A reduction in long-term spatial memory persists after discontinuation of peripubertal GnRH agonist treatment in sheep

Chronic gonadotropin-releasing hormone agonist (GnRHa) administration is used where suppression of hypothalamic-pituitary-gonadal axis activity is beneficial, such as steroid-dependent cancers, early onset gender dysphoria, central precocious puberty and as a reversible contraceptive in veterinary medicine. GnRH receptors, however, are expressed outside the reproductive axis, e.g. brain areas such as the hippocampus which is crucial for learning and memory processes. Previous work, using an ovine model, has demonstrated that long-term spatial memory is reduced in adult rams (45 weeks of age), following peripubertal blockade of GnRH signaling (GnRHa: goserelin acetate), and this was independent of the associated loss of gonadal steroid signaling. The current study investigated whether this effect is reversed after discontinuation of GnRHa-treatment. The results demonstrate that peripubertal GnRHa-treatment suppressed reproductive function in rams, which was restored after cessation of GnRHa-treatment at 44 weeks of age, as indicated by similar testes size (relative to body weight) in both GnRHa-Recovery and Control rams at 81 weeks of age. Rams in which GnRHa-treatment was discontinued (GnRHa-Recovery) had comparable spatial maze traverse times to Controls, during spatial orientation and learning assessments at 85 and 99 weeks of age. Former GnRHa-treatment altered how quickly the rams progressed beyond a specific point in the spatial maze at 83 and 99 weeks of age, and the direction of this effect depended on gonadal steroid exposure, i.e. GnRHa-Recovery rams progressed quicker during breeding season and slower during non-breeding season, compared to Controls. The long-term spatial memory performance of GnRHa-Recovery rams remained reduced (P < 0.05, 1.5-fold slower) after discontinuation of GnRHa, compared to Controls. This result suggests that the time at which puberty normally occurs may represent a critical period of hippocampal plasticity. Perturbing normal hippocampal formation in this peripubertal period may also have long lasting effects on other brain areas and aspects of cognitive function

Spatial memory is impaired by peripubertal GnRH agonist treatment and testosterone replacement in sheep

Chronic gonadotropin-releasing hormone agonist (GnRHa) is used therapeutically to block activity within the reproductive axis through down-regulation of GnRH receptors within the pituitary gland. GnRH receptors are also expressed in non-reproductive tissues, including areas of the brain such as the hippocampus and amygdala. The impact of long-term GnRHa-treatment on hippocampus-dependent cognitive functions, such as spatial orientation, learning and memory, is not well studied, particularly when treatment encompasses a critical window of development such as puberty. The current study used an ovine model to assess spatial maze performance and memory of rams that were untreated (Controls), had both GnRH and testosterone signaling blocked (GnRHa-treated), or specifically had GnRH signaling blocked (GnRHa-treated with testosterone replacement) during the peripubertal period (8, 27 and 41 weeks of age). The results demonstrate that emotional reactivity during spatial tasks was compromised by the blockade of gonadal steroid signaling, as seen by the restorative effects of testosterone replacement, while traverse times remained unchanged during assessment of spatial orientation and learning. The blockade of GnRH signaling alone was associated with impaired retention of long-term spatial memory and this effect was not restored with the replacement of testosterone signaling. These results indicate that GnRH signaling is involved in the retention and recollection of spatial information, potentially via alterations to spatial reference memory, and that therapeutic medical treatments using chronic GnRHa may have effects on this aspect of cognitive function

MacB ABC transporter is a dimer whose ATPase activity and macrolide-binding capacity are regulated by the membrane fusion protein MacA

