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91.
Bruna Gigante Rona J. Strawbridge Ilais Moreno Velasquez Zahra Golabkesh Angela Silveira Anuj Goel Damiano Baldassarre Fabrizio Veglia Elena Tremoli Robert Clarke Hugh Watkins Anders Hamsten Steve E. Humphries Ulf de Faire 《PloS one》2015,10(3)
Variants at the interleukin 6 receptor (IL6R) gene regulate inflammation and are associated with risk of coronary heart disease (CHD). The aim of the present study was to investigate the effects of IL6R haplotypes on circulating levels of inflammatory biomarkers and risk of CHD. We performed a discovery analysis in SHEEP, a myocardial infarction (MI) case control study (n = 2,774) and replicated our results in two large, independent European populations, PROCARDIS, a CHD case control study (n = 7,998), and IMPROVE (n = 3,711) a prospective cardiovascular cohort study. Two major haplotype blocks (rs12083537A/G and rs4075015A/T—block 1; and rs8192282G/A, rs4553185T/C, rs8192284A/C, rs4240872T/C and rs7514452T/C—block 2) were identified in the IL6R gene. IL6R haplotype associations with C-reactive protein (CRP), fibrinogen, IL6, soluble IL6R (sIL6R), IL6, IL8 and TNF-α in SHEEP, CRP and fibrinogen in PROCARDIS and CRP in IMPROVE as well as association with risk of MI and CHD, were analyzed by THESIAS. Haplotypes in block 1 were associated neither with circulating inflammatory biomarkers nor with the MI/CHD risk. Haplotypes in block 2 were associated with circulating levels of CRP, in all three study populations, with fibrinogen in SHEEP and PROCARDIS, with IL8 and sIL6Rin SHEEP and with a modest, non significant, increase (7%) in MI/CHD risk in the three populations studied. Our results indicate that IL6R haplotypes regulate the circulating levels of inflammatory biomarkers. Lack of association with the risk of CHD may be explained by the combined effect of SNPs with opposite effect on the CHD risk, the sample size as well as by structural changes affecting sIL6R stability in the circulation. 相似文献
92.
It appears advantageous for many non-human animals to store energy body fat extensively and efficiently because their food supply is more labile and less abundant than in their human counterparts. The level of adiposity in many of these species often shows predictable increases and decreases with changes in the season. These cyclic changes in seasonal adiposity in some species are triggered by changes in the photoperiod that are faithfully transduced into a biochemical signal through the nightly secretion of melatonin (MEL) via the pineal gland. Here, we focus primarily on the findings from the most commonly studied species showing seasonal changes in adiposity-Siberian and Syrian hamsters. The data to date are not compelling for a direct effect of MEL on white adipose tissue (WAT) and brown adipose tissue (BAT) despite some recent data to the contrary. Thus far, none of the possible hormonal intermediaries for the effects of MEL on seasonal adiposity appear likely as a mechanism by which MEL affects the photoperiodic control of body fat levels indirectly. We also provide evidence pointing toward the sympathetic nervous system as a likely mediator of the effects of MEL on short day-induced body fat decreases in Siberian hamsters through increases in sympathetic drive on WAT and BAT. We speculate that decreases in the SNS drive to these tissues may underlie the photoperiod-induced seasonal increases in body fat of species such as Syrian hamsters. Clearly, we need to deepen our understanding of seasonal adiposity, although, to our knowledge, this is the only form of environmentally induced changes in body fat where the key elements of its external trigger have been identified and can be traced to and through their transduction into a physiological stimulus that ultimately affects identified responses of white adipocyte physiology and cellularity. Finally, the comparative physiological approach to the study of seasonal adiposity seems likely to continue to yield significant insights into the mechanisms underlying this phenomenon and for understanding obesity and its reversal in general. 相似文献
93.
Episomal persistence of recombinant adenoviral vector genomes during the cell cycle in vivo 下载免费PDF全文
Previously we showed that recombinant adenoviral helper-dependent (HD) vectors result in long-term transgene expression levels in vivo which slowly declined by 95% over a period of 1 year. In this study, we further establish that this was not predominantly immune mediated. To determine if cell turnover was responsible for the loss of transgene expression, we induced rapid hepatocyte cell cycling in mouse liver, by performing a surgical two-thirds partial hepatectomy. We observed a 55 and 65% reduction in transgene expression levels and a 50 and 71% loss of vector genomes for the HD vector and the first-generation adenoviral vector. In sharp contrast, in nonviral, episomal plasmid DNA-injected mice, transgene expression levels and DNA copy numbers decreased by 95 and 99%, respectively. These findings suggest that cell division alone was not the primary reason for the slow decrease in transgene expression levels and that recombinant adenoviral vectors have a more robust mechanism for maintaining persistence during cell cycling. Several potential mechanisms are proposed. 相似文献
94.
