http://hdl.handle.net/20.500.12701/1645 PLOS ONE accepts research in over two hundred subject areas across science, engineering, medicine, and the related social sciences and humanities. Fri, 03 May 2024 12:19:41 GMT 2024-05-03T12:19:41Z http://hdl.handle.net/20.500.12701/1835 Название: Association of SNPs of CD40 Gene with Multiple Sclerosis in Russians Авторы: Sokolova, Ekaterina Alekseevna; Malkova, Nadezhda Alekseevna; Korobko, Denis Sergeevich; Rozhdestvenskii, Aleksey Sergeevich; Kakulya, Anastasia Vladimirovna; Khanokh, Elena Vladimirovna; Delov, Roman Andreevich; Platonov, Fedor Alekseevich; Popova, Tatyana Yegorovna; Aref′eva, Elena Gennadievna; Zagorskaya, Natalia Nikolaevna; Alifirova, Valentina Mikhailovna; Titova, Marina Andreevna; Smagina, Inna Vadimovna; El′chaninova, Svetlana Alksandrovna; Popovtseva, Anna Valentinovna; Puzyrev, Valery Pavlovich; Kulakova, Olga Georgievna; Tsareva, Ekaterina Yur'evna; Favorova, Olga Olegovna; Shchur, Sergei Gennadievich; Lashch, Natalia Yurievna; Popova, Natalia Fyodorovna; Popova, Ekaterina Valerievna; Gusev, Evgenii Ivanovich; Boyko, Aleksey Nikolaevich; Aulchenko, Yurii Sergeevich; Filipenko, Maxim Leonidovich Краткий осмотр (реферат): Multiple sclerosis (MS) is a serious, incurable neurological disease. In 2009, the ANZgene studies detected the suggestive association of located upstream of CD40 gene in chromosome 20q13 (p = 1.3×10−7). Identification of the causal variant(s) in the CD40 locus leads to a better understanding of the mechanism underlying the development of autoimmune pathologies. We determined the genotypes of rs6074022, rs1883832, rs1535045, and rs11086996 in patients with MS (n = 1684) and in the control group (n = 879). Two SNPs were significantly associated with MS: rs6074022 (additive model C allele OR = 1.27, 95% CI = [1.12–1.45], p = 3×10−4) and rs1883832 (additive model T allele OR = 1.20, 95% CI = [1.05–1.38], p = 7×10−3). In the meta-analysis of our results and the results of four previous studies, we obtain the association p-value of 2.34×10−12, which confirmed the association between MS and rs6074022 at a genome-wide significant level. Next, we demonstrated that the model including rs6074022 only sufficiently described the association. From our analysis, we can speculate that the association between rs1883832 and MS was induced by LD, whereas rs6074022 was a marker in stronger LD with the functional variant or was the functional variant itself. Our results indicated that the functional variants were located in the upstream region of the gene CD40 and were in higher LD with rs6074022 than LD with rs1883832. Mon, 22 Apr 2013 00:00:00 GMT http://hdl.handle.net/20.500.12701/1835 2013-04-22T00:00:00Z http://hdl.handle.net/20.500.12701/1828 Название: Proteasome Functioning in Breast Cancer: Connection with Clinical-Pathological Factors Авторы: Shashova, Elena E.; Lyupina, Yulia V.; Glushchenko, Svetlana A.; Slonimskaya, Elena M.; Savenkova, Olga V.; Kulikov, Alexey M.; Gornostaev, Nikolay G.; Kondakova, Irina V.; Sharova, Natalia P. Краткий осмотр (реферат): Breast cancer is one of four oncology diseases that are most widespread in the world. Moreover, breast cancer is one of leading causes of cancer-related deaths in female population within economically developed regions of the world. So far, detection of new mechanisms of breast cancer development is very important for discovery of novel areas in which therapy approaches may be elaborated. The objective of the present study is to investigate involvement of proteasomes, which cleave up to 90% of cellular proteins and regulate numerous cellular processes, in mechanisms of breast cancer development. Proteasome characteristics in 106 patient breast carcinomas and adjacent tissues, as well as relationships of detected proteasome parameters with clinical-pathological factors, were investigated. Proteasome chymotrypsin-like activity was evaluated by hydrolysis of fluorogenic peptide Suc-LLVY-AMC. The expression of proteasome subunits was studied by Western-blotting and immunohistochemistry. The wide range of chymotrypsin-like activity in tumors was detected. Activity in tumors was higher if compared to adjacent tissues in 76 from 106 patients. Multiple analysis of generalized linear models discovered that in estrogen α-receptor absence, tumor growth was connected with the enhanced expression of proteasome immune subunit LMP2 and proteasome activator PA700 in tumor (at 95% confidence interval). Besides, by this analysis we detected some phenomena in adjacent tissue, which are important