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991.
992.
Exo1 competes with repair synthesis, converts NER intermediates to long ssDNA gaps, and promotes checkpoint activation 总被引:1,自引:0,他引:1
Giannattasio M Follonier C Tourrière H Puddu F Lazzaro F Pasero P Lopes M Plevani P Muzi-Falconi M 《Molecular cell》2010,40(1):50-62
Ultraviolet (UV) light induces DNA-damage checkpoints and mutagenesis, which are involved in cancer protection and tumorigenesis, respectively. How cells identify DNA lesions and convert them to checkpoint-activating structures is a major question. We show that during repair of UV lesions in noncycling cells, Exo1-mediated processing of nucleotide excision repair (NER) intermediates competes with repair DNA synthesis. Impediments of the refilling reaction allow Exo1 to generate extended ssDNA gaps, detectable by electron microscopy, which drive Mec1 kinase activation and will be refilled by long-patch repair synthesis, as shown by DNA combing. We provide evidence that this mechanism may?be stimulated by closely opposing UV lesions, represents a strategy to redirect problematic repair intermediates to alternative repair pathways, and may also be extended to physically different DNA damages. Our work has significant implications for understanding the coordination between repair of DNA lesions and checkpoint pathways to preserve genome stability. 相似文献
993.
The relocation of nutrients among dominant plant species, along with hydrological functions and soil chemistry in five plant
communities, including Eucalyptus plantation, Pinus plantation, shrubland, semi-natural, and natural secondary forests were investigated in central Yunnan, China. The nutrient
P, N, and K accumulation in above-ground biomass of Eucalyptus smithii (stems, barks, branches, and leaves) were the highest, followed by Pinus yunnanensis of both the Pinus plantation and the semi-natural forest. The nutrient retranslocation efficiency (NRE) of E. smithii was the highest for nutrient P, N, and K with values of 56, 66, and 67%, respectively, among the dominant plant species of
the five plant communities, while the NRE of P. yunnanensis in Pinus plantation had the second highest value of NRE for nutrient N. The nutrient content (available P, N, and soil organic matter)
in the upper two soil layers under Eucalyptus and Pinus plantations was correspondingly found to be lower than that of the other forests. Moreover, under the Eucalyptus and Pinus plantations, surface runoff, soil erosion, and nutrient loss were more serious, and the water storage of litterfall and canopy
interception were significantly lower than that in the other plant communities. Accordingly, we suggest that single-species
plantations cannot present the same ecological benefits as natural forests, because of their simple, uniform structures, and
the characteristics of the dominant plant species. 相似文献
994.
We undertook a comparative immunolocalisation study on type II collagen, aggrecan and perlecan in a number of 12- to 14-week-old
human foetal and postnatal (7–19 months) ovine joints including finger, toe, knee, elbow, hip and shoulder. This demonstrated
that perlecan followed a virtually identical immunolocalisation pattern to that of type II collagen in the foetal tissues,
but a slightly divergent localisation pattern in adult tissues. Aggrecan was also localised in the cartilaginous joint tissues,
which were clearly delineated by toluidine blue staining and the type II collagen immunolocalisations. It was also present
in the capsular joint tissues and in ligaments and tendons in the joint, which stained poorly or not at all with toluidine
blue. In higher power microscopic views, antibodies to perlecan also stained small blood vessels in the synovial lining tissues
of the joint capsule; however, this was not discernable in low power macroscopic views where the immunolocalisation of perlecan
to pericellular regions of cells within the cartilaginous rudiments was a predominant feature. Perlecan was also evident in
small blood vessels in stromal connective tissues associated with the cartilage rudiments and with occasional nerves in the
vicinity of the joint tissues. Perlecan was expressed by rounded cells in the enthesis attachment points of tendons to bone
and in rounded cells in the inner third of the meniscus, which stained prominently with type II collagen and aggrecan identifying
the chondrogenic background of these cells and local compressive loads. Flattened cells within the tendon and in the surface
laminas of articular cartilages and the meniscus did not express perlecan. Collected evidence presented herein, therefore,
indicates that besides being a basement membrane component, perlecan is also a marker of chondrogenic cells in prenatal cartilages.
In postnatal cartilages, perlecan displayed a pericellular localisation pattern rather than the territorial or interterritorial
localisation it displayed in foetal cartilages. This may reflect processing of extracellular perlecan presumably as a consequence
of intrinsic biomechanical loading on these tissues or to divergent functions for perlecan and type II collagen in adult compared
to prenatal tissues. 相似文献
995.
