849 resultados para Undisciplined in first cycle


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The transition of the mammalian cell from quiescence to proliferation is a highly variable process. Over the last four decades, two lines of apparently contradictory, phenomenological models have been proposed to account for such temporal variability. These include various forms of the transition probability (TP) model and the growth control (GC) model, which lack mechanistic details. The GC model was further proposed as an alternative explanation for the concept of the restriction point, which we recently demonstrated as being controlled by a bistable Rb-E2F switch. Here, through a combination of modeling and experiments, we show that these different lines of models in essence reflect different aspects of stochastic dynamics in cell cycle entry. In particular, we show that the variable activation of E2F can be described by stochastic activation of the bistable Rb-E2F switch, which in turn may account for the temporal variability in cell cycle entry. Moreover, we show that temporal dynamics of E2F activation can be recast into the frameworks of both the TP model and the GC model via parameter mapping. This mapping suggests that the two lines of phenomenological models can be reconciled through the stochastic dynamics of the Rb-E2F switch. It also suggests a potential utility of the TP or GC models in defining concise, quantitative phenotypes of cell physiology. This may have implications in classifying cell types or states.

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BACKGROUND: Scythe/BAT3 is a member of the BAG protein family whose role in apoptosis has been extensively studied. However, since the developmental defects observed in Bat3-null mouse embryos cannot be explained solely by defects in apoptosis, we investigated whether BAT3 is also involved in cell-cycle progression. METHODS/PRINCIPAL FINDINGS: Using a stable-inducible Bat3-knockdown cellular system, we demonstrated that reduced BAT3 protein level causes a delay in both G1/S transition and G2/M progression. Concurrent with these changes in cell-cycle progression, we observed a reduction in the turnover and phosphorylation of the CDK inhibitor p21, which is best known as an inhibitor of DNA replication; however, phosphorylated p21 has also been shown to promote G2/M progression. Our findings indicate that in Bat3-knockdown cells, p21 continues to be synthesized during cell-cycle phases that do not normally require p21, resulting in p21 protein accumulation and a subsequent delay in cell-cycle progression. Finally, we showed that BAT3 co-localizes with p21 during the cell cycle and is required for the translocation of p21 from the cytoplasm to the nucleus during the G1/S transition and G2/M progression. CONCLUSION: Our study reveals a novel, non-apoptotic role for BAT3 in cell-cycle regulation. By maintaining a low p21 protein level during the G1/S transition, BAT3 counteracts the inhibitory effect of p21 on DNA replication and thus enables the cells to progress from G1 to S phase. Conversely, during G2/M progression, BAT3 facilitates p21 phosphorylation by cyclin A/Cdk2, an event required for G2/M progression. BAT3 modulates these pro- and anti-proliferative roles of p21 at least in part by regulating cyclin A abundance, as well as p21 translocation between the cytoplasm and the nucleus to ensure that it functions in the appropriate intracellular compartment during each phase of the cell cycle.

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© 2014, Springer-Verlag Berlin Heidelberg.The frequency and severity of extreme events are tightly associated with the variance of precipitation. As climate warms, the acceleration in hydrological cycle is likely to enhance the variance of precipitation across the globe. However, due to the lack of an effective analysis method, the mechanisms responsible for the changes of precipitation variance are poorly understood, especially on regional scales. Our study fills this gap by formulating a variance partition algorithm, which explicitly quantifies the contributions of atmospheric thermodynamics (specific humidity) and dynamics (wind) to the changes in regional-scale precipitation variance. Taking Southeastern (SE) United States (US) summer precipitation as an example, the algorithm is applied to the simulations of current and future climate by phase 5 of Coupled Model Intercomparison Project (CMIP5) models. The analysis suggests that compared to observations, most CMIP5 models (~60 %) tend to underestimate the summer precipitation variance over the SE US during the 1950–1999, primarily due to the errors in the modeled dynamic processes (i.e. large-scale circulation). Among the 18 CMIP5 models analyzed in this study, six of them reasonably simulate SE US summer precipitation variance in the twentieth century and the underlying physical processes; these models are thus applied for mechanistic study of future changes in SE US summer precipitation variance. In the future, the six models collectively project an intensification of SE US summer precipitation variance, resulting from the combined effects of atmospheric thermodynamics and dynamics. Between them, the latter plays a more important role. Specifically, thermodynamics results in more frequent and intensified wet summers, but does not contribute to the projected increase in the frequency and intensity of dry summers. In contrast, atmospheric dynamics explains the projected enhancement in both wet and dry summers, indicating its importance in understanding future climate change over the SE US. The results suggest that the intensified SE US summer precipitation variance is not a purely thermodynamic response to greenhouse gases forcing, and cannot be explained without the contribution of atmospheric dynamics. Our analysis provides important insights to understand the mechanisms of SE US summer precipitation variance change. The algorithm formulated in this study can be easily applied to other regions and seasons to systematically explore the mechanisms responsible for the changes in precipitation extremes in a warming climate.

