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91.
92.
Tobamoviruses, mostly isolated from solanaceous plants, may represent
ancient virus lineages that have codiverged with their hosts. Recently
completed nucleotide sequences of six nonsolanaceous tobamoviruses allowed
assessment of the codivergence hypothesis and support a third subgroup
within tobamoviruses. The genomic sequences of 12 tobamoviruses and the
partial sequences of 11 others have been analyzed. Comparisons of the
predicted protein sequences revealed three clusters of tobamoviruses,
corresponding to those infecting solanaceous species (subgroup 1), those
infecting cucurbits and legumes (subgroup 2), and those infecting
crucifers. The orchid-infecting odontoglossum ringspot tobamovirus was
associated with subgroup 1 genomes by its coat and movement protein
sequences, but with the crucifer-pathogenic tobamoviruses by the remainder
of its genome, suggesting that it is the progeny of a recombinant. For four
of five genomic regions, subgroup 1 and 3 genomes were equidistant from a
subgroup 2 genome chosen for comparison, suggesting uniform rates of
evolution. A phylogenetic tree of plant families based on the tobamoviruses
they harbor was congruent with that based on rubisco sequences but had a
different root, suggesting that codivergence was tempered by rare events of
viruses of one family colonizing another family. The proposed subgroup 3
viruses probably have an origin of virion assembly in the movement protein
gene, a large (25-codon) overlap of movement and coat protein open reading
frames, and a comparably shorter genome. Codon-position- dependent base
compositions and codon prevalences suggested that the coat protein frame of
the overlap region was ancestral. Bootstrapped parsimony analysis of the
nucleotides in the overlap region and of the sequences translated from the
-1 frame (the subgroup 3 movement protein frame) of this region produced
trees inconsistent with those deduced from other regions. The results are
consistent with a model in which a no or short overlap organization was
ancestral. Despite encoding of subgroup 2 and 3 movement protein C-termini
by nonhomologous nucleotides, weak similarities between their amino acid
sequences suggested convergent sequence evolution.
相似文献
93.
Kitagaki H Tomioka S Yoshizawa T Sorimachi H Saido TC Ishiura S Suzuki K 《Bioscience, biotechnology, and biochemistry》2000,64(4):689-695
Calpain, a calcium dependent cysteine protease, consists of a catalytic large subunit and a regulatory small subunit. Two models have been proposed to explain calpain activation: an autolysis model and a dissociation model. In the autolysis model, the autolyzed form is the active species, which is sensitized to Ca2+. In the dissociation model, dissociated large subunit is the active species. We have reported that the Ca2+ concentration regulates reversible dissociation of subunits. We found further that in chicken micro/m-calpain autolysis of the large subunit induces irreversible dissociation from the small subunit as well as activation. So we could propose a new mechanism for activation of the calpain by combining our findings. Our model insists that autolyzed large subunit remains dissociated from the small subunit even after the removal of Ca2+ to keep it sensitized to Ca2+. This model could be expanded to other calpains and give a new perspective on calpain activation. 相似文献
94.
Funamoto S Morishima-Kawashima M Tanimura Y Hirotani N Saido TC Ihara Y 《Biochemistry》2004,43(42):13532-13540
We previously showed that beta-amyloid precursor protein (APP) is cleaved not only in the middle of the membrane (gamma-cleavage) but also at novel cleavage sites close to the membrane/cytoplasmic boundary (epsilon-cleavage), releasing APP intracellular domains (AICDs) 49-99 and 50-99. To learn more about the relationship between gamma- and epsilon-cleavage, C-terminally truncated carboxyl-terminal fragments (CTFs) of APP, especially CTFs1-48 and 1-49 (the postulated products that are generated by epsilon-cleavage), were transiently expressed in CHO cells. Most importantly, the cells expressing CTF1-49 secreted predominantly amyloid beta-protein (Abeta) 40, while those expressing CTF1-48 secreted preferentially Abeta42. This supports our assumption that epsilon-cleavage precedes Alphabeta production and that preceding epsilon-cleavage determines the preference for the final Abeta species. The gamma-secretase inhibitors, L-685,458 and DAPT, suppressed Abeta production from CTF1-49. Regarding Abeta production from CTF1-48, L-685,458 suppressed it, but DAPT failed to do so. A dominant negative mutant of presenilin 1 suppressed the production of Abeta40 and 42 from both CTFs1-48 and 1-49. These data should shed significant light into the mechanism of Abeta production. 相似文献
95.
