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1.
Pauline Ferraris Elodie Beaumont Rustem Uzbekov Denys Brand Julien Gaillard Emmanuelle Blanchard Philippe Roingeard 《Cellular and molecular life sciences : CMLS》2013,70(7):1297-1306
Like most positive-strand RNA viruses, hepatitis C virus (HCV) forms a membrane-associated replication complex consisting of replicating RNA, viral and host proteins anchored to altered cell membranes. We used a combination of qualitative and quantitative electron microscopy (EM), immuno-EM, and the 3D reconstruction of serial EM sections to analyze the host cell membrane alterations induced by HCV. Three different types of membrane alteration were observed: vesicles in clusters (ViCs), contiguous vesicles (CVs), and double-membrane vesicles (DMVs). The main ultrastructural change observed early in infection was the formation of a network of CVs surrounding the lipid droplets. Later stages in the infectious cycle were characterized by a large increase in the number of DMVs, which may be derived from the CVs. These DMVs are thought to constitute the membranous structures harboring the viral replication complexes in which viral replication is firmly and permanently established and to protect the virus against double-stranded RNA-triggered host antiviral responses. 相似文献
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Konstantina Katsarou Alexandros Α. Lavdas Panagiota Tsitoura Elisavet Serti Panagiotis Markoulatos Penelope Mavromara Urania Georgopoulou 《Cellular and molecular life sciences : CMLS》2010,67(14):2491-2506
Although HCV is an enveloped virus, naked nucleocapsids have been reported in the serum of infected patients. The HCV core
particle serves as a protective capsid shell for the viral genome and recombinant in vitro assembled HCV core particles induce
strong specific immunity. We investigated the post-binding mechanism of recombinant core particle uptake and its intracellular
fate. In hepatic cells, these particles are internalized, most likely in a clathrin-dependent pathway, reaching early to late
endosomes and finally lysosomes. The endocytic acidic milieu is implicated in trafficking process. Using specific phosphoantibodies,
signaling pathway inhibitors and chemical agents, ERK1/2 was found to be activated in a sustained way after endocytosis, followed by downstream immediate early genes (c-fos and egr-1) modulation. We propose that the intriguing properties of cellular internalization of HCV non-enveloped particles can induce
specific ERK1/2–MAPKs events that could be important in HCV life cycle and pathogenesis of HCV infection. 相似文献
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In this study, earlier observations concerning the independence of both natural (NCMC) and lectin-dependent cell-mediated cytotoxicity (LDCC) from DNA synthesis have been confirmed. In addition, blocking of RNA synthesis by actinomycin D and of protein synthesis, reversibly by puromycin (PM) and irreversibly by emetine (EM) had different effects on NCMC and LDCC against 3H-thymidine-prelabeled HEp-2 target cells. Similarly to the Con A-induced proliferation of lymphocytes, LDCC activity was also inhibited by blocking of RNA and protein synthesis. NCMC to HEp-2 target cells was not affected by blocking of RNA synthesis, while both PM and EM strongly enhanced NCMC activity. 相似文献
4.
A. Perl R. Gonzalez-Cabello L. Falucskai P. Gergely J. Fehér 《Cellular and molecular life sciences : CMLS》1985,41(10):1344-1346
Summary In this study, earlier observations2,9 concerning the independence of both natural (NCMC) and lectin-dependent cell-mediated cytotoxicity (LDCC) from DNA synthesis have been confirmed. In addition, blocking of RNA synthesis by actinomycin D and of protein synthesis, reversibly by puromycin (PM) and irreversibly by emetine (EM) had different effects on NCMC and LDCC against3H-thymidine-prelabeled HEp-2 target cells. Similarly to the Con A-induced proliferation of lymphocytes, LDCC activity was also inhibited by blocking of RNA and protein synthesis. NCMC to HEp-2 target cells was not affected by blocking of RNA synthesis, while both PM and EM strongly enhanced NCMC activity. 相似文献
5.
Operons (clusters of co-regulated genes with related functions) are common features of bacterial genomes. More recently, functional
gene clustering has been reported in eukaryotes, from yeasts to filamentous fungi, plants, and animals. Gene clusters can
consist of paralogous genes that have most likely arisen by gene duplication. However, there are now many examples of eukaryotic
gene clusters that contain functionally related but non-homologous genes and that represent functional gene organizations
with operon-like features (physical clustering and co-regulation). These include gene clusters for use of different carbon
and nitrogen sources in yeasts, for production of antibiotics, toxins, and virulence determinants in filamentous fungi, for
production of defense compounds in plants, and for innate and adaptive immunity in animals (the major histocompatibility locus).
