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901.
902.
DNA methylation affects nuclear organization, histone modifications, and linker histone binding but not chromatin compaction 总被引:5,自引:0,他引:5
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Gilbert N Thomson I Boyle S Allan J Ramsahoye B Bickmore WA 《The Journal of cell biology》2007,177(3):401-411
DNA methylation has been implicated in chromatin condensation and nuclear organization, especially at sites of constitutive heterochromatin. How this is mediated has not been clear. In this study, using mutant mouse embryonic stem cells completely lacking in DNA methylation, we show that DNA methylation affects nuclear organization and nucleosome structure but not chromatin compaction. In the absence of DNA methylation, there is increased nuclear clustering of pericentric heterochromatin and extensive changes in primary chromatin structure. Global levels of histone H3 methylation and acetylation are altered, and there is a decrease in the mobility of linker histones. However, the compaction of both bulk chromatin and heterochromatin, as assayed by nuclease digestion and sucrose gradient sedimentation, is unaltered by the loss of DNA methylation. This study shows how the complete loss of a major epigenetic mark can have an impact on unexpected levels of chromatin structure and nuclear organization and provides evidence for a novel link between DNA methylation and linker histones in the regulation of chromatin structure. 相似文献
903.
Short AD Catchpole B Kennedy LJ Barnes A Fretwell N Jones C Thomson W Ollier WE 《The Journal of heredity》2007,98(5):518-525
Canine diabetes is a complex genetic disease of unknown aetiology. It affects 0.005-1.5% of the canine population and shows a clear breed predisposition with the Samoyed being at high risk and the Boxer being at low risk of developing the disease. Canine diabetes is considered to be a disease homologue for human type 1 diabetes (T1D). It results in insulin deficiency as a consequence of autoimmune destruction of islet beta-cells in the pancreas and is believed to be mediated by Th1 cytokines (IFNgamma, TNFalpha, and IL-2). A number of genes have been associated with type 1 diabetes in humans, including the human leukocyte antigen region, the insulin variable number tandem repeat, PTPN22, CTLA4, IL-4, and IL-13. As yet, these genes have not been evaluated in canine diabetes. In this study, 483 cases of canine diabetes and 869 controls of known breed were analyzed for association with IFNgamma, IGF2, IL-10, IL-12beta, IL-6, insulin, PTPN22, RANTES, IL-4, IL-1alpha and TNFalpha. Minor allele frequencies were determined for these genes in each breed. These data were used for comparative analyses in a case-control study, and clear associations with diabetes were identified in some breeds with certain alleles of candidate genes. Some associations were with increased susceptibility to the disease (IFNgamma, IL-10, IL-12beta, IL-6, insulin, PTPN22, IL-4, and TNFalpha), whereas others were protective (IL-4, PTPN22, IL-6, insulin, IGF2, TNFalpha). This study demonstrates that a number of the candidate genes previously associated with human T1D also appear to be associated with canine diabetes and identifies an IL-10 haplotype which is associated with diabetes in the Cavalier King Charles Spaniel. This suggests that canine diabetes is an excellent comparative and spontaneously occurring disease model of human T1D. 相似文献
904.
Turnquist HR Raimondi G Zahorchak AF Fischer RT Wang Z Thomson AW 《Journal of immunology (Baltimore, Md. : 1950)》2007,178(11):7018-7031
The ability of dendritic cells (DC) to regulate Ag-specific immune responses via their influence on T regulatory cells (Treg) may be key to their potential as therapeutic tools or targets for the promotion/restoration of tolerance. In this report, we describe the ability of maturation-resistant, rapamycin (RAPA)-conditioned DC, which are markedly impaired in Foxp3(-) T cell allostimulatory capacity, to favor the stimulation of murine alloantigen-specific CD4(+)CD25(+)Foxp3(+) Treg. This was distinct from control DC, especially following CD40 ligation, which potently expanded non-Treg. RAPA-DC-stimulated Treg were superior alloantigen-specific suppressors of T effector responses compared with those stimulated by control DC. Supporting the ability of RAPA to target effector T and B cells, but permit the proliferation and suppressive function of Treg, an infusion of recipient-derived alloantigen-pulsed RAPA-DC followed by a short postoperative course of low-dose RAPA promoted indefinite (>100 day) heart graft survival. This was associated with graft infiltration by CD4(+)Foxp3(+) Treg and the absence of transplant vasculopathy. The adoptive transfer of CD4(+) T cells from animals with long-surviving grafts conferred resistance to rejection. These novel findings demonstrate that, whereas maturation resistance does not impair the capacity of RAPA-DC to modulate Treg, it profoundly impairs their ability to expand T effector cells. A demonstration of this mechanism endorses their potential as tolerance-promoting cellular vaccines. 相似文献
905.
