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991.
Metalloprotease meprin beta generates nontoxic N-terminal amyloid precursor protein fragments in vivo 总被引:1,自引:0,他引:1
Jefferson T Čaušević M auf dem Keller U Schilling O Isbert S Geyer R Maier W Tschickardt S Jumpertz T Weggen S Bond JS Overall CM Pietrzik CU Becker-Pauly C 《The Journal of biological chemistry》2011,286(31):27741-27750
Identification of physiologically relevant substrates is still the most challenging part in protease research for understanding the biological activity of these enzymes. The zinc-dependent metalloprotease meprin β is known to be expressed in many tissues with functions in health and disease. Here, we demonstrate unique interactions between meprin β and the amyloid precursor protein (APP). Although APP is intensively studied as a ubiquitously expressed cell surface protein, which is involved in Alzheimer disease, its precise physiological role and relevance remain elusive. Based on a novel proteomics technique termed terminal amine isotopic labeling of substrates (TAILS), APP was identified as a substrate for meprin β. Processing of APP by meprin β was subsequently validated using in vitro and in vivo approaches. N-terminal APP fragments of about 11 and 20 kDa were found in human and mouse brain lysates but not in meprin β(-/-) mouse brain lysates. Although these APP fragments were in the range of those responsible for caspase-induced neurodegeneration, we did not detect cytotoxicity to primary neurons treated by these fragments. Our data demonstrate that meprin β is a physiologically relevant enzyme in APP processing. 相似文献
992.
Lamon-Fava S Marcovina SM Albers JJ Kennedy H Deluca C White CC Cupples LA McNamara JR Seman LJ Bongard V Schaefer EJ 《Journal of lipid research》2011,52(6):1181-1187
The aim of this study was to assess the independent contributions of plasma levels of lipoprotein(a) (Lp(a)), Lp(a) cholesterol, and of apo(a) isoform size to prospective coronary heart disease (CHD) risk. Plasma Lp(a) and Lp(a) cholesterol levels, and apo(a) isoform size were measured at examination cycle 5 in subjects participating in the Framingham Offspring Study who were free of CHD. After a mean follow-up of 12.3 years, 98 men and 47 women developed new CHD events. In multivariate analysis, the hazard ratio of CHD was approximately two-fold greater in men in the upper tertile of plasma Lp(a) levels, relative to those in the bottom tertile (P < 0.002). The apo(a) isoform size contributed only modestly to the association between Lp(a) and CHD and was not an independent predictor of CHD. In multivariate analysis, Lp(a) cholesterol was not significantly associated with CHD risk in men. In women, no association between Lp(a) and CHD risk was observed. Elevated plasma Lp(a) levels are a significant and independent predictor of CHD risk in men. The assessment of apo(a) isoform size in this cohort does not add significant information about CHD risk. In addition, the cholesterol content in Lp(a) is not a significant predictor of CHD risk. 相似文献
993.
Solis M Nakhaei P Jalalirad M Lacoste J Douville R Arguello M Zhao T Laughrea M Wainberg MA Hiscott J 《Journal of virology》2011,85(3):1224-1236
The rapid induction of type I interferon (IFN) is essential for establishing innate antiviral responses. During infection, cytoplasmic viral RNA is sensed by two DExD/H box RNA helicases, RIG-I and MDA5, ultimately driving IFN production. Here, we demonstrate that purified genomic RNA from HIV-1 induces a RIG-I-dependent type I IFN response. Both the dimeric and monomeric forms of HIV-1 were sensed by RIG-I, but not MDA5, with monomeric RNA, usually found in defective HIV-1 particles, acting as a better inducer of IFN than dimeric RNA. However, despite the presence of HIV-1 RNA in the de novo infection of monocyte-derived macrophages, HIV-1 replication did not lead to a substantial induction of IFN signaling. We demonstrate the existence of an evasion mechanism based on the inhibition of the RIG-I sensor through the action of the HIV-1 protease (PR). Indeed, the ectopic expression of PR resulted in the inhibition of IFN regulatory factor 3 (IRF-3) phosphorylation and decreased expression of IFN and interferon-stimulated genes. A downregulation of cytoplasmic RIG-I levels occurred in cells undergoing a single-cycle infection with wild-type provirus BH10 but not in cells transfected with a protease-deficient provirus, BH10-PR(-). Cellular fractionation and confocal microscopy studies revealed that RIG-I translocated from the cytosol to an insoluble fraction during the de novo HIV-1 infection of monocyte-derived macrophages, in the presence of PR. The loss of cytoplasmic RIG-I was prevented by the lysosomal inhibitor E64, suggesting that PR targets RIG-I to the lysosomes. This study reveals a novel PR-dependent mechanism employed by HIV-1 to counteract the early IFN response to viral RNA in infected cells. 相似文献
994.
