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1

Xanthomonas oryzae pv. oryzae Type III Effector XopN Targets OsVOZ2 and a Putative Thiamine Synthase as a Virulence Factor in Rice  

PubMed Central

Xanthomonasoryzae pv. oryzae (Xoo) is spread systemically through the xylem tissue and causes bacterial blight in rice. We evaluated the roles of Xanthomonas outer proteins (Xop) in the Xoo strain KXO85 in a Japonica-type rice cultivar, Dongjin. Five xop gene knockout mutants (xopQKXO85, xopXKXO85, xopP1KXO85, xopP2KXO85, and xopNKXO85) were generated by EZ-Tn5 mutagenesis, and their virulence was assessed in 3-month-old rice leaves. Among these mutants, the xopNKXO85 mutant appeared to be less virulent than the wild-type KXO85; however, the difference was not statistically significant. In contrast, the xopNKXO85 mutant exhibited significantly less virulence in flag leaves after flowering than the wild-type KXO85. These observations indicate that the roles of Xop in Xoo virulence are dependent on leaf stage. We chose the xopN gene for further characterization because the xopNKXO85 mutant showed the greatest influence on virulence. We confirmed that XopNKXO85 is translocated into rice cells, and its gene expression is positively regulated by HrpX. Two rice proteins, OsVOZ2 and a putative thiamine synthase (OsXNP), were identified as targets of XopNKXO85 by yeast two-hybrid screening. Interactions between XopNKXO85 and OsVOZ2 and OsXNP were further confirmed in planta by bimolecular fluorescence complementation and in vivo pull-down assays. To investigate the roles of OsVOZ2 in interactions between rice and Xoo, we evaluated the virulence of the wild-type KXO85 and xopNKXO85 mutant in the OsVOZ2 mutant line PFG_3A-07565 of Dongjin. The wild-type KXO85 and xopNKXO85 mutant were significantly less virulent in the mutant rice line. These results indicate that XopNKXO85 and OsVOZ2 play important roles both individually and together for Xoo virulence in rice.

Cheong, Hoon; Kim, Chi-Yeol; Jeon, Jong-Seong; Lee, Byoung-Moo; Sun Moon, Jae; Hwang, Ingyu

2013-01-01

2

Bacterial effector HopF2 suppresses Arabidopsis innate immunity at the plasma membrane  

PubMed Central

Many bacterial pathogens inject a cocktail of effector proteins into host cells through type III secretion systems. These effectors act in concert to modulate host physiology and immune signaling, thereby promoting pathogenicity. In search for additional Pseudomonas syringae effectors in suppressing plant innate immunity triggered by pathogen or microbe-associated molecular patterns (PAMPs/MAMPs), we identified P. syringae tomato DC3000 effector HopF2 as a potent suppressor of early immune response gene transcription and MAP kinase (MAPK) signaling activated by multiple MAMPs, including bacterial flagellin, elongation factor Tu, peptidoglycan, lipopolysaccharide and HrpZ1 harpin, and fungal chitin. The conserved surface-exposed residues of HopF2 are essential for its MAMP suppression activity. HopF2 is targeted to the plant plasma membrane through a putative myristoylation site, and the membrane association appears to be required for its MAMP suppression function. Expression of HopF2 in plants potently diminished the flagellin-induced phosphorylation of BIK1, a plasma membrane-associated cytoplasmic kinase, which is rapidly phosphorylated within one minute upon flagellin perception. Thus, HopF2 likely intercepts MAMP signaling at the plasma membrane immediately upon signal perception. Consistent with the potent suppression function of multiple MAMP signaling, expression of HopF2 in transgenic plants compromised plant nonhost immunity to bacteria P. syringae pv. phaseolicola, and plant immunity to a necrotrophic fungal pathogen Botrytis cinerea.

Wu, Shujing; Lu, Dongping; Kabbage, Mehdi; Wei, Hai-Lei; Swingle, Bryan; Records, Angela R.; Dickman, Martin; He, Ping; Shan, Libo

2011-01-01

3

Bacterial effector HopF2 suppresses arabidopsis innate immunity at the plasma membrane.  

PubMed

Many bacterial pathogens inject a cocktail of effector proteins into host cells through type III secretion systems. These effectors act in concert to modulate host physiology and immune signaling, thereby promoting pathogenicity. In a search for additional Pseudomonas syringae effectors in suppressing plant innate immunity triggered by pathogen or microbe-associated molecular patterns (PAMPs or MAMPs), we identified P. syringae tomato DC3000 effector HopF2 as a potent suppressor of early immune-response gene transcription and mitogen-activated protein kinase (MAPK) signaling activated by multiple MAMPs, including bacterial flagellin, elongation factor Tu, peptidoglycan, lipopolysaccharide and HrpZ1 harpin, and fungal chitin. The conserved surface-exposed residues of HopF2 are essential for its MAMP suppression activity. HopF2 is targeted to the plant plasma membrane through a putative myristoylation site, and the membrane association appears to be required for its MAMP-suppression function. Expression of HopF2 in plants potently diminished the flagellin-induced phosphorylation of BIK1, a plasma membrane-associated cytoplasmic kinase that is rapidly phosphorylated within one minute upon flagellin perception. Thus, HopF2 likely intercepts MAMP signaling at the plasma membrane immediately of signal perception. Consistent with the potent suppression function of multiple MAMP signaling, expression of HopF2 in transgenic plants compromised plant nonhost immunity to bacteria P. syringae pv. Phaseolicola and plant immunity to the necrotrophic fungal pathogen Botrytis cinerea. PMID:21198360

Wu, Shujing; Lu, Dongping; Kabbage, Mehdi; Wei, Hai-Lei; Swingle, Bryan; Records, Angela R; Dickman, Martin; He, Ping; Shan, Libo

2011-05-01

4

Suppression of plant resistance gene-based immunity by a fungal effector.  

PubMed

The innate immune system of plants consists of two layers. The first layer, called basal resistance, governs recognition of conserved microbial molecules and fends off most attempted invasions. The second layer is based on Resistance (R) genes that mediate recognition of effectors, proteins secreted by pathogens to suppress or evade basal resistance. Here, we show that a plant-pathogenic fungus secretes an effector that can both trigger and suppress R gene-based immunity. This effector, Avr1, is secreted by the xylem-invading fungus Fusarium oxysporum f.sp. lycopersici (Fol) and triggers disease resistance when the host plant, tomato, carries a matching R gene (I or I-1). At the same time, Avr1 suppresses the protective effect of two other R genes, I-2 and I-3. Based on these observations, we tentatively reconstruct the evolutionary arms race that has taken place between tomato R genes and effectors of Fol. This molecular analysis has revealed a hitherto unpredicted strategy for durable disease control based on resistance gene combinations. PMID:18464895

Houterman, Petra M; Cornelissen, Ben J C; Rep, Martijn

2008-05-01

5

The Pseudomonas syringae effector HopF2 suppresses Arabidopsis immunity by targeting BAK1.  

PubMed

Pseudomonas syringae delivers a plethora of effector proteins into host cells to sabotage immune responses and modulate physiology to favor infection. The P. syringae pv. tomato DC3000 effector HopF2 suppresses Arabidopsis innate immunity triggered by multiple microbe-associated molecular patterns (MAMP) at the plasma membrane. We show here that HopF2 possesses distinct mechanisms for suppression of two branches of MAMP-activated MAP kinase (MAPK) cascades. In addition to blocking MKK5 (MAPK kinase 5) activation in the MEKK1 (MAPK kinase kinase 1)/MEKKs-MKK4/5-MPK3/6 cascade, HopF2 targets additional component(s) upstream of MEKK1 in the MEKK1-MKK1/2-MPK4 cascade and the plasma membrane-localized receptor-like cytoplasmic kinase BIK1 and its homologs. We further show that HopF2 directly targets BAK1, a plasma membrane-localized receptor-like kinase that is involved in multiple MAMP signaling. The interaction between BAK1 and HopF2 and between two other P. syringae effectors, AvrPto and AvrPtoB, was confirmed in vivo and in vitro. Consistent with BAK1 as a physiological target of AvrPto, AvrPtoB and HopF2, the strong growth defects or lethality associated with ectopic expression of these effectors in wild-type Arabidopsis transgenic plants were largely alleviated in bak1 mutant plants. Thus, our results provide genetic evidence to show that BAK1 is a physiological target of AvrPto, AvrPtoB and HopF2. Identification of BAK1 as an additional target of HopF2 virulence not only explains HopF2 suppression of multiple MAMP signaling at the plasma membrane, but also supports the notion that pathogen virulence effectors act through multiple targets in host cells. PMID:24237140

Zhou, Jinggeng; Wu, Shujing; Chen, Xin; Liu, Chenglong; Sheen, Jen; Shan, Libo; He, Ping

2014-01-01

6

Bach2 maintains T cells in a naive state by suppressing effector memory-related genes  

PubMed Central

The transcriptional repressor BTB and CNC homology 2 (Bach2) is thought to be mainly expressed in B cells with specific functions such as class switch recombination and somatic hypermutation, but its function in T cells is not known. We found equal Bach2 expression in T cells and analyzed its function using Bach2-deficient (?/?) mice. Although T-cell development was normal, numbers of peripheral naive T cells were decreased, which rapidly produced Th2 cytokines after TCR stimulation. Bach2?/? naive T cells highly expressed genes related to effector-memory T cells such as CCR4, ST-2 and Blimp-1. Enhanced expression of these genes induced Bach2?/? naive T cells to migrate toward CCR4-ligand and respond to IL33. Forced expression of Bach2 restored the expression of these genes. Using Chromatin Immunoprecipitation (ChIP)-seq analysis, we identified S100 calcium binding protein a, Heme oxigenase 1, and prolyl hydroxylase 3 as Bach2 direct target genes, which are highly expressed in effector-memory T cells. These findings indicate that Bach2 suppresses effector memory-related genes to maintain the naive T-cell state and regulates generation of effector-memory T cells.

Tsukumo, Shin-ichi; Unno, Midori; Muto, Akihiko; Takeuchi, Arata; Kometani, Kohei; Kurosaki, Tomohiro; Igarashi, Kazuhiko; Saito, Takashi

2013-01-01

7

Bach2 maintains T cells in a naive state by suppressing effector memory-related genes.  

PubMed

The transcriptional repressor BTB and CNC homology 2 (Bach2) is thought to be mainly expressed in B cells with specific functions such as class switch recombination and somatic hypermutation, but its function in T cells is not known. We found equal Bach2 expression in T cells and analyzed its function using Bach2-deficient (-/-) mice. Although T-cell development was normal, numbers of peripheral naive T cells were decreased, which rapidly produced Th2 cytokines after TCR stimulation. Bach2(-/-) naive T cells highly expressed genes related to effector-memory T cells such as CCR4, ST-2 and Blimp-1. Enhanced expression of these genes induced Bach2(-/-) naive T cells to migrate toward CCR4-ligand and respond to IL33. Forced expression of Bach2 restored the expression of these genes. Using Chromatin Immunoprecipitation (ChIP)-seq analysis, we identified S100 calcium binding protein a, Heme oxigenase 1, and prolyl hydroxylase 3 as Bach2 direct target genes, which are highly expressed in effector-memory T cells. These findings indicate that Bach2 suppresses effector memory-related genes to maintain the naive T-cell state and regulates generation of effector-memory T cells. PMID:23754397

Tsukumo, Shin-ichi; Unno, Midori; Muto, Akihiko; Takeuchi, Arata; Kometani, Kohei; Kurosaki, Tomohiro; Igarashi, Kazuhiko; Saito, Takashi

2013-06-25

8

Human Regulatory T Cell Suppressive Function Is Independent of Apoptosis Induction in Activated Effector T Cells  

PubMed Central

Background CD4+CD25+FOXP3+ Regulatory T cells (Treg) play a central role in the immune balance to prevent autoimmune disease. One outstanding question is how Tregs suppress effector immune responses in human. Experiments in mice demonstrated that Treg restrict effector T cell (Teff) responses by deprivation of the growth factor IL-2 through Treg consumption, resulting in apoptosis of Teff. Principal Findings In this study we investigated the relevance of Teff apoptosis induction to human Treg function. To this end, we studied naturally occurring Treg (nTreg) from peripheral blood of healthy donors, and, to investigate Treg function in inflammation in vivo, Treg from synovial fluid of Juvenile Idiopathic Arthritis (JIA) patients (SF-Treg). Both nTreg and SF-Treg suppress Teff proliferation and cytokine production efficiently as predicted. However, in contrast with murine Treg, neither nTreg nor SF-Treg induce apoptosis in Teff. Furthermore, exogenously supplied IL-2 and IL-7 reverse suppression, but do not influence apoptosis of Teff. Significance Our functional data here support that Treg are excellent clinical targets to counteract autoimmune diseases. For optimal functional outcome in human clinical trials, future work should focus on the ability of Treg to suppress proliferation and cytokine production of Teff, rather than induction of Teff apoptosis.

van Teijlingen, Nienke H.; de Jager, Wilco; Beekman, Jeffrey M.; Prakken, Berent J.

2009-01-01

9

Phytophthora sojae Effector PsCRN70 Suppresses Plant Defenses in Nicotiana benthamiana  

PubMed Central

Phytophthora sojae, an oomycete pathogen, produces a large number of effector proteins that enter into host cells. The Crinklers (Crinkling and Necrosis, CRN) are cytoplasmic effectors that are conserved in oomycete pathogens and their encoding genes are highly expressed at the infective stages in P. sojae. However, their roles in pathogenesis are largely unknown. Here, we functionally characterized an effector PsCRN70 by transiently and stably overexpressing it in Nicotiana benthamiana. We demonstrated that PsCRN70 was localized to the plant cell nucleus and suppressed cell death elicited by all the tested cell death-inducing proteins, including BAX, PsAvh241, PsCRN63, PsojNIP and R3a/Avr3a. Overexpression of the PsCRN70 gene in N. benthamiana enhanced susceptibility to P. parasitica. The H2O2 accumulation in the PsCRN70-transgenic plants was reduced compared to the GFP-lines. The transcriptional levels of the defense-associated genes, including PR1b, PR2b, ERF1 and LOX, were also down-regulated in the PsCRN70-transgenic lines. Our results suggest that PsCRN70 may function as a universal suppressor of the cell death induced by many elicitors, the host H2O2 accumulation and the expression of defense-associated genes, and therefore promotes pathogen infection.

Ru, Yanyan; Liu, Tingli; Xu, Jing; Liu, Li; Mafurah, Joseph Juma; Dou, Daolong

2014-01-01

10

Molecular Determinants of Resistance Activation and Suppression by Phytophthora infestans Effector IPI-O  

PubMed Central

Despite intensive breeding efforts, potato late blight, caused by the oomycete pathogen Phytophthora infestans, remains a threat to potato production worldwide because newly evolved pathogen strains have consistently overcome major resistance genes. The potato RB gene, derived from the wild species Solanum bulbocastanum, confers resistance to most P. infestans strains through recognition of members of the pathogen effector family IPI-O. While the majority of IPI-O proteins are recognized by RB to elicit resistance (e.g. IPI-O1, IPI-O2), some family members are able to elude detection (e.g. IPI-O4). In addition, IPI-O4 blocks recognition of IPI-O1, leading to inactivation of RB-mediated programmed cell death. Here, we report results that elucidate molecular mechanisms governing resistance elicitation or suppression of RB by IPI-O. Our data indicate self-association of the RB coiled coil (CC) domain as well as a physical interaction between this domain and the effectors IPI-O4 and IPI-O1. We identified four amino acids within IPI-O that are critical for interaction with the RB CC domain and one of these amino acids, at position 129, determines hypersensitive response (HR) elicitation in planta. IPI-O1 mutant L129P fails to induce HR in presence of RB while IPI-O4 P129L gains the ability to induce an HR. Like IPI-O4, IPI-O1 L129P is also able to suppress the HR mediated by RB, indicating a critical step in the evolution of this gene family. Our results point to a model in which IPI-O effectors can affect RB function through interaction with the RB CC domain.

Chen, Yu; Liu, Zhenyu; Halterman, Dennis A.

2012-01-01

11

Molecular determinants of resistance activation and suppression by Phytophthora infestans effector IPI-O.  

PubMed

Despite intensive breeding efforts, potato late blight, caused by the oomycete pathogen Phytophthora infestans, remains a threat to potato production worldwide because newly evolved pathogen strains have consistently overcome major resistance genes. The potato RB gene, derived from the wild species Solanum bulbocastanum, confers resistance to most P. infestans strains through recognition of members of the pathogen effector family IPI-O. While the majority of IPI-O proteins are recognized by RB to elicit resistance (e.g. IPI-O1, IPI-O2), some family members are able to elude detection (e.g. IPI-O4). In addition, IPI-O4 blocks recognition of IPI-O1, leading to inactivation of RB-mediated programmed cell death. Here, we report results that elucidate molecular mechanisms governing resistance elicitation or suppression of RB by IPI-O. Our data indicate self-association of the RB coiled coil (CC) domain as well as a physical interaction between this domain and the effectors IPI-O4 and IPI-O1. We identified four amino acids within IPI-O that are critical for interaction with the RB CC domain and one of these amino acids, at position 129, determines hypersensitive response (HR) elicitation in planta. IPI-O1 mutant L129P fails to induce HR in presence of RB while IPI-O4 P129L gains the ability to induce an HR. Like IPI-O4, IPI-O1 L129P is also able to suppress the HR mediated by RB, indicating a critical step in the evolution of this gene family. Our results point to a model in which IPI-O effectors can affect RB function through interaction with the RB CC domain. PMID:22438813

Chen, Yu; Liu, Zhenyu; Halterman, Dennis A

2012-01-01

12

The Ustilago maydis Effector Pep1 Suppresses Plant Immunity by Inhibition of Host Peroxidase Activity  

PubMed Central

The corn smut Ustilago maydis establishes a biotrophic interaction with its host plant maize. This interaction requires efficient suppression of plant immune responses, which is attributed to secreted effector proteins. Previously we identified Pep1 (Protein essential during penetration-1) as a secreted effector with an essential role for U. maydis virulence. pep1 deletion mutants induce strong defense responses leading to an early block in pathogenic development of the fungus. Using cytological and functional assays we show that Pep1 functions as an inhibitor of plant peroxidases. At sites of ?pep1 mutant penetrations, H2O2 strongly accumulated in the cell walls, coinciding with a transcriptional induction of the secreted maize peroxidase POX12. Pep1 protein effectively inhibited the peroxidase driven oxidative burst and thereby suppresses the early immune responses of maize. Moreover, Pep1 directly inhibits peroxidases in vitro in a concentration-dependent manner. Using fluorescence complementation assays, we observed a direct interaction of Pep1 and the maize peroxidase POX12 in vivo. Functional relevance of this interaction was demonstrated by partial complementation of the ?pep1 mutant defect by virus induced gene silencing of maize POX12. We conclude that Pep1 acts as a potent suppressor of early plant defenses by inhibition of peroxidase activity. Thus, it represents a novel strategy for establishing a biotrophic interaction.

