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141.
Comparative analysis of diffusive and stress induced nutrient transport efficiency in the lacunar-canalicular system of osteons 总被引:3,自引:0,他引:3
Marker migration experiments suggest that cyclic mechanical loading of cortical bone in vivo increases marker penetration into bone. Is this a result of stress induced fluid flow or of stress stimulation of active transport processes? Active lacunar-canalicular transport of nutrients was suggested by Ham in 1979 on the basis of the presence of actin filaments in osteocyte processes and their suspected role in cell motility. In addition, Tanaka in 1984 observed active transport of microperoxidase in bone and Tanaka-Kamioka et al. in 1998 observed experimentally that osteocyte processes are able to actively change their form. In this study we performed parametric and comparative analyses of the transport efficiencies of diffusion and stress generated fluid flow of (glucose) nutrients in lacunar-canalicular systems in cortical bone. The result obtained is that neither diffusion nor stress induced fluid flow is capable of sustaining osteocyte viability. It is possible that cyclic stress stimulates an active nutrient transport mechanism to supplement stress flows. 相似文献
142.
Normal human somatic cells, unlike cancer cells, stop dividing after a limited number of cell divisions through the process termed cellular senescence or replicative senescence, which functions as a tumor-suppressive mechanism and may be related to organismal aging. By means of the cDNA subtractive hybridization, we identified eight genes upregulated during normal chromosome 3-induced cellular senescence in a human renal cell carcinoma cell line. Among them is the DNCI1 gene encoding an intermediate chain 1 of the cytoplasmic dynein, a microtubule motor that plays a role in chromosome movement and organelle transport. The DNCI1 mRNA was also upregulated during in vitro aging of primary human fibroblasts. In contrast, other components of cytoplasmic dynein showed no significant change in mRNA expression during cellular aging. Cell growth arrest by serum starvation, contact inhibition, or gamma-irradiation did not induce the DNCI1 mRNA, suggesting its specific role in cellular senescence. The DNCI1 gene is on the long arm of chromosome 7 where tumor suppressor genes and a senescence-inducing gene for a group of immortal cell lines (complementation group D) are mapped. This is the first report that links a component of molecular motor complex to cellular senescence, providing a new insight into molecular mechanisms of cellular senescence. 相似文献
143.
Shirvan A Kimron M Holdengreber V Ziv I Ben-Shaul Y Melamed S Melamed E Barzilai A Solomon AS 《The Journal of biological chemistry》2002,277(51):49799-49807
Damage to the optic nerve in mammals induces retrograde degeneration and apoptosis of the retinal ganglion cell (RGC) bodies. The mechanisms that mediate the response of the neuronal cells to the axonal injury are still unknown. We have previously shown that semaphorins, axon guidance molecules with repulsive cues, are capable of mediating apoptosis in cultured neuronal cells (Shirvan, A., Ziv, I., Fleminger, G., Shina, R., He, Z., Brudo, I., Melamed, E., and Brazilai, A. (1999) J. Neurochem. 73, 961-971). In this study, we examined the involvement of semaphorins in an in vivo experimental animal model of complete axotomy of the rat optic nerve. We demonstrate that a marked induction of type III semaphorin proteins takes place in ipsilateral retinas at early stages following axotomy, well before any morphological signs of RGC apoptosis can be detected. Time course analysis revealed that a peak of expression occurred after 2-3 days and then declined. A small conserved peptide derived from semaphorin 3A that was previously shown to induce neuronal death in culture was capable of inducing RGC loss upon its intravitreous injection into the rat eye. Moreover, we demonstrate a marked inhibition of RGC loss when axotomized eyes were co-treated by intravitreous injection of function-blocking antibodies against the semaphorin 3A-derived peptide. Marked neuronal protection from degeneration was also observed when the antibodies were applied 24 h post-injury. We therefore suggest that semaphorins are key proteins that modulate the cell fate of axotomized RGC. Neutralization of the semaphorin repulsive function may serve as a promising new approach for treatment of traumatic injury in the adult mammalian central nervous system or of ophthalmologic diseases such as glaucoma and ischemic optic neuropathy that induce apoptotic RGC death. 相似文献
144.
