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951.
The DNA repair protein, O(6)-methylguanine DNA-methyltransferase (MGMT) prevents mutations and cell death that result from aberrant alkylation of DNA. The polymorphic variants Leu84Phe, Ile143Val, and Lys178Arg are frequent in the human population. We review here studies of these and other MGMT polymorphisms and their association with risk for lung, breast, colorectal and endometrial cancer with a consideration of gene-environment interactions. In addition, we review studies of the effects of polymorphic variation on alkyltransferase activity and expression. It is formally possible that polymorphic variation could modify functions of MGMT other than its alkyltransferase activity. While it was previously reported that an alkylated form of MGMT modifies Estrogen Receptor alpha activity, from our studies we conclude that this regulation is not a major function of MGMT. Overall, the effects of polymorphic variation on protein function are subtle, and further investigation is required to provide a comprehensive mechanism that explains the observed associations of these variants with risk for cancer. 相似文献
952.
Han SK Federico S Grillo A Giaquinta G Herzog W 《Biomechanics and modeling in mechanobiology》2007,6(3):139-150
The integrity of articular cartilage depends on the proper functioning and mechanical stimulation of chondrocytes, the cells
that synthesize extracellular matrix and maintain tissue health. The biosynthetic activity of chondrocytes is influenced by
genetic factors, environmental influences, extracellular matrix composition, and mechanical factors. The mechanical environment
of chondrocytes is believed to be an important determinant for joint health, and chondrocyte deformation in response to mechanical
loading is speculated to be an important regulator of metabolic activity. In previous studies of chondrocyte deformation,
articular cartilage was described as a biphasic material consisting of a homogeneous, isotropic, linearly elastic solid phase,
and an inviscid fluid phase. However, articular cartilage is known to be anisotropic and inhomogeneous across its depth. Therefore,
isotropic and homogeneous models cannot make appropriate predictions for tissue and cell stresses and strains. Here, we modelled
articular cartilage as a transversely isotropic, inhomogeneous (TI) material in which the anisotropy and inhomogeneity arose
naturally from the microstructure of the depth-dependent collagen fibril orientation and volumetric fraction, as well as the
chondrocyte shape and volumetric fraction. The purpose of this study was to analyse the deformation behaviour of chondrocytes
using the TI model of articular cartilage. In order to evaluate our model against experimental results, we simulated indentation
and unconfined compression tests for nominal compressions of 15%. Chondrocyte deformations were analysed as a function of
location within the tissue. The TI model predicted a non-uniform behaviour across tissue depth: in indentation testing, cell
height decreased by 43% in the superficial zone and between 11 and 29% in the deep zone. In unconfined compression testing,
cell height decreased by 32% in the superficial zone, 25% in the middle, and 18% in the deep zones. This predicted non-uniformity
is in agreement with experimental studies. The novelty of this study is the use of a cartilage material model accounting for
the intrinsic inhomogeneity and anisotropy of cartilage caused by its microstructure. 相似文献
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Intermolecular failure of L-type Ca2+ channel and ryanodine receptor signaling in hypertrophy 下载免费PDF全文
Xu M Zhou P Xu SM Liu Y Feng X Bai SH Bai Y Hao XM Han Q Zhang Y Wang SQ 《PLoS biology》2007,5(2):e21
Pressure overload–induced hypertrophy is a key step leading to heart failure. The Ca2+-induced Ca2+ release (CICR) process that governs cardiac contractility is defective in hypertrophy/heart failure, but the molecular mechanisms remain elusive. To examine the intermolecular aspects of CICR during hypertrophy, we utilized loose-patch confocal imaging to visualize the signaling between a single L-type Ca2+ channel (LCC) and ryanodine receptors (RyRs) in aortic stenosis rat models of compensated (CHT) and decompensated (DHT) hypertrophy. We found that the LCC-RyR intermolecular coupling showed a 49% prolongation in coupling latency, a 47% decrease in chance of hit, and a 72% increase in chance of miss in DHT, demonstrating a state of “intermolecular failure.” Unexpectedly, these modifications also occurred robustly in CHT due at least partially to decreased expression of junctophilin, indicating that intermolecular failure occurs prior to cellular manifestations. As a result, cell-wide Ca2+ release, visualized as “Ca2+ spikes,” became desynchronized, which contrasted sharply with unaltered spike integrals and whole-cell Ca2+ transients in CHT. These data suggested that, within a certain limit, termed the “stability margin,” mild intermolecular failure does not damage the cellular integrity of excitation-contraction coupling. Only when the modification steps beyond the stability margin does global failure occur. The discovery of “hidden” intermolecular failure in CHT has important clinical implications. 相似文献
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956.
Drug and gene delivery using gold nanoparticles 总被引:2,自引:0,他引:2
Monolayer-functionalized gold nanoparticles provide attractive vehicles for pharmaceutical delivery applications as a result
of their size and the unique properties and release mechanisms imparted by their monolayer. This review provides examples
of recent advances in the field of drug and gene delivery using gold nanoparticles. 相似文献
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