The pan-inhibitor of Aurora kinases danusertib induces apoptosis and autophagy and suppresses epithelial-to-mesenchymal transition in human breast cancer cells

Danusertib (Danu) is a pan-inhibitor of Aurora kinases and a third-generation breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (Bcr-Abl) tyrosine kinase inhibitor, but its antitumor effect and underlying mechanisms in the treatment of human breast cancer remain elusive. This study aimed to investigate the effects of Danu on the growth, apoptosis, autophagy, and epithelial-to-mesenchymal transition (EMT) and the molecular mechanisms in human breast cancer MCF7 and MDA-MB-231 cells. The results demonstrated that Danu remarkably inhibited cell proliferation, induced apoptosis and autophagy, and suppressed EMT in both breast cancer cell lines. Danu arrested MCF7 and MDA-MB-231 cells in G2/M phase, accompanied by the downregulation of cyclin-dependent kinase 1 and cyclin B1 and upregulation of p21 Waf1/Cip1, p27 Kip1, and p53. Danu significantly decreased the expression of B-cell lymphoma-extra-large (Bcl-xl) and B-cell lymphoma 2 (Bcl-2), but increased the expression of Bcl-2-associated X protein (Bax) and p53-upregulated modulator of apoptosis (PUMA), and promoted the cleavage of caspases 3 and 9. Furthermore, Danu significantly increased the expression levels of the membrane-bound microtubule-associated protein 1A/1B-light chain 3 (LC3-II) and beclin 1 in breast cancer cells, two markers for autophagy. Danu induced the activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases 1 and 2 (Erk1/2) and inhibited the activation of protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways in breast cancer cells. Treatment with wortmannin (a phosphatidylinositol 3-kinase inhibitor) markedly inhibited Danu-induced activation of p38 MAPK and conversion of cytosolic LC3-I to membrane-bound LC3-II. Pharmacological inhibition and small interfering RNA-mediated knockdown of p38 MAPK suppressed Akt activation, resulting in LC3-II accumulation and enhanced autophagy. Pharmacological inhibition and small interfering RNA-mediated knockdown of Erk1/2 also remarkably increased the level of LC3-II in MCF7 cells. Moreover, Danu inhibited EMT in both MCF7 and MDA-MB-231 cells with upregulated E-cadherin and zona occludens protein 1 (ZO-1) but downregulated N-cadherin, zinc finger E-box-binding homeobox 1 (TCF8/ZEB1), snail, slug, vimentin, and β-catenin. Notably, Danu showed lower cytotoxicity toward normal breast epithelial MCF10A cells. These findings indicate that Danu promotes cellular apoptosis and autophagy but inhibits EMT in human breast cancer cells via modulation of p38 MAPK/Erk1/2/Akt/mTOR signaling pathways. Danu may represent a promising anticancer agent for breast cancer treatment. More studies are warranted to fully delineate the underlying mechanisms, efficacy, and safety of Danu in breast cancer therapy.

Temperature and grain orientation dependence of mechanical twinning in a high manganese TWIP steel

 This thesis contains fundamental studies of the deformation mechanisms of the third generation steel at different deformation temperatures. To analyse the microstructure of the steel a unique characterisation technique was implemented for the first time. These analyses provided with vital parameters for modelling the stress-strain behaviour of the steel at different deformation temperatures.

Meropenem versus piperacillin-tazobactam for definitive treatment of bloodstream infections due to ceftriaxone non-susceptible Escherichia coli and Klebsiella spp (the MERINO trial): study protocol for a randomised controlled trial

BACKGROUND: Gram-negative bacteria such as Escherichia coli or Klebsiella spp. frequently cause bloodstream infections. There has been a worldwide increase in resistance in these species to antibiotics such as third generation cephalosporins, largely driven by the acquisition of extended-spectrum beta-lactamase or plasmid-mediated AmpC enzymes. Carbapenems have been considered the most effective therapy for serious infections caused by such resistant bacteria; however, increased use creates selection pressure for carbapenem resistance, an emerging threat arising predominantly from the dissemination of genes encoding carbapenemases. Recent retrospective data suggest that beta-lactam/beta-lactamase inhibitor combinations, such as piperacillin-tazobactam, may be non-inferior to carbapenems for the treatment of bloodstream infection caused by extended-spectrum beta-lactamase-producers, if susceptible in vitro. This study aims to test this hypothesis in an effort to define carbapenem-sparing alternatives for these infections.

