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161.
Alice J L Zheng Aikaterini Thermou Chrysoula Daskalogianni Laurence Malbert-Colas Konstantinos Karakostis Ronan Le
Snchal Van Trang
Dinh Maria C Tovar
Fernandez Sbastien Apcher Sa Chen Marc Blondel Robin Fahraeus 《Nucleic acids research》2022,50(17):10110
Protein aggregates and abnormal proteins are toxic and associated with neurodegenerative diseases. There are several mechanisms to help cells get rid of aggregates but little is known on how cells prevent aggregate-prone proteins from being synthesised. The EBNA1 of the Epstein-Barr virus (EBV) evades the immune system by suppressing its own mRNA translation initiation in order to minimize the production of antigenic peptides for the major histocompatibility (MHC) class I pathway. Here we show that the emerging peptide of the disordered glycine–alanine repeat (GAr) within EBNA1 dislodges the nascent polypeptide-associated complex (NAC) from the ribosome. This results in the recruitment of nucleolin to the GAr-encoding mRNA and suppression of mRNA translation initiation in cis. Suppressing NAC alpha (NACA) expression prevents nucleolin from binding to the GAr mRNA and overcomes GAr-mediated translation inhibition. Taken together, these observations suggest that EBNA1 exploits a nascent protein quality control pathway to regulate its own rate of synthesis that is based on sensing the nascent GAr peptide by NAC followed by the recruitment of nucleolin to the GAr-encoding RNA sequence. 相似文献
162.
Yuxuan Wang Suri Guga Kejia Wu Zoe Khaw Konstantinos Tzoumkas Phil Tombleson Mary E. Comeau Carl D. Langefeld Deborah S. Cunninghame Graham David L. Morris Timothy J. Vyse 《PLoS genetics》2022,18(11)
Genome wide association studies show there is a genetic component to severe COVID-19. We find evidence that the genome-wide genetic association signal with severe COVID-19 is correlated with that of systemic lupus erythematosus (SLE), having formally tested this using genetic correlation analysis by LD score regression. To identify the shared associated loci and gain insight into the shared genetic effects, using summary level data we performed meta-analyses, a local genetic correlation analysis and fine-mapping using stepwise regression and functional annotation. This identified multiple loci shared between the two traits, some of which exert opposing effects. The locus with most evidence of shared association is TYK2, a gene critical to the type I interferon pathway, where the local genetic correlation is negative. Another shared locus is CLEC1A, where the direction of effects is aligned, that encodes a lectin involved in cell signaling, and the anti-fungal immune response. Our analyses suggest that several loci with reciprocal effects between the two traits have a role in the defense response pathway, adding to the evidence that SLE risk alleles are protective against infection. 相似文献
163.
DEF6, a novel PH-DH-like domain protein, is an upstream activator of the Rho GTPases Rac1, Cdc42, and RhoA 总被引:1,自引:0,他引:1
In this paper, we describe the characterization of DEF6, a novel PH-DH-like protein related to SWAP-70 that functions as an upstream activator of Rho GTPases. In NIH 3T3 cells, stimulation of the PI 3-kinase signaling pathway with either H2O2 or platelet-derived growth factor (PDGF) resulted in the translocation of an overexpressed DEF6-GFP fusion protein to the cell membrane and induced the formation of filopodia and lamellipodia. In contrast to full-length DEF6, expression of the DH-like (DHL) domain as a GFP fusion protein potently induced actin polymerization, including stress fiber formation in COS-7 cells, in the absence of PI 3-kinase signaling, indicating that it was constitutively active. The GTP-loading of Cdc42 was strongly enhanced in NIH 3T3 cells expressing the DH domain while filopodia formation, membrane ruffling, and stress fiber formation could be inhibited by the co-expression of the DH domain with dominant negative mutants of either N17Rac1, N17Cdc42, or N19RhoA, respectively. This indicated that DEF6 acts upstream of the Rho GTPases resulting in the activation of the Cdc42, Rac1, and RhoA signaling pathways. In vitro, DEF6 specifically interacted with Rac1, Rac2, Cdc42, and RhoA, suggesting a direct role for DEF6 in the activation of Rho GTPases. The ability of DEF6 to both stimulate actin polymerization and bind to filamentous actin suggests a role for DEF6 in regulating cell shape, polarity, and movement. 相似文献
164.
Evangelou A Toliopoulos I Giotis C Metsios A Verginadis I Simos Y Havelas K Hadziaivazis G Karkabounas S 《Electromagnetic biology and medicine》2011,30(1):46-56
The main objective of our study is to investigate whether an enhancement of the immune system in end-stage cancer patients is achieved by exposure to coherent electromagnetic fields. For this reason, 15 end-stage cancer patients were exposed at low intensity, coherent electromagnetic fields at radiofrequencies ranging from 600?kHz-729?Hz, for 8?h/day, 6 days/week for 4 weeks. NKs number and cytotoxicity of NK T-lymphocytes versus K562 cancer cell line were estimated by flow cytometry, before and after exposure. Data showed that the exposure of the end-stage cancer patients to the coherent electromagnetic fields resulted in a significant increase of the number and the cytotoxicity of the NK T-lymphocytes against cancer cells, in all patients. Exposure to coherent EMFs at radiofrequencies increases the number and cytotoxicity of NK T-lymphocytes, which may contribute to the improvement of cancer patients' status. 相似文献
165.
166.