Zechmann, Bernd; Hillmer, Morten; Doehlemann, Gunther

2012-01-01

13

The Anoikis Effector Bit1 Displays Tumor Suppressive Function in Lung Cancer Cells  

PubMed Central

The mitochondrial Bit1 (Bcl-2 inhibitor of transcription 1) protein is a part of an apoptotic pathway that is uniquely regulated by integrin-mediated attachment. As an anoikis effector, Bit1 is released into the cytoplasm following loss of cell attachment and induces a caspase-independent form of apoptosis. Considering that anoikis resistance is a critical determinant of transformation, we hypothesized that cancer cells may circumvent the Bit1 apoptotic pathway to attain anchorage-independence and tumorigenic potential. Here, we provide the first evidence of the tumor suppressive effect of Bit1 through a mechanism involving anoikis induction in human lung adenocarcinoma derived A549 cells. Restitution of Bit1 in anoikis resistant A549 cells is sufficient to induce detachment induced-apoptosis despite defect in caspase activation and impairs their anchorage-independent growth. Conversely, stable downregulation of Bit1 in these cells significantly enhances their anoikis resistance and anchorage-independent growth. The Bit1 knockdown cells exhibit significantly enhanced tumorigenecity in vivo. It has been previously shown that the nuclear TLE1 corepressor is a putative oncogene in lung cancer, and we show here that TLE1 blocks Bit1 mediated anoikis in part by sequestering the pro-apoptotic partner of Bit1, the Amino-terminal Enhancer of Split (AES) protein, in the nucleus. Taken together, these findings suggest a tumor suppressive role of the caspase-independent anoikis effector Bit1 in lung cancer. Consistent with its role as a tumor suppressor, we have found that Bit1 is downregulated in human non-small cell lung cancer (NSCLC) tissues.

Yao, Xin; Jennings, Scott; Ireland, Shubha Kale; Pham, Tri; Temple, Brandi; Davis, Mya; Chen, Renwei; Davenport, Ian; Biliran, Hector

2014-01-01

14

Functionally Redundant RXLR Effectors from Phytophthora infestans Act at Different Steps to Suppress Early flg22-Triggered Immunity  

PubMed Central

Genome sequences of several economically important phytopathogenic oomycetes have revealed the presence of large families of so-called RXLR effectors. Functional screens have identified RXLR effector repertoires that either compromise or induce plant defense responses. However, limited information is available about the molecular mechanisms underlying the modes of action of these effectors in planta. The perception of highly conserved pathogen- or microbe-associated molecular patterns (PAMPs/MAMPs), such as flg22, triggers converging signaling pathways recruiting MAP kinase cascades and inducing transcriptional re-programming, yielding a generic anti-microbial response. We used a highly synchronizable, pathogen-free protoplast-based assay to identify a set of RXLR effectors from Phytophthora infestans (PiRXLRs), the causal agent of potato and tomato light blight that manipulate early stages of flg22-triggered signaling. Of thirty-three tested PiRXLR effector candidates, eight, called Suppressor of early Flg22-induced Immune response (SFI), significantly suppressed flg22-dependent activation of a reporter gene under control of a typical MAMP-inducible promoter (pFRK1-Luc) in tomato protoplasts. We extended our analysis to Arabidopsis thaliana, a non-host plant species of P. infestans. From the aforementioned eight SFI effectors, three appeared to share similar functions in both Arabidopsis and tomato by suppressing transcriptional activation of flg22-induced marker genes downstream of post-translational MAP kinase activation. A further three effectors interfere with MAMP signaling at, or upstream of, the MAP kinase cascade in tomato, but not in Arabidopsis. Transient expression of the SFI effectors in Nicotiana benthamiana enhances susceptibility to P. infestans and, for the most potent effector, SFI1, nuclear localization is required for both suppression of MAMP signaling and virulence function. The present study provides a framework to decipher the molecular mechanisms underlying the manipulation of host MAMP-triggered immunity (MTI) by P. infestans and to understand the basis of host versus non-host resistance in plants towards P. infestans.

Fraiture, Malou; Liu, Xiaoyu; Boevink, Petra C.; Gilroy, Eleanor M.; Chen, Ying; Kandel, Kabindra; Sessa, Guido; Birch, Paul R. J.; Brunner, Frederic

2014-01-01

15

Repression of SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation  

PubMed Central

Regulatory T (Treg) cells are essential for self-tolerance and immune homeostasis. Lack of effector T cell (Teff) function and gain of suppressive activity by Treg are dependent on the transcriptional program induced by Foxp3. Here we report repression of SATB1, a genome organizer regulating chromatin structure and gene expression, as crucial for Treg phenotype and function. Foxp3, acting as a transcriptional repressor, directly suppressed the SATB1 locus and indirectly through induction of microRNAs that bound the SATB1 3?UTR. Release of SATB1 from Foxp3 control in Treg caused loss of suppressive function, establishment of transcriptional Teff programs and induction of Teff cytokines. These data support that inhibition of SATB1-mediated modulation of global chromatin remodelling is pivotal for maintaining Treg functionality.

Beyer, Marc; Thabet, Yasser; Muller, Roman-Ulrich; Sadlon, Timothy; Classen, Sabine; Lahl, Katharina; Basu, Samik; Zhou, Xuyu; Bailey-Bucktrout, Samantha L.; Krebs, Wolfgang; Schonfeld, Eva A.; Bottcher, Jan; Golovina, Tatiana; Mayer, Christian T.; Hofmann, Andrea; Sommer, Daniel; Debey-Pascher, Svenja; Endl, Elmar; Limmer, Andreas; Hippen, Keli L.; Blazar, Bruce R.; Balderas, Robert; Quast, Thomas; Waha, Andreas; Mayer, Gunter; Famulok, Michael; Knolle, Percy A.; Wickenhauser, Claudia; Kolanus, Waldemar; Schermer, Bernhard; Bluestone, Jeffrey A.; Barry, Simon C.; Sparwasser, Tim; Riley, James L.; Schultze, Joachim L.

2013-01-01

16

Suppression of anti-skin-allograft response by photodamaged effector cells--the modulating effects of prednisolone and cyclophosphamide.  

PubMed

Using a murine model of skin allotransplantation, we have demonstrated previously that inhibition of specific response to alloantigen is inducible by immunization of the host with intravenously administered photoinactivated antigraft effector T cells. This hyporesponsiveness, which was demonstrated by specific inhibition of mixed leukocyte culture (MLC), inhibition of cytotoxic T lympholysis (CTL), specific suppression of the delayed type hypersensitivity (DTH) response, and prolongation of specific skin allograft survival, was adoptively transferable by CD8+ radiosensitive T lymphocytes. In this study, we extend those results to evaluate the effects of an immunosuppressive agent (prednisolone) and an alkylating drug (cyclophosphamide) on the induction of this specific suppressive cellular response. Our results reveal that the administration of prednisolone reduces the induction of the specific hyporesponsiveness to alloantigen, as demonstrated by maintenance of the DTH response to alloantigen and continued accelerated rejection of skin allografts. In contrast, the administration of cyclophosphamide augmented this specific suppressive response to alloantigen in the DTH assay and in prolongation of specific skin allograft survival. These results indicate that adjuvant immunomodulating chemotherapy alters the immune response to photoinactivated effector T cells. PMID:1631919

Yamane, Y; Lobo, F M; John, L A; Edelson, R L; Perez, M I

1992-07-01

17

Vibrio parahaemolyticus Effector Proteins Suppress Inflammasome Activation by Interfering with Host Autophagy Signaling  

PubMed Central

Bacterial pathogens utilize pore-forming toxins or sophisticated secretion systems to establish infection in hosts. Recognition of these toxins or secretion system by nucleotide-binding oligomerization domain leucine-rich repeat proteins (NLRs) triggers the assembly of inflammasomes, the multiprotein complexes necessary for caspase-1 activation and the maturation of inflammatory cytokines such as IL-1? or IL-18. Here we demonstrate that both the NLRP3 and NLRC4 inflammasomes are activated by thermostable direct hemolysins (TDHs) and type III secretion system 1 (T3SS1) in response to V. parahaemolyticus infection. Furthermore, we identify T3SS1 secreted effector proteins, VopQ and VopS, which induce autophagy and the inactivation of Cdc42, respectively, to prevent mainly NLRC4 inflammasome activation. VopQ and VopS interfere with the assembly of specks in infected macrophages. These data suggest that bacterial effectors interfere with inflammasome activation and contribute to bacterial evasion from the host inflammatory responses.

Higa, Naomi; Toma, Claudia; Koizumi, Yukiko; Nakasone, Noboru; Nohara, Toshitsugu; Masumoto, Junya; Kodama, Toshio; Iida, Tetsuya; Suzuki, Toshihiko

2013-01-01

18

Targeting Effector Memory T Cells with the Small Molecule Kv1.3 Blocker PAP-1 Suppresses Allergic Contact Dermatitis  

PubMed Central

The voltage-gated potassium channel Kv1.3 has been recently identified as a molecular target that allows for selective pharmacological suppression of effector memory T (TEM) cells without affecting the function of naïve and central memory T cells. We here investigated whether PAP-1, a small molecule Kv1.3 blocker (EC50 = 2nM), could suppress allergic contact dermatitis (ACD). In a rat model of ACD, we first confirmed that the infiltrating cells in the elicitation phase are indeed CD8+ CD45RC? memory T cells with high Kv1.3 expression. In accordance with its selective effect on TEM cells, PAP-1 did not impair sensitization, but potently suppressed oxazolone-induced inflammation by inhibiting the infiltration of CD8+ T cells and reducing the production of the inflammatory cytokines IFN- ?, IL-2, and IL-17 when administered intraperitoneally or orally during the elicitation phase. PAP-1 was equally effective when applied topically, demonstrating that it effectively penetrates skin. We further show that PAP-1 is not a sensitizer or an irritant and exhibits no toxicity in a 28-day toxicity study. Based on these results we propose that PAP-1 could potentially be developed into a drug for the topical treatment of inflammatory skin diseases such as psoriasis.

Azam, Philippe; Sankaranarayanan, Ananthakrishnan; Homerick, Daniel; Griffey, Stephen; Wulff, Heike

2007-01-01

19

The 1,4-benzodiazepine Ro5-4864 (4-chlorodiazepam) suppresses multiple pro-inflammatory mast cell effector functions  

PubMed Central

Activation of mast cells (MCs) can be achieved by the high-affinity receptor for IgE (Fc?RI) as well as by additional receptors such as the lipopolysaccharide (LPS) receptor and the receptor tyrosine kinase Kit (stem cell factor [SCF] receptor). Thus, pharmacological interventions which stabilize MCs in response to different receptors would be preferable in diseases with pathological systemic MC activation such as systemic mastocytosis. 1,4-Benzodiazepines (BDZs) have been reported to suppress MC effector functions. In the present study, our aim was to analyze molecularly the effects of BDZs on MC activation by comparison of the effects of the two BDZs Ro5-4864 and clonazepam, which markedly differ in their affinities for the archetypical BDZ recognition sites, i.e., the GABAA receptor and TSPO (previously termed peripheral-type BDZ receptor). Ro5-4864 is a selective agonist at TSPO, whereas clonazepam is a selective agonist at the GABAA receptor. Ro5-4864 suppressed pro-inflammatory MC effector functions in response to antigen (Ag) (degranulation/cytokine production) and LPS and SCF (cytokine production), whereas clonazepam was inactive. Signaling pathway analyses revealed inhibitory effects of Ro5-4864 on Ag-triggered production of reactive oxygen species, calcium mobilization and activation of different downstream kinases. The initial activation of Src family kinases was attenuated by Ro5-4864 offering a molecular explanation for the observed impacts on various downstream signaling elements. In conclusion, BDZs structurally related to Ro5-4864 might serve as multifunctional MC stabilizers without the sedative effect of GABAA receptor-interacting BDZs.

2013-01-01

20

Regulatory T-cells and cAMP suppress effector T-cells independently of PKA-CREM/ICER: a potential role for Epac.  

PubMed

cAMP signalling is both a major pathway as well as a key therapeutic target for inducing immune tolerance and is involved in Treg cell (regulatory T-cell) function. To achieve potent immunoregulation, cAMP can act through several downstream effectors. One proposed mechanism is that cAMP-mediated suppression, including immunosuppression by Treg cells, results from activation of PKA (protein kinase A) leading to the induction of the transcription factor ICER (inducible cAMP early repressor). In the present study, we examined CD4+CD25- Teff cell (effector T-cell) and CD4+CD25+ Treg cell immune responses in Crem (cAMP-response-element modulator) gene-deficient mice which lack ICER (Crem-/-/ICER-deficient mice). ICER deficiency did not significantly alter the frequency or number of Treg cells and Teff cells. Treg cells or a pharmacological increase in cAMP suppressed Teff cells from Crem+/+ and Crem-/-/ICER-deficient mice to an equivalent degree, demonstrating that ICER is dispensable in these functions. Additionally, activating the cAMP effector Epac (exchange protein directly activated by cAMP) suppressed Teff cells. Treg cells expressed low levels of all cyclic nucleotide Pde (phosphodiesterase) genes tested, but high levels of Epac. These data identify ICER as a redundant mediator of Treg cells and cAMP action on Teff cells and suggest that Epac may function as an alternative effector to promote cAMP-dependent Teff cell suppression. PMID:24007532

Vang, Amanda G; Housley, William; Dong, Hongli; Basole, Chaitali; Ben-Sasson, Shlomo Z; Kream, Barbara E; Epstein, Paul M; Clark, Robert B; Brocke, Stefan

2013-12-15

21

Calcitriol suppresses antiretinal autoimmunity through inhibitory effects on the Th17 effector response.  

PubMed

Experimental autoimmune uveitis (EAU) serves as a model for human autoimmune uveitis and for cell-mediated autoimmunity in general. EAU induced in mice by immunization with the retinal Ag interphotoreceptor retinoid-binding protein in CFA is driven by the Th17 response. Oral calcitriol (1,25-dihydroxyvitamin D(3)) prevented as well as partly reversed disease and suppressed immunological responses. In vitro, calcitriol directly suppressed IL-17 induction in purified naive CD4(+) T cells without inhibiting Th17 lineage commitment, as reflected by unaltered RORgammat, STAT3, and FoxP3 expression. In contrast, in vivo treatment with calcitriol of mice challenged for EAU impaired commitment to the Th17 lineage, as judged by reduction of both RORgammat and IL-17 in CD4(+) T cells. Innate immune response parameters in draining lymph nodes of treated mice were suppressed, as was production of IL-1, IL-6, TNF-alpha, and IL-12/IL-23p40, but not IL-10, by explanted splenic dendritic cells (DC). Finally, supernatants of calcitriol-conditioned bone marrow-derived DC had reduced ability to support Th17 polarization of naive CD4(+) T cells in vitro and in vivo. Thus, calcitriol appears to suppress autoimmunity by inhibiting the Th17 response at several levels, including the ability of DC to support priming of Th17 cells, the ability of CD4(+) T cells to commit to the Th17 lineage, and the ability of committed Th17 T cells to produce IL-17. PMID:19342637

Tang, Jun; Zhou, Ru; Luger, Dror; Zhu, Wei; Silver, Phyllis B; Grajewski, Rafael S; Su, Shao-Bo; Chan, Chi-Chao; Adorini, Luciano; Caspi, Rachel R

2009-04-15

22

The Effector SPRYSEC-19 of Globodera rostochiensis Suppresses CC-NB-LRR-Mediated Disease Resistance in Plants1[C][W][OA  

PubMed Central

The potato cyst nematode Globodera rostochiensis invades roots of host plants where it transforms cells near the vascular cylinder into a permanent feeding site. The host cell modifications are most likely induced by a complex mixture of proteins in the stylet secretions of the nematodes. Resistance to nematodes conferred by nucleotide-binding-leucine-rich repeat (NB-LRR) proteins usually results in a programmed cell death in and around the feeding site, and is most likely triggered by the recognition of effectors in stylet secretions. However, the actual role of these secretions in the activation and suppression of effector-triggered immunity is largely unknown. Here we demonstrate that the effector SPRYSEC-19 of G. rostochiensis physically associates in planta with the LRR domain of a member of the SW5 resistance gene cluster in tomato (Lycopersicon esculentum). Unexpectedly, this interaction did not trigger defense-related programmed cell death and resistance to G. rostochiensis. By contrast, agroinfiltration assays showed that the coexpression of SPRYSEC-19 in leaves of Nicotiana benthamiana suppresses programmed cell death mediated by several coiled-coil (CC)-NB-LRR immune receptors. Furthermore, SPRYSEC-19 abrogated resistance to Potato virus X mediated by the CC-NB-LRR resistance protein Rx1, and resistance to Verticillium dahliae mediated by an unidentified resistance in potato (Solanum tuberosum). The suppression of cell death and disease resistance did not require a physical association of SPRYSEC-19 and the LRR domains of the CC-NB-LRR resistance proteins. Altogether, our data demonstrated that potato cyst nematodes secrete effectors that enable the suppression of programmed cell death and disease resistance mediated by several CC-NB-LRR proteins in plants.

Postma, Wiebe J.; Slootweg, Erik J.; Rehman, Sajid; Finkers-Tomczak, Anna; Tytgat, Tom O.G.; van Gelderen, Kasper; Lozano-Torres, Jose L.; Roosien, Jan; Pomp, Rikus; van Schaik, Casper; Bakker, Jaap; Goverse, Aska; Smant, Geert

2012-01-01

23

Persistent IL-10 production is required for glioma growth suppressive activity by Th1-directed effector cells after stimulation with tumor lysate-loaded dendritic cells.  

PubMed

Injection of dendritic cells (DC) pulsed with tumor antigens is a novel treatment strategy against malignancies, and aims to elicit anti-tumoral cell-mediated immune responses. We studied the in vitro proliferative responses and cytokine production in T cell cultures after 2 stimulations with autologous DC loaded with tumor lysates derived from glioblastoma multiforme (GBM) cells in the presence of recombinant interleukin (rIL)-6/rIL-12 in the first, and rIL-2/rIL-7 in the second stimulation. After the second stimulation, T cells were co-cultured with glioblastoma (GBM) cells and tumor growth suppression by T cells was assessed using a MTT assay. Although loaded DC induced a significant shift towards T helper cell type 1 (Th1) cytokine production as compared to unloaded DC, persistent interleukin (IL)-10 production by T cells both at the end of 2 stimulations with loaded DC and during the effector phase was also required for their tumor suppressive activity. A stronger glioma growth suppressive activity by T cells stimulated with tumor lysate-loaded DC than by control T cells, cultured with unloaded DC, was seen only if the relative IL-10 production after two stimulations with loaded DC was at least 40% of the IL-10 production after two stimulations with unloaded DC. If less than 40% IL-10 was produced in the experimental condition compared to the control condition, T cells also lost their tumor growth suppressive activity. Addition of rIL-10 during stimulation increased the suppressive activity on tumor cell viability and interferon (IFN)-gamma production by T cells that showed Th1 response upon stimulation with loaded DC. The data point towards the production of both IFN-gamma and IL-10 by responding effector T cells, and towards an immune modulatory rather than immune suppressive role of IL-10 to generate anti-tumoral effector T cells against GBM. PMID:17361330

De Vleeschouwer, Steven; Spencer Lopes, Isabel; Ceuppens, Jan L; Van Gool, Stefaan W

2007-09-01

24

Phytophthora infestans RXLR Effector PexRD2 Interacts with Host MAPKKK? to Suppress Plant Immune Signaling[W][OPEN  

PubMed Central

Mitogen-activated protein kinase cascades are key players in plant immune signaling pathways, transducing the perception of invading pathogens into effective defense responses. Plant pathogenic oomycetes, such as the Irish potato famine pathogen Phytophthora infestans, deliver RXLR effector proteins to plant cells to modulate host immune signaling and promote colonization. Our understanding of the molecular mechanisms by which these effectors act in plant cells is limited. Here, we report that the P. infestans RXLR effector PexRD2 interacts with the kinase domain of MAPKKK?, a positive regulator of cell death associated with plant immunity. Expression of PexRD2 or silencing MAPKKK? in Nicotiana benthamiana enhances susceptibility to P. infestans. We show that PexRD2 perturbs signaling pathways triggered by or dependent on MAPKKK?. By contrast, homologs of PexRD2 from P. infestans had reduced or no interaction with MAPKKK? and did not promote disease susceptibility. Structure-led mutagenesis identified PexRD2 variants that do not interact with MAPKKK? and fail to support enhanced pathogen growth or perturb MAPKKK? signaling pathways. Our findings provide evidence that P. infestans RXLR effector PexRD2 has evolved to interact with a specific host MAPKKK to perturb plant immunity–related signaling.