We have previously shown that mice carrying the K644E kinase domain mutation in fibroblast growth factor receptor 3 (Fgfr3) (EIIa;Fgfr3(+/K644E)) have enlarged brains with increased proliferation and decreased apoptosis of the cortical progenitors. Despite its unique rostral-low caudal-high gradient expression in the cortex, how Fgfr3 temporally and spatially influences progenitor proliferation is unknown. In vivo BrdU labelling now showed that progenitor proliferation was 10-46% higher in the EIIa;Fgfr3(+/K644E) cortex compared with wild type during embryonic day 11.5 (E11.5)-E13.5. The difference in proliferation between the EIIa;Fgfr3(+/K644E) and wild-type cortices was the greatest in the caudal cortex at E12.5 and E13.5. Inhibition of mitogen-activated or extracellular signal-regulated protein kinase (MEK) in vitro at E11.5 reduced the proliferation rate of the EIIa;Fgfr3(+/K644E) cortical progenitors to similar levels observed in the wild type, indicating that the majority of the increase in cell proliferation caused by the Fgfr3 mutation is mitogen-activated protein kinase (MAPK) pathway-dependent at this stage. In addition, elevated levels of Sprouty were observed in the EIIa;Fgfr3(+/K644E) telencephalon at E14.5, indicating the presence of negative feedback that may have suppressed further MAPK activation. We suggest that temporal activation of MAPK is largely responsible for cell proliferation caused by the Fgfr3 mutation during early stages of cortical development. 相似文献
906.
In socially living animals, individuals interact through complex networks of contact that may influence the spread of disease.
Whereas traditional epidemiological models typically assume no social structure, network theory suggests that an individual’s
location in the network determines its risk of infection. Empirical, especially experimental, studies of disease spread on
networks are lacking, however, largely due to a shortage of amenable study systems. We used automated video-tracking to quantify
networks of physical contact among individuals within colonies of the social bumble bee Bombus impatiens. We explored the effects of network structure on pathogen transmission in naturally and artificially infected hives. We show
for the first time that contact network structure determines the spread of a contagious pathogen (Crithidia bombi) in social insect colonies. Differences in rates of infection among colonies resulted largely from differences in network
density among hives. Within colonies, a bee’s rate of contact with infected nestmates emerged as the only significant predictor
of infection risk. The activity of bees, in terms of their movement rates and division of labour (e.g., brood care, nest care,
foraging), did not influence risk of infection. Our results suggest that contact networks may have an important influence
on the transmission of pathogens in social insects and, possibly, other social animals. 相似文献
907.
908.
909.
Soils that contain toxic amounts of minerals or are deficient in essential plant nutrients are widespread globally and seriously
constrain rice production. New methods are necessary to incorporate the complex adaptive traits associated with tolerance
of these abiotic stresses, while simultaneously retaining the high yield potential of rice varieties when conditions are favorable.
Significant progress in the genetic characterization of stress response pathways and recent advances in genomics have provided
powerful tools for in-depth dissection of tolerance mechanisms. Additionally, tolerance of most of these abiotic stresses
in rice is controlled by a few QTLs with large effects despite the intricacy of the numerous traits involved. Genetic dissection
of these QTLs and their incorporation into high-yielding varieties will significantly enhance and stabilize rice productivity
in these problem soils. Current efforts at IRRI and in rice breeding programs worldwide are seeking to explore diverse germplasm
collections and genetically dissect the causal mechanisms of tolerance to facilitate their use in breeding. This review focuses
on salinity and P and Zn deficiency as the major problems encountered in rice soils, and examines current understanding of
the mechanisms involved and efforts toward germplasm improvement. 相似文献
910.
Thomson P Naylor MA Stratford MR Lewis G Hill S Patel KB Wardman P Davis PD 《Bioorganic & medicinal chemistry letters》2007,17(15):4320-4322
A novel bioreductive prodrug of 6-thioguanine, 2-amino-6-[2-(4-nitrophenyl)prop-2-ylsulfanyl]-9H-purine, containing a gem-dimethyl thioether linkage, was synthesised and compared with its unsubstituted analogue. In A549 whole cell experiments hypoxia selective release of 6-thioguanine was observed with the substituted prodrug only. 相似文献