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71.
Reppe S Stilgren L Abrahamsen B Olstad OK Cero F Brixen K Nissen-Meyer LS Gautvik KM 《American journal of physiology. Endocrinology and metabolism》2007,292(5):E1465-E1473
In primary hyperparathyroidism (PHPT), excess PTH secretion by adenomatous or hyperplastic parathyroid glands leads to elevated serum [Ca(2+)]. Patients present complex symptoms of muscular fatigue, various neuropsychiatric, neuromuscular, and cardiovascular manifestations, and, in advanced disease, kidney stones and metabolic bone disease. Our objective was to characterize changes in muscle and hematopoietic gene expression in patients with reversible mild PHPT after parathyroidectomy and possibly link molecular pathology to symptoms. Global mRNA profiling using Affymetrix gene chips was carried out in biopsies obtained before and 1 yr after parathyroidectomy in seven patients discovered by routine blood [Ca(2+)] screening. The tissue distribution of PTH receptor (PTHR1 and PTHR2) mRNAs were quantitated using real-time RT-PCR in unrelated persons to define PTH target tissues. Of about 10,000 expressed genes, 175 muscle, 169 hematological, and 99 bone-associated mRNAs were affected. Notably, the major part of muscle-related mRNAs was increased whereas hematological mRNAs were predominantly decreased during disease. Functional and molecular network analysis demonstrated major alterations of several tissue characteristic groups of mRNAs as well as those belonging to common cell signaling and major metabolic pathways. PTHR1 and PTHR2 mRNAs were more abundantly expressed in muscle and brain than in hematopoietic cells. We suggest that sustained stimulation of PTH receptors present in brain, muscle, and hematopoietic cells have to be considered as one independent, important cause of molecular disease in PHPT leading to profound alterations in gene expression that may help explain symptoms like muscle fatigue, cardiovascular pathology, and precipitation of psychiatric illness. 相似文献
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Olesen P Nguyen K Wogensen L Ledet T Rasmussen LM 《American journal of physiology. Heart and circulatory physiology》2007,292(2):H1058-H1064
Arterial medial calcifications occur often in diabetic individuals as part of the diabetic macroangiopathy. The pathogenesis is unknown, but the presence of calcifications predicts risk of cardiovascular events. We examined the effects of insulin on calcifying smooth muscle cells in vitro and measured the expression of the bone-related molecule osteoprotegerin (OPG). Human vascular smooth muscle cells (VSMCs) were grown from aorta from kidney donors. Induction of calcification was performed with beta-glycerophosphate. The influence of insulin (200 microU/ml or 1,000 microU/ml) on calcification was judged by measuring calcium content in the cell layer and by von Kossa staining. OPG was measured in the medium by ELISA. Histochemistry was used for determination of alkaline phosphatase (ALP). Bone sialoprotein (BSP) and OPG mRNA expressions were done by RT-PCR. beta-Glycerophosphate was able to induce calcification in human smooth muscle cells from a series of donors after variable time in culture. Decreased OPG amounts were observed from the cells during the accelerated calcification phase. High dose of insulin (1,000 microU/ml) accelerated the calcification, whereas lower concentrations (200 microU/ml) did not. Calcified cells expressed ALP and BSP activity in high levels. In conclusion, high concentration of insulin enhances in vitro-induced calcification in VSMCs. Altered OPG levels during the calcification raise the possibility that OPG may have a potent function in regulating the calcification process or it may represent a consequence of mineralization. Effects of insulin and modulations by OPG on the calcification process in arterial cells may play a role in the development of calcifications as part of the diabetic macroangiopathy. 相似文献
75.
