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排序方式: 共有172条查询结果,搜索用时 46 毫秒
131.
Almudena Fuster-Matanzo Jerónimo Jurado-Arjona Stefano Benvegnù Esther García Patricia Martín-Maestro Raquel Gómez-Sintes Félix Hernández Jesús Ávila 《Cellular and molecular life sciences : CMLS》2017,74(6):1153-1163
Glycogen synthase kinase-3β (GSK-3β) is a serine-threonine kinase implicated in multiple processes and signaling pathways. Its dysregulation is associated with different pathological conditions including Alzheimer’s disease (AD). Here we demonstrate how changes in GSK-3β activity and/or levels regulate the production and subsequent secretion of fractalkine, a chemokine involved in the immune response that has been linked to AD and to other different neurological disorders. Treatment of primary cultured neurons with GSK-3β inhibitors such as lithium and AR-A014418 decreased full-length fractalkine in total cell extracts. Opposite effects were observed after neuron transduction with a lentiviral vector overexpressing the kinase. Biotinylation assays showed that those changes mainly affect the plasma membrane-associated form of the protein, an observation that positively correlates with changes in the levels of its soluble form. These effects were confirmed in lithium-treated wild type (wt) mice and in GSK-3β transgenic animals, as well as in brain samples from AD patients, evident as age-dependent (animals) or Braak stage dependent changes (humans) in both the membrane-bound and the soluble forms of the protein. Further immunohistochemical analyses demonstrated how GSK-3β exerts these effects by affecting the trafficking of the chemokine from the Golgi to the plasma membrane, in different and opposite ways when the levels/activity of the kinase are increased or decreased. This work provides for the first time a mechanism linking GSK-3β and fractalkine both in vitro and in vivo, with important implications for neurological disorders and especially for AD, in which levels of this chemokine might be useful as a diagnostic tool. 相似文献
132.
Quesada V Conde L Villamor N Ordóñez GR Jares P Bassaganyas L Ramsay AJ Beà S Pinyol M Martínez-Trillos A López-Guerra M Colomer D Navarro A Baumann T Aymerich M Rozman M Delgado J Giné E Hernández JM González-Díaz M Puente DA Velasco G Freije JM Tubío JM Royo R Gelpí JL Orozco M Pisano DG Zamora J Vázquez M Valencia A Himmelbauer H Bayés M Heath S Gut M Gut I Estivill X López-Guillermo A Puente XS Campo E López-Otín C 《Nature genetics》2012,44(1):47-52
Here we perform whole-exome sequencing of samples from 105 individuals with chronic lymphocytic leukemia (CLL), the most frequent leukemia in adults in Western countries. We found 1,246 somatic mutations potentially affecting gene function and identified 78 genes with predicted functional alterations in more than one tumor sample. Among these genes, SF3B1, encoding a subunit of the spliceosomal U2 small nuclear ribonucleoprotein (snRNP), is somatically mutated in 9.7% of affected individuals. Further analysis in 279 individuals with CLL showed that SF3B1 mutations were associated with faster disease progression and poor overall survival. This work provides the first comprehensive catalog of somatic mutations in CLL with relevant clinical correlates and defines a large set of new genes that may drive the development of this common form of leukemia. The results reinforce the idea that targeting several well-known genetic pathways, including mRNA splicing, could be useful in the treatment of CLL and other malignancies. 相似文献
133.
Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium Strange A Capon F Spencer CC Knight J Weale ME Allen MH Barton A Band G Bellenguez C Bergboer JG Blackwell JM Bramon E Bumpstead SJ Casas JP Cork MJ Corvin A Deloukas P Dilthey A Duncanson A Edkins S Estivill X Fitzgerald O Freeman C Giardina E Gray E Hofer A Hüffmeier U Hunt SE Irvine AD Jankowski J Kirby B Langford C Lascorz J Leman J Leslie S Mallbris L Markus HS Mathew CG McLean WH McManus R 《Nature genetics》2010,42(11):985-990
To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These associations were replicated in 9,079 European samples (six loci with a combined P < 5 × 10?? and two loci with a combined P < 5 × 10??). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 × 10??). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele. Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis. 相似文献
134.
This paper utilizes for the first time age‐structured human capital data for economic growth forecasting. We concentrate on pooled cross‐country data of 65 countries over six 5‐year periods (1970–2000) and consider specifications chosen by model selection criteria, Bayesian model averaging methodologies based on in‐sample and out‐of‐sample goodness of fit and on adaptive regression by mixing. The results indicate that forecast averaging and exploiting the demographic dimension of education data improve economic growth forecasts systematically. In particular, the results are very promising for improving economic growth predictions in developing countries. Copyright © 2009 John Wiley & Sons, Ltd. 相似文献
135.
Götz J Eckert A Matamales M Ittner LM Liu X 《Cellular and molecular life sciences : CMLS》2011,68(20):3359-3375
Alzheimer's disease (AD) is reaching epidemic proportions, yet a cure is not yet available. While the genetic causes of the rare familial inherited forms of AD are understood, the causes of the sporadic forms of the disease are not. Histopathologically, these two forms of AD are indistinguishable: they are characterized by amyloid-β (Aβ) peptide-containing amyloid plaques and tau-containing neurofibrillary tangles. In this review we compare AD to frontotemporal dementia (FTD), a subset of which is characterized by tau deposition in the absence of overt plaques. A host of transgenic animal AD models have been established through the expression of human proteins with pathogenic mutations previously identified in familial AD and FTD. Determining how these mutant proteins cause disease in vivo should contribute to an understanding of the causes of the more frequent sporadic forms. We discuss the insight transgenic animal models have provided into Aβ and tau toxicity, also with regards to mitochondrial function and the crucial role tau plays in mediating Aβ toxicity. We also discuss the role of miRNAs in mediating the toxic effects of the Aβ peptide. 相似文献
136.
Sánchez-García Jacqueline Y. Núñez-Ríos Juan E. Soto-Pérez Manuel Cardoso-Castro Pedro Pablo Rodríguez-Magaña Alejandro 《Systemic Practice and Action Research》2020,33(1):1-25
Systemic Practice and Action Research - This article proposes a model based on the integration of systemic mechanisms such as the soft systems methodology, partial least squares path modelling and... 相似文献
137.
Luis A. Cea Carlos Puebla Bruno A. Cisterna Rosalba Escamilla Aníbal A. Vargas Marina Frank Paloma Martínez-Montero Carmen Prior Jesús Molano Isabel Esteban-Rodríguez Ignacio Pascual Pía Gallano Gustavo Lorenzo Héctor Pian Luis C. Barrio Klaus Willecke Juan C. Sáez 《Cellular and molecular life sciences : CMLS》2016,73(13):2583-2599
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139.