Muc4, a heterodimeric transmembrane mucin containing EGF-like domains, has been described as an ErbB2-binding protein which modulates signaling via the ErbB2-ErbB3 pathway. In Muc4-transfected MCF-7 cells, Muc4 expression resulted in alteration of both the time course and phosphorylation levels of NRG beta 1 induced phosphorylation and activation of both ErbB2 and ErbB3. Muc4 significantly enhanced the autophosphorylation of ErbB2 over the early (defined 0-30 min) and intermediate (30-120 min) NRG beta 1 treatment times at three sites, Y1248, Y1221 and Y1139. The sites displayed differential maximal phosphorylation times. At Y1248 and Y1139, maximal phosphorylation occurred entirely during the early treatment phase. However, Y1221/2 showed maximal phosphorylation during the intermediate phase with a smaller peak during the early phase. The ratio of phosphorylated ErbB3 and total receptor level was significantly enhanced (in cells that expressed Muc4 compared without Muc4) over both the early and intermediate NRG beta 1 treatment time at the Y1289 site. This motif is one of several similar ErbB3 motifs whose phosphorylation mediates the binding of PI3-kinase. This phospholipid kinase is a key modulator of numerous cellular pathways leading to proliferation, motility and survival. Aberrancies in the ErbB2-ErbB3 signaling pathway have been implicated in the aggressive behavior of tumor cells, and the identification and characterization of modulators of this pathway are being sought as targets of potential therapeutic interventions. Muc4 significantly enhanced activated ERK in the absence of NRG beta 1 treatment while a NRG beta 1 mediated activation of AKT was observed. At early NRG beta 1 treatment time phases, Muc4 co-localized with phosphorylated ErbB2 (pY1248) independent of NRG beta 1 treatment; co-localization of Muc4 and ErbB2 receptor (activated/receptor forms) was observed at the apical surface or around the cell surface membrane. These data provide evidence in the Muc4-transfected MCF-7 cells for the biological NRG beta 1 mediated ErbB2 and ErbB3 activation. Our data suggests that Muc4 affects steady state phosphorylation levels and duration of the phosphorylation signal of both ErbB receptors, and that NRG beta 1 might affect ErbB2 and ErbB3 signaling differently. Additionally, the results of the timing of phosphorylation studies suggest the possibility that temporal aspects of phosphorylation at different sites may determine the pathways activated preferentially in the subsequent signaling cascades.

Obtemos a expressão da densidade espectral de uma impureza no modelo de Anderson assimétrico. No regime de Kondo de baixas energias o modelo de Anderson descreve sistemas quânticos com impurezas magnéticas em meios não magnéticos. Para energias características do orbital de impureza simples ou duplamente ocupado iguais a εf e 2εf+U, respectivamente, o modelo é chamado simétrico para 2εf + U = 0 e assimétrico quando 2εf + U ≠ 0. Para o caso simétrico existe uma expressão devido a Frota que descreve ressonância de Kondo na densidade espectral. Todavia, no caso assimétrico a expressão de Frota deixa de ser válida e é necessária uma nova abordagem. Nesta dissertação, a partir de dados numéricos obtidos pelo consagrado método do Grupo de Renormalização Numérico criado por Wilson em 1974 e de tópicos da física de muitos corpos estudamos a assimetria do modelo de Anderson no regime de Kondo e propomos uma expressão mais geral que a de Frota para a densidade espectral da impureza. / We propose an analytical expression for the impurity spectral density in the Kondo regime of the spin-degenerate asymmetric Anderson model. The Anderson model describes quantum systems of magnetic impurities in nonmagnetic metals. For characteristic energies of single and double impurity occupations εf and 2εf+U, respectively, the model is particlehole symmetric for 2εf + U = 0 and asymmetrical 2εf + U ≠ 0. In the symmetric case, there is an expression due to Frota that describes the Kondo resonance in the spectral density. However, in the asymmetric case Frota´s expression is not valid, and a new approach is necessary. In this work, starting with numerical data provided by the Numerical Renormalization Group method developed by Wilson in 1974, we study the asymmetric Anderson model in the Kondo regime and propose an expression for the impurity spectral density that is more general than Frota´s.