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BACKGROUND:
Aurora kinases play an essential role in the orchestration of chromosome separation and cytokinesis during mitosis. Small-molecule inhibition of the aurora kinases has been shown to result in inhibition of cell division, phosphorylation of histone H3 and the induction of apoptosis in a number of cell systems. These characteristics have led aurora kinase inhibitors to be considered as potential therapeutic agents.
DESIGN AND METHODS:
Aurora kinase gene expression profiles were assessed in 101 samples from patients with acute myeloid leukemia. Subsequently, aurora kinase inhibitors were investigated for their in vitro effects on cell viability, histone H3 phosphorylation, cell cycle and morphology in acute myeloid leukemia cell lines and primary acute myeloid leukemia samples.
RESULTS:
The aurora kinase inhibitors AZD1152-HQPA and ZM447439 induced growth arrest and the accumulation of hyperploid cells in acute myeloid leukemia cell lines and primary acute myeloid leukemia cultures. Furthermore, both agents inhibited histone H3 phosphorylation and this preceded perturbations in cell cycle and the induction of apoptosis. Single cell cloning assays were performed on diploid and polyploid cells to investigate their colony-forming capacities. Although the polyploid cells showed a reduced capacity for colony formation when compared with their diploid counterparts, they were consistently able to form colonies.
CONCLUSIONS:
AZD1152-HQPA- and ZM447439 are effective apoptosis-inducing agents in acute myeloid leukemia cell lines and primary acute myeloid leukemia cultures. However, their propensity to induce polyploidy does not inevitably result in apoptosis.

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Asking and answering certain types of questions are thought to develop thinking skills in all types of classrooms. Previous research has demonstrated that asking higher order questions and answering with elaborated responses are associated with high achievement in first, second, and foreign language contexts. Typically more attention is paid to question frequency or achievements inferred from individual performances than to the dialogues in which asking and answering occurs. This paper argues for a focus on the construction of responses in interaction as an alternative to the investigation of questions, effects of training or individual measurements of performance. Drawing on interactional data from an adult English as a Second Language classroom, it is argued that constructing an answer to a critical question appears to be a highly collaborative and evaluative affair. The thinking skills literature suggests that responding to higher order questions is an individual higher cognitive function, however it is argued in this paper that in attempting to construct evaluative answers language learners are involved not only in a cognitive task, which may or may not be helpful to language learning, but also in a complex social task in which perspectives need to be negotiated, stances taken and identities navigated. It is suggested that higher order thinking cannot be separated from the social and cultural knowledge through which it is brought into being. It is argued that any implementation of thinking skills in an English language teaching context ought to consider interpersonal and social aspects, particularly in intercultural settings.