Shallom D Belakhov V Solomon D Gilead-Gropper S Baasov T Shoham G Shoham Y 《FEBS letters》2002,514(2-3):163-167
The alpha-L-arabinofuranosidase from Geobacillus stearothermophilus T-6 (AbfA T-6) belongs to the retaining family 51 glycoside hydrolases. The conserved Glu175 was proposed to be the acid-base catalytic residue. AbfA T-6 exhibits residual activity towards aryl beta-D-xylopyranosides. This phenomenon was used to examine the catalytic properties of the putative acid-base mutant E175A. Data from kinetic experiments, pH profiles, azide rescue, and the identification of the xylopyranosyl azide product provide firm support to the assignment of Glu175 as the acid-base catalyst of AbfA T-6. 相似文献
145.
Moriarity JL Hurt KJ Resnick AC Storm PB Laroy W Schnaar RL Snyder SH 《The Journal of biological chemistry》2002,277(19):16968-16975
UDP-glucuronate decarboxylase (UGD) catalyzes the formation of UDP-xylose from UDP-glucuronate. UDP-xylose is then used to initiate glycosaminoglycan biosynthesis on the core protein of proteoglycans. In a yeast two-hybrid screen with the protein kinase Akt (protein kinase B), we detected interactions with a novel sequence, which we cloned and expressed. The expressed protein displayed UGD activity but did not display the activities of homologous nucleotide sugar epimerases or dehydratases. We did not detect phosphorylation of UGD by Akt nor did we detect any influence of Akt on UGD activity. Effects of UGD on Akt kinase activity were also absent. Northern blot and Western blot analyses revealed the presence of UGD in multiple tissues and brain regions. Subcellular studies and histochemistry localized UGD protein to the perinuclear Golgi where xylosylation of proteoglycan core proteins is known to occur. 相似文献
146.
Dynamics of T cells and TCR excision circles differ after treatment of acute and chronic HIV infection 总被引:5,自引:0,他引:5
Lewin SR Ribeiro RM Kaufmann GR Smith D Zaunders J Law M Solomon A Cameron PU Cooper D Perelson AS 《Journal of immunology (Baltimore, Md. : 1950)》2002,169(8):4657-4666
We quantified T cell proliferation and thymic function in primary HIV infection (PHI; n = 19) and chronic HIV infection (CHI; n = 14) by measuring Ki67 staining and TCR excision circle (TREC) number. After antiretroviral therapy of PHI there is a profound decrease in the number and percentage of Ki67(+) T cells (<6% Ki67(+)) with no significant increase in TREC per million cells and a transient increase in TREC per milliliter. In contrast, after antiretroviral therapy of CHI there is a reduction in the percentage but little change in the total number of Ki67(+)CD4(+) T cells associated with increases in both TREC per million cells and TREC per milliliter. Using a mathematical model that accounts for proliferation, death, and redistribution of T cells, we find that redistribution is consistent with the TREC changes observed during treatment of PHI and that an increase in thymic output is needed to explain the increase in TREC during treatment of CHI. Consideration of TREC per milliliter shows that changes in proliferation alone cannot explain the changes in TREC. In addition, although increased proliferation of memory cells in HIV infection has been established, we find no difference in TREC per million CD45RA(-) "memory" T cells between healthy and infected individuals (p = 0.154 for CD4(+); p = 0.383 for CD8(+)). Finally, although the number of TREC per million cells is always much lower in memory T cells than in naive T cells, in the setting of HIV infection, given that memory cells make up a larger proportion of total T cells, we find that 50% of TREC per milliliter in CD4(+) T cells is harbored in the CD45RA(-) "memory" subset of our infected subjects. 相似文献
147.
Dall'Acqua WF Woods RM Ward ES Palaszynski SR Patel NK Brewah YA Wu H Kiener PA Langermann S 《Journal of immunology (Baltimore, Md. : 1950)》2002,169(9):5171-5180
Many biological functions, including control of the homeostasis and maternofetal transfer of serum gamma-globulins, are mediated by the MHC class I-related neonatal FcR (FcRn). A correlation exists in mice between the binding affinity of IgG1/Fc fragments to FcRn at pH 6.0 and their serum t(1/2). To expand this observation, phage display of mutagenized Fc fragments derived from a human IgG1 was used to increase their affinity to both murine and human FcRn. Ten variants were identified that have a higher affinity toward murine and human FcRn at pH 6.0, with DeltaDeltaG (DeltaG(wild type) - DeltaG(mutant)) from 1.0 to 2.0 kcal/mol and from 0.6 to 2.4 kcal/mol, respectively. Those variants exhibit a parallel increase in binding at pH 7.4 to murine, but not human, FcRn. Although not degraded in blood in vitro, accumulated in tissues, nor excreted in urine, their serum concentration in mice is decreased. We propose that higher affinity to FcRn at pH 7.4 adversely affects release into the serum and offsets the benefit of the enhanced binding at pH 6.0. 相似文献
148.