METHODS/DESIGN: The study will use a multicentre randomised controlled open-label non-inferiority trial design comparing two treatments, meropenem (standard arm) and piperacillin-tazobactam (carbapenem-sparing arm) in adult patients with bacteraemia caused by E. coli or Klebsiella spp. demonstrating non-susceptibility to third generation cephalosporins. Recruitment is planned to occur in sites across three countries (Australia, New Zealand and Singapore). A total sample size of 454 patients will be required to achieve 80% power to determine non-inferiority with a margin of 5%. Once randomised, definitive treatment will be for a minimum of 4 days, but up to 14 days with total duration determined by treating clinicians. Data describing demographic information, antibiotic use, co-morbid conditions, illness severity, source of infection and other risk factors will be collected. Vital signs, white cell count, use of vasopressors and days to bacteraemia clearance will be recorded up to day 7. The primary outcome measure will be mortality at 30 days, with secondary outcomes including days to clinical and microbiological resolution, microbiological failure or relapse, isolation of a multi-resistant organism or Clostridium difficile infection.

New York Trade School Graduates David J. Stevens and Ernest Fitzgerald

David J. Stevens and Ernest Fitzgerald were 1948 graduates of the Plumbing Department at the New York Trade School and are pictured with a truck from their successful D.H. Stevens Company in Washington, DC. Original caption reads, "David J. Stevens - Plumbing 1948, is shown here with Ernest Fitzgerald - Plumbing 1948, with two of their thirteen pieces of equipment necessary to satisfy 650 calls per month. David Stevens is the third generation to have graduated from Plumbing." Black and white photograph with caption adhered to reverse.

Políticas de empregabilidade: o estado da arte na virada do século

O crescimento do desemprego involuntário condiciona preocupações recentes com políticas de empregabilidade. Estratégias na regulação do mercado de trabalho e a terceira geração na Teoria do Capital Humano buscam codificar e/ou equacionar essas políticas. O surgimento do conceito de Economia Plural oferece uma revisão para a dinâmica do setor informal, tradicional ou moderno, na geração de empregos atípicos. A noção de Economia Plural ressalta também o papel catalizador das empresas sociais e organizações não governamentais na reinserção dos excluídos sociais. As flexibilizações do tempo de trabalho em políticas de empregabilidade são desenvolvidas através de reflexões, impactos comportamentais na qualidade de vida e experiências negociadas nos setores metalúrgico, de distribuição e de prestação de serviços de saúde. Desafios se colocam para o poder público e entidades de classe na regulamentação e ou negociações da empregabilidades atípica.

Os fatores que influenciam a implementação das boas práticas da governança corporativa nas empresas familiares

