Dissociable effects of 5-HT2C receptor antagonism and genetic inactivation on perseverance and learned non-reward in an egocentric spatial reversal task

Cognitive flexibility can be assessed in reversal learning tests, which are sensitive to modulation of 5-HT2C receptor (5-HT2CR) function. Successful performance in these tests depends on at least two dissociable cognitive mechanisms which may separately dissipate associations of previous positive and negative valence. The first is opposed by perseverance and the second by learned non-reward. The current experiments explored the effect of reducing function of the 5-HT2CR on the cognitive mechanisms underlying egocentric reversal learning in the mouse. Experiment 1 used the 5-HT2CR antagonist SB242084 (0.5 mg/kg) in a between-groups serial design and Experiment 2 used 5-HT2CR KO mice in a repeated measures design. Animals initially learned to discriminate between two egocentric turning directions, only one of which was food rewarded (denoted CS+, CS−), in a T- or Y-maze configuration. This was followed by three conditions; (1) Full reversal, where contingencies reversed; (2) Perseverance, where the previous CS+ became CS− and the previous CS− was replaced by a novel CS+; (3) Learned non-reward, where the previous CS− became CS+ and the previous CS+ was replaced by a novel CS-. SB242084 reduced perseverance, observed as a decrease in trials and incorrect responses to criterion, but increased learned non-reward, observed as an increase in trials to criterion. In contrast, 5-HT2CR KO mice showed increased perseverance. 5-HT2CR KO mice also showed retarded egocentric discrimination learning. Neither manipulation of 5-HT2CR function affected performance in the full reversal test. These results are unlikely to be accounted for by increased novelty attraction, as SB242084 failed to affect performance in an unrewarded novelty task. In conclusion, acute 5-HT2CR antagonism and constitutive loss of the 5-HT2CR have opposing effects on perseverance in egocentric reversal learning in mice. It is likely that this difference reflects the broader impact of 5HT2CR loss on the development and maintenance of cognitive function

Taking stock of current societal, political and academic stakeholders in the Canadian healthcare knowledge translation agenda

<p>Abstract</p> <p>Background</p> <p>In the past 15 years, knowledge translation in healthcare has emerged as a multifaceted and complex agenda. Theoretical and polemical discussions, the development of a science to study and measure the effects of translating research evidence into healthcare, and the role of key stakeholders including academe, healthcare decision-makers, the public, and government funding bodies have brought scholarly, organizational, social, and political dimensions to the agenda.</p> <p>Objective</p> <p>This paper discusses the current knowledge translation agenda in Canadian healthcare and how elements in this agenda shape the discovery and translation of health knowledge.</p> <p>Discussion</p> <p>The current knowledge translation agenda in Canadian healthcare involves the influence of values, priorities, and people; stakes which greatly shape the discovery of research knowledge and how it is or is not instituted in healthcare delivery. As this agenda continues to take shape and direction, ensuring that it is accountable for its influences is essential and should be at the forefront of concern to the Canadian public and healthcare community. This transparency will allow for scrutiny, debate, and improvements in health knowledge discovery and health services delivery.</p

The AMT1 Arginine Methyltransferase Gene Is Important for Plant Infection and Normal Hyphal Growth in Fusarium graminearum

Arginine methylation of non-histone proteins by protein arginine methyltransferase (PRMT) has been shown to be important for various biological processes from yeast to human. Although PRMT genes are well conserved in fungi, none of them have been functionally characterized in plant pathogenic ascomycetes. In this study, we identified and characterized all of the four predicted PRMT genes in Fusarium graminearum, the causal agent of Fusarium head blight of wheat and barley. Whereas deletion of the other three PRMT genes had no obvious phenotypes, the Δamt1 mutant had pleiotropic defects. AMT1 is a predicted type I PRMT gene that is orthologous to HMT1 in Saccharomyces cerevisiae. The Δamt1 mutant was slightly reduced in vegetative growth but normal in asexual and sexual reproduction. It had increased sensitivities to oxidative and membrane stresses. DON mycotoxin production and virulence on flowering wheat heads also were reduced in the Δamt1 mutant. The introduction of the wild-type AMT1 allele fully complemented the defects of the Δamt1 mutant and Amt1-GFP fusion proteins mainly localized to the nucleus. Hrp1 and Nab2 are two hnRNPs in yeast that are methylated by Hmt1 for nuclear export. In F. graminearum, AMT1 is required for the nuclear export of FgHrp1 but not FgNab2, indicating that yeast and F. graminearum differ in the methylation and nucleo-cytoplasmic transport of hnRNP components. Because AMT2 also is a predicted type I PRMT with limited homology to yeast HMT1, we generated the Δamt1 Δamt2 double mutants. The Δamt1 single and Δamt1 Δamt2 double mutants had similar defects in all the phenotypes assayed, including reduced vegetative growth and virulence. Overall, data from this systematic analysis of PRMT genes suggest that AMT1, like its ortholog in yeast, is the predominant PRMT gene in F. graminearum and plays a role in hyphal growth, stress responses, and plant infection

