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81.
Pinto D Kasteleijn-Nolst Trenité DG Cordell HJ Mattheisen M Strauch K Lindhout D Koeleman BP 《Genetic epidemiology》2007,31(1):42-50
In traits suspected to be governed by at least two loci, linkage analysis incorporating the joint action of both loci may improve the power to detect linkage, increase the precision of estimating locus positions and provide insight into the underlying etiological mechanism. Recently, we mapped two susceptibility loci for epilepsy-related photosensitivity (or photoparoxysmal response, PPR) at regions 7q32 (PPR1) and 16p13 (PPR2) in PPR families with prominent myoclonic seizures background (MS-related PPR). To follow-up these results and evaluate interaction effects between these regions, we conducted two-locus (2L) linkage analyses using parametric and non-parametric methods. The 2L linkage was calculated under a multiplicative (MULT) epistasis model, encompassing models where each locus is necessary but not sufficient for MS-related PPR and a heterogeneity (HET) model, encompassing models in which each locus is by itself sufficient but not necessary for MS-related PPR expression. We found maximal 2L linkage under the (MULT) model, which was significantly better than the 2L linkage under the (HET) model (P = 0.001). The 2L analyses gave no increase in power to detect linkage over the single-locus analyses nor did they improve location estimates at PPR1 and PPR2, as expected under a best-fit 2L (MULT) model in an affecteds-only analysis. Our findings suggest that the genes underlying the PPR1 and PPR2 susceptibility loci may have similar functions or act in the same biochemical pathway. 相似文献
82.
Oliver Jansen Oliver Kamp Christian Waydhas Valentin Rausch Thomas Armin Schildhauer Justus Strauch Dirk Buchwald Uwe Hamsen 《Journal of artificial organs》2017,20(4):354-358
Acute respiratory distress syndrome (ARDS) is characterized as an acute hypoxemic and/or hypercapnic respiratory failure seen in critically ill patients and is still, although decreased over the past few years, associated with high mortality. Furthermore, ARDS may be a life-threatening complication of H1N1 pneumonia. We report on a 45-year-old spina bifida patient with confirmed H1N1 influenza virus infection causing acute respiratory failure, who was successfully weaned from 42-day veno-venous extracorporeal membrane oxygenation (vv-ECMO) treatment with an excellent outcome. Due to the physical constitution of spina bifida patients, we experienced challenges concerning cannula positioning and mechanical ventilation settings during weaning. 相似文献
83.
Renee C. Strauch Elisabeth Svedin Brian Dilkes Clint Chapple Xu Li 《Proceedings of the National Academy of Sciences of the United States of America》2015,112(37):11726-11731
Plants produce diverse low-molecular-weight compounds via specialized metabolism. Discovery of the pathways underlying production of these metabolites is an important challenge for harnessing the huge chemical diversity and catalytic potential in the plant kingdom for human uses, but this effort is often encumbered by the necessity to initially identify compounds of interest or purify a catalyst involved in their synthesis. As an alternative approach, we have performed untargeted metabolite profiling and genome-wide association analysis on 440 natural accessions of Arabidopsis thaliana. This approach allowed us to establish genetic linkages between metabolites and genes. Investigation of one of the metabolite–gene associations led to the identification of N-malonyl-d-allo-isoleucine, and the discovery of a novel amino acid racemase involved in its biosynthesis. This finding provides, to our knowledge, the first functional characterization of a eukaryotic member of a large and widely conserved phenazine biosynthesis protein PhzF-like protein family. Unlike most of known eukaryotic amino acid racemases, the newly discovered enzyme does not require pyridoxal 5′-phosphate for its activity. This study thus identifies a new d-amino acid racemase gene family and advances our knowledge of plant d-amino acid metabolism that is currently largely unexplored. It also demonstrates that exploitation of natural metabolic variation by integrating metabolomics with genome-wide association is a powerful approach for functional genomics study of specialized metabolism.Plants have the ability to create over 200,000 small compounds known as secondary or specialized metabolites (1). These chemically diverse compounds help mediate plant adaptation to their environment and play important roles in plant defense mechanisms, pigmentation, and development. In addition, many of these metabolites