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Zhang, Qing, Jero Calafat, Hans Janssen i Steven Greenberg. "ARF6 Is Required for Growth Factor- and Rac-Mediated Membrane Ruffling in Macrophages at a Stage Distal to Rac Membrane Targeting". Molecular and Cellular Biology 19, nr 12 (1.12.1999): 8158–68. http://dx.doi.org/10.1128/mcb.19.12.8158.
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ABSTRACT Activation of Rac1, a member of the Rho family of GTPases, is associated with multiple cellular responses, including membrane ruffling and focal complex formation. The mechanisms by which Rac1 is coupled to these functional responses are not well understood. It was recently shown that ARF6, a GTPase implicated in cytoskeletal alterations and a membrane recycling pathway, is required for Rac1-dependent phagocytosis in macrophages (Q. Zhang et al., J. Biol. Chem. 273:19977–19981, 1998). To determine whether ARF6 is required for Rac1-dependent cytoskeletal responses in macrophages, we expressed wild-type (WT) or guanine nucleotide binding-deficient alleles (T27N) of ARF6 in macrophages coexpressing activated alleles of Rac1 (Q61L) or Cdc42 (Q61L) or stimulated with colony-stimulating factor 1 (CSF-1). Expression of ARF6 T27N but not ARF6 WT inhibited ruffles mediated by Rac1 Q61L or CSF-1. In contrast, expression of ARF6 T27N did not inhibit Rac1 Q61L-mediated focal complex formation and did not impair Cdc42 Q61L-mediated filopodial formation. Cryoimmunogold electron microscopy demonstrated the presence of ARF6 in membrane ruffles induced by either CSF-1 or Rac1 Q61L. Addition of CSF-1 to macrophages led to the redistribution of ARF6 from the interior of the cell to the plasma membrane, suggesting that this growth factor triggers ARF6 activation. Direct targeting of Rac1 to the plasma membrane did not bypass the blockade in ruffling induced by ARF6 T27N, indicating that ARF6 regulates a pathway leading to membrane ruffling that occurs after the activation and membrane association of Rac. These data demonstrate that intact ARF6 function is required for coupling activated Rac to one of several effector pathways and suggest that a principal function of ARF6 is to coordinate Rac activation with plasma membrane-based protrusive events.
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Davies, Tim, i Julie C. Canman. "Stuck in the middle: Rac, adhesion, and cytokinesis". Journal of Cell Biology 198, nr 5 (3.09.2012): 769–71. http://dx.doi.org/10.1083/jcb.201207197.
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Rho family small GTPases (Rac, RhoA, and Cdc42) function at the core of cytokinesis, the physical division of one cell into two. In this issue, Bastos et al. (2012. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201204107) identify a new role for Rac inhibition: to release cell adhesion at the division plane and allow efficient constriction of the contractile ring. They show that the GTPase-activating protein, CYK4, suppresses equatorial cell substrate adhesion by inhibiting Rac and therefore its effectors ARFGEF7 and PAK1/2.
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Dusi, S., M. Donini i F. Rossi. "Mechanisms of NADPH oxidase activation in human neutrophils: p67phox is required for the translocation of rac 1 but not of rac 2 from cytosol to the membranes". Biochemical Journal 308, nr 3 (15.06.1995): 991–94. http://dx.doi.org/10.1042/bj3080991.
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NADPH oxidase is the enzyme complex responsible for the production of oxygen radicals in phagocytes. On neutrophil stimulation, the cytosolic components of NADPH oxidase, p67phox and p47phox, as well as the Ras-related G-protein rac 2, are translocated from the cytosol to cell membranes where they associate with a flavocytochrome b to form a functional complex. Besides rac 2, rac 1 G-protein is also involved in the activation of the NADPH oxidase, but, to date, it has not been documented whether it is also translocated in activated neutrophils. In this paper we show that: (a) in neutrophils stimulated with formylmethionyl-leucylphenylalanine, concanavalin A or phorbol 12-myristate 13-acetate, both rac 1 and rac 2 are translocated from cytosol to the membranes; (b) in neutrophils from a patient with a form of chronic granulomatous disease in which p67phox is absent, rac 2 and p47phox were translocated as in normal neutrophils on stimulation with the above agonists, but rac 1 failed to be translocated from the cytosol to the membranes. This is the first demonstration that, in activated neutrophils, rac 1 is translocated from the cytosol to the membranes and this translocation requires p67phox. These results, coupled with those showing that rac 2 is not translocated in activated neutrophils lacking p47phox [El Benna, Ruedi and Babior (1994) J. Biol. Chem. 269, 6729-6734], may suggest that the assembly of the cytosolic components of NADPH oxidase on the plasma membrane takes place through selective coupling of activated rac 1 and rac 2 with p67phox and p47phox respectively.
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Lerm, Maria, Marius Pop, Gerhard Fritz, Klaus Aktories i Gudula Schmidt. "Proteasomal Degradation of Cytotoxic Necrotizing Factor 1-Activated Rac". Infection and Immunity 70, nr 8 (sierpień 2002): 4053–58. http://dx.doi.org/10.1128/iai.70.8.4053-4058.2002.
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ABSTRACT The cytotoxic necrotizing factor 1 (CNF1) from Escherichia coli has been shown to activate members of the Rho family by deamidation of glutamine 63. This amino acid is essential for hydrolysis of GTP, and any substitution results in a constitutively active Rho. Activation of Rho induces the formation of stress fibers, filopodia, and membrane ruffles due to activation of RhoA, Cdc42, and Rac, respectively. Here we show that the level of endogenous Rac decreased in CNF1-treated HEK293 and HeLa cells. The amount of mRNA remained unaffected, leaving the possibility that Rac is subject to proteolytic degradation. Treatment of cells with lactacystin, an inhibitor of the 26S proteasome, protected Rac from degradation. We have previously shown that CNF1 activates the c-Jun N-terminal kinase (JNK) only transiently in HeLa cells (M. Lerm, J. Selzer, A. Hoffmeyer, U. R. Rapp, K. Aktories, and G. Schmidt, Infect. Immun. 67:496-503, 1998). Here we show that CNF1-induced JNK activation is stabilized in the presence of lactacystin. The data indicate that Rac is degraded by a proteasome-dependent pathway in CNF1-treated cells.
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Shikata, Yasushi, Konstantin G. Birukov i Joe G. N. Garcia. "S1P induces FA remodeling in human pulmonary endothelial cells: role of Rac, GIT1, FAK, and paxillin". Journal of Applied Physiology 94, nr 3 (1.03.2003): 1193–203. http://dx.doi.org/10.1152/japplphysiol.00690.2002.
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Sphingosine 1-phosphate (S1P) enhances human pulmonary endothelial monolayer integrity via Rac GTPase-dependent formation of a cortical actin ring (Garcia et al. J Clin Invest 108: 689–701, 2001). The mechanisms underlying this response are not well understood but may involve rapid redistribution of focal adhesions (FA) as attachment sites for actin filaments. We evaluate the effects of S1P on the redistribution of paxillin, FA kinase (FAK), and the G protein-coupled receptor kinase-interacting proteins (GITs). S1P induced Rac GTPase activation and cortical actin ring formation at physiological concentrations (0.5 μM), whereas 5 μM S1P caused prominent stress fiber formation and activation of Rho and Rac GTPases. S1P (0.5 μM) stimulated the tyrosine phosphorylation of FAK Y576, and paxillin was linked to FA disruption and redistribution to the cell periphery. Furthermore, S1P induced a transient association of GIT1 with paxillin and redistribution of the GIT2-paxillin complex to the cell cortical area without affecting GIT2-paxillin association. These results suggest a role of FA rearrangement in S1P-mediated barrier enhancement via Rac- and GIT-mediated processes.
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Morgan-Spencer, Alex, i Daniel Greenberg. "P-REX1: A Novel RAC Activing Guanine-Nucleotide Exchange Factor in Human Platelets." Blood 110, nr 11 (16.11.2007): 3639. http://dx.doi.org/10.1182/blood.v110.11.3639.3639.
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Abstract A major signaling pathway that regulates platelet shape change and reorganization of the cytoskeleton involves the Rho family of GTPases whose members include Rac, CDC42 and RhoA. These GTPases are converted from their inactive or GDP-loaded state to the active or GTP-loaded state by a class of enzymes called Guanine-nucleotide Exchange Factors (GEFs). GEFs are a family of multi-domain proteins that contain a GDP-GTP exchange domain (DH-PH) as well as other protein interacting domains that are regulated by the activation of receptors present on the platelet surface. We used an affinity binding technique followed by mass spectrometry analysis to identify novel Rac binding GEFs from platelet lysates. Recombinant GST-Rac fusion proteins bound to agarose beads were prepared in the GTP, GDP and nucleotide-free states and incubated with human platelet lysates. Platelet lysate proteins associated with the different GST-Rac preparations (GTP-bound, GDP-bound or nucleotide-free) were eluted and run on SDS-PAGE. Gel slices were then cut out, trypsin digested and analyzed by mass spectrometry. Platelet GEFs were identified by the presence of a DH-PH domain. Using this technique we identified three novel Rac-associated platelet GEFs including P-REX1, a G-βγ protein and phosphatidylinositol (3,4,5)-triphosphate regulated GEF previously found in neutrophils and neurons (Welch, H.C.E et al., Cell108;809–822, 2002). PREX-1 is a 196kDa peptide composed of 1659 amino that specifically activates Rac in neutrophils. In addition to the DH-PH exchange domain, PREX-1 also contains tandem PDZ and DEP domains as well as significant similarity over its C-terminal half to Inositol Polyphosphate 4-Phosphatase. Western analysis with anti-P-REX1 antibody (gift of H.C. Welch, Barbraham Institute, U.K.) showed that PREX-1 is present in purified whole platelet lysates. We have also shown that platelet PREX-1 specifically associates with GST-Rac by affinity pull-down experiments. Functional studies to characterize the exchange activity of platelet PREX-1 are ongoing. PREX-1 is the only known GEF that is directly regulated by G-βγ protein (Hill, K. et al., J Biol Chem280(6):4166–4173, 2005) and represents a novel pathway for platelet G protein coupled receptor signaling through Rac in human platelets.
