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排序方式: 共有117条查询结果,搜索用时 15 毫秒
31.
CH Wu C Fallini N Ticozzi PJ Keagle PC Sapp K Piotrowska P Lowe M Koppers D McKenna-Yasek DM Baron JE Kost P Gonzalez-Perez AD Fox J Adams F Taroni C Tiloca AL Leclerc SC Chafe D Mangroo MJ Moore JA Zitzewitz ZS Xu LH van den Berg JD Glass G Siciliano ET Cirulli DB Goldstein F Salachas V Meininger W Rossoll A Ratti C Gellera DA Bosco GJ Bassell V Silani VE Drory RH Brown JE Landers 《Nature》2012,488(7412):499-503
Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder resulting from motor neuron death. Approximately 10% of cases are familial (FALS), typically with a dominant inheritance mode. Despite numerous advances in recent years, nearly 50% of FALS cases have unknown genetic aetiology. Here we show that mutations within the profilin 1 (PFN1) gene can cause FALS. PFN1 is crucial for the conversion of monomeric (G)-actin to filamentous (F)-actin. Exome sequencing of two large ALS families showed different mutations within the PFN1 gene. Further sequence analysis identified 4 mutations in 7 out of 274 FALS cases. Cells expressing PFN1 mutants contain ubiquitinated, insoluble aggregates that in many cases contain the ALS-associated protein TDP-43. PFN1 mutants also display decreased bound actin levels and can inhibit axon outgrowth. Furthermore, primary motor neurons expressing mutant PFN1 display smaller growth cones with a reduced F/G-actin ratio. These observations further document that cytoskeletal pathway alterations contribute to ALS pathogenesis. 相似文献
32.
Ellinghaus E Ellinghaus D Stuart PE Nair RP Debrus S Raelson JV Belouchi M Fournier H Reinhard C Ding J Li Y Tejasvi T Gudjonsson J Stoll SW Voorhees JJ Lambert S Weidinger S Eberlein B Kunz M Rahman P Gladman DD Gieger C Wichmann HE Karlsen TH Mayr G Albrecht M Kabelitz D Mrowietz U Abecasis GR Elder JT Schreiber S Weichenthal M Franke A 《Nature genetics》2010,42(11):991-995
33.
Tamara Jefferson Ulrich auf dem Keller Caroline Bellac Verena V. Metz Claudia Broder Jana Hedrich Anke Ohler Wladislaw Maier Viktor Magdolen Erwin Sterchi Judith S. Bond Arumugam Jayakumar Heiko Traupe Athena Chalaris Stefan Rose-John Claus U. Pietrzik Rolf Postina Christopher M. Overall Christoph Becker-Pauly 《Cellular and molecular life sciences : CMLS》2013,70(2):309-333
The in vivo roles of meprin metalloproteases in pathophysiological conditions remain elusive. Substrates define protease roles. Therefore, to identify natural substrates for human meprin α and β we employed TAILS (terminal amine isotopic labeling of substrates), a proteomics approach that enriches for N-terminal peptides of proteins and cleavage fragments. Of the 151 new extracellular substrates we identified, it was notable that ADAM10 (a disintegrin and metalloprotease domain-containing protein 10)—the constitutive α-secretase—is activated by meprin β through cleavage of the propeptide. To validate this cleavage event, we expressed recombinant proADAM10 and after preincubation with meprin β, this resulted in significantly elevated ADAM10 activity. Cellular expression in murine primary fibroblasts confirmed activation. Other novel substrates including extracellular matrix proteins, growth factors and inhibitors were validated by western analyses and enzyme activity assays with Edman sequencing confirming the exact cleavage sites identified by TAILS. Cleavages in vivo were confirmed by comparing wild-type and meprin?/? mice. Our finding of cystatin C, elafin and fetuin-A as substrates and natural inhibitors for meprins reveal new mechanisms in the regulation of protease activity important for understanding pathophysiological processes. 相似文献
34.
Claudia Roeder Gisela Haemmerli P. Sträuli 《Cellular and molecular life sciences : CMLS》1976,32(8):1049-1050
Summary Cell electrophoretic data and quantitative sialic acid determination show that, 16 to 20h after i.p. implantation of neuraminidase-treated L 5222 rat leukemia cells, the original sialic acid content at the cell periphery is reconstituted.This investigation was performed within the EORTIC Cell Surface Project Group and supported by the Swiss National Science Foundation, Grant No. 3.901.72, and by the Zürich Cancer League. 相似文献
35.
