Warfarin-induced vitamin K deficiency is associated with cognitive and behavioral perturbations, and alterations in brain sphingolipids in rats

La Vitamine K (VK) est largement reconnue pour son rôle dans la coagulation sanguine toutefois, de plus en plus de travaux indiquent son implication dans la fonction cérébrale. La VK est requise pour l'activation de différentes protéines, par exemple la protéine Gas6, et la ménaquinone-4 (MK-4), le principal vitamère K dans le cerveau, est impliquée dans le métabolisme des sphingolipides. Dans un rapport précédent, nous avons montré qu'un régime alimentaire faible en VK tout au long de la vie était associé à des déficits cognitifs chez des rats âgés. La warfarine sodique est un puissant antagoniste de la VK qui agit en bloquant le cycle de la VK, provoquant un «déficit relatif de VK » au niveau cellulaire. À la lumière du rôle émergent de la VK dans le cerveau, la warfarine pourrait représenter un facteur de risque pour la fonction cérébrale. Ce travail est donc pertinente en raison de la forte proportion d'adultes traîtés à la warfarine sodique. Dans la présente étude, 14 rats mâles Wistar ont été traités avec 14 mg de warfarine/kg /jour (dans l'eau potable) et des injections sous-cutanées de VK (85 mg/kg), 3x/sem, pendant 10 semaines. Quatorze rats témoins ont été traités avec de l'eau normale et injectés avec une solution saline. Les rats ont été soumis à différents tests comportementaux après quoi les niveaux de phylloquinone, MK-4, sphingolipides (cérébroside, sulfatide, sphingomyéline, céramide et gangliosides), et les sous-types de gangliosides (GT1b, GD1a, GM1, GD1b), ont été évalués dans différentes régions du cerveau. Comparativement aux rats du groupe contrôle, les rats traités à la warfarine présentaient des latences plus longues au test de la piscine de Morris (p <0,05) ainsi qu'une hypoactivité et un comportement exploratoire plus faible au test de « l’open field » (p <0,05). Le traitement par warfarine a également entraîné une diminution spectaculaire du niveau de MK-4 dans toutes les régions du cerveau (p <0,001), une altération des concentrations de sphingolipidiques, en particulier dans le cortex frontal et le mésencéphale (p <0,05), et une perte de différences régionales sphingolipidiques, notamment pour les gangliosides. Le traitement par warfarine a été associé à un niveau inférieur de GD1a dans l'hippocampe et un niveau supérieur de GT1b dans le cortex préfrontal et le striatum. En conclusion, la déficience en VK induite par warfarine altère les niveaux de VK et sphingolipides dans le cerveau, avec de potentiels effets néfastes sur les fonctions cérébrales.

Hypertension et régulation de l'expression moléculaire de l'angiotensinogène par la ribonucléoprotéine hétérogène nucléaire K

