The role of the hypothalamic kisspeptin/GPR54 system in the control of GnRH neurons

Summary : The hypothalamus represents less than 1 % of the total volume of the brain tissue, yet it plays a crucial role in endocrine regulations. Puberty is defined as a process leading to physical, sexual and psychosocial maturation. The hypothalamus is central to this process, via the activation of GnRH neurons. Pulsatile GnRH secretion, minimal during childhood, increases with the onset of puberty. The primary function of GnRH is to regulate the growth, development and function of testes in boys and ovaries in girls, by stimulating the pituitary gland secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Several factors contribute to the timing of puberty, including sex and ethnicity, genetics, dietary intake and energy expenditure. Kisspeptins constitute a family of small peptides arising from the proteolytic cleavage of metastin, a peptide with 54 amino acids initially purified from human placenta. These kisspeptins were the subject of much attention following their discovery because of their antimetastatic properties, but it was more recently that their determining role in the reproductive function was demonstrated. It was shown that kisspeptins are ligands of a receptor, GPR54, whose natural inactivating mutation in humans, or knockout in the mouse, lead to infertility. GnRH neurons play a pivotal role in the central regulation of fertility. Kisspeptin greatly increases GnRH release and GnRH neuron firing activity, but the neurobiological mechanisms for these actions are unknown. Gprotein-coupled receptor 54, the receptor for kisspeptin, is expressed by GnRH neurons as well as other hypothalamic neurons, suggesting that both direct and indirect effects are possible. In the first part of my thesis, we investigated a possible connection between the acceleration of sexual development induced by leptin and hypothalamic metastin neurons. However, the data generated by our preliminary experiments confirmed that the commercially available antibodies are non-specific. This finding constituted a major drawback for our studies, which relied heavily upon the neuroanatomical study of the hypothalamic metastinergic pathways to elucidate their sensitivity to exogenous leptin. Therefore, we decided to postpone any further in vivo experiment until a better antibody becomes available, and focused on in vitro studies to better understand the mechanisms of action of kisspeptins in the modulation of the activity of GnRH neurons. We used two GnRH-expressing neuronal cell lines to investigate the cellular and molecular mechanisms of action of metastin in GnRH neurons. We demonstrated that kisspeptin induces an early activation of the MAP kinase intracellular signaling pathway in both cell lines, whereas the SAP/JNK or the Akt pathways were unaffected. Moreover, we found an increase in GnRH mRNA levels after 6h of metastin stimulation. Thus, we can conclude that kisspeptin regulates GnRH neurons both at the secretion and the gene expression levels. The MAPK pathway is the major pathway activated by metastin in GnRH expressing neurons. Taken together, these data provide the first mechanism of action of kisspeptin on GnRH neurons. Résumé : L'hypothalamus est une zone située au centre du cerveau, dont il représente moins de 1 du volume total. La puberté est la période de transition entre l'enfance et l'age adulte, qui s'accompagne de transformations somatiques, psychologiques, métaboliques et hormonales conduisant à la possibilité de procréer. La fonction principale de la GnRH est la régulation de la croissance, du développement et de la fonction des testicules chez les hommes, et des ovaires chez les femmes en stimulant la sécrétion de l'hormone lutéinisante (LH) et de l'hormone folliculostimulante (FSH) par la glande hypophysaire. Plusieurs facteurs contribuent au déclanchement de la puberté, y compris le sexe et l'appartenance ethnique, la génétique, l'apport alimentaire et la dépense énergétique. Les Kisspeptines constituent une famille de peptides résultant de la dissociation proteolytique de la métastine, un peptide de 54 acides aminés initialement purifié à partir de placenta humain. Ces kisspeptines ont fait l'objet de beaucoup d'attention à la suite de leur découverte en raison de leurs propriétés anti-metastatiques, et c'est plus récemment que leur rôle déterminant dans la fonction reproductive a été démontré. Les kisspeptines sont des ligands du récepteur GPR54, dont la mutation inactivatrice chez l'homme, ou le knockout chez la souris, conduisent à l'infertilité par hypogonadisme hypogonadotrope. Les neurones à GnRH jouent un rôle central dans le règlement des fonctions reproductrices et la kisspeptine stimule l'activité des neurones à GnRH et la libération de GnRH par ces neurones. Toutefois, les mécanismes neurobiologiques de ces actions ne sont pas connus. Dans la première partie de ma thèse, nous avons étudié le lien potentiel entre l'accélération du développement sexuel induite par la leptine et les neurones hypothalamiques à metastine. Les données générées dans cette première série d'expériences ont malheureusement confirmé que les anticorps anti-metastine disponibles dans le commerce sont aspécifiques. Ceci a constitué un inconvénient majeur pour nos études, qui devaient fortement s'appuyer sur l' étude neuroanatomique des neurones hypothalamiques à metastine pour évaluer leur sensibilité à la leptine exogène. Nous avons donc décidé de focaliser nos travaux sur une étude in vitro des mécanismes d'action de la kisspeptine pour moduler l'activité des neurones à GnRH. Nous avons utilisé deux lignées de cellules neuronales exprimant la GnRH pour étudier les mécanismes d'action cellulaires et moléculaires de la metastine dans des neurones. Nous avons ainsi pu démontrer que la kisspeptine induit une activation précoce de la voie f de signalisation de la MAP kinase dans les deux lignées cellulaires, alors que nous n'avons observé aucune activation de la voie de signalisation de la P13 Kinase et de la SAP/JNK. Nous avons en outre démontré une augmentation de l'expression de la GnRH par la stimulation avec la Kisspeptine. L'ensemble de ces données contribue à élucider le mécanisme d'action avec lequel la kisspeptine agit dans les neurones à GnRH, en démontrant un effet sur l'expression génique de la GnRH. Nous pouvons également conclure que la voie de la MAPK est la voie principale activée par la metastine dans les neurones exprimant la GnRH.

