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101.
Chen L Grabowski KA Xin JP Coleman J Huang Z Espiritu B Alkan S Xie HB Zhu Y White FA Clancy J Huang H 《Journal of immunology (Baltimore, Md. : 1950)》2004,172(4):2059-2066
Innate effector cells that produce Th2-type cytokines are critical in Th2 cell-mediated immune responses. However, it is not known how these cells acquire the ability to produce Th2 cytokines. IL-4 is a potent inducer that directs differentiation of naive CD4(+) T cells into CD4(+) Th2 effector cells. To determine whether IL-4 can induce differentiation and expansion of Th2 cytokine-producing innate cells, we used mice whose il-4 gene was replaced by a knock-in green fluorescence protein (gfp) gene. We found that, directly ex vivo, IL-4 increased the number of GFP(+) cells in the airway and the lung tissue in an Ag-specific manner. The majority of GFP(+) cells were eosinophils, suggesting that IL-4 plays a pivotal role in expanding IL-4-producing eosinophils in vivo. IL-4-producing eosinophils showed some unique features compared with IL-4-producing CD4(+) T cells. They exhibited biallelic expression of the il-4 gene when stimulated and were more dominant IL-4- and IL-5-producing cells. Furthermore, we show that IL-4 drove bone marrow progenitor cells to differentiate into Th2 cytokine-producing eosinophils in vitro. These results strongly suggest IL-4 is a potent factor in directing bone marrow progenitor cells to differentiate into Th2 cytokine-producing eosinophils. 相似文献
102.
103.
Gaucher disease is a common lysosomal storage disease caused by a defect of acid beta-glucosidase (GCase). The optimal in vitro hydrolase activity of GCase requires saposin C, an activator protein that derives from a precursor, prosaposin. To develop additional models of Gaucher disease and to test in vivo effects of saposin deficiencies, mice expressing low levels (4--45% of wild type) of prosaposin and saposins (PS-NA) were backcrossed into mice with specific point mutations (V394L/V394L or D409H/D409H) of GCase. The resultant mice were designated 4L/PS-NA and 9H/PS-NA, respectively. In contrast to PS-NA mice, the 4L/PS-NA and 9H/PS-NA mice displayed large numbers of engorged macrophages and nearly exclusive glucosylceramide (GC) accumulation in the liver, lung, spleen, thymus, and brain. Electron microscopy of the storage cells showed the characteristic tubular storage material of Gaucher cells. Compared with V394L/V394L mice, 4L/PS-NA mice that expressed 4--6% of wild-type prosaposin levels had approximately 25--75% decreases in GCase activity and protein in liver, spleen, and fibroblasts. These results imply that reduced saposin levels increased the instability of V394L or D409H GCases and that these additional decreases led to large accumulations of GC in all tissues. These models mimic a more severe Gaucher disease phenotype and could be useful for therapeutic intervention studies. 相似文献
104.
105.
A close relationship of light harvesting polypeptides (LHC) of rhodophytes, chromophytes and chlorophytes is inferred from the amino acid sequence similarity in three transmembrane helices, and from the conservation of 8 putative chlorophyll (Chl)-binding sites (Durnford et al. 1999, J. Mol. Evol. 48:59). Differences in Chl and carotenoid pigments have been a major classification feature. Thus, it was of interest to ascertain whether pigments from a diatom ( Thallasiosira fluviatilis ) could be functionally inserted into a red algal ( Porphyridium cruentum ) polypeptide. A recombinant polypeptide, LHCaR1, was reconstituted with pigment extracts from the diatom (Chls a and c , fucoxanthin, diadinoxanthin and β-carotene). The pigments were found attached to protein upon separation on sucrose gradients, and on non-denaturing gels. Absorption and fluorescence excitation spectra revealed individual peaks corresponding to the absorption maxima of Chl a at 438/672 nm; Chl c at 463/638 nm; and fucoxanthin at 493/540 nm. Fluorescence emission and CD spectra showed functional binding and suitable orientation for energy transfer from Chl c and carotenoids to Chl a. The LHCaR1 successfully folded in the presence of the heterologous pigments and bound 7 Chl a , 1 Chl c , 8 fucoxanthin, and 1.9 diadinoxanthin per polypeptide. By comparison, this polypeptide with P. cruentum pigments binds 8 Chl a , and 4 zeaxanthins, thus revealing its capability of functionally binding 8 Chls with variations in carotenoid numbers. Such a trait may have favored the diversification of a large family of LHCs and the successful radiation of photosynthetic eukaryotes into different light environments. 相似文献
106.
