p53 at the crossroads between cancer and neurodegeneration: unveiling molecular circuitries involved in tumorigenesis and neuronal cell death

2012/2013Cancer and neurodegeneration are linked by a relation of inverse comorbidity, cancer patients being at lower risk for neurodegenerative disorders and vice versa. Interestingly, many cellular processes and factors contribute to both pathologies, and a central role is played by the transcription factor p53. Best known for its antiproliferative activities following transformation-related stimuli, p53 acts to maintain genetic stability and prevent tumour onset by transcriptional and non-transcriptional mechanisms. Recently, a contribution of p53 also in neuronal development and death was unveiled. In the case of Huntington’s Disease (HD), p53 mediates cytotoxicity in HD cells and animal models, whereas its inhibition prevents this phenotype. On these premises, we were prompted to investigate the signalling pathways and protein interactions that modulate p53 activation in both cancer and neurodegeneration with the aim of identifying critical hubs as new targets for therapeutic intervention. We discovered that expression of HD causative agent, i.e. mutant Huntingtin (mHtt) protein, behaves like a genotoxic stimulus in inducing phosphorylation of p53 on Ser46, that leads to its modification by phosphorylation-dependent prolyl-isomerase Pin1 and consequent induction of apoptotic target genes. Inhibition of Ser46 phosphorylation by targeting HIPK2, PKCδ, or ATM kinases, as well as inhibition of Pin1, prevented mHtt-dependent apoptosis of neuronal cells. These results provide a rationale for the use of inhibitors of stress-responsive kinases and Pin1 as a potential therapeutic strategy for HD treatment. On the other hand, we investigated the contribution of BRD7, a protein involved in epigenetic regulation, to the p53 pathway. We found that BRD7 is required for the onset of oncogene-induced senescence, a main tumour suppressive p53 activity. In addition, we found that upon oncogene activation BRD7 restrains, independently of p53, the acquisition of malignant phenotypes, such as migration/invasion and stem cell traits. We observed a strong induction of inflammatory genes after depletion of BRD7, whose contribution to this process is still under investigation. BRD7 takes part into SWI/SNF and PRC2 chromatin remodelling complexes, whose pleiotropic roles in tumorigenesis make them appealing targets for cancer therapy. We will discuss how this new generated knowledge could be exploited for the treatment of neurodegenerative diseases, in which chromatin alterations are now recognized as drivers of pathogenesis.XXV Ciclo198

Transparência na casa do cidadão : uma avaliação dos websites de prefeituras da região sul do Brasil

