The Experts below are selected from a list of 237 Experts worldwide ranked by ideXlab platform
Jorn Coers - One of the best experts on this subject based on the ideXlab platform.
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detection of cytosolic shigella flexneri via a c terminal triple arginine motif of gbp1 inhibits actin based motility
Mbio, 2017Co-Authors: Anthony S Piro, Dulcemaria Hernandez, Sarah Luoma, Eric M Feeley, Ryan Finethy, Azeb Yirga, Eva M Frickel, Cammie F Lesser, Jorn CoersAbstract:Dynamin-like guanylate binding proteins (GBPs) are gamma interferon (IFN-γ)-inducible host Defense proteins that can associate with cytosol-invading bacterial pathogens. Mouse GBPs promote the lytic destruction of targeted bacteria in the host cell cytosol, but the antimicrobial function of human GBPs and the mechanism by which these proteins associate with cytosolic bacteria are poorly understood. Here, we demonstrate that human GBP1 is unique among the seven human GBP paralogs in its ability to associate with at least two cytosolic Gram-negative bacteria, Burkholderia thailandensis and Shigella flexneri Rough lipopolysaccharide (LPS) mutants of S. flexneri colocalize with GBP1 less frequently than wild-type S. flexneri does, suggesting that host recognition of O antigen promotes GBP1 targeting to Gram-negative bacteria. The targeting of GBP1 to cytosolic bacteria, via a unique triple-arginine motif present in its C terminus, promotes the corecruitment of four additional GBP paralogs (GBP2, GBP3, GBP4, and GBP6). GBP1-decorated Shigella organisms replicate but fail to form actin tails, leading to their intracellular aggregation. Consequentially, the wild type but not the triple-arginine GBP1 mutant restricts S. flexneri cell-to-cell spread. Furthermore, human-adapted S. flexneri, through the action of one its secreted effectors, IpaH9.8, is more resistant to GBP1 targeting than the non-human-adapted bacillus B. thailandensis These studies reveal that human GBP1 uniquely functions as an intracellular "glue trap," inhibiting the cytosolic movement of normally actin-propelled Gram-negative bacteria. In response to this powerful human Defense Program, S. flexneri has evolved an effective counterDefense to restrict GBP1 recruitment.IMPORTANCE Several pathogenic bacterial species evolved to invade, reside in, and replicate inside the cytosol of their host cells. One adaptation common to most cytosolic bacterial pathogens is the ability to coopt the host's actin polymerization machinery in order to generate force for intracellular movement. This actin-based motility enables Gram-negative bacteria, such as Shigella species, to propel themselves into neighboring cells, thereby spreading from host cell to host cell without exiting the intracellular environment. Here, we show that the human protein GBP1 acts as a cytosolic "glue trap," capturing cytosolic Gram-negative bacteria through a unique protein motif and preventing disseminated infections in cell culture models. To escape from this GBP1-mediated host Defense, Shigella employs a virulence factor that prevents or dislodges the association of GBP1 with cytosolic bacteria. Thus, therapeutic strategies to restore GBP1 binding to Shigella may lead to novel treatment options for shigellosis in the future.
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detection of cytosolic shigella flexneri via a c terminal triple arginine motif of gbp1 inhibits actin based motility
bioRxiv, 2017Co-Authors: Anthony S Piro, Dulcemaria Hernandez, Sarah Luoma, Eric M Feeley, Ryan Finethy, Azeb Yirga, Eva M Frickel, Cammie F Lesser, Jorn CoersAbstract:Dynamin-like guanylate binding proteins (GBPs) are gamma interferon (IFNgamma)-inducible host Defense proteins that can associate with cytosol-invading bacterial pathogens. Mouse GBPs promote the lytic destruction of targeted bacteria in the host cell cytosol but the antimicrobial function of human GBPs and the mechanism by which these proteins associate with cytosolic bacteria are poorly understood. Here, we demonstrate that human GBP1 is unique amongst the seven human GBP paralogs in its ability to associate with at least two cytosolic Gram-negative bacteria, Burkholderia thailandensis and Shigella flexneri. Rough lipopolysaccharide (LPS) mutants of S. flexneri co-localize with GBP1 less frequently than wildtype S. flexneri, suggesting that host recognition of O-antigen promotes GBP1 targeting to Gram-negative bacteria. The targeting of GBP1 to cytosolic bacteria, via a unique triple-arginine motif present in its C-terminus, promotes the co-recruitment of four additional GBP paralogs (GBP2, GBP3, GBP4 and GBP6). GBP1-decorated Shigella replicate but fail to form actin tails leading to their intracellular aggregation. Consequentially, wildtype but not the triple-arginine GBP1 mutant restricts S. flexneri cell-to-cell spread. Furthermore, human-adapted S. flexneri, through the action of one its secreted effectors, IpaH9.8, is more resistant to GBP1 targeting than the non-human-adapted bacillus B. thailandensis. These studies reveal that human GBP1 uniquely functions as an intracellular glue trap inhibiting the cytosolic movement of normally actin-propelled Gram-negative bacteria. In response to this powerful human Defense Program S. flexneri has evolved an effective counter-Defense to restrict GBP1 recruitment.