Some go without a cigarette: characteristics of cannabis users who have never smoked tobacco.

OBJECTIVES: To estimate the prevalence of youth who use cannabis but have never been tobacco smokers and to assess the characteristics that differentiate them from those using both substances or neither substance. DESIGN: School survey. SETTING: Postmandatory schools. PARTICIPANTS: A total of 5263 students (2439 females) aged 16 to 20 years divided into cannabis-only smokers (n = 455), cannabis and tobacco smokers (n = 1703), and abstainers (n = 3105). OUTCOME MEASURES: Regular tobacco and cannabis use; and personal, family, academic, and substance use characteristics. RESULTS: Compared with those using both substances, cannabis-only youth were younger (adjusted odds ratio [AOR], 0.82) and more likely to be male (AOR, 2.19), to play sports (AOR, 1.64), to live with both parents (AOR, 1.33), to be students (AOR, 2.56), and to have good grades (AOR, 1.57) and less likely to have been drunk (AOR, 0.55), to have started using cannabis before the age of 15 years (AOR, 0.71), to have used cannabis more than once or twice in the previous month (AOR, 0.64), and to perceive their pubertal timing as early (AOR, 0.59). Compared with abstainers, they were more likely to be male (AOR, 2.10), to have a good relationship with friends (AOR, 1.62), to be sensation seeking (AOR, 1.32), and to practice sports (AOR, 1.37) and less likely to have a good relationship with their parents (AOR, 0.59). They were more likely to attend high school (AOR, 1.43), to skip class (AOR, 2.28), and to have been drunk (AOR, 2.54) or to have used illicit drugs (AOR, 2.28). CONCLUSIONS: Cannabis-only adolescents show better functioning than those who also use tobacco. Compared with abstainers, they are more socially driven and do not seem to have psychosocial problems at a higher rate.