are desirable to humans as medicinal and nutritional compounds. Therefore, furthering our understanding of plant specialized metabolism will have profound impacts on various applications from crop improvement to human health.To date, only a small fraction of the chemical and catalytic space in plant specialized metabolism has been explored. Even in the best-studied model plant Arabidopsis thaliana, there are still many uncharacterized metabolites, and the vast majority of genes encoding enzymes implied to be involved in specialized metabolism do not have known associations with any metabolites. Several studies of Arabidopsis natural accessions (individuals collected from wild populations) revealed considerable qualitative and quantitative variation in the accumulation of various compounds such as glucosinolates, terpenoids, and phenylpropanoids (2–4). This extensive metabolite variation can be attributed to genetic variation in genes encoding enzymes and regulatory factors of the pathways involved; quantitative trait locus (QTL) mapping has successfully uncovered several genes involved in the production of these metabolites (3–7). Liquid chromatography–mass spectrometry (LC-MS)–based untargeted metabolic profiling has further extended such analysis to unknown metabolites, finding genetic contribution to the variation in at least three-fourths of detected mass peaks (8).Here we describe an integrated transdisciplinary platform, combining metabolomics, genetics, and genomics, to exploit the biochemical and genetic diversity of natural accessions of the model plant A. thaliana to uncover associations between genes and metabolites. Using this platform, we linked a differentially accumulating metabolite, identified through chemical analysis as N-malonyl-d-allo-isoleucine (NMD-Ile), to a previously uncharacterized gene identified as an amino acid racemase through reverse genetics and biochemical analysis.Amino acids exist in two forms; l-amino acids, the proteogenic form, and their enantiomorphs, d-amino acids. d-amino acids also play important structural and physiological roles in diverse life systems. In bacteria, d-amino acids confer cell-wall protease resistance and regulate cell-wall remodeling (9–11). d-amino acids were also found to be involved in signaling mechanisms in animal nervous systems and plant pollination (12, 13). Enzymes that catalyze the conversion of l-amino acids to d-amino acids are a class of isomerases known as amino acid racemases (14). Amino acid racemases are categorized into pyridoxal 5′ phosphate (PLP)-dependent and PLP-independent families. PLP-dependent racemases include AlaR, SerR, ArgR, and AspR and are found in both bacteria and eukaryotes, including mammals and plants. PLP-independent amino acid racemases include bacterial ProR, GluR, AspR, and diaminopimelate (DAP) epimerase. Except for DAP epimerase, which is required for the biosynthesis of Lys in bacteria and plants, ProR in Trypanosoma cruzi, the protozoan parasite responsible for Chagas disease, has been the only known eukaryotic PLP-independent racemase (15). The Arabidopsis amino acid racemase that we describe in this paper is a new member of the PLP-independent family, making its identification a significant addition to this class of enzymes. 相似文献
84.
85.
86.
We examined circadian blood pressure (BP) variation (expressed as a relative night-time BP decline) in subjects with primary aldosteronism (78 patients), pheochromocytoma (n=45) and Cushing's syndrome (n=18). Subjects with aldosterone-producing adenoma (n=21) and pheochromocytoma (n=27) were also investigated after the tumour removal. In all, 65 patients with essential hypertension served as a control group. The night-time BP decline was significantly attenuated in all three forms of endocrine hypertension compared to the control group (primary aldosteronism P<0.0001, pheochromocytoma P<0.0001 for systolic and diastolic BP and Cushing's syndrome P<0.0001/<0.001 vs essential hypertension). In the case of pheochromocytoma, the absence of the night-time BP decrease was more prominent compared to the primary aldosteronism group (P=0.003/0.001) and for the diastolic BP also in comparison with the Cushing's syndrome group (P=0.03). Tumour removal led in both groups to the restoration of the previously altered circadian rhythm (aldosterone-producing adenoma: P=0.0005/0.0009; pheochromocytoma: P=0.001/0.0007). Our study demonstrates a blunted circadian BP variation in all forms of adrenal hypertension in comparison with essential hypertension. This reduction of the night-time BP decrease was more prominent in pheochromocytoma than in primary aldosteronism or Cushing's syndrome. 相似文献
87.
88.
