A doença de Alzheimer é a principal e a mais comum desordem neurodegenerativa relacionada à idade. O número de pessoas afetadas pela doença de Alzheimer vem crescendo bastante nos últimos anos, principalmente devido ao aumento da expectativa de vida da população. As causas para o desenvolvimento da doença de Alzheimer são bastante complexas, envolvendo uma combinação de fatores genéticos, moleculares e ambientais. Os emaranhados neurofibrilares, constituídos pela proteína tau hiperfosforilada, e as placas senis, compostas pelo peptídeo β-amiloide, são as duas principais alterações fisiopatológicas encontradas nessa patologia. Existe uma ampla variedade de evidências genéticas, fisiológicas e bioquímicas que suportam a ideia que o peptídeo β-amiloide é ao menos uma das causas que originam a doença de Alzheimer. Na forma monomérica, o peptídeo β-amiloide parece não exercer efeitos tóxicos. Porém, conforme estas formas monoméricas se polimerizam formando intermediários solúveis denominados oligômeros, e por fim protofibrilas e fibrilas, exercem consideráveis efeitos neurotóxicos. Os oligômeros do peptídeo β-amiloide são capazes de se correlacionar de forma mais consistente com os distúrbios cognitivos observados na doença de Alzheimer. Além disso, diversos trabalhos atribuem às alterações sinápticas um dos principais mecanismos de toxicidade dos oligômeros do peptídeo β- amiloide. Para isso, diversas vias de sinalização sofrem alteração no seu funcionamento, como a via das MAPKs, destacando as proteínas JNK1/2 e ERK1/2, e a via Wnt/β-catenina. Neste trabalho nós procuramos avaliar os mecanismos moleculares de toxicidade dos oligômeros do peptídeo β-amiloide em culturas organotípicas de hipocampo de ratos. Para isso, as culturas foram expostas às concentrações de 0,5; 1 e 2 μM por um período de 48h. A morte celular foi avaliada a partir da incorporação do iodeto de propídeo, um marcador de morte celular de células principalmente em processo de necrose. A exposição das culturas a todas as concentrações testadas não foi capaz de causar um aumento significativo na morte celular. Entretanto, observamos um decréscimo nos níveis da proteína sinaptofisina por Western blotting em todas as concentrações utilizadas. Essas alterações nos níveis de sinaptofisina foram acompanhadas pela ativação da proteína JNK, ou seja, pelo aumento da sua fosforilação, e pela inibição da proteína ERK, que teve seus níveis de fosforilação diminuídos. Nós também observamos uma diminuição no imunoconteúdo da proteína β-catenina. A avaliação dos níveis de fosforilação da GSK-3β e β-catenina não apresentou resultado significativo. Embora mais estudos sejam necessários para avaliar os mecanismos de toxicidade dos oligômeros do peptídeo β-amiloide, nossos resultados sugerem uma perda sináptica nas culturas organotípicas, uma das primeiras características observadas na doença de Alzheimer. Acreditamos que esse modelo possa ser utilizado no estudo de fatores fisiológicos e compostos farmacológicos relacionados com a doença de Alzheimer. / Alzheimer’s disease is the principal and the most common neurodegenerative age-related disorder. The number of patients affected by Alzheimer’s disease has increased greatly in recent years, mainly due to increase in life expectancy of the population. The causes for the development of Alzheimer’s disease are quite complex, involving a combination of genetics, molecular, and environmental factors. Neurofibrillary tangles, formed by hyperphosphorylated tau protein, and senile plaques, composed of amyloid-β peptide, are the two major pathological changes found in Alzheimer’s disease. A wide variety of genetic, physiological, and biochemical evidences support the idea that amyloid-β peptide is at least one of the main causes of Alzheimer’s disease. In monomeric form the amyloid-β peptide appears did not exert toxic effects. However, as these monomers polymerize forming soluble intermediates called oligomers, and after protofibrils and fibrils, exert considerable neurotoxic effects. The amyloid-β oligomers peptide are more consistently correlated to cognitive disturbances observed in Alzheimer’s disease. In addition, several works have attributed to synaptic changes a major mechanism of amyloid-β oligomers toxicity. Several signaling pathways become altered in their work due to amyloid-β oligomers, such as MAPK pathway, highlighting JNK1/2 and ERK1/2 proteins, and Wnt/β-catenina. In this work, we evaluated the molecular mechanisms of amyloid-β oligomers toxicity in rat organotypic hippocampal slice cultures. For this purpose, cultures were exposed to concentrations of 0.5, 1, and 2 μM of amyloid-β oligomers for 48h. Cell death was assessed from the incorporation of propidium iodide, a marker of cell that are mainly in the necrosis process death. Exposure of all concentrations tested was not able to induce a significant increase in cell death in cultures. However, a decrease in synaptophysin protein levels by Western blotting occured in all concentrations. These changes in synaptophysin levels were accompanied by JNK activation and ERK inhibition. We also observed a decrease in β-catenin protein immunocontent. The evaluation of GSK-3β and β-catenin phosphorylation showed no significant alterations. Although further studies are necessary for understanding the mechanisms underlying amyloid-β oligomers toxicity, our data suggest synaptic loss in organotypic cultures, one of the earlier characteristics of AD, may be considered a good model to study physiologic factors and pharmacologic compounds AD-related.

