Optimisation du transfert de gènes dans la rétine par des vecteurs lentiviraux lors de maladies dégénératives de la rétine

Certaines dégénérescences rétiniennes sont engendrées par des mutations¦génétiques et conduisent à la perte des cellules photosensibles, les¦photorécepteurs (cônes et/ou bâtonnets), et donc à la cécité (Roy et al., 2010).¦La prévalence est de 1/3000 chez les Caucasiens. Les Rétinites Pigmentaires¦(RP) en composent la majorité des cas, suivent l'Amaurose congénitale de¦Leber et la maladie de Stargardt. Il n'y a pas une mutation type associés à une¦maladie mais diverses mutations peuvent aboutir à une dégénérescence de la¦rétine. Tout comme le reste du système nerveux central, la rétine lésée n'a pas¦les capacités de se régénérer. Un objectif du traitement est de ralentir la¦dégénérescence de la rétine dans le but de la stabiliser. La thérapie génique¦constitue actuellement la seule approche thérapeutique à même de traiter les¦dégénérescences rétiniennes d'origine génétique. Elle consiste à utiliser un virus¦modifié, qui n'a plus les capacités de se reproduire, appelé vecteur pour cibler¦certaines cellules afin d'ajouter un gène sain ou d'inhiber un gène malade. Les¦virus associés à l'adénovirus (AAV) et les Lentivirus (LV) sont les 2 principaux¦types de virus utilisés en thérapie génique en ophtalmologie. D'autres vecteurs¦existent, comme les adénovirus et le virus de l'anémie infectieuse équine. Des¦études de thérapie génique effectuées chez l'homme avec le vecteur AAV ont¦démontré une sensible amélioration des fonctions visuelles (acuité visuelle,¦champ visuel, pupillométrie et le déplacement dans un environnement avec une¦lumière tamisée) chez des patients atteints d'Amaurose congénitale de Leber¦(Maguire et al., Ali et al., Hauswirth et al., Bennett et al.). Le vecteur utilisé au¦cours de ce travail est un LV, qui a pour avantage de pouvoir transporter de¦grands gènes. Lorsque ce vecteur est pseudotypé avec une enveloppe VSVG, il¦transduit (transférer un gène qui sera fonctionnel dans la cellule cible) bien¦l'épithélium pigmentaire rétinien (nécessaire à la survie et à la fonction des¦photorécepteurs). Afin de changer le tropisme du vecteur, celui testé dans cette¦étude contient une enveloppe de type Mokola qui cible efficacement les cellules¦gliales du cerveau et donc probablement aussi les cellules de Müller de la rétine.¦Le but à court terme est de transformer génétiquement ces cellules pour leur¦faire sécréter des molécules favorisant la survie des photorécepteurs. Pour¦révéler la cellule ciblée par le vecteur, le gène qui sera exprimé dans les cellules¦transduites code pour la protéine fluorescente verte 2 (GFPII) et n'a pas de¦fonction thérapeutique. Après avoir produit le virus, deux types de souris ont été¦injectées : des souris dépourvues du gène de la rhodopsine appelées Rho -/- et¦des souris sauvages appelées C57BL6. Les souris Rho -/- ont été choisies en¦tant que modèle de dégénérescence rétinienne et les souris C57BL6 en tant que¦comparatif. Les souris Rho -/- et C57BL56 ont été injectées entre le 2ème et le¦3ème mois de vie et sacrifiées 7 jours après. Des coupes histologiques de la rétine¦ont permis de mesurer et comparer pour chaque oeil, les distances de¦transduction du RPE et de la neurorétine (= toute la rétine sauf le RPE). La¦distance sur laquelle le RPE est transduit détermine la taille de la bulle¦d'injection alors que la distance sur laquelle la neurorétine est transduite¦détermine la capacité du vecteur à diffuser dans la rétine. Les résultats montrent¦une expression plus importante de la GFPII dans le RPE que dans la neurorétine¦chez les souris Rho -/- et C57BL6. Les principales cellules transduites au¦niveau de la neurorétine sont, comme attendu, les cellules de Müller. Lorsque¦l'on compare les proportions de neurorétine et de RPE transduites, on constate¦qu'il y a globalement eu une meilleure transduction chez les souris Rho -/-¦que chez les souris C57BL6. Cela signifie que le vecteur est plus efficace pour¦transduire une rétine dégénérée qu'une rétine saine. Pour déterminer quels types¦de cellules exprimaient la GFPII, des anticorps spécifiques de certains types de¦cellules ont été utilisés. Ces résultats sont similaires à ceux d'autres études¦effectuées précédemment, dont celle de Calame et al. en 2011, et tendent à¦prouver que le vecteur lentiviral avec l'enveloppe Mokola et le promoteur EFs¦est idéal pour transduire avec un gène thérapeutique des cellules de Müller dans¦des rétines en dégénérescence.

