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721.
Nenad Manevski Johanna Troberg Paolo Svaluto-Moreolo Klaudyna Dziedzic Jari Yli-Kauhaluoma Moshe Finel 《PloS one》2013,8(1)
Human UDP-glucuronosyltransferases (UGTs) are important enzymes in metabolic elimination of endo- and xenobiotics. It was recently shown that addition of fatty acid free bovine serum albumin (BSA) significantly enhances in vitro activities of UGTs, a limiting factor in in vitro–in vivo extrapolation. Nevertheless, since only few human UGT enzymes were tested for this phenomenon, we have now performed detailed enzyme kinetic analysis on the BSA effects in six previously untested UGTs, using 2–4 suitable substrates for each enzyme. We also examined some of the previously tested UGTs, but using additional substrates and a lower BSA concentration, only 0.1%. The latter concentration allows the use of important but more lipophilic substrates, such as estradiol and 17-epiestradiol. In five newly tested UGTs, 1A7, 1A8, 1A10, 2A1, and 2B15, the addition of BSA enhanced, to a different degree, the in vitro activity by either decreasing reaction’s K
m, increasing its V
max, or both. In contrast, the activities of UGT2B17, another previously untested enzyme, were almost unaffected. The results of the assays with the previously tested UGTs, 1A1, 1A6, 2B4, and 2B7, were similar to the published BSA only as far as the BSA effects on the reactions’ K
m are concerned. In the cases of V
max values, however, our results differ significantly from the previously published ones, at least with some of the substrates. Hence, the magnitude of the BSA effects appears to be substrate dependent, especially with respect to V
max increases. Additionally, the BSA effects may be UGT subfamily dependent since K
m decreases were observed in members of subfamilies 1A, 2A and 2B, whereas large V
max increases were only found in several UGT1A members. The results shed new light on the complexity of the BSA effects on the activity and enzyme kinetics of the human UGTs. 相似文献
722.
Nathalie Acevedo Annika S??f Cilla S?derh?ll Erik Melén Jami Mandelin Christina Orsmark Pietras Sini Ezer Piia Karisola Johanna Vendelin Gustav Boije af Genn?s Jari Yli-Kauhaluoma Harri Alenius Erika von Mutius Gert Doekes Charlotte Braun-Fahrl?nder Josef Riedler Marianne van Hage Mauro D’Amato Annika Scheynius G?ran Pershagen Juha Kere Ville Pulkkinen 《PloS one》2013,8(4)
Retinoid acid receptor-related Orphan Receptor Alpha (RORA) was recently identified as a susceptibility gene for asthma in a genome-wide association study. To investigate the impact of RORA on asthma susceptibility, we performed a genetic association study between RORA single nucleotide polymorphisms (SNPs) in the vicinity of the asthma-associated SNP (rs11071559) and asthma-related traits. Because the regulatory region of a previously implicated asthma susceptibility gene, Neuropeptide S receptor 1 (NPSR1), has predicted elements for RORA binding, we hypothesized that RORA may interact biologically and genetically with NPSR1. 37 RORA SNPs and eight NPSR1 SNPs were genotyped in the Swedish birth cohort BAMSE (2033 children) and the European cross-sectional PARSIFAL study (1120 children). Seven RORA SNPs confined into a 49 kb region were significantly associated with physician-diagnosed childhood asthma. The most significant association with rs7164773 (T/C) was driven by the CC genotype in asthma cases (OR = 2.0, 95%CI 1.36–2.93, p = 0.0003 in BAMSE; and 1.61, 1.18–2.19, p = 0.002 in the combined BAMSE-PARSIFAL datasets, respectively), and strikingly, the risk effect was dependent on the Gln344Arg mutation in NPSR1. In cell models, stimulation of NPSR1 activated a pathway including RORA and other circadian clock genes. Over-expression of RORA decreased NPSR1 promoter activity further suggesting a regulatory loop between these genes. In addition, Rora mRNA expression was lower in the lung tissue of Npsr1 deficient mice compared to wildtype littermates during the early hours of the light period. We conclude that RORA SNPs are associated with childhood asthma and show epistasis with NPSR1, and the interaction between RORA and NPSR1 may be of biological relevance. Combinations of common susceptibility alleles and less common functional polymorphisms may modify the joint risk effects on asthma susceptibility. 相似文献
723.
