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排序方式: 共有294条查询结果,搜索用时 10 毫秒
1.
Purification and cloning of amyloid precursor protein beta-secretase from human brain 总被引:40,自引:0,他引:40
Sinha S Anderson JP Barbour R Basi GS Caccavello R Davis D Doan M Dovey HF Frigon N Hong J Jacobson-Croak K Jewett N Keim P Knops J Lieberburg I Power M Tan H Tatsuno G Tung J Schenk D Seubert P Suomensaari SM Wang S Walker D Zhao J McConlogue L John V 《Nature》1999,402(6761):537-540
Proteolytic processing of the amyloid precursor protein (APP) generates amyloid beta (Abeta) peptide, which is thought to be causal for the pathology and subsequent cognitive decline in Alzheimer's disease. Cleavage by beta-secretase at the amino terminus of the Abeta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated carboxy-terminal fragment. Cleavage of the C-terminal fragment by gamma-secretase(s) leads to the formation of Abeta. The pathogenic mutation K670M671-->N670L671 at the beta-secretase cleavage site in APP, which was discovered in a Swedish family with familial Alzheimer's disease, leads to increased beta-secretase cleavage of the mutant substrate. Here we describe a membrane-bound enzyme activity that cleaves full-length APP at the beta-secretase cleavage site, and find it to be the predominant beta-cleavage activity in human brain. We have purified this enzyme activity to homogeneity from human brain using a new substrate analogue inhibitor of the enzyme activity, and show that the purified enzyme has all the properties predicted for beta-secretase. Cloning and expression of the enzyme reveals that human brain beta-secretase is a new membrane-bound aspartic proteinase. 相似文献
2.
Woody plant community composition was analyzed throughout the range of Coleogyne ramosissima in the Spring and Sheep Mountain ranges of southern Nevada. The lower Coleogyne elevational boundary was analyzed in detail in Lucky Strike Canyon, on the eastern edge of the Spring Mountains. TWINSPAN (2-way indicator species analysis) identified 4 primary species and stand groups from the 2 mountain ranges (extensive survey). Analysis of DECORANA (detrended correspondence analysis) results indicated that elevation and soil depth were the environmental factors most significantly associated with distribution of species and stand groups in the extensive survey. Elevation was the only significant physical factor associated with distribution of species and stand groups in the intensive survey. Five vegetation zones form the 2 mountain ranges were identified based on their dominant species in 15 extensive transects. Coleogyne were subdivided into pure stands and upper and lower ecotones for further investigation of species distribution and environmental factors. Selected environmental factors appear to play an important role in structuring the Mojave Desert vegetation zones in southern Nevada. 相似文献
3.
4.
Catastrophic shifts in ecosystems 总被引:140,自引:0,他引:140
All ecosystems are exposed to gradual changes in climate, nutrient loading, habitat fragmentation or biotic exploitation. Nature is usually assumed to respond to gradual change in a smooth way. However, studies on lakes, coral reefs, oceans, forests and arid lands have shown that smooth change can be interrupted by sudden drastic switches to a contrasting state. Although diverse events can trigger such shifts, recent studies show that a loss of resilience usually paves the way for a switch to an alternative state. This suggests that strategies for sustainable management of such ecosystems should focus on maintaining resilience. 相似文献
5.
Zaidi MR Davis S Noonan FP Graff-Cherry C Hawley TS Walker RL Feigenbaum L Fuchs E Lyakh L Young HA Hornyak TJ Arnheiter H Trinchieri G Meltzer PS De Fabo EC Merlino G 《Nature》2011,469(7331):548-553
Cutaneous malignant melanoma is a highly aggressive and frequently chemoresistant cancer, the incidence of which continues to rise. Epidemiological studies show that the major aetiological melanoma risk factor is ultraviolet (UV) solar radiation, with the highest risk associated with intermittent burning doses, especially during childhood. We have experimentally validated these epidemiological findings using the hepatocyte growth factor/scatter factor transgenic mouse model, which develops lesions in stages highly reminiscent of human melanoma with respect to biological, genetic and aetiological criteria, but only when irradiated as neonatal pups with UVB, not UVA. However, the mechanisms underlying UVB-initiated, neonatal-specific melanomagenesis remain largely unknown. Here we introduce a mouse model permitting fluorescence-aided melanocyte imaging and isolation following in vivo UV irradiation. We use expression profiling to show that activated neonatal skin melanocytes isolated following a melanomagenic UVB dose bear a distinct, persistent interferon response signature, including genes associated with immunoevasion. UVB-induced melanocyte activation, characterized by aberrant growth and migration, was abolished by antibody-mediated systemic blockade of interferon-γ (IFN-γ), but not type-I interferons. IFN-γ was produced by macrophages recruited to neonatal skin by UVB-induced ligands to the chemokine receptor Ccr2. Admixed recruited skin macrophages enhanced transplanted melanoma growth by inhibiting apoptosis; notably, IFN-γ blockade abolished macrophage-enhanced melanoma growth and survival. IFN-γ-producing macrophages were also identified in 70% of human melanomas examined. Our data reveal an unanticipated role for IFN-γ in promoting melanocytic cell survival/immunoevasion, identifying a novel candidate therapeutic target for a subset of melanoma patients. 相似文献
6.