Este estudo de caso tem como objetivo investigar quais são os fatores que influenciam a implementação das boas práticas da governança corporativa nas empresas familiares. A partir de uma abordagem qualitativa de pesquisa, adotou-se como método o estudo de caso único. Como instrumento de pesquisa recorreu-se a utilização de entrevistas semi-estruturadas com membros da família proprietária da segunda e terceira geração, representantes do Conselho de administração, sócios atuantes e não atuantes. Para o tratamento dos dados, recorreu-se à análise do conteúdo das entrevistas. Para fundamentar a pesquisa, houve a necessidade de uma revisão bibliográfica envolvendo governança corporativa; empresas familiares e suas particularidades; governança corporativa em empresas familiares e fatores que influenciam e dificultam o processo de implementação das boas práticas de governança corporativa à luz da literatura. A pesquisa aqui apresentada foi realizada na empresa Casa do Alemão Indústria e Comércio de Lanches LTDA, do setor alimentício, que se encontra sob comando da segunda e terceira geração da família fundadora, tendo como dominante a segunda geração. Os resultados obtidos nesta pesquisa apontam que as boas práticas de governança corporativa estão parcialmente presentes na Organização e que para uma implementação por completa, é necessário reformular os elementos já existentes e a criação de novas medidas de governança para melhorar a objetividade nos processos de qualificação, gestão, decisão e sucessão. Os fatores considerados como influentes e positivos para a implementação por completa das boas práticas de governança corporativa nesta Organização são: cultura de transparência; separação do patrimônio pessoal e empresa; predisposição de todos os sócios pela aceitação a utilização de processos mais formais na forma de trabalho. Dentre outros motivos ainda não implementados e que poderiam ser elementos influentes para a implantação são: necessidade de enfrentar os conflitos familiares; custos (investimento); resistência das pessoas (interesses divergentes dos sócios, família, executivos) e mais monitoramento (pessoas não gostam de ser monitoradas e avaliadas). Apesar de carregar a experiência que o tempo atribui aos sexagenários, a empresa também demonstra a agilidade da juventude para se manter com um visual moderno e iniciar uma nova política de expansão.

Inovações tecnológicas no setor de telecomunicações no Brasil: desafios e oportunidades do LTE para expansão da telefonia móvel.

O telefone celular teve uma grande evolução nos últimos anos, o que antes era utilizado exclusivamente para transmissão de voz, hoje tem características avançadíssimas incluindo várias evoluções tecnológicas. Dentro deste aspecto, a inovação que o LTE (Long Term Evolution) vem demonstrando em suas características realmente se destacam em relação as tecnologias que a antecederam e representa grande evolução se comparada com as outras. Foi desenvolvida no âmbito do projeto 3GPP e (3rd Generation Partners Project) promovido pelo Instituto Europeu de Normalização na área de Telecomunicações ETSI (European Telecommunications Standard Institute). As operadoras que demonstram interesse em disponibilizar esta tecnologia buscam introduzir a flexibilidade do LTE para ir ao encontro dos objetivos de suas redes existentes, espectro e negócios para banda larga móvel e serviços multimídia. O LTE promete taxas de download de 326,4Mbps, taxas de upload de 86,4Mbps, RTT ( ROUND TRIP TIME ) menos de 10 mile segundos e raio das células podendo atingir até 100km. O sistema 4G (LTE) é um sistema integrado completamente baseado em IP, que é resultado de tecnologias conectadas por fios e sem fios disponibilizando um custo acessível, atendendo as exigências de uma rede de comunicação (Wireless), serviços de transferência de mensagens multimídias, conversa com vídeo, televisão móvel de alta definição, serviços mínimos como voz e dados entre outras vantagens. Desta forma, este estudo tem por objetivo analisar quais são as oportunidades e os desafios no mercado de telefonia móvel de Telecomunicações ao implantar o sistema de tecnologia LTE demonstrando o benefício dos fabricantes e operadoras no sentido econômico e tecnológico.

Metagenômica comparativa de solo de regiões de mata atlântica e caatinga do estado do Rio Grande do Norte - Brasil