Gram-negative bacteria utilize specialized machinery to translocate drugs and protein toxins across the inner and outer membranes, consisting of a tripartite complex composed of an inner membrane secondary or primary active transporter (IMP), a periplasmic membrane fusion protein, and an outer membrane channel. We have investigated the assembly and function of the MacAB/TolC system that confers resistance to macrolides in Escherichia coli. The membrane fusion protein MacA not only stabilizes the tripartite assembly by interacting with both the inner membrane protein MacB and the outer membrane protein TolC, but also has a role in regulating the function of MacB, apparently increasing its affinity for both erythromycin and ATP. Analysis of the kinetic behavior of ATP hydrolysis indicated that MacA promotes and stabilizes the ATP-binding form of the MacB transporter. For the first time, we have established unambiguously the dimeric nature of a noncanonic ABC transporter, MacB that has an N-terminal nucleotide binding domain, by means of nondissociating mass spectrometry, analytical ultracentrifugation, and atomic force microscopy. Structural studies of ABC transporters indicate that ATP is bound between a pair of nucleotide binding domains to stabilize a conformation in which the substrate-binding site is outward-facing. Consequently, our data suggest that in the presence of ATP the same conformation of MacB is promoted and stabilized by MacA. Thus, MacA would facilitate the delivery of drugs by MacB to TolC by enhancing the binding of drugs to it and inducing a conformation of MacB that is primed and competent for binding TolC. Our structural studies are an important first step in understanding how the tripartite complex is assembled

Spin density wave dislocation in chromium probed by coherent x-ray diffraction

We report on the study of a magnetic dislocation in pure chromium. Coherent x-ray diffraction profiles obtained on the incommensurate Spin Density Wave (SDW) reflection are consistent with the presence of a dislocation of the magnetic order, embedded at a few micrometers from the surface of the sample. Beyond the specific case of magnetic dislocations in chromium, this work may open up a new method for the study of magnetic defects embedded in the bulk.Comment: 8 pages, 7 figure

Essays in international trade and organisational economics

This thesis contains three chapters that examine various facets of how the market and technological environment shapes firms – and how firms shape their environments. The first chapter studies how multinational manufacturing firms organise production in parallel processing supply chains. Using confidential data on international sourcing of French manufacturing firms and an instrumental variables strategy based on selfconstructed input-output tables, the chapter shows that inputs that account for a high cost share – i.e. that are more important for technological reasons – are more likely to be produced by a multinational for itself, while unimportant ones are outsourced to third parties. It provides additional empirical evidence that this main finding is consistent with a property rights model of the boundary of the firm. The second chapter produces empirical facts on how exogenous changes in tariffs on intermediate goods have affected vertical integration patterns in France over the period 1996-2006 and evaluates them in light of the current literature. Using a long differences approach and detailed information on supply relationships, it shows that more protectionist policies by other countries and by the EU discouraged integrated relationships from shifting towards outsourcing and that initial market structure mattered for the impact of trade policy. The third chapter provides rare causal evidence for the relevance of endowment driven comparative advantage. It uses the fracking boom in the US following 2006 as a source of exogenous variation in the endowment of natural gas – and therefore in energy: fracking made energy considerably cheaper in the US compared to the rest of the world. The chapter studies factor, output, and international trade responses across sectors. It finds that energy intensive sectors expand along all dimensions and, most importantly, export more, which validates one of the most important neo-classical theories of why countries trade with each other

Effects of red grape, wild grape and black raspberry wines on ground pork during refrigerated storage

The effects of red grape, wild grape and black raspberry wines on the quality of ground pork during a 15 days refrigerated storage period were investigated. The levels of phenolic compounds were the highest in black raspberry wine (P0.05). The addition of 5% and 10% wine influenced the quality of ground pork by decreasing pH, inhibiting the progression of lipid oxidation and the formation of total volatile basic nitrogen (TVB-N), and stabilizing the red colour of the ground pork compared to control samples to which no wine was added. In ground pork, addition of red grape wine led to lower concentrations of thiobarbituric acid reactive substances (TBARS, 0.19–0.39 mg kg−1) and TVB-N values (69.1–119.9 mg kg−1) than wild grape (0.16–0.43 mg kg−1 and 72.0–194.1 mg kg−1, respectively) or black raspberry wine (0.33–0.58 mg kg−1 and 81.7–225.4 mg kg−1, respectively) up to 10 days of storage. Results from the present study suggested that the quality of ground pork was affected by wine type and storage period. These effects could be due to phenolic compounds as well as other chemical components of the wines

