67,373 research outputs found
Functional characterization of PICH, a DNA-dependent ATPase required for faithful chromosome segregation during mitosis
No full textPICH (Plk1-interacting checkpoint helicase), a DNA-dependent ATPase, was identified as a binding partner and substrate of Plk1. During mitosis, PICH localizes to the centromere/KTs of condensed mitotic chromosomes and to ultra-fine DNA bridges (UFBs) during anaphase. Upon depletion or chemical inhibition of Plk1, PICH localizes to the chromosome arms, suggesting that the kinase activity of Plk1 regulates the dynamic localization of PICH. In addition, PICH (bound to Plk1) has been proposed to function in prometaphase chromosome arm architecture and cohesion. Here, two questions were asked: how is the dynamic localization of PICH regulated and what is the mitotic function of PICH?
In the first part of this thesis, we identify the ATPase activity of PICH as being essential for its correct subcellular localization and show that ATPase-dead mutants of PICH localize to the chromosome arms. Rescue experiments with a mutant of PICH that is unable to interact with Plk1 imply that the kinase activity of Plk1 is only indirectly required to delocalize PICH from the chromosome arms. This suggests that an unknown Plk1 substrate regulates the localization of PICH. PICH-immunoprecipitation and mass spectrometry identified the uncharacterized protein BEND3 as a binding partner. BEND3 localizes to mitotic chromosomes and its depletion results in the loss of PICH and Plk1 from the centromere/KTs. BEND3 depleted cells are unable to align their chromosomes at the metaphase plate and undergo apoptosis within a short time, suggesting that BEND3 regulates not only the localization of PICH and Plk1 but has additional functions.
In the second part of this thesis, we demonstrate that PICH does not function in the spindle assembly checkpoint. Instead, we show that neutralization or depletion of PICH results in chromatin bridges during anaphase. We identify the ATPase activity of PICH as indispensable to prevent the formation of these bridges and show that they most likely arise from non-centromeric chromatin. PICH was previously shown to interact with the BTR complex (composed of BLM, TOP3A and RMI1) that has been linked to the faithful separation of chromosomes during mitosis. It is of great interest, therefore, that we discovered an association of PICH with Rif1, which has recently been shown to provide a DNA-binding interface for the BTR complex. In contrast to the colocalization of PICH and the BTR complex to non-centromeric UFBs, Rif1 localizes to centromeric UFBs in a PICH-dependent manner. Thus, we speculate that PICH, Rif1 and the BTR complex act together to prevent chromatin bridges during mitosis
Neural substrate of nicotine addiction as defined by functional brain maps of gene expression.
No full textA geometry optimization framework for photonic crystal design
No full textThe performance of photonic crystal devices can depend strongly on their geometry. Alas, their fundamental physics offers relatively little by way of pointers in terms of optimum shapes, so numerical design search techniques must be used in an attempt to determine high performance layouts. We discuss strategies for solving this type of optimization problem, the main challenge of which is the conflict between the enormous size of the space of potentially useful designs and the relatively high computational cost of evaluating the performance of putative shapes. The optimization technique proposed here operates over increasing levels of fidelity, both in terms of the resolution of its non-parametric shape definition and in terms of the resolution of the numerical analysis of the performance of putative designs. This is a generic method, potentially applicable to any type of electromagnetic device shape design problem. We also consider a methodology for assessing the robustness of the optima generated through this process, investigating the impact of manufacturing errors on their performance. As an illustration, we apply this technology to the design of a two-dimensional photonic crystal structure; the result features a large complete band gap structure and a topology that is different from previously published designs.<br/
Stress-like effects of intermittent exposures to a strong magnetic field in weanling mice
No full textGut Microbiome-Liver-Brain axis in Alcohol Use Disorder. The role of gut dysbiosis and stress in alcohol-related cognitive impairment progression: possible therapeutic approaches
