Exploring different therapeutic approaches for seizure suppression using the zebrafish model

Orientadores: Cláudia Vianna Maurer Morelli, Iscia Teresinha Lopes-CendesTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: A epilepsia é uma doença neurológica caracterizada pela presença de crises epilépticas espontâneas e recorrentes que afetam em torno de 70 milhões da pessoas no mundo. Embora a grande maioria dos pacientes respondam bem ao tratamento medicamentoso, aproximadamente 30% são farmacorresistentes as drogas antiepiléptica. A farmacorresistência na epilepsia está associada a uma redução da qualidade de vida e ao aumento do risco de morte súbita. Há, portanto, uma grande necessidade de descoberta de novos compostos com propriedades anticonvulsivantes. A compreensão dos mecanismos moleculares que desencadeiam a geração da crise epiléptica é fundamental para o desenvolvimento de novas abordagens terapêuticas. Nesse contexto, o presente estudo investigou o efeito de terapia anti-inflamatória, antioxidante e da hipotermia terapêutica na supressão da geração das crises epilépticas induzidas pelo agente químico convulsivante pentilenotetrazol no modelo zebrafish. Além disso, a ferramenta de edição do genoma CRISPR/Cas9 foi utilizada para criar o modelo da Doença de Lafora, uma forma de epilepsia mioclônica progressiva, com o objetivo de testar o tratamento para esta condição específica. Em conjunto, nossos dados fornecem evidências dos efeitos anticonvulsivantes de cada terapia, além de destacar como cada uma delas pode atuar para minimizar as alterações/danos associados à atividade epilépticaAbstract: Epilepsy is a neurological disease characterized by the presence of spontaneous and recurrent seizures that affect around 70 million people worldwide. Although the vast majority of patients respond well to drug therapy, approximately 30% are pharmacoresistant. Pharmacoresistance in epilepsy is associated with reduced quality of life and an increased risk of sudden death. Therefore, there is a need for the discovery of new compounds with anticonvulsant properties. The understanding of the molecular mechanisms that trigger generation of seizures is essential for the development of new therapeutic approaches. In this context, the present study investigated the effect of anti-inflammatory, antioxidative and hypothermia therapies in suppressing the generation of pentylenetetrazole-induced seizures in the zebrafish model. In addition, the CRISPR/Cas9 genome editing tool was used to create a Lafora Disease model, a form of progressive myoclonic epilepsy, in order to test anti-inflammatory compounds for this specific condition. Taken together, our data provide evidence of the anticonvulsant effects of each therapy and highlight how each therapy can act to minimize the changes/damage associated with seizure activityDoutoradoGenetica MedicaDoutora em Ciências2013/19151-9FAPES

How multiple weak species jeopardise biodiversity in spatial rock-paper-scissors models

We study generalised rock-paper-scissors models with an arbitrary odd number N \geq 5 of species, among which n are weak, with 2 \leq n \leq (N-1)/2. Because of the species' weakness, the probability of individuals conquering territory in the cyclic spatial game is low. Running stochastic simulations, we study the role of unevenness in the rock-paper-scissors game in spatial patterns and population dynamics, considering diverse models where the weak species are in different positions in the cyclic game order. Studying systems with five and seven species, we discover that the individuals' spatial organisation arising from the pattern formation process determines the stability of the cyclic game with multiple weak species. Our outcomes show that the presence of species unbalances the spatial distribution of organisms of the same species bringing consequences on territorial dominance, with the predominant species being determined by the position in the cyclic game order. Our simulations elucidate that, in general, the further apart the regions inhabited by different weak species are, the less the coexistence between the species is jeopardised. We show that if multiple weak species occupy adjacent spatial domains, the unevenness in the cyclic game is reinforced, maximising the chances of biodiversity loss. Our discoveries may also be helpful to biologists in comprehending systems where weak species unbalance biodiversity stability.Comment: 10 pages, 10 figure

Indomethacin Treatment Prior To Pentylenetetrazole-induced Seizures Downregulates The Expression Of Il1b And Cox2 And Decreases Seizure-like Behavior In Zebrafish Larvae

