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JG Hansen W Gao J Dupuis GT O’Connor W Tang M Kowgier A Sood SA Gharib LJ Palmer M Fornage SR Heckbert BM Psaty SL Booth SUNLIGHT Consortium Patricia A Cassano 《Respiratory research》2015,16(1)
Background
Vitamin D is associated with lung function in cross-sectional studies, and vitamin D inadequacy is hypothesized to play a role in the pathogenesis of chronic obstructive pulmonary disease. Further data are needed to clarify the relation between vitamin D status, genetic variation in vitamin D metabolic genes, and cross-sectional and longitudinal changes in lung function in healthy adults.Methods
We estimated the association between serum 25-hydroxyvitamin D [25(OH)D] and cross-sectional forced expiratory volume in the first second (FEV1) in Framingham Heart Study (FHS) Offspring and Third Generation participants and the association between serum 25(OH)D and longitudinal change in FEV1 in Third Generation participants using linear mixed-effects models. Using a gene-based approach, we investigated the association between 241 SNPs in 6 select vitamin D metabolic genes in relation to longitudinal change in FEV1 in Offspring participants and pursued replication of these findings in a meta-analyzed set of 4 independent cohorts.Results
We found a positive cross-sectional association between 25(OH)D and FEV1 in FHS Offspring and Third Generation participants (P = 0.004). There was little or no association between 25(OH)D and longitudinal change in FEV1 in Third Generation participants (P = 0.97). In Offspring participants, the CYP2R1 gene, hypothesized to influence usual serum 25(OH)D status, was associated with longitudinal change in FEV1 (gene-based P < 0.05). The most significantly associated SNP from CYP2R1 had a consistent direction of association with FEV1 in the meta-analyzed set of replication cohorts, but the association did not reach statistical significance thresholds (P = 0.09).Conclusions
Serum 25(OH)D status was associated with cross-sectional FEV1, but not longitudinal change in FEV1. The inconsistent associations may be driven by differences in the groups studied. CYP2R1 demonstrated a gene-based association with longitudinal change in FEV1 and is a promising candidate gene for further studies.Electronic supplementary material
The online version of this article (doi:10.1186/s12931-015-0238-y) contains supplementary material, which is available to authorized users. 相似文献3.
Temperature Adaptation of Active Sodium-Potassium Transport and of Passive Permeability in Erythrocytes of Ground Squirrels 下载免费PDF全文
Unidirectional active and passive fluxes of 42K and 24Na were measured in red blood cells of ground squirrels (hibernators) and guinea pigs (nonhibernators). As temperature is lowered, "active" (ouabain-sensitive) K influx and Na efflux were more greatly diminished in guinea pig cells than in those of ground squirrels. The fraction of total K influx which is ouabain sensitive in red blood cells of ground squirrels was virtually constant at all temperatures, whereas it decreased abruptly in guinea pig cells as temperature was lowered. All the passive fluxes (i.e., Na influx, K efflux, and ouabain-insensitive K influx and Na efflux) decreased logarithmically with decrease in temperature in both species, but in ground squirrels the temperature dependence (Q10 2.5–3.0) was greater than in guinea pig (Q10 1.6–1.9). Thus, red blood cells of ground squirrel are able to resist loss of K and gain of Na at low temperature both because of relatively greater Na-K transport (than in cells of nonhibernators) and because of reduced passive leakage of ions. 相似文献
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We recently demonstrated that microsomes from nicardipine-treated rats will form cytochrome P450 3A (CYP3A) aggregates when incubated at 37 degrees C. CYP3A substrates inhibited the protein aggregation and subsequent degradation, suggesting that this process is important in substrate-mediated stabilization of CYP3A. In this paper, we demonstrate that oxidative stress is a key factor in the formation of CYP3A aggregates in incubated microsomes and in a reconstituted system with purified enzymes. Our data further suggest that the effects of oxidative stress are mediated by lipid hydroperoxides, which are efficiently metabolized by CYP3A. In the presence of substrate, the CYP3A-mediated lipid hydroperoxide metabolism is inhibited along with the associated protein aggregation. Therefore, these studies provide a mechanistic model of why CYP3A has a relatively short half-life and how substrates stabilize CYP3A. 相似文献
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Out of Africa and back again: nested cladistic analysis of human Y chromosome variation 总被引:18,自引:3,他引:15
Hammer MF; Karafet T; Rasanayagam A; Wood ET; Altheide TK; Jenkins T; Griffiths RC; Templeton AR; Zegura SL 《Molecular biology and evolution》1998,15(4):427-441
We surveyed nine diallelic polymorphic sites on the Y chromosomes of 1,544
individuals from Africa, Asia, Europe, Oceania, and the New World.
