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991.
Michael J. Kelley Jianxin Shi Bari Ballew Paula L. Hyland Wen-Qing Li Melissa Rotunno David A. Alcorta Norbert J. Liebsch Jason Mitchell Sara Bass David Roberson Joseph Boland Michael Cullen Ji He Laurie Burdette Meredith Yeager Stephen J. Chanock Dilys M. Parry Alisa M. Goldstein Xiaohong R. Yang 《Human genetics》2014,133(10):1289-1297
Chordoma is a rare bone cancer that is believed to originate from notochordal remnants. We previously identified germline T duplication as a major susceptibility mechanism in several chordoma families. Recently, a common genetic variant in T (rs2305089) was significantly associated with the risk of sporadic chordoma. We sequenced all T exons in 24 familial cases and 54 unaffected family members from eight chordoma families (three with T duplications), 103 sporadic cases, and 160 unrelated controls. We also measured T copy number variation in all sporadic cases. We confirmed the association between the previously reported variant rs2305089 and risk of familial [odds ratio (OR) = 2.6, 95 % confidence interval (CI) = 0.93, 7.25, P = 0.067] and sporadic chordoma (OR = 2.85, 95 % CI = 1.89, 4.29, P < 0.0001). We also identified a second common variant, rs1056048, that was strongly associated with chordoma in families (OR = 4.14, 95 % CI = 1.43, 11.92, P = 0.0086). Among sporadic cases, another common variant (rs3816300) was significantly associated with risk when jointly analyzed with rs2305089. The association with rs3816300 was significantly stronger in cases with early age onset. In addition, we identified three rare variants that were only observed among sporadic chordoma cases, all of which have potential functional relevance based on in silico predictions. Finally, we did not observe T duplication in any sporadic chordoma case. Our findings further highlight the importance of the T gene in the pathogenesis of both familial and sporadic chordoma and suggest a complex susceptibility related to T. 相似文献
992.
Christos Stritsis Bernd Steingrobe Norbert Claassen 《International journal of phytoremediation》2014,16(11):1104-1118
Maize, sunflower, flax, and spinach differed in the accumulation of Cd when grown on a Cd contaminated soil. This was mainly due to the different Cd net influx, In , that varied among species by a factor of up to 30. The objective of this study was to find possible reasons for the different Cd In by using a mechanistic model. After 14 days of Cd uptake the model calculated only a small Cd depletion at the root surface, e.g. from 0.22 μmol L?1down to 0.19 μmol L?1for maize and from 0.48 μmol L?1down to 0.35 μmol L?1for spinach. Even so the model always overestimated the Cd In , for spinach by a factor of 1.5 and for maize by a factor of 10. Only simulating a decrease of CLi or the root absorbing power, α, by 40% to 90% gave an agreement of calculated and measured In . This may be interpreted as that about 40% in the case of spinach and 90% in the case of maize of the Cd in soil solution were not accessible for plant uptake. The high sensitivity to α also shows that not the Cd transport to the root but α was limiting the step for Cd uptake. 相似文献
993.
Samia Aci-Sèche Paul Sawma Pierre Hubert James N. Sturgis Dominique Bagnard Laurent Jacob Monique Genest Norbert Garnier 《PloS one》2014,9(5)
The cancer associated class 3 semaphorins require direct binding to neuropilins and association to plexins to trigger cell signaling. Here, we address the role of the transmembrane domains of neuropilin 1 and plexin A1 for the dimerization of the two receptors by characterizing the assembly in lipid bilayers using coarse-grained molecular dynamics simulations. From experimental evidence using a two-hybrid system showing the biochemical association of the two receptors transmembrane domains, we performed molecular simulations in DOPC and POPC demonstrating spontaneously assembly to form homodimers and heterodimers with a very high propensity for right-handed packing of the helices. Inversely, left-handed packing was observed with a very low propensity. This mode of packing was observed uniquely when the plexin A1 transmembrane domain was involved in association. Potential of mean force calculations were used to predict a hierarchy of self-association for the monomers: the two neuropilin 1 transmembrane domains strongly associated, neuropilin 1 and plexin A1 transmembrane domains associated less and the two plexin A1 transmembrane domains weakly but significantly associated. We demonstrated that homodimerization and heterodimerization are driven by GxxxG motifs, and that the sequence context modulates the packing mode of the plexin A1 transmembrane domains. This work presents major advances towards our understanding of membrane signaling platforms assembly through membrane domains and provides exquisite information for the design of antagonist drugs defining a novel class of therapeutic agents. 相似文献
994.
