1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

Understanding sources of the change in international business cycles

Macroeconomic activity has become less volatile over the past three decades in most G7 economies. Current literature focuses on the characterization of the volatility reduction and explanations for this so called "moderation" in each G7 economy separately. In opposed to individual country analysis and individual variable analysis, this paper focuses on common characteristics of the reduction and common explanations for the moderation in G7 countries. In particular, we study three explanations: structural changes in the economy, changes in common international shocks and changes in domestic shocks. We study these explanations in a unified model structure. To this end, we propose a Bayesian factor structural vector autoregressive model. Using the proposed model, we investigate whether we can find common explanations for all G7 economies when information is pooled from multiple domestic and international sources. Our empirical analysis suggests that volatility reductions can largely be attributed to the decline in the magnitudes of the shocks in most G7 countries while only for the U.K., the U.S. and Italy they can partially be attributed to structural changes in the economy. Analyzing the components of the volatility, we also find that domestic shocks rather than common international shocks can account for a large part of the volatility reduction in most of the G7 countries. Finally, we find that after mid-1980s the structure of the economy changes substantially in five of the G7 countries: Germany, Italy, Japan, the U.K. and the U.S..

Price level convergence, purchasing power parity and multiple structural breaks: an application to US cities

This article provides a fresh methodological and empirical approach for assessing price level convergence and its relation to purchasing power parity (PPP) using annual price data for seventeen US cities. We suggest a new procedure that can handle a wide range of PPP concepts in the presence of multiple structural breaks using all possible pairs of real exchange rates. To deal with cross-sectional dependence, we use both cross-sectional demeaned data and a parametric bootstrap approach. In general, we find more evidence for stationarity when the parity restriction is not imposed, while imposing parity restriction provides leads toward the rejection of the panel stationar- ity. Our results can be embedded on the view of the Balassa-Samuelson approach, but where the slope of the time trend is allowed to change in the long-run. The median half-life point estimate are found to be lower than the consensus view regardless of the parity restriction.

Testing for sufficient information in structural VARs

We derive necessary and sufficient conditions under which a set of variables is informationally sufficient, i.e. it contains enough information to estimate the structural shocks with a VAR model. Based on such conditions, we suggest a procedure to test for informational sufficiency. Moreover, we show how to amend the VAR if informational sufficiency is rejected. We apply our procedure to a VAR including TFP, unemployment and per-capita hours worked. We find that the three variables are not informationally sufficient. When adding missing information, the effects of technology shocks change dramatically.

Biodiversity and global change in Mediterranean benthic communities: perspectives over large spatial and long temporal scales

Many terrestrial and marine systems are experiencing accelerating decline due to the effects of global change. This situation has raised concern about the consequences of biodiversity losses for ecosystem function, ecosystem service provision, and human well-being. Coastal marine habitats are a main focus of attention because they harbour a high biological diversity, are among the most productive systems of the world and present high anthropogenic interaction levels. The accelerating degradation of many terrestrial and marine systems highlights the urgent need to evaluate the consequence of biodiversity loss. Because marine biodiversity is a dynamic entity and this study was interested global change impacts, this study focused on benthic biodiversity trends over large spatial and long temporal scales. The main aim of this project was to investigate the current extent of biodiversity of the high diverse benthic coralligenous community in the Mediterranean Sea, detect its changes, and predict its future changes over broad spatial and long temporal scales. These marine communities are characterized by structural species with low growth rates and long life spans; therefore they are considered particularly sensitive to disturbances. For this purpose, this project analyzed permanent photographic plots over time at four locations in the NW Mediterranean Sea. The spatial scale of this study provided information on the level of species similarity between these locations, thus offering a solid background on the amount of large scale variability in coralligenous communities; whereas the temporal scale was fundamental to determine the natural variability in order to discriminate between changes observed due to natural factors and those related to the impact of disturbances (e.g. mass mortality events related to positive thermal temperatures, extreme catastrophic events). This study directly addressed the challenging task of analyzing quantitative biodiversity data of these high diverse marine benthic communities. Overall, the scientific knowledge gained with this research project will improve our understanding in the function of marine ecosystems and their trajectories related to global change.

