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921.
Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia 总被引:55,自引:0,他引:55
Allen TM O'Connor DH Jing P Dzuris JL Mothé BR Vogel TU Dunphy E Liebl ME Emerson C Wilson N Kunstman KJ Wang X Allison DB Hughes AL Desrosiers RC Altman JD Wolinsky SM Sette A Watkins DI 《Nature》2000,407(6802):386-390
Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections are characterized by early peaks of viraemia that decline as strong cellular immune responses develop. Although it has been shown that virus-specific CD8-positive cytotoxic T lymphocytes (CTLs) exert selective pressure during HIV and SIV infection, the data have been controversial. Here we show that Tat-specific CD8-positive T-lymphocyte responses select for new viral escape variants during the acute phase of infection. We sequenced the entire virus immediately after the acute phase, and found that amino-acid replacements accumulated primarily in Tat CTL epitopes. This implies that Tat-specific CTLs may be significantly involved in controlling wild-type virus replication, and suggests that responses against viral proteins that are expressed early during the viral life cycle might be attractive targets for HIV vaccine development. 相似文献
922.
923.
A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease 总被引:50,自引:0,他引:50
Janus C Pearson J McLaurin J Mathews PM Jiang Y Schmidt SD Chishti MA Horne P Heslin D French J Mount HT Nixon RA Mercken M Bergeron C Fraser PE St George-Hyslop P Westaway D 《Nature》2000,408(6815):979-982
Much evidence indicates that abnormal processing and extracellular deposition of amyloid-beta peptide (A beta), a proteolytic derivative of the beta-amyloid precursor protein (betaAPP), is central to the pathogenesis of Alzheimer's disease (reviewed in ref. 1). In the PDAPP transgenic mouse model of Alzheimer's disease, immunization with A beta causes a marked reduction in burden of the brain amyloid. Evidence that A beta immunization also reduces cognitive dysfunction in murine models of Alzheimer's disease would support the hypothesis that abnormal A beta processing is essential to the pathogenesis of Alzheimer's disease, and would encourage the development of other strategies directed at the 'amyloid cascade'. Here we show that A beta immunization reduces both deposition of cerebral fibrillar A beta and cognitive dysfunction in the TgCRND8 murine model of Alzheimer's disease without, however, altering total levels of A beta in the brain. This implies that either a approximately 50% reduction in dense-cored A beta plaques is sufficient to affect cognition, or that vaccination may modulate the activity/abundance of a small subpopulation of especially toxic A beta species. 相似文献
924.
925.
The type III inositol 1,4,5-trisphosphate receptor (InsP3R) is an important intracellular calcium (Ca2+) release channel in the pancreatic beta cell. Pancreatic beta cells secrete insulin following a characteristic change in membrane potential that leads to an increase in cytoplasmic Ca2+. Both extracellular Ca2+ and Ca2+ mobilized from InsP3-sensitive stores contribute to this increase. RIN-m5F cells, an insulin-secreting beta cell line, preferentially express the type III InsP3R. These cells have been useful in determining the regulatory properties of the type III InsP3R and the role of this isoform in an intact cell. The type III InsP3R is ideal for signal initiation because high cytoplasmic Ca2+ does not inhibit its activity. Altered insulin secretion, the result of changes in Ca2+ handling by the beta cell, has significant clinical consequences. 相似文献
926.
927.
