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Two independent relaxation kinetics methods were used to study samples of α-hemocyanin kindly furnished to us by members of the Biochemical Laboratory of the University of Groningen. A Durrum-Gibson stopped-flow apparatus was used to obtain concentration-jump data in the light-scattering mode. A recently developed pressurejump light-scattering apparatus was used to obtain completely independent data. The studies were made in 0.1 m acetate buffer at pH 5.7 containing 0.4 m NaCl, conditions under which equilibrium light-scattering studies had been reported by Engelborghs and Lontie (1973, J. Mol. Biol., 77, 577–587). In the companion paper (Kegeles, 1977, Arch. Biochem. Biophys., 180, 530–536), a model is proposed, consisting of a system containing a mixture of reactive and unreactive whole molecules, from which data are derived for the formation constant of whole molecules from halves and the fraction of material which is capable of undergoing reaction. The present study uses this estimate of this fraction of reactive material to permit the evaluation of overall rate constants and equilibrium constants. When the estimate of 65% of reactive material derived without making nonideality corrections is applied to the kinetics data, very satisfactory agreement is obtained between the equilibrium constant acquired from equilibrium data and the equilibrium constants derived from the kinetics data. 相似文献
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Yang DS Tandon A Chen F Yu G Yu H Arawaka S Hasegawa H Duthie M Schmidt SD Ramabhadran TV Nixon RA Mathews PM Gandy SE Mount HT St George-Hyslop P Fraser PE 《The Journal of biological chemistry》2002,277(31):28135-28142
Nicastrin is an integral component of the high molecular weight presenilin complexes that control proteolytic processing of the amyloid precursor protein and Notch. We report here that nicastrin is most probably a type 1 transmembrane glycoprotein that is expressed at moderate levels in the brain and in cultured neurons. Immunofluorescence studies demonstrate that nicastrin is localized in the endoplasmic reticulum, Golgi, and a discrete population of vesicles. Glycosidase analyses reveal that endogenous nicastrin undergoes a conventional, trafficking-dependent maturation process. However, when highly expressed in transfected cells, there is a disproportionate accumulation of the endo-beta-N-acetylglucosaminidase H-sensitive, immature form, with no significant increase in the levels of the fully mature species. Immunoprecipitation revealed that presenilin-1 interacts preferentially with mature nicastrin, suggesting that correct trafficking and co-localization of the presenilin complex components are essential for activity. These findings demonstrate that trafficking and post-translational modifications of nicastrin are tightly regulated processes that accompany the assembly of the active presenilin complexes that execute gamma-secretase cleavage. These results also underscore the caveat that simple overexpression of nicastrin in transfected cells may result in the accumulation of large amounts of the immature protein, which is apparently unable to assemble into the active complexes capable of processing amyloid precursor protein and Notch. 相似文献
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Caroline Schmutz Alison Cartwright Helen Williams Oliver Haworth John HH Williams Andrew Filer Mike Salmon Christopher D Buckley Jim Middleton 《Arthritis research & therapy》2010,12(4):R161
Introduction
Monocytes/macrophages accumulate in the rheumatoid (RA) synovium where they play a central role in inflammation and joint destruction. Identification of molecules involved in their accumulation and differentiation is important to inform therapeutic strategies. This study investigated the expression and function of chemokine receptor CCR9 in the peripheral blood (PB) and synovium of RA, non-RA patients and healthy volunteers. 相似文献5.
Yu WH Matsuoka Y Sziráki I Hashim A Lafrancois J Sershen H Duff KE 《Neurochemical research》2008,33(5):902-911
Familial Parkinson’s disease (PD) has been linked to point mutations and duplication of the α-synuclein gene and mutant α-synuclein
expression increases the vulnerability of neurons to exogenous insults. In this study, we analyzed the levels of dopamine
and its metabolites in the olfactory bulb (OB), and nigrostriatal regions of transgenic mice expressing human, mutant A53T
α-synuclein (α-syn tg) and their non-transgenic (ntg) littermates using a sub-toxic, moderate dose of MPTP to determine if
mutant human α-synuclein sensitizes the central dopaminergic systems to oxidative stress. We observed that after a single,
sub-lethal MPTP injection, dopamine levels were reduced in striatum and SN in both the α-syn tg and ntg mice. In the olfactory
bulb, a region usually resistant to MPTP toxicity, levels were reduced only in the α-syn tg mice. In addition, we identified
a significant increase in dopamine metabolism in the α-syn transgenic, but not ntg mice. Finally, MPTP treatment of α-syn
tg mice was associated with a marked elevation in the oxidative product, 3-nitrotyrosine that co-migrated with α-synuclein.