Le diabète est une maladie chronique dont la principale caractéristique est un niveau plasmatique élevé de glucose, qui est causé soit par un défaut dans la production d’insuline, l’action de l’insuline, ou les deux à la fois. Plusieurs études ont démontré que l’hyperglycémie chronique peut mener à la dysfonction et même la défaillance de plusieurs organes, dont le coeur, le système vasculaire, les yeux et les reins, se traduisant par des infarctus du myocarde, des accidents cérébro-vasculaires et des complications rétinales et rénales, respectivement. La néphropathie diabétique (DN) est la principale cause de déficience rénale et affecte près de 25-40% des patients diabétiques. La DN est invariablement associée à un risque élevé d’accident cérébrovasculaire et de dysfonction cardivasculaire. L’angiotensinogène (Agt) est l’unique précurseur de tous les types d’angiotensines. En plus du système rénine-angiotensine (RAS) sytémique, le rein possède son propre système intrarénal et exprime tous les composants du RAS. L’Agt est fortement exprimé dans les cellules du tubule proximal rénal (RPTC) et y est converti en angiotensine II (AngII), le peptide biologiquement actif du RAS. Les patients diabétiques présentent de hauts niveaux d’AngII et une augmentation de l’expression des gènes du RAS, suggérant que l’activation du RAS intrarénal joue un rôle important dans la progression de la DN. Les mécanismes qui contrôlent la régulation du niveau rénal d’Agt par l’hyperglycémie et l’insuline demeurent mal compris. Le but global de cette thèse est de mieux comprendre les mécanismes moléculaires qui contrôlent l’expression du gène Agt chez la souris Akita (un modèle murin de diabète de type 1). Dans cette optique, la première partie de la thèse se concentre sur deux facteurs de transcription de la famille des ribonucléoprotéines nucléaires hétérogènes (hnRNP). Chan et collaborateurs ont déjà identifié 2 protéines nucléaires hnRNP F et hnRNP K, de 48kD et 70kD respectivement. HnRNP F et hnRNP K forment un hétérodimère et se lient à l’élément de réponse à l’insuline (IRE) présent dans le promoteur du gène Agt du rat et inhibent la transcription du gène Agt in vitro. Afin de déterminer si hnRNP F / K sont responsables de l’inhibition de l’expression rénale de Agt par l’insuline in vivo, nous avons étudié des souris Akita males traités ou non avec des implants d’insuline pour une période de 4 semaines. Des souris non-Akita males ont été employées comme contrôles. Les souris Akita développent de l’hypertension et de l’hypertrophie rénale. Le traitement à l’insuline rétablit les niveaux de glucose plasmatiques et la pression systolique (SBP), et atténue l’hypertrophie rénale, l’albuminurie (ratio albumine/créatinine urinaire, ACR) et les niveaux urinaires d’Agt et AngII chez les souris Akita. De plus, le traitement à l’insuline inhibe l’expression rénale du gène Agt, tout en augmentant l’expression des gènes hnRNP F, hnRNP K et ACE2 (enzyme de conversion de l’angiotensine-2). Dans des RPTC in vitro, l’insuline inhibe Agt, mais stimule l’expression de hnRNP F et hnRNP K en présence de hautes concentrations de glucose, et ce via la voie de signalisation MAPK p44/42 (protéine kinase activée par un mitogène). La transfection avec des petits ARN interférents (siRNA) contre hnRNP F et hnRNP K prévient l’inhibition de l’expression d’Agt par l’insuline dans les RPTC. Cette étude démontre bien que l’insuline prévient l’hypertension et atténue les dommages rénaux observés chez les souris Akita diabétiques, en partie grâce à la suppression de la transcription rénale de Agt, via une augmentation de l’expression de hnRNP F et hnRNP K. La seconde partie de cette thèse change de focus et se tourne vers le facteur Nrf2 (nuclear factor erythroid 2-related factor 2). Nrf2 est un facteur de transcription qui contrôle les gènes de la réponse antioxydante cellulaire en réponse au stress oxydant ou aux électrophiles. Le but de cette étude est d’examiner l’impact de la surexpression de la catalase (Cat) dans les RPTC sur l’expression du gène Agt via Nrf2 et sur le développement de l’hypertension et des dommages rénaux résultants chez les souris diabétiques Akita transgéniques (Tg). Nos études ont démontré que la surexpression de Cat dans les souris Akita Cat-Tg normalise la SBP, atténue les dommages rénaux et inhibe l’expression des gènes Nrf2 et Agt dans les RPTC. In vitro, le glucose élevé (HG) et l’oltipraz (un activateur de Nrf2) stimulent l’expression de Nrf2 et Agt, et cet effet peut être bloqué par la trigonelline (inhibiteur de Nrf2), des siRNA contre Nrf2, des antioxydants ou des inhibiteurs pharmacologiques NF-κB et MAPK p38. La suppression de sites de réponse à Nrf2 présents dans le promoteur du gène Agt du rat abolit la stimulation par l’oltipraz. Finalement, des souris males adultes non-transgéniques traitées avec l’oltipraz montrent une augmentation de l’expression de Nrf2 et Agt dans leurs RPTC et cette augmentation peut être normalisée par la trigonelline. Ces données permettent d’identifier un nouveau mécanisme d’action de Nrf2, par la stimulation du gène Agt intrarénal et l’activation du RAS, qui induisent l’hypertension et les dommages rénaux par le glucose élevé et les espèces réactives de l’oxygène chez les souris diabétiques. Nos conclusions permettent de démontrer que l’insuline induit l’expression de hnRNP F et hnRNP K, qui jouent ensuite un rôle protecteur en prévenant l’hypertension. La surexpression de la catalase dans les RPTC vient quant à elle atténuer l’activation de Nrf2 et ainsi réduit la SBP chez les souris Akita.