New insights into copper monooxygenases and peptide amidation: structure, mechanism and function 总被引:9,自引:0,他引:9
Prigge ST Mains RE Eipper BA Amzel LM 《Cellular and molecular life sciences : CMLS》2000,57(8-9):1236-1259
Many bioactive peptides must be amidated at their carboxy terminus to exhibit full activity. Surprisingly, the amides are not generated by a transamidation reaction. Instead, the hormones are synthesized from glycine-extended intermediates that are transformed into active amidated hormones by oxidative cleavage of the glycine N-C alpha bond. In higher organisms, this reaction is catalyzed by a single bifunctional enzyme, peptidylglycine alpha-amidating monooxygenase (PAM). The PAM gene encodes one polypeptide with two enzymes that catalyze the two sequential reactions required for amidation. Peptidylglycine alpha-hydroxylating monooxygenase (PHM; EC 1.14.17.3) catalyzes the stereospecific hydroxylation of the glycine alpha-carbon of all the peptidylglycine substrates. The second enzyme, peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL; EC 4.3.2.5), generates alpha-amidated peptide product and glyoxylate. PHM contains two redox-active copper atoms that, after reduction by ascorbate, catalyze the reduction of molecular oxygen for the hydroxylation of glycine-extended substrates. The structure of the catalytic core of rat PHM at atomic resolution provides a framework for understanding the broad substrate specificity of PHM, identifying residues critical for PHM activity, and proposing mechanisms for the chemical and electron-transfer steps in catalysis. Since PHM is homologous in sequence and mechanism to dopamine beta-monooxygenase (DBM; EC 1.14.17.1), the enzyme that converts dopamine to norepinephrine during catecholamine biosynthesis, these structural and mechanistic insights are extended to DBM. 相似文献
928.
Peschke E Ebelt H Brömme HJ Peschke D 《Cellular and molecular life sciences : CMLS》2000,57(1):158-164
This study compares functional and morphological alterations caused by application of alloxan, streptozotocin, xanthine oxidase/hypoxanthine
(generation of reactive oxygen species), or S-nitroso-N-acetyl-D,L-penicillamine (SNAP, liberation of nitric oxide) to isolated
rat pancreatic islets in vitro. In perifusion experiments, membrane leakage—detected by non-stimulated insulin release—was
found after application of all drugs, but showed a substance-specific time pattern. Twenty-four hours after application of
the classical diabetogens (alloxan or streptozotocin), potassium chloride- and glucose-stimulated insulin secretion were markedly
reduced, while a persistent reduction was observed neither after exposure to xanthine oxidase/hypoxanthine, nor to SNAP. Morphological
analysis of the islets revealed that nearly all β-cells were destroyed following alloxan or streptozotocin treatment, while the majority of β-cells were configured regularly after application of xanthine oxidase/hypoxanthine or SNAP. Necrotic cells found after xanthine
oxidase/hypoxanthine usually differed in morphology from those observed after application of the classical diabetogens. While
the former cells were characterised by swollen nuclei, the latter had shrunken nuclei with irregular condensed chromatin.
Apoptosis was found only following nitric oxide exposure. Due to these differences, it seems unlikely that alloxan, streptozotocin,
xanthine oxidase/hypoxanthine, and nitric oxide have a common major feature in their toxic action.
Received 16 September 1999; received after revision 15 November 1999; accepted 26 November 1999 相似文献
929.
Rieger syndrome: a clinical, molecular, and biochemical analysis 总被引:6,自引:0,他引:6
930.
The activins (dimers of betaA or betaB subunits, encoded by the genes Inhba and Inhbb, respectively) are TGF-beta superfamily members that have roles in reproduction and development. Whereas mice homozygous for the Inhba-null allele demonstrate disruption of whisker, palate and tooth development, leading to neonatal lethality, homozygous Inhbb-null mice are viable, fertile and have eye defects. To determine if these phenotypes were due to spatiotemporal expression differences of the ligands or disruption of specific ligand-receptor interactions, we replaced the region of Inhba encoding the mature protein with Inhbb, creating the allele Inhbatm2Zuk (hereafter designated InhbaBK). Although the craniofacial phenotypes of the Inhba-null mutation were rescued by the InhbaBK allele, somatic, testicular, genital and hair growth were grossly affected and influenced by the dosage and bioactivity of the allele. Thus, functional compensation within the TGF-beta superfamily can occur if the replacement gene is expressed appropriately. The novel phenotypes in these mice further illustrate the usefulness of insertion strategies for defining protein function. 相似文献