Orientador: Prof. Dr. Francisco Paulo Jamil Almeida MarquesDissertação (mestrado) - Universidade Federal do Paraná, Setor de Artes, Comunicação e Design, Programa de Pós-Graduação em Comunicação. Defesa : Curitiba, 25/02/2021Inclui referências: p. 178-190Resumo: As administrações municipais são a instância de poder público mais próxima do cidadão. As decisões tomadas pelos gestores, os investimentos e a forma como são realizados impactam diretamente na vida da população local. Desta forma, é importante verificar de que modo as prefeituras divulgam informações que permitem aos cidadãos compreender o funcionamento e acompanhar tais decisões, assim como avaliar e questionar as políticas implementadas e o uso dos recursos públicos. Esta pesquisa tem o objetivo de avaliar a qualidade de ferramentas de transparência pública disponíveis em websites de diferentes municípios da Região Sul do Brasil. São analisados os sites de 21 cidades (seis do Paraná, sete de Santa Catarina e oito do Rio Grande do Sul), definidas por meio das Regiões Geográficas Intermediárias (IBGE, 2017), de forma a se alcançar uma representação regional a partir de locais que atuam como referência para municípios de seu entorno. No âmbito de tal proposta, foram definidos como objetivos específicos: 1) Verificar de que modo os sites de prefeituras da Região Sul fornecem informações e canais de comunicação capazes de favorecer a transparência pública; 2) Examinar as similaridades e/ou diferenças no que concerne ao nível de transparência dos sites dos municípios aqui considerados; 3) Averiguar se, e em que medida, aspectos econômicos e sociodemográficos dos municípios podem estar relacionados aos níveis de transparência dos websites. A fundamentação teórica debate conceitos e características da transparência pública de uma forma geral e da transparência digital, em particular. A metodologia para análise dos sites das prefeituras envolve observação sistemática com navegação orientada, a partir de critérios divididos em duas dimensões: aspectos da legislação e elementos associados a iniciativas além das exigências legais. O percurso metodológico compreende, ademais, o estudo de possíveis impactos de variáveis como população e PIB per capita, por meio de testes de correlação. Os resultados apontam que muitas das imposições legais têm sido efetivamente cumpridas pelas cidades pesquisadas por meio de seus sites, apesar de falhas ainda serem identificadas. Já no que se refere a iniciativas e ferramentas que extrapolam as exigências legais, ainda que seja possível identificar algumas ações que podem facilitar acesso e o entendimento por parte dos munícipes, há grandes possibilidades de aperfeiçoamento de uma forma geral. Sobre os possíveis fatores a influenciarem a qualidade dos websites, constatou-se que há associação positiva entre o nível de transparência e as variáveis propostas. A investigação aqui apresentada colabora com a ampliação do escopo dos estudos de transparência em nível municipal, assim como traz contribuições ao trabalho prático realizado por profissionais da comunicação e outros servidores públicos envolvidos no processo de abertura e controle social. Palavras-chave: Comunicação Política. Comunicação Governamental. Democracia Digital. Transparência. Administração Municipal.Abstract: The municipal administrations are the public authority closest to the citizen. The decisions made by the managers, the investments and the way they are allocated have a straight impact on the life of the local population. Thus, it is important to check how the municipal government spreads the information that allows citizens to understand how these processes work and to keep track of these decisions, as well as evaluate and question the implemented policies and the use of the public resources. This research aims to evaluate the quality of public transparency tools available on websites of different cities in Brazil's Southern Region. Websites of 21 cities were analyzed (six from Parana, seven from Santa Catarina and eight from Rio Grande do Sul), defined by the Intermediate Geographic Regions (IBGE, 2017), in order to achieve a regional representation through places that are a reference for cities nearby their location. Within the scope of this proposal, the following specific objectives were defined: 1) Checking how the Southern Region municipal governments' websites offer information and communication channels capable to support the public transparency; 2) Analyzing the similarities and/or differences regarding the transparency level in the websites of the cities considered; 3) Finding out if - and how much - economic and socio demographic aspects of the cities may be related to the transparency level on the websites. The theoretical foundation debates public transparency's concepts and features in a general way and digital transparency, in particular. The methodology to analyse the cities' websites involve systematic observation with guided navigation, based on a criteria divided on two dimensions: legislation aspects and elements related to initiatives beyond the legal requirements. The methodological path also includes the study of possible impacts of variables such as population and GDP per capita, through correlation tests. The results show that many of the legal impositions have been effectively fulfilled by the searched cities through their websites. However, some problems are still identified. About the initiatives and tools that go beyond the legal requirements, even being possible to identify some actions that may help the citizens to access and understand the information, there are still great possibilities for improvement in general. Regarding the possible factors that can play a role on the websites' quality, there is a positive association between the transparency level and the proposed variables. This investigation collaborates with the expansion of the scope of transparency studies in a municipal level, as well as it brings contributions to the practical work done by communication workers and other public servants involved in the opening process and social control. Key-words: Political Communication. Government Communication. Digital Democracy. Transparency. Municipal Administration

Biodégradation anaérobie de l'acide crotonique par une biomasse bactérienne spécialisée dans la dégradation de l'acide butyrique

