Acid-sensing ion channel 1a drives AMPA receptor plasticity following ischemia and acidosis in hippocampal CA1 neurons

The CA1 region of the hippocampus is particularly vulnerable to ischemic damage. While NMDA receptors play a major role in excitotoxicity, it is thought to be exacerbated in this region by two forms of post-ischemic AMPA receptor (AMPAR) plasticity - namely, anoxic long-term potentiation (a-LTP), and a delayed increase in the prevalence of Ca2+ -permeable GluA2-lacking AMPARs (CP-AMPARs). The acid-sensing ion channel 1a (ASIC1a) which is expressed in CA1 pyramidal neurons, is also known to contribute to post-ischemic neuronal death and to physiologically induced LTP. This raises the question - does ASIC1a activation drive the post-ischemic forms of AMPAR plasticity in CA1 pyramidal neurons? We have tested this by examining organotypic hippocampal slice cultures (OHSCs) exposed to oxygen glucose deprivation (OGD), and dissociated cultures of hippocampal pyramidal neurons (HPN) exposed to low pH (acidosis). We find that both a-LTP and the delayed increase in the prevalence of CP-AMPARs are dependent on ASIC1a activation during ischemia. Indeed, acidosis alone is sufficient to induce the increase in CP-AMPARs. We also find that inhibition of ASIC1a channels circumvents any potential neuroprotective benefit arising from block of CP-AMPARs. By demonstrating that ASIC1a activation contributes to post-ischemic AMPAR plasticity, our results identify a functional interaction between acidotoxicity and excitotoxicity in hippocampal CA1 cells, and provide insight into the role of ASIC1a and CP-AMPARs as potential drug targets for neuroprotection. We thus propose that ASIC1a activation can drive certain forms of CP-AMPAR plasticity, and that inhibiting ASIC1a affords neuroprotection.

Role of Reactive Gliosis and Neuroinflammation in Experimental Glaucoma

Le glaucome est la principale cause de cécité irréversible dans le monde. Chez les patients atteints de cette pathologie, la perte de la vue résulte de la mort sélective des cellules ganglionnaires (CGR) de la rétine ainsi que de la dégénérescence axonale. La pression intraoculaire élevée est considérée le facteur de risque majeur pour le développement de cette maladie. Les thérapies actuelles emploient des traitements pharmacologiques et/ou chirurgicaux pour diminuer la pression oculaire. Néanmoins, la perte du champ visuel continue à progresser, impliquant des mécanismes indépendants de la pression intraoculaire dans la progression de la maladie. Il a été récemment démontré que des facteurs neuroinflammatoires pourraient être impliqués dans le développement du glaucome. Cette réponse est caractérisée par une régulation positive des cytokines pro-inflammatoires, en particulier du facteur de nécrose tumorale alpha (TNFα). Cependant, le mécanisme par lequel le processus neuroinflammatoire agit sur la mort neuronale reste à clarifier. L’hypothèse principale de ce doctorat propose que les facteurs pro-inflammatoires comme le TNFα et la phosphodiestérase 4 (PDE4) interagissent avec les mécanismes moléculaires de la mort neuronale, favorisant ainsi la survie et la protection des CGRs au cours du glaucome. Dans la première partie de ma thèse, J’ai utilisé un modèle in vivo de glaucome chez des rats Brown Norway pour montrer que l’expression du TNFα est augmentée après l'induction de l'hypertension oculaire. L'hypothèse spécifique de cette étude suggère que les niveaux élevés de TNFα provoquent la mort des CGRs en favorisant l'insertion de récepteurs AMPA perméables au calcium (CP-AMPAR) à la membrane cytoplasmique. Pour tester cette hypothèse, j’ai utilisé un inhibiteur sélectif de la forme soluble du TNFα, le XPro1595. L'administration de cet agent pharmacologique a induit une protection significative des somas et des axones des neurones rétiniens. L'évaluation de la perméabilité au cobalt a montré que le TNFα soluble est impliqué dans l'insertion de CP-AMPAR à la membrane des CGRs lors du glaucome. L’exposition des neurones à une pression oculaire élevée est à l’origine de la hausse de la densité membranaire des CP-AMPARs, grâce à une diminution de l’expression de la sous-unité GluA2. La présence de GluA2 au sein du récepteur ne permet pas l’entrée du calcium à l’intérieur de la cellule. L'administration intraoculaire d’antagonistes spécifiques des CP-AMPARs promeut la protection des somas et des axones des CGRs. Ces résultats montrent que les CP-AMPARs jouent un rôle important dans la pathologie du glaucome. Dans la deuxième partie de ma thèse, j’ai caractérisé l'effet neuroprotecteur d’un inhibiteur de la PDE4, l’ibudilast, dans notre modèle de glaucome. L'hypothèse spécifique s’oriente vers une atténuation de la réponse neuroinflammatoire et de la gliose par l’administration d’ibudilast, favorisant ainsi la protection neuronale. Les résultats montrent que dans les rétines glaucomateuses, l’ibudilast diminue la gliose et l'expression de plusieurs facteurs tels que le TNFα, l'interleukine-1β (IL-1β), l’interleukine-6 (IL-6) et le facteur inhibiteur de la migration des macrophages (MIF). Chez les rats glaucomateux, nous avons observé une expression notable de PDE4A dans les cellules de Müller, qui est en corrélation avec l'accumulation de l’AMP cyclique (AMPc) dans ces cellules après un traitement d’ibudilast. Finalement, nous avons démontré que la protection des CGRs via l’administration d’ibudilast est un mécanisme dépendent de l’AMPc et de la protéine kinase A (PKA). En conclusion, les résultats présentés dans cette thèse identifient deux mécanismes différents impliqués dans la perte des CGRs au cours du glaucome. Ces mécanismes pourraient fournir des perspectives potentielles pour le développement de nouvelles stratégies de traitement du glaucome.