No full textThe Gut Microbiome-Liver-Brain Axis is a relatively novel construct with promising potential to enhance our understanding of Alcohol Use Disorder (AUD), and its therapeutic approaches. Significant alterations in the gut microbiome occur in AUD even before any other systemic signs or symptoms manifest. Prolonged and inappropriate alcohol consumption, by affecting the gut microbiota and gut mucosa permeability, is thought to contribute to the development of behavioral and cognitive impairments, leading to Alcohol-Related Liver Disorders and potentially progressing into alcoholic cirrhosis, which is often associated with severe cognitive impairment related to neurodegeneration, such as hepatic encephalopathy and alcoholic dementia. The critical role of the gut microbiota is further supported by the efficacy of FDA-approved treatments for hepatic encephalopathy in alcoholic cirrhosis (i.e., lactulose and rifaximin). To stimulate new research, we hypothesize that interactions between a maladaptive stress response and a constitutional predisposition to neurodegeneration underlie the progression of AUD to conditions of Alcohol-Related Clinical Concerns with severe cognitive impairment, which represent a significant and costly burden to society. Early identification of AUD individuals at risk for developing these conditions could help to prioritize integrated therapeutic interventions targeting different substrates of the Gut Microbiome-Liver-Brain axis. Specifically, addiction medications, microbiome modulators, stress-reducing interventions, and, possibly soon, novel agents that reduce hepatic steatosis/fibrosis will be discussed in the context of digitally supported integrated therapeutic approaches. The explicit goal of this AUD treatment performed on the early stage of the disorder would be to reduce the transition from AUD to those conditions of Alcohol-Related Common Clinical Concerns associated with severe cognitive impairment, a strategy recommended for most neurological neurodegenerative disorders
Aspects on the information handling by the central nervous system: Focus on cotransmission in the aged rat brain
No full textMining e-mail content for author identification forensics
No full textWe describe an investigation into e-mail content mining for author identification, or authorship attribution, for the purpose of forensic investigation. We focus our discussion on the ability to discriminate between authors for the case of both aggregated e-mail topics as well as across different email topics. An extended set of e-mail document features including structural characteristics and linguistic patterns were derived and, together with a Support Vector Machine learning algorithm, were used for mining the e-mail content. Experiments using a number of e-mail documents generated by different authors on a set of topics gave promising results for both aggregated and multi-topic author categorisation
Molecular mechanisms of the positive reinforcing effect of nicotine.
No full textAnimal models of nicotine dependence are fundamental experimental tools for the understanding of the neurobiological and molecular processes underlying smoking behaviour. Substance use is controlled by four main processes: positive reinforcing effects, aversive effects, discriminative effects and stimulus conditioned effects of the drug. In this article, the molecular and neural bases of the positive reinforcing effects of nicotine are summarized, focusing on data obtained in experiments including unambiguous and objective measurements of the reinforcing properties of nicotine. Operant behaviour paradigms, in particular intravenous nicotine self-administration, offer such a possibility within a solid theoretical framework. Nicotine self-administration produces changes in the mesocorticolimbic DA system, a key component of the reward system, as do other addictive drugs. The role of the mesocorticolimbic DA system as the main substrate of the reinforcing properties of nicotine is supported by converging experiments, including the evidence that nicotine self-administration is attenuated in mutant mice lacking the β2 subunit of neural acetylcholine nicotinic receptor. The long-term adaptive molecular changes in the target neurons of the terminal fields of the mesocorticolimbic DA system, including transcriptional regulation mediated by c-fos family gene products on other genes, suggest that the mesolimbic DA projection to the nucleus accumbens is mainly involved in the stimulus-reward learning process. These data represent an initial set of information only, which may help to develop a more complete and reliable model of the molecular dynamics underlying the reinforcing effects of nicotine
