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91.
Antoni Camins Javier G. Pizarro Daniel Alvira Javier Gutierrez-Cuesta Aurelio Vazquez de la Torre Jaume Folch Francesc X. Sureda Ester Verdaguer Felix Junyent Joaquín Jordán Isidre Ferrer Mercè Pallàs 《Cellular and molecular life sciences : CMLS》2010,67(22):3865-3882
In the present study we demonstrated that neurotoxin MPP+-induced DNA damage is followed by ataxia telangiectasia muted (ATM) activation either in cerebellar granule cells (CGC) or in B65 cell line. In CGC, the selective ATM inhibitor KU-55933 showed neuroprotective effects against MPP+-induced neuronal cell loss and apoptosis, lending support to the key role of ATM in experimental models of Parkinson’s disease. Likewise, we showed that knockdown of ATM levels in neuroblastoma B65 cells using an ATM-specific siRNA attenuates the phosphorylation of retinoblastoma protein without affecting other cell-cycle proteins involved in the G0/G1 cell-cycle phase. Moreover, we demonstrated DNA damage, in human brain samples of PD patients. These findings support a model in which MPP+ leads to ATM activation with a subsequent DNA damage response and activation of pRb. Therefore, this study demonstrates a new link between DNA damage by MPP+ and cell-cycle re-entry through retinoblastoma protein phosphorylation. 相似文献
92.
Alcázar R García AV Kronholm I de Meaux J Koornneef M Parker JE Reymond M 《Nature genetics》2010,42(12):1135-1139
Accumulation of genetic incompatibilities within species can lead to reproductive isolation and, potentially, speciation. In this study, we show that allelic variation at SRF3 (Strubbelig Receptor Family 3), encoding a receptor-like kinase, conditions the occurrence of incompatibility between Arabidopsis thaliana accessions. The geographical distribution of SRF3 alleles reveals that allelic forms causing epistatic incompatibility with a Landsberg erecta allele at the RPP1 resistance locus are present in A. thaliana accessions in central Asia. Incompatible SRF3 alleles condition for an enhanced early immune response to pathogens as compared to the resistance-dampening effect of compatible SRF3 forms in isogenic backgrounds. Variation in disease susceptibility suggests a basis for the molecular patterns of a recent selective sweep detected at the SRF3 locus in central Asian populations. 相似文献
93.
Sieni E Cetica V Mastrodicasa E Pende D Moretta L Griffiths G Aricò M 《Cellular and molecular life sciences : CMLS》2012,69(1):29-40
Cytotoxic T lymphocytes, natural killer cells, and NKT cells are effector cells able to kill infected cells. In some inherited
human disorders, a defect in selected proteins involved in the cellular cytotoxicity mechanism results in specific clinical
syndromes, grouped under the name of familial hemophagocytic lymphohistiocytosis. Recent advances in genetic studies of these
patients has allowed the identification of different genetic subsets. Additional genetic immune deficiencies may also induce
a similar clinical picture. International cooperation and prospective trials resulted in refining the diagnostic and therapeutic
approach to these rare diseases with improved outcome but also with improved knowledge of the mechanisms underlying granule-mediated
cellular cytotoxicity in humans. 相似文献
94.
van der Meijden PE Feijge MA Swieringa F Gilio K Nergiz-Unal R Hamulyák K Heemskerk JW 《Cellular and molecular life sciences : CMLS》2012,69(20):3481-3492
The fibrin(ogen) receptor, integrin α(IIb)β(3), has a well-established role in platelet spreading, aggregation and clot retraction. How α(IIb)β(3) contributes to platelet-dependent coagulation is less well resolved. Here, we demonstrate that the potent suppressing effect of clinically used α(IIb)β(3) blockers on tissue factor-induced thrombin generation is linked to diminished platelet Ca(2+) responses and phosphatidylserine (PS) exposure. The same blockers suppress these responses in platelets stimulated with collagen and thrombin receptor agonists, whereas added fibrinogen potentiates these responses. In platelets spreading on fibrinogen, outside-in α(IIb)β(3) signaling similarly enhances thrombin-induced Ca(2+) rises and PS exposure. These responses are reduced in α(IIb)β(3)-deficient platelets from patients with Glanzmann's thrombasthenia. Furthermore, the contribution of α(IIb)β(3) to tissue factor-induced platelet Ca(2+) rises, PS exposure and thrombin generation in plasma are fully dependent on Syk kinase activity. Tyrosine phosphorylation analysis confirms a key role of Syk activation, which is largely but not exclusively dependent on α(IIb)β(3) activation. It is concluded that the majority of tissue factor-induced procoagulant activity of platelets relies on Syk activation and ensuing Ca(2+) signal generation, and furthermore that a considerable part of Syk activation relies on α(IIb)β(3) signaling. These results hence point to a novel role of Syk in integrin-dependent thrombin generation. 相似文献
95.
