Primary and malignant cholangiocytes undergo CD40 mediated Fas dependent Apoptosis, but are insensitive to direct activation with exogenous fas ligand

Introduction Cholangiocarcinoma is a rare malignancy of the biliary tract, the incidence of which is rising, but the pathogenesis of which remains uncertain. No common genetic defects have been described but it is accepted that chronic inflammation is an important contributing factor. We have shown that primary human cholangiocyte and hepatocyte survival is tightly regulated via co-operative interactions between two tumour necrosis family (TNF) receptor family members; CD40 and Fas (CD95). Functional deficiency of CD154, the ligand for CD40, leads to a failure of clearance of biliary tract infections and a predisposition to cholangiocarcinoma implying a direct link between TNF receptor-mediated apoptosis and the development of cholangiocarcinoma. Aims To determine whether malignant cholangiocytes display defects in CD40 mediated apoptosis. By comparing CD40 and Fas-mediated apoptosis and intracellular signalling in primary human cholangiocytes and three cholangiocyte cell lines. Results Primary cholangiocytes and cholangiocyte cell lines were relatively insensitive to direct Fas-mediated killing with exogenous FasL when compared with Jurkat cells, which readily underwent Fas-mediated apoptosis, but were extremely sensitive to CD154 stimulation. The sensitivity of cells to CD40 activation was similar in magnitude in both primary and malignant cells and was STAT-3 and AP-1 dependent in both. Conclusions 1) Both primary and malignant cholangiocytes are relatively resistant to Fas–mediated killing but show exquisite sensitivity to CD154, suggesting that the CD40 pathway is intact and fully functional in both primary and malignant cholangiocytes 2) The relative insensitivity of cholangiocytes to Fas activation demonstrates the importance of CD40 augmentation of Fas dependent death in these cells. Agonistic therapies which target CD40 and associated intracellular signalling pathways may be effective in promoting apoptosis of malignant cholangiocytes

Compromise Between Incommensurable Ethical Values

In this chapter I will concentrate on compromise in ethical conflict and disagreement. I will discuss compromises related to disagreement with respect to public decisions between options that represent conflicting incommensurable human values. The central question will be whether in those cases a principled compromise is possible. A ‘principled compromise’ can be defined as a rational way to achieve a trade-off or balance between conflicting values, for instance, by rational assignment of relative weights. I will argue that in some cases incommensurability will prevent a principled compromise in the defined sense. I will show why phrases used by some philosophers, such as ‘making a rational trade-off’, ‘striking the right balance’, ‘finding the Aristotelian Mean’ or ‘splitting the difference’, are based on misunderstandings about the characteristics of incommensurable values that are usually at stake in the pursuit of a compromise. I will show that incommensurable values lack an equivalence relation and how this prevents a determinate trade-off or balance between them. This is especially important with respect to the pursuit of compromises in ethical conflicts, including conflicts of justice, where we need a rational and ethical justification for the final decision. I will argue that the model of deliberative democracy presents a promising procedure for making the final decision legitimate but that, in the relevant cases, it cannot avoid an ethical deficit

Satisfação no trabalho da equipe de enfermagem: revisão integrativa

Job satisfaction consists of a feeling of wellbeing, resulting from the interaction of several occupational aspects, and may influence the worker's relationship with the organization, clients and family. Hence, it becomes important for the quality of nursing care to reflect on this topic in depth. Therefore, this study aimed to examine the scientific evidence related to job satisfaction in Brazilian nursing. An integrative literature review was carried out in the databases LILACS, MEDLINE, BDENF and Cochrane Library, totaling 17 publications, categorized in: Job Satisfaction, Job Dissatisfaction and Associated Factors. It was concluded that job satisfaction is determined by a complex network of factors and may vary depending on the group studied. Additional research, particularly of evidence level III in different nursing fields, covering all of Brazil, is necessary to support the implementation of occupational improvements.La satisfacción en el trabajo consiste en un sentimiento de bienestar resultante de la interacción de varios aspectos ocupacionales, pudiendo influenciar la relación del trabajador con la organización, clientes y familia. Es importante para la calidad de la asistencia de enfermería realizar una reflexión profunda sobre este tema, por eso se objetivó en este estudio analizar las evidencias científicas referentes a la satisfacción en el trabajo del equipo de enfermería brasileño. Se trató de una revisión integradora de la literatura en las bases de datos LILACS, MEDLINE, BDENF y Biblioteca Cochrane, totalizando 17 publicaciones categorizadas en: Satisfacción en el Trabajo, Insatisfacción en el Trabajo y Factores Asociados. Se concluyó que la satisfacción en el trabajo es determinada por una red compleja de factores, pudiendo variar conforme el grupo estudiado. Investigaciones adicionales, especialmente con niveles de evidencias III, en diferentes campos de actuación de la enfermería, abarcando todo el Brasil, son necesarias para subsidiar la implantación de mejorías ocupacionales.A satisfação no trabalho consiste em sentimento de bem-estar. resultante da interação de vários aspectos ocupacionais, podendo influenciar a relação do trabalhador com a organização, clientes e família. Torna-se importante, para a qualidade da assistência de enfermagem, reflexão aprofundada sobre esse tema, e, por isso, objetivou-se neste estudo analisar as evidências científicas referentes à satisfação no trabalho da equipe de enfermagem brasileira. Trata-se de revisão integrativa da literatura nas bases de dados LILACS, MEDLINE, BDENF e Biblioteca Cochrane, totalizando 17 publicações categorizadas em: satisfação no trabalho, insatisfação no trabalho e fatores associados. Conclui-se que a satisfação no trabalho é determinada por rede complexa de fatores, podendo variar conforme o grupo estudado. Pesquisas adicionais, especialmente com níveis de evidências III, em diferentes campos de atuação da enfermagem, abrangendo todo Brasil, são necessárias para subsidiar a implantação de melhorias ocupacionais