Anja B?hm Anna Halama Tobias Meile Marty Zdichavsky Rainer Lehmann Cora Weigert Andreas Fritsche Norbert Stefan Alfred K?nigsrainer Hans-Ulrich H?ring Martin Hrabě de Angelis Jerzy Adamski Harald Staiger 《PloS one》2014,9(4)
Background and Aims
Among obese subjects, metabolically healthy and unhealthy obesity (MHO/MUHO) can be differentiated: the latter is characterized by whole-body insulin resistance, hepatic steatosis, and subclinical inflammation. Aim of this study was, to identify adipocyte-specific metabolic signatures and functional biomarkers for MHO versus MUHO.Methods
10 insulin-resistant (IR) vs. 10 insulin-sensitive (IS) non-diabetic morbidly obese (BMI >40 kg/m2) Caucasians were matched for gender, age, BMI, and percentage of body fat. From subcutaneous fat biopsies, primary preadipocytes were isolated and differentiated to adipocytes in vitro. About 280 metabolites were investigated by a targeted metabolomic approach intracellularly, extracellularly, and in plasma.Results/Interpretation
Among others, aspartate was reduced intracellularly to one third (p = 0.0039) in IR adipocytes, pointing to a relative depletion of citric acid cycle metabolites or reduced aspartate uptake in MUHO. Other amino acids, already known to correlate with diabetes and/or obesity, were identified to differ between MUHO''s and MHO''s adipocytes, namely glutamine, histidine, and spermidine. Most species of phosphatidylcholines (PCs) were lower in MUHO''s extracellular milieu, though simultaneously elevated intracellularly, e.g., PC aa C32∶3, pointing to increased PC synthesis and/or reduced PC release. Furthermore, altered arachidonic acid (AA) metabolism was found: 15(S)-HETE (15-hydroxy-eicosatetraenoic acid; 0 vs. 120pM; p = 0.0014), AA (1.5-fold; p = 0.0055) and docosahexaenoic acid (DHA, C22∶6; 2-fold; p = 0.0033) were higher in MUHO. This emphasizes a direct contribution of adipocytes to local adipose tissue inflammation. Elevated DHA, as an inhibitor of prostaglandin synthesis, might be a hint for counter-regulatory mechanisms in MUHO.Conclusion/Interpretation
We identified adipocyte-inherent metabolic alterations discriminating between MHO and MUHO. 相似文献995.
J?rg Wiltink Matthias Michal Philipp S. Wild Astrid Schneider Jochem K?nig Maria Blettner Thomas Münzel Andreas Schulz Matthias Weber Christian Fottner Norbert Pfeiffer Karl Lackner Manfred E. Beutel 《PloS one》2014,9(8)
Objectives
While a bidirectional relationship between diabetes and depression has been established, there is little knowledge if the associations are due to somatic-affective or cognitive-affective dimensions of depression.Research Design and Methods
In a population-based, representative survey of 15.010 participants we therefore studied the associations of the two dimensions of depression with diabetes and health care utilization among depressed and diabetic participants. Depression was assessed by the Patient Health Questionnaire PHQ-9.Results
We found a linear and consistent association between the intensity of depression and the presence of diabetes increasing from 6.9% in no or minimal depression to 7.6% in mild, 9% in moderate and 10.5% in severe depression. There was a strong positive association between somatic-affective symptoms but not with cognitive-affective symptoms and diabetes. Depression and diabetes were both independently related to somatic health care utilisation.Conclusions
Diabetes and depression are associated, and the association is primarily driven by the somatic-affective component of depression. The main limitation of our study pertains to the cross-sectional data acquisition. Further longitudinal work on the relationship of obesity and diabetes should differentiate the somatic and the cognitive symptoms of depression. 相似文献996.
997.
Leitinger N 《Molecular aspects of medicine》2003,24(4-5):239-250
Lipid oxidation products are formed at sites of increased oxidant stress and have been shown to accumulate in atherosclerotic lesions. Although recent studies have focused on the formation and metabolism of oxidized lipids, very little is known about their biological activities and possible (patho)physiological functions. Oxidation of cholesteryl esters containing unsaturated fatty acids leads to the formation of hydroperoxides that are either reduced to alcohols or degrade into biologically active "core-aldehydes". In this review, the mechanisms of formation and metabolic fate of oxidized cholesteryl esters, their occurrence, as well as possible biological activities are discussed. Based on the current knowledge, cholesteryl ester oxidation leads to the formation of biologically active substances, which could actively contribute to the progression of atherosclerotic lesions and their resulting complications. 相似文献
998.
Synthesis of non-immunosuppressive cyclophilin-Binding cyclosporin A derivatives as potential anti-HIV-1 drugs 总被引:1,自引:0,他引:1
Evers M Barrière JC Bashiardes G Bousseau A Carry JC Dereu N Filoche B Henin Y Sablé S Vuilhorgne M Mignani S 《Bioorganic & medicinal chemistry letters》2003,13(24):4415-4419
Original cyclosporin A (CsA) derivatives bearing various alkylthio side chains at the sarcosine residue 3 (R configuration) and for the most potent and selective compounds a 4′-hydroxyl group at the Me-Leucine residue 4 were prepared in one or two steps from commercially available CsA. The [2-(dimethyl or diethylamino)-ethylthio-Sar]3-[(4′-OH)MeLeu]4-CsA derivatives 3k and 3l displayed potent in vitro anti-HIV-1 (IC50 46 nM) and low immunosuppressive activities (IC50≥1500 nM). 相似文献
999.