Depletion of Vitamin E Increases Amyloid �� Accumulation by Decreasing Its Clearances from Brain and Blood in a Mouse Model of Alzheimer Disease 总被引:1,自引:0,他引:1
Yoichiro Nishida Shingo Ito Sumio Ohtsuki Naoki Yamamoto Tsubura Takahashi Nobuhisa Iwata Kou-ichi Jishage Hiromi Yamada Hiroki Sasaguri Shigefumi Yokota Wenying Piao Hiroyuki Tomimitsu Takaomi C. Saido Katsuhiko Yanagisawa Tetsuya Terasaki Hidehiro Mizusawa Takanori Yokota 《The Journal of biological chemistry》2009,284(48):33400-33408
Increased oxidative damage is a prominent and early feature in Alzheimer disease. We previously crossed Alzheimer disease transgenic (APPsw) model mice with α-tocopherol transfer protein knock-out (Ttpa−/−) mice in which lipid peroxidation in the brain was significantly increased. The resulting double-mutant (Ttpa−/−APPsw) mice showed increased amyloid β (Aβ) deposits in the brain, which was ameliorated with α-tocopherol supplementation. To investigate the mechanism of the increased Aβ accumulation, we here studied generation, degradation, aggregation, and efflux of Aβ in the mice. The clearance of intracerebral-microinjected 125I-Aβ1–40 from brain was decreased in Ttpa−/− mice to be compared with wild-type mice, whereas the generation of Aβ was not increased in Ttpa−/−APPsw mice. The activity of an Aβ-degrading enzyme, neprilysin, did not decrease, but the expression level of insulin-degrading enzyme was markedly decreased in Ttpa−/− mouse brain. In contrast, Aβ aggregation was accelerated in Ttpa−/− mouse brains compared with wild-type brains, and well known molecules involved in Aβ transport from brain to blood, low density lipoprotein receptor-related protein-1 (LRP-1) and p-glycoprotein, were up-regulated in the small vascular fraction of Ttpa−/− mouse brains. Moreover, the disappearance of intravenously administered 125I-Aβ1–40 was decreased in Ttpa−/− mice with reduced translocation of LRP-1 in the hepatocytes. These results suggest that lipid peroxidation due to depletion of α-tocopherol impairs Aβ clearances from the brain and from the blood, possibly causing increased Aβ accumulation in Ttpa−/−APPsw mouse brain and plasma. 相似文献
96.
Gang Li Tianming Liu Ashley Tarokh Jingxin Nie Lei Guo Andrew Mara Scott Holley Stephen TC Wong 《BMC cell biology》2007,8(1):40
Background
Reliable segmentation of cell nuclei from three dimensional (3D) microscopic images is an important task in many biological studies. We present a novel, fully automated method for the segmentation of cell nuclei from 3D microscopic images. It was designed specifically to segment nuclei in images where the nuclei are closely juxtaposed or touching each other. The segmentation approach has three stages: 1) a gradient diffusion procedure, 2) gradient flow tracking and grouping, and 3) local adaptive thresholding. 相似文献97.
Per Nilsson Nobuhisa Iwata Shin‐ichi Muramatsu Lars O. Tjernberg Bengt Winblad Takaomi C. Saido 《Journal of cellular and molecular medicine》2010,14(4):741-757
- ? Introduction
- ? Targets and ongoing research
- ‐ NGF
- ‐ Neurotrophic function of NGF
- ‐ Levels of NGF in AD
- ‐ Role of NGF in AD
- ‐ NGF as a therapeutic agent
- ‐ Development of NGF gene therapy
- ‐ In vivo gene delivery of NGF
- ‐ BDNF
- ‐ Neurotrophic function of BDNF
- ‐ BDNF levels in AD
- ‐ BDNF function in AD
- ? Towards BDNF gene therapy
- ‐ Neprilysin
- ‐ Role of neprilysin in AD
- ‐ Neprilysin levels in AD
- ‐ Gene delivery of neprilysin in AD animal models
- ‐ NGF
- ? Potential gene therapy target candidates
- ‐ APOE
- ‐ ECE
- ‐ Cathepsin B
- ‐ Other Aβ degrading enzymes
- ? Down‐regulation of AD‐associated proteins by siRNA
- ‐ BACE1
- ‐ APP
- ? Concluding remarks
98.