King, Stuart R.F.; McLellan, Hazel; Boevink, Petra C.; Armstrong, Miles R.; Bukharova, Tatyana; Sukarta, Octavina; Win, Joe; Kamoun, Sophien; Birch, Paul R.J.; Banfield, Mark J.

2014-01-01

25

Optimization of the End-Effector Trajectory to Suppress the Attitude Variation and Reduce Impulsive Force Simultaneously at Capturing a Target  

NASA Astrophysics Data System (ADS)

This paper is devoted to optimize the trajectory of the end-effector of space robot to suppress the attitude variation of the main body and to reduce impulsive force at capturing a target as well as to preserve the manipulability during manipulator motions. The B spline curve is applied to represent the trajectory shape. Constrained parameters of the manipulation include relative velocities and attitude between the target and the end-effector and the approach direction to the target at the capture. The knot vectors and control points of the curve at the end of the trajectory are determined to meet the constraints. By discretizing states variables, the problem is formulated as the non-linear optimization problem. The optimal trajectories for five approach directions are obtained by using Sequential Quadratic Programming (SQP) method. Effect of difference of the approaching direction on the manipulability, impulsive forces, attitude variation and optimal trajectory is investigated, and a basic strategy for planning the end-effector trajectory is discussed to conclude the present result of study.

Kojima, Hirohisa

26

Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production  

Microsoft Academic Search

Forkhead box P3 (FOXP3) is currently thought to be the most specific marker for naturally occurring CD41CD251 T regulatory cells (nTregs). In mice, expression of FoxP3 is strictly correlated with regulatory activity, whereas increasing evidence suggests that in humans, activated T effector cells (Teffs) may also express FOXP3. In order to better define the role of FOXP3 in human Teff

Sarah E. Allan; Sarah Q. Crome; Natasha K. Crellin; Laura Passerini; Theodore S. Steiner; Rosa Bacchetta; Maria G. Roncarolo; Megan K. Levings

2007-01-01

27

IL-10 directly suppresses CD4 but not CD8 T cell effector and memory responses following acute viral infection.  

PubMed

Mounting effective T cell responses is critical for eliciting long-lasting immunity following viral infection and vaccination. A multitude of inhibitory and stimulatory factors are induced following infection, and it is the compilation of these signals that quantitatively and qualitatively program the ensuing effector and memory T cell response. In response to lymphocytic choriomeningitis virus (LCMV) infection, the immunosuppressive cytokine IL-10 is rapidly up-regulated; however, how IL-10 is regulating what is often considered an "optimal" immune response is unclear. We demonstrate that IL-10 directly inhibits effector and memory CD4 T cell responses following an acutely resolved viral infection. Blockade of IL-10 enhanced the magnitude and the functional capacity of effector CD4 T cells that translated into increased and more effective memory responses. On the other hand, lack of IL-10 signaling did not impact memory CD8 T cell development. We propose that blockade of IL-10 may be an effective adjuvant to specifically enhance CD4 T cell immunity and protection following vaccination. PMID:20133700

Brooks, David G; Walsh, Kevin B; Elsaesser, Heidi; Oldstone, Michael B A

2010-02-16

28

IL-10 directly suppresses CD4 but not CD8 T cell effector and memory responses following acute viral infection  

PubMed Central

Mounting effective T cell responses is critical for eliciting long-lasting immunity following viral infection and vaccination. A multitude of inhibitory and stimulatory factors are induced following infection, and it is the compilation of these signals that quantitatively and qualitatively program the ensuing effector and memory T cell response. In response to lymphocytic choriomeningitis virus (LCMV) infection, the immunosuppressive cytokine IL-10 is rapidly up-regulated; however, how IL-10 is regulating what is often considered an “optimal” immune response is unclear. We demonstrate that IL-10 directly inhibits effector and memory CD4 T cell responses following an acutely resolved viral infection. Blockade of IL-10 enhanced the magnitude and the functional capacity of effector CD4 T cells that translated into increased and more effective memory responses. On the other hand, lack of IL-10 signaling did not impact memory CD8 T cell development. We propose that blockade of IL-10 may be an effective adjuvant to specifically enhance CD4 T cell immunity and protection following vaccination.

Brooks, David G.; Walsh, Kevin B.; Elsaesser, Heidi; Oldstone, Michael B. A.

2010-01-01

29

CMPG1-dependent cell death follows perception of diverse pathogen elicitors at the host plasma membrane and is suppressed by Phytophthora infestans RXLR effector AVR3a.  

PubMed

• Little is known about how effectors from filamentous eukaryotic plant pathogens manipulate host defences. Recently, Phytophthora infestans RXLR effector AVR3a has been shown to target and stabilize host E3 ligase CMPG1, which is required for programmed cell death (PCD) triggered by INF1. We investigated the involvement of CMPG1 in PCD elicited by perception of diverse pathogen proteins, and assessed whether AVR3a could suppress each. • The role of CMPG1 in PCD events was investigated using virus-induced gene silencing, and the ability of AVR3a to suppress each was determined by transient expression of natural forms (AVR3a(KI) and AVR3a(EM)) and a mutated form, AVR3a(KI/Y147del) , which is unable to interact with or stabilize CMPG1. • PCD triggered at the host plasma membrane by Cf-9/Avr9, Cf-4/Avr4, Pto/AvrPto or the oomycete pathogen-associated molecular pattern (PAMP), cellulose-binding elicitor lectin (CBEL), required CMPG1 and was suppressed by AVR3a, but not by the AVR3a(KI/Y147del) mutant. Conversely, PCD triggered by nucleotide-binding site-leucine-rich repeat (NBS-LRR) proteins R3a, R2 and Rx was independent of CMPG1 and unaffected by AVR3a. • CMPG1-dependent PCD follows perception of diverse pathogen elicitors externally or in association with the inner surface of the host plasma membrane. We argue that AVR3a targets CMPG1 to block initial signal transduction/regulatory processes following pathogen perception at the plasma membrane. PMID:21348873

Gilroy, Eleanor M; Taylor, Rosalind M; Hein, Ingo; Boevink, Petra; Sadanandom, Ari; Birch, Paul R J

2011-05-01

30

Autonomous translocation and intracellular trafficking of the cell-penetrating and immune-suppressive effector protein YopM.  

PubMed

Extracellular Gram-negative pathogenic bacteria target essential cytoplasmic processes of eukaryotic cells by using effector protein delivery systems such as the type III secretion system (T3SS). These secretion systems directly inject effector proteins into the host cell cytoplasm. Among the T3SS-dependent Yop proteins of pathogenic Yersinia, the function of the effector protein YopM remains enigmatic. In a recent study, we demonstrated that recombinant YopM from Yersinia enterocolitica enters host cells autonomously without the presence of bacteria and thus identified YopM as a novel bacterial cell-penetrating protein. Following entry YopM down-regulates expression of pro-inflammatory cytokines such as tumor necrosis factor ?. These properties earmark YopM for further development as a novel anti-inflammatory therapeutic. To elucidate the uptake and intracellular targeting mechanisms of this bacterial cell-penetrating protein, we analyzed possible routes of internalization employing ultra-cryo electron microscopy. Our results reveal that under physiological conditions, YopM enters cells predominantly by exploiting endocytic pathways. Interestingly, YopM was detected free in the cytosol and inside the nucleus. We could not observe any colocalization of YopM with secretory membranes, which excludes retrograde transport as the mechanism for cytosolic release. However, our findings indicate that direct membrane penetration and/or an endosomal escape of YopM contribute to the cytosolic and nuclear localization of the protein. Surprisingly, even when endocytosis is blocked, YopM was found to be associated with endosomes. This suggests an intracellular endosome-associated transport of YopM. PMID:23835836

Scharnert, Julia; Greune, Lilo; Zeuschner, Dagmar; Lubos, Marie-Luise; Alexander Schmidt, M; Rüter, Christian

2013-12-01

31

The Magnaporthe oryzae Effector AvrPiz-t Targets the RING E3 Ubiquitin Ligase APIP6 to Suppress Pathogen-Associated Molecular Pattern-Triggered Immunity in Rice[W][OA  

PubMed Central

Although the functions of a few effector proteins produced by bacterial and oomycete plant pathogens have been elucidated in recent years, information for the vast majority of pathogen effectors is still lacking, particularly for those of plant-pathogenic fungi. Here, we show that the avirulence effector AvrPiz-t from the rice blast fungus Magnaporthe oryzae preferentially accumulates in the specialized structure called the biotrophic interfacial complex and is then translocated into rice (Oryza sativa) cells. Ectopic expression of AvrPiz-t in transgenic rice suppresses the flg22- and chitin-induced generation of reactive oxygen species (ROS) and enhances susceptibility to M. oryzae, indicating that AvrPiz-t functions to suppress pathogen-associated molecular pattern (PAMP)-triggered immunity in rice. Interaction assays show that AvrPiz-t suppresses the ubiquitin ligase activity of the rice RING E3 ubiquitin ligase APIP6 and that, in return, APIP6 ubiquitinates AvrPiz-t in vitro. Interestingly, agroinfection assays reveal that AvrPiz-t and AvrPiz-t Interacting Protein 6 (APIP6) are both degraded when coexpressed in Nicotiana benthamiana. Silencing of APIP6 in transgenic rice leads to a significant reduction of flg22-induced ROS generation, suppression of defense-related gene expression, and enhanced susceptibility of rice plants to M. oryzae. Taken together, our results reveal a mechanism in which a fungal effector targets the host ubiquitin proteasome system for the suppression of PAMP-triggered immunity in plants.

Park, Chan-Ho; Chen, Songbiao; Shirsekar, Gautam; Zhou, Bo; Khang, Chang Hyun; Songkumarn, Pattavipha; Afzal, Ahmed J.; Ning, Yuese; Wang, Ruyi; Bellizzi, Maria; Valent, Barbara; Wang, Guo-Liang

2012-01-01

32

Regulatory T Lymphocytes from ALS Mice Suppress Microglia and Effector T Lymphocytes Through Different Cytokine-Mediated Mechanisms  

PubMed Central

Activated microglia and infiltrating lymphocytes are neuropathological hallmarks of amyotrophic lateral sclerosis (ALS), a fatal motoneuron disease. Although both cell types play pivotal roles in the ALS pathogenic process, the interactions between microglia and lymphocytes, specifically regulatory CD4+CD25High T lymphocytes (Tregs) and cytotoxic CD4+CD25? T lymphocytes (Teffs), have not been addressed. When co-cultured with mSOD1 adult microglia, mSOD1 Tregs suppressed the cytotoxic microglial factors NOX2 and iNOS through an IL-4-mediated mechanism, whereas Teffs were only minimally effective; IL-4 inhibitory antibodies blocked the suppressive function of mSOD1 Tregs, and conditioned media from mSOD1 Tregs or the addition of IL-4 reduced microglial NOX2 expression. During the stable disease phase, the total number of Tregs, specifically the numbers of CD4+CD25HighIL-4+, CD4+CD25HighIL-10+ and CD4+CD25HighTGF-?+ Tregs, were increased in ALS mice compared with WT mice; Tregs isolated during this phase reduced Teffs proliferation. In contrast, during the rapidly progressing phase, the number of mSOD1 Tregs decreased while the proliferation of mSOD1 Teffs increased. The combination of IL-4, IL-10, and TGF-? was required to inhibit the proliferation of mSOD1 Teffs by mSOD1 Tregs that were isolated during the slow phase, while inhibition of mSOD1 Teffs by mSOD1 Tregs during the rapid phase, as well as WT Teffs, was not dependent on these factors. Thus, mSOD1 Tregs at the slow phase suppressed microglial toxicity and SOD1 Teffs proliferation through different mechanisms; microglial activation was suppressed through IL-4 whereas mSOD1 Teffs were suppressed by IL-4, IL-10 and TGF-?. These data suggest that mSOD1 Tregs contribute to the slowly progressing phase in ALS mice and may offer a novel therapeutic option for ALS patients.

Zhao, Weihua; Beers, David R.; Liao, Bing; Henkel, Jenny S.; Appel, Stanley H.

2012-01-01

33

Regulatory T lymphocytes from ALS mice suppress microglia and effector T lymphocytes through different cytokine-mediated mechanisms.  

PubMed

Activated microglia and infiltrating lymphocytes are neuropathological hallmarks of amyotrophic lateral sclerosis (ALS), a fatal motoneuron disease. Although both cell types play pivotal roles in the ALS pathogenic process, the interactions between microglia and lymphocytes, specifically regulatory CD4+CD25High T lymphocytes (Tregs) and cytotoxic CD4+CD25- T lymphocytes (Teffs), have not been addressed. When co-cultured with mSOD1 adult microglia, mSOD1 Tregs suppressed the cytotoxic microglial factors NOX2 and iNOS through an IL-4-mediated mechanism, whereas Teffs were only minimally effective; IL-4 inhibitory antibodies blocked the suppressive function of mSOD1 Tregs, and conditioned media from mSOD1 Tregs or the addition of IL-4 reduced microglial NOX2 expression. During the stable disease phase, the total number of Tregs, specifically the numbers of CD4+CD25HighIL-4+, CD4+CD25HighIL-10+ and CD4+CD25HighTGF-?+ Tregs, were increased in ALS mice compared with WT mice; Tregs isolated during this phase reduced Teff proliferation. In contrast, during the rapidly progressing phase, the number of mSOD1 Tregs decreased while the proliferation of mSOD1 Teffs increased. The combination of IL-4, IL-10, and TGF-? was required to inhibit the proliferation of mSOD1 Teffs by mSOD1 Tregs that were isolated during the slow phase, while inhibition of mSOD1 Teffs by mSOD1 Tregs during the rapid phase, as well as WT Teffs, was not dependent on these factors. Thus, mSOD1 Tregs at the slow phase suppressed microglial toxicity and SOD1 Teff proliferation through different mechanisms; microglial activation was suppressed through IL-4 whereas mSOD1 Teffs were suppressed by IL-4, IL-10 and TGF-?. These data suggest that mSOD1 Tregs contribute to the slowly progressing phase in ALS mice and may offer a novel therapeutic option for ALS patients. PMID:22820142

Zhao, Weihua; Beers, David R; Liao, Bing; Henkel, Jenny S; Appel, Stanley H

2012-12-01

34

The interaction of the novel 30C02 cyst nematode effector protein with a plant ?-1,3-endoglucanase may suppress host defence to promote parasitism  

PubMed Central

Phytoparasitic nematodes secrete an array of effector proteins to modify selected recipient plant cells into elaborate and essential feeding sites. The biological function of the novel 30C02 effector protein of the soybean cyst nematode, Heterodera glycines, was studied using Arabidopsis thaliana as host and the beet cyst nematode, Heterodera schachtii, which contains a homologue of the 30C02 gene. Expression of Hg30C02 in Arabidopsis did not affect plant growth and development but increased plant susceptibility to infection by H. schachtii. The 30C02 protein interacted with a specific (AT4G16260) host plant ?-1,3-endoglucanase in both yeast and plant cells, possibly to interfere with its role as a plant pathogenesis-related protein. Interestingly, the peak expression of 30C02 in the nematode and peak expression of At4g16260 in plant roots coincided at around 3–5 d after root infection by the nematode, after which the relative expression of At4g16260 declined significantly. An Arabidopsis At4g16260 T-DNA mutant showed increased susceptibility to cyst nematode infection, and plants that overexpressed At4g16260 were reduced in nematode susceptibility, suggesting a potential role of host ?-1,3-endoglucanase in the defence response against H. schachtii infection. Arabidopsis plants that expressed dsRNA and its processed small interfering RNA complementary to the Hg30C02 sequence were not phenotypically different from non-transformed plants, but they exhibited a strong RNA interference-mediated resistance to infection by H. schachtii. The collective results suggest that, as with other pathogens, active suppression of host defence is a critical component for successful parasitism by nematodes and a vulnerable target to disrupt the parasitic cycle.

Hamamouch, Noureddine; Hewezi, Tarek; Baum, Thomas J.; Mitchum, Melissa G.; Hussey, Richard S.; Vodkin, Lila O.; Davis, Eric L.

2012-01-01

35

TLR2 ligation protects effector T cells from regulatory T-cell mediated suppression and repolarizes T helper responses following MVA-based cancer immunotherapy.  