S Vaughn - One of the best experts on this subject based on the ideXlab platform.
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Way out there in the blue: Reagan star wars and the end of the Cold War.
AMERICAN HISTORICAL REVIEW, 2001Co-Authors: S VaughnAbstract:Way Out There in the Blue is a major work of history by the Pulitzer Prizewinning author of Fire in the Lake. Using the Star Wars missile Defense Program as a magnifying glass on his presidency, Frances FitzGerald gives us a wholly original portrait of Ronald Reagan, the most puzzling president of the last half of the twentieth century. Reagan's presidency and the man himself have always been difficult to fathom. His influence was enormous, and the few powerful ideas he espoused remain with us still -- yet he seemed nothing more than a charming, simple-minded, inattentive actor. FitzGerald shows us a Reagan far more complex than the man we thought we knew. A master of the American language and of self-presentation, the greatest storyteller ever to occupy the Oval Office, Reagan created a compelling public persona that bore little relationship to himself. The real Ronald Reagan -- the Reagan who emerges from FitzGerald's book -- was a gifted politician with a deep understanding of the American national psyche and at the same time an executive almost totally disengaged from the policies of his administration and from the people who surrounded him. The idea that America should have an impregnable shield against nuclear weapons was Reagan's invention. His famous Star Wars speech, in which he promised us such a shield and called upon scientists to produce it, gave rise to the Strategic Defense Initiative. Reagan used his sure understanding of American mythology, history and politics to persuade the country that a perfect Defense against Soviet nuclear weapons would be possible, even though the technology did not exist and was not remotely feasible. His idea turned into a multibillion-dollar research Program. SDI played a central role in U.S.-Soviet relations at a crucial juncture in the Cold War, and in a different form it survives to this day. Drawing on prodigious research, including interviews with the participants, FitzGerald offers new insights into American foreign policy in the Reagan era. She gives us revealing portraits of major players in Reagan's administration, including George Shultz, Caspar Weinberger, Donald Regan and Paul Nitze, and she provides a radically new view of what happened at the Reagan-Gorbachev summits in Geneva, Reykjavik, Washington and Moscow. FitzGerald describes the fierce battles among Reagan's advisers and the frightening increase of Cold War tensions during Reagan's first term. She shows how the president who presided over the greatest peacetime military buildup came to espouse the elimination of nuclear weapons, and how the man who insisted that the Soviet Union was an "evil empire" came to embrace the Soviet leader, Mikhail Gorbachev, and to proclaim an end to the Cold War long before most in Washington understood that it had ended. Way Out There in the Blue is a ground-breaking history of the American side of the end of the Cold War. Both appalling and funny, it is a black comedy in which Reagan, playing the role he wrote for himself, is the hero.
Christiane Gatz - One of the best experts on this subject based on the ideXlab platform.
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tga transcription factors activate the salicylic acid suppressible branch of the ethylene induced Defense Program by regulating ora59 expression
Plant Physiology, 2014Co-Authors: Mark Zander, Corinna Thurow, Christiane GatzAbstract:Salicylic acid (SA), a hormone essential for Defense against biotrophic pathogens, triggers increased susceptibility of plants against necrotrophic attackers by suppressing the jasmonic acid-ethylene (ET) Defense response. Here, we show that this disease-promoting SA effect is abolished in plants lacking the three related TGACG sequence-specific binding proteins TGA2, TGA5, and TGA6 (class II TGAs). After treatment of plants with the ET precursor 1-aminocyclopropane-1-carboxylic acid (ACC), activation of all those genes that are suppressed by SA depended on class II TGAs. Rather than TGA binding sites, GCC-box motifs were significantly enriched in the corresponding promoters. GCC-box motifs are recognized by members of the superfamily of APETALA2/ETHYLENE RESPONSE FACTORs (ERFs). Of 11 activating ACC-induced APETALA2/ERFs, only ORA59 (for OCTADECANOID-RESPONSIVE ARABIDOPSIS APETALA2/ETHYLENE RESPONSE FACTOR domain protein59) and ERF96 were strongly suppressed by SA. ORA59 is the master regulator of the jasmonic acid-ET-induced Defense Program. ORA59 transcript levels do not reach maximal levels in the tga2 tga5 tga6 triple mutant, and this residual activity cannot be suppressed by SA. The ORA59 promoter contains an essential TGA binding site and is a direct target of class II TGAs as revealed by chromatin immunoprecipitation experiments. We suggest that class II TGAs at the ORA59 promoter constitute an important regulatory hub for the activation and SA suppression of ACC-induced genes.