Optimal feedback control rules sensitive to controlled endogenous risk-aversion

The objective of this paper is to correct and improve the results obtained by Van der Ploeg (1984a, 1984b) and utilized in the theoretical literature related to feedback stochastic optimal control sensitive to constant exogenous risk-aversion (see, Jacobson, 1973, Karp, 1987 and Whittle, 1981, 1989, 1990, among others) or to the classic context of risk-neutral decision-makers (see, Chow, 1973, 1976a, 1976b, 1977, 1978, 1981, 1993). More realistic and attractive, this new approach is placed in the context of a time-varying endogenous risk-aversion which is under the control of the decision-maker. It has strong qualitative implications on the agent's optimal policy during the entire planning horizon.

Strong solutions for stochastic porous media equations with jumps

We prove global well-posedness in the strong sense for stochastic generalized porous media equations driven by locally square integrable martingales with stationary independent increments.

Barriers to innovation and public policy in Catalonia

The present paper analyses the link between firms’ decisions to innovate and the barriers that prevent them from being innovative. The aim is twofold. First, it analyses three groups of barriers to innovation: the cost of innovation projects, lack of knowledge and market conditions. Second, it presents the main steps taken by Catalan Government to promote the creation of new firms and to reduce barriers to innovation. The data set used is based on the 2004 official innovation survey of Catalonia which was taken from the Spanish CIS-4 sample. This sample includes individual information on 2,954 Catalan firms in manufacturing industries and knowledge-intensive services (KIS). The empirical analysis reveals pronounced differences regarding a firm’s propensity to innovate and its perception of barriers. Moreover, the results show that cost and knowledge barriers seem to be the most important and that there are substantial sectoral differences in the way that firms react to barriers. The results of this paper have important implications for the design of future public policy to promote entrepreneurship and innovation together.

Sustaining sleep spindles through enhanced SK2-channel activity consolidates sleep and elevates arousal threshold.

Sleep spindles are synchronized 11-15 Hz electroencephalographic (EEG) oscillations predominant during nonrapid-eye-movement sleep (NREMS). Rhythmic bursting in the reticular thalamic nucleus (nRt), arising from interplay between Ca(v)3.3-type Ca(2+) channels and Ca(2+)-dependent small-conductance-type 2 (SK2) K(+) channels, underlies spindle generation. Correlative evidence indicates that spindles contribute to memory consolidation and protection against environmental noise in human NREMS. Here, we describe a molecular mechanism through which spindle power is selectively extended and we probed the actions of intensified spindling in the naturally sleeping mouse. Using electrophysiological recordings in acute brain slices from SK2 channel-overexpressing (SK2-OE) mice, we found that nRt bursting was potentiated and thalamic circuit oscillations were prolonged. Moreover, nRt cells showed greater resilience to transit from burst to tonic discharge in response to gradual depolarization, mimicking transitions out of NREMS. Compared with wild-type littermates, chronic EEG recordings of SK2-OE mice contained less fragmented NREMS, while the NREMS EEG power spectrum was conserved. Furthermore, EEG spindle activity was prolonged at NREMS exit. Finally, when exposed to white noise, SK2-OE mice needed stronger stimuli to arouse. Increased nRt bursting thus strengthens spindles and improves sleep quality through mechanisms independent of EEG slow waves (<4 Hz), suggesting SK2 signaling as a new potential therapeutic target for sleep disorders and for neuropsychiatric diseases accompanied by weakened sleep spindles.

Expectations, Learning and Monetary Policy: An Overview of Recent Research

Expectations about the future are central for determination of current macroeconomic outcomes and the formulation of monetary policy. Recent literature has explored ways for supplementing the benchmark of rational expectations with explicit models of expectations formation that rely on econometric learning. Some apparently natural policy rules turn out to imply expectational instability of private agents’ learning. We use the standard New Keynesian model to illustrate this problem and survey the key results about interest-rate rules that deliver both uniqueness and stability of equilibrium under econometric learning. We then consider some practical concerns such as measurement errors in private expectations, observability of variables and learning of structural parameters required for policy. We also discuss some recent applications including policy design under perpetual learning, estimated models with learning, recurrent hyperinflations, and macroeconomic policy to combat liquidity traps and deflation.

Threshold Effects of Dismissal Protection Regulation and the Emergence of Temporary Work Agencies

Labour market regulations aimed at enhancing job-security are dominant in several OECD countries. These regulations seek to reduce dismissals of workers and fluctuations in employment. The main theoretical contribution is to gauge the effects of such regulations on labour demand across establishment sizes. In order to achieve this, we investigate an optimising model of labour demand under uncertainty through the application of real option theory. We also consider other forms of employment which increase the flexibility of the labour market. In particular, we are modelling the contribution of temporary employment agencies (Zeitarbeit) allowing for quick personnel adjustments in client firms. The calibration results indicate that labour market rigidities may be crucial for understanding sluggishness in firms´ labour demand and the emergence and growth of temporary work.