PubMed

Cancer immunotherapy is hampered by the immunosuppression maintained by regulatory T cells (Tregs) in tumor-bearing hosts. Stimulation of the Toll-like receptor 2 (TLR2) by Pam3Cys is known to affect Treg-mediated suppression. We found that Pam3Cys increases the proliferation of both CD4(+) effector T cells (Teffs) and Tregs co-cultured in vitro, but did not induce the proliferation of Tregs alone upon CD3 and CD28 stimulation. In a mouse model of RMA-MUC1 tumors, Pam3Cys was administered either alone or in combination with a modified vaccinia ankara (MVA)-based mucin 1 (MUC1) therapeutic vaccine. The combination of Pam3Cys with MVA-MUC1 (1) diminished splenic Treg/CD4(+) T-cell ratios to those found in tumor-free mice, (2) stimulated a specific anti-MUC1 interferon ? (IFN?) response and (3) had a significant therapeutic effect on tumor growth and mouse survival. When CD4(+) Teffs and Tregs were isolated from Pam3Cys-treated mice, Teffs had become resistant to Treg-mediated suppression while upregulating the expression of BclL-x(L). Tregs from Pam3Cys-treated mice were fully suppressive for Teffs from naïve mice. Bcl-x(L) was induced by Pam3Cys with different kinetics in Tregs and Teffs. Teff from Pam3Cys-treated mice produced increased levels of Th1 and Th2-type cytokines and an interleukin (IL)-6-dependent secretion of IL-17 was observed in Teff:Treg co-cultures, suggesting that TLR2 stimulation had skewed the immune response toward a Th17 profile. Our results show for the first time that in a tumor-bearing host, TLR2 stimulation with Pam3Cys affects both Tregs and Teffs, protects Teff from Treg-mediated suppression and has strong therapeutic effects when combined with an MVA-based antitumor vaccine. PMID:23243590

Amiset, Laurent; Fend, Laetitia; Gatard-Scheikl, Tania; Rittner, Karola; Duong, Vanessa; Rooke, Ronald; Muller, Sylviane; Bonnefoy, Jean-Yves; Préville, Xavier; Haegel, Hélène

2012-11-01

36

Silymarin inhibits ultraviolet radiation-induced immune suppression through DNA repair-dependent activation of dendritic cells and stimulation of effector T cells  

PubMed Central

Silymarin inhibits UVB-induced immunosuppression in mouse skin. To identify the molecular mechanisms underlying this effect, we used an adoptive transfer approach in which dendritic cells (DCs) from the draining lymph nodes of donor mice that had been UVB-exposed and sensitized to 2,4,-dinitrofluorobenzene (DNFB) were transferred into naïve recipient mice. The contact hypersensitivity (CHS) response of the recipient mice to DNFB was then measured. When DCs were obtained from UVB-exposed donor mice that were not treated with silymarin, the CHS response was suppressed confirming the role of DCs in the UVB-induced immunosuppression. Silymarin treatment of UVB-exposed donor mice relieved this suppression of the CHS response in the recipients. Silymarin treatment was associated with rapid repair of UVB-induced cyclobutane pyrimidine dimers (CPDs) in DCs and silymarin treatment did not prevent UV-induced immunosuppression in XPA-deficient mice which are unable to repair UV-induced DNA damage. The CHS response in mice receiving DCs from silymarin-treated UV-exposed donor mice also was associated with enhanced secretion of Th1-type cytokines and stimulation of T cells. Adoptive transfer of T cells revealed that transfer of either CD8+ or CD4+ cells from silymarin-treated, UVB-exposed donors resulted in enhancement of the CHS response. Cell culture study showed enhanced secretion of IL-2 and IFN? by CD8+ T cells, and reduced secretion of Th2 cytokines by CD4+ cells, obtained from silymarin-treated UVB-exposed mice. These data suggest that DNA repair-dependent functional activation of DCs, a reduction in CD4+ regulatory T-cell activity, and stimulation of CD8+ effector T cells contribute to silymarin-mediated inhibition of UVB-induced immunosuppression.

Vaid, Mudit; Prasad, Ram; Singh, Tripti; Elmets, Craig A.; Xu, Hui; Katiyar, Santosh K.

2013-01-01

37

Effector-Mediated Suppression of Chitin-Triggered Immunity by Magnaporthe oryzae Is Necessary for Rice Blast Disease[C][W  

PubMed Central

Plants use pattern recognition receptors to defend themselves from microbial pathogens. These receptors recognize pathogen-associated molecular patterns (PAMPs) and activate signaling pathways that lead to immunity. In rice (Oryza sativa), the chitin elicitor binding protein (CEBiP) recognizes chitin oligosaccharides released from the cell walls of fungal pathogens. Here, we show that the rice blast fungus Magnaporthe oryzae overcomes this first line of plant defense by secreting an effector protein, Secreted LysM Protein1 (Slp1), during invasion of new rice cells. We demonstrate that Slp1 accumulates at the interface between the fungal cell wall and the rice plasma membrane, can bind to chitin, and is able to suppress chitin-induced plant immune responses, including generation of reactive oxygen species and plant defense gene expression. Furthermore, we show that Slp1 competes with CEBiP for binding of chitin oligosaccharides. Slp1 is required by M. oryzae for full virulence and exerts a significant effect on tissue invasion and disease lesion expansion. By contrast, gene silencing of CEBiP in rice allows M. oryzae to cause rice blast disease in the absence of Slp1. We propose that Slp1 sequesters chitin oligosaccharides to prevent PAMP-triggered immunity in rice, thereby facilitating rapid spread of the fungus within host tissue.

Mentlak, Thomas A.; Kombrink, Anja; Shinya, Tomonori; Ryder, Lauren S.; Otomo, Ippei; Saitoh, Hiromasa; Terauchi, Ryohei; Nishizawa, Yoko; Shibuya, Naoto; Thomma, Bart P.H.J.; Talbot, Nicholas J.

2012-01-01

38

The Xanthomonas campestris Type III Effector XopJ Targets the Host Cell Proteasome to Suppress Salicylic-Acid Mediated Plant Defence  

PubMed Central

The phytopathogenic bacterium Xanthomonas campestris pv. vesicatoria (Xcv) requires type III effector proteins (T3Es) for virulence. After translocation into the host cell, T3Es are thought to interact with components of host immunity to suppress defence responses. XopJ is a T3E protein from Xcv that interferes with plant immune responses; however, its host cellular target is unknown. Here we show that XopJ interacts with the proteasomal subunit RPT6 in yeast and in planta to inhibit proteasome activity. A C235A mutation within the catalytic triad of XopJ as well as a G2A exchange within the N-terminal myristoylation motif abolishes the ability of XopJ to inhibit the proteasome. Xcv ?xopJ mutants are impaired in growth and display accelerated symptom development including tissue necrosis on susceptible pepper leaves. Application of the proteasome inhibitor MG132 restored the ability of the Xcv ?xopJ to attenuate the development of leaf necrosis. The XopJ dependent delay of tissue degeneration correlates with reduced levels of salicylic acid (SA) and changes in defence- and senescence-associated gene expression. Necrosis upon infection with Xcv ?xopJ was greatly reduced in pepper plants with reduced expression of NPR1, a central regulator of SA responses, demonstrating the involvement of SA-signalling in the development of XopJ dependent phenotypes. Our results suggest that XopJ-mediated inhibition of the proteasome interferes with SA-dependent defence response to attenuate onset of necrosis and to alter host transcription. A central role of the proteasome in plant defence is discussed.

Bornke, Frederik

2013-01-01

39

Tolerance induced by anti-DNA Ig peptide in (NZB x NZW)F1 lupus mice impinges on the resistance of effector T cells to suppression by regulatory T cells  

PubMed Central

We have previously shown that immune tolerance induced by the anti-DNA Ig peptide pCons in (NZB × NZW)F1 (NZB/W) lupus mice prolonged survival of treated animals and delayed the appearance of autoantibodies and glomerulonephritis. Part of the protection conferred by pCons could be ascribed to the induction of regulatory T cells (TReg) that suppressed the production of anti-DNA antibodies in a p38 MAPK-dependent fashion. Here we show that another effect of pCons in the induction of immune tolerance in NZB/W lupus mice is the facilitation of effector T cell suppression by TReg. These new findings indicate that pCons exerts protective effects in NZB/W lupus mice by differentially modulating the activity of different T cell subsets, implying new considerations in the design of TReg–based approaches to modulate T cell autoreactivity in SLE.

Yu, Yiyun; Liu, Yaoyang; Shi, Fu-Dong; Zou, Hejian; Hahn, Bevra H.; Cava, Antonio La

2011-01-01

40

High Titers of Circulating Maternal Antibodies Suppress Effector and Memory B-Cell Responses Induced by an Attenuated Rotavirus Priming and Rotavirus-Like Particle-Immunostimulating Complex Boosting Vaccine Regimen  

PubMed Central

We investigated maternal antibody (MatAb) effects on protection and immune responses to rotavirus vaccines. Gnotobiotic pigs were injected intraperitoneally at birth with pooled serum from sows hyperimmunized with human rotavirus (HRV); control pigs received no sow serum. Pigs with or without MatAbs received either sequential attenuated HRV (AttHRV) oral priming and intranasal boosting with VP2/VP6 virus-like particle (VLP)-immunostimulating complex (ISCOM) (AttHRV/VLP) or intranasal VLP-ISCOM prime/boost (VLP) vaccines at 3 to 5 days of age. Subsets of pigs were challenged at 28 or 42 days postinoculation with virulent Wa HRV to assess protection. Isotype-specific antibody-secreting cell (ASC) responses to HRV were quantitated by enzyme-linked immunospot assay to measure effector and memory B-cell responses in intestinal and systemic lymphoid tissues pre- and/or postchallenge. Protection rates against HRV challenge (contributed by active immunity and passive circulating MatAbs) were consistently (but not significantly) lower in the MatAb-AttHRV/VLP groups than in the corresponding groups without MatAbs. Intestinal B-cell responses in the MatAb-AttHRV/VLP group were most suppressed with significantly reduced or no intestinal immunoglobulin A (IgA) and IgG effector and memory B-cell responses or antibody titers pre- and postchallenge. This suppression was not alleviated but was enhanced after extending vaccination/challenge from 28 to 42 days. In pigs vaccinated with nonreplicating VLP alone that failed to induce protection, MatAb effects differed, with intestinal and systemic IgG ASCs and prechallenge memory B cells suppressed but the low intestinal IgA and IgM ASC responses unaffected. Thus, we demonstrate that MatAbs differentially affect both replicating and nonreplicating HRV vaccines and suggest mechanisms of MatAb interference. This information should facilitate vaccine design to overcome MatAb suppression.

Nguyen, Trang V.; Yuan, Lijuan; Azevedo, Marli S. P.; Jeong, Kwang-il; Gonzalez, Ana M.; Iosef, Cristiana; Lovgren-Bengtsson, Karin; Morein, Bror; Lewis, Peggy; Saif, Linda J.

2006-01-01

41

Myeloid Dendritic Cells (DCs) of Mice Susceptible to Paracoccidioidomycosis Suppress T Cell Responses whereas Myeloid and Plasmacytoid DCs from Resistant Mice Induce Effector and Regulatory T Cells  

PubMed Central

The protective adaptive immune response in paracoccidioidomycosis, a mycosis endemic among humans, is mediated by T cell immunity, whereas impaired T cell responses are associated with severe, progressive disease. The early host response to Paracoccidioides brasiliensis infection is not known since the disease is diagnosed at later phases of infection. Our laboratory established a murine model of infection where susceptible mice reproduce the severe disease, while resistant mice develop a mild infection. This work aimed to characterize the influence of dendritic cells in the innate and adaptive immunity of susceptible and resistant mice. We verified that P. brasiliensis infection induced in bone marrow-derived dendritic cells (DCs) of susceptible mice a prevalent proinflammatory myeloid phenotype that secreted high levels of interleukin-12 (IL-12), tumor necrosis factor alpha, and IL-?, whereas in resistant mice, a mixed population of myeloid and plasmacytoid DCs secreting proinflammatory cytokines and expressing elevated levels of secreted and membrane-bound transforming growth factor ? was observed. In proliferation assays, the proinflammatory DCs from B10.A mice induced anergy of naïve T cells, whereas the mixed DC subsets from resistant mice induced the concomitant proliferation of effector and regulatory T cells (Tregs). Equivalent results were observed during pulmonary infection. The susceptible mice displayed preferential expansion of proinflammatory myeloid DCs, resulting in impaired proliferation of effector T cells. Conversely, the resistant mice developed myeloid and plasmacytoid DCs that efficiently expanded gamma interferon-, IL-4-, and IL-17-positive effector T cells associated with increased development of Tregs. Our work highlights the deleterious effect of excessive innate proinflammatory reactions and provides new evidence for the importance of immunomodulation during pulmonary paracoccidioidomycosis.

Pina, Adriana; Frank de Araujo, Eliseu; Felonato, Maira; Loures, Flavio V.; Feriotti, Claudia; Bernardino, Simone; Barbuto, Jose Alexandre M.

2013-01-01

42

The cyclin dependent kinase inhibitor (R)-roscovitine mediates selective suppression of alloreactive human T cells but preserves pathogen-specific and leukemia-specific effectors.  

PubMed

Graft versus host disease (GvHD), mediated by donor T cells, remains the primary cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation and novel therapeutic approaches are required. Cdk2 is a critical node of signal integration and programming of T cell responses towards immunity versus anergy but is dispensable for hematopoiesis and thymocyte development. We examined the effects of pharmacologic Cdk2 inhibition on alloreactive human T cells. Inhibition of Cdk2 blocked expansion of alloreactive T cells upon culture with HLA-mismatched dendritic cells and prevented generation of IFN-?-producing alloantigen-specific effectors. In contrast, Cdk2 inhibition preserved effectors specific for Wilms' tumor 1 (WT1) leukemia antigen and for CMV as determined by WT1-specific and CMV-specific pentamers. Cdk2 inhibition preserved Treg cells, which have the ability to prevent GvHD while maintaining GvL. Thus, Cdk inhibitors may improve allogeneic HSCT by reducing alloreactivity and GvHD without loss of pathogen-specific and leukemia-specific immunity. PMID:24631965

Nellore, Anoma; Liu, Bianling; Patsoukis, Nikolaos; Boussiotis, Vassiliki A; Li, Lequn

2014-01-01

43

[Effector proteins of Clamidia].  

PubMed

The review summarizes the recent published data on molecular mechanisms of Chlamidiae - host cell interaction, first of all on chlamydial effector proteins. Such proteins as well as III transport system proteins that transfer many effector proteins into host cytoplasm are attractive targets for drug therapy of chlamydial infections. The majority of the data concerns two species, Chlamydia trachomatis and Chlamydophila pneumoniae. C. trachomatis protein TARP, which is presynthesized in elementary bodies, plays an essential role in the initial stages of the infection. Patogen proteins participating in the next stage, that is the intracellular inclusion traffic to the centrosome, are CT229 of C. trachomatis and Cpn0585 of C. pneumoniae, which interact with cellular Rab GTPases. In C. trachomatis, IncA protein plays a key role in chlamydial inclusions fusion, CT847 modulates life cycle of the host cell, LDA3 is essential in acquisition of nutrients. CPAF protease and inclusion membrane proteins IncG and CADD participate in suppression of apoptosis of infected cells. The proteases CPAF and CT441, as well as deubiquitinating ChlaDub1 protein, contribute to avoiding the immune response. PMID:20088373

Kariagina, A S; Alekseevski?, A V; Spirin, S A; Zigangirova, N A; Gintsburg, A L

2009-01-01

44

CpG DNA inhibits CD4+CD25+ Treg suppression through direct MyD88-dependent costimulation of effector CD4+ T cells  

Microsoft Academic Search

Toll-like receptor (TLR) ligands are notable for their ability to induce APC maturation, which in turn facilitates optimal T cell mediated immune responses. Toll-like receptor ligands, such as CpG DNA, can also modulate immune responses by blocking the suppressive effects of CD4+CD25+ regulatory T cells (Tregs). Recently, we have demonstrated that CpG DNA, in addition to its actions on APCs

David F. LaRosa; Andrew E. Gelman; Adeeb H. Rahman; Jidong Zhang; Laurence A. Turka; Patrick T. Walsh

2007-01-01

45

Levels of Human Immunodeficiency Virus Type 1Specific Cytotoxic T-Lymphocyte Effector and Memory Responses Decline after Suppression of Viremia with Highly Active Antiretroviral Therapy  

Microsoft Academic Search

Therapeutic suppression of human immunodeficiency virus type 1 (HIV-1) replication may help elucidate interactions between the host cellular immune responses and HIV-1 infection. We performed a detailed longitudinal evaluation of two subjects before and after the start of highly active antiretroviral therapy (HAART). Both subjects had evidence of in vivo-activated and memory cytotoxic T-lymphocyte precursor (CTLp) activity against multiple HIV-1

SPYROS A. KALAMS; PHILIP J. GOULDER; AMY K. SHEA; NORMAN G. JONES; ALICJA K. TROCHA; GRAHAM S. OGG; BRUCE D. WALKER

1999-01-01

46

XopR, a type III effector secreted by Xanthomonas oryzae pv. oryzae, suppresses microbe-associated molecular pattern-triggered immunity in Arabidopsis thaliana.  

PubMed

Xanthomonas oryzae pv. oryzae is the causal agent of bacterial blight of rice. The XopR protein, secreted into plant cells through the type III secretion apparatus, is widely conserved in xanthomonads and is predicted to play important roles in bacterial pathogenicity. Here, we examined the function of XopR by constructing transgenic Arabidopsis thaliana plants expressing it under control of the dexamethasone (DEX)-inducible promoter. In the transgenic plants treated with DEX, slightly delayed growth and variegation on leaves were observed. Induction of four microbe-associated molecular pattern (MAMP)-specific early-defense genes by a nonpathogenic X. campestris pv. campestris hrcC deletion mutant were strongly suppressed in the XopR-expressing plants. XopR expression also reduced the deposition of callose, an immune response induced by flg22. When transiently expressed in Nicotiana benthamiana, a XopR::Citrine fusion gene product localized to the plasma membrane. The deletion of XopR in X. oryzae pv. oryzae resulted in reduced pathogenicity on host rice plants. Collectively, these results suggest that XopR inhibits basal defense responses in plants rapidly after MAMP recognition. PMID:22204644

Akimoto-Tomiyama, Chiharu; Furutani, Ayako; Tsuge, Seiji; Washington, Erica J; Nishizawa, Yoko; Minami, Eiichi; Ochiai, Hirokazu

2012-04-01

47

Gene transfer of human interferon gamma complementary DNA into a renal cell carcinoma line enhances MHC-restricted cytotoxic T lymphocyte recognition but suppresses non-MHC-restricted effector cell activity.  

PubMed

Even though renal cell carcinomas (RCC) are thought to be immunogenic, many tumors express variations in surface molecules and intracellular proteins that hinder induction of optimal antitumor responses. Interferon gamma (IFNgamma) stimulation can correct some of these deficiencies. Therefore, we introduced the complementary DNA (cDNA) encoding human IFNgamma into a well-characterized RCC line that has been selected for development of an allogeneic tumor cell vaccine for treatment of patients with metastatic disease. Studies were performed to determine how endogenous IFNgamma expression influences tumor cell immunogenicity. IFNgamma transductants showed minimal increases in surface expression of MHC class I and adhesion molecules but expression of class II molecules was induced. Proteins of the transporter associated with antigen processing (TAP) and low molecular weight polypeptide (LMP) were constitutively expressed at high levels. The transductants stimulated allospecific cytotoxic T lymphocytes (CTL); however, they were not better than unmodified tumor cells in this capacity. Endogenous IFNgamma expression enhanced tumor cell recognition by MHC-restricted, tumor antigen-specific CTL but suppressed recognition by non-MHC-restricted cytotoxic cells. Thus, the functional consequences of IFNgamma expression varied with respect to the type of effector cell and were not always beneficial for tumor cell recognition. PMID:10849555

Schendel, D J; Falk, C S; Nössner, E; Maget, B; Kressenstein, S; Urlinger, S; Tampé, R; Gansbacher, B

2000-06-01

48

PIAS3 suppresses acute graft-versus-host disease by modulating effector T and B cell subsets through inhibition of STAT3 activation.  

