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101.
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The wizards and the gatekeepers were unhappy. There were many reasons for their unhappiness. They worked hard but felt that too much was being demanded of them. The poorly people''s charter was resulting in unrealistic expectations, and changes in the apprenticeship for wizards were putting great strain on their mentors. The wizards enjoyed their work less and less, and it was getting difficult to find new gatekeepers. On the other hand, the way the system worked meant that there had to be plenty of goblins and the number of scrolls that had to be filled in was rising sharply. The wizards and gatekeepers tried to point out ways to improve things that would ensure that poorly people were better treated, but there was no easy solution. With the ominous sign that the recruitment of wizards and gatekeepers was becoming more difficult, an answer was needed--and soon. 相似文献
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Henri S. Tapp Daniel M. Commane D. Michael Bradburn Ramesh Arasaradnam John C. Mathers Ian T. Johnson Nigel J. Belshaw 《Aging cell》2013,12(1):148-155
Aberrant methylation of CpG islands (CGI) occurs in many genes expressed in colonic epithelial cells, and may contribute to the dysregulation of signalling pathways associated with carcinogenesis. This cross‐sectional study assessed the relative importance of age, nutritional exposures and other environmental factors in the development of CGI methylation. Rectal biopsies were obtained from 185 individuals (84 male, 101 female) shown to be free of colorectal disease, and for whom measurements of age, body size, nutritional status and blood cell counts were available. We used quantitative DNA methylation analysis combined with multivariate modelling to investigate the relationships between nutritional, anthropometric and metabolic factors and the CGI methylation of 11 genes, together with LINE‐1 as an index of global DNA methylation. Age was a consistent predictor of CGI methylation for 9/11 genes but significant positive associations with folate status and negative associations with vitamin D and selenium status were also identified for several genes. There was evidence for positive associations with blood monocyte levels and anthropometric factors for some genes. In general, CGI methylation was higher in males than in females and differential effects of age and other factors on methylation in males and females were identified. In conclusion, levels of age‐related CGI methylation in the healthy human rectal mucosa are influenced by gender, the availability of folate, vitamin D and selenium, and perhaps by factors related to systemic inflammation. 相似文献
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Eduardo AVF Ramalho Jo?o LQ Silva-Filho Marina FS Cartaxo Carmelita BL Cavalcanti Moacyr JBM Rêgo Maria BM Oliveira Eduardo IC Beltr?o 《Biological research》2014,47(1)
Background
BRCA protein interacts with at least 13 different proteins that have been implicated with cancer susceptibility and loss of BRCA function is correlated to sensitivity to DNA crosslinking agents in preclinical models.Results
BRCA2 methylation frequency was 44%, p53 Pro22 allele frequency was 32% and heterozygous frequency of Arg/Pro72 genotype was 60% which could be associated as risk factor for metastasis (p = 0.046 OR = 4.190). Regarding to polymorphism of codon 249 the frequency of Arg249 allele presented 82% which was considered not statistically significant.Conclusions
There was not statistical significance to BRCA2 promoter methylation with any parameters chosen. However, our findings suggest that patients who present heterozygous genotype at codon 72 of p53 gene may have a major susceptibility to any type of metastasis and this could serve as potential auxiliary biomarker for poor prognosis. 相似文献106.
Caitríona E. McInerney Louise Maurice Anne L. Robertson Lee R. F. D. Knight Jörg Arnscheidt Chris Venditti James S. G. Dooley Thomas Mathers Severine Matthijs Karin Eriksson Graham S. Proudlove Bernd Hänfling 《Molecular ecology》2014,23(5):1153-1166
Global climate changes during the Cenozoic (65.5–0 Ma) caused major biological range shifts and extinctions. In northern Europe, for example, a pattern of few endemics and the dominance of wide‐ranging species is thought to have been determined by the Pleistocene (2.59–0.01 Ma) glaciations. This study, in contrast, reveals an ancient subsurface fauna endemic to Britain and Ireland. Using a Bayesian phylogenetic approach, we found that two species of stygobitic invertebrates (genus Niphargus) have not only survived the entire Pleistocene in refugia but have persisted for at least 19.5 million years. Other Niphargus species form distinct cryptic taxa that diverged from their nearest continental relative between 5.6 and 1.0 Ma. The study also reveals an unusual biogeographical pattern in the Niphargus genus. It originated in north‐west Europe approximately 87 Ma and underwent a gradual range expansion. Phylogenetic diversity and species age are highest in north‐west Europe, suggesting resilience to extreme climate change and strongly contrasting the patterns seen in surface fauna. However, species diversity is highest in south‐east Europe, indicating that once the genus spread to these areas (approximately 25 Ma), geomorphological and climatic conditions enabled much higher diversification. Our study highlights that groundwater ecosystems provide an important contribution to biodiversity and offers insight into the interactions between biological and climatic processes. 相似文献
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Valentine RA Jackson KA Christie GR Mathers JC Taylor PM Ford D 《The Journal of biological chemistry》2007,282(19):14389-14393
Zinc is an essential micronutrient, so it is important to elucidate the molecular mechanisms of zinc homeostasis, including the functional properties of zinc transporters. Mammalian zinc transporters are classified in two major families: the SLC30 (ZnT) family and the SLC39 family. The prevailing view is that SLC30 family transporters function to reduce cytosolic zinc concentration, either through efflux across the plasma membrane or through sequestration in intracellular compartments, and that SLC39 family transporters function in the opposite direction to increase cytosolic zinc concentration. We demonstrated that human ZnT5 variant B (ZnT5B (hZTL1)), an isoform expressed at the plasma membrane, operates in both the uptake and the efflux directions when expressed in Xenopus laevis oocytes. We measured increased activity of the zinc-responsive metallothionein 2a (MT2a) promoter when ZnT5b was co-expressed with an MT2a promoter-reporter plasmid construct in human intestinal Caco-2 cells, indicating increased total intracellular zinc concentration. Increased cytoplasmic zinc concentration mediated by ZnT5B, in the absence of effects on intracellular zinc sequestration by the Golgi apparatus or endoplasmic reticulum, was also confirmed by a dramatically enhanced signal from the zinc fluorophore Rhodzin-3 throughout the cytoplasm of Caco-2 cells overexpressing ZnT5B at the plasma membrane when compared with control cells. Our findings demonstrate clearly that, in addition to mediating zinc efflux, ZnT5B at the plasma membrane can function to increase cytoplasmic zinc concentration, thus indicating a need to reevaluate the current paradigm that SLC30 family zinc transporters operate exclusively to decrease cytosolic zinc concentration. 相似文献
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