Precise measurements of direct CP violation, CPT symmetry, and other parameters in the neutral kaon system

We present precise tests of CP and CPT symmetry based on the full data set of K -> pi pi decays collected by the KTeV experiment at Fermi National Accelerator Laboratory during 1996, 1997, and 1999. This data set contains 16 x 10(6) K -> pi(0)pi(0) and 69 x 10(6) K -> pi(+)pi(-) decays. We measure the direct CP violation parameter Re(epsilon'/epsilon) = (19.2 +/- 2.1) x 10(-4). We find the K(L) -> K(S) mass difference Delta m = (5270 +/- 12) x 10(6) (h) over tilde s(-1) and the K(S) lifetime tau(S) = (89.62 +/- 0.05) x 10(-12) s. We also measure several parameters that test CPT invariance. We find the difference between the phase of the indirect CP violation parameter epsilon and the superweak phase: phi(epsilon) - phi(SW) =(0.40 +/- 0.56)degrees. We measure the difference of the relative phases between the CP violating and CP conserving decay amplitudes for K -> pi(+)pi(-) (phi(+-)) and for K -> pi(0)pi(0) (phi(00)): Delta phi = (0.30 +/- 0.35)degrees. From these phase measurements, we place a limit on the mass difference between K(0) and (K) over bar (0): Delta M < 4.8 x 10(-19) GeV/c(2) at 95% C.L. These results are consistent with those of other experiments, our own earlier measurements, and CPT symmetry.

Some (3+1)-dimensional vortex solutions of the CP(N) model

We present a class of solutions of the CP(N) model in (3 + 1) dimensions. We suggest that they represent vortexlike configurations. We also discuss some of their properties. We show that some configurations of vortices have a divergent energy per unit length while for the others such an energy has a minimum for a very special orientation of vortices. We also discuss the Noether charge densities of these vortices.