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Lerm, M., J. Selzer, A. Hoffmeyer, U. R. Rapp, K. Aktories i G. Schmidt. "Deamidation of Cdc42 and Rac by Escherichia coliCytotoxic Necrotizing Factor 1: Activation of c-Jun N-Terminal Kinase in HeLa Cells". Infection and Immunity 67, nr 2 (1.02.1999): 496–503. http://dx.doi.org/10.1128/iai.67.2.496-503.1999.
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ABSTRACT Recently, Escherichia coli cytotoxic necrotizing factor 1 (CNF1) was shown to activate the low-molecular-mass GTPase RhoA by deamidation of Gln63, thereby inhibiting intrinsic and GTPase-activating protein (GAP)-stimulated GTPase activities (G. Schmidt, P. Sehr, M. Wilm, J. Selzer, M. Mann, and K. Aktories, Nature 387:725–729, 1997; G. Flatau, E. Lemichez, M. Gauthier, P. Chardin, S. Paris, C. Fiorentini, and P. Boquet, Nature 387:729–733, 1997). Here we report that in addition to RhoA, Cdc42 and Rac also are targets for CNF1 in vitro and in intact cells. Treatment of HeLa cells with CNF1 induced a transient formation of microspikes and formation of membrane ruffles. CNF1 caused a transient 10- to 50-fold increase in the activity of the c-Jun N-terminal kinase. Tryptic peptides of Cdc42 obtained from CNF1-treated cells by immunoprecipitation exhibited an increase in mass of 1 Da compared to control peptides, indicating the deamidation of glutamine 61 by the toxin. The same increase in mass was observed with the respective peptides obtained from CNF1-modified recombinant Cdc42 and Rac1. Modification of recombinant Cdc42 and Rac1 by CNF1 inhibited intrinsic and GAP-stimulated GTPase activities and retarded binding of 2′(3′)- O-(N -methylanthraniloyl)GDP. The data suggest that recombinant as well as cellular Cdc42 and Rac are substrates for CNF1.
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Girard, I., J. L. Aalhus, J. A. Basarab, I. L. Larsen i H. L. Bruce. "Modification of muscle inherent properties through age at slaughter, growth promotants and breed crosses". Canadian Journal of Animal Science 91, nr 4 (grudzień 2011): 635–48. http://dx.doi.org/10.4141/cjas2011-058.
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Girard, I., Aalhus, J. L., Basarab, J. A., Larsen, I. L. and Bruce, H. L. 2011. Modification of muscle inherent properties through age at slaughter, growth promotants and breed crosses. Can. J. Anim. Sci. 91: 635–648. A 24 factorial experiment tested the interactions of slaughter age (12–13 or 18–20 mo), growth hormone use, β-adrenergic agonist (β-AA) use and breed cross [Hereford–Aberdeen Angus (HAA) or Charolais–Red Angus (CRA)] on the composition, fibre types, and connective tissue characteristics of m. semitendinosus (ST) and m. gluteus medius (GM) from 112 crossbred steers. Muscle weights increased with slaughter age, implantation and CRA genetics (P<0.05), but were not affected by ractopamine hydrochloride (RAC) (P>0.10).Animal age increased fast glycolytic (FG) and decreased fast oxidative glycolytic (FOG) fibre percentages by 7.2 and 6.6%, respectively, in the ST and increased slow oxidative (SO) and FOG fibre areas in both muscles (P<0.05). Cross-sectional areas of all fibre types were increased in the ST with implantation. In the GM, implantation increased SO (3.1%) and reduced FOG (3.2%) fibre percentages, while RAC reduced the SO (3.8%) and increased the FG (6.1%) fibre percentages (P<0.05).Only GM total collagen content increased with slaughter age (P<0.05),but collagen solubility decreased with slaughter age for both muscles (P<0.05). CRA genetics increased FG percentage in the GM of yearling-fed steers and increased moisture and protein and reduced fat contents of both muscles (P<0.05). In the muscles studied, IMP, slaughter age and animal genetics induced greater changes in muscle inherent properties than RAC.
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Waschke, J., W. Baumgartner, R. H. Adamson, M. Zeng, K. Aktories, H. Barth, C. Wilde, F. E. Curry i D. Drenckhahn. "Requirement of Rac activity for maintenance of capillary endothelial barrier properties". American Journal of Physiology-Heart and Circulatory Physiology 286, nr 1 (styczeń 2004): H394—H401. http://dx.doi.org/10.1152/ajpheart.00221.2003.
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Our previous experiments indicated that GTPases, other than RhoA, are important for the maintenance of endothelial barrier integrity in both intact microvessels of rats and mice and cultured mouse myocardial endothelial (MyEnd) cell monolayers ( J Physiol 539: 295–308, 2002). In the present study, we inhibited the endothelial GTPase Rac by Clostridium sordellii lethal toxin (LT) and investigated the relation between the degree of inhibition of Rac by glucosylation and increased endothelial barrier permeability. In rat venular microvessels, LT (200 ng/ml) increased hydraulic conductivity from a control value of 2.5 ± 0.6 to 100.8 ± 18.7 × 10–7 cm·s–1·cmH2O–1 after 80 min. In cultured MyEnd cells exposed to LT (200 ng/ml), up to 60% of cellular Rac was glucosylated after 90 min, resulting in depolymerization of F-actin and interruptions of junctional distribution of vascular endothelial cadherin (VE-cadherin) and β-catenin as well as the formation of intercellular gaps. To understand the mechanism by which inhibition of Rac caused disassembly of adherens junctions, we used laser tweezers to quantify VE-cadherin-mediated adhesion. LT and cytochalasin D, an actin depolymerizing agent, both reduced adhesion of VE-cadherin-coated microbeads to the endothelial cell surface, whereas the inhibitor of Rho kinase Y-27632 did not. Stabilization of actin filaments by jasplakinolide completely blocked the effect of cytochalasin D but not of LT on bead adhesion. We conclude that Rac regulates endothelial barrier properties in vivo and in vitro by 1) modulation of actin filament polymerization and 2) acting directly on the tether between VE-cadherin and the cytoskeleton.
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Karbstein, Katrin. "Chaperoning ribosome assembly". Journal of Cell Biology 189, nr 1 (5.04.2010): 11–12. http://dx.doi.org/10.1083/jcb.201002102.
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Chaperones help proteins fold in all cellular compartments, and many associate directly with ribosomes, capturing nascent chains to assist their folding and prevent aggregation. In this issue, new data from Koplin et al. (2010. J. Cell Biol. doi: 10.1083/jcb.200910074) and Albanèse et al. (2010. J. Cell Biol. doi: 10.1083/jcb.201001054) suggest that in addition to promoting protein folding, the chaperones ribosome-associated complex (RAC), nascent chain–associated complex (NAC), and Jjj1 also help in the assembly of ribosomes.
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Girard, I., J. L. Aalhus, J. A. Basarab, I. L. Larsen i H. L. Bruce. "Modification of beef quality through steer age at slaughter, breed cross and growth promotants". Canadian Journal of Animal Science 92, nr 2 (czerwiec 2012): 175–88. http://dx.doi.org/10.4141/cjas2012-001.
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Girard, I., Aalhus, J. L., Basarab, J. A., Larsen, I. L. and Bruce, H. L. 2012. Modification of beef quality through steer age at slaughter, breed cross and growth promotants. Can. J. Anim. Sci. 92: 175–188. A 23 factorial experiment tested the interactions of slaughter age (12–13 or 18–20 mo), growth implants use (Component E-S, TE-S), ractopamine hydrochloride (RAC) feed supplementation use and breed cross [Hereford–Aberdeen Angus (HAA) or Charolais–Red Angus (CRA)] on pH, temperature, objective colour measurements, relative myoglobin states, sarcomere lengths, shear force, and water losses of m. semitendinosus (ST) and m. gluteus medius (GM) from 112 crossbred steers. In the ST, age affected objective colour measurements by increasing chroma and decreasing lightness (L*) and hue angle (P<0.05). Metmyoglobin (MMB) content of the ST also increased with steer age (P<0.05). In the GM, yearling-fed steers had greater MMB content than calf-fed steers, while hue angle varied the opposite way (P<0.05). Other variations in meat colour and myoglobin contents were more complex in the GM than the ST as they involved three-way interactions between the different treatments. Shear force and purge loss of the ST increased with implantation (P<0.05) with no change in sarcomere length (P>0.05). Shear force standard deviation was similar for breed crosses when yearling-fed but greatest for CRA breed cross when calf-fed (P<0.05). In both muscles, purge loss was increased by RAC supplementation (P<0.05). RAC supplementation did not affect sarcomere length and shear force in both muscles (P>0.10). In the GM, shear force increased with age and with CRA genetics (P<0.05). Results indicated that producers seeking to reduce beef toughness should consider using British crossbreds, exclude the use of hormonal implants and slaughter process steers at 12 to13 mo of age.
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Bastin, Benjamin, Nicole Klass, Erin Crowley, James Agin, Charlotte Lindhardt i Renaud Chollet. "Evaluation of the MC-Media Pad® Rapid Aerobic Count Device for the Enumeration of Total Aerobic Counts in a Variety of Foods: Collaborative Study, First Action Official MethodSM 2019.02". Journal of AOAC INTERNATIONAL 103, nr 5 (30.03.2020): 1318–25. http://dx.doi.org/10.1093/jaoacint/qsaa040.