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Background: In the Medical Research Council (MRC) COIN trial, the epidermal growth factor receptor (EGFR)-targeted antibody cetuximab was added to standard chemotherapy in first-line treatment of advanced colorectal cancer with the aim of assessing effect on overall survival.
Methods: In this randomised controlled trial, patients who were fit for but had not received previous chemotherapy for advanced colorectal cancer were randomly assigned to oxaliplatin and fluoropyrimidine chemotherapy (arm A), the same combination plus cetuximab (arm B), or intermittent chemotherapy (arm C). The choice of fluoropyrimidine therapy (capecitabine or infused fluouroracil plus leucovorin) was decided before randomisation. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and C is described in a companion paper. Here, we present the comparison of arm A and B, for which the primary outcome was overall survival in patients with KRAS wild-type tumours. Analysis was by intention to treat. Further analyses with respect to NRAS, BRAF, and EGFR status were done. The trial is registered, ISRCTN27286448.
Findings: 1630 patients were randomly assigned to treatment groups (815 to standard therapy and 815 to addition of cetuximab). Tumour samples from 1316 (81%) patients were used for somatic molecular analyses; 565 (43%) had KRAS mutations. In patients with KRAS wild-type tumours (arm A, n=367; arm B, n=362), overall survival did not differ between treatment groups (median survival 17·9 months [IQR 10·3—29·2] in the control group vs 17·0 months [9·4—30·1] in the cetuximab group; HR 1·04, 95% CI 0·87—1·23, p=0·67). Similarly, there was no effect on progression-free survival (8·6 months [IQR 5·0—12·5] in the control group vs 8·6 months [5·1—13·8] in the cetuximab group; HR 0·96, 0·82—1·12, p=0·60). Overall response rate increased from 57% (n=209) with chemotherapy alone to 64% (n=232) with addition of cetuximab (p=0·049). Grade 3 and higher skin and gastrointestinal toxic effects were increased with cetuximab (14 vs 114 and 67 vs 97 patients in the control group vs the cetuximab group with KRAS wild-type tumours, respectively). Overall survival differs by somatic mutation status irrespective of treatment received: BRAF mutant, 8·8 months (IQR 4·5—27·4); KRAS mutant, 14·4 months (8·5—24·0); all wild-type, 20·1 months (11·5—31·7).
Interpretation: This trial has not confirmed a benefit of addition of cetuximab to oxaliplatin-based chemotherapy in first-line treatment of patients with advanced colorectal cancer. Cetuximab increases response rate, with no evidence of benefit in progression-free or overall survival in KRAS wild-type patients or even in patients selected by additional mutational analysis of their tumours. The use of cetuximab in combination with oxaliplatin and capecitabine in first-line chemotherapy in patients with widespread metastases cannot be recommended.

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The paper reports data from an on-line peer tutoring project. In the project 78, 9–12-year-old students from Scotland and Catalonia peer tutored each other in English and Spanish via a managed on-line envi- ronment. Significant gains in first language (Catalonian pupils) modern language (Scottish pupils) and attitudes towards modern languages (both Catalonian and Scottish pupils) were reported for the exper- imental group as compared to the control group. Results indicated that pupils tutored each other in using Piagetian techniques of error correction during the project. Error correction provided by tutors to tutees focussed on morph syntaxys, more specifically the correction of verbs. Peer support provided via the on- line environment was predominantly based on the tutor giving the right answer to the tutee. High rates of impact on tutee corrected messages were observed. The implications for peer tutoring initiative taking place via on-line environments are discussed. Implications for policy and practice are explored

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At its core, Duverger’s Law—holding that the number of viable parties in first-past-the-post systems should not exceed two—applies primarily at the district level. While the number of parties nationally may exceed two, district-level party system fragmentation should not. Given that a growing body of research shows that district-level party system fragmentation can indeed exceed two in first-past-the-post systems, I explore whether the major alternative explanation for party system fragmentation—the social cleavage approach—can explain such violations of Duverger’s Law. Testing this argument in several West European elections prior to the adoption of proportional representation, I find evidence favouring a social cleavage explanation: with the expansion of the class cleavage, the average district-level party system eventually came to violate the two-party predictions associated with Duverger’s Law. This suggests that sufficient social cleavage diversity may produce multiparty systems in other first-past-the-post systems.