for tumor growth and progression of lymph node metastasis in estrogen α-receptor absence. These phenomena are related to the enhanced expression of activator PA700 and immune subunit LMP7. Thus, breast cancer development is connected with functioning of immune proteasome forms and activator PA700 in patients without estrogen α-receptors in tumor cells. These results could indicate a field for search of new therapy approaches for this category of patients, which has the worst prognosis of health recovery. Fri, 17 Oct 2014 00:00:00 GMT http://hdl.handle.net/20.500.12701/1828 2014-10-17T00:00:00Z http://hdl.handle.net/20.500.12701/1827 Название: Transcriptomic Changes Triggered by Hypoxia: Evidence for HIF-1α -Independent, [Na+]i/[K+]i-Mediated, Excitation-Transcription Coupling Авторы: Koltsova, Svetlana V.; Shilov, Boris; Birulina, Julia G.; Akimova, Olga A.; Haloui, Mounsif; Kapilevich, Leonid V.; Gusakova, Svetlana V.; Tremblay, Johanne; Hamet, Pavel; Orlov, Sergei N. Краткий осмотр (реферат): This study examines the relative impact of canonical hypoxia-inducible factor-1alpha- (HIF-1α and Na+i/K+i-mediated signaling on transcriptomic changes evoked by hypoxia and glucose deprivation. Incubation of RASMC in ischemic conditions resulted in ∼3-fold elevation of [Na+]i and 2-fold reduction of [K+]i. Using global gene expression profiling we found that Na+,K+-ATPase inhibition by ouabain or K+-free medium in rat aortic vascular smooth muscle cells (RASMC) led to the differential expression of dozens of genes whose altered expression was previously detected in cells subjected to hypoxia and ischemia/reperfusion. For further investigations, we selected Cyp1a1, Fos, Atf3, Klf10, Ptgs2, Nr4a1, Per2 and Hes1, i.e. genes possessing the highest increments of expression under sustained Na+,K+-ATPase inhibition and whose implication in the pathogenesis of hypoxia was proved in previous studies. In ouabain-treated RASMC, low-Na+, high-K+ medium abolished amplification of the [Na+]i/[K+]i ratio as well as the increased expression of all tested genes. In cells subjected to hypoxia and glucose deprivation, dissipation of the transmembrane gradient of Na+ and K+ completely eliminated increment of Fos, Atf3, Ptgs2 and Per2 mRNAs and sharply diminished augmentation expression of Klf10, Edn1, Nr4a1 and Hes1. In contrast to low-Na+, high-K+ medium, RASMC transfection with Hif-1a siRNA attenuated increments of Vegfa, Edn1, Klf10 and Nr4a1 mRNAs triggered by hypoxia but did not impact Fos, Atf3, Ptgs2 and Per2 expression. Thus, our investigation demonstrates, for the first time, that Na+i/K+i-mediated, Hif-1α- -independent excitation-transcription coupling contributes to transcriptomic changes evoked in RASMC by hypoxia and glucose deprivation. Thu, 06 Nov 2014 00:00:00 GMT http://hdl.handle.net/20.500.12701/1827 2014-11-06T00:00:00Z http://hdl.handle.net/20.500.12701/1764 Название: Downregulation of TGF-β Receptor-2 Expression and Signaling through Inhibition of Na/K-ATPase Авторы: La, Jennifer; Reed, Eleanor; Chan, Lan; Smolyaninova, Larisa V.; Akomova, Olga A.; Mutlu, Gökhan M.; Orlov, Sergei N.; Dulin, Nickolai O. Краткий осмотр (реферат): Transforming growth factor-beta (TGF-β) is a multi-functional cytokine implicated in the control of cell growth and differentiation. TGF-β signals through a complex of TGF-β receptors 1 and 2 (TGFβR1 and TGFβR2) that phosphorylate and activate Smad2/3 transcription factors driving transcription of the Smad-target genes. The Na+/K+-ATPase is an integral plasma membrane protein critical for maintaining the electro-chemical gradient of Na+ and K+ in the cell. We found that inhibition of the Na+/K+ ATPase by ouabain results in a dramatic decrease in the expression of TGFβR2 in human lung fibrobalsts (HLF) at the mRNA and protein levels. This was accompanied by inhibition of TGF-β-induced Smad phosphorylation and the expression of TGF-β target genes, such as fibronectin and smooth muscle alpha-actin. Inhibition of Na+/K+ ATPase by an alternative approach (removal of extracellular potassium) had a similar effect in HLF. Finally, treatment of lung alveolar epithelial cells (A549) with ouabain also resulted in the downregulation of TGFβR2, the inhibition of TGF-β-induced Smad phosphorylation and of the expression of mesenchymal markers, vimentin and fibronectin. Together, these data demonstrate a critical role of Na+/K+-ATPase in the control of TGFβR2 expression, TGF-β signaling and cell responses to TGF-β. Thu, 22 Dec 2016 00:00:00 GMT http://hdl.handle.net/20.500.12701/1764 2016-12-22T00:00:00Z