Quantum walks: a comprehensive review

Quantum walks, the quantum mechanical counterpart of classical random walks, is an advanced tool for building quantum algorithms that has been recently shown to constitute a universal model of quantum computation. Quantum walks is now a solid field of research of quantum computation full of exciting open problems for physicists, computer scientists, mathematicians and engineers. In this paper we review theoretical advances on the foundations of both discrete- and continuous-time quantum walks, together with the role that randomness plays in quantum walks, the connections between the mathematical models of coined discrete quantum walks and continuous quantum walks, the quantumness of quantum walks, a summary of papers published on discrete quantum walks and entanglement as well as a succinct review of experimental proposals and realizations of discrete-time quantum walks. Furthermore, we have reviewed several algorithms based on both discrete- and continuous-time quantum walks as well as a most important result: the computational universality of both continuous- and discrete- time quantum walks.Comment: Paper accepted for publication in Quantum Information Processing Journa

Leukaemia incidence among workers in the shoe and boot manufacturing industry: a case-control study

BACKGROUND: Previous reports have indicated an excess of leukaemia in Broome County, New York, particularly in the Town of Union. Surveillance of cancer incidence data indicates that a large proportion of these cases occurred among males ages 65 and older. Shoe and boot manufacturing has been the largest single industry in this area throughout much of the past century. Occupational studies from Europe suggest a link between leukaemia and employment in the shoe and boot manufacturing industry. However, researchers have not found a positive association between leukaemia and employment in the shoe industry among workers in the United States. METHODS: A matched case-control study was conducted to investigate the association between leukaemia incidence among males 65 and older and employment in the shoe and boot manufacturing industry. Thirty-six cases of leukaemia occurring between 1981–1990; among males age 65 and older; residing in the town of Union met the study case criteria. Death certificates were obtained for each of the cases. These were matched to death certificates of 144 controls on date of death and date of birth +/- 1 year. Death certificates were then examined to determine the employer and occupation of each study subject. Conditional logistic regression was used to determine the risk of leukaemia among those working in the industry. RESULTS: The risk of both leukaemia (OR = 1.47; 95% CI 0.70, 3.09) and acute myeloid leukaemia (OR = 1.19; 95% CI 0.33, 4.28) were elevated among those employed in the shoe and boot manufacturing industry, however neither was statistically significant. CONCLUSION: The results, though suggestive of an association between leukaemia and employment in the shoe and boot manufacturing industry, were not statistically conclusive due mainly to limited study power. Several additional limitations may also have prevented the observance of more conclusive findings. Better exposure assessment, information on length of exposure and types of job held, control of confounding factors and information on chemicals used by this company would strengthen any future investigation

High Purcell factor generation of indistinguishable on-chip single photons

On-chip single-photon sources are key components for integrated photonic quantum technologies. Semiconductor quantum dots can exhibit near-ideal single-photon emission, but this can be significantly degraded in on-chip geometries owing to nearby etched surfaces. A long-proposed solution to improve the indistinguishablility is to use the Purcell effect to reduce the radiative lifetime. However, until now only modest Purcell enhancements have been observed. Here we use pulsed resonant excitation to eliminate slow relaxation paths, revealing a highly Purcell-shortened radiative lifetime (22.7 ps) in a waveguide-coupled quantum dot–photonic crystal cavity system. This leads to near-lifetime-limited single-photon emission that retains high indistinguishablility (93.9%) on a timescale in which 20 photons may be emitted. Nearly background-free pulsed resonance fluorescence is achieved under π-pulse excitation, enabling demonstration of an on-chip, on-demand single-photon source with very high potential repetition rates

Mutations in the Catalytic Loop HRD Motif Alter the Activity and Function of Drosophila Src64

The catalytic loop HRD motif is found in most protein kinases and these amino acids are predicted to perform functions in catalysis, transition to, and stabilization of the active conformation of the kinase domain. We have identified mutations in a Drosophila src gene, src64, that alter the three HRD amino acids. We have analyzed the mutants for both biochemical activity and biological function during development. Mutation of the aspartate to asparagine eliminates biological function in cytoskeletal processes and severely reduces fertility, supporting the amino acid's critical role in enzymatic activity. The arginine to cysteine mutation has little to no effect on kinase activity or cytoskeletal reorganization, suggesting that the HRD arginine may not be critical for coordinating phosphotyrosine in the active conformation. The histidine to leucine mutant retains some kinase activity and biological function, suggesting that this amino acid may have a biochemical function in the active kinase that is independent of its side chain hydrogen bonding interactions in the active site. We also describe the phenotypic effects of other mutations in the SH2 and tyrosine kinase domains of src64, and we compare them to the phenotypic effects of the src64 null allele