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Before commencement of the academic year 2012/2013 the social sciences, public health and the biomedical sciences were taught to separate modules. This reinforced the idea off separate disciplines certainly for some of the younger students and a failure to appreciate the interconnectedness (whole person) perspective on health; separately modules taught and assessed in separate silos. There was limited understanding by the lecturers of the other areas that they were not teaching to -reflecting perhaps a dis-coordinated approach to health sciences (Mason and Whitehead 2003). As a result of significant discussion and interdisciplinary negotiation the life, social sciences public health/ health education were drawn together in the one module for the academic year 2012/13. The module provides the undergraduate students with an introduction to an understanding of Life Sciences, psychology, sociology and public health and their contribution within the context of nursing and midwifery. Each week’s teaching seeks to reflect against the other module delivered in first year - addressing clinical skills. The teaching is developing innovative e-learning approaches, including the use of a virtual community. The intention is to provide the student with a more integrated understanding and teaching to the individual’s health and to health within a social context (Lin 2001; Iles- Shih 2011). The focus is on health promotion rather than disease management. The module runs in three phases across the student’s first-year and teachers to the field of adult mental health, learning disability, children’s nursing and the midwifery students -progressively building on the student’s clinical experience. The predominant focus of the module remains on health and reflecting aspects of life and social life within N. Ireland. One of the particular areas of interest and an area of particular sensitivity is engaging the students to the context of the Northern Ireland civil unrest (the Troubles); this involves a co-educational initiative with service users, only previously attempted with social work students (Duffy 2012). The service users are represented by WAVE an organisation offering care and support to bereaved, traumatised or injured as a result of the violent civil conflict `the Troubles’. The `Troubles’ had ranged over an extended period and apart from the more evident and visual impact of death and injury, the community is marked by a disproportionate level of civil unrest, the extremes of bereavement, imprisonment, displacement antisocial behaviour and family dysfunction (Coulter et al. 2012). As co-educators with the School of Nursing and Midwifery, WAVE deliver a core lecture (augmented by online material), then followed by tutorials. The tutorials are substantially led by those who had been involved with and experienced loss and trauma as a result of the conflict (Health Service users) as `citizen trainers’ and provide an opportunity for them to share their experience and their recollection of personal interaction with nursing and midwifery students; in improving their understanding of the impact of `The Troubles’ on patients and clients affected by the events (Coulter et al. 2012) and to help better provide a quality of care cognisant of the particular needs of those affected by `the Troubles’ in N.Ireland. This approach is relatively unique to nursing in N. Ireland in that it involves many of those directly involved with and injured by the `Troubles’ as `citizen trainers’ and clearly reflects the School’s policy of progressively engaging with users and carers of nursing and midwifery services as co-educators to students (Repper & Breeze 2006). Only now could perhaps such a sensitive level of training to student nurses and midwives be delivered across communities with potential educative lessons for other communities experiencing significant civil unrest and sectarian conflict.

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Recent evidence indicates a potential prognostic and predictive value for germline polymorphisms in genes involved in cell cycle control. We investigated the effect of cyclin D1 (CCND1) rs9344 G>A in stage II/III colon cancer patients and validated the findings in an independent study cohort. For evaluation and validation set, a total of 264 and 234 patients were included. Patients treated with 5-fluorouracil-based chemotherapy, carrying the CCND1 rs9344 A/A genotype had significantly decreased time-to-tumor recurrence (TTR) in univariate analysis and multivariate analysis (hazard ratio (HR) 2.47; 95% confidence interval (CI) 1.16-5.29; P=0.019). There was no significant association between CCND1 rs9344 G>A and TTR in patients with curative surgery alone. In the validation set, the A allele of CCND1 rs9344 G>A remained significantly associated with decreased TTR in univariate and multivariate analyses (HR 1.94; 95% CI 1.05-3.58; P=0.035). CCND1 rs9344 G>A may be a predictive and/or prognostic biomarker in stage II/III colon cancer patients, however, prospective trials are warranted to confirm our findings.

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Background: Outwith clinical trials, patient outcomes specifically related to SACT (systemic anti-cancer therapy) are not well reported despite a significant proportion of patients receiving active treatment at the end of life. The NCEPOD reviewing deaths within 30 days of SACT found SACT caused or hastened death in 27% of cases.

