Dopamine D2 receptor gene variants and response to rasagiline in early Parkinson's disease:a pharmacogenetic study

The treatment of early Parkinson's disease with dopaminergic agents remains the mainstay of symptomatic therapy for this incurable neurodegenerative disorder. However, clinical responses to dopaminergic drugs vary substantially from person to person due to individual-, drug- and disease-related factors that may in part be genetically determined. Using clinical data and DNA samples ascertained through the largest placebo-controlled clinical trial of the monoamine oxidase B inhibitor, rasagiline (ClinicalTrials.gov number, NCT00256204), we examined how polymorphisms in candidate genes associate with the clinical response to rasagiline in early Parkinson's disease. Variants in genes that express proteins involved in the pharmacokinetics and pharmacodynamics of rasagiline, and genes previously associated with the risk to develop Parkinson's disease were genotyped. The LifeTechnologies OpenArray NT genotyping platform and polymerase chain reaction-based methods were used to analyse 204 single nucleotide polymorphisms and five variable number tandem repeats from 30 candidate genes in 692 available DNA samples from this clinical trial. The peak symptomatic response to rasagiline, the rate of symptom progression, and their relation to genetic variation were examined controlling for placebo effects using general linear and mixed effects models, respectively. Single nucleotide polymorphisms, rs2283265 and rs1076560, in the dopamine D2 receptor gene (DRD2) were found to be significantly associated with a favourable peak response to rasagiline at 12 weeks in early Parkinson's disease after controlling for multiple testing. From a linear regression, the betas were 2.5 and 2.38, respectively, with false discovery rate-corrected P-values of 0.032. These polymorphisms were in high linkage disequilibrium with each other (r(2) = 0.96) meaning that the same clinical response signal was identified by each of them. No polymorphisms were associated with slowing the rate of worsening in Parkinson symptoms from Weeks 12 to 36 after correction for multiple testing. This is the largest and most comprehensive pharmacogenetics study to date examining clinical response to an anti-parkinsonian drug and the first to be conducted in patients with early stage Parkinson's disease receiving monotherapy. The results indicate a clinically meaningful benefit to rasagiline in terms of the magnitude of improvement in parkinsonian symptoms for those with the favourable response genotypes. Future work is needed to elucidate the specific mechanisms through which these DRD2 variants operate in modulating the function of the nigrostriatal dopaminergic system

Auxiliary gauge mediation: a new route to mini-split supersymmetry

The discovery of a standard-model-like Higgs at 126 GeV and the absence of squark signals thus far at the LHC both point towards a mini-split spectrum for supersymmetry. Within standard paradigms, it is non-trivial to realize a mini-split spectrum with heavier sfermions but lighter gauginos while simultaneously generating Higgs sector soft terms of the correct magnitude, suggesting the need for new models of supersymmetry breaking and mediation. In this paper, we present a new approach to mini-split model building based on gauge mediation by “auxiliary groups”, which are the anomaly-free continuous symmetries of the standard model in the limit of vanishing Yukawa couplings. In addition to the well-known flavor SU(3) [subscript F] and baryon-minus-lepton U(1) [subscript B−L] groups, we find that an additional U(1) [subscript H] acting on the Higgs doublets alone can be used to generate Higgs soft masses and B-terms necessary for a complete model of mini-split. Auxiliary gauge mediation is a special case of Higgsed gauge mediation, and we review the resulting two-loop scalar soft terms as well as three-loop gaugino masses. Along the way, we present a complete two-loop calculation of A-terms and B-terms in gauge mediation, which — contrary to a common misconception — includes a non-zero contribution at the messenger threshold which can be sizable in models with light gauginos. We present several phenomenologically acceptable mini-split spectra arising from auxiliary gauge mediation and highlight a complete minimal model which realizes the required spectrum and Higgs sector soft terms with a single U(1) [subscript X] auxiliary gauge symmetry. We discuss possible experimental consequences.United States. Dept. of Energy (Cooperative Research Agreement DE-FG02-05ER-41360)National Science Foundation (U.S.). Graduate Research Fellowship ProgramSimons Foundation (Postdoctoral Fellowship)United States. Dept. of Energy (Early Career Research Program DE-FG02-11ER-41741