Cumulatively, the data support the hypothesis that mutant α-synuclein sensitizes dopaminergic neurons to neurotoxic insults
and is associated with greater oxidative stress. The α-syn tg line is therefore useful to study the genetic and environmental
inter-relationship in PD. 相似文献
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Jamil M Neto Marina GM Viturino Galina Ananina Flvia F Bajano Sueli M da S Costa Alicia B Roque Gessica FS Borges Raissa Franchi Priscila HH Rim Flvio M Medina Fernando F Costa Mnica B de Melo Jos PC de Vasconcellos 《Experimental biology and medicine (Maywood, N.J.)》2021,246(21):2290
This study aimed to investigate the association among genetic variants of the complement pathway CFB R32Q (rs641153), C3 R102G (rs2230199), and CFH (rs1410996) with age-related macular degeneration (AMD) in a sample of the Brazilian population. In a case-control study, 484 AMD patients were classified according to the clinical age-related maculopathy grading system (CARMS) and compared to 479 unrelated controls. The genetic variants rs1410996 of complement H (CFH), rs641153 of complement factor B (CFB), and rs2230199 of complement 3 (C3) were evaluated through polymerase chain reaction (PCR) and direct sequencing. The associations between single nucleotide polymorphisms (SNPs) and AMD, adjusted by age, were assessed by using logistic regression models. A statistically significant association was observed between AMD risk and rs2230199 variant with an OR of 2.01 (P = 0.0002) for CG individuals compared to CC individuals. Regarding the comparison of advanced AMD versus the control group, the OR was 2.12 (P = 0.0036) for GG versus AA genotypes for rs1410996 variant. Similarly, the OR for rs2230199 polymorphism was 2.3034 (P = 5.47e-05) when comparing CG individuals to CC carriers. In contrast, the rs641153 variant showed a significant protective effect against advanced AMD for GA versus GG genotype (OR = 0.4406; P = 0.0019). When comparing wet AMD versus controls, a significant association was detected for rs1410996 variant (OR = 2.16; P = 0.0039) comparing carriers of the homozygous GG versus AA genotype, as well as in the comparisons of GG (OR = 3.0713; P = 0.0046) and CG genotypes (OR = 2.2249; P = 0.0002) versus CC genotype for rs2230199 variant, respectively. The rs641153 variant granted a significant protective effect against wet AMD for GA versus GG genotypes (OR = 0.4601; P = 0.0044). Our study confirmed the risk association between rs2230199 and rs1410996 variants and AMD, and the protective role against AMD for rs641153 variant. 相似文献
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Belen Tizon Susmita Sahoo Haung Yu Sebastien Gauthier Asok R. Kumar Panaiyur Mohan Matthew Figliola Monika Pawlik Anders Grubb Yasuo Uchiyama Urmi Bandyopadhyay Ana Maria Cuervo Ralph A. Nixon Efrat Levy 《PloS one》2010,5(3)
Cystatin C (CysC) expression in the brain is elevated in human patients with epilepsy, in animal models of neurodegenerative conditions, and in response to injury, but whether up-regulated CysC expression is a manifestation of neurodegeneration or a cellular repair response is not understood. This study demonstrates that human CysC is neuroprotective in cultures exposed to cytotoxic challenges, including nutritional-deprivation, colchicine, staurosporine, and oxidative stress. While CysC is a cysteine protease inhibitor, cathepsin B inhibition was not required for the neuroprotective action of CysC. Cells responded to CysC by inducing fully functional autophagy via the mTOR pathway, leading to enhanced proteolytic clearance of autophagy substrates by lysosomes. Neuroprotective effects of CysC were prevented by inhibiting autophagy with beclin 1 siRNA or 3-methyladenine. Our findings show that CysC plays a protective role under conditions of neuronal challenge by inducing autophagy via mTOR inhibition and are consistent with CysC being neuroprotective in neurodegenerative diseases. Thus, modulation of CysC expression has therapeutic implications for stroke, Alzheimer''s disease, and other neurodegenerative disorders. 相似文献
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