Method: Across the Northern Ireland cancer network, 95 patients who died within 30 days of SACT for solid tumours were discussed at the Morbidity and Mortality monthly meeting during 2013. Using a structured template, each case was independently reviewed, with particular focus on whether SACT caused or hastened death.

Results: Lung, GI and breast cancers were the most common sites. Performance status was recorded in 92% at time of final SACT cycle (ECOG PS 0-2 89%).

In 57% the cause of death was progressive disease. Other causes included thromboembolism (13%) and infection (5% neutropenic sepsis, 6% non-neutropenic sepsis). In 26% with death from progressive disease, the patient was first cycle of first line treatment for metastatic disease. In the majority discussion regarding treatment aims and risks was documented. Only one patient was receiving SACT with curative intent, who died from appropriately managed neutropenic sepsis.

A definitive decision regarding SACT's role in death was made in 60%: in 49% SACT was deemed non-contributory and in 11% SACT was deemed the cause of death. In 40% SACT did not play a major role, but a definitive negative association could not be made.

Conclusion: Development of a robust review process of 30-day mortality after SACT established a benchmark for SACT delivery for future comparisons and identified areas for SACT service organisation improvement. Moreover it encourages individual practice reflection and highlights the importance of balancing patients' needs and concerns with realistic outcomes and risks, particularly in heavily pre-treated patients or those of poor performance status.

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Relatório de Estágio para a obtenção do grau de Mestre em Educação Pré-escolar e em Ensino do 1º Ciclo do Ensino Básico

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O desenvolvimento das ferramentas Web 2.0 tem estado a impulsionar mudanças significativas no modo de interação entre os utilizadores da Internet. No âmbito educacional, estas ferramentas podem enriquecer as práticas pedagógicas e promover ações que envolvam a participação ativa, a colaboração, a cooperação e a partilha de saberes. Num contexto de ensino e aprendizagem em que se assume que, os estudantes de pós-graduação em Ciências de Educação apresentam deficiências ao nível do pensamento crítico, a utilização pedagógica das ferramentas Web 2.0 pode ser, deste modo, considerada como um fator promotor do pensamento crítico. Nesta linha de pensamento, o presente estudo surge com o objetivo principal de contribuir para uma compreensão mais profunda relativamente à utilização de tecnologias Web 2.0 como um fator potencial de promoção do desenvolvimento do pensamento crítico na Universidade Eduardo Mondlane (UEM) através da aplicação e análise de algumas estratégias pedagógicas baseadas em blogs e wikis. Em função do objetivo do estudo, a parte empírica foi conduzida na forma de uma investigação-ação e compreendeu dois ciclos. A seleção dos participantes foi feita por conveniência. O 1º ciclo de investigação incidiu sobre catorze participantes matriculados no ano académico de 2009/2010 para o módulo Desenvolvimento Profissional e Aprendizagem ao Longo da Vida, lecionado na fase de especialização de mestrado em Educação de Adultos. O 2º ciclo compreendeu dezoito participantes também inscritos para o mesmo módulo, mas no ano académico de 2010/2011. A recolha de dados foi feita por meio de observação, inquérito por entrevista do tipo semiestruturada, diário de bordo, inquérito por questionário, ensaios argumentativos e pesquisa documental. Um modelo de análise adaptado a partir da tipologia de pensamento crítico de Ennis (1987) foi utilizado na recolha e análise dos dados. Uma análise interpretativa dos dados foi efetuada com ajuda do software Nvivo8. Os resultados do estudo demonstraram que é possível promover as capacidades e disposições de pensamento crítico nos estudantes mediante a utilização de algumas estratégias pedagógicas que recorrem a ferramentas Web 2.0, como sejam o blog de discussão, os blogs de grupos e a wiki da turma. Apesar das diversas dificuldades enfrentadas pelos estudantes no desenrolar do módulo, os participantes de ambos os ciclos reconhecem que as ferramentas Web 2.0 têm um grande potencial para a promoção do pensamento crítico e que a sua aplicação é fortemente recomendável para o processo de ensino e aprendizagem. O estudo concluiu também que o modelo de análise adaptado de Ennis (1987) que orientou a pesquisa revelou ser fundamental na observância da ocorrência de capacidades e disposições de pensamento crítico nos blogs de discussão, blogs de grupos e na wiki da turma.

