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81.
Hrebícek M Mrázová L Seyrantepe V Durand S Roslin NM Nosková L Hartmannová H Ivánek R Cízkova A Poupetová H Sikora J Urinovská J Stranecký V Zeman J Lepage P Roquis D Verner A Ausseil J Beesley CE Maire I Poorthuis BJ van de Kamp J van Diggelen OP Wevers RA Hudson TJ Fujiwara TM Majewski J Morgan K Kmoch S Pshezhetsky AV 《American journal of human genetics》2006,79(5):807-819
Mucopolysaccharidosis IIIC (MPS IIIC, or Sanfilippo C syndrome) is a lysosomal storage disorder caused by the inherited deficiency of the lysosomal membrane enzyme acetyl-coenzyme A: alpha -glucosaminide N-acetyltransferase (N-acetyltransferase), which leads to impaired degradation of heparan sulfate. We report the narrowing of the candidate region to a 2.6-cM interval between D8S1051 and D8S1831 and the identification of the transmembrane protein 76 gene (TMEM76), which encodes a 73-kDa protein with predicted multiple transmembrane domains and glycosylation sites, as the gene that causes MPS IIIC when it is mutated. Four nonsense mutations, 3 frameshift mutations due to deletions or a duplication, 6 splice-site mutations, and 14 missense mutations were identified among 30 probands with MPS IIIC. Functional expression of human TMEM76 and the mouse ortholog demonstrates that it is the gene that encodes the lysosomal N-acetyltransferase and suggests that this enzyme belongs to a new structural class of proteins that transport the activated acetyl residues across the cell membrane. 相似文献
82.
Mosyak L Wood A Dwyer B Buddha M Johnson M Aulabaugh A Zhong X Presman E Benard S Kelleher K Wilhelm J Stahl ML Kriz R Gao Y Cao Z Ling HP Pangalos MN Walsh FS Somers WS 《The Journal of biological chemistry》2006,281(47):36378-36390
Nogo receptor (NgR)-mediated control of axon growth relies on the central nervous system-specific type I transmembrane protein Lingo-1. Interactions between Lingo-1 and NgR, along with a complementary co-receptor, result in neurite and axonal collapse. In addition, the inhibitory role of Lingo-1 is particularly important in regulation of oligodendrocyte differentiation and myelination, suggesting that pharmacological modulation of Lingo-1 function could be a novel approach for nerve repair and remyelination therapies. Here we report on the crystal structure of the ligand-binding ectodomain of human Lingo-1 and show it has a bimodular, kinked structure composed of leucine-rich repeat (LRR) and immunoglobulin (Ig)-like modules. The structure, together with biophysical analysis of its solution properties, reveals that in the crystals and in solution Lingo-1 persistently associates with itself to form a stable tetramer and that it is its LRR-Ig-composite fold that drives such assembly. Specifically, in the crystal structure protomers of Lingo-1 associate in a ring-shaped tetramer, with each LRR domain filling an open cleft in an adjacent protomer. The tetramer buries a large surface area (9,200 A2) and may serve as an efficient scaffold to simultaneously bind and assemble the NgR complex components during activation on a membrane. Potential functional binding sites that can be identified on the ectodomain surface, including the site of self-recognition, suggest a model for protein assembly on the membrane. 相似文献
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85.
Activity plays critical roles in development and maintenance of the olfactory system, which undergoes considerable neurogenesis throughout life. In the mouse olfactory epithelium, each olfactory sensory neuron (OSN) stably expresses a single odorant receptor (OR) type out of a repertoire of ∼1200 and the OSNs with the same OR identity are distributed within one of the few broadly-defined zones. However, it remains elusive whether and how activity modulates such OR expression patterns. Here we addressed this question by investigating OR gene expression via in situ hybridization when sensory experience or neuronal excitability is manipulated. We first examined the expression patterns of fifteen OR genes in mice which underwent neonatal, unilateral naris closure. After four-week occlusion, the cell density in the closed (sensory-deprived) side was significantly lower (for four ORs), similar (for three ORs), or significantly higher (for eight ORs) as compared to that in the open (over-stimulated) side, suggesting that sensory inputs have differential effects on OSNs expressing different OR genes. We next examined the expression patterns of seven OR genes in transgenic mice in which mature OSNs had reduced neuronal excitability. Neuronal silencing led to a significant reduction in the cell density for most OR genes tested and thinner olfactory epithelium with an increased density of apoptotic cells. These results suggest that sensory experience plays important roles in shaping OR gene expression patterns and the neuronal activity is critical for survival of OSNs. 相似文献
86.