The aim of this article is to review features of functional gene clusters in prokaryotes and eukaryotes and the significance
of clustering for effective function. 相似文献
6.
Clustering of neurotransmitter receptors in the postsynaptic membrane is critical for efficient synaptic transmission. During
neuromuscular synaptogenesis, clustering of acetylcholine receptors (AChRs) is an early sign of postsynaptic differentiation.
Recent studies have revealed that the earliest AChR clusters can form in the muscle independent of motorneurons. Neurally
released agrin, acting through the muscle-specific kinase MuSK and rapsyn, then causes further clustering and localization
of clusters underneath the nerve terminal. AChRs themselves are required for agrin-induced clustering of several postsynaptic
proteins, most notably rapsyn. Once formed, AChR clusters are stabilized by several tyrosine kinases and by components of
the dystrophin/utrophin glycoprotein complex, some of which also direct postnatal synaptic maturation such as formation of
postjunctional folds. This review summarizes these recent results about AChR clustering, which indicate that early clustering
can occur in the absence of nerves, that AChRs play an active role in the clustering process and that partly different mechanisms
direct formation versus stabilization of AChR clusters.
Received 10 April 2002; received after revision 4 June 2002; accepted 10 June 2002 相似文献
7.
本文基于建模同步动力学行为的Kuramoto模型提出了一种新的有效层次聚类方法.本文提出的方法基于局部邻域的概念,能够实现稳定的局部同步聚类.通过不断扩大对象同步的邻域半径,所提出的方法能够实现层次化的同步聚类.此外,提出对象邻域闭包的概念,在对象间到达完全同步之前就能预测出聚类的形成,从而减少对象动态交互的时间.本文的方法不依赖于任何数据分布假设,无需任何手工参数设置,可以检测出任意数量、形状和大小的聚类.由于同步过程能够有效地规避离群点,该方法有较强的噪声数据抑制能力.在大量真实数据集和人工合成数据集上的实验结果表明本文的方法聚类准确率高,且运行时间较同类基准算法显著缩短. 相似文献
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J. Dubail F. Kesteloot C. Deroanne P. Motte V. Lambert J.-M. Rakic C. Lapière B. Nusgens A. Colige 《Cellular and molecular life sciences : CMLS》2010,67(24):4213-4232
ADAMTS-2 is a metalloproteinase that plays a key role in the processing of fibrillar procollagen precursors into mature collagen
molecules by excising the amino-propeptide. We demonstrate that recombinant ADAMTS-2 is also able to reduce proliferation
of endothelial cells, and to induce their retraction and detachment from the substrate resulting in apoptosis. Dephosphorylation
of Erk1/2 and MLC largely precedes the ADAMTS-2 induced morphological alterations. In 3-D culture models, ADAMTS-2 strongly
reduced branching of capillary-like structures formed by endothelial cells and their long-term maintenance and inhibited vessels
formation in embryoid bodies (EB). Growth and vascularization of tumors formed in nude mice by HEK 293-EBNA cells expressing
ADAMTS-2 were drastically reduced. A similar anti-tumoral activity was observed when using cells expressing recombinant deleted
forms of ADAMTS-2, including catalytically inactive enzyme. Nucleolin, a nuclear protein also found to be associated with
the cell membrane, was identified as a potential receptor mediating the antiangiogenic properties of ADAMTS-2. 相似文献
11.
Q.-Q. Li X.-X. Cao J.-D. Xu Q. Chen W.-J. Wang F. Tang Z.-Q. Chen X.-P. Liu Z.-D. Xu 《Cellular and molecular life sciences : CMLS》2009,66(3):504-515
We previously reported that treatment with P-glycoprotein (P-gp) substrates promotes in vitro invasion in multidrug-resistant (MDR) breast cancer cells. This effect is initiated by the P-gp pump function and mediated
by interaction of P-gp with some unknown component(s). However, the underlying mechanism(s) remains poorly understood. Here
we confirm a novel physical interaction between P-gp and cellular prion protein (PrPc). Blocking P-gp activity or depletion of PrPc inhibited paclitaxel (P-gp substrate)- induced invasion. Paclitaxel further facilitated the formation of P-gp/PrPc clusters residing in caveolar domains and promoted the association of P-gp with caveolin-1. Both caveolin-1 and the integrity
of caveolae were required for the drug-induced invasion. In addition, the P-gp/PrPc complex also played an important role in anti-apoptotic activity of MCF7/Adr cells.These data provide new insights into the
mode by which MDR breast cancers evade cytotoxic attacks from P-gp substrates and also suggest a role for P-gp/ PrPc interaction in this process.