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Abstract Background The MC-Media Pad® Rapid Aerobic Count (RAC) is a ready-to-use culture device combining a test pad coated with medium and water absorption polymers that are designed for the rapid quantification of total aerobic bacteria in food products. Objective The MC-Media Pad RAC was compared to the U.S. Department of Agriculture Food Safety and Inspection Service Microbiology Laboratory Guidebook, Chapter 3.02: Quantitative Analysis of Bacteria in Foods as Sanitary Indicators for raw ground pork and the Standard Methods for the Examination of Dairy Products, Chapter 6: Microbial Count Methods for yogurt drink. Method The candidate method was evaluated against the reference methods using a paired study design in a multi-collaborator study, following the current AOAC INTERNATIONAL Official Methods of AnalysisSM Appendix J guidelines. Three target contamination levels (low, medium, and high) were evaluated. MC-Media Pad RAC devices were enumerated after 24 and 48 h of incubation. Results Plate counts obtained by both methods were log10-transformed and the difference of means (including 95% confidence intervals), repeatability SD, and reproducibility SD were determined for each contamination level. All 95% confidence intervals for mean difference fell easily within ±0.10, the performance requirement being ±0.5. Conclusion The MC-Media Pad RAC (for both 24 and 48 h) and both reference methods for each contamination level were therefore shown to be equivalent, with 97.5% confidence. Highlights The new method offers a convenient alternative to the reference methods for detection of aerobic plate count in food products, yielding reliable and comparable results in 24 or 48 h compared to 48 h for the reference methods.
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Balikesir, Hulya Kara. "A Dimeric Mn(III) Complex of a Quadridentate Schiff Base Ligand. Synthesis, Structure and Ferromagnetic Exchange". Zeitschrift für Naturforschung B 63, nr 1 (1.01.2008): 6–10. http://dx.doi.org/10.1515/znb-2008-0102.
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The synthesis, crystal structure and magnetic properties of [Mn(III)L(H2O)]2(H2O)(ClO4) (1)(L = N,N'-bis(rac-5-chlorosalicylidenato)-1,2-diaminopropane) are reported. Compound 1 consists of a structurally dinuclear system in which two Mn ions are bridged by the oxygen atoms of μ-phenoxo ligands. Low temperature magnetic susceptibility measurements show a ferromagnetic intra-dimer interaction with J = +1.75 cm−1, g = 2.01 and α = −0.32.
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Song, Sheng, Wei Chen i Feifan Zhou. "Effects of LPLI on microglial phagocytosis in LPS-induced neuroinflammation model". Journal of Innovative Optical Health Sciences 07, nr 03 (maj 2014): 1350049. http://dx.doi.org/10.1142/s1793545813500491.
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Microglial activation plays an important role in neurodegenerative diseases. Once activated, they have macrophage-like capabilities, which can be beneficial by phagocytosis and harmful by secretion of neurotoxins. However, the resident microglia always fail to trigger an effective phagocytic response to clear dead cells or Aβ deposits during the progression of neurodegeneration. Therefore, the regulation of microglial phagocytosis is considered a useful strategy in searching for neuroprotective treatments. In this study, our results showed that low-power laser irradiation (LPLI) (20 J/cm2) could enhance microglial phagocytic function in LPS-activated microglia. We found that LPLI-mediated microglial phagocytosis is a Rac-1-dependent actin-based process, that a constitutively activated form of Rac1 (Rac1Q61L) induced a higher level of actin polymerization than cells transfected with wild-type Rac1, whereas a dominant negative form of Rac1 (Rac1T17N) markedly suppressed actin polymerization. In addition, the involvement of Rac1 activation after LPLI treatment was also observed by using a Raichu fluorescence resonance energy transfer (FRET)-based biosensor. We also found that PI3K/Akt pathway was required in the LPLI-induced Rac1 activation. Our research may provide a feasible therapeutic approach to control the progression of neurodegenerative diseases.
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Sixt, Michael. "Cell migration: Fibroblasts find a new way to get ahead". Journal of Cell Biology 197, nr 3 (30.04.2012): 347–49. http://dx.doi.org/10.1083/jcb.201204039.
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Fibroblasts migrate on two-dimensional (2D) surfaces by forming lamellipodia—actin-rich extensions at the leading edge of the cell that have been well characterized. In this issue, Petrie et al. (2012. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201201124) show that in some 3D environments, including tissue explants, fibroblasts project different structures, termed lobopodia, at the leading edge. Lobopodia still assemble focal adhesions; however, similar to membrane blebs, they are driven by actomyosin contraction and do not accumulate active Rac, Cdc42, and phosphatidylinositol 3-kinases.
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Guidetti, Gianni F., Bruno Bernardi, Lucia Stefanini, Francesca Campus, Cesare Balduini i Mauro Torti. "Tyrosine Phosphorylation-Independent Activation of PLCγ2 Downstream Integrin α2β1 in Platelets: A Possible Role for the Small GTPase Rac." Blood 108, nr 11 (16.11.2006): 1532. http://dx.doi.org/10.1182/blood.v108.11.1532.1532.
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Abstract We have recently documented the existence of a cross-talk between platelet integrins α2β1 and αIIbβ3 involving phospholipase C (PLC)-mediated activation of the small GTPase Rap1b (Bernardi B et al, Blood2006; 107:2728–35). Here we report that integrin α2β1-mediated platelet adhesion to monomeric collagen and to other specific ligands, such as decorin and collagen-derived peptides, actually induced a robust activation of PLC, evaluated as phosphorylation of pleckstrin, the main platelet substrate for protein kinase C. This was paralleled by a robust tyrosine phosphorylation of the PLCγ2. We found that inhibition of Src kinases by PP2 completely abolished integrin α2β1-promoted PLCγ2 tyrosine phosphorylation, but did not affect either Rap1b stimulation or integrin αIIbβ3 activation in adherent platelets. Surprisingly, phosphorylation of pleckstrin occurred normally under conditions in which tyrosine phosphorylation of PLCγ2 was totally suppressed. The Src-kinase-independent PLC activity in integrin α2β1-adherent cells was not inhibited by pretreatment of platelets with aspirin and apyrase, excluding any possible contribution of Gq-regulated PLCβ isoforms stimulated by released thromboxane A2 or secreted ADP. In addition, PLC-dependent activation of Rap1b and integrin αIIbβ3 were not affected by aspirin and apyrase. Phosphorylation of pleckstrin induced by adhesion to monomeric collagen was not detected in platelets from PLCγ2 knockout mice, confirming that this was the only isoform activated downstream of integrin α2β1. In addition, mouse platelets lacking PLCγ2 showed impaired integrin α2β1-mediated outside-in signaling, and were unable to promote both GTP binding to Rap1b and integrin αIIbβ3 activation. These results indicate that although PLCγ2 is the only PLC isoform stimulated downstream integrin α2β1 and is responsible for the cross-talk to integrin αIIbβ3 through the small GTPase Rap1b, its activation in adherent platelets can occur independently of Src-mediated tyrosine phosphorylation. A recent work has reported that, in vitro, the activity of PLCγ2, but not that of PLCγ1, can be stimulated by the active, GTP-bound form of the small GTPase Rac, with a mechanism independent of phosphorylation on tyrosine residues (Piechlek T el al, J Biol Chem2005; 208:38923–31). In platelets adherent through integrin α2β1, Rac was found to be activated upstream PLC. Activation of Rac was efficiently prevented by the inhibitor NSC23766, which is able to bind and block Rac-specific GEFs. In integrin α2β1-adherent platelets, inhibition of Rac by NSC23766 did not affect PLCγ2 tyrosine phosphorylation and activation of PLC and Rap1b. However, upon inhibition of Src kinases by PP2 and consequent prevention of PLCγ2 tyrosine phosphorylation, NSC23766 almost completely abolished PLC activation, GTP binding to Rap1b and integrin αIIbβ3 stimulation. These results demonstrate that PLCγ2 is the main PLC isoform involved in integrin α2β1-mediated activation of Rap1b and integrin αIIbβ3, and that its activation can occur through two alternative mechanisms involving either tyrosine phosphorylation or stimulation by Rac GTPase.
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Lefebvre, P., D. S. Berard, M. G. Cordingley i G. L. Hager. "Two regions of the mouse mammary tumor virus long terminal repeat regulate the activity of its promoter in mammary cell lines". Molecular and Cellular Biology 11, nr 5 (maj 1991): 2529–37. http://dx.doi.org/10.1128/mcb.11.5.2529-2537.1991.
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In vivo expression of the mouse mammary tumor virus (MMTV) is restricted to a few organs, with the highest rate of transcription found in the mammary gland. Using a series of mammary and nonmammary murine cell lines, we have identified two regulatory elements, located upstream of the hormone responsive element, that specifically regulate the MMTV promoter. The first element displays an enhancerlike activity and is coincident with the binding of a nuclear factor (designated MP4; position -1078 to -1052 in the long terminal repeat) whose presence is apparently restricted to mammary cell lines. The second regulatory region mediates a repressive activity and is mapped to the long terminal repeat segment from -415 to -483. This repression is specific for a particular subtype of mammary cells (RAC cells) able to grow under two differentiation states (A. Sonnenberg, H. Daams, J. Calafat, and J. Hilgers, Cancer Res. 46:5913-5922, 1986). The MMTV promoter in mammary cell lines thus appears to be modulated by two cis-acting elements that are likely to be involved in tissue-specific expression in vivo.
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Murzyn, K., i M. Pasenkiewicz-Gierula. "Construction and optimisation of a computer model for a bacterial membrane." Acta Biochimica Polonica 46, nr 3 (30.09.1999): 631–39. http://dx.doi.org/10.18388/abp.1999_4135.
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The main steps in the construction of a computer model for a bacterial membrane are described. The membrane has been built of 72 lipid molecules, 54 of which being 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphatidylethanolamine (POPE) and 18--1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphatidyl-rac-glycerol (POPG) molecules (thus in the proportion of 3:1). The membrane was hydrated with 1955 water molecules (approximately 27 water molecules per lipid). To neutralise the electronic charge (-e) on each POPG molecule, 18 sodium ions (Na+) were added to the membrane close to the POPG phosphate groups. The atomic charges on the POPE and POPG headgroups were obtained from ab initio quantum mechanical restrained electrostatic potential fitting (RESP) (Bayly et al., 1993, J. Phys. Chem. 97, 10269) using the GAMESS program at the 6-31G* level (Schmidt et al., 1993, J. Comput. Chem. 14, 1347). The model constructed in this way provided an initial structure for subsequent molecular dynamics simulation studies intended to elucidate the atomic level interactions responsible for the structure and dynamics of the bacterial membrane.