Yahata N Asai M Kitaoka S Takahashi K Asaka I Hioki H Kaneko T Maruyama K Saido TC Nakahata T Asada T Yamanaka S Iwata N Inoue H 《PloS one》2011,6(9):e25788
Background
Alzheimer''s disease (AD) is a neurodegenerative disorder that causes progressive memory and cognitive decline during middle to late adult life. The AD brain is characterized by deposition of amyloid β peptide (Aβ), which is produced from amyloid precursor protein by β- and γ-secretase (presenilin complex)-mediated sequential cleavage. Induced pluripotent stem (iPS) cells potentially provide an opportunity to generate a human cell-based model of AD that would be crucial for drug discovery as well as for investigating mechanisms of the disease.Methodology/Principal Findings
We differentiated human iPS (hiPS) cells into neuronal cells expressing the forebrain marker, Foxg1, and the neocortical markers, Cux1, Satb2, Ctip2, and Tbr1. The iPS cell-derived neuronal cells also expressed amyloid precursor protein, β-secretase, and γ-secretase components, and were capable of secreting Aβ into the conditioned media. Aβ production was inhibited by β-secretase inhibitor, γ-secretase inhibitor (GSI), and an NSAID; however, there were different susceptibilities to all three drugs between early and late differentiation stages. At the early differentiation stage, GSI treatment caused a fast increase at lower dose (Aβ surge) and drastic decline of Aβ production.Conclusions/Significance
These results indicate that the hiPS cell-derived neuronal cells express functional β- and γ-secretases involved in Aβ production; however, anti-Aβ drug screening using these hiPS cell-derived neuronal cells requires sufficient neuronal differentiation. 相似文献99.
Shirotani K Tsubuki S Iwata N Takaki Y Harigaya W Maruyama K Kiryu-Seo S Kiyama H Iwata H Tomita T Iwatsubo T Saido TC 《The Journal of biological chemistry》2001,276(24):21895-21901
To identify the amyloid beta peptide (Abeta) 1-42-degrading enzyme whose activity is inhibited by thiorphan and phosphoramidon in vivo, we searched for neprilysin (NEP) homologues and cloned neprilysin-like peptidase (NEPLP) alpha, NEPLP beta, and NEPLP gamma cDNAs. We expressed NEP, phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PEX), NEPLPs, and damage-induced neuronal endopeptidase (DINE) in 293 cells as 95- to 125-kDa proteins and found that the enzymatic activities of PEX, NEPLP alpha, and NEPLP beta, as well as those of NEP and DINE, were sensitive to thiorphan and phosphoramidon. Among the peptidases tested, NEP degraded both synthetic and cell-secreted Abeta1-40 and Abeta1-42 most rapidly and efficiently. PEX degraded cold Abeta1-40 and NEPLP alpha degraded both cold Abeta1-40 and Abeta1-42, although the rates and the extents of the digestion were slower and less efficient than those exhibited by NEP. These data suggest that, among the endopeptidases whose activities are sensitive to thiorphan and phosphoramidon, NEP is the most potent Abeta-degrading enzyme in vivo. Therefore, manipulating the activity of NEP would be a useful approach in regulating Abeta levels in the brain. 相似文献
100.
A phorbol ester receptor/protein kinase, nPKC eta, a new member of the protein kinase C family predominantly expressed in lung and skin 总被引:21,自引:0,他引:21
S Osada K Mizuno T C Saido Y Akita K Suzuki T Kuroki S Ohno 《The Journal of biological chemistry》1990,265(36):22434-22440
Protein kinase C (PKC)-related cDNA clones isolated from mouse epidermis cDNA library encoded a 78-kDa protein, nPKC eta. nPKC eta contains a characteristic cysteine-rich repeat sequence (C1 region) and a protein kinase domain sequence (C3 region), both of which are conserved among PKC family members. However, nPKC eta lacks a putative Ca2+ binding region (C2 region) that is seen in conventional PKCs (alpha, beta I, beta II, gamma), but not in novel PKCs (nPKC delta, -epsilon, -zeta). nPKC eta shows the highest sequence similarity to nPKC epsilon (59.4% identity). The similarity extends to the NH2-terminal sequence (E region) which corresponds to one of the divergent regions (D1 region). Northern blot analysis showed that the mRNA for nPKC eta is highly expressed in the lung and skin but, in contrast to other members of the PKC family, only slightly expressed in the brain. nPKC eta expressed in COS cells shows phorbol ester binding activity with a similar affinity to nPKC epsilon. Antiserum raised against a COOH-terminal peptide of nPKC eta identified an 82-kDa protein in mouse lung extract as well as in an extract from COS cells transfected with the nPKC eta-cDNA expression plasmid. Autophosphorylation of nPKC eta immunoprecipitated with the specific antiserum was observed, indicating that nPKC eta is a protein kinase. These results clearly demonstrate the existence and the possible importance of nPKC eta as a member of the phorbol ester receptor/protein kinase, PKC, family. 相似文献