Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.352

Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits

Background Over the last several years, it has become apparent that there are critical problems with the hypothesis that brain dopamine (DA) systems, particularly in the nucleus accumbens, directly mediate the rewarding or primary motivational characteristics of natural stimuli such as food. Hypotheses related to DA function are undergoing a substantial restructuring, such that the classic emphasis on hedonia and primary reward is giving way to diverse lines of research that focus on aspects of instrumental learning, reward prediction, incentive motivation, and behavioral activation. Objective The present review discusses dopaminergic involvement in behavioral activation and, in particular, emphasizes the effort-related functions of nucleus accumbens DA and associated forebrain circuitry. Results The effects of accumbens DA depletions on food-seeking behavior are critically dependent upon the work requirements of the task. Lever pressing schedules that have minimal work requirements are largely unaffected by accumbens DA depletions, whereas reinforcement schedules that have high work (e.g., ratio) requirements are substantially impaired by accumbens DA depletions. Moreover, interference with accumbens DA transmission exerts a powerful influence over effort-related decision making. Rats with accumbens DA depletions reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and instead, these rats select a less-effortful type of food-seeking behavior. Conclusions Along with prefrontal cortex and the amygdala, nucleus accumbens is a component of the brain circuitry regulating effort-related functions. Studies of the brain systems regulating effort-based processes may have implications for understanding drug abuse, as well as energy-related disorders such as psychomotor slowing, fatigue, or anergia in depression

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Platinum terpyridine acetylide complexes for photo-induced charge separation and the photogeneration of hydrogen from aqueous media

Thesis (Ph. D.)--University of Rochester. Dept. of Chemistry, 2008.Platinum terpyridyl acetylides are well-studied complexes with many favorable properties for the design of molecular assemblies to achieve photo-induced charge separation. The design and synthesis of such compounds is facilitated by the directionality of charge transfer in the excited state, with the energetic electron residing in the π* of the terpyridyl ligand. This thesis describes the synthesis of several platinum terpyridyl acetylide complexes in the pursuit of efficient charge transfer dyads and triads. Also described are efforts to couple these charge transfer complexes to catalysts to drive the reduction of protons in aqueous media. The most successful of this work is a system which employs a platinized titanium dioxide catalyst which is sensitized by several of the platinum terpyridyl acetylide compounds described. Chapter 2 describes a continuation of previous efforts to make molecular triads which employ pyridinium acceptors, including the viologen moiety. These efforts required a modification of synthetic methodology to accommodate the sensitivity of these pyridinium compounds to nucleophiles. Chapter 3 illustrates subsequent efforts to design more chemically robust complexes for photo-induced charge transfer. Nitrophenyl groups were proposed as acceptors on the basis of results obtained previously for a functional platinum terpyridyl acetylide triad with a nitrostilbene acceptor. These syntheses rely on a Suzuki coupling to halogenated nitrobenzenes, using a particularly valuable boronic acid-substituted terpyridyl ligand, which has previously been reported only once by a far more arduous route than is described here. Chapter 4 discusses a shift in focus to anchoring platinum chromophores on titanium dioxide. Modification of the titanium dioxide with nanoparticles of platinum metal yields a system that is capable of producing hydrogen under visible light irradiation under suitable conditions. Similar systems have been previously realized with other chromophores, but their study remains sparse and their efficiencies low. Efforts are described to improve overall efficiency as well as system longevity. In particular, oxidative degradation of the chromophores appears to be a limiting factor in these systems. This chapter also describes the synthesis of two dyads with phenothiazine donors for attachment to TiO2 in an effort to improve hydrogen production and specifically address the oxidative degradation of the chromophores

Seduced by the dark side: integrating molecular and ecological perspectives on the influence of light on plant defence against pests and pathogens.

Plants frequently suffer attack from herbivores and microbial pathogens, and have evolved a complex array of defence mechanisms to resist defoliation and disease. These include both preformed defences, ranging from structural features to stores of toxic secondary metabolites, and inducible defences, which are activated only after an attack is detected. It is well known that plant defences against pests and pathogens are commonly affected by environmental conditions, but the mechanisms by which responses to the biotic and abiotic environments interact are only poorly understood. In this review, we consider the impact of light on plant defence, in terms of both plant life histories and rapid scale molecular responses to biotic attack. We bring together evidence that illustrates that light not only modulates defence responses via its influence on biochemistry and plant development but, in some cases, is essential for the development of resistance. We suggest that the interaction between the light environment and plant defence is multifaceted, and extends across different temporal and biological scales

Population dynamics of a non-cultivated biennial plant Tragopogon pratensis infected by the autoecious demicyclic rust fungus Puccinia hysterium

Population dynamics of the biennial plant Tragopogon pratensis have been monitored in the Park Grass Experiment at Rothamsted Research, Harpenden, UK, over many years. Observations of diseased T. pratensis, systemically infected by the autoecious demicyclic rust Puccinia hysterium, were made over the period 1995–2008, and confirmed an outbreak pattern of dynamics, characterised by an increase to a relatively high incidence followed by a reduction to low almost indiscernible levels. An epidemiological model was developed taking into account the biennial habit of the host plant, and the systemic nature of infection during the winter period, and the partial sterilisation of infected second year plants. Seedling emergence rate and natural mortality between seasons and within season were key parameters affecting host performance. The transmission rate between infected second year plants and susceptible first year seedlings, and the probability that the fungus would survive the winter systemically as mycelium producing aecia and telia on emerging second year plants, were key parameters associated with pathogenicity. Furthermore the possibility of pathogen-induced additional mortality was modelled. The model predicted that outbreak dynamics of T. pratensis would occur with high pathogenicity and medium or high host performance. In the former case the population dynamics would be cyclical with, in some cases, infected plants going to extinction. In the latter case both host and pathogen would go to extinction. The model predicted that the two pathogenicity parameters were critical in determining whether the pathogen would invade a healthy population; whereas pathogen-induced mortality had little influence, a result also obtained in some limited potted plant experiments. Fitting the model to the field data indicated that there was little or no density-dependence in seedling emergence rate, and again that pathogen-induced mortality played little role in the observed population dynamics

Efficient Evaluation and Learning in Multilevel Parallel Constraint Grammars

In multilevel parallel Optimality Theory grammars, the number of candidates (possible paths from the input to the output level) increases exponentially with the number of levels of representation. The problem with this is that with the customary strategy of listing all candidates in a tableau, the computation time for evaluation (i.e., choosing the winning candidate) and learning (i.e., reranking the constraints on the basis of language data) increases exponentially with the number of levels as well. This article proposes instead to collect the candidates in a graph in which the number of nodes and the number of connections increase only linearly with the number of levels of representation. As a result, there exist procedures for evaluation and learning that increase only linearly with the number of levels. These efficient procedures help to make multilevel parallel constraint grammars more feasible as models of human language processing. We illustrate visualization, evaluation, and learning with a toy grammar for a traditional case that has already previously been analyzed in terms of parallel evaluation, namely, French liaison