Nucleases sintéticas: análise da atividade de clivagem de DNA, de clivagem de proteína e genotóxica de compostos metálicos
No full textTese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-Graduação em Biotecnologia, Florianópolis, 2009.Quatro séries de compostos metálicos foram analisadas com o objetivo de avaliar sua atividade de clivagem de DNA, de clivagem de proteína e biológica. Foram determinadas suas concentrações efetivas, pHs ótimos, formas de atuação, cinética de reação, especificidade de sítio de ação, capacidade de interação por estudos espectrofotométricos e atividade toxica e genotóxica em modelos diversos. Os compostos binucleares de cobre [Cu2( -OH)L2], miméticos de catecol-oxidases, demonstraram atividades de clivagem de DNA e de clivagem de proteína variadas dependentes da estrutura de seus ligantes. Estudos espectrofotométricos revelaram sua interação com DNA e proteína BSA além de citotoxiciade e genotoxicidade em todos os sistemas testados. Os compostos mono e binucleares de Ferro - Fe(HPClNOL) apresentaram atividade de clivagem de DNA e de clivagem de proteína bastante intensa estando entre os mais ativos compostos já descritos. Estudos espectrofotométricos revelaram sua interação com DNA e proteína BSA, mas também sua instabilidade em solução. Estudos de genotoxicidade e toxicidade demonstraram ambas as atividades para estes compostos. Os compostos binucleares de FeZnR (7, 8, 9 e 10) tiveram seus prováveis modos de ação e cinética de reação determinados bem como suas atividade sobre células bacterianas podendo em termos de eficiência serem classificados na seguinte ordem: 10 > 9 > 8 > 7. O composto 11, o qual não foi testado em presença de luz, demonstrou atividade de clivagem de DNA de grande eficiência de forma hidrolítica, mas ausência de atividade de clivagem de proteína e atividade antibacteriana não significante. Os compostos 12, 13 e 14, tiveram sua atividade testada em presença e ausência de luz e diferenças significativas foram encontradas. A presença de luz levou a uma maior atividade de clivagem de DNA e ao desenvolvimento de atividade de clivagem de proteína de todos os compostos. Estes, por não sofrerem inibição de atividadde por DMSO, agem provavelmente de maneira oxidativa livre da formação de radicais OH
O processo de convers?o a Deus pela via racional e m?stica
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Previous issue date: 2012-03-30The process of conversion to God, through rational and mystical way, when approached from the perspective of faith and human reason, is studied both by philosophy and theology. Conversion is the realization of the human being, a meeting with the Supreme Good and Truth, which involves an ascent of the soul and intelligence to God, walking on the path of renunciation to the sin and the search of holiness. In this way, Plotinus, a pagan philosopher, presents it as a epistroph?; in other wise, Augustine identifies it to Christian met?noia. Both approaches make use of a metaphysical structure that serves as the support for mystic, where it is possible to estabilish a rapprochement between the two systems. Thus, the religious philosophy of Plotinus will greatly influence the thinking of Augustine in a first step of his life, but he (Augustine) progressively overcomes at the same time in wich he enters, more and more, into the knolodge of the Sacred Scriptures mainly by reading St. Paul.O processo de convers?o a Deus, pela via racional e m?stica, ao ser abordado pela ?tica da f? e da raz?o humana, ? objeto de estudo tanto da filosofia, quanto da teologia. A convers?o ? a realiza??o plena do ser humano, um encontro com a Verdade e o Sumo Bem, que implica uma ascens?o da alma e da intelig?ncia at? Deus, percorrendo a via da ren?ncia ao pecado e a busca da santidade. Nesse percurso, Plotino, um fil?sofo pag?o, a apresenta como sendo uma epistroph?; por sua vez, Santo Agostinho a identifica com a met?noia crist?. Ambas abordagens utilizam-se de uma estrutura metaf?sica que serve de suporte para a m?stica, onde ? poss?vel determinar uma aproxima??o entre os dois sistemas. Assim, a filosofia religiosa de Plotino vai influenciar sobremaneira o pensamento de Agostinho numa primeira etapa de sua vida, mas ele (Agostinho) a ultrapassa progressivamente, na medida em que adentra, cada vez mais, no conhecimento das Escrituras Sagradas, m?xime, a leitura de S?o Paulo
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