Characterization of functional role of α-ketoglutarate receptor in the kidney : role of the intrinsic circadian timing system in renin expressing cells

Le rein joue un rôle essential dans le maintien de l'homéostasie des fluides extracellulaires (FEC) et la pression artérielle. L'objectif de notre groupe est d'identifier de nouveaux mécanismes impliqués dans le contrôle de l'homéostasie des FEC et de la pression artérielle par le rein. Projet 1) Caractérisation du rôle fonctionnel du récepteur à l'a-cétogluatarate Oxgrl dans le rein Oxgrl est le récepteur spécifique de l'a-cétogluatarate, une moléule intermédiaire du cycle de l'acide citrique, filtrée par le rein et réabsorbée ou secrétée au niveau des tubules proximaux. Le rôle fonctionnel de ces deux récepteurs reste inconnu. Nos résultats montrent qu'Oxgrl est localisé au niveau des cellules intercalaires du tube collecteur (CCD). Des souris (Oxgrr/_) montrent une diminution du pH urinaire ,une augmentation de la concentration de l'acide urinaire titrable et une augmentation des niveaux d'a-cétoglutarate. Le traitement au Na-bicarbonate provoque une augmentation plus prononcée de l'alcalose métabolique chez les souris Oxgrl"7"' accompagnée d'une augmentation de la concentration de bicarbonate et une diminution du niveau de chlore plasmatique. En parallèle, des études de microperfusion ont montré que a-cétoglutarate stimule la réabsorption éléctroneutre de NaCl dans le CCD des souris de type sauvage mais pas des souris Oxgrl"7". En résumé, ces résultats montrent que l'a-cétoglutarate joue un rôle de molécule messagère du tubule proximal jusqu'au tube collecteur au niveau du rein et qu'Oxgrl pourrait être impliqué dans la régulation de l'échange Cl/bicarbonate et la réabsorption du NaCl dans les cellules intercalées. Projet 2) Rôle du système circadien dans les cellules productrices de rénine. Le système chronologique circadien est un mécanisme moléculaire ubiquitaire qui permet à l'organisme de coordonner ses fonctions principales en fonction du temps géophysique. Comme l'activité de la rénine plasmatique montre une rythmicité circadienne nette chez l'homme et la souris ; dans ce projet, nous avons abordé la question à savoir dans quelle mesure le système circadien est impliqué dans cette variabilité circadienne. Pour cela, le gène Bmall, élément principal de l'horloge moléculaire, a été perturbé dans les cellules granulaires productrices de rénine par le système Cre-LoxP. Nos résultats montrent que les souris Renld- Cre/Bmalllox/lox (cKO) présentent de faibles taux d'ARNm de Reni, altèrent la dynamique d'expression de la protéine rénine, mais il le niveau de concentration plasmatique de la rénine reste le même. Cependant, les souris cKO montrent une réduction significative de la concentration plasmatique de l'aldostérone. Nos analyses de l'urine récupérée dans des intervalles de temps de 24 et 1 heure montrent une augmentation du volume urinaire, une tendance à une hypercalciurie, ainsi qu'une altération de la dynamique d'excrétion urinaire de sodium chez les souris cKO. Plusieurs gènes impliqués dans la production/sécrétion de la rénine et dans le contrôle de la fonction rénale montrent une altération de l'expression circadienne d'ARNm. Par ailleurs, les souris cKO montrent une baisse significative de la pression artérielle. Nos résultats suggèrent que l'horloge intrinsèque des cellules productrices de la rénine joue un rôle important dans le control des FEC et l'homéostasie de la pression artérielle via régulation de la fonction rénale.

Generic entry into a regulated pharmaceutical market

The aim of this paper is to analyse empirically entry decisions by generic firms intomarkets with tough regulation. Generic drugs might be a key driver of competitionand cost containment in pharmaceutical markets. The dynamics of reforms ofpatents and pricing across drug markets in Spain are useful to identify the impact ofregulations on generic entry. Estimates from a count data model using a panel of 86active ingredients during the 1999 2005 period show that the drivers of genericentry in markets with price regulations are similar to less regulated markets: genericfirms entries are positively affected by the market size and time trend, and negativelyaffected by the number of incumbent laboratories and the number of substitutesactive ingredients. We also find that contrary to what policy makers expected, thesystem of reference pricing restrains considerably the generic entry. Short run brandname drug price reductions are obtained by governments at the cost of long runbenefits from fostering generic entry and post-patent competition into the markets.