Orientador: Veronica Andrea Gonzales-Lopez / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Matematica, Estatistica e Computação Cientifica / Made available in DSpace on 2018-08-11T07:35:52Z (GMT). No. of bitstreams: 1 Bianchi_MartaCristinaColozza_M.pdf: 1867659 bytes, checksum: dbaca8bf802bf1568b0603fd248dc31f (MD5) Previous issue date: 2008 / Resumo: A crescente utilização de cópulas para modelagem de dependência em dados multivariados leva ao estudo de metodologias para o ajuste de cópulas. Este estudo é recente, assim como a plena utilização da teoria de cópulas para modelagem padrão. Grande parte das metodologias existentes ainda encontra-se em fase de estudo e somente alguns métodos foram validados recentemente. Há a necessidade de mecanismos de fácil acesso a detecção de estruturas de dependência ainda escassos na literatura. Nesta dissertação, é apresentado um método gráfico para o ajuste de cópulas, adaptado do QQplot, denominado Kendall Plot. Este método torna-se mais completo que o QQplot ao se postular a adição de bandas de confiança ao gráfico Kendall Plot, que permitem tomar uma decisão em relação a uma estrutura de dependência fixa, expressa por uma cópula, a ser testada para a amostra disponível. A redução de dimensão dos dados a uma variável unidimensional denominada BIPIT, que carrega informação a respeito da estrutura de dependência dos dados, permite a utilização da adaptação do QQplot com o fim de se testar estruturas de dependência / Abstract: The growing utilization of copulas to the dependency fitting of multi-variated data leads to the study of methodologies for copulas fitting. This study is recent, such as the complete utilization of the theory of copulas to standard fitting. Many of the existing methodologies are still in studies and only some have been recently validated. There is a need for easy-access mechanisms to detect dependency structures still missing in the statistical literature. It is presented in this dissertation a graphic method to the copulas fitting adapted from QQplot denominated Kendall Plot. This method is more complete than the QQplot due to the addition of confidence bands to the Kendall Plot graphic that allows the researcher to make a decision related to a fixed dependency structure, expressed by a copula, to be tested to the available sample. The reduction of the data dimension to a one-dimensional random variable, called BIPIT, which carries information about dependency data structure, allows the utilization of the QQplot adaptation for testing dependency structures / Mestrado / Teoria de Copulas / Mestre em Estatística

No description available.