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arabidopsis thaliana class ii tga transcription factors are essential activators of jasmonic acid ethylene induced Defense responses
Plant Journal, 2009Co-Authors: Mark Zander, Sylvain La Camera, Olivier Lamotte, Jeanpierre Metraux, Christiane GatzAbstract:The three closely related Arabidopsis basic leucine zipper (bZIP) transcription factors TGA2, TGA5 and TGA6 are required for the establishment of the salicylic acid (SA)-dependent plant Defense response systemic acquired resistance, which is effective against biotrophic pathogens. Here we show that the same transcription factors are essential for the activation of jasmonic acid (JA)- and ethylene (ET)-dependent Defense mechanisms that counteract necrotrophic pathogens: the tga256 triple mutant is impaired in JA/ET-induced PDF1.2 and b-CHI expression, which correlates with a higher susceptibility against the necrotroph Botrytis cinerea. JA/ET induction of the trans-activators ERF1 and ORA59, which act upstream of PDF1.2, was slightly increased (ERF1) or unaffected (ORA59). PDF1.2 expression can be restored in the tga256 mutant by increased expression of ORA59, as observed in the tga256 jin1 quadruple mutant, which lacks the transcription factor JIN1/AtMYC2 that functions as a negative regulator of the JA/ET-dependent anti-fungal Defense Program. Whereas JA/ET-induced PDF1.2 expression is strongly suppressed by SA in wild-type plants, no negative effect of SA on PDF1.2 expression was observed in the tga256 jin1 quadruple mutant. These results imply that the antagonistic effects of TGA factors and JIN1/AtMYC2 on the JA/ET pathway are necessary to evoke the SA-mediated suppression of JA/ET-induced Defense responses.
Anthony S Piro - One of the best experts on this subject based on the ideXlab platform.
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detection of cytosolic shigella flexneri via a c terminal triple arginine motif of gbp1 inhibits actin based motility
Mbio, 2017Co-Authors: Anthony S Piro, Dulcemaria Hernandez, Sarah Luoma, Eric M Feeley, Ryan Finethy, Azeb Yirga, Eva M Frickel, Cammie F Lesser, Jorn CoersAbstract:Dynamin-like guanylate binding proteins (GBPs) are gamma interferon (IFN-γ)-inducible host Defense proteins that can associate with cytosol-invading bacterial pathogens. Mouse GBPs promote the lytic destruction of targeted bacteria in the host cell cytosol, but the antimicrobial function of human GBPs and the mechanism by which these proteins associate with cytosolic bacteria are poorly understood. Here, we demonstrate that human GBP1 is unique among the seven human GBP paralogs in its ability to associate with at least two cytosolic Gram-negative bacteria, Burkholderia thailandensis and Shigella flexneri Rough lipopolysaccharide (LPS) mutants of S. flexneri colocalize with GBP1 less frequently than wild-type S. flexneri does, suggesting that host recognition of O antigen promotes GBP1 targeting to Gram-negative bacteria. The targeting of GBP1 to cytosolic bacteria, via a unique triple-arginine motif present in its C terminus, promotes the corecruitment of four additional GBP paralogs (GBP2, GBP3, GBP4, and GBP6). GBP1-decorated Shigella organisms replicate but fail to form actin tails, leading to their intracellular aggregation. Consequentially, the wild type but not the triple-arginine GBP1 mutant restricts S. flexneri cell-to-cell spread. Furthermore, human-adapted S. flexneri, through the action of one its secreted effectors, IpaH9.8, is more resistant to GBP1 targeting than the non-human-adapted bacillus B. thailandensis These studies reveal that human GBP1 uniquely functions as an intracellular "glue trap," inhibiting the cytosolic movement of normally actin-propelled Gram-negative bacteria. In response to this powerful human Defense Program, S. flexneri has evolved an effective counterDefense to restrict GBP1 recruitment.IMPORTANCE Several pathogenic bacterial species evolved to invade, reside in, and replicate inside the cytosol of their host cells. One adaptation common to most cytosolic bacterial pathogens is the ability to coopt the host's actin polymerization machinery in order to generate force for intracellular movement. This actin-based motility enables Gram-negative bacteria, such as Shigella species, to propel themselves into neighboring cells, thereby spreading from host cell to host cell without exiting the intracellular environment. Here, we show that the human protein GBP1 acts as a cytosolic "glue trap," capturing cytosolic Gram-negative bacteria through a unique protein motif and preventing disseminated infections in cell culture models. To escape from this GBP1-mediated host Defense, Shigella employs a virulence factor that prevents or dislodges the association of GBP1 with cytosolic bacteria. Thus, therapeutic strategies to restore GBP1 binding to Shigella may lead to novel treatment options for shigellosis in the future.