Ecology and neurophysiology of sleep in two wild sloth species

Study Objectives: Interspecific variation in sleep measured in captivity correlates with various physiological and environmental factors, including estimates of predation risk in the wild. However, it remains unclear whether prior comparative studies have been confounded by the captive recording environment. Herein we examine the impact of predation pressure on sleep in sloths living in the wild. Design: Comparison of two closely related sloth species, one exposed to predation and one free from predation. Setting: Panamanian mainland rainforest (predators present) and island mangrove (predators absent). Participants: Mainland (Bradypus variegatus, 5 males and 4 females) and island (Bradypus pygmaeus, 6 males) sloths. Interventions: None. Measurements and Results: EEG and EMG activity were recorded using a miniature data logger. Although both species spent between 9 and 10 hours per day sleeping, the mainland sloths showed a preference for sleeping at night, whereas island sloths showed no preference for sleeping during the day or night. EEG activity during NREM sleep showed lower low-frequency power, and increased spindle and higher frequency power in island sloths when compared to mainland sloths. Conclusions: In sloths sleeping in the wild, predation pressure influenced the timing of sleep, but not the amount of time spent asleep. The preference for sleeping at night in mainland sloths may be a strategy to avoid detection by nocturnal cats. The pronounced differences in the NREM sleep EEG spectrum remain unexplained, but might be related to genetic or environmental factors.

Development and current use of parenteral nutrition in critical care - an opinion paper.

Critically ill patients depend on artificial nutrition for the maintenance of their metabolic functions and lean body mass, as well as for limiting underfeeding-related complications. Current guidelines recommend enteral nutrition (EN), possibly within the first 48 hours, as the best way to provide the nutrients and prevent infections. EN may be difficult to realize or may be contraindicated in some patients, such as those presenting anatomic intestinal continuity problems or splanchnic ischemia. A series of contradictory trials regarding the best route and timing for feeding have left the medical community with great uncertainty regarding the place of parenteral nutrition (PN) in critically ill patients. Many of the deleterious effects attributed to PN result from inadequate indications, or from overfeeding. The latter is due firstly to the easier delivery of nutrients by PN compared with EN increasing the risk of overfeeding, and secondly to the use of approximate energy targets, generally based on predictive equations: these equations are static and inaccurate in about 70% of patients. Such high uncertainty about requirements compromises attempts at conducting nutrition trials without indirect calorimetry support because the results cannot be trusted; indeed, both underfeeding and overfeeding are equally deleterious. An individualized therapy is required. A pragmatic approach to feeding is proposed: at first to attempt EN whenever and as early as possible, then to use indirect calorimetry if available, and to monitor delivery and response to feeding, and finally to consider the option of combining EN with PN in case of insufficient EN from day 4 onwards.

China´s new labour contract law: no harm to employment?

In January 2008, China imposed a new labour contract law. This new law is the most significant reform to the law of employment relations in mainland China in more than a decade. The paper provides a theoretical framework on the inter-linkages between labour market regulation, option value and the choice and timing of employment. All in all, the paper demonstrates that the Labour Contract Law in it´s own right will have only small impacts upon employment in the fast-growing Chinese economy. On the contrary, induced increasing unit labour costs represent the real issue and may reduce employment.

On Public Inefficiencies in a Mixed Duopoly

The aim of this paper is to investigate the welfare effect of a change in the public firms objective function in oligopoly when the government takes into account the distortionary effect of rising funds by taxation (shadow cost of public funds). We analyze the impact of a shift from welfare- to profit-maximizing behaviour of the public firm on the timing of competition by endogenizing the determination of simultaneous (Nash-Cournot) versus sequential (Stackelberg) games using the game with observable delay proposed by Hamilton and Slutsky (1990). Differently from previous work that assumed the timing of competition, we show that, absent efficiency gains, instructing the public firm to play as a private one never increases welfare. Moreover, even when large efficiency gains result from the shift in public firm's objective, an inefficient public firm that maximizes welfare may be preferred.