Les analyses génomiques ont permis d’identifier des gènes et des protéinesimpliqués dans la maladie d’Alzheimer (MA). Au laboratoire, des approchesdifférentes ont mis en évidence deux gènes différentiellement exprimés dans lamaladie : le gène IL-33, retrouvé comme étant sous-exprimé chez les patientsatteints de MA, et le gène BIN1, identifié par des approches de GWAS et retrouvécomme étant sur-exprimés dans le cerveau des patients.Nous avons observé que la protéine IL-33 avait un impact sur le métabolismedu précurseur du peptide amyloïde (APP) de par sa fonction de facteur de régulationtranscriptionnelle. Nous avons alors cherché à identifier les gènes modulés par IL-33ainsi que des sites potentiels de fixation de la protéine sur l’ADN par des analyses àhaut débit. Il a été observé qu’IL-33 avait une forte implication dans la transcriptiondes gènes et pouvait agir directement sur l’ADN de par son impact sur les histones.De plus, IL-33 augmenterait l’expression de la préséniline 2, ce qui expliquerait alorsson impact sur le métabolisme de l’APP.Nous avons identifié un polymorphisme fonctionnel dans la région régulatricedu gène BIN1 associé à la maladie et pouvant expliquer la variation de sonexpression retrouvée dans le cerveau des patients. Nous avons également retrouvéune interaction de la protéine BIN1 avec Tau. BIN1 est alors le premier déterminantgénétique de la MA retrouvé comme étant associé à Tau et pourrait expliquer le lienentre la pathologie amyloïde et la pathologie Tau.Nos analyses nous ont donc permis, à partir des résultats d’analysesgénomiques, de mieux comprendre les mécanismes impliqués dans laphysiopathologie de la MA. / Genomic analyses allowed to identify genes and proteins involved inAlzheimer’s Disease (AD). In the laboratory, genetic and transcriptomic approachesrevealed two genes differentially expressed in AD: IL-33 gene, found to be underexpressedin AD cases brain, and BIN1 gene, found by GWAS analyses and overexpressedin brains of AD cases.As regards to IL-33, we observed that this protein have an impact on amyloidprecursor protein (APP) metabolism by its transcriptional regulation properties. So,we tried to identify the genes modulated by IL-33 using transcriptomic high-troughputanalyses and we identified IL-33 DNA binding sites by ChIP-on-chip approaches. Weobserved that IL-33 was involved in gene transcription and could act directly on DNAby interaction with histones. We also observed that IL-33 increase the expression ofpresenilin 2, which can explain its effect on APP metabolism.As regards to BIN1, we identified one functional polymorphism in regulatoryregion of this gene associated with AD and allowed to explain the expressionvariation of BIN1 in AD brains. We also found an interaction of BIN1 with Tau. So,BIN1 would be the first genetic risk factor for AD linked to the “Tau pathway” andcould explain the link between amyloid pathology and Tau pathology.The analyses performed in the laboratory allowed to, from genomic analysesresults, a better understanding of mechanisms involved in AD physiopathology.

This thesis presents work carried out using data from the LHCb experiment during the first three years of data taking, 2010 - 2012. A study of the effects of radiation damage on the silicon sensors of the LHCb Vertex Locator is performed, with an emphasis on the implications for the long term performance of the detector. Following three years of operation the sensors have received a maximum delivered neutron equivalent fluence of approximately 1.6E12 per square centimeter, leading to a number of radiation induced effects. In particular the change in charge collection efficiency and signal/noise with fluence is compared to theoretical expectations, and the current trends are extrapolated to the fluences expected at the end of the LHCb detector lifetime. The development of an unexpected effect due to the structure of the routing lines in the sensors is described in detail. Searches for lepton flavour and baryon number violating decays of the tau lepton using the 2011 LHCb dataset are described. Observation of any lepton flavour or baryon number violation would be an unambiguous sign of new physics, whilst setting improved limits helps to constrain a number of Beyond the Standard Model theories. First LHCb limits are set on the branching fractions of the decays tau- to mu- mu+ mu-, tau- to anti-proton mu+ mu- and tau- to proton mu- mu-, with these results also representing the first limits on lepton flavour violating tau decays at a hadron collider. The limit on tau- to mu- mu+ mu- is expected to approach the world's best result from Belle in the coming years whilst the tau- to anti-proton mu+ mu- and tau- to proton mu- mu- results constitute the first limits on the branching fractions of these decays. The future prospects for these measurements with further data are briefly described.

The Standard Model of elementary particles (SM) predicts the existence of a neutral scalar Higgs boson. However, there are also extensions of the SM (such as the MSSM) in which a number of Higgs bosons is predicted. Especially the additional presence of pseudoscalar and charged Higgs bosons represents one of the crucial differences between the SM and its exten- sions. This work develops a method for determination of the spin and parity of the Higgs boson in several H → ττ decays, namely: H→ τ+ τ− → (h+ ντ )(h− ¯ντ ), H→ τ+ τ− → ( + ντ ¯ν )(π− ¯ντ ) and H→ τ+ τ− → ( + ντ ¯ν )( − ¯ντ ν ), where h denotes π or ρ meson. The method is based on the angular and energy correlations of charged final products from the decays mentioned above. Additionally, the work studies the possibility of signal (Higgs boson decay) and background (Z → ττ decay) discrimination, when one considers a decaying boson with spin 1. All calcula- tions are done in the leading order of perturbation theory. 1