The microorganisms play very important roles in maintaining ecosystems, which explains the enormous interest in understanding the relationship between these organisms as well as between them and the environment. It is estimated that the total number of prokaryotic cells on Earth is between 4 and 6 x 1030, constituting an enormous biological and genetic pool to be explored. Although currently only 1% of all this wealth can be cultivated by standard laboratory techniques, metagenomic tools allow access to the genomic potential of environmental samples in a independent culture manner, and in combination with third generation sequencing technologies, the samples coverage become even greater. Soils, in particular, are the major reservoirs of this diversity, and many important environments around us, as the Brazilian biomes Caatinga and Atlantic Forest, are poorly studied. Thus, the genetic material from environmental soil samples of Caatinga and Atlantic Forest biomes were extracted by direct techniques, pyrosequenced, and the sequences generated were analyzed by bioinformatics programs (MEGAN MG-RAST and WEBCarma). Taxonomic comparative profiles of the samples showed that the phyla Proteobacteria, Actinobacteria, Acidobacteria and Planctomycetes were the most representative. In addition, fungi of the phylum Ascomycota were identified predominantly in the soil sample from the Atlantic Forest. Metabolic profiles showed that despite the existence of environmental differences, sequences from both samples were similarly placed in the various functional subsystems, indicating no specific habitat functions. This work, a pioneer in taxonomic and metabolic comparative analysis of soil samples from Brazilian biomes, contributes to the knowledge of these complex environmental systems, so far little explored

O desenvolvimento sustentável na ordem constitucional e sua promoção através do planejamento urbano

The man, being subject and object of their changes, has passed by many process to find a better life way. Since your existence, he finds to live in groups for make easy your life and make concrete yours desires. All by history, when the individual´s rights was establishment, collectives and lonely way, contribute for evaluate the relationship between individuals and they own, and them and state, which has a duty to those, positive or negative, depending on the case. The circle of fundamentals rights has been sustainable development and the concept of growth economy associated to the environment protection. This association reflect a apparent conflict between values very distinct, but the constitutional interpretation can be reunite both of them and make it live in harmony; values of environmental order and economical order can be exist together, as long as the state contribute to this. On the city, where the most of relationships happening, the urban plan appear how a effective way of sustainable development, finding the harmony between the growth economy and environment protection. To effective the socials functions of the city (inhabit, circulate, work and entertainment) and the citizen´s life quality, the city is the scenery that show how the urban plan, across established previously legal instruments, like the governmental public politics, to effective the right to development, right of third generation. The director plan how effective tool for local needs - obligation defined by Citizen Statute that contribute for the program linked defined by the urban plan. The state´s intervention on the private sector of citizen, and the restriction on their rights are be justified by the collective´s rights and their quality of life. So, in front the urban scenery has been the plan to make social functions of city, the healthy way of life, which is the sustainable development

Construção e implementação do Balanced Scorecard em uma organização educacional: o caso do Serviço Nacional de Aprendizagem Comercial do Rio Grande do Norte SENAC RN

The changes that have taken place in the organizational environment in recent decades have led to new performance measurement systems being proposed, given the inadequacy of traditional models. The Balanced Scorecard (BSC) emerged as an instrument to translate financial and non-financial assets into real values for all interested parties in the organization, allowing the introduction of strategies to achieve the desired goals. Research shows that most errors committed with the use of this method are related to the implementation process. Thus, the aim of this dissertation is to analyze the process of building and implementing the BSC in an organization. This empirical exploratory study is based on the classic case study method, which enables the researcher to work with a set of evidence, including direct observation, interviews and document analysis. The results show that the use of BSC in the company investigated posed problems during the process of building and implementing the method. These problems were caused mainly by the lack of involvement on the part of upper management and the team s scant knowledge of Balanced Scorecard. One of the gains obtained from adopting the system was the introduction and/or consolidation of a culture of strategic planning and participative management. The continuous implementation phase was highlighted in the monitoring program, created by the organization in an attempt to reverse existing problems, using the BSC as a third generation strategic management system, which led to significant gains, better use of the system and stronger management practices