PubMed

Graft-versus-host disease (GVHD) caused by transplanted donor T cells remains the major obstacle of allogeneic bone marrow transplantation (BMT). Previous reports have suggested that IL-17-producing helper T (Th17) cells mediate the development of acute GVHD (aGVHD). Protein inhibitor of activated STAT3 (PIAS) inhibits the activity of the transcription factor STAT3, which is a pivotal transcription factor for Th17 differentiation. To elucidate whether PIAS3 could inhibit the development of aGVHD, pcDNA-PIAS3 or mock vector was administered in a murine model of aGVHD by intramuscular injection and subsequent electroporation. The results demonstrated that PIAS3 overexpression by pcDNA-vector administration significantly attenuated the clinical severity and histopathological severities of aGHVD involving the skin, liver, intestine, and lung. Additionally, the STAT3 activities in aGVHD target organs were suppressed by PIAS3 overexpression. Furthermore, phosphorylated (p) STAT3 activity in the spleen was profoundly attenuated in PIAS3-overexpressing GVHD mice. Interestingly, flow cytometric analysis demonstrated that the populations of CD21(high)CD23(low) marginal zone B cells were dramatically expanded in PIAS3-overexpressing mice. PIAS3-induced inhibition of aGVHD was largely related to the downregulation of Th1 and Th17 and the upregulation of Th2 and Treg populations. Both populations of pSTAT3(Tyr705)-expressing Th17 cells and B cells were significantly reduced in the spleens of PIAS3-overexpressing mice, whereas pSTAT5 activity was increased. In addition to CD4(+)CD25(+)Foxp3(+) Treg cells, the populations of CD8(+)CD25(+)Foxp3(+) Treg cells were also expanded by treatment with PIAS3. These data suggest the therapeutic potential of PIAS3 in the development of aGVHD through reciprocal regulation of Th17/Treg lineages. PMID:24718277

Lee, Sung-Hee; Moon, Su-Jin; Park, Min-Jung; Kim, Eun-Kyung; Moon, Young-Mee; Cho, Mi-La

2014-07-01

49

Translocated effectors of Yersinia  

PubMed Central

Summary Currently, all known translocated effectors of Yersinia are delivered into host cells by type III secretion systems (T3SSs). Pathogenic Yersinia maintain the plasmid-encoded Ysc T3SS for the specific delivery of the well-studied Yop effectors. New horizons for effector biology have opened with the discovery of the Ysps of Y. enterocolitica Biovar 1B, which are translocated into host cells by the chromosome-endoded Ysa T3SS. The reported arsenal of effectors is likely to expand since genomic analysis has revealed gene-clusters in some Yersinia that code for other T3SSs. These efforts also revealed possible type VI secretion (T6S) systems, which may indicate translocation of effectors occurs by multiple mechanisms.

Matsumoto, Hiroyuki; Young, Glenn M.

2009-01-01

50

Advanced Aerodynamic Control Effectors  

NASA Technical Reports Server (NTRS)

A 1990 research program that focused on the development of advanced aerodynamic control effectors (AACE) for military aircraft has been reviewed and summarized. Data are presented for advanced planform, flow control, and surface contouring technologies. The data show significant increases in lift, reductions in drag, and increased control power, compared to typical aerodynamic designs. The results presented also highlighted the importance of planform selection in the design of a control effector suite. Planform data showed that dramatic increases in lift (greater than 25%) can be achieved with multiple wings and a sawtooth forebody. Passive porosity and micro drag generator control effector data showed control power levels exceeding that available from typical effectors (moving surfaces). Application of an advanced planform to a tailless concept showed benefits of similar magnitude as those observed in the generic studies.

Wood, Richard M.; Bauer, Steven X. S.

1999-01-01

51

Orbital Maneuvering End Effectors.  

National Technical Information Service (NTIS)

This invention relates to an end effector device for grasping and maneuvering objects such as berthing handles of a space telescope. The device includes a V-shaped capture window defined as inclined surfaces in parallel face plates which converge toward a...

W. N. Myers J. C. Forbes W. L. Barnes

1986-01-01

52

Antibodies as effectors.  

PubMed

Antibodies are critical in protection against extracellular microbial pathogens. Although antibodies also play a role in transplant/tumor rejection and in autoimmune disease, this paper focuses on defense against bovine infections. Effector mechanisms of different bovine isotypes, subisotypes and allotypes are discussed. The importance of antigen specificity is also stressed. PMID:12072231

Corbeil, L B

2002-09-10

53

Robotic end effector  

DOEpatents

An end effector for use in probing a surface with a robotic arm. The end effector has a first portion that carries a gimbal with a probe, the gimbal holding the probe normal to the surface, and a second portion with a set of three shafts within a housing for urging the gimbal and probe against the surface. The second portion contains a potentiometer connected by another shaft to the first portion to measure the position of the first portion with respect to the second so that the second portion can be moved to place and maintain the shafts at the midpoint of their travel. Then, as irregularities in the surface are encountered, the first portion can respond by moving closer to or farther from the second portion.

Minichan, Richard L. (23 Pineview Dr., Warrenville, SC 29851)

1993-01-01

54

G Protein Effectors  

NSDL National Science Digital Library

This Teaching Resource provides lecture notes and slides for a class covering two aspects of G protein–mediated signaling and is part of the course "Cell Signaling Systems: A Course for Graduate Students." The lecture begins with a discussion of the regulation of receptor-G protein coupling and then proceeds to describe the specificity of the response achieved through regulation of specific isoforms of effectors.

Maria Diverse-Pierluissi (Mount Sinai School of Medicine;Department of Pharmacology and Biological Chemistry REV)

2005-04-26

55

Host Inhibition of a Bacterial Virulence Effector Triggers Immunity to Infection  

Microsoft Academic Search

Plant pathogenic bacteria secrete effector proteins that attack the host signaling machinery to suppress immunity. Effectors can be recognized by hosts leading to immunity. One such effector is AvrPtoB of Pseudomonas syringae, which degrades host protein kinases, such as tomato Fen, through an E3 ligase domain. Pto kinase, which is highly related to Fen, recognizes AvrPtoB in conjunction with the

Vardis Ntoukakis; Tatiana S. Mucyn; Selena Gimenez-Ibanez; Helen C. Chapman; Jose R. Gutierrez; Alexi L. Balmuth; Alexandra M. E. Jones; John P. Rathjen

2009-01-01

56

T Cell Signaling Targets for Enhancing Regulatory or Effector Function  

NSDL National Science Digital Library

To respond to infection, resting or naïve T cells must undergo activation, clonal expansion, and differentiation into specialized functional subsets of effector T cells. However, to prevent excessive or self-destructive immune responses, regulatory T cells (Tregs) are instrumental in suppressing the activation and function of effector cells, including effector T cells. The transcription factor Forkhead box P3 (Foxp3) regulates the expression of genes involved in the development and function of Tregs. Foxp3 interacts with other transcription factors and with epigenetic elements such as histone deacetylases (HDACs) and histone acetyltransferases. Treg suppressive function can be increased by exposure to HDAC inhibitors. The individual contributions of different HDAC family members to Treg function and their respective mechanisms of action, however, remain unclear. A study showed that HDAC6, HDAC9, and Sirtuin-1 had distinct effects on Foxp3 expression and function, suggesting that selectively targeting HDACs individually or in combination may enhance Treg stability and suppressive function. Another study showed that the receptor programmed death 1 (PD-1), a well-known inhibitor of T cell activation, halted cell cycle progression in effector T cells by inhibiting the transcription of the gene encoding the substrate-recognition component (Skp2) of the ubiquitin ligase SCFSkp2. Together, these findings reveal new signaling targets for enhancing Treg or effector T cell function that may be helpful in designing future therapies, either to increase Treg suppressive function in transplantation and autoimmune diseases or to block PD-1 function, thus increasing the magnitude of antiviral or antitumor immune responses of effector T cells.

Fan Pan (Johns Hopkins University School of Medicine;Department of Oncology REV); Huimin Fan (Shanghai;Shanghai East Hospital of Tongji University REV); Zhongmin Liu (Shanghai;Shanghai East Hospital of Tongji University REV); Shuiping Jiang (Shanghai;Shanghai East Hospital of Tongji University REV)

2012-07-31

57

Two-axis angular effector  

DOEpatents

A new class of coplanar two-axis angular effectors. These effectors combine a two-axis rotational joint analogous to a Cardan joint with linear actuators in a manner to produce a wider range of rotational motion about both axes defined by the joint. This new class of effectors also allows design of robotic manipulators having very high strength and efficiency. These effectors are particularly suited for remote operation in unknown surroundings, because of their extraordinary versatility. An immediate application is to the problems which arise in nuclear waste remediation.

Vaughn, Mark R. (Albuquerque, NM); Robinett, III, Rush D. (Tijeras, NM); Phelan, John R. (Albuquerque, NM); Van Zuiden, Don M. (Albuquerque, NM)

1997-01-21

58

Signaling and effector pathways.  

PubMed

There is increasing evidence that distinct signaling and effector pathways in the rheumatoid synovium result in a cascade of pathophysiologic events. These interactions, which finally lead to progressive joint destruction, are different from all other joint diseases in numerous aspects. As outlined in this review, molecular biology techniques allow detection of key pathways ranging from external stimuli to subcellular gene regulation mechanisms operative in various cells within the rheumatoid synovium. To alter these pathways, inhibitory factors need to be applied to these "hot zones" for an extended period, which can be achieved either by repeated drug administration or by local synthesis using genetically altered synovial cells. Both adenovirus and retroviral constructs, as well as ex vivo and in vivo strategies, can be used for gene transfer into these cells, and routine delivery of "protective" genes into the affected joints might be achieved within the next decade. PMID:10328579

Müller-Ladner, U; Gay, R E; Gay, S

1999-05-01

59

End Effector Coupler/Decoupler  

NASA Technical Reports Server (NTRS)

Coupling/decoupling device offers benefits of both stiffness and repositioning. Permits end effector to be released (decoupled) from robot arm while attached to workpiece, and realigned and recoupled to arm when end effector task completed. Relieves necessity for accurate positioning of robot and workpiece, and compensates for deformations initiated by changes in temperature as well as normal machining variations.

Smith, Russell W.; Rhodes, Marvin D.

1995-01-01

60

Inactivation of Effector Caspases through Nondegradative Polyubiquitylation  

PubMed Central

SUMMARY Ubiquitin-mediated inactivation of caspases has long been postulated to contribute to the regulation of apoptosis. However, detailed mechanisms and functional consequences of caspase ubiquitylation have not been demonstrated. Here we show that the Drosophila Inhibitor of Apoptosis 1, DIAP1, blocks effector caspases by targeting them for polyubiquitylation and nonproteasomal inactivation. We demonstrate that the conjugation of ubiquitin to drICE suppresses its catalytic potential in cleaving caspase substrates. Our data suggest that ubiquitin conjugation sterically interferes with substrate entry and reduces the caspase’s proteolytic velocity. Disruption of drICE ubiquitylation, either by mutation of DIAP1’s E3 activity or drICE’s ubiquitin-acceptor lysines, abrogates DIAP1’s ability to neutralize drICE and suppress apoptosis in vivo. We also show that DIAP1 rests in an “inactive” conformation that requires caspase-mediated cleavage to subsequently ubiquitylate caspases. Taken together, our findings demonstrate that effector caspases regulate their own inhibition through a negative feedback mechanism involving DIAP1 “activation” and nondegradative polyubiquitylation.

Ditzel, Mark; Broemer, Meike; Tenev, Tencho; Bolduc, Clare; Lee, Tom V.; Rigbolt, Kristoffer T.G.; Elliott, Richard; Zvelebil, Marketa; Blagoev, Blagoy; Bergmann, Andreas; Meier, Pascal

2009-01-01

61

Inactivation of effector caspases through nondegradative polyubiquitylation.  

PubMed

Ubiquitin-mediated inactivation of caspases has long been postulated to contribute to the regulation of apoptosis. However, detailed mechanisms and functional consequences of caspase ubiquitylation have not been demonstrated. Here we show that the Drosophila Inhibitor of Apoptosis 1, DIAP1, blocks effector caspases by targeting them for polyubiquitylation and nonproteasomal inactivation. We demonstrate that the conjugation of ubiquitin to drICE suppresses its catalytic potential in cleaving caspase substrates. Our data suggest that ubiquitin conjugation sterically interferes with substrate entry and reduces the caspase's proteolytic velocity. Disruption of drICE ubiquitylation, either by mutation of DIAP1's E3 activity or drICE's ubiquitin-acceptor lysines, abrogates DIAP1's ability to neutralize drICE and suppress apoptosis in vivo. We also show that DIAP1 rests in an "inactive" conformation that requires caspase-mediated cleavage to subsequently ubiquitylate caspases. Taken together, our findings demonstrate that effector caspases regulate their own inhibition through a negative feedback mechanism involving DIAP1 "activation" and nondegradative polyubiquitylation. PMID:19026784

Ditzel, Mark; Broemer, Meike; Tenev, Tencho; Bolduc, Clare; Lee, Tom V; Rigbolt, Kristoffer T G; Elliott, Richard; Zvelebil, Marketa; Blagoev, Blagoy; Bergmann, Andreas; Meier, Pascal

2008-11-21

62

The Alpha-Melanocyte Stimulating Hormone Induces Conversion of Effector T Cells into Treg Cells  

PubMed Central

The neuropeptide alpha-melanocyte stimulating hormone (?-MSH) has an important role in modulating immunity and homeostasis. The production of IFN-? by effector T cells is suppressed by ?-MSH, while TGF-? production is promoted in the same cells. Such ?-MSH-treated T cells have immune regulatory activity and suppress hypersensitivity, autoimmune diseases, and graft rejection. Previous characterizations of the ?-MSH-induced Treg cells showed that the cells are CD4+ T cells expressing the same levels of CD25 as effector T cells. Therefore, we further analyzed the ?-MSH-induced Treg cells for expression of effector and regulatory T-cell markers. Also, we examined the potential for ?-MSH-induced Treg cells to be from the effector T-cell population. We found that the ?-MSH-induced Treg cells are CD25+??CD4+ T cells that share similar surface markers as effector T cells, except that they express on their surface LAP. Also, the ?-MSH treatment augments FoxP3 message in the effector T cells, and ?-MSH induction of regulatory activity was limited to the effector CD25+ T-cell population. Therefore, ?-MSH converts effector T cells into Treg cells, which suppress immunity targeting specific antigens and tissues.

Taylor, Andrew W.; Lee, Darren J.

2011-01-01

63

In planta effector competition assays detect Hyaloperonospora arabidopsidis effectors that contribute to virulence and localize to different plant subcellular compartments.  

PubMed

The genome of the pathogenic oomycete Hyaloperonospora arabidopsidis is predicted to encode at least 134 high-confidence effectors (HaRxL) carrying the RxLR motif implicated in their translocation into plant cells. However, only four avirulence genes (ATR1, ATR13, ATR5, and ATR39) have been isolated. This indicates that identification of HaRxL effectors based on avirulence is low throughput. We aimed at rapidly identifying H. arabidopsidis effectors that contribute to virulence by developing methods to detect and quantify multiple candidates in bacterial mixed infections using either Illumina sequencing or capillary electrophoresis. In these assays, referred to here as in planta effector competition assays, we estimate the contribution to virulence of individual effectors by calculating the abundance of each HaRxL in the bacterial population recovered from leaves 3 days after inoculation relative to abundance in the initial mixed inoculum. We identified HaRxL that enhance Pseudomonas syringae pv. tomato DC3000 growth in some but not all Arabidopsis accessions. Further analysis showed that HaRxLL464, HaRxL75, HaRxL22, HaRxLL441, and HaRxL89 suppress pathogen-associated molecular pattern-triggered immunity (PTI) and localize to different subcellular compartments in Nicotiana benthamiana, providing evidence for a multilayered suppression of PTI by pathogenic oomycetes and molecular probes for the dissection of PTI. PMID:23734779

Badel, Jorge Luis; Piquerez, Sophie J M; Greenshields, David; Rallapalli, Ghanasyam; Fabro, Georgina; Ishaque, Naveed; Jones, Jonathan D G

2013-07-01

64

A Functional Genomics Approach Identifies Candidate Effectors from the Aphid Species Myzus persicae (Green Peach Aphid)  

PubMed Central

Aphids are amongst the most devastating sap-feeding insects of plants. Like most plant parasites, aphids require intimate associations with their host plants to gain access to nutrients. Aphid feeding induces responses such as clogging of phloem sieve elements and callose formation, which are suppressed by unknown molecules, probably proteins, in aphid saliva. Therefore, it is likely that aphids, like plant pathogens, deliver proteins (effectors) inside their hosts to modulate host cell processes, suppress plant defenses, and promote infestation. We exploited publicly available aphid salivary gland expressed sequence tags (ESTs) to apply a functional genomics approach for identification of candidate effectors from Myzus persicae (green peach aphid), based on common features of plant pathogen effectors. A total of 48 effector candidates were identified, cloned, and subjected to transient overexpression in Nicotiana benthamiana to assay for elicitation of a phenotype, suppression of the Pathogen-Associated Molecular Pattern (PAMP)–mediated oxidative burst, and effects on aphid reproductive performance. We identified one candidate effector, Mp10, which specifically induced chlorosis and local cell death in N. benthamiana and conferred avirulence to recombinant Potato virus X (PVX) expressing Mp10, PVX-Mp10, in N. tabacum, indicating that this protein may trigger plant defenses. The ubiquitin-ligase associated protein SGT1 was required for the Mp10-mediated chlorosis response in N. benthamiana. Mp10 also suppressed the oxidative burst induced by flg22, but not by chitin. Aphid fecundity assays revealed that in planta overexpression of Mp10 and Mp42 reduced aphid fecundity, whereas another effector candidate, MpC002, enhanced aphid fecundity. Thus, these results suggest that, although Mp10 suppresses flg22-triggered immunity, it triggers a defense response, resulting in an overall decrease in aphid performance in the fecundity assays. Overall, we identified aphid salivary proteins that share features with plant pathogen effectors and therefore may function as aphid effectors by perturbing host cellular processes.

Bos, Jorunn I. B.; Prince, David; Pitino, Marco; Maffei, Massimo E.; Win, Joe; Hogenhout, Saskia A.

2010-01-01

65

A functional genomics approach identifies candidate effectors from the aphid species Myzus persicae (green peach aphid).  