Phylogenetic analyses of these nine sites resulted in a tree for 10
distinct Y haplotypes with a coalescence time of approximately 150,000
years. The 10 haplotypes were unevenly distributed among human populations:
5 were restricted to a particular continent, 2 were shared between Africa
and Europe, 1 was present only in the Old World, and 2 were found in all
geographic regions surveyed. The ancestral haplotype was limited to African
populations. Random permutation procedures revealed statistically
significant patterns of geographical structuring of this paternal genetic
variation. The results of a nested cladistic analysis indicated that these
geographical associations arose through a combination of processes,
including restricted, recurrent gene flow (isolation by distance) and range
expansions. We inferred that one of the oldest events in the nested
cladistic analysis was a range expansion out of Africa which resulted in
the complete replacement of Y chromosomes throughout the Old World, a
finding consistent with many versions of the Out of Africa Replacement
Model. A second and more recent range expansion brought Asian Y chromosomes
back to Africa without replacing the indigenous African male gene pool.
Thus, the previously observed high levels of Y chromosomal genetic
diversity in Africa may be due in part to bidirectional population
movements. Finally, a comparison of our results with those from nested
cladistic analyses of human mtDNA and beta-globin data revealed different
patterns of inferences for males and females concerning the relative roles
of population history (range expansions) and population structure
(recurrent gene flow), thereby adding a new sex-specific component to
models of human evolution.
相似文献
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Summary Microsomal and soluble fractions of Pleurotus pulmonarius exhibited a reduced carbon monoxide difference spectrum with P450 maxima at 448nm and 450–452nm respectively. Substrate induced Type I spectra were observed on addition of benzo(a)pyrene to both fractions. Benzo(a)pyrene hydroxylation was measured using the aryl hydrocarbon hydroxylase assay and was observed to be P450 dependent as indicated by carbon monoxide inhibition together with the substrate binding characteristics. The activity of the fractions were observed to give Km of 200mM and 660mM and Vmax of 1.25 nmol/min/nmol P450 and 0.57 nmol/min/nmol P450 for the microsomal and cytosolic fractions respectively. 相似文献
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Hardies SC; Martin SL; Voliva CF; Hutchison CA d; Edgell MH 《Molecular biology and evolution》1986,3(2):109-125
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Ku protein binds broken DNA ends, triggering a double-strand DNA break repair pathway. The spatial arrangement of the two Ku subunits in the initial Ku-DNA complex, when the Ku protein first approaches the broken DNA end, is not well defined. We have investigated the geometry of the complex using a novel set of photocross-linking probes that force Ku protein to be constrained in position and orientation, relative to a single free DNA end. Results suggest that this complex is roughly symmetric and that both Ku subunits make contact with an approximately equal area of the DNA. The complex has a strongly preferred orientation, with Ku70-DNA backbone contacts located proximal and Ku80-DNA backbone contacts located distal to the free end. Ku70 also contacts functional groups in the major groove proximal to the free end. Ku80 apparently does not make major groove contacts. Results are consistent with a model where the Ku70 and Ku80 subunits contact the major and minor grooves of DNA, respectively. 相似文献
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The methyl group from S-adenosylmethionine (AdoMet) is transferred into hemoglobin without any evident involvement of an enzyme. There are multiple sites for incorporation of the methyl group into hemoglobin, since both and chains are methylated. The methyl linkages formed in hemoglobin are stable at both alkaline and acidicpH, and the reaction occurs optimally at slightly below neutralpH. Only a small fraction (2%) of hemoglobin tetramers are methylated under the conditions tested. Acid hydrolysis of [3H-methyl]-labeled hemoglobin and determination of phenylisothiocynate derivatives yields N-methyl lysine, which accounts for about one-half of the incorporated [3H-methyl] radioactivity. Other amino acids are methylated as well, with much of the remaining radioactivity being distributed among one or more of the side chains of histidine, cysteine, and arginine. Methyl group transfer to hemoglobin from AdoMet is slow and inefficient (k
cat/K
m5×10–2), but the reaction velocity tends toward a plateau with increasing AdoMet concentration in a manner suggesting that saturable binding of AdoMet onto hemoglobin is involved in methyl transfer. The velocity of hemoglobin methylation is inhibited by S-adenosylhomocysteine, the known end-product inhibitor of methyltransferases, a further indication that methyl group transfer involves binding and catalysis by a specific site (or sites) in the hemoglobin molecule. These observations may help to explain the known existence of methylated hemoglobins in erythrocyte. 相似文献
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Yan Lu Shulin/SL Li Shiguo/SG Zhu Yabin/YB Gong Jun/J Shi Ling/ L Xu 《Biological procedures online》2017,19(1):2
DNA/RNA methylation plays an important role in lung cancer initiation and progression. Liquid biopsy makes use of cells, nucleotides and proteins released from tumor cells into body fluids to help with cancer diagnosis and prognosis. Methylation of circulating tumor DNA (ctDNA) has gained increasing attention as biomarkers for lung cancer. Here we briefly introduce the biological basis and detection method of ctDNA methylation, and review various applications of methylated DNA in body fluids in lung cancer screening, diagnosis, prognosis, monitoring and treatment prediction. We also discuss the emerging role of RNA methylation as biomarkers for cancer. 相似文献