Codificació i transmissió interactiva d'imatges en dispositius mòbils

JPEG2000 és el nou estàndard de compressió d’imatges impulsat pel Joint Photographics Experts Group, el qual defineix un protocol eficient per la transmissió interactiva d’imatges, anomenat JPIP. El Group on Interactive Coding of Images (GICI) té una implementació d’aquest protocol, CADI. En aquest projecte es realitza l’implementació del client d’aquest protocol en un dispositiu mòbil. Per això s’ha realitzat un estudi de les plataformes mòbils que hi ha actualment en el mercat. Finalment s’han proposat millores, en el descodificador, per reduir el temps de computació i la carrega de memòria.

Optimal Climate Change Policies When Governments Cannot Commit

This paper examines the optimal design of climate change policies in the context where governments want to encourage the private sector to undertake significant immediate investment in developing cleaner technologies, but the carbon taxes and other environmental policies that could in principle stimulate such investment will be imposed over a very long future. The conventional claim by environmental economists is that environmental policies alone are sufficient to induce firms to undertake optimal investment. However this argument requires governments to be able to commit to these future taxes, and it is far from clear that governments have this degree of commitment. We assume instead that governments cannot commit, and so both they and the private sector have to contemplate the possibility of there being governments in power in the future that give different (relative) weights to the environment. We show that this lack of commitment has a significant asymmetric effect. Compared to the situation where governments can commit it increases the incentive of the current government to have the investment undertaken, but reduces the incentive of the private sector to invest. Consequently governments may need to use additional policy instruments – such as R&D subsidies – to stimulate the required investment.

Does Semantic Context Benefit Speech Understanding through "Top-Down" Processes? Evidence from Time-resolved Sparse fMRI.

When speech is degraded, word report is higher for semantically coherent sentences (e.g., her new skirt was made of denim) than for anomalous sentences (e.g., her good slope was done in carrot). Such increased intelligibility is often described as resulting from "top-down" processes, reflecting an assumption that higher-level (semantic) neural processes support lower-level (perceptual) mechanisms. We used time-resolved sparse fMRI to test for top-down neural mechanisms, measuring activity while participants heard coherent and anomalous sentences presented in speech envelope/spectrum noise at varying signal-to-noise ratios (SNR). The timing of BOLD responses to more intelligible speech provides evidence of hierarchical organization, with earlier responses in peri-auditory regions of the posterior superior temporal gyrus than in more distant temporal and frontal regions. Despite Sentence content × SNR interactions in the superior temporal gyrus, prefrontal regions respond after auditory/perceptual regions. Although we cannot rule out top-down effects, this pattern is more compatible with a purely feedforward or bottom-up account, in which the results of lower-level perceptual processing are passed to inferior frontal regions. Behavioral and neural evidence that sentence content influences perception of degraded speech does not necessarily imply "top-down" neural processes.

Non-cooperative incentives to share knowledge in competitive environments

In this paper we study a model where non-cooperative agents may exchange knowledge in a competitive environment. As a potential factor that could induce the knowledge disclosure between humans we consider the timing of the moves of players. We develop a simple model of a multistage game in which there are only three players and competition takes place only within two stages. Players can share their private knowledge with their opponents and the knowledge is modelled as in uencing their marginal cost of e¤ort. We identify two main mechanisms that work towards knowledge disclosure. One of them is that before the actual competition starts, the stronger player of the rst stage of a game may have desire to share his knowledge with the "observer", be- cause this reduces the valuation of the prize of the weaker player of that stage and as a result his e¤ort level and probability of winning in a ght. Another mechanism is that the "observer" may have sometimes desire to share knowledge with the weaker player of the rst stage, because in this way, by increasing his probability of winning in that stage, he decreases the probability of winning of the stronger player. As a result, in the second stage the "observer" may have greater chances to meet the weaker player rather than the stronger one. Keywords: knowledge sharing, strategic knowledge disclosure, multistage contest game, non-cooperative games

The effects of the generalized use of iodized salt on occupational patterns in Switzerland.