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detection of cytosolic shigella flexneri via a c terminal triple arginine motif of gbp1 inhibits actin based motility
bioRxiv, 2017Co-Authors: Anthony S Piro, Dulcemaria Hernandez, Sarah Luoma, Eric M Feeley, Ryan Finethy, Azeb Yirga, Eva M Frickel, Cammie F Lesser, Jorn CoersAbstract:Dynamin-like guanylate binding proteins (GBPs) are gamma interferon (IFNgamma)-inducible host Defense proteins that can associate with cytosol-invading bacterial pathogens. Mouse GBPs promote the lytic destruction of targeted bacteria in the host cell cytosol but the antimicrobial function of human GBPs and the mechanism by which these proteins associate with cytosolic bacteria are poorly understood. Here, we demonstrate that human GBP1 is unique amongst the seven human GBP paralogs in its ability to associate with at least two cytosolic Gram-negative bacteria, Burkholderia thailandensis and Shigella flexneri. Rough lipopolysaccharide (LPS) mutants of S. flexneri co-localize with GBP1 less frequently than wildtype S. flexneri, suggesting that host recognition of O-antigen promotes GBP1 targeting to Gram-negative bacteria. The targeting of GBP1 to cytosolic bacteria, via a unique triple-arginine motif present in its C-terminus, promotes the co-recruitment of four additional GBP paralogs (GBP2, GBP3, GBP4 and GBP6). GBP1-decorated Shigella replicate but fail to form actin tails leading to their intracellular aggregation. Consequentially, wildtype but not the triple-arginine GBP1 mutant restricts S. flexneri cell-to-cell spread. Furthermore, human-adapted S. flexneri, through the action of one its secreted effectors, IpaH9.8, is more resistant to GBP1 targeting than the non-human-adapted bacillus B. thailandensis. These studies reveal that human GBP1 uniquely functions as an intracellular glue trap inhibiting the cytosolic movement of normally actin-propelled Gram-negative bacteria. In response to this powerful human Defense Program S. flexneri has evolved an effective counter-Defense to restrict GBP1 recruitment.
Neville H Golden - One of the best experts on this subject based on the ideXlab platform.
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a self Defense Program reduces the incidence of sexual assault in kenyan adolescent girls
Journal of Adolescent Health, 2013Co-Authors: Jake Sinclair, Lee Sinclair, Evans Otieno, Munyae M Mulinge, Cynthia J Kapphahn, Neville H GoldenAbstract:Abstract Purpose To determine the effect of a standardized 6-week self-Defense Program on the incidence of sexual assault in adolescent high school girls in an urban slum in Nairobi, Kenya. Methods Population-based survey of 522 high school girls in the Korogocho-Kariobangi locations in Nairobi, Kenya, at baseline and 10 months later. Subjects were assigned by school attended to either a "No Means No Worldwide" self-Defense course (eight schools; N = 402) or to a life-skills class (two schools; N = 120). Both the intervention and the life-skills classes were taught in the schools by trained instructors. Participants were administered the same survey at baseline and follow-up. Results A total of 522 girls (mean age, 16.7 ± 1.5 years; range, 14–21 years) completed surveys at baseline, and 489 at 10-month follow-up. At baseline, 24.5% reported sexual assault in the prior year, with the majority (90%) reporting assault by someone known to them (boyfriend, 52%; relative, 17%; neighbor, 15%; teacher or pastor, 6%). In the self-Defense intervention group, the incidence of sexual assault decreased from 24.6% at baseline to 9.2% at follow-up ( p p = .10). Over half the girls in the intervention group reported having used the self-Defense skills to avert sexual assault in the year after the training. Rates of disclosure increased in the intervention group, but not in controls. Conclusions A standardized 6-week self-Defense Program is effective in reducing the incidence of sexual assault in slum-dwelling high school girls in Nairobi, Kenya.
