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Cav1.3 channels control D2-autoreceptor responses via NCS-1 in substantia nigra dopamine neurons
(2014)
Dopamine midbrain neurons within the substantia nigra are particularly prone to degeneration in Parkinson's disease. Their selective loss causes the major motor symptoms of Parkinson's disease, but the causes for the high vulnerability of SN DA neurons, compared to neighbouring, more resistant ventral tegmental area dopamine neurons, are still unclear. Consequently, there is still no cure available for Parkinson's disease. Current therapies compensate the progressive loss of dopamine by administering its precursor l-DOPA and/or dopamine D2-receptor agonists. D2-autoreceptors and Cav1.3-containing L-type Ca2+ channels both contribute to Parkinson’s disease pathology. L-type Ca2+ channel blockers protect SN DA neurons from degeneration in Parkinson's disease and its mouse models, and they are in clinical trials for neuroprotective Parkinson's disease therapy. However, their physiological functions in SN DA neurons remain unclear. D2-autoreceptors tune firing rates and dopamine release of SN DA neurons in a negative feedback loop through activation of G-protein coupled potassium channels (GIRK2, or KCNJ6). Mature SN DA neurons display prominent, non-desensitizing somatodendritic D2-autoreceptor responses that show pronounced desensitization in PARK-gene Parkinson’s disease mouse models. We analysed surviving human SN DA neurons from patients with Parkinson's disease and from controls, and detected elevated messenger RNA levels of D2-autoreceptors and GIRK2 in Parkinson's disease. By electrophysiological analysis of postnatal juvenile and adult mouse SN DA neurons in in vitro brain-slices, we observed that D2-autoreceptor desensitization is reduced with postnatal maturation. Furthermore, a transient high-dopamine state in vivo, caused by one injection of either l-DOPA or cocaine, induced adult-like, non-desensitizing D2-autoreceptor responses, selectively in juvenile SN DA neurons, but not ventral tegmental area dopamine neurons. With pharmacological and genetic tools, we identified that the expression of this sensitized D2-autoreceptor phenotype required Cav1.3 L-type Ca2+ channel activity, internal Ca2+, and the interaction of the neuronal calcium sensor NCS-1 with D2-autoreceptors. Thus, we identified a first physiological function of Cav1.3 L-type Ca2+ channels in SN DA neurons for homeostatic modulation of their D2-autoreceptor responses. L-type Ca2+ channel activity however, was not important for pacemaker activity of mouse SN DA neurons. Furthermore, we detected elevated substantia nigra dopamine messenger RNA levels of NCS-1 (but not Cav1.2 or Cav1.3) after cocaine in mice, as well as in remaining human SN DA neurons in Parkinson's disease. Thus, our findings provide a novel homeostatic functional link in SN DA neurons between Cav1.3- L-type-Ca2+ channels and D2-autoreceptor activity, controlled by NCS-1, and indicate that this adaptive signalling network (Cav1.3/NCS-1/D2/GIRK2) is also active in human SN DA neurons, and contributes to Parkinson's disease pathology. As it is accessible to pharmacological modulation, it provides a novel promising target for tuning substantia nigra dopamine neuron activity, and their vulnerability to degeneration.
Rising powers are fundamentally shifting the relations of power in the global economic and political landscape. International political theory, however, has so far failed to evaluate this nascent multipolarity. This article fills this lacuna by synthesizing empirical and normative modes of inquiry. It examines the transformation of sovereignty exercised by emerging democracies and focuses especially on the case of Brazil. The paper shows that – in stark contrast to emerging democracies' foreign policy rhetoric – the "softening" of sovereignty, which means that emerging powers gain as well as lose certain aspects of sovereignty, has become the norm. The paper explores this softening of sovereignty from the perspective of global justice by assessing it on the basis of globalist, statist, and internationalist conceptions of global justice. We find that the emergent multipolarity contributes in various ways to the realization of the distinct socioeconomic and political criteria of these three conceptions of global justice. However, we also point out that the transformation of sovereignty generates particular problems for the realization of all three conceptions.