Atherogenic, enlarged, and dysfunctional HDL in human PLTP/apoA-I double transgenic mice 总被引:1,自引:0,他引:1
Moerland M Samyn H van Gent T Jauhiainen M Metso J van Haperen R Grosveld F van Tol A de Crom R 《Journal of lipid research》2007,48(12):2622-2631
In low density lipoprotein receptor (LDLR)-deficient mice, overexpression of human plasma phospholipid transfer protein (PLTP) results in increased atherosclerosis. PLTP strongly decreases HDL levels and might alter the antiatherogenic properties of HDL particles. To study the potential interaction between human PLTP and apolipoprotein A-I (apoA-I), double transgenic animals (hPLTPtg/hApoAItg) were compared with hApoAItg mice. PLTP activity was increased 4.5-fold. Plasma total cholesterol and phospholipid were decreased. Average HDL size (analyzed by gel filtration) increased strongly, hPLTPtg/hApoAItg mice having very large, LDL-sized, HDL particles. Also, after density gradient ultracentrifugation, a substantial part of the apoA-I-containing lipoproteins in hPLTPtg/hApoAItg mice was found in the LDL density range. In cholesterol efflux studies from macrophages, HDL isolated from hPLTPtg/hApoAItg mice was less efficient than HDL isolated from hApoAItg mice. Furthermore, it was found that the largest subfraction of the HDL particles present in hPLTPtg/hApoAItg mice was markedly inferior as a cholesterol acceptor, as no labeled cholesterol was transferred to this fraction. In an LDLR-deficient background, the human PLTP-expressing mouse line showed a 2.2-fold increased atherosclerotic lesion area. These data demonstrate that the action of human PLTP in the presence of human apoA-I results in the formation of a dysfunctional HDL subfraction, which is less efficient in the uptake of cholesterol from cholesterol-laden macrophages. 相似文献
724.
Fucosylated glycoconjugates play a role in a wide variety of biological processes, including immune responses, signal transduction, ontogenic events and pathogenesis of several human diseases. Alpha-L-fucosidases, which are responsible for their processing, have been demonstrated to be involved in lysosomal storage disease, inflammation, cystic fibrosis, cancer development and in the interactions between gametes in vertebrates as well as invertebrates. The sequence and comparative genomic analysis of these glycosyl hydrolases and the study of their evolutionary relationships appear therefore to be of considerable interest. In this work we carried out extensive similarity searches and comparative analyses to identify sequences encoding alpha-L-fucosidases. We have identified novel alpha-L-fucosidase coding sequences in worms, insects, sea urchin, ascidians, fish, chicken, amphibians, mammals and various bacteria resulting in a total of 39 alpha-L-fucosidase sequences. Two alpha-L-fucosidases that are present in all vertebrates likely reflect a distinct biological role for paralogous genes. Comparative sequence analysis of all metazoan alpha-L-fucosidases reveals a broad conservation of features, including the aspartate residue that constitutes the catalytic nucleophile. However, a cysteine which is thought to be part of the active site is also conserved in metazoa but not in arthropods, where it is replaced by an alanine. Phylogenetic analysis suggests a gene duplication event very early in metazoan evolution with the subsequent differential loss of isoforms in various metazoan lineages. 相似文献
725.
Tissue heterogeneity, radioactive decay and measurement noise are the main error sources in compartmental modeling used to
estimate the physiologic rate constants of various radiopharmaceuticals from a dynamic PET study. We introduce a new approach
to this problem by modeling the tissue heterogeneity with random rate constants in compartment models. In addition, the Poisson
nature of the radioactive decay is included as a Poisson random variable in the measurement equations. The estimation problem
will be carried out using the maximum likelihood estimation. With this approach, we do not only get accurate mean estimates
for the rate constants, but also estimates for tissue heterogeneity within the region of interest and other possibly unknown
model parameters, e.g. instrument noise variance, as well. We also avoid the problem of the optimal weighting of the data
related to the conventionally used weighted least-squares method. The new approach was tested with simulated time–activity
curves from the conventional three compartment – three rate constants model with normally distributed rate constants and with
a noise mixture of Poisson and normally distributed random variables. Our simulation results showed that this new model gave
accurate estimates for the mean of the rate constants, the measurement noise parameter and also for the tissue heterogeneity,
i.e. for the variance of the rate constants within the region of interest. 相似文献
726.
