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101.
Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss 下载免费PDF全文
Jelena Scekic‐Zahirovic Oliver Sendscheid Hajer El Oussini Mélanie Jambeau Ying Sun Sina Mersmann Marina Wagner Stéphane Dieterlé Jérome Sinniger Sylvie Dirrig‐Grosch Kevin Drenner Marie‐Christine Birling Jinsong Qiu Yu Zhou Hairi Li Xiang‐Dong Fu Caroline Rouaux Tatyana Shelkovnikova Anke Witting Albert C Ludolph Friedemann Kiefer Erik Storkebaum Clotilde Lagier‐Tourenne Luc Dupuis 《The EMBO journal》2016,35(10):1077-1097
FUS is an RNA‐binding protein involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS‐containing aggregates are often associated with concomitant loss of nuclear FUS. Whether loss of nuclear FUS function, gain of a cytoplasmic function, or a combination of both lead to neurodegeneration remains elusive. To address this question, we generated knockin mice expressing mislocalized cytoplasmic FUS and complete FUS knockout mice. Both mouse models display similar perinatal lethality with respiratory insufficiency, reduced body weight and length, and largely similar alterations in gene expression and mRNA splicing patterns, indicating that mislocalized FUS results in loss of its normal function. However, FUS knockin mice, but not FUS knockout mice, display reduced motor neuron numbers at birth, associated with enhanced motor neuron apoptosis, which can be rescued by cell‐specific CRE‐mediated expression of wild‐type FUS within motor neurons. Together, our findings indicate that cytoplasmic FUS mislocalization not only leads to nuclear loss of function, but also triggers motor neuron death through a toxic gain of function within motor neurons. 相似文献
102.
Summary The isoenzyme patterns of phosphoglucomutase (PGM1) were investigated in human spermatozoa (Sp.-PGM1). The three phenotypes of PGM1-polymorphism commonly found in erythrocytes could also be demonstrated in spermatozoa. It was also found that these patterns differ in spermatozoa quantitatively and in the case of phenotype PGM1 1-1 a qualitative difference could also be observed. The eventual significance of these findings in forensic medicine were briefly mentioned. 相似文献
103.
Condensation of 2,3,4-tri-O-benzyl-alpha-L-fucopyranosyl bromide with benzyl 2-acetamido-3,6-di-O-benzyl-alpha-D-glucopyranoside in dichloromethane-N,N-dimethylformamide, in the presence of tetraethylammonium bromide, diisopropylethylamine, and molecular sieve (halide ion-catalyzed reaction), gave benzyl 2-acetamido-3,6-di-O-benzyl-2 deoxy-4-O-(2,3,4-tri-O-benzyl-alpha-L-fucopyranosyl)-alpha-D-glucopyranoside in crystalline form in 82% yield. Hydrogenolysis of the benzyl groups gave the title disaccharide, in crystalline form in 90% yield, which was characterized by a crystalline peracetylated alpha-D derivative. 相似文献
104.
V N Reinhold S A Carr B N Green M Petitou J Choay P Sina? 《Carbohydrate research》1987,161(2):305-313
We report herein the results of f.a.b.-m.s. experiments conducted on synthetic fragments of glycosaminoglycans, one of them representing the pentasaccharidic sequence present in heparin and responsible for the binding to antithrombin III, and the others being related to this sequence. The results indicate that f.a.b.-m.s. can be very useful for the structural analysis of sulfated glycosaminoglycans. The relatively small amounts of sample required enable molecular characterization at physiologically significant levels. In contrast to the chondroitin sulfates, the heparin saccharides analyzed and reported here do not provide sequence information. The data indicate that glycosidic rupture is not a process competing with the much more facile loss of N-sulfite residues. Dominating the spectra are a series of molecular-weight-related ions (distributed to indicate the associated countercation composition), and fragments related directly to sulfite elimination. This f.a.b.-induced, facile loss of sulfite may impose limitations in molecular-weight analysis for the larger oligomers. 相似文献
105.
Paul-Henri Amvam Zollo Jean-Claude Jacquinet Pierre Sinaÿ 《Carbohydrate research》1983,122(2):201-208
Condensation of known benzyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-4-O-(2,3,6-tri-O-benzyl-beta-D- galactopyranosyl)-alpha-D-glucopyranoside with 2,3,4,6-tetra-O-benzyl-alpha-D-galactopyranosyl chloride in dichloromethane in the presence of 2,4,6-trimethylpyridine, silver triflate, and molecular sieve 4A gave benzyl O-(2,3,4,6-tetra-O-benzyl-alpha-D-galactopyranosyl)-(1 leads to 4)-O-(2,3,6-tri-O-benzyl-beta-D-galactopyranosyl)-(1 leads to 4)-2-acetamido-3,6-di-O-benzyl-2-deoxy-alpha-D-glucopyranoside. Catalytic hydrogenolysis gave crystalline O-alpha-D-galactopyranosyl-(1 leads to 4)-O-beta-D-galactopyranosyl-(1 leads to 4)-2-acetamido-2-deoxy-alpha -D-glucopyranose, the human blood-group P1-antigenic determinant. A similar sequence of reactions was performed starting from allyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-beta-D-glucopyranoside, in order to prepare a derivative of this determinant suitable for linkage to carrier molecules. 相似文献
106.
107.
Gabriela Campanholle Kristen Mittelsteadt Shunsaku Nakagawa Akio Kobayashi Shuei-Liong Lin Sina A. Gharib Jay W. Heinecke Jessica A. Hamerman William A. Altemeier Jeremy S. Duffield 《PloS one》2013,8(7)
Inflammatory macrophages are abundant in kidney disease, stimulating repair, or driving chronic inflammation and fibrosis. Damage associated molecules (DAMPs), released from injured cells engage pattern recognition receptors (PRRs) on macrophages, contributing to activation. Understanding mechanisms of macrophage activation during kidney injury may lead to strategies to alleviate chronic disease. We identified Triggering-Receptor-in-Myeloid-cells (TREM)-1, a regulator of TLR signaling, as highly upregulated in kidney inflammatory macrophages and tested the roles of these receptors in macrophage activation and kidney disease. Kidney DAMPs activated macrophages in vitro, independently of TREM-1, but partially dependent on TLR-2/−4, MyD88. In two models of progressive interstitial kidney disease, TREM-1 blockade had no impact on disease or macrophage activation in vivo, but TLR-2/−4, or MyD88 deficiency was anti-inflammatory and anti-fibrotic. When MyD88 was mutated only in the myeloid lineage, however, there was no bearing on macrophage activation or disease progression. Instead, TLR-2/−4 or MyD88 deficiency reduced activation of mesenchyme lineage cells resulting in reduced inflammation and fibrosis, indicating that these pathways play dominant roles in activation of myofibroblasts but not macrophages. To conclude, TREM-1, TLR2/4 and MyD88 signaling pathways are redundant in myeloid cell activation in kidney injury, but the latter appear to regulate activation of mesenchymal cells. 相似文献
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110.
Alexander Radbruch Oliver Eidel Benedikt Wiestler Daniel Paech Sina Burth Philipp Kickingereder Martha Nowosielski Philipp B?umer Wolfgang Wick Heinz-Peter Schlemmer Martin Bendszus Mark Ladd Armin Michael Nagel Sabine Heiland 《PloS one》2014,9(11)