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41.
Residual dipolar couplings (RDCs) observed between nuclear spins in molecules in partially oriented media have become a valuable source of information for NMR spectroscopists seeking to structurally characterize biological macromolecules. Examination of the form of the direct (D) and indirect (J) nuclear spin-spin coupling Hamiltonians indicates that all observed RDCs contain an unknown contribution from the anisotropic part of J (J) in addition to the direct dipolar contribution, D
PQ. Here, we evaluate the influence of J on RDCs through a series of DFT calculations on model peptides. Very small corrections to one-bond RDCs measured between heavy atoms in peptides and proteins are recommended: +0.51% for N-C spin pairs, and +0.45% for C-C spin pairs. The corrections to RDCs involving at least one proton are negligible. This latter point is likely to be equally applicable to nucleic acids and oligosaccharides in addition to peptides and proteins. Finally, the orientations of the J(N, C) and J(C, C) tensors in the molecular framework are reported for glycylglycine. 相似文献
42.
Peroxisome proliferator activated receptor-gamma (PPAR-gamma) mediates the action of gamma linolenic acid in breast cancer cells 总被引:6,自引:0,他引:6
Jiang WG Redfern A Bryce RP Mansel RE 《Prostaglandins, leukotrienes, and essential fatty acids》2000,62(2):119-127
Gamma linolenic acid (GLA) is a polyunsaturated fatty acid, which induces cytotoxicity and regulates cell adhesion in cancer cells. The molecular mechanism of these actions is not clear. We have shown that GLA acts via peroxisome proliferator activated receptors (PPARs), by stimulating their phosphorylation and translocation to the nucleus. Removing PPAR gamma with antisense oligos abolished the effect of GLA on the expression of adhesion molecules and tumour suppressor genes, whereas removal of PPAR alpha had no effect. Tissues from patients with breast cancer showed a reduction of expression of both PPARs in cancer tissues, as compared with normal. Thus, PPAR gamma serves as the receptor for GLA in the regulation of gene expression in breast cancer cells. 相似文献
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Katarzyna A. Rejniak Shizhen E. Wang Nicole S. Bryce Hang Chang Bahram Parvin Jerome Jourquin Lourdes Estrada Joe W. Gray Carlos L. Arteaga Alissa M. Weaver Vito Quaranta Alexander R. A. Anderson 《PLoS computational biology》2010,6(8)
Most tumors arise from epithelial tissues, such as mammary glands and lobules, and their initiation is associated with the disruption of a finely defined epithelial architecture. Progression from intraductal to invasive tumors is related to genetic mutations that occur at a subcellular level but manifest themselves as functional and morphological changes at the cellular and tissue scales, respectively. Elevated proliferation and loss of epithelial polarization are the two most noticeable changes in cell phenotypes during this process. As a result, many three-dimensional cultures of tumorigenic clones show highly aberrant morphologies when compared to regular epithelial monolayers enclosing the hollow lumen (acini). In order to shed light on phenotypic changes associated with tumor cells, we applied the bio-mechanical IBCell model of normal epithelial morphogenesis quantitatively matched to data acquired from the non-tumorigenic human mammary cell line, MCF10A. We then used a high-throughput simulation study to reveal how modifications in model parameters influence changes in the simulated architecture. Three parameters have been considered in our study, which define cell sensitivity to proliferative, apoptotic and cell-ECM adhesive cues. By mapping experimental morphologies of four MCF10A-derived cell lines carrying different oncogenic mutations onto the model parameter space, we identified changes in cellular processes potentially underlying structural modifications of these mutants. As a case study, we focused on MCF10A cells expressing an oncogenic mutant HER2-YVMA to quantitatively assess changes in cell doubling time, cell apoptotic rate, and cell sensitivity to ECM accumulation when compared to the parental non-tumorigenic cell line. By mapping in vitro mutant morphologies onto in silico ones we have generated a means of linking the morphological and molecular scales via computational modeling. Thus, IBCell in combination with 3D acini cultures can form a computational/experimental platform for suggesting the relationship between the histopathology of neoplastic lesions and their underlying molecular defects. 相似文献
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Kim DY Carey BW Wang H Ingano LA Binshtok AM Wertz MH Pettingell WH He P Lee VM Woolf CJ Kovacs DM 《Nature cell biology》2007,9(7):755-764
BACE1 activity is significantly increased in the brains of Alzheimer's disease patients, potentially contributing to neurodegeneration. The voltage-gated sodium channel (Na(v)1) beta2-subunit (beta2), a type I membrane protein that covalently binds to Na(v)1 alpha-subunits, is a substrate for BACE1 and gamma-secretase. Here, we find that BACE1-gamma-secretase cleavages release the intracellular domain of beta2, which increases mRNA and protein levels of the pore-forming Na(v)1.1 alpha-subunit in neuroblastoma cells. Similarly, endogenous beta2 processing and Na(v)1.1 protein levels are elevated in brains of BACE1-transgenic mice and Alzheimer's disease patients with high BACE1 levels. However, Na(v)1.1 is retained inside the cells and cell surface expression of the Na(v)1 alpha-subunits and sodium current densities are markedly reduced in both neuroblastoma cells and adult hippocampal neurons from BACE1-transgenic mice. BACE1, by cleaving beta2, thus regulates Na(v)1 alpha-subunit levels and controls cell-surface sodium current densities. BACE1 inhibitors may normalize membrane excitability in Alzheimer's disease patients with elevated BACE1 activity. 相似文献
48.