Received 4 September 2008; received after revision 16 November 2008; accepted 18 November 2008 相似文献
12.
Uusi-Rauva K Kyttälä A van der Kant R Vesa J Tanhuanpää K Neefjes J Olkkonen VM Jalanko A 《Cellular and molecular life sciences : CMLS》2012,69(12):2075-2089
CLN3 is an endosomal/lysosomal transmembrane protein mutated in classical juvenile onset neuronal ceroid lipofuscinosis, a fatal inherited neurodegenerative lysosomal storage disorder. The function of CLN3 in endosomal/lysosomal events has remained elusive due to poor understanding of its interactions in these compartments. It has previously been shown that the localisation of late endosomal/lysosomal compartments is disturbed in cells expressing the most common disease-associated CLN3 mutant, CLN3?ex7-8 (c.462-677del). We report here that a protracted disease causing mutant, CLN3E295K, affects the properties of late endocytic compartments, since over-expression of the CLN3E295K mutant protein in HeLa cells induced relocalisation of Rab7 and a perinuclear clustering of late endosomes/lysosomes. In addition to the previously reported disturbances in the endocytic pathway, we now show that the anterograde transport of late endosomal/lysosomal compartments is affected in CLN3 deficiency. CLN3 interacted with motor components driving both plus and minus end microtubular trafficking: tubulin, dynactin, dynein and kinesin-2. Most importantly, CLN3 was found to interact directly with active, guanosine-5'-triphosphate (GTP)-bound Rab7 and with the Rab7-interacting lysosomal protein (RILP) that anchors the dynein motor. The data presented in this study provide novel insights into the role of CLN3 in late endosomal/lysosomal membrane transport. 相似文献
13.
Hoi-Hin Kwok Po-Ying Poon Kylie Hin-Man Mak Lin-Yao Zhang Pei Liu Huoming Zhang Nai-Ki Mak Patrick Ying-Kit Yue Ricky Ngok-Shun Wong 《Cellular and molecular life sciences : CMLS》2017,74(19):3613-3630
MicroRNAs (miRNAs) are a family of non-coding RNAs that play crucial roles in regulating various normal cellular responses. Recent studies revealed that the canonical miRNA biogenesis pathway is subject to sophisticated regulation. Hormonal control of miRNA biogenesis by androgen and estrogen has been demonstrated, but the direct effects of the glucocorticoid receptor (GR) on miRNA biogenesis are unknown. This study revealed the role of GR in miRNA maturation. We showed that two GR agonists, dexamethasone and ginsenoside-Rg1 rapidly suppressed the expression of mature miR-15b, miR-23a, and miR-214 in human endothelial cells. RNA pulldown coupled with proteomic analysis identified GTPase-activating protein (SH3 domain) binding protein 1 (G3BP1) as one of the RNA-binding proteins mediating GR-regulated miRNA maturation. Activated GR induced phosphorylation of v-AKT Murine Thymoma Viral Oncogene Homologue (AKT) kinase, which in turn phosphorylated and promoted nuclear translocation of G3BP1. The nuclear G3BP1 bound to the G3BP1 consensus sequence located on primary miR-15b~16-2 and miR-23a~27a~24-2 to inhibit their maturation. The findings from this study have advanced our understanding of the non-genomic effects of GR in the vascular system. 相似文献
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层次形成的正确性决定了层次聚类的质量,通常围绕对象类内类间关系评价实现。本文基于聚类目标,综合考虑类内类问关系,借鉴网络分析中模块性评价准则,设计用于层次聚类的模块性指标,并采用自底向上合并的途径实现指标优化从而完成聚类,提出一种基于模块性指标优化的层次聚类算法。仿真试验表明,和谱聚类算法相比,本文介绍的算法实现简单,能以较少的计算代价,准确地获得样本特征,实现聚类。 相似文献
17.