PubMed

Aphids are amongst the most devastating sap-feeding insects of plants. Like most plant parasites, aphids require intimate associations with their host plants to gain access to nutrients. Aphid feeding induces responses such as clogging of phloem sieve elements and callose formation, which are suppressed by unknown molecules, probably proteins, in aphid saliva. Therefore, it is likely that aphids, like plant pathogens, deliver proteins (effectors) inside their hosts to modulate host cell processes, suppress plant defenses, and promote infestation. We exploited publicly available aphid salivary gland expressed sequence tags (ESTs) to apply a functional genomics approach for identification of candidate effectors from Myzus persicae (green peach aphid), based on common features of plant pathogen effectors. A total of 48 effector candidates were identified, cloned, and subjected to transient overexpression in Nicotiana benthamiana to assay for elicitation of a phenotype, suppression of the Pathogen-Associated Molecular Pattern (PAMP)-mediated oxidative burst, and effects on aphid reproductive performance. We identified one candidate effector, Mp10, which specifically induced chlorosis and local cell death in N. benthamiana and conferred avirulence to recombinant Potato virus X (PVX) expressing Mp10, PVX-Mp10, in N. tabacum, indicating that this protein may trigger plant defenses. The ubiquitin-ligase associated protein SGT1 was required for the Mp10-mediated chlorosis response in N. benthamiana. Mp10 also suppressed the oxidative burst induced by flg22, but not by chitin. Aphid fecundity assays revealed that in planta overexpression of Mp10 and Mp42 reduced aphid fecundity, whereas another effector candidate, MpC002, enhanced aphid fecundity. Thus, these results suggest that, although Mp10 suppresses flg22-triggered immunity, it triggers a defense response, resulting in an overall decrease in aphid performance in the fecundity assays. Overall, we identified aphid salivary proteins that share features with plant pathogen effectors and therefore may function as aphid effectors by perturbing host cellular processes. PMID:21124944

Bos, Jorunn I B; Prince, David; Pitino, Marco; Maffei, Massimo E; Win, Joe; Hogenhout, Saskia A

2010-11-01

66

Phytopathogen type III effector weaponry and their plant targets  

PubMed Central

Summary Phytopathogenic bacteria suppress plant innate immunity and promote pathogenesis by injecting proteins called type III effectors into plant cells using a type III protein secretion system. These type III effectors use at least three major strategies to alter host responses. One strategy is to alter host protein turnover, either by direct cleavage or by modulating ubiquitination and targeting to the 26S proteasome. Another strategy involves alteration of RNA metabolism by transcriptional activation or ADP-ribosylation of RNA-binding proteins. A third major strategy is to inhibit the kinases involved in plant defence signalling, either by removing phosphates or by direct inhibition. The wide array of strategies bacterial pathogens employ to suppress innate immunity suggest that circumvention of innate immunity is critical for bacterial pathogenicity of plants.

Block, Anna; Li, Guangyong; Fu, Zheng Qing; Alfano, James R.

2008-01-01

67

Distinct Pseudomonas type-III effectors use a cleavable transit peptide to target chloroplasts.  

PubMed

The pathogen Pseudomonas syringae requires a type-III protein secretion system and the effector proteins it injects into plant cells for pathogenesis. The primary role for P. syringae type-III effectors is the suppression of plant immunity. The P. syringae pv. tomato DC3000 HopK1 type-III effector was known to suppress the hypersensitive response (HR), a programmed cell death response associated with effector-triggered immunity. Here we show that DC3000 hopK1 mutants are reduced in their ability to grow in Arabidopsis, and produce reduced disease symptoms. Arabidopsis transgenically expressing HopK1 are reduced in PAMP-triggered immune responses compared with wild-type plants. An N-terminal region of HopK1 shares similarity with the corresponding region in the well-studied type-III effector AvrRps4; however, their C-terminal regions are dissimilar, indicating that they have different effector activities. HopK1 is processed in planta at the same processing site found in AvrRps4. The processed forms of HopK1 and AvrRps4 are chloroplast localized, indicating that the shared N-terminal regions of these type-III effectors represent a chloroplast transit peptide. The HopK1 contribution to virulence and the ability of HopK1 and AvrRps4 to suppress immunity required their respective transit peptides, but the AvrRps4-induced HR did not. Our results suggest that a primary virulence target of these type-III effectors resides in chloroplasts, and that the recognition of AvrRps4 by the plant immune system occurs elsewhere. Moreover, our results reveal that distinct type-III effectors use a cleavable transit peptide to localize to chloroplasts, and that targets within this organelle are important for immunity. PMID:24299018

Li, Guangyong; Froehlich, John E; Elowsky, Christian; Msanne, Joseph; Ostosh, Andrew C; Zhang, Chi; Awada, Tala; Alfano, James R

2014-01-01

68

Improving a Gripper End Effector  

SciTech Connect

This paper discusses the improvement made to an existing four-bar linkage gripping end effector to adapt it for use in a current project. The actuating linkage was modified to yield higher jaw force overall and particularly in the critical range of jaw displacement

Mullen, O Dennis; Smith, Christopher M.; Gervais, Kevin L.

2001-01-31

69

Establishment of an inducing medium for type III effector secretion in Xanthomonas campestris pv. campestris  

PubMed Central

It is well known that the type III secretion system (T3SS) and type III (T3) effectors are essential for the pathogenicity of most bacterial phytopathogens and that the expression of T3SS and T3 effectors is suppressed in rich media but induced in minimal media and plants. To facilitate in-depth studies on T3SS and T3 effectors, it is crucial to establish a medium for T3 effector expression and secretion. Xanthomonas campestris pv. campestris (Xcc) is a model bacterium for studying plant-pathogen interactions. To date no medium for Xcc T3 effector secretion has been defined. Here, we compared four minimal media (MME, MMX, XVM2, and XOM2) which are reported for T3 expression induction in Xanthomonas spp. and found that MME is most efficient for expression and secretion of Xcc T3 effectors. By optimization of carbon and nitrogen sources and pH value based on MME, we established XCM1 medium, which is about 3 times stronger than MME for Xcc T3 effectors secretion. We further optimized the concentration of phosphate, calcium, and magnesium in XCM1 and found that XCM1 with a lower concentration of magnesium (renamed as XCM2) is about 10 times as efficient as XCM1 (meanwhile, about 30 times stronger than MME). Thus, we established an inducing medium XCM2 which is preferred for T3 effector secretion in Xcc.

Jiang, Guo-Feng; Jiang, Bo-Le; Yang, Mei; Liu, San; Liu, Jiao; Liang, Xiao-Xia; Bai, Xian-Fang; Tang, Dong-Jie; Lu, Guang-Tao; He, Yong-Qiang; Yu, Di-Qiu; Tang, Ji-Liang

2013-01-01

70

Agents, affecting the hyperactivated immunological effector cells  

US Patent & Trademark Office Database

A method to reduce hyperactivated immunologic effector cells involves the administration (I) a Ca-antagonist and (II) an agent, to reduce the intracellular cAMP/cGMP-ratio. A treatment for eliminating the hyperactivated effector cells utilizes a combination of an agent to eliminate the hyperactivated effector cells and alloreactive cells with predetermined cell death.

2000-12-05

71

Dexterous end effector flight demonstration  

NASA Technical Reports Server (NTRS)

The Dexterous End Effector Flight Experiment is a flight demonstration of newly developed equipment and methods which make for more dexterous manipulation of robotic arms. The following concepts are to be demonstrated: The Force Torque Sensor is a six axis load cell located at the end of the RMS which displays load data to the operator on the orbiter CCTV monitor. TRAC is a target system which provides six axis positional information to the operator. It has the characteristic of having high sensitivity to attitude misalignment while being flat. AUTO-TRAC is a variation of TRAC in which a computer analyzes a target, displays translational and attitude misalignment information, and provides cues to the operator for corrective inputs. The Magnetic End Effector is a fault tolerant end effector which grapples payloads using magnetic attraction. The Carrier Latch Assembly is a fault tolerant payload carrier, which uses mechanical latches and/or magnetic attraction to hold small payloads during launch/landing and to release payloads as desired. The flight experiment goals and objectives are explained. The experiment equipment is described, and the tasks to be performed during the demonstration are discussed.

Carter, Edward L.; Monford, Leo G.

1994-01-01

72

Using Hierarchical Clustering of Secreted Protein Families to Classify and Rank Candidate Effectors of Rust Fungi  

PubMed Central

Rust fungi are obligate biotrophic pathogens that cause considerable damage on crop plants. Puccinia graminis f. sp. tritici, the causal agent of wheat stem rust, and Melampsora larici-populina, the poplar leaf rust pathogen, have strong deleterious impacts on wheat and poplar wood production, respectively. Filamentous pathogens such as rust fungi secrete molecules called disease effectors that act as modulators of host cell physiology and can suppress or trigger host immunity. Current knowledge on effectors from other filamentous plant pathogens can be exploited for the characterisation of effectors in the genome of recently sequenced rust fungi. We designed a comprehensive in silico analysis pipeline to identify the putative effector repertoire from the genome of two plant pathogenic rust fungi. The pipeline is based on the observation that known effector proteins from filamentous pathogens have at least one of the following properties: (i) contain a secretion signal, (ii) are encoded by in planta induced genes, (iii) have similarity to haustorial proteins, (iv) are small and cysteine rich, (v) contain a known effector motif or a nuclear localization signal, (vi) are encoded by genes with long intergenic regions, (vii) contain internal repeats, and (viii) do not contain PFAM domains, except those associated with pathogenicity. We used Markov clustering and hierarchical clustering to classify protein families of rust pathogens and rank them according to their likelihood of being effectors. Using this approach, we identified eight families of candidate effectors that we consider of high value for functional characterization. This study revealed a diverse set of candidate effectors, including families of haustorial expressed secreted proteins and small cysteine-rich proteins. This comprehensive classification of candidate effectors from these devastating rust pathogens is an initial step towards probing plant germplasm for novel resistance components.

Saunders, Diane G. O.; Win, Joe; Cano, Liliana M.; Szabo, Les J.; Kamoun, Sophien; Raffaele, Sylvain

2012-01-01

73

Using hierarchical clustering of secreted protein families to classify and rank candidate effectors of rust fungi.  

PubMed

Rust fungi are obligate biotrophic pathogens that cause considerable damage on crop plants. Puccinia graminis f. sp. tritici, the causal agent of wheat stem rust, and Melampsora larici-populina, the poplar leaf rust pathogen, have strong deleterious impacts on wheat and poplar wood production, respectively. Filamentous pathogens such as rust fungi secrete molecules called disease effectors that act as modulators of host cell physiology and can suppress or trigger host immunity. Current knowledge on effectors from other filamentous plant pathogens can be exploited for the characterisation of effectors in the genome of recently sequenced rust fungi. We designed a comprehensive in silico analysis pipeline to identify the putative effector repertoire from the genome of two plant pathogenic rust fungi. The pipeline is based on the observation that known effector proteins from filamentous pathogens have at least one of the following properties: (i) contain a secretion signal, (ii) are encoded by in planta induced genes, (iii) have similarity to haustorial proteins, (iv) are small and cysteine rich, (v) contain a known effector motif or a nuclear localization signal, (vi) are encoded by genes with long intergenic regions, (vii) contain internal repeats, and (viii) do not contain PFAM domains, except those associated with pathogenicity. We used Markov clustering and hierarchical clustering to classify protein families of rust pathogens and rank them according to their likelihood of being effectors. Using this approach, we identified eight families of candidate effectors that we consider of high value for functional characterization. This study revealed a diverse set of candidate effectors, including families of haustorial expressed secreted proteins and small cysteine-rich proteins. This comprehensive classification of candidate effectors from these devastating rust pathogens is an initial step towards probing plant germplasm for novel resistance components. PMID:22238666

Saunders, Diane G O; Win, Joe; Cano, Liliana M; Szabo, Les J; Kamoun, Sophien; Raffaele, Sylvain

2012-01-01

74

Translocation and functional analysis of Pseudomonas savastanoi pv. savastanoi NCPPB 3335 type III secretion system effectors reveals two novel effector families of the Pseudomonas syringae complex.  

PubMed

Pseudomonas savastanoi pv. savastanoi NCPPB 3335 causes olive knot disease and is a model pathogen for exploring bacterial infection of woody hosts. The type III secretion system (T3SS) effector repertoire of this strain includes 31 effector candidates plus two novel candidates identified in this study which have not been reported to translocate into plant cells. In this work, we demonstrate the delivery of seven NCPPB 3335 effectors into Nicotiana tabacum leaves, including three proteins from two novel families of the P. syringae complex effector super-repertoire (HopBK and HopBL), one of which comprises two proteins (HopBL1 and HopBL2) that harbor a SUMO protease domain. When delivered by P. fluorescens heterologously expressing a P. syringae T3SS, all seven effectors were found to suppress the production of defense-associated reactive oxygen species. Moreover, six of these effectors, including the truncated versions of HopAA1 and HopAZ1 encoded by NCPPB 3335, suppressed callose deposition. The expression of HopAZ1 and HopBL1 by functionally effectorless P. syringae pv. tomato DC3000D28E inhibited the hypersensitive response in tobacco and, additionally, expression of HopBL2 by this strain significantly increased its competitiveness in N. benthamiana. DNA sequences encoding HopBL1 and HopBL2 were uniquely detected in a collection of 31 P. savastanoi pv. savastanoi strains and other P. syringae strains isolated from woody hosts, suggesting a relevant role of these two effectors in bacterial interactions with olive and other woody plants. PMID:24329173

Matas, Isabel M; Castañeda-Ojeda, M Pilar; Aragón, Isabel M; Antúnez-Lamas, María; Murillo, Jesús; Rodríguez-Palenzuela, Pablo; López-Solanilla, Emilia; Ramos, Cayo

2014-05-01

75

Space Station end effector strategy study  

NASA Technical Reports Server (NTRS)

The results of a study are presented for terminology definition, identification of functional requirements, technolgy assessment, and proposed end effector development strategies for the Space Station Program. The study is composed of a survey of available or under-developed end effector technology, identification of requirements from baselined Space Station documents, a comparative assessment of the match between technology and requirements, and recommended strategies for end effector development for the Space Station Program.

Katzberg, Stephen J.; Jensen, Robert L.; Willshire, Kelli F.; Satterthwaite, Robert E.

1987-01-01

76

IAPs are functionally non-equivalent and regulate effector caspases through distinct mechanisms.  

PubMed

Some members of the inhibitor of apoptosis (IAP) family suppress apoptosis by neutralizing caspases. The current model suggests that all caspase-regulatory IAPs function as direct enzyme inhibitors, blocking effector caspases by binding to their catalytically active pockets. Here we show that IAPs are functionally non-equivalent and regulate effector caspases through distinct mechanisms. Whereas XIAP binds directly to the active-site pockets of effector caspases, we find that regulation of effector caspases by Drosophila IAP1 (DIAP1) requires an evolutionarily conserved IAP-binding motif (IBM) at the neo-amino terminus of the large caspase subunit. Remarkably, unlike XIAP, DIAP1-sequestered effector caspases remain catalytically active, suggesting that DIAP1 does not function as a bona fide enzyme inhibitor. Moreover, we demonstrate that the mammalian IAP c-IAP1 interacts with caspase-7 in an exclusively IBM-dependent, but active site pocket-independent, manner that is mechanistically similar to DIAP1. The importance of IBM-mediated regulation of effector-caspases in vivo is substantiated by the enhanced apoptotic potency of IBM-mutant versions of drICE, DCP-1 and caspase-7. PMID:15580265

Tenev, Tencho; Zachariou, Anna; Wilson, Rebecca; Ditzel, Mark; Meier, Pascal

2005-01-01

77

Distinct Functions of Autoreactive Memory and Effector CD4+ T Cells in Experimental Autoimmune Encephalomyelitis  

PubMed Central

The persistence of human autoimmune diseases is thought to be mediated predominantly by memory T cells. We investigated the phenotype and migration of memory versus effector T cells in vivo in experimental autoimmune encephalomyelitis (EAE). We found that memory CD4+ T cells up-regulated the activation marker CD44 as well as CXCR3 and ICOS, proliferated more and produced more interferon-? and less interleukin-17 compared to effector T cells. Moreover, adoptive transfer of memory T cells into T cell receptor (TCR)???/? recipients induced more severe disease than did effector CD4+ T cells with marked central nervous system inflammation and axonal damage. The uniqueness of disease mediated by memory T cells was confirmed by the differential susceptibility to immunomodulatory therapies in vivo. CD28-B7 T cell costimulatory signal blockade by CTLA4Ig suppressed effector cell-mediated EAE but had minimal effects on disease induced by memory cells. In contrast, ICOS-B7h blockade exacerbated effector T cell-induced EAE but protected from disease induced by memory T cells. However, blockade of the OX40 (CD134) costimulatory pathway ameliorated disease mediated by both memory and effector T cells. Our data extend the understanding of the pathogenicity of autoreactive memory T cells and have important implications for the development of novel therapies for human autoimmune diseases.

Elyaman, Wassim; Kivisakk, Pia; Reddy, Jay; Chitnis, Tanuja; Raddassi, Khadir; Imitola, Jaime; Bradshaw, Elizabeth; Kuchroo, Vijay K.; Yagita, Hideo; Sayegh, Mohamed H.; Khoury, Samia J.

2008-01-01

78

Robust Position Control of End-Effector Considering Gear Stiffness and Arm Stiffness for Industrial Robot  

NASA Astrophysics Data System (ADS)

Industrial robot with two-inertia model and resonant vibration suppression by using parameters from resonant identification method are addressed in this paper. By using only D-PD control with vibration suppression scheme for two-inertia model of flexible joint robot, the end-effector position does not perfectly reach the desired position owing to the effect of external force to the elastic arm. However, only gear stiffness parameter of two-inertia model is not enough, the new equivalent spring constant parameter including the stiffness of link and gear of the robot is introduced as the total arm spring constant. The novel load-side disturbance compensation considering total arm elasticity is proposed in this paper. The proposed control system is based on inner-loop vibration suppression feedback control and load-side disturbance suppression which motivates the simple consideration of the elastic joint under external torque. Moreover, the experimental results show the effectiveness of the proposed robust position control of end-effector with disturbance compensation considering total arm stiffness. The experimentation on workspace impedance control with inner-loop disturbance suppression implementing on the three degree-of-freedom (3-DOF) robot manipulator is also presented and discussed. The performance and feasibility of the proposed position control of end-effector is confirmed to apply to industrial robot manipulator without additional device.

Tungpataratanawong, Somsawas; Chitbanchong, Satit; Miyazaki, Toshimasa; Katsura, Seiichiro; Ohishi, Kiyoshi

79

Distinct Sets of Rab6 Effectors Contribute to ZW10- and COG-Dependent Golgi Homeostasis.  

PubMed

The organization of the Golgi apparatus is determined in part by the interaction of Rab proteins and their diverse array of effectors. Here, we used multiple approaches to identify and characterize a small subset of effectors that mimicked the effects of Rab6 on Golgi ribbon organization. In a visual-based, candidate protein screen, we found that the individual depletion of any of three Rab6 effectors, myosin IIA (MyoIIA), Kif20A and Bicaudal D (BicD), was sufficient to suppress Golgi ribbon fragmentation/dispersal coupled to retrograde tether proteins in a manner paralleling Rab6. MyoIIA and Kif20A depletions were pathway selective and suppressed ZW10-dependent Golgi ribbon fragmentation/dispersal only whereas BicD depletion, like Rab6, suppressed both ZW10- and COG-dependent Golgi ribbon fragmentation. The MyoIIA effects could be produced in short-term assays by the reversible myosin inhibitor, blebbistatin. At the electron microscope level, the effects of BicD-depletion mimicked many of those of Rab6-depletion: longer and more continuous Golgi cisternae and a pronounced accumulation of coated vesicles. Functionally, BicD-depleted cells were inhibited in transport of newly synthesized VSV-G protein to the cell surface. In summary, our results indicate small, partially overlapping subsets of Rab6 effectors are differentially important to two tether-dependent pathways essential to Golgi organization and function. PMID:24575842

Majeed, Waqar; Liu, Shijie; Storrie, Brian

2014-06-01

80

Deciphering and reversing tumor immune suppression.  