95.
96.
Frank Lovering Steve Kirincich Weiheng Wang Kerry Combs Lynn Resnick Joan E. Sabalski John Butera Julie Liu Kevin Parris J.B. Telliez 《Bioorganic & medicinal chemistry》2009,17(9):3342-3351
A novel series of inhibitors for mitogen activated protein kinase-activated protein kinase 2 (MK-2) are reported. These squarate based inhibitors were identified via a high-throughput screen. An MK2 co-structure with the starting ligand was obtained and a structure based approach was followed to optimize potency and selectivity. 相似文献
97.
Simulation and experiment have been used to establish that significant artifacts can be generated in X-pulse CPMG relaxation dispersion experiments recorded on heteronuclear ABX spin-systems, such as 13C
i
–13C
j
–1H, where 13C
i
and 13C
j
are strongly coupled. A qualitative explanation of the origin of these artifacts is presented along with a simple method
to significantly reduce them. An application to the measurement of 1H CPMG relaxation dispersion profiles in an HIV-2 TAR RNA molecule where all ribose sugars are protonated at the 2′ position,
deuterated at all other sugar positions and 13C labeled at all sugar carbons is presented to illustrate the problems that strong 13C–13C coupling introduces and a simple solution is proposed. 相似文献
98.
Cristina E. Tognon Heather E. Kirk Lori A. Passmore Ian P. Whitehead Channing J. Der Robert J. Kay 《Molecular and cellular biology》1998,18(12):6995-7008
As part of a cDNA library screen for clones that induce transformation of NIH 3T3 fibroblasts, we have isolated a cDNA encoding the murine homolog of the guanine nucleotide exchange factor RasGRP. A point mutation predicted to prevent interaction with Ras abolished the ability of murine RasGRP (mRasGRP) to transform fibroblasts and to activate mitogen-activated protein kinases (MAP kinases). MAP kinase activation via mRasGRP was enhanced by coexpression of H-, K-, and N-Ras and was partially suppressed by coexpression of dominant negative forms of H- and K-Ras. The C terminus of mRasGRP contains a pair of EF hands and a C1 domain which is very similar to the phorbol ester- and diacylglycerol-binding C1 domains of protein kinase Cs. The EF hands could be deleted without affecting the ability of mRasGRP to transform NIH 3T3 cells. In contrast, deletion of the C1 domain or an adjacent cluster of basic amino acids eliminated the transforming activity of mRasGRP. Transformation and MAP kinase activation via mRasGRP were restored if the deleted C1 domain was replaced either by a membrane-localizing prenylation signal or by a diacylglycerol- and phorbol ester-binding C1 domain of protein kinase C. The transforming activity of mRasGRP could be regulated by phorbol ester when serum concentrations were low, and this effect of phorbol ester was dependent on the C1 domain of mRasGRP. The C1 domain could also confer phorbol myristate acetate-regulated transforming activity on a prenylation-defective mutant of K-Ras. The C1 domain mediated the translocation of mRasGRP to cell membranes in response to either phorbol ester or serum stimulation. These results suggest that the primary mechanism of activation of mRasGRP in fibroblasts is through its recruitment to diacylglycerol-enriched membranes. mRasGRP is expressed in lymphoid tissues and the brain, as well as in some lymphoid cell lines. In these cells, RasGRP has the potential to serve as a direct link between receptors which stimulate diacylglycerol-generating phospholipase Cs and the activation of Ras. 相似文献
99.
Daiwen Yang Ronald A. Venters Geoffrey A. Mueller W.Y. Choy Lewis E. Kay 《Journal of biomolecular NMR》1999,14(4):333-343
HNCO-based 3D pulse schemes are presented for measuring 1HN-15N,15N-13CO, 1HN-13CO,13CO-13C and 1HN-13C dipolar couplings in 15N,13C,2-labeled proteins. The experiments are based on recently developed TROSY methodology for improving spectral resolution and sensitivity. Data sets recorded on a complex of Val, Leu, Ile (1 only) methyl protonated 15N,13C,2H-labeled maltose binding protein and -cyclodextrin as well as 15N,13C,2H-labeled human carbonic anhydrase II demonstrate that precise dipolar couplings can be obtained on proteins in the 30–40 kDa molecular weight range. These couplings will serve as powerful restraints for obtaining global folds of highly deuterated proteins. 相似文献
100.
Gustavo Boitt Amanda Black Steve A. Wakelin Richard W. McDowell Leo M. Condron 《Plant and Soil》2018,427(1-2):163-174