Modern tests of Lorentz invariance

Motivated by ideas about quantum gravity, a tremendous amount of effort over the past decade has gone into testing Lorentz invariance in various regimes. This review summarizes both the theoretical frameworks for tests of Lorentz invariance and experimental advances that have made new high precision tests possible. The current constraints on Lorentz violating effects from both terrestrial experiments and astrophysical observations are presented.Comment: Modified and expanded discussions of various points. Numerous references added. Version matches that accepted by Living Reviews in Relativit

Quantum Spacetime Phenomenology

I review the current status of phenomenological programs inspired by quantum-spacetime research. I stress in particular the significance of results establishing that certain data analyses provide sensitivity to effects introduced genuinely at the Planck scale. And my main focus is on phenomenological programs that managed to affect the directions taken by studies of quantum-spacetime theories.Comment: 125 pages, LaTex. This V2 is updated and more detailed than the V1, particularly for quantum-spacetime phenomenology. The main text of this V2 is about 25% more than the main text of the V1. Reference list roughly double

Chronic lymphocytic leukaemia and small lymphocytic lymphoma: overview of the descriptive epidemiology

The 2001 World Health Organization classification scheme considers B-cell chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL) in an aggregate category (CLL/SLL) because of shared clinicopathological features. We have estimated age-adjusted incidence rates (IRs) of CLL and SLL in the population-based Surveillance, Epidemiology and End Results Program in the United States to analyse patterns of CLL and SLL separately and jointly. Age-standardized to the 2000 US population, overall IRs were 3.83 per 100 000 person-years for CLL (n = 15 676) and 1.31 for SLL (n = 5382) during 1993-2004. Incidence of the combined entity, CLL/SLL, was 90% higher among males compared to females, and the male:female IR ratio was significantly higher for CLL (1.98) than for SLL (1.67). CLL/SLL IRs were 25% and 77% lower among Blacks and Asian/Pacific Islanders, respectively, compared to Whites. A significant reporting delay was evident for CLL but not for SLL, so that CLL/SLL temporal trends must be interpreted cautiously. CLL and SLL IRs increased exponentially with age among all gender/race groups, with CLL IRs increasing more steeply with advancing age than SLL. Avenues of future research include assessment of delayed- and under-reporting to cancer registries and exploration of race, gender, and age effects in epidemiological studies

Migraine History and Breast Cancer Risk Among Postmenopausal Women

PURPOSE Both migraine and breast cancer are hormonally mediated. Two recent reports indicate that women with a migraine history may have a lower risk of postmenopausal breast cancer than those who never suffered migraines. This finding requires confirmation; in particular, an assessment of the influence of use of nonsteroidal anti-inflammatory drugs (NSAID) is needed, because many studies indicate that NSAID use also may confer a reduction in breast cancer risk. METHODS We assessed the relationship between self-reported history of migraine and incidence of postmenopausal breast cancer in 91,116 women enrolled on the Women's Health Initiative Observational Study prospective cohort from 1993 to 1998 at ages 50 to 79 years. Through September 15, 2005, there were 4,006 eligible patients with breast cancer diagnosed. Results Women with a history of migraine had a lower risk of breast cancer (hazard ratio [HR], 0.89; 95% CI, 0.80 to 98) than women without a migraine history. This risk did not vary by recent NSAID use. The lower risk was somewhat more pronounced for invasive estrogen-receptor-positive and progesterone-receptor-positive tumors (HR, 0.83; 95% CI, 0.71 to 0.97), as no reduction in risk was observed for invasive ER-negative/PR-negative tumors (HR, 1.16; 95% CI, 0.86 to 1.57), and this difference in risk estimates was borderline statistically significant (P = .06). CONCLUSION This study supports the hypothesis that a history of migraine is associated with a lower risk of breast cancer and that this relationship is independent of recent NSAID use