Comparison of Cardiovascular Risk Factors for Coronary Heart Disease and Stroke Type in Women

Background Cardiovascular risk factors have differential effects on various manifestations of cardiovascular disease, but to date direct formal comparisons are scarce, have been conducted primarily in men, and include only traditional risk factors. Methods and Results Using data from the multi-ethnic Women's Health Initiative Observational Study, we used a case-cohort design to compare 1731 women with incident cardiovascular disease during follow-up to a cohort of 1914 women. The direction of effect of all 24 risk factors (including various apolipoproteins, hemoglobin A1c, high-sensitivity C-reactive protein, N-terminal pro-brain natriuretic peptide, and tissue plasminogen activator antigen) was concordant for coronary heart disease (CHD, defined as myocardial infarction and CHD death) and ischemic stroke; however, associations were generally stronger with CHD. Significant differences for multiple risk factors, including blood pressure, lipid levels, and measures of inflammation, were observed when comparing the effects on hemorrhagic stroke with those on ischemic outcomes. For instance, multivariable adjusted hazard ratios per standard deviation increase in non-high-density lipoprotein cholesterol were 1.16 (95% confidence interval, 1.06-1.28) for CHD, 0.97 (0.88-1.07) for ischemic stroke, and 0.76 (0.63-0.91) for hemorrhagic stroke ( P<0.05 for equal association). Model discrimination was better for models predicting CHD or ischemic stroke than for models predicting hemorrhagic stroke or a combined end point. Conclusions Cardiovascular risk factors have largely similar effects on incidence of CHD and ischemic stroke in women, although the magnitude of association varies. Determinants of ischemic and hemorrhagic stroke substantially differ, underscoring their distinct biology. Cardiovascular disease risk may be more accurately reflected when combined cardiovascular disease or cerebrovascular outcomes are broken down into different first manifestations, or when restricted to ischemic outcomes

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Search for displaced vertices arising from decays of new heavy particles in 7 TeV pp collisions at ATLAS

We present the results of a search for new, heavy particles that decay at a significant distance from their production point into a final state containing charged hadrons in association with a high-momentum muon. The search is conducted in a pp-collision data sample with a center-of-mass energy of 7 TeV and an integrated luminosity of 33 pb^-1 collected in 2010 by the ATLAS detector operating at the Large Hadron Collider. Production of such particles is expected in various scenarios of physics beyond the standard model. We observe no signal and place limits on the production cross-section of supersymmetric particles in an R-parity-violating scenario as a function of the neutralino lifetime. Limits are presented for different squark and neutralino masses, enabling extension of the limits to a variety of other models.Comment: 8 pages plus author list (20 pages total), 8 figures, 1 table, final version to appear in Physics Letters

Measurement of the polarisation of W bosons produced with large transverse momentum in pp collisions at sqrt(s) = 7 TeV with the ATLAS experiment

This paper describes an analysis of the angular distribution of W->enu and W->munu decays, using data from pp collisions at sqrt(s) = 7 TeV recorded with the ATLAS detector at the LHC in 2010, corresponding to an integrated luminosity of about 35 pb^-1. Using the decay lepton transverse momentum and the missing transverse energy, the W decay angular distribution projected onto the transverse plane is obtained and analysed in terms of helicity fractions f0, fL and fR over two ranges of W transverse momentum (ptw): 35 < ptw < 50 GeV and ptw > 50 GeV. Good agreement is found with theoretical predictions. For ptw > 50 GeV, the values of f0 and fL-fR, averaged over charge and lepton flavour, are measured to be : f0 = 0.127 +/- 0.030 +/- 0.108 and fL-fR = 0.252 +/- 0.017 +/- 0.030, where the first uncertainties are statistical, and the second include all systematic effects.Comment: 19 pages plus author list (34 pages total), 9 figures, 11 tables, revised author list, matches European Journal of Physics C versio