Obtemos a expressão da densidade espectral de uma impureza no modelo de Anderson assimétrico. No regime de Kondo de baixas energias o modelo de Anderson descreve sistemas quânticos com impurezas magnéticas em meios não magnéticos. Para energias características do orbital de impureza simples ou duplamente ocupado iguais a εf e 2εf+U, respectivamente, o modelo é chamado simétrico para 2εf + U = 0 e assimétrico quando 2εf + U ≠ 0. Para o caso simétrico existe uma expressão devido a Frota que descreve ressonância de Kondo na densidade espectral. Todavia, no caso assimétrico a expressão de Frota deixa de ser válida e é necessária uma nova abordagem. Nesta dissertação, a partir de dados numéricos obtidos pelo consagrado método do Grupo de Renormalização Numérico criado por Wilson em 1974 e de tópicos da física de muitos corpos estudamos a assimetria do modelo de Anderson no regime de Kondo e propomos uma expressão mais geral que a de Frota para a densidade espectral da impureza. / We propose an analytical expression for the impurity spectral density in the Kondo regime of the spin-degenerate asymmetric Anderson model. The Anderson model describes quantum systems of magnetic impurities in nonmagnetic metals. For characteristic energies of single and double impurity occupations εf and 2εf+U, respectively, the model is particlehole symmetric for 2εf + U = 0 and asymmetrical 2εf + U ≠ 0. In the symmetric case, there is an expression due to Frota that describes the Kondo resonance in the spectral density. However, in the asymmetric case Frota´s expression is not valid, and a new approach is necessary. In this work, starting with numerical data provided by the Numerical Renormalization Group method developed by Wilson in 1974, we study the asymmetric Anderson model in the Kondo regime and propose an expression for the impurity spectral density that is more general than Frota´s.

Tese de Mestrado Integrado. Engenharia Mecânica. Faculdade de Engenharia. Universidade do Porto. 2012

No description available.

Objective: This research aimed at reviewing the information provided by the online drug misuse communities with reference to the available evidence-based literature on the novel psychoactive substances. Methodology: Among hundreds of novel psychoactive substances, four groups (phenethylamines, tryptamines, piperazines and miscellaneous) were selected for the study. Various website drug fora were identified by Google and Yahoo search engines using a set of specific key words. The methods consisted of extracting and analysing qualitative data from the identified website fora. This was also supplemented by critical reviewing the existing evidence-based literature search for each of the selected psychoactive compounds. Results: The combined search results identified 84 unique website fora from which qualitative data were extracted for thirty novel psychoactive substances and organised into technical folders. This data extracted from online communities has thrown some light on factors such as the mode of purchase, subjective experiences, reasons for use, combinations, legislation, mechanisms of action in the CNS, side effects, toxicity and its management. This would enable the clinicians to be obtain full history when assessing and would inform better treatment choices. Conclusions: A range of novel psychoactive substances have been made recently available across the globe. The sale is easily achieved through the Internet. New legislations are made to control some recreational substances whilst newer substances appear. Furthermore, the distributors sell the backlog of products even after controlling of the substance has occured and hence are liable to potentiating criminal investigations. It is here suggested as well that the 'genuinity' of each onlince susbtance is questionable. Evidence-based literature is scant for the vast majority of these substances. Accidental overdoses are common occurences and some of the potential life-threatening clinical situations include sympathomimetic toxidrome and serotonin syndrome. Benzodiazepines appear to help with agitation and neuropsychiatric manifestations. Better levels of international cooperation and rapid share of available information may be needed to tackle the emerging problem of the novel psychoactive substances.

No description available.