Shubha Gururaja Rao Michal M. Janiszewski Edward Duca Bryce Nelson Kanishk Abhinav Ioanna Panagakou Sharron Vass Margarete M.S. Heck 《Nucleic acids research》2015,43(7):3546-3562
Identification of components essential to chromosome structure and behaviour remains a vibrant area of study. We have previously shown that invadolysin is essential in Drosophila, with roles in cell division and cell migration. Mitotic chromosomes are hypercondensed in length, but display an aberrant fuzzy appearance. We additionally demonstrated that in human cells, invadolysin is localized on the surface of lipid droplets, organelles that store not only triglycerides and sterols but also free histones H2A, H2Av and H2B. Is there a link between the storage of histones in lipid droplets and the aberrantly structured chromosomes of invadolysin mutants? We have identified a genetic interaction between invadolysin and nonstop, the de-ubiquitinating protease component of the SAGA (Spt-Ada-Gcn5-acetyltransferase) chromatin-remodelling complex. invadolysin and nonstop mutants exhibit phenotypic similarities in terms of chromosome structure in both diploid and polyploid cells. Furthermore, IX-141/not1 transheterozygous animals accumulate mono-ubiquitinated histone H2B (ubH2B) and histone H3 tri-methylated at lysine 4 (H3K4me3). Whole mount immunostaining of IX-141/not1 transheterozygous salivary glands revealed that ubH2B accumulates surprisingly in the cytoplasm, rather than the nucleus. Over-expression of the Bre1 ubiquitin ligase phenocopies the effects of mutating either the invadolysin or nonstop genes. Intriguingly, nonstop and mutants of other SAGA subunits (gcn5, ada2b and sgf11) all suppress an invadolysin-induced rough eye phenotype. We conclude that the abnormal chromosome phenotype of invadolysin mutants is likely the result of disrupting the histone modification cycle, as accumulation of ubH2B and H3K4me3 is observed. We further suggest that the mislocalization of ubH2B to the cytoplasm has additional consequences on downstream components essential for chromosome behaviour. We therefore propose that invadolysin plays a crucial role in chromosome organization via its interaction with the SAGA complex. 相似文献
49.
Sarah N. Fontaine Jennifer N. Rauch Bryce A. Nordhues Victoria A. Assimon Andrew R. Stothert Umesh K. Jinwal Jonathan J. Sabbagh Lyra Chang Stanley M. Stevens Jr. Erik R. P. Zuiderweg Jason E. Gestwicki Chad A. Dickey 《The Journal of biological chemistry》2015,290(21):13115-13127
The constitutively expressed heat shock protein 70 kDa (Hsc70) is a major chaperone protein responsible for maintaining proteostasis, yet how its structure translates into functional decisions regarding client fate is still unclear. We previously showed that Hsc70 preserved aberrant Tau, but it remained unknown if selective inhibition of the activity of this Hsp70 isoform could facilitate Tau clearance. Using single point mutations in the nucleotide binding domain, we assessed the effect of several mutations on the functions of human Hsc70. Biochemical characterization revealed that one mutation abolished both Hsc70 ATPase and refolding activities. This variant resembled the ADP-bound conformer at all times yet remained able to interact with cofactors, nucleotides, and substrates appropriately, resembling a dominant negative Hsc70 (DN-Hsc70). We then assessed the effects of this DN-Hsc70 on its client Tau. DN-Hsc70 potently facilitated Tau clearance via the proteasome in cells and brain tissue, in contrast to wild type Hsc70 that stabilized Tau. Thus, DN-Hsc70 mimics the action of small molecule pan Hsp70 inhibitors with regard to Tau metabolism. This shift in Hsc70 function by a single point mutation was the result of a change in the chaperome associated with Hsc70 such that DN-Hsc70 associated more with Hsp90 and DnaJ proteins, whereas wild type Hsc70 was more associated with other Hsp70 isoforms. Thus, isoform-selective targeting of Hsc70 could be a viable therapeutic strategy for tauopathies and possibly lead to new insights in chaperone complex biology. 相似文献
50.
Ermentrout GB Beverlin B Troyer T Netoff TI 《Journal of computational neuroscience》2011,31(2):185-197
Phase resetting curves (PRCs) provide a measure of the sensitivity of oscillators to perturbations. In a noisy environment,
these curves are themselves very noisy. Using perturbation theory, we compute the mean and the variance for PRCs for arbitrary
limit cycle oscillators when the noise is small. Phase resetting curves and phase dependent variance are fit to experimental
data and the variance is computed using an ad-hoc method. The theoretical curves of this phase dependent method match both
simulations and experimental data significantly better than an ad-hoc method. A dual cell network simulation is compared to
predictions using the analytical phase dependent variance estimation presented in this paper. We also discuss how entrainment
of a neuron to a periodic pulse depends on the noise amplitude. 相似文献