PubMed

Generating an anti-tumor immune response is a multi-step process that is executed by effector T cells that can recognize and kill tumor targets. However, tumors employ multiple strategies to attenuate the effectiveness of T-cell-mediated attack. They achieve this by interfering with nearly every step required for effective immunity, from deregulation of antigen-presenting cells to establishment of a physical barrier at the vasculature that prevents homing of effector tumor-rejecting cells and the suppression of effector lymphocytes through the recruitment and activation of immunosuppressive cells such as myeloid-derived suppressor cells, tolerogenic monocytes, and T regulatory cells. Here, we review the ways in which tumors exert immune suppression and highlight the new therapies that seek to reverse this phenomenon and promote anti-tumor immunity. Understanding anti-tumor immunity, and how it becomes disabled by tumors, will ultimately lead to improved immune therapies and prolonged survival of patients. PMID:23890064

Motz, Greg T; Coukos, George

2013-07-25

81

ROBOTIC TANK INSPECTION END EFFECTOR  

SciTech Connect

The objective of this contract between Oceaneering Space Systems (OSS) and the Department of Energy (DOE) was to provide a tool for the DOE to inspect the inside tank walls of underground radioactive waste storage tanks in their tank farms. Some of these tanks are suspected to have leaks, but the harsh nature of the environment within the tanks precludes human inspection of tank walls. As a result of these conditions only a few inspection methods can fulfill this task. Of the methods available, OSS chose to pursue Alternating Current Field Measurement (ACFM), because it does not require clean surfaces for inspection, nor any contact with the Surface being inspected, and introduces no extra by-products in the inspection process (no coupling fluids or residues are left behind). The tool produced by OSS is the Robotic Tank Inspection End Effector (RTIEE), which is initially deployed on the tip of the Light Duty Utility Arm (LDUA). The RTEE combines ACFM with a color video camera for both electromagnetic and visual inspection The complete package consists of an end effector, its corresponding electronics and software, and a user's manual to guide the operator through an inspection. The system has both coarse and fine inspection modes and allows the user to catalog defects and suspected areas of leakage in a database for further examination, which may lead to emptying the tank for repair, decommissioning, etc.. The following is an updated report to OSS document OSS-21100-7002, which was submitted in 1995. During the course of the contract, two related subtasks arose, the Wall and Coating Thickness Sensor and the Vacuum Scarifying and Sampling Tool Assembly. The first of these subtasks was intended to evaluate the corrosion and wall thinning of 55-gallon steel drums. The second was retrieved and characterized the waste material trapped inside the annulus region of the underground tanks on the DOE's tank farms. While these subtasks were derived from the original intent of the contract, the focus remains on the RTIEE.

Rachel Landry

1999-10-01

82

Oxysterols and their cellular effectors.  

PubMed

Oxysterols are oxidized 27-carbon cholesterol derivatives or by-products of cholesterol biosynthesis, with a spectrum of biologic activities. Several oxysterols have cytotoxic and pro-apoptotic activities, the ability to interfere with the lateral domain organization, and packing of membrane lipids. These properties may account for their suggested roles in the pathology of diseases such as atherosclerosis, age-onset macular degeneration and Alzheimer's disease. Oxysterols also have the capacity to induce inflammatory responses and play roles in cell differentiation processes. The functions of oxysterols as intermediates in the synthesis of bile acids and steroid hormones, and as readily transportable forms of sterol, are well established. Furthermore, their actions as endogenous regulators of gene expression in lipid metabolism via liver X receptors and the Insig (insulin-induced gene) proteins have been investigated in detail. The cytoplasmic oxysterol-binding protein (OSBP) homologues form a group of oxysterol/cholesterol sensors that has recently attracted a lot of attention. However, their mode of action is, as yet, poorly understood. Retinoic acid receptor-related orphan receptors (ROR) ? and ?, and Epstein-Barr virus induced gene 2 (EBI2) have been identified as novel oxysterol receptors, revealing new physiologic oxysterol effector mechanisms in development, metabolism, and immunity, and evoking enhanced interest in these compounds in the field of biomedicine. PMID:24970128

Olkkonen, Vesa M; Béaslas, Olivier; Nissilä, Eija

2012-01-01

83

Oxysterols and Their Cellular Effectors  

PubMed Central

Oxysterols are oxidized 27-carbon cholesterol derivatives or by-products of cholesterol biosynthesis, with a spectrum of biologic activities. Several oxysterols have cytotoxic and pro-apoptotic activities, the ability to interfere with the lateral domain organization, and packing of membrane lipids. These properties may account for their suggested roles in the pathology of diseases such as atherosclerosis, age-onset macular degeneration and Alzheimer’s disease. Oxysterols also have the capacity to induce inflammatory responses and play roles in cell differentiation processes. The functions of oxysterols as intermediates in the synthesis of bile acids and steroid hormones, and as readily transportable forms of sterol, are well established. Furthermore, their actions as endogenous regulators of gene expression in lipid metabolism via liver X receptors and the Insig (insulin-induced gene) proteins have been investigated in detail. The cytoplasmic oxysterol-binding protein (OSBP) homologues form a group of oxysterol/cholesterol sensors that has recently attracted a lot of attention. However, their mode of action is, as yet, poorly understood. Retinoic acid receptor-related orphan receptors (ROR) ? and ?, and Epstein-Barr virus induced gene 2 (EBI2) have been identified as novel oxysterol receptors, revealing new physiologic oxysterol effector mechanisms in development, metabolism, and immunity, and evoking enhanced interest in these compounds in the field of biomedicine.

Olkkonen, Vesa M.; Beaslas, Olivier; Nissila, Eija

2012-01-01

84

The role of effectors of biotrophic and hemibiotrophic fungi in infection  

PubMed Central

Biotrophic and hemibiotrophic fungi are successful groups of plant pathogens that require living plant tissue to survive and complete their life cycle. Members of these groups include the rust fungi and powdery mildews and species in the Ustilago, Cladosporium and Magnaporthe genera. Collectively, they represent some of the most destructive plant parasites, causing huge economic losses and threatening global food security. During plant infection, pathogens synthesise and secrete effector proteins, some of which are translocated into the plant cytosol where they can alter the host’s response to the invading pathogen. In a successful infection, pathogen effectors facilitate suppression of the plant’s immune system and orchestrate the reprogramming of the infected tissue so that it becomes a source of nutrients that are required by the pathogen to support its growth and development. This review summarizes our current understanding of the function of fungal effectors in infection.

Koeck, Markus; Hardham, Adrienne R.; Dodds, Peter N.

2011-01-01

85

Host inhibition of a bacterial virulence effector triggers immunity to infection.  

PubMed

Plant pathogenic bacteria secrete effector proteins that attack the host signaling machinery to suppress immunity. Effectors can be recognized by hosts leading to immunity. One such effector is AvrPtoB of Pseudomonas syringae, which degrades host protein kinases, such as tomato Fen, through an E3 ligase domain. Pto kinase, which is highly related to Fen, recognizes AvrPtoB in conjunction with the resistance protein Prf. Here we show that Pto is resistant to AvrPtoB-mediated degradation because it inactivates the E3 ligase domain. AvrPtoB ubiquitinated Fen within the catalytic cleft, leading to its breakdown and loss of the associated Prf protein. Pto avoids this by phosphorylating and inactivating the AvrPtoB E3 domain. Thus, inactivation of a pathogen virulence molecule is one mechanism by which plants resist disease. PMID:19423826

Ntoukakis, Vardis; Mucyn, Tatiana S; Gimenez-Ibanez, Selena; Chapman, Helen C; Gutierrez, Jose R; Balmuth, Alexi L; Jones, Alexandra M E; Rathjen, John P

2009-05-01

86

Characterizing and measuring endocytosis of lipid-binding effectors in mammalian cells.  

PubMed

Pathogen-host interactions are mediated in part by secreted microbial proteins capable of exploiting host cells for their survival. Several of these manipulations involve, but are not limited to, suppression of defense responses, alterations in host vesicular trafficking, and manipulation of gene expression. The delivery of such molecules from microbe to host has been of intense interest in several microbe-host systems. Several well-studied bacterial effectors are delivered directly into host cells through a needle injection apparatus. Conversely, there have been several examples of secreted effectors and protein toxins from bacteria and eukaryotic microbes, such as fungi and oomycetes, being internalized into host cells by receptor-mediated endocytosis. In the following chapter, we discuss various techniques utilized to measure these endocytosed lipid-binding effectors that can be delivered in the absence of the pathogen. PMID:24377920

Clark, Helen R; Hayes, Tristan A; Kale, Shiv D

2014-01-01

87

Jet Engine Exhaust Nozzle Flow Effector  

NASA Technical Reports Server (NTRS)

A jet engine exhaust nozzle flow effector is a chevron formed with a radius of curvature with surfaces of the flow effector being defined and opposing one another. At least one shape memory alloy (SMA) member is embedded in the chevron closer to one of the chevron's opposing surfaces and substantially spanning from at least a portion of the chevron's root to the chevron's tip.

Turner, Travis L. (Inventor); Cano, Roberto J. (Inventor); Silcox, Richard J. (Inventor); Buehrle, Ralph D. (Inventor); Cagle, Christopher M. (Inventor); Cabell, Randolph H. (Inventor); Hilton, George C. (Inventor)

2011-01-01

88

Heterotrimeric G Proteins and Their Effector Pathways  

Microsoft Academic Search

Almost 30 yr have passed since the discovery of the heptahelical transmembrane (TM) receptors and their connection to heterotrimeric\\u000a G proteins and sequential signal flow to intracellular effectors (1–3). Many hormones, sensory stimuli, and neurotransmitters use this signaling system to convert chemical or physical information\\u000a from the G protein-coupled receptor (GPCR) through a transducer (G protein) to an effector into

Tracy Nguyen Hwangpo; Ravi Iyengar

89

Spiral lead platen robotic end effector  

NASA Technical Reports Server (NTRS)

A robotic end effector is disclosed which makes use of a rotating platen with spiral leads used to impact lateral motion to gripping fingers. Actuation is provided by the contact of rolling pins with the walls of the leads. The use of the disclosed method of actuation avoids jamming and provides excellent mechanical advantage while remaining light in weight and durable. The entire end effector is compact and easily adapted for attachment to robotic arms currently in use.

Beals, David C. (inventor)

1990-01-01

90

Rho GTPases and their effector proteins.  

PubMed Central

Rho GTPases are molecular switches that regulate many essential cellular processes, including actin dynamics, gene transcription, cell-cycle progression and cell adhesion. About 30 potential effector proteins have been identified that interact with members of the Rho family, but it is still unclear which of these are responsible for the diverse biological effects of Rho GTPases. This review will discuss how Rho GTPases physically interact with, and regulate the activity of, multiple effector proteins and how specific effector proteins contribute to cellular responses. To date most progress has been made in the cytoskeleton field, and several biochemical links have now been established between GTPases and the assembly of filamentous actin. The main focus of this review will be Rho, Rac and Cdc42, the three best characterized mammalian Rho GTPases, though the genetic analysis of Rho GTPases in lower eukaryotes is making increasingly important contributions to this field.

Bishop, A L; Hall, A

2000-01-01

91

Cellular senescence and its effector programs  

PubMed Central

Cellular senescence is a stress response that accompanies stable exit from the cell cycle. Classically, senescence, particularly in human cells, involves the p53 and p16/Rb pathways, and often both of these tumor suppressor pathways need to be abrogated to bypass senescence. In parallel, a number of effector mechanisms of senescence have been identified and characterized. These studies suggest that senescence is a collective phenotype of these multiple effectors, and their intensity and combination can be different depending on triggers and cell types, conferring a complex and diverse nature to senescence. Series of studies on senescence-associated secretory phenotype (SASP) in particular have revealed various layers of functionality of senescent cells in vivo. Here we discuss some key features of senescence effectors and attempt to functionally link them when it is possible.

Salama, Rafik; Sadaie, Mahito; Hoare, Matthew; Narita, Masashi

2014-01-01

92

Identification of candidate effector genes in the transcriptome of the rice root knot nematode Meloidogyne graminicola.  

PubMed

Plant-parasitic nematodes secrete so-called effectors into their host plant which are able to suppress the plant's defence responses, alter plant signalling pathways and, in the case of root knot nematodes, induce the formation of giant cells. Putative effectors have been successfully identified by genomics, transcriptomics and proteomics approaches. In this study, we investigated the transcriptome of the rice root knot nematode Meloidogyne graminicola by 454 sequencing of second-stage juveniles as well as mRNA-seq of rice infected tissue. Over 350?000 reads derived from M.?graminicola preparasitic juveniles were assembled, annotated and checked for homologues in different databases. From infected rice tissue, 1.4% of all reads generated were identified as being derived from the nematode. Using multiple strategies, several putative effector genes were identified, both pioneer genes and genes corresponding to already known effectors. To check whether these genes could be involved in the interaction with the plant, in?situ hybridization was performed on a selection of genes to localize their expression in the nematode. Most were expressed in the gland cells or amphids of the nematode, confirming possible secretion of the proteins and hence a role in infection. Other putative effectors showed a different expression pattern, potentially linked with the excretory/secretory system. This transcriptome study is a good starting point to functionally investigate novel effectors derived from M.?graminicola. This will lead to better insights into the interaction between these nematodes and the model plant rice. Moreover, the transcriptome can be used to identify possible target genes for RNA interference (RNAi)-based control strategies. Four genes proved to be interesting targets by showing up to 40% higher mortality relative to the control treatment when soaked in gene-specific small interfering RNAs (siRNAs). PMID:23279209

Haegeman, Annelies; Bauters, Lander; Kyndt, Tina; Rahman, Mohammad Masuder; Gheysen, Godelieve

2013-05-01

93

Gene Duplication and Fragment Recombination Drive Functional Diversification of a Superfamily of Cytoplasmic Effectors in Phytophthora sojae  

PubMed Central

Phytophthora and other oomycetes secrete a large number of putative host cytoplasmic effectors with conserved FLAK motifs following signal peptides, termed crinkling and necrosis inducing proteins (CRN), or Crinkler. Here, we first investigated the evolutionary patterns and mechanisms of CRN effectors in Phytophthora sojae and compared them to two other Phytophthora species. The genes encoding CRN effectors could be divided into 45 orthologous gene groups (OGG), and most OGGs unequally distributed in the three species, in which each underwent large number of gene gains or losses, indicating that the CRN genes expanded after species evolution in Phytophthora and evolved through pathoadaptation. The 134 expanded genes in P. sojae encoded family proteins including 82 functional genes and expressed at higher levels while the other 68 genes encoding orphan proteins were less expressed and contained 50 pseudogenes. Furthermore, we demonstrated that most expanded genes underwent gene duplication or/and fragment recombination. Three different mechanisms that drove gene duplication or recombination were identified. Finally, the expanded CRN effectors exhibited varying pathogenic functions, including induction of programmed cell death (PCD) and suppression of PCD through PAMP-triggered immunity or/and effector-triggered immunity. Overall, these results suggest that gene duplication and fragment recombination may be two mechanisms that drive the expansion and neofunctionalization of the CRN family in P. sojae, which aids in understanding the roles of CRN effectors within each oomycete pathogen.

Shen, Danyu; Liu, Tingli; Ye, Wenwu; Liu, Li; Liu, Peihan; Wu, Yuren; Wang, Yuanchao; Dou, Daolong

2013-01-01

94

Gene duplication and fragment recombination drive functional diversification of a superfamily of cytoplasmic effectors in Phytophthora sojae.  

PubMed

Phytophthora and other oomycetes secrete a large number of putative host cytoplasmic effectors with conserved FLAK motifs following signal peptides, termed crinkling and necrosis inducing proteins (CRN), or Crinkler. Here, we first investigated the evolutionary patterns and mechanisms of CRN effectors in Phytophthora sojae and compared them to two other Phytophthora species. The genes encoding CRN effectors could be divided into 45 orthologous gene groups (OGG), and most OGGs unequally distributed in the three species, in which each underwent large number of gene gains or losses, indicating that the CRN genes expanded after species evolution in Phytophthora and evolved through pathoadaptation. The 134 expanded genes in P. sojae encoded family proteins including 82 functional genes and expressed at higher levels while the other 68 genes encoding orphan proteins were less expressed and contained 50 pseudogenes. Furthermore, we demonstrated that most expanded genes underwent gene duplication or/and fragment recombination. Three different mechanisms that drove gene duplication or recombination were identified. Finally, the expanded CRN effectors exhibited varying pathogenic functions, including induction of programmed cell death (PCD) and suppression of PCD through PAMP-triggered immunity or/and effector-triggered immunity. Overall, these results suggest that gene duplication and fragment recombination may be two mechanisms that drive the expansion and neofunctionalization of the CRN family in P. sojae, which aids in understanding the roles of CRN effectors within each oomycete pathogen. PMID:23922898

Shen, Danyu; Liu, Tingli; Ye, Wenwu; Liu, Li; Liu, Peihan; Wu, Yuren; Wang, Yuanchao; Dou, Daolong

2013-01-01

95

The downy mildew effector proteins ATR1 and ATR13 promote disease susceptibility in Arabidopsis thaliana.  

PubMed

The downy mildew (Hyaloperonospora parasitica) effector proteins ATR1 and ATR13 trigger RPP1-Nd/WsB- and RPP13-Nd-dependent resistance, respectively, in Arabidopsis thaliana. To better understand the functions of these effectors during compatible and incompatible interactions of H. parasitica isolates on Arabidopsis accessions, we developed a novel delivery system using Pseudomonas syringae type III secretion via fusions of ATRs to the N terminus of the P. syringae effector protein, AvrRPS4. ATR1 and ATR13 both triggered the hypersensitive response (HR) and resistance to bacterial pathogens in Arabidopsis carrying RPP1-Nd/WsB or RPP13-Nd, respectively, when delivered from P. syringae pv tomato (Pst) DC3000. In addition, multiple alleles of ATR1 and ATR13 confer enhanced virulence to Pst DC3000 on susceptible Arabidopsis accessions. We conclude that ATR1 and ATR13 positively contribute to pathogen virulence inside host cells. Two ATR13 alleles suppressed bacterial PAMP (for Pathogen-Associated Molecular Patterns)-triggered callose deposition in susceptible Arabidopsis when delivered by DC3000 DeltaCEL mutants. Furthermore, expression of another allele of ATR13 in plant cells suppressed PAMP-triggered reactive oxygen species production in addition to callose deposition. Intriguingly, although Wassilewskija (Ws-0) is highly susceptible to H. parasitica isolate Emco5, ATR13Emco5 when delivered by Pst DC3000 triggered localized immunity, including HR, on Ws-0. We suggest that an additional H. parasitica Emco5 effector might suppress ATR13-triggered immunity. PMID:18165328

Sohn, Kee Hoon; Lei, Rita; Nemri, Adnane; Jones, Jonathan D G

2007-12-01

96

Polypeptide variants with altered effector function  

US Patent & Trademark Office Database

The present invention concerns polypeptides comprising a variant Fc region. More particularly, the present invention concerns Fc region-containing polypeptides that have altered effector function as a consequence of one or more amino acid modifications in the Fc region thereof.