La connaissance, actuellement très limitée, du métabolisme des bactéries acétogènes intervenant dans la biodégradation anaérobie de l'acide butyrique et d'un de ses sous-produits, l'acide crotonique, est à l'origine de cette étude.Après avoir mis au point un réacteur anaérobie à biomasse fixée, cette dernière a, dans un premier temps, été adaptée à la biodégradation exclusive du butyrate. La dégradation du crotonate a ensuite été étudiée, selon différents protocoles expérimentaux (pulses de crotonate en alimentation continue avec du butyrate puis alimentation continue avec du crotonate). Des injections de crotonate ont également été effectuées en circuit fermé, avec une biomasse adaptée dans un premier temps à la dégradation d'un mélange d'AGV, le réacteur étant ensuite alimenté avec du propionate puis du butyrate seuls.Contrairement à ce que laissait penser la bibliographie, il a été constaté que les bactéries adaptées à la dégradation exclusive du butyrate sons très rapidement à même de dégrader le crotonate.Les résultats obtenus permettent d'approcher les spécificités bactériennes, la voie catabolique suivie par le crotonate, son mode de régulation enzymatique et les équilibres qui la gouvernent. C'est ainsi qu'il est possible de proposer un modèle explicatif relativement simple du mécanisme de biodégradation du crotonate.Volatile Fatty Acids (VFAs) are intermediate metabolites formed in the anaerobic biodegradation of organic matter. They are commonly found in sewage, municipal sanitary landfill leachate and effluents from agricultural and food-processing industries. A good knowledge of the microorganisms involved in VFA biodegradation is necessary to operate satisfactory biotreatment of those effluents.The objective of the present study is to better understand the metabolism of the anaerobic bacteria responsible for the degradation of butyric acid and one of its metabolites (crotonic acid), which is still poorly known.Syntrophomonaswolfei is one of the few butyrate-degrading acetogenic bacteria that bas been documented. First studios have shown that this microorganism is not capable of degrading crotonic acid (MCINERNEY et al., 1979, 1981). This is surprising since crotonyl-Coenzyme A, in its activated form, is an intermediate metabolite of n-butyrate ß-oxidation, which is the most common mechanism of butyrate biodegradation. In addition, ß-oxidatlon of crotonate is thermodynamically possible, even under standard conditions.These observations are al the origin of the present study, which investigates the anaerobic biodegradation of crotonate. Other Investigators have followed a similar approach and isolated S. wolfei in pure culture on crotonate.The degradation of crotonate was studied in a bench-scale up-flow anaerobic filter of twenty liters, operated in the dark, at 35 °C.A first set of experiments was carried out with a biomass exclusively adapted to the biodegradation of butyrate. Heat-expansed vermiculite was used as a packing medium. Various experimental protocols were successive followed. First, pulses of crotonate were injected into the reactor under conditions of continuous feeding with butyrate, and then, the reactor was continuously fed with crotonate. The objective was to determine whether a bacterial population exclusively adapted to butyrate biodegradation would be capable of degrading crotonate.It was found that crotonate was actually biodegraded in the reactor. Woth the first protocol, when pulses of crotonate were injected into the reactor, crotonate was totally removed in 55 hours (fig. 3). Butyrate and acetate concentrations increased as crotonate was degraded, but no significant increase in biogas production was observed. On the other hand, under the same conditions, it was found that iso-butyrate was not degraded, which is consistent with other published data (MCINERNEY et al., 1979, 1981 ; STIEB and SCHINK, 1985,1989).With the second protocol (continuous feeding with crotonate at 5.2 gg/l), crotonate was totally biodegraded in 48 hours after a 24 hours lag period. This biodegradation resulted in the accumulation of acetate and, in a lower extend, butyrate (fig.4).Following this stage, the reactor was fed with a higher crotonate concentration (12 g/l), and it was observed that crotonate was totally degraded in 20 hours, without any lag period (fig. 5).These results showed that butyrate-degrading bacteria were capable of degrading crotonate effectively after a short period of adaptation.Further experiments were conducted with a biomass previously adapted to the degradation of a mixture of VFAs (acetate, propionate, iso-butyrate, butyrate and caproate). Berl saddles were used as a support for bacterial growth. The reactor was operated in a recirculated batch mode and spiked with crotonate. Finally, the reactor was successively fed for four weeks with propionate and for two weeks with butyrate, before being spiked with crotonate.In all these experiments, crotonate biodegradation was observed, but, in contrast to the results obtained with the “vermiculite reactor”, no butyrate accumulation occured (fig.6).These results show that a bacterial population adapted to the degradation of a mixture of VFAs or to the degradation of individual VFAs such as propionate and n-butyrate, is capable of degrading crotonate.Based on the present study and on literature data, the following mechanism can be proposed for the biodegradation of crotonate (fig.7). The first stage is the activation of crotonate into crotonyl-Coenzyme A by an acetyl-CoA/crotonyl-CoA transferase, as recently isolated from S. wolfei (BEATY and MCINERNEY, 1987). When present at low concentrations, crotonate is probably directly degraded into acetate, as shown by the results obtained with the “selles de Berl reactor”, in which no intermediate metabolite has been detected. At higher concentrations, enzymatic sites may be saturated and an equilibrium be established with butyrate, which is then released into the medium. This has been shown by the accumulation of butyrate under conditions of continuous feeding with crotonate. In addition, another intermediate metabolite has been formed, which has not been identified in the present study. This product is most probably poly-ß-hydroxy-butyrate, which has been found in S.wolfei (MCINERNEY et al, 1979) although if is not very common in chemiotrophic bacteria