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Num planeta finito, a impossibilidade de um crescimento contínuo e a necessidade de preservar os seus recursos naturais e ambientais, tendo em vista assegurar opções de qualidade de vida e bem-estar das gerações futuras, fez emergir e estruturar o conceito de Desenvolvimento Sustentável. Perante os múltiplos desafios que o futuro coloca, a educação constitui-se como uma via para alcançar um desenvolvimento mais harmonioso das relações entre os seres humanos e entre estes e a natureza, indispensável à humanidade na persecução dos seus legítimos anseios de paz, liberdade e justiça social. A importância atribuída à educação no sentido de uma adequada perceção da situação do planeta levou as Nações Unidas a proclamarem, no início deste século (dezembro de 2002), a Década da Educação para o Desenvolvimento Sustentável (2005-2014): um desafio internacional lançado aos países para que recorram à educação como ferramenta essencial na promoção de Desenvolvimento Sustentável. A vida nas sociedades contemporâneas é, como nunca antes, influenciada por desenvolvimentos científicos e tecnológicos e dependente dos respetivos progressos. Assim, a Educação Científica assume um papel fundamental na compreensão das problemáticas que enfrentamos e na consciencialização da responsabilidade do ser humano na situação planetária atual, devendo promover o desenvolvimento de cidadanias proativas, fundamentadas e responsáveis, no sentido da mudança, numa perspetiva crítica global que garanta a sustentabilidade do planeta. Estas finalidades são alvo de reflexão por parte de diversas instâncias da sociedade – nas quais se incluem organismos como a UNESCO, comunidades nacionais e internacionais de investigação em Educação Científica, e o poder político – e espelham-se em propostas de reforma e de revisão curricular em diversos países. Ora, sem ser exclusiva, a educação formal nos primeiros anos de escolaridade tem um papel fundamental, por ter caráter obrigatório na maioria dos países. Paralelamente existe um crescente reconhecimento a nível internacional em torno da importância de se iniciar precocemente a Educação Científica com vista a alcançar esses propósitos. Resultados alcançados em diversas investigações evidenciam que a Educação Científica nos primeiros anos de escolaridade tem impacte positivo relevante no desenvolvimento de literacia científica e no desenvolvimento de atitudes positivas face à Ciência e a aprendizagens de Ciências. A presente investigação pretende ser um contributo para a Década da Educação para o Desenvolvimento Sustentável no Primeiro Ciclo do Ensino Básico. O percurso de investigação, de natureza qualitativa, foi desenvolvido em três fases distintas mas articuladas entre si: a fase I integrou processos interpretativos de investigação documental e teve como principais objetivos o estabelecimento do quadro teórico de suporte à problemática de Educação para Desenvolvimento Sustentável e a caraterização de perspetivas de Educação Científica decorrentes de política educativa em Portugal; na fase II caraterizou-se a importância atribuída por professores do Primeiro Ciclo do Ensino Básico à Educação Científica e respetiva componente experimental, bem como as suas conceções acerca de Literacia Científica, orientações Ciência-Tecnologia-Sociedade no ensino das Ciências, Desenvolvimento Sustentável e o modo como dizem articular as referidas conceções com as suas práticas de sala de aula; na fase III apresentou-se um Programa de Ciências, concebido segundo os referenciais atrás definidos e avaliado por um painel de peritos, para Educação para Desenvolvimento Sustentável, “A Terra e os seres vivos: conhecer para valorizar e proteger”, para implementação em cada um dos quatro anos de escolaridade do Primeiro Ciclo do Ensino Básico. O presente estudo assume-se como um contributo para a inovação na Educação Científica no Primeiro Ciclo do Ensino Básico e fundamenta a necessidade de a reorientar, tendo em vista a resposta a compromissos internacionais assumidos por Portugal no âmbito da Década da Educação para o Desenvolvimento Sustentável, bem como a importância de acompanhar orientações e políticas recomendadas a nível internacional, numa perspetiva de educação num contexto de globalização.