This thesis focuses on the development and analysis of efficient simulation and inference techniques for Markovian pure jump processes with a view towards applications in dense communication networks. These techniques are especially relevant for modeling networks of smart devices —tiny, abundant microprocessors with integrated sensors and wireless communication abilities— that form highly complex and diverse communication networks. During 2010, the number of devices connected to the Internet exceeded the number of people on Earth: over 12.5 billion devices. By 2015, Cisco’s Internet Business Solutions Group predicts that this number will exceed 25 billion. The first part of this work proposes novel numerical methods to estimate, in an efficient and accurate way, observables from realizations of Markovian jump processes. In particular, hybrid Monte Carlo type methods are developed that combine the exact and approximate simulation algorithms to exploit their respective advantages. These methods are tailored to keep a global computational error below a prescribed global error tolerance and within a given statistical confidence level. Indeed, the computational work of these methods is similar to the one of an exact method, but with a smaller constant. Finally, the methods are extended to systems with a disparity of time scales. The second part develops novel inference methods to estimate the parameters of Markovian pure jump process. First, an indirect inference approach is presented, which is based on upscaled representations and does not require sampling. This method is simpler than dealing directly with the likelihood of the process, which, in general, cannot be expressed in closed form and whose maximization requires computationally intensive sampling techniques. Second, a forward-reverse Monte Carlo Expectation-Maximization algorithm is provided to approximate a local maximum or saddle point of the likelihood function of the parameters given a set of observations. The third part is devoted to applications in communication networks where also mean field or fluid approximations techniques, to substantially reduce the computational work of simulating large communication networks are explored. These methods aim to capture the global behaviour of systems with large state spaces by using an aggregate approximation, which is often described by means of a non-linear dynamical system.

Resistence population of pollen beattle on selected locations of Moravia and Silesia were observed during the 2017. Beattles were taked off in the field during spring and their sensitivity to insecticides active substances indoxacarb, chlorpyrifos, thiacloprid, tau-fluvalinate, cypermethrin and lambda-cyhalothrin were tested in laboratory. Tested using methods of IRAC – 11, 21, 25 and 27. Mortality of beattles at various concentrations of active substances was evaluated after 24 hours. Levels of resistance were changed for individual location.

No description available.

Alzheimer's disease (AD) is the most common form of dementia, afflicting almost 5 million patients in the US, and impacting millions more, financially, physically and emotionally. Coming in as the 6th leading cause of death in the US, and showing no signs of slowing its annually increasing rates, the world is in desperate need of improved understanding of the disease's multifaceted pathogenesis and progression, more accurate forms of detection and diagnosis, and more effective prevention and treatment. While many are focused on the noble pursuit of understanding the genetic contributions to the appearance of the pathological amyloid beta (Aβ)) plaques and tau tangles seen in AD, the majority of cases are not explained by genes or allele risk. Instead environmental, dietary and lifestyle contributors may be the key to understanding, diagnosing and treating this awful disease. Diet especially may impact the body's ability to regulate oxidative stress, which will cause damage within the cell and lead to further dysregulation of iron storage and metabolism. Iron storage is heavily monitored through cellular mechanisms, and the way in which the body reacts involves creation of the Aβ plaques and tau tangles as receptacles for the molecule it has deemed as the cause of the problem, iron. We have aptly named our theory, the Iron Hypothesis, and in the following document will outline the evidence for this hypothesis, and the experiments designed and performed to prove it.First, we aimed to examine the impacts that various treatments would have on a transgenic in-vivo model, examining the cohorts' behavior over several time points. We report a significant difference in the behavioral measures of time, distance, errors and failed trials in the radial arm maze existed between genotype, treatment and sex of the mice. Tissue of the experimental mice was collected, but will be processed and analyzed at a later date.Secondly, we aimed to examine the same cohorts of the in-vivo mouse model for minute anatomical changes that took place over the course of the aforementioned behavioral trials using novel MRI scanning sequences sensitive to the low levels of iron build up. We report significant differences in the UTE scan measures for our western diet treatment at TE's of 1.2ms. Additionally, further investigation and optimization of the protocol may be required to further expand the findings.