Wright SW Carlo AA Danley DE Hageman DL Karam GA Mansour MN McClure LD Pandit J Schulte GK Treadway JL Wang IK Bauer PH 《Bioorganic & medicinal chemistry letters》2003,13(12):2055-2058
3-(2-Carboxyethyl)-4,6-dichloro-1H-indole-2-carboxylic acid (MDL-29951), an antagonist of the glycine site of the NMDA receptor, has been found to be an allosteric inhibitor of the enzyme fructose 1,6-bisphosphatase. The compound binds at the AMP regulatory site by X-ray crystallography. This represents a new approach to inhibition of fructose 1,6-bisphosphatase and serves as a lead for further drug design. 相似文献
995.
In an influential paper, Kirkpatrick and Barton (Am Nat 150:1–23 1997) presented a system of diffusive partial differential equations modeling the joint evolution of population density and the mean of a quantitative trait when the trait optimum varies over a continuous spatial domain. We present a stability theorem for steady states of a simplified version of the system, originally studied in Kirkpatrick and Barton (Am Nat 150:1–23 1997). We also present a derivation of the system. 相似文献
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999.
Biochar Decelerates Soil Organic Nitrogen Cycling but Stimulates Soil Nitrification in a Temperate Arable Field Trial 总被引:1,自引:0,他引:1
Judith Prommer Wolfgang Wanek Florian Hofhansl Daniela Trojan Pierre Offre Tim Urich Christa Schleper Stefan Sassmann Barbara Kitzler Gerhard Soja Rebecca Clare Hood-Nowotny 《PloS one》2014,9(1)
Biochar production and subsequent soil incorporation could provide carbon farming solutions to global climate change and escalating food demand. There is evidence that biochar amendment causes fundamental changes in soil nutrient cycles, often resulting in marked increases in crop production, particularly in acidic and in infertile soils with low soil organic matter contents, although comparable outcomes in temperate soils are variable. We offer insight into the mechanisms underlying these findings by focusing attention on the soil nitrogen (N) cycle, specifically on hitherto unmeasured processes of organic N cycling in arable soils. We here investigated the impacts of biochar addition on soil organic and inorganic N pools and on gross transformation rates of both pools in a biochar field trial on arable land (Chernozem) in Traismauer, Lower Austria. We found that biochar increased total soil organic carbon but decreased the extractable organic C pool and soil nitrate. While gross rates of organic N transformation processes were reduced by 50–80%, gross N mineralization of organic N was not affected. In contrast, biochar promoted soil ammonia-oxidizer populations (bacterial and archaeal nitrifiers) and accelerated gross nitrification rates more than two-fold. Our findings indicate a de-coupling of the soil organic and inorganic N cycles, with a build-up of organic N, and deceleration of inorganic N release from this pool. The results therefore suggest that addition of inorganic fertilizer-N in combination with biochar could compensate for the reduction in organic N mineralization, with plants and microbes drawing on fertilizer-N for growth, in turn fuelling the belowground build-up of organic N. We conclude that combined addition of biochar with fertilizer-N may increase soil organic N in turn enhancing soil carbon sequestration and thereby could play a fundamental role in future soil management strategies. 相似文献
1000.
Elizabeth L. Barry Leila A. Mott Michal L. Melamed Judith R. Rees Anastasia Ivanova Robert S. Sandler Dennis J. Ahnen Robert S. Bresalier Robert W. Summers Roberd M. Bostick John A. Baron 《PloS one》2014,9(10)