Determinação quantitativa de corantes sulfurosos por potenciometria

Os corantes sulfurosos têm, desde o início da sua aplicação há mais de um século1, uma grande aplicação na Indústria Têxtil. De facto, embora quase todas as cores possam ser obtidas com corantes de outros tipos, a utilização de corantes sulfurosos para a obtenção de tons escuros (como o preto e o azul marinho) em fibras celulósicas continua a ser muito elevada2 . No entanto, devido à baixa solubilidade em água deste tipo de corantes, a sua quantificação é difícil. Associado a este problema encontram-se, ainda, várias dificuldades inerentes às técnicas analíticas. Nesta comunicação, é apresentada uma técnica de doseamento por titulação potenciométrica, baseada no método para doseamento de sulfuretos solúveis5. O procedimento consiste numa titulação potenciométrica por retorno, com sulfureto de sódio, após oxidação completa do corante com hexacianoferrato (III) de potássi

Proposta de implementação de um fluxo de caixa em uma pequena empresa no ramo da modelaria

Monografia apresentada para a obtenção do grau de Bacharel em Administração, no Curso de Administração – Linha de Formação Específica em Administração de Empresas da Universidade do Extremo Sul Catarinense – UNESC.A administração financeira exerce uma função de alguma importância numa organização, os planejamentos financeiros e a execução de suas ferramentas para gestão são fundamentais. A administração financeira por meio do seu planejamento, busca o controle e a organização das contas da empresa, de forma que os objetivos almejados sejam de fato alcançados mediante um plano, controlado e organizado. O responsável por esse planejamento terá as informações necessárias conforme as ferramentas implantadas, que auxiliarão nas tomadas de decisões, uma dessas ferramentas é o fluxo de caixa. O fluxo de caixa é o elemento que controla as entradas e saídas de caixa, por meio dele se obtém todas as movimentações feitas com o dinheiro da organização, e se o que está arrecadando vai suprir as despesas da empresa. O trabalho aqui realizado teve como enfoque esta ferramenta, e qual a maneira de utiliza-la para um melhor controle financeiro, e como deve ser feito a sua implantação numa empresa de pequeno porte. A realização da pesquisa é de caráter qualitativo. Foi verificado a disponibilidade de implantação da ferramenta, pois a empresa não exercia esse controle, as respostas e analises obtidas buscaram no auxílio para suprir tal necessidade, não só dessa empresa, mas de qualquer outra de pequeno porte na utilização do fluxo de caixa, visando a gerencia dos ganhos com relação aos gastos, e o planejamento do futuro aspirando melhorias