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Lefebvre, P., D. S. Berard, M. G. Cordingley i G. L. Hager. "Two regions of the mouse mammary tumor virus long terminal repeat regulate the activity of its promoter in mammary cell lines." Molecular and Cellular Biology 11, nr 5 (maj 1991): 2529–37. http://dx.doi.org/10.1128/mcb.11.5.2529.
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In vivo expression of the mouse mammary tumor virus (MMTV) is restricted to a few organs, with the highest rate of transcription found in the mammary gland. Using a series of mammary and nonmammary murine cell lines, we have identified two regulatory elements, located upstream of the hormone responsive element, that specifically regulate the MMTV promoter. The first element displays an enhancerlike activity and is coincident with the binding of a nuclear factor (designated MP4; position -1078 to -1052 in the long terminal repeat) whose presence is apparently restricted to mammary cell lines. The second regulatory region mediates a repressive activity and is mapped to the long terminal repeat segment from -415 to -483. This repression is specific for a particular subtype of mammary cells (RAC cells) able to grow under two differentiation states (A. Sonnenberg, H. Daams, J. Calafat, and J. Hilgers, Cancer Res. 46:5913-5922, 1986). The MMTV promoter in mammary cell lines thus appears to be modulated by two cis-acting elements that are likely to be involved in tissue-specific expression in vivo.
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Traeger, J., A. Kelling, U. Schilde i H. J. Holdt. "rac-1-[(2-Methoxyethyl)sulfanyl]-2-[(2-methoxyethyl)sulfinyl]benzene and its PdCl2complex". Acta Crystallographica Section C Crystal Structure Communications 68, nr 9 (1.08.2012): m238—m241. http://dx.doi.org/10.1107/s0108270112032192.
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As an extension of recent findings on the recovery of palladium with dithioether extractants, single crystals of the chelating vicinal thioether sulfoxide ligandrac-1-[(2-methoxyethyl)sulfanyl]-2-[(2-methoxyethyl)sulfinyl]benzene, C12H18O3S2, (I), and its square-planar dichloridopalladium complex,rac-dichlorido{1-[(2-methoxyethyl)sulfanyl]-2-[(2-methoxyethyl)sulfinyl]benzene-κ2S,S′}palladium(II), [PdCl2(C12H18O3S2)], (II), have been synthesized and their structures analysed. The molecular structure of (II) is the first ever characterized involving a dihalogenide–PdIIcomplex in which the palladium is bonded to both a thioether and a sulfoxide functional group. The structural and stereochemical characteristics of the ligand are compared with those of the analogous dithioether compound [Traegeret al.(2012).Eur. J. Inorg. Chem.pp. 2341–2352]. The sulfinyl O atom suppresses the electron-pushing and mesomeric effect of the S—C...;C—S unit in ligand (I), resulting in bond lengths significantly different than in the dithioether reference compound. In contrast, in complex (II), those bond lengths are nearly the same as in the analogous dithioether complex. As observed previously, there is an interaction between the central PdIIatom and the O atom that is situated above the plane.
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Rosen, Tomer, Yanay Popowski, Israel Goldberg i Moshe Kol. "Inside Back Cover: Zinc Complexes of Sequential Tetradentate Monoanionic Ligands in the Isoselective Polymerization of rac -Lactide (Chem. Eur. J. 33/2016)". Chemistry - A European Journal 22, nr 33 (7.07.2016): 11871. http://dx.doi.org/10.1002/chem.201603081.
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Brachmann, Saskia M., Claudine M. Yballe, Metello Innocenti, Jonathan A. Deane, David A. Fruman, Sheila M. Thomas i Lewis C. Cantley. "Role of Phosphoinositide 3-Kinase Regulatory Isoforms in Development and Actin Rearrangement". Molecular and Cellular Biology 25, nr 7 (1.04.2005): 2593–606. http://dx.doi.org/10.1128/mcb.25.7.2593-2606.2005.
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ABSTRACT Class Ia phosphoinositide 3-kinases (PI3Ks) are heterodimers of p110 catalytic and p85 regulatory subunits that mediate a variety of cellular responses to growth and differentiation factors. Although embryonic development is not impaired in mice lacking all isoforms of the p85α gene (p85α−/− p55α−/− p50α−/−) or in mice lacking the p85β gene (p85β−/−) (D. A. Fruman, F. Mauvais-Jarvis, D. A. Pollard, C. M. Yballe, D. Brazil, R. T. Bronson, C. R. Kahn, and L. C. Cantley, Nat Genet. 26:379-382, 2000; K. Ueki, C. M. Yballe, S. M. Brachmann, D. Vicent, J. M. Watt, C. R. Kahn, and L. C. Cantley, Proc. Natl. Acad. Sci. USA 99:419-424, 2002), we show here that loss of both genes results in lethality at embryonic day 12.5 (E12.5). The phenotypes of these embryos, including subepidermal blebs flanking the neural tube at E8 and bleeding into the blebs during the turning process, are similar to defects observed in platelet-derived growth factor receptor α null (PDGFRα−/−) mice (P. Soriano, Development 124:2691-2700, 1997), suggesting that PI3K is an essential mediator of PDGFRα signaling at this developmental stage. p85α−/− p55α+/+ p50α+/+ p85β−/− mice had similar but less severe defects, indicating that p85α and p85β have a critical and redundant function in development. Mouse embryo fibroblasts deficient in all p85α and p85β gene products (p85α−/− p55α−/− p50α−/− p85β−/−) are defective in PDGF-induced membrane ruffling. Overexpression of the Rac-specific GDP-GTP exchange factor Vav2 or reintroduction of p85α or p85β rescues the membrane ruffling defect. Surprisingly, reintroduction of p50α also restored PDGF-dependent membrane ruffling. These results indicate that class Ia PI3K is critical for PDGF-dependent actin rearrangement but that the SH3 domain and the Rho/Rac/Cdc42-interacting domain of p85, which lacks p50α, are not required for this response.
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Tian, Wei, Xing Jun Li, Natalie D. Stull, Chang-Il Suh, Sergio Grinstein, MIchael B. Yaffe, Simon J. Atkinson i Mary C. Dinauer. "The Phosphoinositide-Binding Protein p40phox Regulates NADPH Oxidase Activation Rather Than Assembly during FcγIIA Receptor-Induced Phagocytosis." Blood 108, nr 11 (16.11.2006): 678. http://dx.doi.org/10.1182/blood.v108.11.678.678.
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Abstract Many critical features of the organization and regulation of the phagocyte NADPH oxidase, a complex multi-subunit enzyme that generates superoxide for microbial killing, remain poorly defined. The active enzyme includes a membrane-bound flavocytochrome b along with p47phox, p67phox, p40phox, and Rac-GTP that are present in the cytosol of resting cells. p67phox is linked by high affinity interactions with both p47phox and p40phox, which appear to translocate as a trimeric complex upon cellular activation. The p47phox subunit acts as an adaptor to promote translocation by docking at a proline-rich target sequence on the flavocytochrome, and p67phox is a Rac-GTP effector containing a domain that activates electron transport. In contrast, the function of p40phox, which is not required for high level oxidase activity in cell free systems, is poorly understood. Recently, our group showed that p40phox plays key role in the activation of superoxide production during phagocytosis of IgG-opsonized targets in COSphoxFcγR cells. This model cell line contains stable transgenes for the flavocytochrome, p47phox, p67phox, and the FcγIIA receptor, without or with an additional transgene for p40phox. p40phox-dependent coupling of FcγR-mediated phagocytosis to superoxide production required an intact p40phox PX domain, which binds to phosphatidylinositol-3-phosphate (PI3P), a phosphoinositide generated by class III PI3 kinases in phagosome membranes (Suh et al J Exp Med 203, 1915Suh et al J Exp Med 203, 2006). Furthermore, a newly developed p40phox-null mouse exhibits reduced neutrophil NADPH oxidase activity in response to selected agonists, including IgG-opsonized targets (Ellson et al J Exp Med 203, 1927Ellson et al J Exp Med 203, 2006). In the current study, we investigated whether p40phox is required for translocation of p67phox during phagocytosis. We generated COSphoxFcγR cells expressing YFP-tagged p67phox from a stable transgene instead of untagged p67phox. Following incubation with IgG-opsonized sheep red blood cells (IgG-RBC), p67phox was detected on phagosome membranes at both early stages of phagosome cup formation and after closure, independent of whether or not p40phox was also co-expressed. However, NADPH oxidase activity was not detected in IgG-RBC phagosomes in COSphoxFcγR-p67phox-YFP cells unless p40phox was present. PMA-activated superoxide production was independent of p40phox, and Western blotting indicated there was no significant difference in expression of the other oxidase subunits in COSphoxFcγR-p67phox-YFP cells without or with the p40phox transgene. Further studies in PLB-985 granulocytes expressing stable transgenes for either YFP-tagged p67phox or p40phox showed that the PI3K inhibitor wortmannin inhibited phagosome NADPH oxidase activity and translocation of p40phox, but localization of p67phox to phagosomes was unaffected. These results indicate that although p40phox positively regulates NADPH oxidase activation during phagocytosis, recruitment of p67phox to the phagosome is independent of p40phox. Taken together, these data suggest that the PX domain of p40phox acts as a PI3P-dependent switch to activate the membrane-assembled NADPH oxidase complex.
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Antre, R. V., A. Cendilkumar, R. R. Nagarajan, D. Goli i R. J. Oswal. "Synthesis, Antitumor and Antimicrobial Activities of Some Novel 1-(Substituted)-3-Methyl-1H-Pyrazol-5(4H)-One". Journal of Scientific Research 4, nr 1 (26.12.2011): 183. http://dx.doi.org/10.3329/jsr.v4i1.7027.