With a bang, not a whimper: Pricking Germany's "stock market bubble" in 1927 and the slide into depression

In May 1927, the German central bank intervenedindirectly to reduce lending to equity investors.The crash that followed ended the only stockmarket boom during Germany s relative stabilization 1924-28. This paper examines thefactors that lead to the intervention as well asits consequences. We argue that genuine concernabout the exuberant level of the stock market,in addition to worries about an inflow offoreign funds, tipped the scales in favour ofintervention. The evidence strongly suggeststhat the German central bank under HjalmarSchacht was wrong to be concerned aboutstockprices-there was no bubble. Also, theReichsbank was mistaken in its belief thata fall in the market would reduce theimportance of short-term foreign borrowing,and help to ease conditions in the money market.The misguided intervention had important realeffects. Investment suffered, helping to tipGermany into depression.

A century of global equity market correlations

In this paper, we use a unique long-run dataset of regulatory constraints on capital account openness to explain stock market correlations. Since stock returns themselves are highly volatile, any examination of what drives correlations needs to focus on long runs of data. This is particularly true since some of the short-term changes in co-movements appear to reverse themselves (Delroy Hunter 2005). We argue that changes in the co-movement of indices have not been random. Rather, they are mainly driven by greater freedom to move funds from one country to another. In related work, Geert Bekaert and Campbell Harvey (2000) show that equity correlations increase after liberalization of capital markets, using a number of case studies from emerging countries. We examine this pattern systematically for the last century, and find it to be most pronounced in the recent past. We compare the importance of capital account openness with one main alternative explanation, the growing synchronization of economic fundamentals. We conclude that greater openness has been the single most important cause of growing correlations during the last quarter of a century, though increasingly correlated economic fundamentals also matter. In the conclusion, we offer some thoughts on why the effects of greater openness appear to be so much stronger today than they were during the last era of globalization before 1914.

Contrasting magma types and timing of intrusion in the Permian layered mafic complex of Mont Collon (Western Alps, Valais, Switzerland): evidence from U/Pb zircon and 40Ar/39Ar amphibole dating

We have selected and dated three contrasting rock-types representative of the magmatic activity within the Permian layered mafic complex of Mont Collon, Austroalpine Dent Blanche nappe, Western Alps. A pegmatitic gabbro associated to the main cumulus sequence yields a concordant U/Pb zircon age of 284.2 +/- 0.6 Ma, whereas a pegmatitic granite dike crosscutting the latter yields a concordant age of 282.9 +/- 0.6 Ma. A Fe-Ti-rich ultrabasic lamprophyre, crosscutting all other lithologies of the complex, yields an 40Ar/39Ar plateau age of 260.2 +/- 0.7 Ma on a kaersutite concentrate. All ages are interpreted as magmatic. Sub-contemporaneous felsic dikes within the Mont Collon complex are ascribed to anatectic back-veining from the country-rock, related to the emplacement of the main gabbroic body in the continental crust, which is in accordance with new isotopic data. The lamprophyres have isotopic compositions typical of a depleted mantle, in contrast to those of the cumulate gabbros, close to values of the Bulk Silicate Earth. This indicates either contrasting sources for the two magma pulses - the subcontinental lithospheric mantle for the gabbros and the underlying asthenosphere for the lamprophyres - or a single depleted lithospheric source with variable degrees of crustal contamination of the gabbroic melts during their emplacement in the continental crust. The Mont Collon complex belongs to a series of Early Permian mafic massifs, which emplaced in a short time span about 285-280 Ma ago, in a limited sector of the post-Variscan continental crust now corresponding to the Austroalpine/ Southern Alpine domains and Corsica. This magmatic activity was controlled in space and time by crustal-scale transtensional shear zones.

Judges' cognition and market order

We argue that during the crystallization of common and civil law in the 19th century, the optimal degree of discretion in judicial rulemaking, albeit influenced by the comparative advantages of both legislative and judicial rulemaking, was mainly determined by the anti-market biases of the judiciary. The different degrees of judicial discretion adopted in both legal traditions were thus optimally adapted to different circumstances, mainly rooted in the unique, market-friendly, evolutionary transition enjoyed by English common law as opposed to the revolutionary environment of the civil law. On the Continent, constraining judicial discretion was essential for enforcing freedom of contract and establishing a market economy. The ongoing debasement of pro-market fundamentals in both branches of the Western legal system is explained from this perspective as a consequence of increased perceptions of exogenous risks and changes in the political system, which favored the adoption of sharing solutions and removed the cognitive advantage of parliaments and political leaders.

Adverse selection, credit and efficiency: The case of the missing market

We analyze a standard environment of adverse selection in credit markets. In our environment,entrepreneurs who are privately informed about the quality of their projects needto borrow in order to invest. Conventional wisdom says that, in this class of economies, thecompetitive equilibrium is typically inefficient.We show that this conventional wisdom rests on one implicit assumption: entrepreneurscan only access monitored lending. If a new set of markets is added to provide entrepreneurswith additional funds, efficiency can be attained in equilibrium. An important characteristic ofthese additional markets is that lending in them must be unmonitored, in the sense that it doesnot condition total borrowing or investment by entrepreneurs. This makes it possible to attainefficiency by pooling all entrepreneurs in the new markets while separating them in the marketsfor monitored loans.