Vajdos FF Hoth LR Geoghegan KF Simons SP LeMotte PK Danley DE Ammirati MJ Pandit J 《Protein science : a publication of the Protein Society》2007,16(5):897-905
Lasofoxifene is a new and potent selective estrogen receptor modulator (SERM). The structural basis of its interaction with the estrogen receptor has been investigated by crystallographic analysis of its complex with the ligand-binding domain of estrogen receptor alpha at a resolution of 2.0 A. As with other SERMs, lasofoxifene diverts the receptor from its agonist-bound conformation by displacing the C-terminal AF-2 helix into the site at which the LXXLL motif of coactivator proteins would otherwise be able to bind. Lasofoxifene achieves this effect by occupying the space normally filled by residue Leu 540, as well as by modulating the conformation of residues of helix 11 (His 524, Leu 525). A well-defined salt bridge between lasofoxifene and Asp 351 suggests that charge neutralization in this region of the receptor may explain the some of the antiestrogenic effects of lasofoxifene. The results suggest general features of ERalpha/SERM recognition, and add a new dimension to efforts to rationalize differences between the biological activity profiles exhibited by these important pharmacological agents. 相似文献
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Climate change is expected to bring about profound rearrangement of ecological communities by affecting individual species distributions. The resulting communities arise from the idiosyncratic responses of species to future changes, which ultimately relate to both shrinking and expanding species ranges. While spatial patterns of colonisation and extirpation events have received great attention, the identification of specific drivers remains poorly explored. This study aims to investigate the relative contribution of species gain and loss to the turnover of fish assemblages in French rivers under future climate change, and to identify their principal drivers. Future projections of potential habitat suitability in 2080 derived from species distribution models for 40 fish species showed that colonisations and extirpations could play counterbalancing roles in the reshuffling of communities. Simultaneously, these two processes exhibited patchy spatial patterns, segregated along the longitudinal and altitudinal gradients, resulting in dramatic species turnover of ~ 60% of the current composition of species assemblages. Beyond the effect of topographic location, colonisations were found to be driven by temperature seasonality while extirpations were affected by modifications in both thermal and precipitation regimes. These results generate the possibility of developing ecosystem‐based management tools focused on the early identification of areas where particular species may be sensitive to climate changes. Disentangling the drivers of colonisation and extirpation processes provides ready‐to‐use information that may be easily integrated into conservation planning. This information could be used to identify potential hotspots of species gain and loss and to then compare these hotspots with newly favourable areas so as to consider their actual accessibility in order to facilitate future range shifts. 相似文献
79.
Formalin fixation has been the standard method for conservation of clinical specimens for decades. However, a major drawback is the high degradation of nucleic acids, which complicates its use in genome-wide analyses. Unbiased identification of biomarkers, however, requires genome-wide studies, precluding the use of the valuable archives of specimens with long-term follow-up data. Therefore, restoration protocols for DNA from formalin-fixed and paraffin-embedded (FFPE) samples have been developed, although they are cost-intensive and time-consuming. An alternative to FFPE and snap-freezing is the PAXgene Tissue System, developed for simultaneous preservation of morphology, proteins, and nucleic acids. In the current study, we compared the performance of DNA from either PAXgene or formalin-fixed tissues to snap-frozen material for genome-wide DNA methylation analysis using the Illumina 450K BeadChip. Quantitative DNA methylation analysis demonstrated that the methylation profile in PAXgene-fixed tissues showed, in comparison with restored FFPE samples, a higher concordance with the profile detected in frozen samples. We demonstrate, for the first time, that DNA from PAXgene conserved tissue performs better compared with restored FFPE DNA in genome-wide DNA methylation analysis. In addition, DNA from PAXgene tissue can be directly used on the array without prior restoration, rendering the analytical process significantly more time- and cost-effective. 相似文献
80.
Nahla V Bassil Thomas M Davis Hailong Zhang Stephen Ficklin Mike Mittmann Teresa Webster Lise Mahoney David Wood Elisabeth S Alperin Umesh R Rosyara Herma Koehorst-vanc Putten Amparo Monfort Daniel J Sargent Iraida Amaya Beatrice Denoyes Luca Bianco Thijs van Dijk Ali Pirani Amy Iezzoni Dorrie Main Cameron Peace Yilong Yang Vance Whitaker Sujeet Verma Laurent Bellon Fiona Brew Raul Herrera Eric van de Weg 《BMC genomics》2015,16(1)