SERRATE coordinates shoot meristem function and leaf axial patterning in Arabidopsis 总被引:1,自引:0,他引:1
Leaves of flowering plants are determinate organs produced by pluripotent structures termed shoot apical meristems. Once specified, leaves differentiate an adaxial (upper) side specialized for light capture, and an abaxial (lower) side specialized for gas exchange. A functional relationship between meristem activity and the differentiation of adaxial leaf fate has been recognized for over fifty years, but the molecular basis of this interaction is unclear. In Arabidopsis thaliana, activity of the class I KNOX (KNOTTED1-like homeobox) genes SHOOTMERISTEMLESS (STM) and BREVIPEDICELLUS (BP) is required for meristem function but excluded from leaves, whereas members of the HD-Zip III (class III homeodomain leucine zipper) protein family function to promote both meristem activity and adaxial leaf fate. Here we show that the zinc-finger protein SERRATE acts in a microRNA (miRNA) gene-silencing pathway to regulate expression of the HD-Zip III gene PHABULOSA (PHB) while also limiting the competence of shoot tissue to respond to KNOX expression. Thus, SERRATE acts to coordinately regulate meristem activity and leaf axial patterning. 相似文献
36.
Long-standing controversy surrounds the question of whether living bird lineages emerged after non-avian dinosaur extinction at the Cretaceous/Tertiary (K/T) boundary or whether these lineages coexisted with other dinosaurs and passed through this mass extinction event. Inferences from biogeography and molecular sequence data (but see ref. 10) project major avian lineages deep into the Cretaceous period, implying their 'mass survival' at the K/T boundary. By contrast, it has been argued that the fossil record refutes this hypothesis, placing a 'big bang' of avian radiation only after the end of the Cretaceous. However, other fossil data--fragmentary bones referred to extant bird lineages--have been considered inconclusive. These data have never been subjected to phylogenetic analysis. Here we identify a rare, partial skeleton from the Maastrichtian of Antarctica as the first Cretaceous fossil definitively placed within the extant bird radiation. Several phylogenetic analyses supported by independent histological data indicate that a new species, Vegavis iaai, is a part of Anseriformes (waterfowl) and is most closely related to Anatidae, which includes true ducks. A minimum of five divergences within Aves before the K/T boundary are inferred from the placement of Vegavis; at least duck, chicken and ratite bird relatives were coextant with non-avian dinosaurs. 相似文献
37.
38.
Bartkova J Horejsí Z Koed K Krämer A Tort F Zieger K Guldberg P Sehested M Nesland JM Lukas C Ørntoft T Lukas J Bartek J 《Nature》2005,434(7035):864-870
During the evolution of cancer, the incipient tumour experiences 'oncogenic stress', which evokes a counter-response to eliminate such hazardous cells. However, the nature of this stress remains elusive, as does the inducible anti-cancer barrier that elicits growth arrest or cell death. Here we show that in clinical specimens from different stages of human tumours of the urinary bladder, breast, lung and colon, the early precursor lesions (but not normal tissues) commonly express markers of an activated DNA damage response. These include phosphorylated kinases ATM and Chk2, and phosphorylated histone H2AX and p53. Similar checkpoint responses were induced in cultured cells upon expression of different oncogenes that deregulate DNA replication. Together with genetic analyses, including a genome-wide assessment of allelic imbalances, our data indicate that early in tumorigenesis (before genomic instability and malignant conversion), human cells activate an ATR/ATM-regulated DNA damage response network that delays or prevents cancer. Mutations compromising this checkpoint, including defects in the ATM-Chk2-p53 pathway, might allow cell proliferation, survival, increased genomic instability and tumour progression. 相似文献
39.
40.
Mikko Hellgren Jonas Carlsson Linus J. Östberg Claudia A. Staab Bengt Persson Jan-Olov Höög 《Cellular and molecular life sciences : CMLS》2010,67(17):3005-3015
Alcohol dehydrogenase 3 (ADH3) has been assigned a role in nitric oxide homeostasis due to its function as an S-nitrosoglutathione reductase. As altered S-nitrosoglutathione levels are often associated with disease, compounds that modulate ADH3 activity might be of therapeutic
interest. We performed a virtual screening with molecular dockings of more than 40,000 compounds into the active site of human
ADH3. A novel knowledge-based scoring method was used to rank compounds, and several compounds that were not known to interact
with ADH3 were tested in vitro. Two of these showed substrate activity (9-decen-1-ol and dodecyltetraglycol), where calculated
binding scoring energies correlated well with the logarithm of the k
cat/K
m values for the substrates. Two compounds showed inhibition capacity (deoxycholic acid and doxorubicin), and with these data
three different lines for specific inhibitors for ADH3 are suggested: fatty acids, glutathione analogs, and cholic acids. 相似文献