Patterns of recruitment for Yucca brevifolia (Joshua tree) were investigated on 3 elevational transects, 1000-2000 m, in the Spring and Sheep Mountain ranges of southern Nevada. Yucca brevifolia is distributed throughout a broad range of plant communities dominated by Larrea tridentata and Ambrosia dumosa at low elevations, Coleogyne ramosissima at middle elevations, and an Artemisia-Pinus-Juniperus community at upper elevations. The density of Y. brevifolia gradually increased from the lowest elevations, peaked at 1600 m, and remained at intermediate levels at high elevations until reaching an abrupt upper elevational limit at 2000 m. Open substrate dominated the study areas; however, a large majority of Y. brevifolia seedlings were found growing under the canopy of other woody shrubs. This pattern of recruitment did not vary by site or elevation. Thirty-five species of perennial shrubs were identified in the study areas, 16 of which were found in association with at least 1 Y. brevifolia seedling. However, 4 shrubs were found in a nurse plant relationship with Y. brevifolia above the frequency predicted by either their canopy area or numerical dominance. Seedlings exhibited significant variation in aspect, relative to the center of the nurse shrub. In Lee and Lucky Strike canyons, recruitment occurred predominantly on the east and west sides of nurse shrubs, indicating the importance of specific microhabitats. Local presence of specific perennial shrubs resulted in higher levels of recruitment, causing a distinct pattern of community development, resumably through amelioration of abiotic stresses. 相似文献
7.
Dawn M. Walker Steve Oghumu Gaurav Gupta Bradford S. McGwire Mark E. Drew Abhay R. Satoskar 《Cellular and molecular life sciences : CMLS》2014,71(7):1245-1263
Numerous disease-causing parasites must invade host cells in order to prosper. Collectively, such pathogens are responsible for a staggering amount of human sickness and death throughout the world. Leishmaniasis, Chagas disease, toxoplasmosis, and malaria are neglected diseases and therefore are linked to socio-economical and geographical factors, affecting well-over half the world’s population. Such obligate intracellular parasites have co-evolved with humans to establish a complexity of specific molecular parasite–host cell interactions, forming the basis of the parasite’s cellular tropism. They make use of such interactions to invade host cells as a means to migrate through various tissues, to evade the host immune system, and to undergo intracellular replication. These cellular migration and invasion events are absolutely essential for the completion of the lifecycles of these parasites and lead to their for disease pathogenesis. This review is an overview of the molecular mechanisms of protozoan parasite invasion of host cells and discussion of therapeutic strategies, which could be developed by targeting these invasion pathways. Specifically, we focus on four species of protozoan parasites Leishmania, Trypanosoma cruzi, Plasmodium, and Toxoplasma, which are responsible for significant morbidity and mortality. 相似文献
8.
MicroRNA Mirn140 modulates Pdgf signaling during palatogenesis 总被引:2,自引:0,他引:2
Eberhart JK He X Swartz ME Yan YL Song H Boling TC Kunerth AK Walker MB Kimmel CB Postlethwait JH 《Nature genetics》2008,40(3):290-298
Disruption of signaling pathways such as those mediated by sonic hedgehog (Shh) or platelet-derived growth factor (Pdgf) causes craniofacial abnormalities, including cleft palate. The role that microRNAs play in modulating palatogenesis, however, is completely unknown. We show that, in zebrafish, the microRNA Mirn140 negatively regulates Pdgf signaling during palatal development, and we provide a mechanism for how disruption of Pdgf signaling causes palatal clefting. The pdgf receptor alpha (pdgfra) 3' UTR contained a Mirn140 binding site functioning in the negative regulation of Pdgfra protein levels in vivo. pdgfra mutants and Mirn140-injected embryos shared a range of facial defects, including clefting of the crest-derived cartilages that develop in the roof of the larval mouth. Concomitantly, the oral ectoderm beneath where these cartilages develop lost pitx2 and shha expression. Mirn140 modulated Pdgf-mediated attraction of cranial neural crest cells to the oral ectoderm, where crest-derived signals were necessary for oral ectodermal gene expression. Mirn140 loss of function elevated Pdgfra protein levels, altered palatal shape and caused neural crest cells to accumulate around the optic stalk, a source of the ligand Pdgfaa. These results suggest that the conserved regulatory interactions of mirn140 and pdgfra define an ancient mechanism of palatogenesis, and they provide candidate genes for cleft palate. 相似文献
9.
HIV-1 superinfection despite broad CD8+ T-cell responses containing replication of the primary virus 总被引:21,自引:0,他引:21
Altfeld M Allen TM Yu XG Johnston MN Agrawal D Korber BT Montefiori DC O'Connor DH Davis BT Lee PK Maier EL Harlow J Goulder PJ Brander C Rosenberg ES Walker BD 《Nature》2002,420(6914):434-439
Early treatment of acute HIV-1 infection followed by treatment interruptions has shown promise for enhancing immune control of infection. A subsequent loss of control, however, allows the correlates of protective immunity to be assessed. Here we show that sudden breakthrough of plasma viraemia occurred after prolonged immune containment in an individual infected with HIV-1 at a time when 25 distinct CD8+ T-cell epitopes in the viral proteins Gag, RT, Integrase, Env, Nef, Vpr, Vif and Rev were being targeted. Sequencing of the virus in plasma and cells showed that superinfection with a second clade-B virus was coincident with the loss of immune control. This sudden increase in viraemia was associated with a decline in half of the CD8+ T-cell responses. The declining CD8+ T-cell responses were coupled with sequence changes relative to the initial virus that resulted in impaired recognition. Our data show that HIV-1 superinfection can occur in the setting of a strong and broadly directed virus-specific CD8+ T-cell response. The lack of cross-protective immunity for closely related HIV-1 strains, despite persistent recognition of multiple CD8 epitopes, has important implications for public health and vaccine development. 相似文献
10.
Structure of tumour necrosis factor 总被引:27,自引:0,他引:27
Tumour necrosis factor is a trimeric molecule, each subunit of which consists of an antiparallel beta-sandwich. Individual subunits from the trimer by a novel edge-to-face packing of beta-sheets. A comparison of the subunit fold with that of other proteins reveals a remarkable similarity to the 'jelly-roll' structural motif characteristic of viral coat proteins. 相似文献