Comprehensive study of surface chemistry of MCM-41 using Si-29 CP/MAS NMR, FTIR, pyridine-TPD, and TGA

A comprehensive study was conducted on mesoporous MCM-41. Spectroscopic examinations demonstrated that three types of silanol groups, i.e., single, (SiO)(3)Si-OH, hydrogen-bonded, (SiO)(3)Si-OH-OH-Si(SiO)(3), and geminal, (SiO)(2)Si(OH)(2), can be observed. The number of silanol groups/nm(2), alpha(OH), as determined by NMR, varies between 2.5 and 3.0 depending on the template-removal methods. All these silanol groups were found to be the active sites for adsorption of pyridine with desorption energies of 91.4 and 52.2 kJ mol(-1), respectively. However, only free silanol groups (involving single and geminal silanols) are highly accessible to the silylating agent, chlorotrimethylsilane. Silylation can modify both the physical and chemical properties of MCM-41.

Effect of argon purity on mechanical properties, microstructure and fracture mode of commercially pure (cp) Ti and Ti-6Al-4V alloys for ceramometal dental prostheses

Provision of an inert gas atmosphere with high-purity argon gas is recommended for preventing titanium castings from contamination although the effects of the level of argon purity on the mechanical properties and the clinical performance of Ti castings have not yet been investigated. The purpose of this study was to evaluate the effect of argon purity on the mechanical properties and microstructure of commercially pure (cp) Ti and Ti-6Al-4V alloys. The castings were made using either high-purity and/or industrial argon gas. The ultimate tensile strength (UTS), proportional limit (PL), elongation (EL) and microhardness (VHN) at different depths were evaluated. The microstructure of the alloys was also revealed and the fracture mode was analyzed by scanning electron microscopy. The data from the mechanical tests and hardness were subjected to a two-and three-way ANOVA and Tukey`s test (alpha = 0.05). The mean values of mechanical properties were not affected by the argon gas purity. Higher UTS, PL and VHN, and lower EL were observed for Ti-6Al-4V. The microhardness was not influenced by the argon gas purity. The industrial argon gas can be used to cast cp Ti and Ti-6Al-4V.

Impact of land-use on soil organic matter quality in south-western Australia - characterization with C-13 CP/MAS NMR spectroscopy

The influence of change in land-use from native vegetation to pasture (20-71 yr after conversion), and subsequent change from pasture to eucalypt plantation (7-10 yr after conversion) on soil organic matter quality was investigated using C-13 CP/MAS NMR spectroscopy. We studied surface soil (0-10 cm) from six sites representing a range of soil, and climate types from south-western Australia. Total C in the samples ranged from 1.6 to 5.5%, but the relative proportions of the four primary spectral regions (alkyl, O-alkyl, aromatic and carboxylic) were similar across the sites, and changes due to land-use at each site were relatively minor. Main impacts of changed land-use were higher O-alkyl (carbohydrate) material under pasture than under native vegetation and plantation (P = 0.048), and lower aromatic C under pasture than under native vegetation (P = 0.027). The decrease in aromatic C in pasture soils was related to time since clearing. (C) 2002 Elsevier Science Ltd. All rights reserved.

Optimização da afectação de recursos à produção de serviços da CP regional

O investimento efectuado na últimas décadas, em Portugal, nas infra-estruturas de transporte de longa duração, permitiu o desenvolvimento da rede rodoviária, quer em extensão quer em qualidade, enquanto pelo contrário, a Rede Ferroviária Nacional (RFN), entrou num processo contínuo de degradação, percebido pela redução das velocidades máximas permitidas e pelo elevado número e dispersão de limitações (reduções) de velocidades impostas na via-férrea. Actualmente, um comboio ao circular na RFN, fica sujeito a variadíssimas reduções de velocidade, recorrendo obrigatoriamente à utilização do freio, com impacto na eficiência energética e na redução das velocidades comerciais. Estes factores, associados às baixas performances do material, nomeadamente o reduzido esforço acelerador, em particular no diesel, resulta no aumento dos tempos de percurso e na redução do conforto, factores que constituem sem dúvida, as principais causas de perda de competitividade do sector ferroviário, tendo culminado na perda de 30% dos passageiros transportados, para o modo rodoviário, nas últimas décadas. Constituiu o objectivo deste trabalho, criar um modelo dinâmico, que permita identificar os pontos críticos da RFN, medindo o impacto das reduções de velocidade nas circulações ferroviárias, em tempo perdido, em termos energéticos, ambientais e financeiros. Os indicadores obtidos através da aplicação do modelo, são produzidos com auxílio do computador, identificando os pontos críticos da infra-estrutura e ordenando-os em função do impacto financeiro na oferta comercial da CP regional. Este relatório, será efectuado com uma periodicidade concertada com a REFER e permitirá ao gestor da infra-estrutura, programar de forma objectiva as intervenções na RFN, eliminando os pontos críticos. Contibui-se assim, para a melhoria da qualidade do serviço, para o aumento da competitividade e da sustentabilidade do sector ferroviário em Portugal.