Zinc protoporphyrin in anemia of chronic disorders 总被引:1,自引:1,他引:1
Hematofluorometric determination of zinc protoporphyrin (ZPP) is a screening method for the assessment of iron deficiency (ID). Chronic disorders are frequently accompanied by anemias of unclear origin, most probably caused by an impairment of iron metabolism. We investigated the relevance of ZPP for the detection of derangements of iron metabolism in anemias of chronic disorders (ACD). In 19 patients with ACD caused by chronic inflammatory non-neoplastic diseases, ZPP was determined and correlated with ferritin, transferrin saturation, and hemoglobin (Hb). Marrow sideroblast counts and semiquantitative grading of the marrow hemosiderin were performed in all patients to exclude ID and to show the decreased iron bioavailability. In all ACD patients who exhibited the typical laboratory findings of disturbed iron metabolism, such as hypoferremia, decreased transferrin saturation, decreased bone marrow sideroblasts, and increased marrow hemosiderin, strongly elevated ZPP levels were found (131 +/- 23 mumol/mol heme). ZPP returned to normal after successful treatment of the underlying disease. This is shown in three patients with polymyalgia rheumatica. We conclude that the fluorometric determination of ZPP allows detection and quantification of derangements of iron metabolism associated with chronic inflammatory disorders. By recording the derangements quantitatively, ZPP allows monitoring of therapy of chronic inflammatory diseases. 相似文献
89.
Harris SE MacDougall M Horn D Woodruff K Zimmer SN Rebel VI Fajardo R Feng JQ Gluhak-Heinrich J Harris MA Abboud Werner S 《BONE》2012,50(1):42-53
CSF-1, a key regulator of mononuclear phagocyte production, is highly expressed in the skeleton by osteoblasts/osteocytes and in a number of nonskeletal tissues such as uterus, kidney and brain. The spontaneous mutant op/op mouse has been the conventional model of CSF-1 deficiency and exhibits a pleiotropic phenotype characterized by osteopetrosis, and defects in hematopoiesis, fertility and neural function. Studies to further delineate the biologic effect of CSF-1 within various tissues have been hampered by the lack of suitable models. To address this issue, we generated CSF-1 floxed/floxed mice and demonstrate that Cre-mediated recombination using Meox2Cre, a Cre line expressed in epiblast during early embryogenesis, results in mice with ubiquitous CSF-1 deficiency (CSF-1KO). Homozygous CSF-1KO mice lacked CSF-1 in all tissues and displayed, in part, a similar phenotype to op/op mice that included: failure of tooth eruption, osteopetrosis, reduced macrophage densities in reproductive and other organs and altered hematopoiesis with decreased marrow cellularity, circulating monocytes and B cell lymphopoiesis. In contrast to op/op mice, CSF-1KO mice showed elevated circulating and splenic T cells. A striking feature in CSF-1KO mice was defective osteocyte maturation, bone mineralization and osteocyte-lacunar system that was associated with reduced dentin matrix protein 1 (DMP1) expression in osteocytes. CSF-1KO mice also showed a dramatic reduction in osteomacs along the endosteal surface that may have contributed to the hematopoietic and cortical bone defects. Thus, our findings show that ubiquitous CSF-1 gene deletion using a Cre-based system recapitulates the expected osteopetrotic phenotype. Moreover, results point to a novel link between CSF-1 and osteocyte survival/function that is essential for maintaining bone mass and strength during skeletal development. 相似文献
90.
In the present study we test whether variation in resistance to paraquat (PQ), a free radical generator, correlates with variation in longevity in two sets of seed beetles (Acanthoscelides obtectus) experimental lines that were selected either for early reproduction and short-life or late reproduction and long-life. Long-lived late reproduction lines (L) showed increased resistance to PQ, while opposite was true for short-lived early reproduction line (E). Striking outcome of the selection for early and late reproduction in A. obtectus is asymmetry of responses to alternate mating schedules. The intensity of response depended on selection regime, sex and PQ dose. Evolution of longevity and PQ resistance was faster in L than E selection regime, and in females than males. To understand how age-specific mortality rates are affected by PQ we decomposed post-stress mortality data (using Gompertz mortality model) into initial mortality rate, which reflects basal vulnerability to stresses and age-specific mortality rate, which concerns the rate of increase in stress vulnerability, i.e. the rate of senescence. By estimating the parameters of the Gompertz mortality model we have shown that longevity reduction caused by PQ was the consequence of the increased baseline mortality rather than a speed up of the rate of ageing. 相似文献