Miranda de Graaf Sander Herfst Jamil Aarbiou Peter C. Burgers Fatiha Zaaraoui-Boutahar Maarten Bijl Wilfred van IJcken Eefje J. A. Schrauwen Albert D. M. E. Osterhaus Theo M. Luider Bob J. Scholte Ron A. M. Fouchier Arno C. Andeweg 《PloS one》2013,8(3)
Human metapneumovirus (HMPV) encodes a small hydrophobic (SH) protein of unknown function. HMPV from which the SH open reading frame was deleted (HMPVΔSH) was viable and displayed similar replication kinetics, cytopathic effect and plaque size compared with wild type HMPV in several cell-lines. In addition, no differences were observed in infection efficiency or cell-to-cell spreading in human primary bronchial epithelial cells (HPBEC) cultured at an air-liquid interphase. Host gene expression was analyzed in A549 cells infected with HMPV or HMPVΔSH using microarrays and mass spectrometry (MS) based techniques at multiple time points post infection. Only minor differences were observed in mRNA or protein expression levels. A possible function of HMPV SH as apoptosis blocker, as proposed for several members of the family Paramyxoviridae, was rejected based on this analysis. So far, a clear phenotype of HMPV SH deletion mutants in vitro at the virus and host levels is absent. 相似文献
87.
Mohammed El-Kebir Benjamin J. Raphael Ron Shamir Roded Sharan Simone Zaccaria Meirav Zehavi Ron Zeira 《Algorithms for molecular biology : AMB》2017,12(1):13
Background
Cancer is an evolutionary process characterized by the accumulation of somatic mutations in a population of cells that form a tumor. One frequent type of mutations is copy number aberrations, which alter the number of copies of genomic regions. The number of copies of each position along a chromosome constitutes the chromosome’s copy-number profile. Understanding how such profiles evolve in cancer can assist in both diagnosis and prognosis.Results
We model the evolution of a tumor by segmental deletions and amplifications, and gauge distance from profile \(\mathbf {a}\) to \(\mathbf {b}\) by the minimum number of events needed to transform \(\mathbf {a}\) into \(\mathbf {b}\). Given two profiles, our first problem aims to find a parental profile that minimizes the sum of distances to its children. Given k profiles, the second, more general problem, seeks a phylogenetic tree, whose k leaves are labeled by the k given profiles and whose internal vertices are labeled by ancestral profiles such that the sum of edge distances is minimum.Conclusions
For the former problem we give a pseudo-polynomial dynamic programming algorithm that is linear in the profile length, and an integer linear program formulation. For the latter problem we show it is NP-hard and give an integer linear program formulation that scales to practical problem instance sizes. We assess the efficiency and quality of our algorithms on simulated instances.Availability
https://github.com/raphael-group/CNT-ILP88.
Kinetics and mechanism of the comproportionation reaction between oxoammonium cation and hydroxylamine derived from cyclic nitroxides 总被引:2,自引:0,他引:2
Israeli A Patt M Oron M Samuni A Kohen R Goldstein S 《Free radical biology & medicine》2005,38(3):317-324
Cyclic nitroxides demonstrate antioxidative activity in numerous in vitro and in vivo models, which frequently involves the participation of the reduced and oxidized forms of the nitroxide, namely, the hydroxylamine and oxoammonium cation. Generally, cellular reducing equivalents facilitate rapid enzymatic as well as nonenzymatic reduction of nitroxides in the tissue. On the other hand, the reaction of nitroxides with various radicals yields the highly oxidizing oxoammonium cation, which mediates the catalytic effect of nitroxides in selective oxidation of alcohols. Hence, nitroxides might act as both anti- and pro-oxidants. Therefore, the comproportionation reaction between the oxoammonium cation and the hydroxylamine might play a role in lowering the pro-oxidative activity of nitroxides. Although the comproportionation reaction has previously been studied, there is no agreement regarding its kinetic features. We investigated the reaction of the reduced forms of 2,2,6,6-tetramethylpiperidinoxyl (TPO) and 4-OH-2,2,6,6-tetramethylpiperidinoxyl (4-OH-TPO) with the oxoammonium cation derived from TPO at various pHs using rapid-mixing stopped-flow and EPR spectrometry. From the pH dependence of the reaction rate constants we determined the pK(1) of the respective hydroxylamines to be 7.5 and 6.9, respectively. The reduction potentials of the hydroxylamines were determined by cyclic voltammetry, and from their dependence on pH, we obtained the same pK(1) values. The rate constant of the comproportionation reaction does not exceed 20 M(-1) s(-1) in the physiological pH range and, therefore, cannot greatly contribute toward recycling of the nitroxides in the tissue. 相似文献
89.