Jari Ilmonen 《ZooKeys》2014,(441):91-95
A checklist of the family Simuliidae (Diptera) is provided for Finland and recognizes 56 species. One new record has been added (Simulium
latipes) and one name sunken in synonymy (Simulium
carpathicum). Furthermore, Simulium
tsheburovae is treated as a doubtful record. 相似文献
727.
728.
Salla T. Jaakkola Karolin Zerulla Qinggong Guo Ying Liu Hongling Ma Chunhe Yang Dennis H. Bamford Xiangdong Chen J?rg Soppa Hanna M. Oksanen 《PloS one》2014,9(10)
Live bacteria and archaea have been isolated from several rock salt deposits of up to hundreds of millions of years of age from all around the world. A key factor affecting their longevity is the ability to keep their genomic DNA intact, for which efficient repair mechanisms are needed. Polyploid microbes are known to have an increased resistance towards mutations and DNA damage, and it has been suggested that microbes from deeply buried rock salt would carry several copies of their genomes. Here, cultivable halophilic microbes were isolated from a surface sterilized middle-late Eocene (38–41 million years ago) rock salt sample, drilled from the depth of 800 m at Yunying salt mine, China. Eight unique isolates were obtained, which represented two haloarchaeal genera, Halobacterium and Halolamina. We used real-time PCR to show that our isolates are polyploid, with genome copy numbers of 11–14 genomes per cell in exponential growth phase. The ploidy level was slightly downregulated in stationary growth phase, but the cells still had an average genome copy number of 6–8. The polyploidy of halophilic archaea living in ancient rock salt might be a factor explaining how these organisms are able to overcome the challenge of prolonged survival during their entombment. 相似文献
729.
Objective
To examine whether workplace social capital improved after implementing a workplace social capital intervention in community health centers in China.Methods
This study was conducted in 20 community health centers of similar size in Jinan of China during 2012–2013. Using the stratified site randomization, 10 centers were randomized into the intervention group; one center was excluded due to leadership change in final analyses. The baseline survey including 447 staff (response rate: 93.1%) was conducted in 2012, and followed by a six-month workplace social capital intervention, including team building courses for directors of community health centers, voluntarily public services, group psychological consultation, and outdoor training. The follow-up survey in July 2013 was responded to by 390 staff members (response rate: 86.9%). Workplace social capital was assessed with the translated and culturally adapted scale, divided into vertical and horizontal dimensions. The facility-level intervention effects were based on all baseline (n = 427) and follow-up (n = 377) respondents, except for Weibei respondents. We conducted a bivariate Difference-in-Difference analysis to estimate the facility-level intervention effects.Results
No statistically significant intervention effects were observed at the center level; the intervention increased the facility-level workplace social capital, and its horizontal and vertical dimensions by 1.0 (p = 0.24), 0.4 (p = 0.46) and 0.8 (p = 0.16), respectively.Conclusions
The comprehensive intervention seemed to slightly improve workplace social capital in community health centers of urban China at the center level. High attrition rate limits any causal interpretation of the results. Further studies are warranted to test these findings. 相似文献730.
Early exposure to steroid hormones can permanently and dramatically alter neural development. This is best understood in the organizational effects of hormones during development of brain regions involved in reproductive behaviors or neuroendocrine function. However, recent evidence strongly suggests that steroid hormones play a vital role in shaping brain regions involved in cognitive behavior such as the cerebral cortex. The most abundantly expressed steroid hormone receptor in the developing rodent cortex is the progesterone receptor (PR). In the rat, PR is initially expressed in the developmentally‐critical subplate at E18, and subsequently in laminas V and II/III through the first three postnatal weeks (Quadros et al. [2007] J Comp Neurol 504:42–56; Lopez & Wagner [2009]: J Comp Neurol 512:124–139), coinciding with significant periods of dendritic maturation, the arrival of afferents and synaptogenesis. In the present study, we investigated PR expression in the neonatal mouse somatosensory cortex. Additionally, to investigate the potential role of PR in developing cortex, we examined sensorimotor function in the first two postnatal weeks in PR knockout mice and their wildtype (WT) and heterozygous (HZ) counterparts. While the three genotypes were similar in most regards, PRKO and HZ mice lost the rooting reflex 2–3 days earlier than WT mice. These studies represent the first developmental behavioral assessment of PRKO mice and suggest PR expression may play an important role in the maturation of cortical connectivity and sensorimotor integration. © 2013 Wiley Periodicals, Inc. Develop Neurobiol 74: 16–24, 2014 相似文献