Implementação de processador banda base ofdma para downlink lte em fpga

This work treats of an implementation OFDMA baseband processor in hardware for LTE Downlink. The LTE or Long Term Evolution consist the last stage of development of the technology called 3G (Mobile System Third Generation) which offers an increasing in data rate and more efficiency and flexibility in transmission with application of advanced antennas and multiple carriers techniques. This technology applies in your physical layer the OFDMA technical (Orthogonal Frequency Division Multiple Access) for generation of signals and mapping of physical resources in downlink and has as base theoretical to OFDM multiple carriers technique (Orthogonal Frequency Division Multiplexing). With recent completion of LTE specifications, different hardware solutions have been developed, mainly, to the level symbol processing where the implementation of OFDMA processor in base band is commonly considered, because it is also considered a basic architecture of others important applications. For implementation of processor, the reconfigurable hardware offered by devices as FPGA are considered which shares not only to meet the high requirements of flexibility and adaptability of LTE as well as offers possibility of an implementation quick and efficient. The implementation of processor in reconfigurable hardware meets the specifications of LTE physical layer as well as have the flexibility necessary for to meet others standards and application which use OFDMA processor as basic architecture for your systems. The results obtained through of simulation and verification functional system approval the functionality and flexibility of processor implemented

Um estudo do aumento da capacidade de sistemas 3g WCDMA usando técnicas 3.5G de expansão do enlace reverso

The introduction of new digital services in the cellular networks, in transmission rates each time more raised, has stimulated recent research that comes studying ways to increase the data communication capacity and to reduce the delays in forward and reverse links of third generation WCDMA systems. These studies have resulted in new standards, known as 3.5G, published by 3GPP group, for the evolution of the third generation of the cellular systems. In this Masters Thesis the performance of a 3G WCDMA system, with diverse base stations and thousand of users is developed with assists of the planning tool NPSW. Moreover the performance of the 3.5G techniques hybrid automatic retransmission and multi-user detection with interference cancellation, candidates for enhance the WCDMA uplink capacity, is verified by means of computational simulations in Matlab of the increase of the data communication capacity and the reduction of the delays in the retransmission of packages of information

Estrutura do dossel e acúmulo de forragem dos capins piatã e marandu sob pastejo com ovinos

The objective of this scientific work was to evaluate the tillering and mass production of Brachiaria brizantha Piatã and Marandu grasses with two statures of post-grazing. The experimental lineation was in factorial arrangement (2 pastures x 2 residue stature) with subplots (grazing cycle). The experimental period was from March to October of 2012. The target stature on pre-grazing was 50 cm and on post-grazing 15 and 25 for each cultivar. The following variables were analyzed: tiller population density, forage mass, morphological components, accumulation and accumulation rate. Three grazing cycles were obtained. Marandu grass presented larger forage mass on pre-grazing and lower stem production than piatã grass. No difference was observed between the two cultivars regarding the leaf blade production. There was no difference on forage mass, leaf blade, stem, and dead material production between the two statures of post-grazing. The pastures managed at 25 cm presented accumulation rate compared to those with 15 cm. Concerning the accumulation rate on the two cultivars, piatã and marandu grasses, Marandu grass presented higher amount than the piatã grass, and also presented higher values on the rate of basal tiller appearing on 15 cm stature post-pasture feature. Piatã grass managed at 25 cm developed smaller tiller amount on the second generation and greater tiller amount on the third generation than marandu grass. The greater tiller population density was observed on 25cm post-grazing pastures. There was no statistical difference of density between the two cultivars and between the cycles. Accordingly, it is concluded that piatã and marandu cultivars can be managed with 15cm and 25 cm post-grazing statures

Copper Hexacyanoferrate Formation on the Modified Silica Surface with DAB-Am-16 Dendrimer

The third generation (G-3) polypropylenimine hexadecaamine dendrimer (DAB-Am-16) was grafted onto the silica gel surface. The modified silica interacts easily with Cu(2+) and then with potassium ferrocyanide to form copper hexacyanoferrate. The modified silica was characterized by the following techniques: Nuclear Magnetic Resonance (NMR), FTIR spectroscopy, Energy Dispersive X-ray (EDX) and Cyclic Voltammetry. The modified silica containing copper hexacyanoferrate (CuHCFSD) was tested for a voltammetric determination of nitrite using a modified graphite paste electrode.

Investigation about the copper adsorption on the chloropropylsilica gel surface modified with a nanostructured dendrimer DAB-Am-16: an analytical application for determination of copper in different samples

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)