Svetlana?Minakhina Ron?Myers Marina?Druzhinina Ruth?StewardEmail author 《BMC cell biology》2005,6(1):32
Background
Transport of macromolecules into and out of the nucleus is a highly regulated process. The RanGTP/RanGDP gradient controls the trafficking of molecules exceeding the diffusion limit of the nuclear pore across the nuclear envelope. 相似文献90.
Weems YS Randel RD Tatman S Lewis AW Neuendorff DA Weems CW 《Prostaglandins & other lipid mediators》2005,78(1-4):264-278
Synchronization of estrus with progestins in cows has been reported to inhibit nitric oxide (NO) and endothelin-1 (ET-1)-stimulated bovine luteal PGE secretion without affecting prostaglandin F2alpha (PGF2alpha) secretion in vitro [Weems YS, Randel RD, Tatman S, Lewis A, Neuendorff DA, Weems CW. Does estrous synchronization affect corpus luteum (CL) function? Prostaglandins Other Lipid Mediat 2004;74:45-59]. Two experiments were conducted to determine the effects of NO donors, endothelin-1 (ET-1), and NO synthase (NOS) inhibitors on bovine caruncular endometrial secretion of PGE and PGF2alpha in vitro. In Experiment 1, estrus was synchronized in Brahman cows with Synchromate-B ear implants, which contained the synthetic progestin norgestamet. Days 14-15 caruncular endometrial slices were weighed, diced, and incubated in vitro with treatments. Treatments (100 ng/ml) were: Vehicle (control), l-NAME (NOS inhibitor), l-NMMA (NOS inhibitor), DETA (control), DETA-NONOate (NO donor), sodium nitroprusside (NO donor), or ET-1. In Experiment 2, estrus was synchronized in Brahman cows with either Lutalyse (PGF2alpha) or a controlled intravaginal drug releasing device (CIDR-containing progesterone) or estrus was not synchronized. Days 14-15 caruncular endometrial slices were weighed, diced, and incubated in vitro with treatments. Treatments (100 ng/ml) were: vehicle, l-NAME, l-NMMA, DETA, DETA-NONOate, sodium nitroprusside, SNAP (NO donor) or ET-1. Tissues were incubated in M-199 for 1h without treatments and with treatments for 4 and 8h in both experiments. Media were analyzed for concentrations of PGE and PGF2alpha by radioimmunoassay (RIA). Hormone data in Experiments 1 and 2 were analyzed by 2x7 and 3x2x8 factorial design for ANOVA, respectively. Concentrations of PGE and PGF2alpha in media increased (P< or =0.05) from 4 to 8 h regardless of treatment group in Experiment 1, but did not differ (P> or =0.05) among treatments. In Experiment 2, concentrations of PGE and PGF2alpha increased (P< or =0.05) with time in all treatment groups of all three synchronization regimens. DETA-NONOate, SNAP, and sodium nitroprusside (NO donors) and ET-1 increased caruncular endometrial (P< or =0.05) secretion of PGE2 in unsynchronized and Lutalyse synchronized cows, but not when estrus was synchronized with a CIDR (P> or =0.05). No treatment increased (P> or =0.05) PGF2alpha in any synchronization regimen. It is concluded that norgestamet in Synchromate-B ear implants or progesterone in a CIDR alters NO or ET-1-induced secretion of PGE by bovine caruncular endometrium and could interfere with implantation by altering the PGE:PGF2alpha ratio resulting in increased embryonic losses during early pregnancy. 相似文献