This paper examines the impact of salt iodization in Switzerland in the 1920s and 1930s on occupational patterns of cohorts born after the intervention. The generalized use of iodized salt successfully combatted iodine deficiency disorders, which were previously endemic in some areas of Switzerland. The most important effect of universal prophylaxis by means of iodized salt was the eradication of mental retardation inflicted in utero by lack of iodine. This paper looks for evidence of increased cognitive ability of those treated with iodine in utero by examining the occupational choice and characteristics of occupations chosen by cohorts born after the intervention. By exploiting variation in pre-existing conditions and in the timing of the intervention, I find that cohorts born in previously highly-deficient areas after the introduction of iodized salt self-selected into higher-paying occupations. I also find that the characteristics of occupations in those areas changed, and that cohorts born after the intervention engaged to a higher degree in occupations with higher cognitive demands, whereas they opted out of physical-labor-intensive occupations.

Uncertain Fiscal Consolidations

The paper explores the macroeconomic consequences of fiscal consolidations whose timing and composition are uncertain. Drawing on the evidence in Alesina and Ardagna (2010), we emphasize whether or not the fiscal consolidation is driven by tax rises or expenditure cuts. We find that the composition of the fiscal consolidation, its duration, the monetary policy stance, the level of government debt and expectations over the likelihood and composition of fiscal consolidations all matter in determining the extent to which a given consolidation is expansionary and/or successful in stabilizing government debt.

Dark Clouds or Silver Linings? Knightian Uncertainty and Climate Change

This paper examines the impact of Knightian uncertainty upon optimal climate policy through the prism of a continuous-time real option modelling framework. We analytically determine optimal intertemporal climate policies under ambiguous assessments of climate damages. Additionally, numerical simulations are provided to illustrate the properties of the model. The results indicate that increasing Knightian uncertainty accelerates climate policy, i.e. policy makers become more reluctant to postpone the timing of climate policies into the future.

Shallow-level migmatization of gabbros in a metamorphic contact aureole, Fuerteventura Basal Complex, Canary Islands

Migmatization of gabbroic rocks at 2-3 kbar has occurred in the metamorphic contact aureole of a mafic pluton in the Fuerteventura Basal Complex (Canary Island;). Migmatites are characterized by a dense network: of closely spaced millimetre-wide leucocratic veins with perfectly preserved igneous textures. They are all relatively enriched in Al, Na I: Sr Ba, Nb, Y and the rare earth elements compared with the unaffected country rock beyond the aureole. Migmatization under such low-pressure conditions war possible because of the unusual tectonic and magmatic contact in which ii occurred. Multiple basic intrusions associated with extrusive volcanic activity created high heat flow in a small area. Alkaline and metasomatized rocks present in the country rock of the intruding pluton were leached by high-temperature fluids during contact metamorphism. These enriched fluids then favoured partial melting of the host gabbroic rocks, and contaminated both the leucosomes and melanosomes. A transpressive tectonic setting at the time of intrusion created shearing along the contact between the intrusion and its host rock. This shearing enhanced circulation of the fluids and allowed segregation of the nea-formed melts from their restite by opening tension veins into which the melts migrated. Depending on the relative timing of melt segregation and recrystallization leucosomes range in composition from a 40-60% mixture of clinopyroxene (+/- amphibole) and plagioclase to almost pure feldspathic veins. Comparable occurrences of gabbros migmatized at low pressure are expected only at a snail scale in localized areas of high heat flow in the presence of fluids, such as in. mid-ocean ridges or ocean-islands.

Domestic Violence and Football in Glasgow: Are Reference Points Relevant?

Much research suggests that sporting events can trigger domestic violence with recent evidence suggesting that pre-match expectations (which can be interpreted as reference points) play an especially important role in this relationship. In particular, unexpectedly disappointing results have been associated with large increases in domestic violence. This paper contributes to this literature using a new data set containing every domestic violence incident in Glasgow over a period of more than eight years. We find that Old Firm matches, where Glasgow rivals Celtic and Rangers play, are associated with large increases in domestic violence (regardless of the timing or the outcome of the match). Non-Old Firm matches tend to have little impact on domestic violence. Furthermore, we fi nd little evidence for the importance of reference points. Matches with disappointing outcomes, relative to pre-match expectations, are found to be associated with unusual increases in domestic violence only in a very limited set of matches.