Political Risk, Economic Integration, and the Foreign Direct Investment Decision

In this paper we analyse the impact of policy uncertainty on foreign direct investment strategies. We also consider the impact of economic integration upon FDI decisions. The paper follows the real options approach, which allows investigating the value to a firm of waiting to invest and/or disinvest, when payoffs are stochastic due to political uncertainty and investments are partially reversible. Across the board we find that political uncertainty can be very detrimental to FDI decisions while economic integration leads to an increasing benefit of investing abroad.

Tax Structure, Growth and Welfare in the UK

This paper studies the quantitative implications of changes in the composition of taxes for long-run growth and expected lifetime utility in the UK economy over 1970-2005. Our setup is a dynamic stochastic general equilibrium model incorporating a detailed scal policy struc- ture, and where the engine of endogenous growth is human capital accumulation. The government s spending instruments include pub- lic consumption, investment and education spending. On the revenue side, labour, capital and consumption taxes are employed. Our results suggest that if the goal of tax policy is to promote long-run growth by altering relative tax rates, then it should reduce labour taxes while simultaneously increasing capital or consumption taxes to make up for the loss in labour tax revenue. In contrast, a welfare promoting policy would be to cut capital taxes, while concurrently increasing labour or consumption taxes to make up for the loss in capital tax revenue.

Countercyclical Fiscal Policy and Cyclical Factor Utilization

In a neoclassical growth model with monopolistic competition in the product market, the presence of cyclical factor utilization enhances the stabilization role of countercyclical taxes. The costs of varying capital utilization take the form of varying rates of depreciation, which in turn have amplifying effect on investment decisions as well as the volatility of most aggregate variables. This creates an additional channel through which taxes affect the economy, a channel that enhances the stabilization role of countercyclical taxes, with particularly strong effects in the labor market. However, in terms of welfare, countercyclical taxes are welfare inferior due to reduced precautionary saving motives.

Optimal Monetary Policy in a New Keynesian Model with Habits in Consumption

While consumption habits have been utilised as a means of generating a humpshaped output response to monetary policy shocks in sticky-price New Keynesian economies, there is relatively little analysis of the impact of habits (particularly,external habits) on optimal policy. In this paper we consider the implications of external habits for optimal monetary policy, when those habits either exist at the level of the aggregate basket of consumption goods (‘superficial’ habits) or at the level of individual goods (‘deep’ habits: see Ravn, Schmitt-Grohe, and Uribe (2006)). External habits generate an additional distortion in the economy, which implies that the flex-price equilibrium will no longer be efficient and that policy faces interesting new trade-offs and potential stabilisation biases. Furthermore, the endogenous mark-up behaviour, which emerges when habits are deep, can also significantly affect the optimal policy response to shocks, as well as dramatically affecting the stabilising properties of standard simple rules.

Welfare Implications of Public Education Spending Rules

In this paper, we quantitatively assess the welfare implications of alternative public education spending rules. To this end, we employ a dynamic stochastic general equilibrium model in which human capital externalities and public education expenditures, nanced by distorting taxes, enhance the productivity of private education choices. We allow public education spending, as share of output, to respond to various aggregate indicators in an attempt to minimize the market imperfection due to human capital externalities. We also expose the economy to varying degrees of uncertainty via changes in the variance of total factor productivity shocks. Our results indicate that, in the face of increasing aggregate uncertainty, active policy can signi cantly outperform passive policy (i.e. maintaining a constant public education to output ratio) but only when the policy instrument is successful in smoothing the growth rate of human capital.

When is Monetary Policy All we Need?

We consider optimal monetary and scal policies in a New Keynesian model of a small open economy with sticky prices and wages. In this benchmark setting monetary policy is all we need - analytical results demonstrate that variations in government spending should play no role in the stabilization of shocks. In extensions we show, rstly, that this is even when true when allowing for in ation inertia through backward-looking rule-of-thumb price and wage-setting, as long as there is no discrepancy between the private and social evaluation of the marginal rate of substitution between consumption and leisure. Secondly, the optimal neutrality of government spending is robust to the issuance of public debt. In the presence of debt government spending will deviate from the optimal steady-state but only to the extent required to cover the deficit, not to provide any additional macroeconomic stabilization. However, unlike government spending variations in tax rates can play a complementary role to monetary policy, as they change relative prices rather than demand.

Shocks, Monetary Policy and Institutions: Explaining Unemployment Persistence in Persistence in “Europe” and the United States

This paper examines the rise in European unemployment since the 1970s by introducing endogenous growth into an otherwise standard New Keynesian model with capital accumulation and unemployment. We subject the model to an uncorrelated cost push shock, in order to mimic a scenario akin to the one faced by central banks at the end of the 1970s. Monetary policy implements a disinfl ation by following an interest feedback rule calibrated to an estimate of a Bundesbank reaction function. 40 quarters after the shock has vanished, unemployment is still about 1.8 percentage points above its steady state. Our model also broadly reproduces cross country differences in unemployment by drawing on cross country differences in the size of cost push shock and the associated disinfl ation, the monetary policy reaction function and the wage setting structure.