State dependent choice

We propose a theory of choices that are influenced by the psychological state of the agent. The central hypothesis is that the psychological state controls the urgency of the attributes sought by the decision maker in the available alternatives. While state dependent choice is less restricted than rational choice, our model does have empirical content, expressed by simple "revealed preference" type of constraints on observable choice data. We demonstrate the applicability of simple versions of the framework to economic contexts. We show in particular that it can explain widely researched anomalies in the labour supply of taxi drivers

Significant quantum effects in hydrogen activation

Dissociation of molecular hydrogen is an important step in a wide variety of chemical, biological, and physical processes. Due to the light mass of hydrogen, it is recognized that quantum effects are often important to its reactivity. However, understanding how quantum effects impact the reactivity of hydrogen is still in its infancy. Here, we examine this issue using a well-defined Pd/Cu(111) alloy that allows the activation of hydrogen and deuterium molecules to be examined at individual Pd atom surface sites over a wide range of temperatures. Experiments comparing the uptake of hydrogen and deuterium as a function of temperature reveal completely different behavior of the two species. The rate of hydrogen activation increases at lower sample temperature, whereas deuterium activation slows as the temperature is lowered. Density functional theory simulations in which quantum nuclear effects are accounted for reveal that tunneling through the dissociation barrier is prevalent for H2 up to ∼190 K and for D2 up to ∼140 K. Kinetic Monte Carlo simulations indicate that the effective barrier to H2 dissociation is so low that hydrogen uptake on the surface is limited merely by thermodynamics, whereas the D2 dissociation process is controlled by kinetics. These data illustrate the complexity and inherent quantum nature of this ubiquitous and seemingly simple chemical process. Examining these effects in other systems with a similar range of approaches may uncover temperature regimes where quantum effects can be harnessed, yielding greater control of bond-breaking processes at surfaces and uncovering useful chemistries such as selective bond activation or isotope separation

Language in international business: a review and agenda for future research

A fast growing number of studies demonstrates that language diversity influences almost all management decisions in modern multinational corporations. Whereas no doubt remains about the practical importance of language, the empirical investigation and theoretical conceptualization of its complex and multifaceted effects still presents a substantial challenge. To summarize and evaluate the current state of the literature in a coherent picture informing future research, we systematically review 264 articles on language in international business. We scrutinize the geographic distributions of data, evaluate the field’s achievements to date in terms of theories and methodologies, and summarize core findings by individual, group, firm, and country levels of analysis. For each of these dimensions, we then put forward a future research agenda. We encourage scholars to transcend disciplinary boundaries and to draw on, integrate, and test a variety of theories from disciplines such as psychology, linguistics, and neuroscience to gain a more profound understanding of language in international business. We advocate more multi-level studies and cross-national research collaborations and suggest greater attention to potential new data sources and means of analysis

A Climate-Change Policy Induced Shift from Innovations in Energy Production to Energy Savings

We develop an endogenous growth model with capital, labor and energy as production factors and three productivity variables that measure accumulated innovations for energy production, energy savings, and neutral growth. All markets are complete and perfect, except for research, for which we assume that the marginal social value exceeds marginal costs by factor four. The model constants are calibrated so that the model reproduces the relevant trends over the 1970-2000 period. The model contains a simple climate module, and is used to assess the impact of Induced Technological Change (ITC) for a policy that aims at a maximum level of atmospheric CO2 concentration (450 ppmv). ITC is shown to reduce the required carbon tax by about a factor 2, and to reduce costs of such a policy by about factor 10. Numerical simulations show that knowledge accumulation shifts from energy production to energy saving technology

Strategic Intellectual Property Rights Policy and North-South Technology Transfer

This paper analyzes welfare implications of protecting intellectual property rights (IPR) in the framework of TRIPS for developing countries (South) through its impact on innovation, market structure and technology transfer. In a North-South trade environment, the South sets its IPR policy strategically to manipulate multinationals decisions on innovation and location. Firms can protect their technology by exporting or risk spillovers by undertaking FDI to avoid tariffs. A stringent IPR regime is always optimal for the South as it triggers technology transfer by inducing FDI in less R&D-intensive industries and stimulates innovation by pushing multinationals to deter entry in high-technology sectors