107.
Benjamin Liou Wendy D. Haffey Kenneth D. Greis Gregory A. Grabowski 《The Journal of biological chemistry》2014,289(43):30063-30074
The acid β-glucosidase (glucocerbrosidase (GCase)) binding sequence to LIMP-2 (lysosomal integral membrane protein 2), the receptor for intracellular GCase trafficking to the lysosome, has been identified. Heterologous expression of deletion constructs, the available GCase crystal structures, and binding and co-localization of identified peptides or mutant GCases were used to identify and characterize a highly conserved 11-amino acid sequence, DSPIIVDITKD, within human GCase. The binding to LIMP-2 is not dependent upon a single amino acid, but the interactions of GCase with LIMP-2 are heavily influenced by Asp399 and the di-isoleucines, Ile402 and Ile403. A single alanine substitution at any of these decreases GCase binding to LIMP-2 and alters its pH-dependent binding as well as diminishing the trafficking of GCase to the lysosome and significantly increasing GCase secretion. Enterovirus 71 also binds to LIMP-2 (also known as SCARB2) on the external surface of the plasma membrane. However, the LIMP-2/SCARB2 binding sequences for enterovirus 71 and GCase are not similar, indicating that LIMP-2/SCARB2 may have multiple or overlapping binding sites with differing specificities. These findings have therapeutic implications for the production of GCase and the distribution of this enzyme that is delivered to various organs. 相似文献
108.
109.
M J Grabowski A M Brzozowski Z S Derewenda T Skar?nński M Cygler A Stepień A E Derewenda 《The Biochemical journal》1978,171(1):277-279
Crystals of human oxyhaemoglobin were obtained from poly(ethylene glycol) solutions. Spectroscopic and spectrophotometric measurements on the solutions during crystallization and on the dissolved crystals indicate that the method yields stable crystals of oxyhaemoglobin. Preliminary X-ray studies showed that the crystals obtained are isomorphous with those of deoxyhaemoglobin obtained from poly(ethylene glycol) solutions [Ward, Wishner, Lattman & Love (1975) J. Mol. Biol. 98, 161-177]. 相似文献
110.
Ying Sun Jane Florer Christopher N. Mayhew Zhanfeng Jia Zhiying Zhao Kui Xu Huimin Ran Benjamin Liou Wujuan Zhang Kenneth D. R. Setchell Jianguo Gu Gregory A. Grabowski 《PloS one》2015,10(3)
Gaucher disease (GD) is caused by insufficient activity of acid β-glucosidase (GCase) resulting from mutations in GBA1. To understand the pathogenesis of the neuronopathic GD, induced pluripotent stem cells (iPSCs) were generated from fibroblasts isolated from three GD type 2 (GD2) and 2 unaffected (normal and GD carrier) individuals. The iPSCs were converted to neural precursor cells (NPCs) which were further differentiated into neurons. Parental GD2 fibroblasts as well as iPSCs, NPCs, and neurons had similar degrees of GCase deficiency. Lipid analyses showed increases of glucosylsphingosine and glucosylceramide in the GD2 cells. In addition, GD2 neurons showed increased α-synuclein protein compared to control neurons. Whole cell patch-clamping of the GD2 and control iPSCs-derived neurons demonstrated excitation characteristics of neurons, but intriguingly, those from GD2 exhibited consistently less negative resting membrane potentials with various degree of reduction in action potential amplitudes, sodium and potassium currents. Culture of control neurons in the presence of the GCase inhibitor (conduritol B epoxide) recapitulated these findings, providing a functional link between decreased GCase activity in GD and abnormal neuronal electrophysiological properties. To our knowledge, this study is first to report abnormal electrophysiological properties in GD2 iPSC-derived neurons that may underlie the neuropathic phenotype in Gaucher disease. 相似文献