of the pituitary, adrenal medulla, renal pelvis and ovary of both rat and mouse. Double immunofluorescence revealed GPR30 was present in both oxytocin and vasopressin neurones of the paraventricular nucleus and SON of the rat and mouse brain. The distribution of GPR30 is distinct from the other traditional ERs and offers an additional way in which oestrogen may mediate its effects in numerous brain regions and endocrine systems in the rodent

Treatment response and remission in a double-blind, randomized, head-to-head study of lisdexamfetamine dimesylate and atomoxetine in children and adolescents with attention-deficit hyperactivity disorder

The Author(s) 2014. This article is published with open access at Springerlink.com Objectives A secondary objective of this head-to-head study of lisdexamfetamine dimesylate (LDX) and ato-moxetine (ATX) was to assess treatment response rates in children and adolescents with attention-deficit hyperactiv-ity disorder (ADHD) and an inadequate response to methylphenidate (MPH). The primary efficacy and safety outcomes of the study, SPD489-317 (ClinicalTrials.gov NCT01106430), have been published previously. Methods In this 9-week, double-blind, active-controlled study, patients aged 6–17 years with a previous inadequate response to MPH were randomized (1:1) to dose-optimized LDX (30, 50 or 70 mg/day) or ATX (patients \70 kg: 0.5–1.2 mg/kg/day, not to exceed 1.4 mg/kg/day; patients C70 kg: 40, 80 or 100 mg/day). Treatment response was a secondary efficacy outcome and was predefined as a reduction from baseline in ADHD Rating Scale IV (ADHD-RS-IV) total score of at least 25, 30 or 50 %. Sustained response was predefined as a reduction from baseline in ADHD-RS-IV total score (C25, C30 or C50 %) or a Clinical Global Impressions (CGI)–Improvement (CGI–I) score of 1 or 2 throughout weeks 4–9. CGI– Severity (CGI–S) scores were also assessed, as an indicator of remission. Results A total of 267 patients were enrolled (LDX, n = 133; ATX, n = 134) and 200 completed the study (LDX, n = 99; ATX, n = 101). By week 9, significantly (p \ 0.01) greater proportions of patients receiving LDX than ATX met the response criteria of a reduction from baseline in ADHD-RS-IV total score of at least 25 % (90.5 vs. 76.7 %), 30 % (88.1 vs. 73.7 %) or 50 % (73.0 vs. 50.4 %). Sustained response rates were also signifi-cantly (p \ 0.05) higher among LDX-treated patient

Atomically dispersed Pt-N-4 sites as efficient and selective electrocatalysts for the chlorine evolution reaction

Chlorine evolution reaction (CER) is a critical anode reaction in chlor-alkali electrolysis. Although precious metal-based mixed metal oxides (MMOs) have been widely used as CER catalysts, they suffer from the concomitant generation of oxygen during the CER. Herein, we demonstrate that atomically dispersed Pt-N-4 sites doped on a carbon nanotube (Pt-1/CNT) can catalyse the CER with excellent activity and selectivity. The Pt-1/CNT catalyst shows superior CER activity to a Pt nanoparticle-based catalyst and a commercial Ru/Ir-based MMO catalyst. Notably, Pt-1/CNT exhibits near 100% CER selectivity even in acidic media, with low Cl- concentrations (0.1M), as well as in neutral media, whereas the MMO catalyst shows substantially lower CER selectivity. In situ electrochemical X-ray absorption spectroscopy reveals the direct adsorption of Cl- on Pt-N-4 sites during the CER. Density functional theory calculations suggest the PtN4C12 site as the most plausible active site structure for the CER

Epigenetic regulation of F2RL3 associates with myocardial infarction and platelet function

DNA hypomethylation at the F2RL3 (F2R like thrombin or trypsin receptor 3) locus has been associated with both smoking and atherosclerotic cardiovascular disease; whether these smoking-related associations form a pathway to disease is unknown. F2RL3 encodes protease-activated receptor 4, a potent thrombin receptor expressed on platelets. Given the role of thrombin in platelet activation and the role of thrombus formation in myocardial infarction, alterations to this biological pathway could be important for ischemic cardiovascular disease. METHODS: We conducted multiple independent experiments to assess whether DNA hypomethylation at F2RL3 in response to smoking is associated with risk of myocardial infarction via changes to platelet reactivity. Using cohort data (N=3205), we explored the relationship between smoking, DNA hypomethylation at F2RL3, and myocardial infarction. We compared platelet reactivity in individuals with low versus high DNA methylation at F2RL3 (N=41). We used an in vitro model to explore the biological response of F2RL3 to cigarette smoke extract. Finally, a series of reporter constructs were used to investigate how differential methylation could impact F2RL3 gene expression. RESULTS: Observationally, DNA methylation at F2RL3 mediated an estimated 34% of the smoking effect on increased risk of myocardial infarction. An association between methylation group (low/high) and platelet reactivity was observed in response to PAR4 (protease-activated receptor 4) stimulation. In cells, cigarette smoke extract exposure was associated with a 4.9% to 9.3% reduction in DNA methylation at F2RL3 and a corresponding 1.7-(95% CI, 1.2–2.4, P=0.04) fold increase in F2RL3 mRNA. Results from reporter assays suggest the exon 2 region of F2RL3 may help control gene expression. CONCLUSIONS: Smoking-induced epigenetic DNA hypomethylation at F2RL3 appears to increase PAR4 expression with potential downstream consequences for platelet reactivity. Combined evidence here not only identifies F2RL3 DNA methylation as a possible contributory pathway from smoking to cardiovascular disease risk but from any feature potentially influencing F2RL3 regulation in a similar manner