Low Level Jet stream of Asian Summer Monsoon and its Variability

The main objective of the of present study are to study the intraseasonal variability of LLJ and its relation with convective heating of the atmosphere, to establish whether LLJ splits into two branches over the Arabian sea as widely believed, the role of horizonatal wind shear of LLJ in the episodes of intense rainfall events observed over the west coast of India, to perform atmospheric modeling work to test whether small (meso) scale vortices form during intense rainfall events along the west coast; and to study the relation between LLJ and monsoon depression genesis. The results of a study on the evolution of Low Level Jetstream (LLJ) prior to the formation of monsoon depressions are presented. A synoptic model of the temporal evolution of monsoon depression has been produced. There is a systematic temporal evolution of the field of deep convection strength and position of the LLJ axis leading to the genesis of monsoon depression. One of the significant outcomes of the present thesis is that the LLJ plays an important role in the intraseasonal and the interannual variability of Indian monsoon activity. Convection and rainfall are dependent mainly on the cyclonic vorticity in the boundary layer associated with LLJ. Monsoon depression genesis and the episodes of very heavy rainfall along the west coast of India are closely related to the cyclonic shear of the LLJ in the boundary layer and the associated deep convection. Case studies by a mesoscale numerical model (MM5) have shown that the heavy rainfall episodes along the west coast of India are associated with generation of mesoscale cyclonic vortices in the boundary layer.

Thermal characterisation of dye-intercalated K-10 montmorillonite ceramics using photoacoustic technique

Thermal diffusivity (TD) measurements were performed on some industrially important dyes – auramine O (AO), malachite green and methylene blue (MB) – adsorbed K-10 montmorillonites using photoacoustic method. The TD value for the dye-adsorbed clay mineral was observed to change with a variation in dye concentration. The contribution of the dye towards TD was also determined. The repeatedly adsorbed samples with MB and AO exhibited a lower TD than the single-adsorbed samples. TD values of sintered MB samples were also obtained experimentally. These sintered samples exhibit a higher TD, although they show a trend similar to that of non-sintered pellets. A variation in dye concentration and sintering temperature can be used for tuning the TD value of the clay mineral to the desired level.

Preparation and Characterization ofHigh-k Aluminum Oxide Thin Films by Atomic Layer Deposition for Gate Dielectric Applications

Present work deals with the Preparation and characterization of high-k aluminum oxide thin films by atomic layer deposition for gate dielectric applications.The ever-increasing demand for functionality and speed for semiconductor applications requires enhanced performance, which is achieved by the continuous miniaturization of CMOS dimensions. Because of this miniaturization, several parameters, such as the dielectric thickness, come within reach of their physical limit. As the required oxide thickness approaches the sub- l nm range, SiO 2 become unsuitable as a gate dielectric because its limited physical thickness results in excessive leakage current through the gate stack, affecting the long-term reliability of the device. This leakage issue is solved in the 45 mn technology node by the integration of high-k based gate dielectrics, as their higher k-value allows a physically thicker layer while targeting the same capacitance and Equivalent Oxide Thickness (EOT). Moreover, Intel announced that Atomic Layer Deposition (ALD) would be applied to grow these materials on the Si substrate. ALD is based on the sequential use of self-limiting surface reactions of a metallic and oxidizing precursor. This self-limiting feature allows control of material growth and properties at the atomic level, which makes ALD well-suited for the deposition of highly uniform and conformal layers in CMOS devices, even if these have challenging 3D topologies with high aspect-ratios. ALD has currently acquired the status of state-of-the-art and most preferred deposition technique, for producing nano layers of various materials of technological importance. This technique can be adapted to different situations where precision in thickness and perfection in structures are required, especially in the microelectronic scenario.

Development Planning at the State Level in India - A Case Study with Reference to Kerala, 1957-'84

This thesis entitled “Development planning at the state level in india a case study with reference to kerala1957-84.Planning in India is a concurrent subject with the Centre and the States having well-defined domains of jurisdiction with regard to planning functions and sources of resource mobilisation.The genesis of the lack of academic interest in state level planning is in the widely held belief that in the extent scheme of Centre-State economic relations, the states have little scope for initiative in planning.Both at the theoretical and empirical levels, Kerala has attached very great importance to planning.It has been the localeof wide and deep discussions on the various dimensions of planning.In Kerala's development process, the leading sector consists of social services such as education and public healthOne point that needs special emphasis in this regard is that the high demand for education in Kerala cannot be attributed to the Keralites' ‘unique urge‘ for education. Rather, it is related to the very high level of unemployment in the state (Kerala has the highest level of unemployment in the country.In resource allocation under the Five Year Plans, Kerala attached the highest weightage to power generation, hydro-electric projects being the major source of power in the state. Nearly one-fourth of the plan resources has been claimed by hydro-electric projects.In the agricultural sector, Kera1a's level of productive use of electric power is one of the lowest.As is evident.from above, planning in Kerala has not enabled us to solve the basic problems of the state. More 'scientific' planning in the sense of applying mre sophisticated planning techniques is obviously not the answer. It, on the contrary, consists of more fundamental changes some of which can be brought about through an effective use of measures well within the power of the State Government.