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Several 1-(substituted)-3-methyl-1H-pyrazol-5(4H)-one as RA1-RA9 were synthesized and compounds were screened for antitumor activity against Ehrlich ascites carcinoma (EAC) cells and antimicrobial activity. Elemental analysis, mass spectral data, 1H-NMR, and IR confirmed the structure of the newly synthesized compounds. Some of the tested compounds showed good antitumor and antimicrobial activity. Compounds RA1, RA4, and RA9 exhibit highest antitumor activity against EAC cells in comparison with 5-flurouracil as standard drug.Keywords: Ehrlich ascites carcinoma; Pyrazolone; Antitumor; N-substitution; Antimicrobial.© 2012 JSR Publications. ISSN: 2070-0237 (Print); 2070-0245 (Online). All rights reserved.doi: http://dx.doi.org/10.3329/jsr.v4i1.7027 J. Sci. Res. 4 (1), 183-192 (2012)
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Schreck, VA, AK Serelis i DH Solomon. "Self-Reactions of 1,3-Diphenylpropyl and 1,3,5-Triphenylpentyl Radicals: Models for Termination in Styrene Polymerization". Australian Journal of Chemistry 42, nr 3 (1989): 375. http://dx.doi.org/10.1071/ch9890375.
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Quantitative determination of the products from thermal decomposition of 1,1?,3,3'- tetraphenylazopropane (2) and 1,1',3,3',5,5?-hexaphenylazopentane (5) shows that the respective derived title radicals (1) and (4) undergo self-reactions with a similar preference for combination over disproportionation. The proportion of combination increases from 86 to 93% ( E+c-E+d = 9.6 � 1.2 kJ mol-1 and ΔSc+:- Δ Sd + : =43 �7 JK-1 mol-l) for (1), and from 86 to 93% ( E+c-E+d = 10.6 � 1.4 kJ mol-1 and ΔSc- Δ Sd : = 45 � 6 J K-1 mol-1) for (4) over the temperature range 80-161°. The relevance of these results to the termination mechanism in the radical polymerization of styrene is discussed. Some minor by-products (28)-(30) which arise by addition of 1,3-diphenylpropyl (1) to 1,3-diphenylpropene (14)/(15) have also been detected. The syntheses of the azo compounds (2) and (5), the former as separate, pure meso - and rac-diastereomers (2m) and (2r), and of their various expected decomposition products are described.
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Tanase, Tomoaki, Risa Otaki, Ayumi Okue, Kanako Nakamae i Takayuki Nakajima. "Front Cover: Dinuclear Copper Complexes Triply Bridged by a Tetraphosphane, rac -Ph2 PCH2 P(Ph)CH2 P(Ph)CH2 PPh2 (Eur. J. Inorg. Chem. 37/2019)". European Journal of Inorganic Chemistry 2019, nr 37 (1.10.2019): 3990. http://dx.doi.org/10.1002/ejic.201901013.
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Bondeva, Tzvetanka, Stefanie Wojciech i Gunter Wolf. "Advanced glycation end products inhibit adhesion ability of differentiated podocytes in a neuropilin-1-dependent manner". American Journal of Physiology-Renal Physiology 301, nr 4 (październik 2011): F852—F870. http://dx.doi.org/10.1152/ajprenal.00575.2010.
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Podocyte injury can occur by a number of stimuli. Maintaining of an intact podocyte structure is essential for glomerular filtration; therefore, podocyte damage severely impairs renal function. Recently, we have reported that addition of glycated BSA [advanced glycation end products (AGE)-BSA] to differentiated murine podocytes inhibited neuropilin-1 (NRP1) expression and dramatically influenced podocyte migration ability (Bondeva T, Ruster C, Franke S, Hammerschmid E, Klagsbrun M, Cohen CD, Wolf G. Kidney Int 75: 605–616, 2009; Bondeva T, Wolf G. Am J Nephrol 30: 336–345, 2009). The present study analyzes the influence of AGEs and NRP1 on podocyte adhesion and cytoskeleton reorganization. We show that treatment with AGE-BSA significantly reduced podocyte adhesion to collagen IV, laminin, and fibronectin compared with Co-BSA (nonglycated BSA)-incubated cells, which was further augmented by transient inhibition of NRP1 expression using NRP1 short interference (si) RNA. On the other hand, forced overexpression of NRP1 markedly increased the adhesion ability of podocytes to the ECMs despite the AGE-BSA treatment. No changes were observed when podocyte adhesion to collagen I was assayed. These findings were also manifested with disorganization of podocyte actin stress fibers and decreased lamellipodia formation processes due to AGE-BSA treatment or NRP1 suppression. In addition, AGE-BSA or suppression of NRP1 both reduced the phosphorylation of focal adhesion kinase (FAK) and Erk1/2 in PMA-stimulated differentiated podocytes. Analysis of RhoA family GTPase activity demonstrated that treatment with AGE-BSA or NRP1 depletion inhibited as well the activation of the Rac-1 and Cdc42 but did not affect RhoA activity. All these effects were reversed by forced overexpression of full-length NRP1 cloned into the pcDNA3 vector in differentiated podocytes. Our study demonstrates that AGEs, in part via suppression of NRP1 expression, decreased podocyte adhesion and contribute to reduction of Rac-1 and Cdc42 GTPase activity. These effects may be further responsible for the podocytes damage and loss in diabetic nephropathy. Our findings suggest a role for NRP1 in regulating the podocyte actin cytoskeleton, and therefore reduction of NRP1 expression could be critical for podocyte function.
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Brock, J., K. Midwinter, J. Lewis i P. Martin. "Healing of incisional wounds in the embryonic chick wing bud: characterization of the actin purse-string and demonstration of a requirement for Rho activation." Journal of Cell Biology 135, nr 4 (15.11.1996): 1097–107. http://dx.doi.org/10.1083/jcb.135.4.1097.
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Small skin wounds in the chick embryo do not heal by lamellipodial crawling of cells at the wound edge as a skin wound does in the adult, but rather by contraction of an actin purse-string that rapidly assembles in the front row of epidermal cells (Martin, P., and J. Lewis. 1992. Nature (Lond.). 360:179-183). To observe the early time course of actin purse-string assembly and to characterize other cytoskeletal components of the contractile machinery, we have followed the healing of incisional or slash wounds on the dorsum of the chick wing; these wounds take only seconds to create and heal within approximately 6 h. Healing of the epithelium depends on a combination of purse-string contraction and zipper-like closure of the gap between the cut edges of the epithelium. Confocal laser scanning microscope studies show that actin initially aligns into a cable at the wound margin in the basal layer of the epidermis within approximately 2 min of wounding. Coincident with actin cable assembly, we see localization of cadherins into clusters at the wound margin, presumably marking the sites where segments of the cable in adjacent cells are linked via adherens junctions. A few minutes later we also see localization of myosin II at the wound margin, as expected if myosin is being recruited into the cable to generate a contractile force for wound healing. At the time of wounding, cells at the wound edge become transiently leaky, allowing us to load them with reagents that block the function of two small GTPases, Rho and Rac, which recently have been shown to play key roles in reorganiztion of the actin cytoskeleton in tissue-culture cells (Hall, A. 1994. Annu. Rev. Cell Biol. 10:31-54). Loading wound edge epidermal cells with C3 transferase, a bacterial exoenzyme that inactivates endogenous Rho, prevents assembly of an actin cable and causes a failure of healing. No such effects are seen with N17rac, a dominant inhibitory mutant Rac protein. These findings support the view that in this system the actin cable is required for healing-both the purse-string contraction and the zipping up-and that Rho is required for formation of the actin cable.
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Stopper, Ayellet, Tomer Rosen, Vincenzo Venditto, Israel Goldberg i Moshe Kol. "Cover Picture: Group 4 Metal Complexes of Phenylene-Salalen Ligands in rac -Lactide Polymerization Giving High Molecular Weight Stereoblock Poly(lactic acid) (Chem. Eur. J. 48/2017)". Chemistry - A European Journal 23, nr 48 (4.07.2017): 11452. http://dx.doi.org/10.1002/chem.201702896.
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ARAR, Chantal, Marie-Odile OTT, Aminata TOURÉ i Gérard GACON. "Structure and expression of murine mgcRacGAP: its developmental regulation suggests a role for the Rac/MgcRacGAP signalling pathway in neurogenesis". Biochemical Journal 343, nr 1 (24.09.1999): 225–30. http://dx.doi.org/10.1042/bj3430225.
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Rho-family GTPases regulate a wide range of biological functions including cell migration, cell adhesion and cell growth. Recently, results from studies in vivo in Drosophila, mouse and humans have demonstrated the involvement of these GTPases in mechanisms controlling neuronal differentiation and the development of the central nervous system (CNS). However, the signalling pathways underlying these functions and the proteins directly regulating RhoGTPases in developing neurons are poorly defined. Here we report the structure and expression pattern of the murine orthologue of mgcRacGAP, a human gene encoding a RacGTPase partner expressed in male germ cells [Touré, Dorseuil, Morin, Timmons, Jegou, Reibel and Gacon (1998) J. Biol. Chem. 273, 6019-6023]. In contrast with that from humans, murine mgcRacGAP encodes two distinct transcripts. Both are developmentally regulated. A 2.2 kb transcript is strongly expressed in mature testis and is up-regulated with spermatogenesis. A 3 kb RNA is predominant in the embryo and is expressed primarily in the CNS during the neurogenic phase, decreasing after birth. In situ hybridization analysis in embryonic-day 14.5 mouse embryos demonstrates a preferential expression of mgcRacGAP in the proliferative ventricular zone of the cortex. In addition to the expression of mgcRacGAP in male germ cells already reported in humans and suggesting an involvement in spermatogenesis, we characterize an embryonic transcript whose expression is closely correlated with neurogenesis. This result addresses the question of the role of Rac/MgcRacGAP pathway in neuronal proliferation.
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Chatterjee, Shankha Subhra, Mayukh Biswas, Liberalis Debraj Boila, Sayan Chakraborty, Sayantani Sinha, Debasis Banerjee i Amitava Sengupta. "UTX and MBD3 Epistasis Regulates Rac Gtpase Activation and Sensitizes Human Acute Myeloid Leukemia Cells to Dock Inhibition". Blood 132, Supplement 1 (29.11.2018): 3880. http://dx.doi.org/10.1182/blood-2018-99-113843.