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)It has been demonstrated that the zebrafish model of pentylenetetrazole (PTZ)-evoked seizures and the well-established rodent models of epilepsy are similar pertaining to behavior, electrographic features, and c-fos expression. Although this zebrafish model is suitable for studying seizures, to date, inflammatory response after seizures has not been investigated using this model. Because a relationship between epilepsy and inflammation has been established, in the present study we investigated the transcript levels of the proinflammatory cytokines inter-leukin-1 beta (il1b) and cyclooxygenase-2 (cox2a and cox2b) after PTZ-induced seizures in the brain of zebrafish 7 days post fertilization. Furthermore, we exposed the fish to the nonsteroidal anti-inflammatory drug indomethacin prior to PTZ, and we measured its effect on seizure latency, number of seizure behaviors, and mRNA expression of il1b, cox2b, and c-fos. We used quantitative real-time PCR to assess the mRNA expression of il1b, cox2a, cox2b, and c-fos, and visual inspection was used to monitor seizure latency and the number of seizure-like behaviors. Results: We found a short-term upregulation of il1b, and we revealed that cox2b, but not cox2a, was induced after seizures. Indomethacin treatment prior to PTZ-induced seizures downregulated the mRNA expression of il1b, cox2b, and c-fos. Moreover, we observed that in larvae exposed to indomethacin, seizure latency increased and the number of seizure-like behaviors decreased. Conclusions: This is the first study showing that il1b and cox-2 transcripts are upregulated following PTZ-induced seizures in zebrafish. In addition, we demonstrated the anticonvulsant effect of indomethacin based on (1) the inhibition of PTZ-induced c-fos transcription, (2) increase in seizure latency, and (3) decrease in the number of seizure-like behaviors. Furthermore, anti-inflammatory effect of indomethacin is clearly demonstrated by the downregulation of the mRNA expression of il1b and cox2b. Our results are supported by previous evidences suggesting that zebrafish is a suitable alternative for studying inflammation, seizures, and the effect of anti-inflammatory compounds on seizure suppression.17Brazilian Institute of Neuroscience and Neuro-technology BRAINN-CEPID [2013/07559-3]Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2014/15640-8, 2013/19151-9]Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [475405/2010-2]FAPESPFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Gestão de Pessoas e Capital Intelectual no Mundo Acadêmico Brasileiro

As saídas estruturais para a universidade pautadas nos limites das manifestações do problema político-econômico que a sociedade brasileira enfrenta atualmente, exigem uma melhor compreensão do sentido de seu capital intelectual. Este problema manifesta-se na universidade ( e ,evidentemente, não apenas nela ) por meio de aguçamento do crônico problema da falta de recursos. Diante dessa manifestação, alguns intelectuais que atuam na Universidade particular, como a PUC/SP, são levados a propor modelos alternativos de direção e manutenção da universidade, onde os recursos, continuando a vir dos alunos, deveriam passar a vir, também, de ex-alunos, de organismos da sociedade civil e, mais regularmente e em quantidade mais substantiva, do governo. A realização de tal modelo produziria a publicação da universidade particulares endomarketing é extremamente, relevante para a compreensão do papel do professor neste momento de crise pelo qual a universidade passa, o artigo compara duas instituições, buscando entender os reflexos da crise sobre seus professores

The balance between project performance and stakeholders ́ satisfaction in projects with the support of project management offices

PMOs emerged as entities dedicated to support management in organizations which run large and/or complex projects. PMOs have been used in several companies and have a wide variety of roles. Our recent research shows some relations between PMO functions and project´s performance in new product development (NPD) projects. Nevertheless, deepening our study we found some evidences that show a difficult relation among project´s stakeholders and performance. We run two deep case studies about the relations between project performance and stakeholders´ satisfaction. The first was done in a company that develops new products. The second in a public organization devoted to industryuniversity programs. Our results suggest that even in highly effective project management in terms of performance, stakeholders’ satisfaction is more important than the risk of declining this own organizational performance. Therefore, managers must take a balance between projects´ performance and stakeholder´s satisfaction in form to avoid abrupt changes in project management structure and practice with the risk of declining project successes

Indomethacin Treatment Prior To Pentylenetetrazole-induced Seizures Downregulates The Expression Of Il1b And Cox2 And Decreases Seizure-like Behavior In Zebrafish Larvae

