Observations of elevated basal cortisol levels in Alzheimer's disease (AD) patients prompted the hypothesis that stress and glucocorticoids (GC) may contribute to the development and/or maintenance of AD. Consistent with that hypothesis, we show that stress and GC provoke misprocessing of amyloid precursor peptide in the rat hippocampus and prefrontal cortex, resulting in increased levels of the peptide C-terminal fragment 99 (C99), whose further proteolytic cleavage results in the generation of amyloid-b (Ab). We also show that exogenous Ab can reproduce the effects of stress and GC on C99 production and that a history of stress strikingly potentiates the C99-inducing effects of Ab and GC. Previous work has indicated a role for Ab in disruption of synaptic function and cognitive behaviors, and AD patients reportedly show signs of heightened anxiety. Here, behavioral analysis revealed that like stress and GC, Ab administration causes spatial memory deficits that are exacerbated by stress and GC; additionally, Ab, stress and GC induced a state of hyperanxiety. Given that the intrinsic properties of C99 and Ab include neuroendangerment and behavioral impairment, our findings suggest a causal role for stress and GC in the etiopathogenesis of AD, and demonstrate that stressful life events and GC therapy can have a cumulative impact on the course of AD development and progression.

Elevated glucocorticoids, during pregnancy, alter emotionality and increase propensity to drug abuse later in life, albeit through substrates and mechanisms are largely unknown. In this study, we examined whether antenatal glucocorticoid exposure induces enduring structural changes in the nucleus accumbens (NAcc), an important relay point in the reward limbic circuitry. To this end, rat dams were exposed to the synthetic glucocorticoid dexamethasone (DEX) on days 18 and 19 of gestation, and stereological tools were used to assess the total volume of, and neuronal numbers in, the NAcc, as well as the density of mesencephalic dopaminergic inputs from the ventral tegmental area (VTA) to the NAcc in their adult offspring. Further, we used measures of bromodeoxyuridine incorporation into NAcc cells to examine whether DEX-induced effects on cell proliferation represent another mechanism through which glucocorticoids alter the structure of mesolimbic pathways and might influence addictive behavior. Our studies show that exposure to DEX during late gestation results in significantly reduced volumes and cell numbers in the NAcc. The latter measure correlated strongly with a reduced rate of cell proliferation in DEX-exposed animals. Moreover, the treatment resulted in a decreased number of cells expressing tyrosine hydroxylase in the VTA and an impoverished dopaminergic innervation of the NAcc. These observations, which identify glucocorticoid-sensitive structures and neurochemical targets within the developing "reward pathway," pave way for future studies designed to understand how early life events can predispose individuals for developing drug dependence in adolescent and adult life.

Slurry pipe transport has directed the efforts of researchers for decades, not only for the practical impact of this problem, but also for the challenges in understanding and modelling the complex phenomena involved. The increase in computer power and the diffusion of multipurpose codes based on Computational Fluid Dynamics (CFD) have opened up the opportunity to gather information on slurry pipe flows at the local level, in contrast with the traditional approaches of simplified theoretical modelling which are mainly based on a macroscopic description of the flow. This review paper discusses the potential of CFD for simulating slurry pipe flows. A comprehensive description of the modelling methods will be presented, followed by an overview of significant publications on the topic. However, the main focus will be the assessment of the potential and the challenges of the CFD approach, underlying the essential interplay between CFD simulations and experiments, discussing the main sources of uncertainty of CFD models, and evaluating existing models based on their interpretative or predictive capacity. This work aims at providing a solid ground for students, academics, and professional engineers dealing with slurry pipe transport, but it will also provide a methodological approach that goes beyond the specific application.

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This paper studies the impact of institutional reforms on innovation. We use the timing and geography of the French occupation of dierent regions of Germany after the French Revolution of 1789 as an exogenous shock to the institutions of those regions. Combining novel countylevel data on Imperial Germany with data on patents per capita, we show that counties whose institutions are more inclusive as a result of the French occupation become more innovative. The institutional reforms that are associated with comparing a county with no occupation to a county with the longest occupation, result in a 129% increase in the number of patents per capita. This result is robust to alternative explanations, such as reverse causality, human capital and nancial development. Our ndings point to institutions as a rst order determinant of innovation and highlight the role of innovation as a key mechanism through which institutions may lead to economic growth.