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861.
E. Hubin N. A. J. van Nuland K. Broersen K. Pauwels 《Cellular and molecular life sciences : CMLS》2014,71(18):3507-3521
The aggregation and deposition of the amyloid-β peptide (Aβ) in the brain has been linked with neuronal death, which progresses in the diagnostic and pathological signs of Alzheimer’s disease (AD). The transition of an unstructured monomeric peptide into self-assembled and more structured aggregates is the crucial conversion from what appears to be a harmless polypeptide into a malignant form that causes synaptotoxicity and neuronal cell death. Despite efforts to identify the toxic form of Aβ, the development of effective treatments for AD is still limited by the highly transient and dynamic nature of interconverting forms of Aβ. The variability within the in vivo “pool” of different Aβ peptides is another complicating factor. Here we review the dynamical interplay between various components that influence the heterogeneous Aβ system, from intramolecular Aβ flexibility to intermolecular dynamics between various Aβ alloforms and external factors. The complex dynamics of Aβ contributes to the causative role of Aβ in the pathogenesis of AD. 相似文献
862.
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
863.
Altenhöfer S Kleikers PW Radermacher KA Scheurer P Rob Hermans JJ Schiffers P Ho H Wingler K Schmidt HH 《Cellular and molecular life sciences : CMLS》2012,69(14):2327-2343
Reactive oxygen species (ROS) are cellular signals but also disease triggers; their relative excess (oxidative stress) or shortage (reductive stress) compared to reducing equivalents are potentially deleterious. This may explain why antioxidants fail to combat diseases that correlate with oxidative stress. Instead, targeting of disease-relevant enzymatic ROS sources that leaves physiological ROS signaling unaffected may be more beneficial. NADPH oxidases are the only known enzyme family with the sole function to produce ROS. Of the catalytic NADPH oxidase subunits (NOX), NOX4 is the most widely distributed isoform. We provide here a critical review of the currently available experimental tools to assess the role of NOX and especially NOX4, i.e. knock-out mice, siRNAs, antibodies, and pharmacological inhibitors. We then focus on the characterization of the small molecule NADPH oxidase inhibitor, VAS2870, in vitro and in vivo, its specificity, selectivity, and possible mechanism of action. Finally, we discuss the validation of NOX4 as a potential therapeutic target for indications including stroke, heart failure, and fibrosis. 相似文献
864.
de Oliveira JC 《Studies in history and philosophy of science》2012,43(1):115-121
In this paper I identify a tension between the two sets of works by Kuhn regarding the genesis of the "new historiography of science". In the first, it could be said that the change from the traditional to the new historiography is strictly endogenous (referring to internal causes or reasons). In the second, the change is predominantly exogenous. To address this question, I draw on a text that is considered to be less important among Kuhn's works, but which, as shall be argued, allows some contact between Kuhn's two approaches via Koyré. I seek to point out and differentiate the roles of Koyré and Kuhn--from Kuhn's point of view--in the development of the historiography of science and, as a complement, present some reflections regarding the justification of the new historiography. 相似文献
865.
Age is an important risk for autoimmunity, and many autoimmune diseases preferentially occur in the second half of adulthood
when immune competence has declined and thymic T cell generation has ceased. Many tolerance checkpoints have to fail for an
autoimmune disease to develop, and several of those are susceptible to the immune aging process. Homeostatic T cell proliferation
which is mainly responsible for T cell replenishment during adulthood can lead to the selection of T cells with increased
affinity to self- or neoantigens and enhanced growth and survival properties. These cells can acquire a memory-like phenotype,
in particular under lymphopenic conditions. Accumulation of end-differentiated effector T cells, either specific for self-antigen
or for latent viruses, have a low activation threshold due to the expression of signaling and regulatory molecules and generate
an inflammatory environment with their ability to be cytotoxic and to produce excessive amounts of cytokines and thereby inducing
or amplifying autoimmune responses. 相似文献
866.
Over the last two decades the molecular and cellular mechanisms underlying T cell activation, expansion, differentiation,
and memory formation have been intensively investigated. These studies revealed that the generation of memory T cells is critically
impacted by a number of factors, including the magnitude of the inflammatory response and cytokine production, the type of
dendritic cell [DC] that presents the pathogen derived antigen, their maturation status, and the concomitant provision of
costimulation. Nevertheless, the primary stimulus leading to T cell activation is generated through the T cell receptor [TCR]
following its engagement with a peptide MHC ligand [pMHC]. The purpose of this review is to highlight classical and recent
findings on how antigen recognition, the degree of TCR stimulation, and intracellular signal transduction pathways impact
the formation of effector and memory T cells. 相似文献
867.
868.
869.
Xue B Mizianty MJ Kurgan L Uversky VN 《Cellular and molecular life sciences : CMLS》2012,69(8):1211-1259
Many proteins and protein regions are disordered in their native, biologically active states. These proteins/regions are abundant
in different organisms and carry out important biological functions that complement the functional repertoire of ordered proteins.
Viruses, with their highly compact genomes, small proteomes, and high adaptability for fast change in their biological and
physical environment utilize many of the advantages of intrinsic disorder. In fact, viral proteins are generally rich in intrinsic
disorder, and intrinsically disordered regions are commonly used by viruses to invade the host organisms, to hijack various
host systems, and to help viruses in accommodation to their hostile habitats and to manage their economic usage of genetic
material. In this review, we focus on the structural peculiarities of HIV-1 proteins, on the abundance of intrinsic disorder
in viral proteins, and on the role of intrinsic disorder in their functions. 相似文献
870.
Extremely low-coverage sequencing and imputation increases power for genome-wide association studies 总被引:1,自引:0,他引:1
Pasaniuc B Rohland N McLaren PJ Garimella K Zaitlen N Li H Gupta N Neale BM Daly MJ Sklar P Sullivan PF Bergen S Moran JL Hultman CM Lichtenstein P Magnusson P Purcell SM Haas DW Liang L Sunyaev S Patterson N de Bakker PI Reich D Price AL 《Nature genetics》2012,44(6):631-635
Genome-wide association studies (GWAS) have proven to be a powerful method to identify common genetic variants contributing to susceptibility to common diseases. Here, we show that extremely low-coverage sequencing (0.1-0.5×) captures almost as much of the common (>5%) and low-frequency (1-5%) variation across the genome as SNP arrays. As an empirical demonstration, we show that genome-wide SNP genotypes can be inferred at a mean r(2) of 0.71 using off-target data (0.24× average coverage) in a whole-exome study of 909 samples. Using both simulated and real exome-sequencing data sets, we show that association statistics obtained using extremely low-coverage sequencing data attain similar P values at known associated variants as data from genotyping arrays, without an excess of false positives. Within the context of reductions in sample preparation and sequencing costs, funds invested in extremely low-coverage sequencing can yield several times the effective sample size of GWAS based on SNP array data and a commensurate increase in statistical power. 相似文献