On the drivers of commodity co-movement: Evidence from biofuels

We use the recent introduction of biofuels to study the effect of industry factors on the relationshipsbetween wholesale commodity prices. Correlations between agricultural products and oilare strongest in the 2005-09 period, coinciding with the boom of biofuels, and remain substantialuntil 2011. We disentangle three possible drivers for the linkage: substitution, energy costs, andfinancialization. The timing and magnitude of the biofuels-to-oil relationships are different to thoseof other commodities, and far higher than can be justified by costs and financialization. Substitutionand costs drive the monthly correlations of long-term futures, and each of the three contributeequally to the daily co-movement of the short-term ones. The findings survive many robustnesschecks and appear in the stock market.

Impact of navigator timing on free-breathing submillimeter 3D coronary magnetic resonance angiography.

The purpose of this study was to investigate the impact of navigator timing on image quality in navigator-gated and real-time motion-corrected, free-breathing, three-dimensional (3D) coronary MR angiography (MRA) with submillimeter spatial image resolution. Both phantom and in vivo investigations were performed. 3D coronary MRA with real-time navigator technology was applied using variable navigator time delays (time delay between the navigator and imaging sequences) and varying spatial resolutions. Quantitative objective and subjective image quality parameters were assessed. For high-resolution imaging, reduced image quality was found as a function of increasing navigator time delay. Lower spatial resolution coronary MRA showed only minor sensitivity to navigator timing. These findings were consistent among volunteers and phantom experiments. In conclusion, for submillimeter navigator-gated and real-time motion-corrected 3D coronary MRA, shortening the time delay between the navigator and the imaging portion of the sequence becomes increasingly important for improved spatial resolution.

Assesing the political viability of labour market reform: The case of employment protection

We analyze the political support for employment protection legislation.Unlike my previous work on the same topic, this paper pays a lot ofattention to the role of obsolescence in the growth process.In voting in favour of employment protection, incumbent employeestrade off lower living standards (because employment protectionmaintains workers in less productive activities) against longer jobduration. The support for employment protection will then depend onthe value of the latter relative to the cost of the former. Wehighlight two key deeterminants of this trade-off: first, the workers'bargaining power, second, the economy's growth rate-more preciselyits rate of creative destruction.

Labour market in the Catalan cotton textile sector: Employment and fertility (1850-1913)

This paper deals whit the dynamics of the Catalan textile labour market (theSpanish region that concentrated most of the industrial and factory activity duringthe 19 Century) and offers hypotheses and results on the impact it had on livingstandards and fertility levels. We observe the formation of an uneven labourmarket in which male supply for labour (excluding women and children) grewmuch faster than the demand. We stress the fact that labour supply is verydependant on institutional factors liked to the transmition of household propertybetween generations. Instead the slow path of growth of adult males demand forlabour is witnessing the limits of this industry to expand and to compete ininternational markets. The strategy of working class families to adapt to scarceopportunities of employment we document here is the diminution of legitimatefertility levels. Fertility control is the direct instrument we think workers have tocontrol their number in a situation that was likely to create labour surpluses in theshort and mid run.

Product market deregulation and the U.S. employment miracle

We consider the dynamic relationship between product market entry regulation and equilibrium unemployment. The main theoretical contribution is combining a job matchingmodel with monopolistic competition in the goods market and individual wage bargaining.Product market competition affects unemployment by two channels: the output expansion effect and a countervailing effect due to a hiring externality. Competition is then linked to barriers to entry. We calibrate the model to US data and perform a policy experiment to assess whether the decrease in trend unemployment during the 1980 s and 1990 s could be attributed to product market deregulation. Our quantitative analysis suggests that under individual bargaining, a decrease of less than two tenths of a percentage point of unemployment rates can be attributed to product market deregulation, a surprisingly small amount.

Overconfidence and market efficiency with heterogeneous agents

We study financial markets in which both rational and overconfident agents coexist and make endogenous information acquisition decisions. We demonstrate the following irrelevance result: when a positive fraction of rational agents (endogeneously) decides to become informed in equilibrium, prices are set as if all investors were rational, and as a consequence the overconfidence bias does not aect informational efficiency, price volatility, rational traders expected profits or their welfare. Intuitively, as overconfidence goes up, so does price infornativeness, which makes rational agents cut their information acquisition activities, effectively undoing the standard effect of more aggressive trading by the overconfident.

Composition of electricity generation portfolios, pivotal dynamics and market prices

We use a simulation model to study how the diversification of electricity generation portfoliosinfluences wholesale prices. We find that technological diversification generally leads to lower market prices but that the relationship is mediated by the supply to demand ratio. In each demand case there is a threshold where pivotal dynamics change. Pivotal dynamics pre- and post-threshold are the cause of non-linearities in the influence of diversification on market prices. The findings are robust to our choice of behavioural parameters and match close-form solutions where those are available.