Studies of black diamond as an antibacterial surface for gram negative bacteria: the interplay between chemical and mechanical bactericidal activity

‘Black silicon’ (bSi) samples with surfaces covered in nanoneedles of length ~5 μm were fabricated using a plasma etching process and then coated with a conformal uniform layer of diamond using hot filament chemical vapour deposition to produce ‘black diamond’ (bD) nanostructures. The diamond needles were then chemically terminated with H, O, NH2 or F using plasma treatment, and the hydrophilicity of the resulting surfaces were assessed using water droplet contact-angle measurements, and scaled in the order O > H ≈NH2 >F, with the F-terminated surface being superhydrophobic. The effectiveness of these differently terminated bD needles in killing the Gram-negative bacterium E. coli was semiquantified by Live/Dead staining and fluorescence microscopy, and visualised by environmental scanning electron microscopy. The total number of adhered bacteria was consistent for all the nanostructured bD surfaces at around 50% of the value for the flat diamond control. This, combined with a chemical bactericidal effect of 20–30%, shows that the nanostructured bD surfaces supported significantly fewer viable E. coli than flat surfaces. Moreover, the bD surfaces were particularly effective at preventing the establishment of bacterial aggregates – a precursor to biofilm formation. The percentage of dead bacteria also decreased as a function of hydrophilicity. These results are consistent with a predominantly mechanical mechanism for bacteria death based on the stretching and disruption of the cell membrane, combined with an additional effect from the chemical nature of the surface

An operational approach to high resolution agro-ecological zoning in West-Africa

Research ArticleThe objective of this work is to develop a simple methodology for high resolution crop suitability analysis under current and future climate, easily applicable and useful in Least Developed Countries. The approach addresses both regional planning in the context of climate change projections and pre-emptive short-term rural extension interventions based on same-year agricultural season forecasts, while implemented with off-the-shelf resources. The developed tools are applied operationally in a case-study developed in three regions of Guinea-Bissau and the obtained results, as well as the advantages and limitations of methods applied, are discussed. In this paper we show how a simple approach can easily generate information on climate vulnerability and how it can be operationally used in rural extension servicesinfo:eu-repo/semantics/publishedVersio

Cigarette smoke extract profoundly suppresses TNFα-mediated proinflammatory gene expression through upregulation of ATF3 in human coronary artery endothelial cells

Endothelial dysfunction caused by the combined action of disturbed flow, inflammatory mediators and oxidants derived from cigarette smoke is known to promote coronary atherosclerosis and increase the likelihood of myocardial infarctions and strokes. Conversely, laminar flow protects against endothelial dysfunction, at least in the initial phases of atherogenesis. We studied the effects of TNFα and cigarette smoke extract on human coronary artery endothelial cells under oscillatory, normal laminar and elevated laminar shear stress for a period of 72 hours. We found, firstly, that laminar flow fails to overcome the inflammatory effects of TNFα under these conditions but that cigarette smoke induces an anti-oxidant response that appears to reduce endothelial inflammation. Elevated laminar flow, TNFα and cigarette smoke extract synergise to induce expression of the transcriptional regulator activating transcription factor 3 (ATF3), which we show by adenovirus driven overexpression, decreases inflammatory gene expression independently of activation of nuclear factor-κB. Our results illustrate the importance of studying endothelial dysfunction in vitro over prolonged periods. They also identify ATF3 as an important protective factor against endothelial dysfunction. Modulation of ATF3 expression may represent a novel approach to modulate proinflammatory gene expression and open new therapeutic avenues to treat proinflammatory diseases

Business unusual: collective action against bribery in international business

Collective action initiatives in which governments and companies make anti-corruption commitments have proliferated in recent years. This apparently prosocial behavior defies the logic of collective action and, given that bribery often goes undetected and unpunished, is not easily explained by principal-agent theory. Club theory suggests that the answer lies in the institutional design of anti-corruption clubs: collective action can work as long as membership has high entry costs, members receive selective benefits, and compliance is adequately policed. This article contributes to the debate by examining how these conditions manifest in the case of anti-corruption clubs in the realm of international business, with particular focus on the international dimension of many initiatives. This vertical aspect of institutional design creates a richer, more complex set of reputational and material benefits for members, as well as allowing for more credible and consistent monitoring and enforcement