Seasonal and interannual variability of sea level and associated surface meteorological parameters at Cochin

This thesis entitled seasonal and interannual variability of sea level and associated surface meteorological parameters at cochin.The interesting aspect of studying sea level variability on different time scales can be attributed to the diversity of its applications.Study of tides could perhaps be the oldest branch of physical oceanography.The thesis is presented in seven chapters. The first chapter gives, apart from a general introduction, a survey of literature on sea level variability on different time scales - tidal, seasonal and interannual (geological scales excluded), with particular emphasis on the work carried out in the Indian waters. The second chapter is devoted to the study of observed tides at Cochin on seasonal and interannual time scales using hourly water level data for the period 1988-1993. The third chapter describes the long-term climatology of some important surface oceanographic and meteorological parameters (at Cochin) which are supposed to affect the sea level. The fourth chapter addresses the problem of seasonal forecasting of the meteorological and oceanographic parameters at Cochin using autoregressive, sinusoidal and exponentially weighted moving average techniques and testing their accuracy with the observed data for the period 1991-1993. The fifth chapter describes the seasonal cycles of sea level and the driving forces at 16 stations along the Indian subcontinent. It also addresses the observed interannual variability of sea level at 15 stations using available multi-annual data sets. The sixth chapter deals with the problem of coastal trapped waves between Cochin and Beypore off the Kerala coast using sea level and atmospheric pressure data sets for the year 1977. The seventh and the last chapter contains the summary and conclusions and future outlook based on this study.

District Level Planning In Kerala And Karnataka - A Comparative Study

When we consider Kerala and Karnataka States according to their levels of decentralisation. Kerala is at the beginning of the scale of decentralisation whereas Kamataka has moved far ahead along this scale. Therefore I in order to conduct a comparative study of the SUbject under analysis t Kamataka has been selected owing to the fact that it is in an advanced stage in the experience of district planning compared to Kerala , Karnataka could successfully implement district planning and it is me of the pioneering states in this regard. But Kerala has not gained much experience in the field of decentralised district planning till now. Furthermore Kerala and Kamataka states are selected for the present study due to operational reasons I besides the author I s familiarity with the socia-economic conditions of these states. Thus. an analysis of the district planning experience of Kamataka will provide constructive and valuable information. which will be of great importance to Kerala State, which is now aspiring to introduce ful.I-f'Iedge district planning by constituting elected District Coancils in every district of Kerala. Moreover. the findings and policy implications of the present study will be of immense help to planners, politicians. administrators, academicians and people at large.

Content Based Image Retrieval Using Low Level Features of Automatically Extracted Regions of Interest

This paper proposes a region based image retrieval system using the local colour and texture features of image sub regions. The regions of interest (ROI) are roughly identified by segmenting the image into fixed partitions, finding the edge map and applying morphological dilation. The colour and texture features of the ROIs are computed from the histograms of the quantized HSV colour space and Gray Level co- occurrence matrix (GLCM) respectively. Each ROI of the query image is compared with same number of ROIs of the target image that are arranged in the descending order of white pixel density in the regions, using Euclidean distance measure for similarity computation. Preliminary experimental results show that the proposed method provides better retrieving result than retrieval using some of the existing methods.

Thermal characterisation of dye-intercalated K-10 montmorillonite ceramics using photoacoustic technique

Thermal diffusivity (TD) measurements were performed on some industrially important dyes – auramine O (AO), malachite green and methylene blue (MB) – adsorbed K-10 montmorillonites using photoacoustic method. The TD value for the dye-adsorbed clay mineral was observed to change with a variation in dye concentration. The contribution of the dye towards TD was also determined. The repeatedly adsorbed samples with MB and AO exhibited a lower TD than the single-adsorbed samples. TD values of sintered MB samples were also obtained experimentally. These sintered samples exhibit a higher TD, although they show a trend similar to that of non-sintered pellets. A variation in dye concentration and sintering temperature can be used for tuning the TD value of the clay mineral to the desired level

Studies on the interaction of two level atoms with quantized electromagnetic field