Malamitsi-Puchner A Economou E Boutsikou T Nikolaou KE Vrachnis N 《Mediators of inflammation》2005,2005(1):53-56
Our aim is to determine--in 30 healthy full-term infants and their mothers--circulating levels of neurotrophin-3 (NT-3) (important for antenatal and postnatal brain development and implicated in the immune response) and FLT3 tyrosine kinase receptor (FLT3) (controlling hematopoiesis and found in the nervous tissue), in the fetal and neonatal life. NT-3 levels, in contrast to FLT3 ones, increased significantly on the fourth postnatal day in relation to the low levels found in the mother, fetus, and day 1 neonate (P = .03, respectively). Maternal and umbilical NT3 levels positively correlated with respective FLT3 levels (P = .003 and P = .03). Circulating NT-3 levels increased in early neonatal life, possibly due to exposure to various stimuli soon after birth. FLT3 levels do not seem to behave accordingly, although these two substances probably synergize. 相似文献
167.
Pu Wang Fei Zhu Norman H. Lee Konstantinos Konstantopoulos 《The Journal of biological chemistry》2010,285(32):24793-24804
Mechanical overloading of cartilage producing hydrostatic stress, tensile strain, and fluid flow can adversely affect chondrocyte function and precipitate osteoarthritis (OA). Application of high fluid shear stress to chondrocytes recapitulates the earmarks of OA, as evidenced by the release of pro-inflammatory mediators, matrix degradation, and chondrocyte apoptosis. Elevated levels of cyclooxygenase-2 (COX-2), prostaglandin (PG) E2, and interleukin (IL)-6 have been reported in OA cartilage in vivo, and in shear-activated chondrocytes in vitro. Although PGE2 positively regulates IL-6 synthesis in chondrocytes, the underlying signaling pathway of shear-induced IL-6 expression remains unknown. Using the human T/C-28a2 chondrocyte cell line as a model system, we demonstrate that COX-2-derived PGE2 signals via up-regulation of E prostanoid (EP) 2 and down-regulation of EP3 receptors to raise intracellular cAMP, and activate protein kinase A (PKA) and phosphatidylinositol 3-kinase (PI3-K)/Akt pathways. PKA and PI3-K/Akt transactivate the NF-κB p65 subunit via phosphorylation at Ser-276 and Ser-536, respectively. Binding of p65 to the IL-6 promoter elicits IL-6 synthesis in sheared chondrocytes. Selective knockdown of EP2 or ectopic expression of EP3 blocks PKA- and PI3-K/Akt-dependent p65 activation and markedly diminishes shear-induced IL-6 expression. Similar inhibitory effects on IL-6 synthesis were observed by inhibiting PKA, PI3-K, or NF-κB using pharmacological and/or genetic interventions. Reconstructing the signaling network regulating shear-induced IL-6 expression in chondrocytes may provide insights for developing therapeutic strategies for arthritic disorders and for culturing artificial cartilage in bioreactors. 相似文献
168.
In the neural superposition eye of a dipteran fly every ommatidium has eight photoreceptors, each associated with a rhabdomere, two central and six peripheral, which altogether result in seven functional light guides. Groups of eight rhabdomeres in neighboring ommatidia have largely overlapping fields of view. Based on the hypothesis that the light signals collected by these rhabdomeres can be used individually, we investigated the feasibility of estimating 3D scene information. According to Pick (Biol Cybern 26:215–224, 1977) the visual axes of these rhabdomeres are not parallel, but converge to a point 3–6 mm in front of the cornea. Such a structure theoretically could estimate depth in a very simple way by assuming that locally the image intensity is well approximated by a linear function of the spatial coordinates. Using the measurements of Pick (Biol Cybern 26:215–224, 1977) we performed simulation experiments to find whether this is practically possible. Our results indicate that depth estimation at small distances (up to about 1.5–2 cm) is reasonably accurate. This would allow the insect to obtain at least an ordinal spatial layout of its operational space when walking. 相似文献
169.
Blood vessel development is in part regulated by pericytes/presumptive vascular smooth muscle cells (PC/pvSMCs). Here, we demonstrate that interactions between PC/pvSMCs and extracellular matrix play a critical role in this event. We show that the cranial vessels in alpha4 integrin-deficient mouse embryos at the stage of vessel remodeling are increased in diameter. This defect is accompanied by a failure of PC/pvSMCs, which normally express alpha4beta1 integrin, to spread uniformly along the vessels. We also find that fibronectin but not VCAM-1 is localized in the cranial vessels at this stage. Furthermore, cultured alpha4 integrin-null PC/pvSMCs plated on fibronectin display a delay in initiating migration, a reduction in migration speed, and a decrease in directional persistence in response to a polarized force of shear flow. These results suggest that specific motile activities of PC/pvSMCs regulated by mechanical signals imposed by the interstitial extracellular matrix may also be required in vivo for the distribution and function of the PC/pvSMCs during blood vessel development. 相似文献
170.
Zifa E Daniil Z Skoumi E Stavrou M Papadimitriou K Terzenidou M Kostikas K Bagiatis V Gourgoulianis KI Mamuris Z 《Molecular biology reports》2012,39(4):4697-4708
A number of studies suggest that mitochondrial dysfunction plays a role in the pathogenesis of asthma. To shed light for the
first time on the role of the mitochondrial genome in the etiology of asthma we analyzed the mitochondrial tRNA genes and
part of their flanking regions in patients with asthma compared with a set of healthy controls. We found a total of 10 mutations
in 56 out of 76 asthmatic patients. Four of these mutations were not found in the control group, five were observed at a significantly
lower frequency in controls, but none of the combinations of mutations detected in asthma patients was observed in the controls.
Furthermore, we observed that 27.6% of the asthma patients (vs. 4% of the controls) belonged to the haplogroup U (Fisher test
P = 0.00) and a positive significant correlation was found between the occurrence of the haplogroup U and the severity of the
disease (Fisher test P = 0.02). Whereas further studies in larger cohorts are needed to confirm these observations we suggest that the mitochondrial
genetic background plays a key role in asthma development. 相似文献