Roscioli T Kamsteeg EJ Buysse K Maystadt I van Reeuwijk J van den Elzen C van Beusekom E Riemersma M Pfundt R Vissers LE Schraders M Altunoglu U Buckley MF Brunner HG Grisart B Zhou H Veltman JA Gilissen C Mancini GM Delrée P Willemsen MA Ramadža DP Chitayat D Bennett C Sheridan E Peeters EA Tan-Sindhunata GM de Die-Smulders CE Devriendt K Kayserili H El-Hashash OA Stemple DL Lefeber DJ Lin YY van Bokhoven H 《Nature genetics》2012,44(5):581-585
Walker-Warburg syndrome (WWS) is an autosomal recessive multisystem disorder characterized by complex eye and brain abnormalities with congenital muscular dystrophy (CMD) and aberrant a-dystroglycan glycosylation. Here we report mutations in the ISPD gene (encoding isoprenoid synthase domain containing) as the second most common cause of WWS. Bacterial IspD is a nucleotidyl transferase belonging to a large glycosyltransferase family, but the role of the orthologous protein in chordates is obscure to date, as this phylum does not have the corresponding non-mevalonate isoprenoid biosynthesis pathway. Knockdown of ispd in zebrafish recapitulates the human WWS phenotype with hydrocephalus, reduced eye size, muscle degeneration and hypoglycosylated a-dystroglycan. These results implicate ISPD in a-dystroglycan glycosylation in maintaining sarcolemma integrity in vertebrates. 相似文献
96.
A mixed-model approach for genome-wide association studies of correlated traits in structured populations 总被引:1,自引:0,他引:1
Genome-wide association studies (GWAS) are a standard approach for studying the genetics of natural variation. A major concern in GWAS is the need to account for the complicated dependence structure of the data, both between loci as well as between individuals. Mixed models have emerged as a general and flexible approach for correcting for population structure in GWAS. Here, we extend this linear mixed-model approach to carry out GWAS of correlated phenotypes, deriving a fully parameterized multi-trait mixed model (MTMM) that considers both the within-trait and between-trait variance components simultaneously for multiple traits. We apply this to data from a human cohort for correlated blood lipid traits from the Northern Finland Birth Cohort 1966 and show greatly increased power to detect pleiotropic loci that affect more than one blood lipid trait. We also apply this approach to an Arabidopsis thaliana data set for flowering measurements in two different locations, identifying loci whose effect depends on the environment. 相似文献
97.
An efficient multi-locus mixed-model approach for genome-wide association studies in structured populations 总被引:2,自引:0,他引:2
Segura V Vilhjálmsson BJ Platt A Korte A Seren Ü Long Q Nordborg M 《Nature genetics》2012,44(7):825-830
Population structure causes genome-wide linkage disequilibrium between unlinked loci, leading to statistical confounding in genome-wide association studies. Mixed models have been shown to handle the confounding effects of a diffuse background of large numbers of loci of small effect well, but they do not always account for loci of larger effect. Here we propose a multi-locus mixed model as a general method for mapping complex traits in structured populations. Simulations suggest that our method outperforms existing methods in terms of power as well as false discovery rate. We apply our method to human and Arabidopsis thaliana data, identifying new associations and evidence for allelic heterogeneity. We also show how a priori knowledge from an A. thaliana linkage mapping study can be integrated into our method using a Bayesian approach. Our implementation is computationally efficient, making the analysis of large data sets (n > 10,000) practicable. 相似文献
98.
Gutiérrez-López MD Gilsanz A Yáñez-Mó M Ovalle S Lafuente EM Domínguez C Monk PN González-Alvaro I Sánchez-Madrid F Cabañas C 《Cellular and molecular life sciences : CMLS》2011,68(19):3275-3292
ADAM17/TACE is a metalloproteinase responsible for the shedding of the proinflammatory cytokine TNF-α and many other cell
surface proteins involved in development, cell adhesion, migration, differentiation, and proliferation. Despite the important
biological function of ADAM17, the mechanisms of regulation of its metalloproteinase activity remain largely unknown. We report
here that the tetraspanin CD9 and ADAM17 partially co-localize on the surface of endothelial and monocytic cells. In situ
proximity ligation, co-immunoprecipitation, crosslinking, and pull-down experiments collectively demonstrate a direct association
between these molecules. Functional studies reveal that treatment with CD9-specific antibodies or neoexpression of CD9 exert
negative regulatory effects on ADAM17 sheddase activity. Conversely, CD9 silencing increased the activity of ADAM17 against
its substrates TNF-α and ICAM-1. Taken together, our results show that CD9 associates with ADAM17 and, through this interaction,
negatively regulates the sheddase activity of ADAM17. 相似文献
99.
100.
Biegel E Schmidt S González JM Müller V 《Cellular and molecular life sciences : CMLS》2011,68(4):613-634
Microbes have a fascinating repertoire of bioenergetic enzymes and a huge variety of electron transport chains to cope with
very different environmental conditions, such as different oxygen concentrations, different electron acceptors, pH and salinity.
However, all these electron transport chains cover the redox span from NADH + H+ as the most negative donor to oxygen/H2O as the most positive acceptor or increments thereof. The redox range more negative than −320 mV has been largely ignored.
Here, we have summarized the recent data that unraveled a novel ion-motive electron transport chain, the Rnf complex, that
energetically couples the cellular ferredoxin to the pyridine nucleotide pool. The energetics of the complex and its biochemistry,
as well as its evolution and cellular function in different microbes, is discussed. 相似文献