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Abstract Transcriptional plasticity is an evolving phenomenon in cancer biology. Mutational profiling alone may not suffice to dissect transcriptional dependency and underlying epigenetic vulnerabilities in tumorigenesis. Histone 3 lysine 27 (H3K27) demethylases (UTX, UTY and JMJD3) critically regulate transcriptional architecture. Recently it has been demonstrated that Utx (Kdm6a) plays tumor suppressor role in myeloid leukemogenesis through noncatalytic activity (Gozdecka M, et al., Nat Genet, 2018). Conditional (Mx1-Cre) deletion of Utx caused development of acute myeloid leukemia (AML) in ~ 60% of the mice; wherein, only Utx-/-, but not Utx+/-, aged (22 months) mice presented with AML. Paradoxically, previous report suggested that Utx conditional (Vav1-Cre) knock out male/female mice did not develop leukemia over 18 months (Tian, L., et al., Blood, 2015). In our recent report we have identified that expression of UTX is significantly increased in human primary AML, and pharmacological inhibition of H3K27 demethylase catalytic activity attenuated survival of AML cells (Boila L.D. et al,. Exp Hematol, 2017). Therefore the contribution of UTX in AML pathogenesis remains context dependent, and probably contentious, and warrants further investigations. ATP-dependent chromatin remodelers have been implicated in AML pathobiology (Chatterjee S.S., et al., Mol Cancer Res, 2018). We reported that loss of MBD3, a scaffold of NuRD chromatin remodeler, in human primary AML cells associates with nucleation of leukemic NuRD (Biswas M et al., Blood, 2017). Loss of Mbd3(Vav1-Cre) has been shown to disrupt NuRD complex integrity and causes T-cell lymphoma, suggesting tissue-specific function of NuRD (Loughran, S.J., et al., J Exp Med, 2017). Interestingly, in our present study we have identified for the first time that endogenous UTX, but not JMJD3, reversibly co-immunoprecipitates with NuRD in AML cells. These findings led us to test the hypothesis whether UTX would participate with NuRD in AML. ChIP-seq analysis in AML blasts using antibodies against UTX and CHD4 (intact ATPase component of leukemic NuRD) along with H3K27ac identified the co-localized genes. ChIP-qPCR, transcriptome, pathway analysis (P<0.001) performed in paired AML, and MBD3loss of function experiments suggested an enrichment of Dedicator of Cytokinesis (DOCK) transcripts as bona fide effectors of UTX and NuRD in AML. DOCK proteins are conserved atypical guanine nucleotide exchange factors (GEFs) for Rho GTPase activation, regulating cell motility and invasion. Earlier we had shown that small GTPases regulate myeloid leukemia cell engraftment, survival in vivo (Sengupta A et al., Blood, 2010). DOCK1 upregulation is associated with a poor prognosis in AML (Hwei, L.S., Blood, 2016). TCGA cross-cancer analysis showed that UTX is maximally expressed, whereas MBD3 is downregulated in AML among all cancer types. Consistent with this observation, DOCK expression was significantly (P<0.001) increased in MBD3loUTXhi AML cohort compared to MBD3hiUTXlo AML. Importantly, MBD3loUTXhi patients have relatively poor survival compared to MBD3hiUTXhi individuals, indicating that a combination of high UTX and low MBD3 expression could be a marker of poor prognosis in AML. Mechanistically, MBD3 deficiency caused loss of HDAC1 occupancy with a corresponding increase in UTX, CBP and H3K27ac on target DOCK loci leading to de-repression of gene expression. In agreement with this finding, loss of MBD3 resulted in ~ 2-fold increase in active Rac GTP and promoted AML cell migration to CXCL12. Interestingly, UTX silencing opposed DOCK expression, Rac activation and reversed hyper-migratory phenotype of MBD3-deficient AML cells. Together, these data account for UTX and MBD3 epistasis in regulating DOCK-Rac signalling in AML. Finally, treatment with DOCK inhibitor CPYPP dramatically inhibited survival of AML cells while having minimal effect on the survival of normal CD34+ cells. In unison, our findings highlight UTX as a putative oncogene in conjunction with leukemic NuRDand posit DOCK proteins as an important target of UTX-NuRD axis in human AML cells. To conclude, we provide evidence for MBD3-deficient NuRD in leukemia pathobiology, and inform a novel epistasis between UTX and NuRD towards maintenance of oncogenic gene expression in AML, and rationalize DOCK inhibition as a novel therapeutic modality for precision medicine in AML. Disclosures No relevant conflicts of interest to declare.
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van der LUIT, Arnold H., Marianne BUDDE, Marcel VERHEIJ i Wim J. van BLITTERSWIJK. "Different modes of internalization of apoptotic alkyl-lysophospholipid and cell-rescuing lysophosphatidylcholine". Biochemical Journal 374, nr 3 (15.09.2003): 747–53. http://dx.doi.org/10.1042/bj20030179.
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The synthetic alkyl-lysophospholipid (ALP), Et-18-OCH3 (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine), can induce apoptosis in tumour cells. Unlike conventional chemotherapeutic drugs, ALP acts at the cell-membrane level. We have reported previously that ALP is internalized, and interferes with phosphatidylcholine (PC) biosynthesis de novo, which appeared to be essential for survival in lymphoma cells [Van der Luit, Budde, Ruurs, Verheij and Van Blitterswijk (2002) J. Biol. Chem. 277, 39541–39547]. Here, we report that, in HeLa cells, ALP accumulates in lipid rafts, and that internalization is inhibited by low temperature, monensin, disruption of lipid rafts and expression of a dominant-negative mutant of dynamin bearing a replacement of Lys44 with alanine (K44A). Thus ALP is internalized via raft- and dynamin-mediated endocytosis. Dynamin-K44A alleviated the ALP-induced inhibition of PC synthesis and rescued the cells from apoptosis induction. Additional cell rescue was attained by exogenous lysoPC, which after internalization serves as an alternative substrate for PC synthesis (through acylation). Unlike ALP, and despite the high structural similarity to ALP, lysoPC uptake did not occur via lipid rafts and did not depend on functional dynamin, indicating no involvement of endocytosis. Albumin back-extraction experiments suggested that (radiolabelled) lysoPC undergoes transbilayer movement (flipping). We conclude that ALP is internalized by endocytosis via lipid rafts to cause apoptosis, while exogenous cell-rescuing lysoPC traverses the plasma membrane outside rafts by flipping. Additionally, our data imply the importance of ether bonds in lyso-phospholipids, such as in ALP, for partitioning in lipid rafts.
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Rosenfeldt, H. M., J. P. Hobson, S. Milstien i S. Spiegel. "The sphingosine-I -phosphate receptor EDG-I is essential for platelet-derived growth factor-induced cell motility". Biochemical Society Transactions 29, nr 6 (1.11.2001): 836–39. http://dx.doi.org/10.1042/bst0290836.
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EDG-1, encoded by the endothelial differentiation gene-1, is a heterotrimeric guanine nucleotide binding protein-coupled receptor (GPCR) for sphingosine-1-phosphate (SPP) that has been shown to stimulate angiogenesis and cell migration in cultured endothelial cells. Unexpectedly, EDG-1 knockout embryos had a normal blood vessel network, vasculogenesis and angiogenesis, but died in utero owing to massive haemorrhaging as a result of failure of smooth muscle cells and pericytes to migrate around the circumference and reinforce endothelial tubes [Liu, Wada, Yamashita, Mi, Deng, Hobson, Rosenfeldt, Nava, Chae, Lee, et al. (2000) J. Clin. Invest. 106, 951–961]. This vascular maturation defect is similar to the phenotype of mice homozygous for disrupted alleles of platelet-derived growth factor B-subunit homodimer (PDGF-BB) or its receptor PDGFR-β. We found that fibroblasts from EDG-1 null embryos did not migrate toward PDGF or SPP, and inhibition of motility correlated with defective activation of the small guanosine triphosphatase Rac, which is required for lamellipodia formation and directional locomotion [Hobson, Rosenfeldt, Barak, Olivera, Poulton, Caron, Milstien, and Spiegel (2001) Science 291, 1800–1803]. Moreover, we showed that PDGF-directed cell migration requires both sphingosine kinase activation and expression of EDG-1, suggesting a functional link between PDGF signalling and EDG-1. Indeed, treatment of wild-type cells with PDGF transactivated EDG-1 as determined by translocation of β-arrestin and phosphorylation of EDG-1. These findings reveal a new paradigm for receptor cross-communication in which activation of a GPCR by a receptor tyrosine kinase is critical for cell motility. Our observations might also clarify the role of EDG-1 in vascular maturation and angiogenesis.
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GILLIBERT, Maggaly, Zakia DEHRY, Micheline TERRIER, Jamel EL BENNA i Florence LEDERER. "Another biological effect of tosylphenylalanylchloromethane (TPCK): it prevents p47phox phosphorylation and translocation upon neutrophil stimulation". Biochemical Journal 386, nr 3 (8.03.2005): 549–56. http://dx.doi.org/10.1042/bj20041475.
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TPCK (tosylphenylalanylchloromethane), first discovered as a serine protease inhibitor, has been described to affect in diverse systems a number of physiological events probably unrelated to its antiprotease effect, such as proliferation, apoptosis and tumour formation. In the present study, we focus on its inhibition of the neutrophil respiratory burst, an important element of non-specific immunological defence. The superoxide anion-producing enzyme, NADPH oxidase, is quiescent in resting cells. Upon cell stimulation, the redox component, membrane-bound flavocytochrome b558, is activated when the cytosolic factors (p47phox, p67phox and p40phox, as well as the small GTPase Rac) associate with it after translocating to the membrane. This requires the phosphorylation of several p47phox serine residues. The signal transduction events leading to enzyme activation are not completely understood. In the past, the use of diverse protease inhibitors suggested that proteases were involved in NADPH oxidase activation. We suggested previously that TPCK could prevent enzyme activation by the phorbol ester PMA, not due to inhibition of a protease, but possibly to inhibition of the cytosolic factor translocation [Chollet-Przednowed and Lederer (1993) Eur. J. Biochem. 218, 83–93]. In the present work, we show that TPCK, when added to cells before PMA, prevents p47phox phosphorylation and hence its translocation; moreover, when PMA-stimulated cells are incubated with TPCK, p47phox is dephosphorylated and dissociates from the membrane. These results are in line with previous suggestions that the respiratory burst is the result of a series of continuous phosphorylation and dephosphorylation events. They suggest that TPCK leads indirectly to activation of a phosphatase or inactivation of a kinase, and provide the first clue towards understanding the steps leading to its inhibition of NADPH oxidase activation.