The present study described about the interaction of a two level atom and squeezed field with time varying frequency. By applying a sinusoidal variation in the frequency of the field, the randomness in population inversion is reduced and the collapses and periodic revivals are regained. Quantum optics is an emerging field in physics which mainly deals with the interaction of atoms with quantised electromagnetic fields. Jaynes-Cummings Model (JCM) is a key model among them, which describes the interaction between a two level atom and a single mode radiation field. Here the study begins with a brief history of light, atom and their interactions. Also discussed the interaction between atoms and electromagnetic fields. The study suggest a method to manipulate the population inversion due to interaction and control the randomness in it, by applying a time dependence on the frequency of the interacting squeezed field.The change in behaviour of the population inversion due to the presence of a phase factor in the applied frequency variation is explained here.This study also describes the interaction between two level atom and electromagnetic field in nonlinear Kerr medium. It deals with atomic and field state evolution in a coupled cavity system. Our results suggest a new method to control and manipulate the population of states in two level atom radiation interaction,which is very essential for quantum information processing.We have also studied the variation of atomic population inversion with time, when a two level atom interacts with light field, where the light field has a sinusoidal frequency variation with a constant phase. In both coherent field and squeezed field cases, the population inversion variation is completely different from the phase zero frequency modulation case. It is observed that in the presence of a non zero phase φ, the population inversion oscillates sinusoidally.Also the collapses and revivals gradually disappears when φ increases from 0 to π/2. When φ = π/2 the evolution of population inversion is identical to the case when a two level atom interacts with a Fock state. Thus, by applying a phase shifted frequency modulation one can induce sinusoidal oscillations of atomic inversion in linear medium, those normally observed in Kerr medium. We noticed that the entanglement between the atom and field can be controlled by varying the period of the field frequency fluctuations. The system has been solved numerically and the behaviour of it for different initial conditions and different susceptibility values are analysed. It is observed that, for weak cavity coupling the effect of susceptibility is minimal. In cases of strong cavity coupling, susceptibility factor modifies the nature in which the probability oscillates with time. Effect of susceptibility on probability of states is closely related to the initial state of the system.

Inclusive probability calculations for the K-vacancy transfer in collisions of S{^15+} on Ar

Using the single-particle amplitudes from a 20-level coupled-channel calculation with ab initio relativistic self consistent LCAO-MO Dirac-Fock-Slater energy eigenvalues and matrix elements we calculate within the frame of the inclusive probability formalism impact-parameter-dependent K-hole transfer probabilities. As an example we show results for the heavy asymmetric collision system S{^15+} on Ar for impact energies from 4.7 to 16 MeV. The inclusive probability formalism which reinstates the many-particle aspect of the collision system permits a qualitative and quantitative agreement with the experiment which is not achieved by the single-particle picture.

A Two-level Prediction Model for Deep Reactive Ion Etch (DRIE)

We contribute a quantitative and systematic model to capture etch non-uniformity in deep reactive ion etch of microelectromechanical systems (MEMS) devices. Deep reactive ion etch is commonly used in MEMS fabrication where high-aspect ratio features are to be produced in silicon. It is typical for many supposedly identical devices, perhaps of diameter 10 mm, to be etched simultaneously into one silicon wafer of diameter 150 mm. Etch non-uniformity depends on uneven distributions of ion and neutral species at the wafer level, and on local consumption of those species at the device, or die, level. An ion–neutral synergism model is constructed from data obtained from etching several layouts of differing pattern opening densities. Such a model is used to predict wafer-level variation with an r.m.s. error below 3%. This model is combined with a die-level model, which we have reported previously, on a MEMS layout. The two-level model is shown to enable prediction of both within-die and wafer-scale etch rate variation for arbitrary wafer loadings.

K.O. Apel: transcendentalisme i praxi de la veritat.

L'objectiu d'aquest treball és explicar i fer la crítica de la Teoria de la Veritat recentment defensada per Apel. En primer lloc, el consens i pragmàtica de la Teoria de la Veritat d'Apel es presenta en relació amb el projecte de la Teoria Crítica de la Societat de Habermas i el problema dels fonaments en el raonament ètic. En segon lloc, la seva versió idealitzada i transcendental de la Veritat que invoca la noció de convergència en una comunitat ideal d'investigadors lliures és analitzada. Finalment, les entranyes de l'esperit wingensteinià i després de l'últim anàlisi de Putnam, s’ha intentat fer una avaluació crítica. El resultat de tot això serà una més modesta concepció de la Veritat com a tan sols una qualitat de la praxi lingüística humana, però no la seva primera pedra