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)It has been demonstrated that the zebrafish model of pentylenetetrazole (PTZ)-evoked seizures and the well-established rodent models of epilepsy are similar pertaining to behavior, electrographic features, and c-fos expression. Although this zebrafish model is suitable for studying seizures, to date, inflammatory response after seizures has not been investigated using this model. Because a relationship between epilepsy and inflammation has been established, in the present study we investigated the transcript levels of the proinflammatory cytokines inter-leukin-1 beta (il1b) and cyclooxygenase-2 (cox2a and cox2b) after PTZ-induced seizures in the brain of zebrafish 7 days post fertilization. Furthermore, we exposed the fish to the nonsteroidal anti-inflammatory drug indomethacin prior to PTZ, and we measured its effect on seizure latency, number of seizure behaviors, and mRNA expression of il1b, cox2b, and c-fos. We used quantitative real-time PCR to assess the mRNA expression of il1b, cox2a, cox2b, and c-fos, and visual inspection was used to monitor seizure latency and the number of seizure-like behaviors. Results: We found a short-term upregulation of il1b, and we revealed that cox2b, but not cox2a, was induced after seizures. Indomethacin treatment prior to PTZ-induced seizures downregulated the mRNA expression of il1b, cox2b, and c-fos. Moreover, we observed that in larvae exposed to indomethacin, seizure latency increased and the number of seizure-like behaviors decreased. Conclusions: This is the first study showing that il1b and cox-2 transcripts are upregulated following PTZ-induced seizures in zebrafish. In addition, we demonstrated the anticonvulsant effect of indomethacin based on (1) the inhibition of PTZ-induced c-fos transcription, (2) increase in seizure latency, and (3) decrease in the number of seizure-like behaviors. Furthermore, anti-inflammatory effect of indomethacin is clearly demonstrated by the downregulation of the mRNA expression of il1b and cox2b. Our results are supported by previous evidences suggesting that zebrafish is a suitable alternative for studying inflammation, seizures, and the effect of anti-inflammatory compounds on seizure suppression.1712Brazilian Institute of Neuroscience and Neuro-technology BRAINN-CEPID [2013/07559-3]Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2014/15640-8, 2013/19151-9]Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [475405/2010-2]FAPESPFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Entre o WhatsApp e a praça da “família”: relato de uma experiência teórico-metodológica

This article reports the theoretical and methodological experience enabled by the research that aimed to understand the processes of sociability among young people gathered around the group self called “família Os poderosos e as ponderosas”, who contacted themselves through social networks and in the city squares of Fortaleza, Ceará. The generating question was: how are these relations, their dislocations and ruptures constituted from the convergence between the use of communication and information technologies and squares? For the purposes of the research, ethnography and netnography were used as main methodological procedures.Este artigo reflete a experiência teórico-metodológica possibilitada pela pesquisa que teve como objetivo compreender os processos de sociabilidade entre jovens reunidos em torno do grupamento autodenominado “família Os poderosos e as poderosas” e que se conectavam por meio de redes sociais e nas praças da cidade de Fortaleza, Ceará, entre março e novembro de 2015. A questão geradora era: como se constituíam essas relações, seus deslocamentos e rupturas, a partir da convergência entre os usos de tecnologias de comunicação e informação e das praças? Para os fins da pesquisa, utilizou-se como procedimentos metodológicos principais a etnografia e a netnografia

Indomethacin treatment prior to pentylenetetrazole-induced seizures downregulates the expression of Il1b and cox2 and decreases seizure-like behavior in zebrafish larvae

It has been demonstrated that the zebrafish model of pentylenetetrazole (PTZ)‑evoked seizures and the well‑established rodent models of epilepsy are similar pertaining to behavior, electrographic features, and c‑fosexpression. Although this zebrafish mode1712FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO2014/15640‑8; 2013/19151‑9475405/2010‑

Orientando a Cultura: O Conselho de Cultura do Ceará nos anos 1960-70

Este artigo analisa a criação e a efetivação do Conselho Estadual de Cultura (CEC) do Ceará durante os anos 1960 e 1970. Em um primeiro momento observa a criação da Secretaria de Cultura do Estado, bem como sua relação com o CEC. Na segunda parte, observa a relação entre as políticas estadual e federal de cultura e o papel do CEC nesse contexto. PALAVRAS-CHAVE: Conselho de Cultura; Política Cultural; Regime Militar This article analyses the creation and the accomplishment of the Conselho Estadual de Cultura do Ceará during the 60’ and the 70’. At first moment, observes the creation of the Secretaria de Cultura do Estado, and your relation with CEC. At second part, notices the relation between the federal and the local cultural policy and the function of the CEC in this context. KEYWORDS: Council of Culture; Cultural Policy; Military Government