Production of Low-Carbon Magnetic Steel for the LHC Superconducting Dipole and Quadrupole Magnets

In 1996 CERN negotiated a contract with Cockerill Sambre â ARCELOR Group for the supply of 50 000 tonnes of low-carbon steel for the LHC main magnets: this was the first contract to be placed for the project, and one of the single largest. In 2005 â after nine years of work â the contract is being successfully completed. This paper describes the steel specifically developed, known as MAGNETILâ¢, its manufacturing and quality control process, organization of production, logistics and contract follow-up. Extensive statistics have been collected relating to physical, mechanical and technological parameters. Specific attention is dedicated to magnetic measurements (coercivity and permeability) performed at both room and cryogenic temperatures, the equipment used and statistical results. Reference is also made to the resulting precision of the fineblanked laminations used for the magnet yoke. The technology transfer from the particle accelerator domain to industry is ongoing, for example for the screening of high voltage cables buried in the ground

Towards the production of 50'000 tonnes of low-carbon steel sheet for the LHC superconducting dipole and quadrupole magnets

A total of 50'000 tonnes of low-carbon steel sheet has been ordered for the LHC main magnets. After three years of production, about 10'000 tonnes of steel sheet have been produced by Cockerill-Sambre Groupe Usinor. This paper gives a summary of the manufacturing process and improvements implemented as well as an overview of the difficulties encountered during this production. Preliminary statistics obtained for the mechanical and magnetic steel properties are presented

Synthesis of 5-aryl-5´-formyl-2,2´-bithiophenes as new precursors for nonlinear optical (NLO) materials

A series of formyl-substituted 5-aryl-2,2´-bithiophenes 5 were synthesized using two different methods: Vilsmeier-Haack-Arnold reaction (VHA) or through Suzuki coupling. The synthesis of compounds 5 through the Vilsmeier-Haack-Arnold reaction, starting from inexpensive and easily available precursors such as acetophenones, gave the title compounds in low yields after four reaction steps. On the other hand Suzuki coupling of functionalized aryl boronic acids 7 and the 5-bromo-5´-formyl-2,2´-bithiophene 6 gave compounds 5 in good yields in only one step.Fundação para a Ciência e a Tecnologia (FCT

Variation of glucosinolate contents in clubroot-resistant and-susceptible brassica napus cultivars in response to virulence of plasmodiophora brassicae

The present study investigated the changes in total and individual glucosinolates (GSLs) in roots and leaves of different clubroot-resistant and -susceptible oilseed rape cultivars following artificial inoculation with Plasmodiophora brassicae isolates with different virulence. The results showed significant differences in clubroot incidence and severity as well as in the amount of total and individual glucosinolates between oilseed rape cultivars in response to virulence of the pathogen. Single among with total aliphatic and total indolic glucosinolate contents were significantly lower in leaves of susceptible cultivars compared to resistant ones due to the infection. Similarly, single and total aliphatic as well as indolic glucosinolate contents in roots were lower in susceptible cultivars compared to resistant cultivars analyzed. The different isolates of P. brassicae seem to differ in their ability to reduce gluconasturtiin contents in the host. The more aggressive isolate P1 (+) might be able to suppress gluconasturtiin synthesis of the host in a more pronounced manner compared to the isolate P1. A possible interaction of breakdown products of glucobrassicin with the auxin receptor transport inhibitor response 1 (TIR1) is hypothesized and its possible effects on auxin signaling in roots and leaves of resistant and susceptible cultivars is discussed. A potential interplay between aliphatic and indolic glucosinolates that might be involved in water homeostasis in resistant cultivars is explained. © 2021 by the authors. Licensee MDPI, Basel, Switzerland