A two-Higgs doublet model with remarkable CP properties

We analyze generalized CP symmetries of two-Higgs doublet models, extending them from the scalar to the fermion sector of the theory. We show that, other than the usual CP transformation, there is only one of those symmetries which does not imply massless charged fermions. That single model which accommodates a fermionic mass spectrum compatible with experimental data possesses a remarkable feature. Through a soft breaking of the symmetry it displays a new type of spontaneous CP violation, which does not occur in the scalar sector responsible for the symmetry breaking mechanism but, rather, in the fermion sector.

CP properties of symmetry-constrained two-Higgs-doublet models

The two-Higgs-doublet model can be constrained by imposing Higgs-family symmetries and/or generalized CP symmetries. It is known that there are only six independent classes of such symmetry-constrained models. We study the CP properties of all cases in the bilinear formalism. An exact symmetry implies CP conservation. We show that soft breaking of the symmetry can lead to spontaneous CP violation (CPV) in three of the classes.

Leptonic CP violation

Several topics on CP violation in the lepton sector are reviewed. A few theoretical aspects concerning neutrino masses, leptonic mixing, and CP violation will be covered, with special emphasis on seesaw models. A discussion is provided on observable effects which are manifest in the presence of CP violation, particularly, in neutrino oscillations and neutrinoless double beta decay processes, and their possible implications in collider experiments such as the LHC. The role that leptonic CP violation may have played in the generation of the baryon asymmetry of the Universe through the mechanism of leptogenesis is also discussed.

Spontaneous leptonic CP violation and nonzero theta(13)

We consider a simple extension of the Standard Model by adding two Higgs triplets and a complex scalar singlet to its particle content. In this framework, the CP symmetry is spontaneously broken at high energies by the complex vacuum expectation value of the scalar singlet. Such a breaking leads to leptonic CP violation at low energies. The model also exhibits an A(4) X Z(4) flavor symmetry which, after being spontaneously broken at a high-energy scale, yields a tribimaximal pattern in the lepton sector. We consider small perturbations around the tribimaximal vacuum alignment condition in order to generate nonzero values of theta(13), as required by the latest neutrino oscillation data. It is shown that the value of theta(13) recently measured by the Daya Bay Reactor Neutrino Experiment can be accommodated in our framework together with large Dirac-type CP violation. We also address the viability of leptogenesis in our model through the out-of-equilibrium decays of the Higgs triplets. In particular, the CP asymmetries in the triplet decays into two leptons are computed and it is shown that the effective leptogenesis and low-energy CP-violating phases are directly linked.

A soft origin for CKM-type CP violation

We present a two-Higgs-doublet model, with a Z(3) symmetry, in which CP violation originates solely in a soft (dimension-2) coupling in the scalar potential, and reveals itself solely in the CKM (quark mixing) matrix. In particular, in the mass basis the Yukawa interactions of the neutral scalars are all real. The model has only eleven parameters to fit the six quark masses and the four independent CKM-matrix observables. We find regions of parameter space in which the flavour-changing neutral couplings are so suppressed that they allow the scalars to be no heavier than a few hundred GeV. (C) 2011 Elsevier B.V. All rights reserved.