The growth of the biotrophic pathogen Cladosporium fulvum within the tomato (Lycopersicon esculentum Mill.) leaf is restricted to the intercellular space. Previous studies from this laboratory have demonstrated that gamma-aminobutyric acid (GABA) accumulates to millimolar concentrations in the apoplast during a compatible interaction. We decided to further investigate the role of GABA during infection. A gene encoding a required enzyme for GABA metabolism, GABA transaminase (Gat1), was cloned and sequenced from C. fulvum. The predicted protein sequence of Gat1 had high homology to other fungal GABA transaminases, particularly from Aspergillus nidulans. In vitro expression experiments revealed Gat1 to be strongly expressed during fungal growth on both GABA and glutamate whereas nearly no expression was evident during nitrogen starvation conditions. Expression of Gat1 was also apparent during infection, suggesting for the first time that C. fulvum actively metabolises GABA during infection. This indicates that the fungus may be utilising the GABA in the apoplast as a nutrient source. Further analysis revealed that the expression of tomato glutamate decarboxylase, the enzyme responsible for GABA synthesis, appeared appreciably higher during a compatible interaction than in the incompatible interaction. These findings imply that the infecting fungus may alter the physiology of the tomato leaf with the result that a source of nitrogen is supplied. 相似文献
149.
Hung CS Bouckaert J Hung D Pinkner J Widberg C DeFusco A Auguste CG Strouse R Langermann S Waksman G Hultgren SJ 《Molecular microbiology》2002,44(4):903-915
The first step in the colonization of the human urinary tract by pathogenic Escherichia coli is the mannose-sensitive binding of FimH, the adhesin present at the tip of type 1 pili, to the bladder epithelium. We elucidated crystallographically the interactions of FimH with D-mannose. The unique site binding pocket occupied by D-mannose was probed using site-directed mutagenesis. All but one of the mutants examined had greatly diminished mannose-binding activity and had also lost the ability to bind human bladder cells. The binding activity of the mono-saccharide D-mannose was delineated from this of mannotriose (Man(alpha 1-3)[Man(alpha 1-6)]Man) by generating mutants that abolished D-mannose binding but retained mannotriose binding activity. Our structure/function analysis demonstrated that the binding of the monosaccharide alpha-D-mannose is the primary bladder cell receptor for uropathogenic E. coli and that this event requires a highly conserved FimH binding pocket. The residues in the FimH mannose-binding pocket were sequenced and found to be invariant in over 200 uropathogenic strains of E. coli. Only enterohaemorrhagic E. coli (EHEC) possess a sequence variation within the mannose-binding pocket of FimH, suggesting a naturally occurring mechanism of attenuation in EHEC bacteria that would prevent them from being targeted to the urinary tract. 相似文献
150.
Wacker DA Santella JB Gardner DS Varnes JG Estrella M DeLucca GV Ko SS Tanabe K Watson PS Welch PK Covington M Stowell NC Wadman EA Davies P Solomon KA Newton RC Trainor GL Friedman SM Decicco CP Duncia JV 《Bioorganic & medicinal chemistry letters》2002,12(13):1785-1789
CCR3 antagonist leads with IC(50) values in the microM range were converted into low nM binding compounds that displayed in vitro inhibition of human eosinophil chemotaxis induced by human eotaxin. In particular, 4-benzylpiperidin-1-yl-n-propylureas and erythro-3-(4-benzyl-2-(alpha-hydroxyalkyl)piperidin-1-yl)-n-propylureas (obtained via Beak reaction of N-BOC-4-benzylpiperidine) exhibited single digit nanomolar IC(50) values for CCR3. 相似文献