Kelly-Ann S. Schlegel Zhi-Qiang Yang Thomas S. Reger Youheng Shu Rowena Cube Kenneth E. Rittle Phung Bondiskey Mark G. Bock George D. Hartman Cuyue Tang Jeanine Ballard Yuhsin Kuo Thomayant Prueksaritanont Cindy E. Nuss Scott M. Doran Steven V. Fox Susan L. Garson Richard L. Kraus Yuxing Li Victor N. Uebele James C. Barrow 《Bioorganic & medicinal chemistry letters》2010,20(17):5147-5152
The discovery and synthesis of 4,4-disubstituted quinazolinones as T-type calcium channel antagonists is reported. Based on lead compounds 2 and 3, a focused SAR campaign driven by the optimization of potency, metabolic stability, and pharmacokinetic profile identified 45 as a potent T-type Ca2+ channel antagonist with minimized PXR activation. In vivo, 45 suppressed seizure frequency in a rat model of absence epilepsy and showed significant alterations of sleep architecture after oral dosing to rats as measured by EEG. 相似文献
996.
Lily Jakulj Maud N. Vissers Jelske N. van der Veen Cindy Kunne John J.P. Kastelein 《FEBS letters》2010,584(16):3625-3628
Ezetimibe stimulates faecal neutral sterol (FNS) excretion in mice, which cannot be explained by cholesterol absorption inhibition alone. We investigated whether these effects are mediated via the sterol exporter ATP binding cassette transporter G8 (abcg8). Ezetimibe increased FNS excretion 2.7-fold in WT mice and 1.5-fold in abcg8−/− mice, without affecting biliary cholesterol secretion. Daily FNS excretion exceeded the sum of dietary cholesterol intake and biliary secretion by about 60%. Ezetimibe enhanced this ‘extra’ FNS excretion by 3.5-fold and 1.5-fold in wildtype (WT) and abcg8−/− mice, respectively. Ezetimibe stimulates fecal sterol excretion of non-biliary and non-dietary origin, probably through stimulation of trans-intestinal cholesterol excretion. We show that this effect depends on intact abcg8 function. 相似文献
997.
998.
Receptor internalization from the cell surface occurs through several mechanisms. Some of these mechanisms, such as clathrin coated pits, are well understood. The M(2) muscarinic acetylcholine receptor undergoes internalization via a poorly-defined clathrin-independent mechanism. We used isotope coded affinity tagging and mass spectrometry to identify the scaffolding protein, receptor for activated C kinase (RACK1) as a protein enriched in M(2)-immunoprecipitates from M(2)-expressing cells over those of non-M(2) expressing cells. Treatment of cells with the agonist carbachol disrupted the interaction of RACK1 with M(2). We further found that RACK1 overexpression inhibits the internalization and subsequent down regulation of the M(2) receptor in a receptor subtype-specific manner. Decreased RACK1 expression increases the rate of agonist internalization of the M(2) receptor, but decreases the extent of subsequent down-regulation. These results suggest that RACK1 may both interfere with agonist-induced sequestration and be required for subsequent targeting of internalized M(2) receptors to the degradative pathway. 相似文献
999.
Stephanie C. Terrizzi Cindy Banh Laurent Brossay 《Journal of visualized experiments : JoVE》2010,(35)
Killer cell lectin-like receptor G1 (KLRG1) is a type II transmembrane glycoprotein inhibitory receptor belonging to the C type lectin-like superfamily. KLRG1 exists both as a monomer and as a disulfide-linked homodimer. This well-conserved receptor is found on the most mature and recently activated NK cells as well as on a subset of effector/memory T cells.Using KLRG1 tetramer as well as other methods, E-, N-, and R-cadherins were identified as KLRG1 ligands. These Ca2+-dependent cell-cell adhesion molecules comprises of an extracellular domain containing five cadherin repeats responsible for cell-cell interactions, a transmembrane domain and a cytoplasmic domain that is linked to the actin cytoskeleton. Generation of the KLRG1 tetramer was essential to the identification of the KLRG1 ligands. KLRG1 tetramer is also a unique tool to elucidate the roles cadherin and KLRG1 play in regulating the immune response and tissue integrity.Open in a separate windowClick here to view.(43M, flv) 相似文献
1000.
David H. Small Lisa R. Fodero Dusan Losic Cindy Chu Marie-Isabel Aguilar Lisandra L. Martin Mary Chebib 《International journal of peptide research and therapeutics》2003,10(5-6):401-404
Alzheimer's disease (AD) is caused by the accumulation of β-amyloid protein (Aβ) in the brain. The aggregation of β-amyloid
protein to higher molecular weight fibrillar forms is also considered to be an important step in the pathogenesis of the disease.
The memory problems associated with AD are likely to be caused by changes in synaptic plasticity. Recent studies suggest that
Aβ binds to the α 7 nicotinic acetylcholine receptor (α 7 nAChR), which plays an important role in synaptic plasticity and
memory. A loop domain localized towards the C-terminus of the extracellular region of the receptor has been identified as
forming part of a putative Aβ-binding site. In cell culture experiments, the binding of Aβ to the α 7 nAChR has been found
to cause an increase in the level of acetylcholinesterase, which is also increased around amyloid plaques in the AD brain.
These studies indicate that the Aβ-binding site on the α 7 nAChR receptor is an important new target for therapeutic development
in AD. 相似文献