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Leznoff, Daniel. "Phthalocyanines with Non-Traditional Early Transition-Metals". ECS Meeting Abstracts MA2022-01, nr 14 (7.07.2022): 950. http://dx.doi.org/10.1149/ma2022-0114950mtgabs.
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The synthesis, spectroscopic and redox properties of new metallophthalocyanines (PcM) are active areas of research. The rings of PcM complexes can be successively reduced using chemical, electrochemical, or photochemical methods to give rise to species containing ring-reduced Pc(3-), Pc(4-) or Pc(5-) ligands ; in the other direction, both ring-oxidized Pc(-1) and Pc(0)-containing systems can be accessed. These species are usually generated and characterized in situ and have only recently begun to be isolated and structurally characterized. In particular, there are few examples of phthalocyanines with early-transition and f-block metals - despite the rich organometallic-type reactivity of these metals - and thus we targeted new PcM complexes in this underdeveloped area of the periodic table. Given their larger ionic size, the unusual structural feature of the metal centre protruding far out of the Pc cavity is observed. Hence, the exposure of the coordination sphere of these Lewis-acidic (often d0) metals makes these PcM complexes attractive catalysts; this cis-oriented axial ligation also drastically improves the solubility, despite the Pc-ring remaining unsubstituted. In this presentation the isolation and structural characterization of new PcM materials with M = scandium, zirconium, niobium and (time-permitting) molybdenum will be described, along with rare structurally characterized examples of their reduced Pc(4-) and Pc(3-)complexes. Their electronic structure and electrochemical behaviour will be discussed using a combination of spectroscopic and structural techniques. A series of moisture-sensitive, soluble PcZr(IV) and PcNb(V) alkoxides were prepared, characterized, and their catalytic activity towards the ring-opening polymerization of rac-lactide was studied and will be detailed. Reaction of PcScCl with LiO i Pr and NaO t Bu yielded two hydroxide complexes containing the PcScOH unit, obtained from the hydrolysis of the putative PcSc-alkoxide intermediate. The two structurally characterized systems have a tilted “butterfly” shape structure, reminiscent of bent metallocenes. The solubility of these early transition-metal based complexes present new opportunities for the advancement of this underdeveloped area of PcM chemistry. Time permitting, our related work on organometallic PcLnX complexes will also be described. References Zhou, D.B. Leznoff, Chem. Commun., 2018, 54, 1829-1832. W. Zhou, J.R. Thompson, C.C. Leznoff, D.B. Leznoff, Chem. Eur. J., 2017, 23, 2323-2331; R. Platel, W. Zhou, T.T. Tasso, T. Furuyama, N. Kobayashi, D.B. Leznoff, Chem. Commun., 2015, 5986-89; D. McKearney, W. Zhou, V.E. Williams, D.B. Leznoff, Chem. Commun., 2019, 55, 6696-6699; Y. Ganga-Sah, E. Tajbakhsh, R.H. Platel, W. Zhou, D.B. Leznoff, J. Porph. Phthalocyanines, 2019, 23, 1592-1602; W. Zhou, D. McKearney, D.B. Leznoff, Chem. Eur. J., 2020, 26, 1027-31.
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Wolfl, Jutta, Marie-Claire Dagher, Alexandra Fuchs, Miklos Geiszt i Erzsebet Ligeti. "In vitro Activation of the NADPH Oxidase by Fluoride. Possible Involvement of a Factor Activating GTP Hydrolysis on Rac (Rac-GAP)". European Journal of Biochemistry 239, nr 2 (15.07.1996): 369–75. http://dx.doi.org/10.1111/j.1432-1033.1996.0369u.x.
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Cancelas, J. A. "On how Rac controls hematopoietic stem cell activity". Transfusion 51 (listopad 2011): 153S—159S. http://dx.doi.org/10.1111/j.1537-2995.2011.03378.x.
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Chen, Changbin, i Martin B. Dickman. "Dominant active Rac and dominant negative Rac revert the dominant active Ras phenotype in Colletotrichum trifolii by distinct signalling pathways". Molecular Microbiology 51, nr 5 (23.02.2004): 1493–507. http://dx.doi.org/10.1111/j.1365-2958.2003.03932.x.
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Bryan Bademan, R. "“Monkeying with the Bible”: Edgar J. Goodspeed's American Translation". Religion and American Culture: A Journal of Interpretation 16, nr 1 (2006): 55–93. http://dx.doi.org/10.1525/rac.2006.16.1.55.
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AbstractDevotion to the Bible remains an underappreciated aspect of American religious life partly because it fails to generate controversy. This essay opens a window onto America's relationship with the Bible by exploring a controversial moment in the history of the Bible in America: the public reception of University of Chicago professor Edgar J. Goodspeed's American Translation (1923). Initially, at least, most Americans flatly rejected Goodspeed's impeccably credentialed attempt to cast the language of the Bible in contemporary “American” English. Accusations of the professor's irreligion, bad taste, vulgarity, and crass modernity emerged from nearly every quarter of the Protestant establishment (with the exception of some card-carrying theological modernists), testifying to a widespread but unexplored attachment to the notion of a traditional Bible in the early twentieth century. By examining this barrage of reaction, “Monkeying with the Bible” argues that Protestants, along with some others in 1920s America, believed that traditional biblical language was among the forces that helped stabilize the development of American civilization.
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Scott, Glynis. "Rac and Rho: The Story Behind Melanocyte Dendrite Formation". Pigment Cell Research 15, nr 5 (5.09.2002): 322–30. http://dx.doi.org/10.1034/j.1600-0749.2002.02056.x.
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Kaverina, Irina, Olga Krylyshkina i J. Victor Small. "Microtubule Targeting of Substrate Contacts Promotes Their Relaxation and Dissociation". Journal of Cell Biology 146, nr 5 (6.09.1999): 1033–44. http://dx.doi.org/10.1083/jcb.146.5.1033.
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We recently showed that substrate contact sites in living fibroblasts are specifically targeted by microtubules (Kaverina, I., K. Rottner, and J.V. Small. 1998. J. Cell Biol. 142:181–190). Evidence is now provided that microtubule contact targeting plays a role in the modulation of substrate contact dynamics. The results are derived from spreading and polarized goldfish fibroblasts in which microtubules and contact sites were simultaneously visualized using proteins conjugated with Cy-3, rhodamine, or green fluorescent protein. For cells allowed to spread in the presence of nocodazole the turnover of contacts was retarded, as compared with controls and adhesions that were retained under the cell body were dissociated after microtubule reassembly. In polarized cells, small focal complexes were found at the protruding cell front and larger adhesions, corresponding to focal adhesions, at the retracting flanks and rear. At retracting edges, multiple microtubule contact targeting preceded contact release and cell edge retraction. The same effect could be observed in spread cells, in which microtubules were allowed to reassemble after local disassembly by the application of nocodazole to one cell edge. At the protruding front of polarized cells, focal complexes were also targeted and as a result remained either unchanged in size or, more rarely, were disassembled. Conversely, when contact targeting at the cell front was prevented by freezing microtubule growth with 20 nM taxol and protrusion stimulated by the injection of constitutively active Rac, peripheral focal complexes became abnormally enlarged. We further found that the local application of inhibitors of myosin contractility to cell edges bearing focal adhesions induced the same contact dissociation and edge retraction as observed after microtubule targeting. Our data are consistent with a mechanism whereby microtubules deliver localized doses of relaxing signals to contact sites to retard or reverse their development. We propose that it is via this route that microtubules exert their well-established control on cell polarity.
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Naranatt, Pramod P., Harinivas H. Krishnan, Marilyn S. Smith i Bala Chandran. "Kaposi's Sarcoma-Associated Herpesvirus Modulates Microtubule Dynamics via RhoA-GTP-Diaphanous 2 Signaling and Utilizes the Dynein Motors To Deliver Its DNA to the Nucleus". Journal of Virology 79, nr 2 (15.01.2005): 1191–206. http://dx.doi.org/10.1128/jvi.79.2.1191-1206.2005.
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ABSTRACT Human herpesvirus 8 (HHV-8; also called Kaposi's sarcoma-associated herpesvirus), which is implicated in the pathogenesis of Kaposi's sarcoma (KS) and lymphoproliferative disorders, infects a variety of target cells both in vivo and in vitro. HHV-8 binds to several in vitro target cells via cell surface heparan sulfate and utilizes the α3β1 integrin as one of its entry receptors. Interactions with cell surface molecules induce the activation of host cell signaling cascades and cytoskeletal changes (P. P. Naranatt, S. M. Akula, C. A. Zien, H. H. Krishnan, and B. Chandran, J. Virol. 77:1524-1539, 2003). However, the mechanism by which the HHV-8-induced signaling pathway facilitates the complex events associated with the internalization and nuclear trafficking of internalized viral DNA is as yet undefined. Here we examined the role of HHV-8-induced cytoskeletal dynamics in the infectious process and their interlinkage with signaling pathways. The depolymerization of microtubules did not affect HHV-8 binding and internalization, but it inhibited the nuclear delivery of viral DNA and infection. In contrast, the depolymerization of actin microfilaments did not have any effect on virus binding, entry, nuclear delivery, or infection. Early during infection, HHV-8 induced the acetylation of microtubules and the activation of the RhoA and Rac1 GTPases. The inactivation of Rho GTPases by Clostridium difficile toxin B significantly reduced microtubular acetylation and the delivery of viral DNA to the nucleus. In contrast, the activation of Rho GTPases by Escherichia coli cytotoxic necrotizing factor significantly augmented the nuclear delivery of viral DNA. Among the Rho GTPase-induced downstream effector molecules known to stabilize the microtubules, the activation of RhoA-GTP-dependent diaphanous 2 was observed, with no significant activation in the Rac- and Cdc42-dependent PAK1/2 and stathmin molecules. The nuclear delivery of viral DNA increased in cells expressing a constitutively active RhoA mutant and decreased in cells expressing a dominant-negative mutant of RhoA. HHV-8 capsids colocalized with the microtubules, as observed by confocal microscopic examination, and the colocalization was abolished by the destabilization of microtubules with nocodazole and by the phosphatidylinositol 3-kinase inhibitor affecting the Rho GTPases. These results suggest that HHV-8 induces Rho GTPases, and in doing so, modulates microtubules and promotes the trafficking of viral capsids and the establishment of infection. This is the first demonstration of virus-induced host cell signaling pathways in the modulation of microtubule dynamics and in the trafficking of viral DNA to the infected cell nucleus. These results further support our hypothesis that HHV-8 manipulates the host cell signaling pathway to create an appropriate intracellular environment that is conducive to the establishment of a successful infection.