Introduction - Issue 7
(2014)
Este artigo aborda criticamente alguns conceitos referentes ao vínculo entre racionalidade, abstração e poder, tomados em contraste com a noção de mímesis, tal como Adorno e Horkheimer concebem na Dialética do esclarecimento. Partindo da diferenciação de quatro conceitos de esclarecimento, procuramos demonstrar o caráter inadequado da equalização entre esclarecimento e exercício violento e ideológico do poder, mostrando como o conceito de abstração, que nos parece servir de base para o primeiro capítulo daquela obra, permite delinear melhor a cisão entre as formas de conhecimento miméticas e as que lhe sucederam, tomando como ponto de partida a concepção mítica grega arcaica.
La revitalització de les grans religions: un repte per a l’autocomprensió secular de la modernitat?
(2014)
La vitalitat de la religió ha conduït a un qüestionament de la tesi que vincula la modernització i la secularització. Cal, doncs, repensar el mateix significat de la “modernitat” per tal d’adaptar-la a l’escala mundial. A l’hora de dur a terme un diàleg intercultural ja no es pot confiar en un suposat universalisme de la raó. La raó secular no pot pretendre establir els criteris de la racionalitat sense prendre en consideració també altres tradicions, com les que beuen de la religió. Es planteja, doncs, la pregunta si el pensament postmetafísic por aprendre alguna cosa de les tradicions religioses i si per fer-ho cal que s’hi relacioni de manera agnòstica.
The prediction of climate on time scales of years to decades is attracting the interest of both climate researchers and stakeholders. The German Ministry for Education and Research (BMBF) has launched a major research programme on decadal climate prediction called MiKlip (Mittelfristige Klimaprognosen, Decadal Climate Prediction) in order to investigate the prediction potential of global and regional climate models (RCMs). In this paper we describe a regional predictive hindcast ensemble, its validation, and the added value of regional downscaling. Global predictions are obtained from an ensemble of simulations by the MPI-ESM-LR model (baseline 0 runs), which were downscaled for Europe using the COSMO-CLM regional model. Decadal hindcasts were produced for the 5 decades starting in 1961 until 2001. Observations were taken from the E-OBS data set. To identify decadal variability and predictability, we removed the long-term mean, as well as the long-term linear trend from the data. We split the resulting anomaly time series into two parts, the first including lead times of 1–5 years, reflecting the skill which originates mainly from the initialisation, and the second including lead times from 6–10 years, which are more related to the representation of low frequency climate variability and the effects of external forcing. We investigated temperature averages and precipitation sums for the summer and winter half-year. Skill assessment was based on correlation coefficient and reliability. We found that regional downscaling preserves, but mostly does not improve the skill and the reliability of the global predictions for summer half-year temperature anomalies. In contrast, regionalisation improves global decadal predictions of half-year precipitation sums in most parts of Europe. The added value results from an increased predictive skill on grid-point basis together with an improvement of the ensemble spread, i.e. the reliability.
U uvodu rada diferenciraju se morfološka (i „pravomorfološka”) i pravopisna norma, pri čemu se govori i o svojevrsnome paradoksu pravopisne norme. Metodom komparativne i kontrastivne analize u središnjem se dijelu rada raščlanjuju neki relevantni morfološki aspekti koji sudjeluju u definiranju pravopisnih načela i pravopisnih pravila. Cilj je rada osvješćivanje teorijsko-metodoloških aspekata kojima se naznačuju vidovi svojevrsna preklapanja morfologije i pravopisa, i to kroz prizmu hrvatske pravopisne norme, ali i norme nekih slavenskih jezika. U skladu s tim u zaključku se progovara o povezanosti pravopisne norme s morfološkom normom, odnosno kako posebnosti morfološke norme postaju pitanje pravopisne norme.
A versatile synthetic procedure is described to prepare the benzimidazole-fused 1,2,4-thiadiazoles 2a–c via a methanesulfonyl chloride initiated multistep cyclization involving the intramolecular reaction of an in-situ generated carbodiimide with a thiourea unit. The structure of the intricate heterocycle 2a was confirmed by single-crystal X-ray analysis and its mechanism of formation supported by DFT computations.