D. Lamošová M. Zeman M. Macková E. Gwinner 《Cellular and molecular life sciences : CMLS》1995,51(9-10):970-975
The chick pineal gland exhibits circadian rhythms in melatonin synthesis under in vivo and in vitro conditions. A daily rhythm of melatonin production was first detectable in pineal glands isolated from chick embryos at embryonic day 16 and incubated under a LD cycle. All pineal glands isolated from 17-day-old and older embryos were rhythmic while no gland isolated at embryonic day 14 and 15 exhibited a daily rhythm in melatonin synthesis. Melatonin production in static cultures of embryonic pineal cells was rhythmic over 48 h if the cells were kept under a LD cycle. When embryonic pineal cells were incubated in constant darkness the rhythm in melatonin production was damped within 48 h. These results suggest that chick pineal cells from embryonic day 16 onwards are photosensitive but that the endogenous component of the melatonin rhythm is not completely developed at that age. A soluble analogue of cAMP stimulated and norepinephrine inhibited melatonin synthesis in cultured embryonic pineal cells. These findings indicate that the stimulatory and inhibitory pathways controlling melatonin synthesis in the mature pineal gland are effective in pineal cells isolated from chick embryos at least 2 days before hatching. 相似文献
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Henriikka Kentala Annika Koponen Helena Vihinen Juho Pirhonen Gerhard Liebisch Zoltan Pataj Annukka Kivelä Shiqian Li Leena Karhinen Eeva Jääskeläinen Robert Andrews Leena Meriläinen Silke Matysik Elina Ikonen You Zhou Eija Jokitalo Vesa M. Olkkonen 《Cellular and molecular life sciences : CMLS》2018,75(21):4041-4057
ORP2 is a ubiquitously expressed OSBP-related protein previously implicated in endoplasmic reticulum (ER)—lipid droplet (LD) contacts, triacylglycerol (TG) metabolism, cholesterol transport, adrenocortical steroidogenesis, and actin-dependent cell dynamics. Here, we characterize the role of ORP2 in carbohydrate and lipid metabolism by employing ORP2-knockout (KO) hepatoma cells (HuH7) generated by CRISPR-Cas9 gene editing. The ORP2-KO and control HuH7 cells were subjected to RNA sequencing, analyses of Akt signaling, carbohydrate and TG metabolism, the extracellular acidification rate, and the lipidome, as well as to transmission electron microscopy. The loss of ORP2 resulted in a marked reduction of active phosphorylated Akt(Ser473) and its target Glycogen synthase kinase 3β(Ser9), consistent with defective Akt signaling. ORP2 was found to form a physical complex with the key controllers of Akt activity, Cdc37, and Hsp90, and to co-localize with Cdc37 and active Akt(Ser473) at lamellipodial plasma membrane regions, in addition to the previously reported ER–LD localization. ORP2-KO reduced glucose uptake, glycogen synthesis, glycolysis, mRNA-encoding glycolytic enzymes, and SREBP-1 target gene expression, and led to defective TG synthesis and storage. ORP2-KO did not reduce but rather increased ER–LD contacts under basal culture conditions and interfered with their expansion upon fatty acid loading. Together with our recently published work (Kentala et al. in FASEB J 32:1281–1295, 2018), this study identifies ORP2 as a new regulatory nexus of Akt signaling, cellular energy metabolism, actin cytoskeletal function, cell migration, and proliferation. 相似文献
20.
Bidart M Ricard N Levet S Samson M Mallet C David L Subileau M Tillet E Feige JJ Bailly S 《Cellular and molecular life sciences : CMLS》2012,69(2):313-324
Bone Morphogenetic Protein 9 (BMP9) has been recently found to be the physiological ligand for the activin receptor-like kinase
1 (ALK1), and to be a major circulating vascular quiescence factor. Moreover, a soluble chimeric ALK1 protein (ALK1-Fc) has
recently been developed and showed powerful anti-tumor growth and anti-angiogenic effects. However, not much is known concerning
BMP9. This prompted us to investigate the human endogenous sources of this cytokine and to further characterize its circulating
form(s) and its function. Analysis of BMP9 expression reveals that BMP9 is produced by hepatocytes and intrahepatic biliary
epithelial cells. Gel filtration analysis combined with ELISA and biological assays demonstrate that BMP9 circulates in plasma
(1) as an unprocessed inactive form that can be further activated by furin a serine endoprotease, and (2) as a mature and
fully active form (composed of the mature form associated with its prodomain). Analysis of BMP9 circulating levels during
mouse development demonstrates that BMP9 peaks during the first 3 weeks after birth and then decreases to 2 ng/mL in adulthood.
We also show that circulating BMP9 physiologically induces a constitutive Smad1/5/8 phosphorylation in endothelial cells.
Taken together, our results argue for the role of BMP9 as a hepatocyte-derived factor, circulating in inactive (40%) and active
(60%) forms, the latter constantly activating endothelial cells to maintain them in a resting state. 相似文献