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Kim, Eun Jeong, Krishnamoorthy Srikanth, Eunae Lee i Sung Soo Whang. "Opuntia humifusa (Raf.) Raf. f. jeollaensis E. J. Kim & S. S. Whang, a new forma based on three DNA markers". Korean Journal of Plant Taxonomy 44, nr 3 (26.09.2014): 181–87. http://dx.doi.org/10.11110/kjpt.2014.44.3.181.
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Robin, Deborah W., i Randy J. Gershwin. "RAC Attack-Medicare Recovery Audit Contractors: What Geriatricians Need to Know". Journal of the American Geriatrics Society 58, nr 8 (19.07.2010): 1576–78. http://dx.doi.org/10.1111/j.1532-5415.2010.02974.x.
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Sogabe, Yoko, Masatoshi Abe, Yoko Yokoyama i Osamu Ishikawa. "Basic fibroblast growth factor stimulates human keratinocyte motility by Rac activation". Wound Repair and Regeneration 14, nr 4 (lipiec 2006): 457–62. http://dx.doi.org/10.1111/j.1743-6109.2006.00143.x.
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Schaffert, Courtney S., Sandra L. Todero, Carol A. Casey, Geoffrey M. Thiele, Michael F. Sorrell i Dean J. Tuma. "Chronic Ethanol Treatment Impairs Rac and Cdc42 Activation in Rat Hepatocytes". Alcoholism: Clinical and Experimental Research 30, nr 7 (lipiec 2006): 1208–13. http://dx.doi.org/10.1111/j.1530-0277.2006.00135.x.
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Best, Wallace. "“The Right Achieved and the Wrong Way Conquered”: J. H. Jackson, Martin Luther King, Jr., and the Conflict over Civil Rights". Religion and American Culture: A Journal of Interpretation 16, nr 2 (2006): 195–226. http://dx.doi.org/10.1525/rac.2006.16.2.195.
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AbstractThe infamous conflict between Joseph Harrison Jackson, longtime president of the National Baptist Convention, Inc. (NBC), and Martin Luther King, Jr., has attracted considerable scholarly attention. For nearly a decade, the two Baptist clerics fought for control of the largest African American religious organization in the country as King sought to use it as the “institutional basis for the Civil Rights Movement.” Treated as a simple confrontation between the “radicalism” of King and the”conservatism” of Jackson, however, the conflict has been misinterpreted and, therefore, undervalued by scholars. It was not a struggle between conservative and progressive forces within the NBC, and Jackson and King were not ideological polar opposites. Their conflict was essentially religious in nature and was predicated on questions regarding what constituted church work among black Baptists. In retaining control of the NBC, Jackson wanted to make sure that the answers to those questions would reflect what he perceived to be the “vital center” of American culture. He was convinced that his commitment to “correct” the social ills of society through national and religious unity would achieve that which was right while conquering that which was wrong. Faced also with the challenges of an increasingly global context within which black religious leaders were compelled to operate, Jackson envisioned the NBC as an organization involved with efforts to bring peace and economic parity around the world. In Jackson's view, King's aim to use the NBC as the “institutional basis for the Civil Rights Movement” was both “anti-American” and limited in scope. Jackson's “gradual” stance on civil rights and his confidence in the democratic process to bring about social change reveal one of the many options employed in post -WWII African American religious and political culture.
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King, Nancy M. P. "RAC Oversight of Gene Transfer Research: A Model Worth Extending?" Journal of Law, Medicine & Ethics 30, nr 3 (2002): 381–89. http://dx.doi.org/10.1111/j.1748-720x.2002.tb00407.x.
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Clinical gene transfer research (GTR) has both a unique history and a complex and layered system of research oversight, featuring a unique review body, the Recombinant DNA Advisory Committee (RAC). This paper briefly describes the process of decision-making about clinical GTR, considers whether the questions, problems, and issues raised in clinical GTR are unique, and concludes by examining whether the RAC's oversight is a useful model that should be reproduced for other similar areas of clinical research.Clinical GTR is governed by the same oversight system as most clinical trials, with a significant addition: the RAC. Like other research with human subjects, GTR, if it is affiliated with a federally funded institution, must be approved by an institutional review board (IRB) whose activities are governed by the common rule, that is, the federal regulations for protection of human subjects in research. Like other research intended to produce a drug, device, or biologic to be marketed in the United States, GTR is also overseen by the Food and Drug Administration (FDA).
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Teran, Oriana Y., Miao-chong J. Lin, Matthew R. Zanotelli, Kristin F. Wilson i Richard A. Cerione. "Abstract 139: Dock7 regulates the AKT/mTOR pathway to promote survival and sustain the transformative properties of cancer cells". Cancer Research 82, nr 12_Supplement (15.06.2022): 139. http://dx.doi.org/10.1158/1538-7445.am2022-139.
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Abstract Akt is a well-known target of mitogenic signaling, which is activated by phosphoinositide 3-kinase, PDK1 and mTORC2, and is commonly regarded as a master regulator of cell survival. However, there is still a good deal to learn regarding how Akt can promote survival when cancer cells are faced by the multitude of challenges they need to overcome during the process of malignant transformation. While investigating the role of Dock7, a Cdc42 and Rac guanine nucleotide exchange factor of the Dock180 family, in tumorigenesis, we discovered an unexpected connection between Dock7, Akt and cell survival. Specifically, we found that Dock7 is necessary for cancer cells to survive under the stressful conditions that arise due to the loss of a substratum or serum deprivation, through its ability to stabilize a low, basal level of Akt kinase activity. Dock7 binds to Akt, as well as associates with the known Akt substrate, TSC2, promoting its phosphorylation. Since the phosphorylation of TSC2 eliminates its ability to work with its partner TSC1 to deactivate the Rheb GTPase, a direct activator of mTORC1, we probed whether mTORC1 function is also necessary for Dock7-dependent cancer cell survival. Indeed, we determined that Dock7, as well as its signaling partner Cdc42, is required to maintain a functional level of S6 kinase activity, a downstream target of mTORC1, which was prevented by the mTORC1 inhibitor rapamycin. We further show an association between mTOR, Rheb and Dock7, but not Raptor, the defining component of mTORC1. Additionally, Raptor is dispensable for the Dock7-dependent S6 kinase activity, despite its rapamycin sensitivity. Together, these findings elucidate a novel Dock7-Akt-mTOR signaling node which promotes cancer cell survival in the absence of classical mTORC1 function to allow cells to overcome stresses faced during the development of cancer. Citation Format: Oriana Y. Teran, Miao-chong J. Lin, Matthew R. Zanotelli, Kristin F. Wilson, Richard A. Cerione. Dock7 regulates the AKT/mTOR pathway to promote survival and sustain the transformative properties of cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 139.
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Ali, Amjad, Ahmad Naveed, Tahir Rasheed, Tariq Aziz, Muhammad Imran, Ze-Kun Zhang, Muhammad Wajid Ullah i in. "Methods for Predicting Ethylene/Cyclic Olefin Copolymerization Rates Promoted by Single-Site Metallocene: Kinetics Is the Key". Polymers 14, nr 3 (24.01.2022): 459. http://dx.doi.org/10.3390/polym14030459.
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In toluene at 50 °C, the vinyl addition polymerization of 4-vinyl-cyclohexene (VCH) comonomers with ethylene is investigated using symmetrical metallocene (rac-Et(Ind)2ZrCl2) combined with borate/TIBA. To demonstrate the polymerizations’ living character, cyclic VCH with linear-exocyclicπ and endocyclicπ bonds produces monomodal polymers, but the dispersity (Ɖ) was broader. The copolymers obtained can be dissolved in conventional organic solvent and have excellent thermal stability and crystalline temperature (ΔHm), and their melting temperature (Tm) varies from 109 to 126 °C, and ΔHm ranges from 80 to 128 (J/g). Secondly, the distribution of polymeric catalysts engaged in polymer chain synthesis and the nature of the dormant state are two of the most essential yet fundamentally unknown aspects. Comprehensive and exhaustive kinetics of E/VCH have shown numerous different kinetic aspects that are interpreted as manifestations of polymeric catalysts or of the instability of several types of active center [Zr]/[C*] fluctuations and formation rates of chain propagation RpE, RpVCH, and propagation rate constants kpE and kpVCH, the quantitative relationship between RpE, RpVCH and kpE, kpVCH and catalyst structures, their constituent polymer Mw, and their reactivity response to the endocyclic and exocyclic bonds of VCH. The kinetic parameters RpE, RpVCH, kpE, and kpVCH, which are the apparent rates for the metallocene-catalyzed E/VCH, RpE, and kpE values, are much more significant than RpVCH and kpVCH at 120 s, RpE and RpVCH 39.63 and 0.78, and the kpE and kpVCH values are 6461 and 93 L/mol·s, respectively, and minor diffusion barriers are recommended in the early stages. Compared with previously reported PE, RpE and kpE values are 34.2 and 7080 L/mol·s. VCH increases the RpE in the initial stage, as we are expecting; this means that the exocyclic bond of VCH is more active at the initial level, and that the chain transfer reaction of cyclic internal π double is increased with the reaction time. The tp versus Rp, kp, and [Zr]/[C*] fraction count may be fitted to a model that invokes deactivation of growing polymer chains. At tp 120–360 s higher, the incorporation rate of VCH suppresses E insertion, resulting in reduced molecular weight.