Cyclical Skill-Biased Technological Change

Over the past two decades, technological progress has been biased towards making skilled labor more productive. The evidence for this finding is based on the persistent parallel increase in the skill premium and the supply of skilled workers. What are the implications of skill-biased technological change for the business cycle? To answer this question, we use the CPS outgoing rotation groups to construct quarterly series for the price and quantity of skill. The unconditional correlation of the skill premium with the cycle is zero. However, using a structural VAR with long run restrictions, we find that technology shocks substantially increase the premium. Investment-specific technology shocks are not skill-biased and our findings suggest that capital and skill are (mildly) substitutable in aggregate production.

Slow recoveries: A structural interpretation

An analysis of the performance of GDP, employment and otherlabor market variables following the troughs in postwar U.S. businesscycles points to much slower recoveries in the three most recentepisodes, but does not reveal any significant change over time in therelation between GDP and employment. This leads us to characterizethe last three episodes as slow recoveries, as opposed to jobless recoveries.We use the estimated New Keynesian model in Galí-Smets-Wouters (2011) to provide a structural interpretation for the slowerrecoveries since the early nineties.

Non-stationary job search when jobs are not forever: A structural estimation

This paper considers a job search model where the environment is notstationary along the unemployment spell and where jobs do not lastforever. Under this circumstance, reservation wages can be lower thanwithout separations, as in a stationary environment, but they can alsobe initially higher because of the non-stationarity of the model. Moreover,the time-dependence of reservation wages is stronger than with noseparations. The model is estimated structurally using Spanish data forthe period 1985-1996. The main finding is that, although the decrease inreservation wages is the main determinant of the change in the exit ratefrom unemployment for the first four months, later on the only effect comesfrom the job offer arrival rate, given that acceptance probabilities areroughly equal to one.

Magnetic field induced entropy change and magnetoelasticity in Ni-Mn-Ga alloys

The magnetocaloric effect that originates from the martensitic transition in the ferromagnetic Ni-Mn-Gashape-memory alloy is studied. We show that this effect is controlled by the magnetostructural coupling at boththe martensitic variant and magnetic domain length scales. A large entropy change induced by moderatemagnetic fields is obtained for alloys in which the magnetic moment of the two structural phases is not verydifferent. We also show that this entropy change is not associated with the entropy difference between themartensitic and the parent phase arising from the change in the crystallographic structure which has beenfound to be independent of the magnetic field within this range of fields.

Magnetic field induced entropy change and magnetoelasticity in Ni-Mn-Ga alloys

The magnetocaloric effect that originates from the martensitic transition in the ferromagnetic Ni-Mn-Gashape-memory alloy is studied. We show that this effect is controlled by the magnetostructural coupling at boththe martensitic variant and magnetic domain length scales. A large entropy change induced by moderatemagnetic fields is obtained for alloys in which the magnetic moment of the two structural phases is not verydifferent. We also show that this entropy change is not associated with the entropy difference between themartensitic and the parent phase arising from the change in the crystallographic structure which has beenfound to be independent of the magnetic field within this range of fields.

Structural development accounting

We construct and estimate a unified model combining three of the main sources ofcross-country income disparities: differences in factor endowments, barriers to technologyadoption and the inappropriateness of frontier technologies to local conditions. The keycomponents are different types of workers, distortions to capital accumulation, directedtechnical change, costly adoption and spillovers from the world technology frontier. Despiteits parsimonious parametrization, our empirical model provides a good fit of GDP data forup to 86 countries in 1970 and 122 countries in 2000. Removing barriers to technologyadoption would increase the output per worker of the average non-OECD country relativeto the US from 0.19 to 0.61, while increasing skill premia in all countries. Removing barriersto trade in goods amplifies income disparities, induces skill-biased technology adoptionand increases skill premia in the majority of countries. These results are reverted if tradeliberalization is coupled with international IPR protection.

Agricultural productivity and structural transformation. Evidence from Brazil

We study the effects of the adoption of new agricultural technologies on structural transformation. To guide empirical work, we present a simple model where the effect of agriculturalproductivity on industrial development depends on the factor bias of technical change. We testthe predictions of the model by studying the introduction of genetically engineered soybeanseeds in Brazil, which had heterogeneous effects on agricultural productivity across areas withdifferent soil and weather characteristics. We find that technical change in soy production wasstrongly labor saving and lead to industrial growth, as predicted by the model.