2014-03-18

97

Kinematic evaluation of end effector design  

NASA Astrophysics Data System (ADS)

The complex, many degree-of-freedom end effectors at the leading edge of technology would be unusable in the sea bottom research environment. Simpler designs are required to provide adequate reliability for subsea use. This work examines selection of end effector designs to achieve optimum grasping ability with minimal mechanical complexity. A new method of calculating grasp stability is developed, incorporating elements of previous works in the field. Programs are developed which evaluate the ability of different end effector configurations to grasp representative objects (a cube, sphere, and infinite cylinder). End effector designs considered had circular palms with fingers located at the periphery, oriented so that each pointed to the center of the palm. The program tested configurations of from 1 to 4 fingers and from 1 to 3 links per finger. Three sets of finger proportions were considered: equal length links, half length links, and anthropomorphic proportions. The 2 finger, 2 link per finger configuration was determined to be the optimum design, and the half length proportions were selected as the best set of proportions.

Edwards, Gary W.

1992-09-01

98

In planta expression screens of Phytophthora infestans RXLR effectors reveal diverse phenotypes, including activation of the Solanum bulbocastanum disease resistance protein Rpi-blb2.  

PubMed

The Irish potato famine pathogen Phytophthora infestans is predicted to secrete hundreds of effector proteins. To address the challenge of assigning biological functions to computationally predicted effector genes, we combined allele mining with high-throughput in planta expression. We developed a library of 62 infection-ready P. infestans RXLR effector clones, obtained using primer pairs corresponding to 32 genes and assigned activities to several of these genes. This approach revealed that 16 of the 62 examined effectors cause phenotypes when expressed inside plant cells. Besides the well-studied AVR3a effector, two additional effectors, PexRD8 and PexRD36(45-1), suppressed the hypersensitive cell death triggered by the elicitin INF1, another secreted protein of P. infestans. One effector, PexRD2, promoted cell death in Nicotiana benthamiana and other solanaceous plants. Finally, two families of effectors induced hypersensitive cell death specifically in the presence of the Solanum bulbocastanum late blight resistance genes Rpi-blb1 and Rpi-blb2, thereby exhibiting the activities expected for Avrblb1 and Avrblb2. The AVRblb2 family was then studied in more detail and found to be highly variable and under diversifying selection in P. infestans. Structure-function experiments indicated that a 34-amino acid region in the C-terminal half of AVRblb2 is sufficient for triggering Rpi-blb2 hypersensitivity and that a single positively selected AVRblb2 residue is critical for recognition by Rpi-blb2. PMID:19794118

Oh, Sang-Keun; Young, Carolyn; Lee, Minkyoung; Oliva, Ricardo; Bozkurt, Tolga O; Cano, Liliana M; Win, Joe; Bos, Jorunn I B; Liu, Hsin-Yin; van Damme, Mireille; Morgan, William; Choi, Doil; Van der Vossen, Edwin A G; Vleeshouwers, Vivianne G A A; Kamoun, Sophien

2009-09-01

99

The RXLR motif of oomycete effectors is not a sufficient element for binding to phosphatidylinositol monophosphates.  

PubMed

The translocation of effector proteins into the host plant cells is essential for pathogens to suppress plant immune responses. The oomycete pathogen Phytophthora infestans secretes AVR3a, a crucial virulence effector protein with an N-terminal RXLR motif that is required for this translocation. It has been reported that the RXLR motif of P. sojae Avr1b, which is a close homolog of AVR3a, is required for binding to phosphatidylinositol monophosphates (PIPs). However, in our previous report, AVR3a as well as Avr1b bind to PIPs not via RXLR but via lysine residues forming a positively-charged area in the effector domain. In this report, we examined whether other RXLR effectors whose structures have been determined bind to PIPs. Both P. capsici AVR3a11 and Hyaloperonospora arabidopsidis ATR1 have an RXLR motif in their N-terminal regions but did not bind to any PIPs. These results suggest that the RXLR motif is not sufficient for PIP binding. PMID:23425855

Yaeno, Takashi; Shirasu, Ken

2013-04-01

100

Pneumatically Actuated Flexible Coupling end Effectors for Lapping/Polishing.  

National Technical Information Service (NTIS)

Methods and apparatus for end effectors for performing surface lapping using a robotic system are provided. In one embodiment, a lapping system includes a robotic arm and a pneumatic end effector unit. The pneumatic end effector unit includes a first base...

J. H. Wood

2004-01-01

101

Computational and Biochemical Analysis of the Xanthomonas Effector AvrBs2 and Its Role in the Modulation of Xanthomonas Type Three Effector Delivery  

PubMed Central

Effectors of the bacterial type III secretion system provide invaluable molecular probes to elucidate the molecular mechanisms of plant immunity and pathogen virulence. In this report, we focus on the AvrBs2 effector protein from the bacterial pathogen Xanthomonas euvesicatoria (Xe), the causal agent of bacterial spot disease of tomato and pepper. Employing homology-based structural analysis, we generate a three-dimensional structural model for the AvrBs2 protein and identify catalytic sites in its putative glycerolphosphodiesterase domain (GDE). We demonstrate that the identified catalytic region of AvrBs2 was able to functionally replace the GDE catalytic site of the bacterial glycerophosphodiesterase BhGlpQ cloned from Borrelia hermsii and is required for AvrBs2 virulence. Mutations in the GDE catalytic domain did not disrupt the recognition of AvrBs2 by the cognate plant resistance gene Bs2. In addition, AvrBs2 activation of Bs2 suppressed subsequent delivery of other Xanthomonas type III effectors into the host plant cells. Investigation of the mechanism underlying this modulation of the type III secretion system may offer new strategies to generate broad-spectrum resistance to bacterial pathogens.

Zhao, Bingyu; Dahlbeck, Douglas; Krasileva, Ksenia V.; Fong, Richard W.; Staskawicz, Brian J.

2011-01-01

102

Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection  

PubMed Central

Using a model of lethal oral infection with Toxoplasma gondii, we examined the fate of both induced and natural regulatory T (Treg) cells in the face of strong inflammatory responses occurring in a tolerogenic-prone environment. We found that during highly T helper 1 (Th1) cell-polarized mucosal immune responses, Treg cell numbers collapsed via multiple pathways including blockade of Treg cell induction and disruption of endogenous Treg cell homeostasis. In particular, shutdown of interleukin 2 (IL-2) in the highly Th1 cell-polarized environment triggered by infection directly contributed to Treg cell incapacity to suppress effector responses and eventually leads to immunopathogenesis. Furthermore, we found that environmental cues provided by both local dendritic cells and effector T cells can induce the expression of T-bet transcription factor and IFN-? by Treg cells. These data reveal a mechanism for Th1 cell pathogenicity that extends beyond their proinflammatory program to limit Treg cell survival.

Oldenhove, Guillaume; Bouladoux, Nicolas; Wohlfert, Elizabeth A.; Hall, Jason; Chou, David; Dos santos, Liliane; O'Brien, Shaun; Blank, Rebecca; Lamb, Erika; Natarajan, Sundar; Kastenmayer, Robin; Hunter, Christopher; Grigg, Michael E.; Belkaid, Yasmine

2009-01-01

103

Fire Suppression  

Microsoft Academic Search

\\u000a Water sprinkler sprays (with relatively large droplet sizes) in residential and commercial structures are probably the most\\u000a well-known application of sprays in fire suppression. In more recent years, water mists (characterized by reduced droplet\\u000a sizes, which may contain additives) have been considered as a replacement for Halon 1301, the most common fire suppressant\\u000a chemical aboard aircraft and ships, but banned

C. Presser; J. C. Yang

104

Mutagenesis of 18 type III effectors reveals virulence function of XopZ(PXO99) in Xanthomonas oryzae pv. oryzae.  

PubMed

Xanthomonas oryzae pv. oryzae depends on a type III secretion system (T3SS) to translocate effectors into host cells for its ability to cause bacterial blight of rice. All type III (T3) effectors with known function in X. oryzae pv. oryzae belong to a family of transcription activator-like (TAL) effectors. However, other, non-TAL-related effector genes are present in the genome, although their role in virulence and their mode of action have yet to be elucidated. Here, we report the generation of mutants for 18 non-TAL T3 effector genes and the identification of one that contributes to the virulence of strain PXO99(A). XopZ(PXO99) encodes a predicted 1,414-amino-acid protein of unknown function. PXO99(A) contains two identical copies of the gene due to a duplication of 212 kb in the genome. Strains with knockout mutations of one copy of XopZ(PXO99) did not exhibit any visible virulence defect. However, strains with mutations in both copies of XopZ(PXO99) displayed reduced virulence in terms of lesion length and bacterial multiplication compared with PXO99(A). The introduction of one genomic copy of XopZ(PXO99) restores the mutant to full virulence. Transient expression of XopZ(PXO99) in Nicotiana benthamiana leaves suppresses host basal defense, which is otherwise induced by a T3SS mutant of PXO99(A), suggesting a role for XopZ(PXO99) in interfering with host innate immunity during X. oryzae pv. oryzae infection. XopZ(PXO99)-related genes are found in all Xanthomonas spp. whose genomic sequences have been determined, suggesting a conserved role for this type of effector gene in pathogenesis of Xanthomonas spp. Our results indicate that XopZ(PXO99) encodes a novel T3 effector and contributes virulence to X. oryzae pv. oryzae strains for bacterial blight of rice. PMID:20521952

Song, Congfeng; Yang, Bing

2010-07-01

105

Identification of Two Legionella pneumophila Effectors that Manipulate Host Phospholipids Biosynthesis  

PubMed Central

The intracellular pathogen Legionella pneumophila translocates a large number of effector proteins into host cells via the Icm/Dot type-IVB secretion system. Some of these effectors were shown to cause lethal effect on yeast growth. Here we characterized one such effector (LecE) and identified yeast suppressors that reduced its lethal effect. The LecE lethal effect was found to be suppressed by the over expression of the yeast protein Dgk1 a diacylglycerol (DAG) kinase enzyme and by a deletion of the gene encoding for Pah1 a phosphatidic acid (PA) phosphatase that counteracts the activity of Dgk1. Genetic analysis using yeast deletion mutants, strains expressing relevant yeast genes and point mutations constructed in the Dgk1 and Pah1 conserved domains indicated that LecE functions similarly to the Nem1-Spo7 phosphatase complex that activates Pah1 in yeast. In addition, by using relevant yeast genetic backgrounds we examined several L. pneumophila effectors expected to be involved in phospholipids biosynthesis and identified an effector (LpdA) that contains a phospholipase-D (PLD) domain which caused lethal effect only in a dgk1 deletion mutant of yeast. Additionally, LpdA was found to enhance the lethal effect of LecE in yeast cells, a phenomenon which was found to be dependent on its PLD activity. Furthermore, to determine whether LecE and LpdA affect the levels or distribution of DAG and PA in-vivo in mammalian cells, we utilized fluorescent DAG and PA biosensors and validated the notion that LecE and LpdA affect the in-vivo levels and distribution of DAG and PA, respectively. Finally, we examined the intracellular localization of both LecE and LpdA in human macrophages during L. pneumophila infection and found that both effectors are localized to the bacterial phagosome. Our results suggest that L. pneumophila utilize at least two effectors to manipulate important steps in phospholipids biosynthesis.

Viner, Ram; Chetrit, David; Ehrlich, Marcelo; Segal, Gil

2012-01-01

106

Novel type of Ras effector interaction established between tumour suppressor NORE1A and Ras switch II.  

PubMed

A class of putative Ras effectors called Ras association domain family (RASSF) represents non-enzymatic adaptors that were shown to be important in tumour suppression. RASSF5, a member of this family, exists in two splice variants known as NORE1A and RAPL. Both of them are involved in distinct cellular pathways triggered by Ras and Rap, respectively. Here we describe the crystal structure of Ras in complex with the Ras binding domain (RBD) of NORE1A/RAPL. All Ras effectors share a common topology in their RBD creating an interface with the switch I region of Ras, whereas NORE1A/RAPL RBD reveals additional structural elements forming a unique Ras switch II binding site. Consequently, the contact area of NORE1A is extended as compared with other Ras effectors. We demonstrate that the enlarged interface provides a rationale for an exceptionally long lifetime of the complex. This is a specific attribute characterizing the effector function of NORE1A/RAPL as adaptors, in contrast to classical enzymatic effectors such as Raf, RalGDS or PI3K, which are known to form highly dynamic short-lived complexes with Ras. PMID:18596699

Stieglitz, Benjamin; Bee, Christine; Schwarz, Daniel; Yildiz, Ozkan; Moshnikova, Anna; Khokhlatchev, Andrei; Herrmann, Christian

2008-07-23

107

Design and fabrication of an end effector  

NASA Technical Reports Server (NTRS)

The construction is described of a prototype mechanical hand or 'end effector' for use on a remotely controlled robot, but with possible application as a prosthetic device. An analysis of hand motions is reported, from which it is concluded that the two most important manipulations (apart from grasps) are to be able to pick up a tool and draw it into a nested grip against the palm, and to be able to hold a pistol-grip tool such as an electric drill and pull the trigger. A model was tested and found capable of both these operations.

Crossley, F. R. E.; Umholtz, F. G.

1975-01-01

108

TAL Effector-Nucleotide Targeter (TALE-NT) 2.0: tools for TAL effector design and target prediction  

PubMed Central

Transcription activator-like (TAL) effectors are repeat-containing proteins used by plant pathogenic bacteria to manipulate host gene expression. Repeats are polymorphic and individually specify single nucleotides in the DNA target, with some degeneracy. A TAL effector-nucleotide binding code that links repeat type to specified nucleotide enables prediction of genomic binding sites for TAL effectors and customization of TAL effectors for use in DNA targeting, in particular as custom transcription factors for engineered gene regulation and as site-specific nucleases for genome editing. We have developed a suite of web-based tools called TAL Effector-Nucleotide Targeter 2.0 (TALE-NT 2.0; https://boglab.plp.iastate.edu/) that enables design of custom TAL effector repeat arrays for desired targets and prediction of TAL effector binding sites, ranked by likelihood, in a genome, promoterome or other sequence of interest. Search parameters can be set by the user to work with any TAL effector or TAL effector nuclease architecture. Applications range from designing highly specific DNA targeting tools and identifying potential off-target sites to predicting effector targets important in plant disease.

Doyle, Erin L.; Booher, Nicholas J.; Standage, Daniel S.; Voytas, Daniel F.; Brendel, Volker P.; VanDyk, John K.; Bogdanove, Adam J.

2012-01-01

109

IgG2a Monoclonal Antibodies Inhibit Human Tumor Growth through Interaction with Effector Cells  

NASA Astrophysics Data System (ADS)

Monoclonal antibodies of IgG2a isotype specifically inhibited growth of human tumors in nude mice. Twentythree monoclonal antibodies of other isotypes showed no tumoricidal reactivity. Complement depletion of nude mice had no effect on tumor suppression by monoclonal antibody. The role of T and killer cells as mediators of the monoclonal antibody effect in nude mice was virtually excluded. On the other hand, macrophages were strongly incriminated as effector cells because silica treatment of nude mice abolished the tumoricidal effect of monoclonal antibody. IgG2a monoclonal antibody-dependent macrophagemediated cytotoxicity assays with human tumor cells in culture resulted in specific lysis of tumor cells.

Herlyn, Dorothee; Koprowski, Hilary

1982-08-01

110

Adenosine A2A receptor activation inhibits T helper 1 and T helper 2 cell development and effector function  

Microsoft Academic Search

Adenosine is an immunosuppressive nu- cleoside, and adenosine A2A receptors inhibit T-cell acti- vation. We investigated the role of A2A receptors in regulating T helper (Th)1- and Th2-cell development and effector function. A2A-receptor stimulation suppressed the development of T-cell receptor (TCR) -stimulated naive T cells into both Th1 and Th2 cells, as indicated by decreased IFN- production by cells developed

Balazs Csoka; Leonora Himer; Zsolt Selmeczy; E. Sylvester Vizi; Pal Pacher; Catherine Ledent; Edwin A. Deitch; Zoltan Spolarics; Zoltan H. Nemeth; Gyorgy Hasko

2008-01-01

111

Stress protein-induced immunosuppression: inhibition of cellular immune effector functions following overexpression of haem oxygenase (HSP 32)  

Microsoft Academic Search

This is the first report on suppression of immune effector functions following upregulation of heat shock protein 32 (HSP 32), known as haem oxygenase (HO-1). Here we evaluated the effect of cobalt-protoporphyrin (CoPP)-induced HO-1 expression on cell-mediated immune responses. Administration of CoPP to CBA mice resulted in overexpression of HO-1 in the spleen, liver and kidneys. In vitro measurements of

Jacky Woo; Suhasini Iyer; Marie-Christine Cornejo; Nancy Mori; Lan Gao; Isabelle Sipos; Mahin Maines; Roland Buelow

1998-01-01

112

New perspectives on effector mechanisms in uveitis.  

PubMed

Experimental autoimmune uveitis (EAU) in its several variants represents human autoimmune uveitis and has been instrumental in obtaining insights into the basic mechanisms of disease. Studies have uncovered that in addition to CD4+ Th1 cells, uveitis can be induced also by CD8+ T cells. Antibodies may have a secondary role after the blood-retinal barrier has been broken. The role in uveitis of a recently discovered IL-17-producing effector T cell type, Th17, is being intensively studied. Th17 cells elicit EAU, can be found in uveitic eyes along with Th1 cells, and are dominant in some types of EAU. In other types of EAU, Th1 cells have a dominant role. The dominant effector type is at least in part determined by conditions under which initial exposure to self-antigen occurs. These findings shed light on the heterogeneity of human disease and may ultimately help to develop better and more rational treatment strategies for human uveitis. PMID:18317764

Luger, Dror; Caspi, Rachel R

2008-04-01

113

Exploitation of Eukaryotic Subcellular Targeting Mechanisms by Bacterial Effectors  

PubMed Central

Several bacteria have evolved specialized secretion systems to deliver bacterial effector proteins into eukaryotic cells with the capacity to modulate cellular pathways to promote bacterial survival and replication. The spatial and temporal context in which effectors exert their biochemical activities is critical for their function. Understanding the mechanisms that lead to their precise subcellular localization following delivery into host cells is essential for understanding effector function in the context of infection. Recent studies have shown that bacterial effectors exploit host cellular machinery to accurately target their biochemical activities within the host cell.

Hicks, Stuart W.; Galan, Jorge E.

2013-01-01

114

Pseudomonas syringae effector AvrPto blocks innate immunity by targeting receptor kinases.  

PubMed

Plants use receptor kinases, such as FLS2 and EFR, to perceive bacterial pathogens and initiate innate immunity. This immunity is often suppressed by bacterial effectors, allowing pathogen propagation. To counteract, plants have evolved disease resistance genes that detect the bacterial effectors and reinstate resistance. The Pseudomonas syringae effector AvrPto promotes infection in susceptible plants but triggers resistance in plants carrying the protein kinase Pto and the associated resistance protein Prf. Here we show that AvrPto binds receptor kinases, including Arabidopsis FLS2 and EFR and tomato LeFLS2, to block plant immune responses in the plant cell. The ability to target receptor kinases is required for the virulence function of AvrPto in plants. The FLS2-AvrPto interaction and Pto-AvrPto interaction appear to share similar sequence requirements, and Pto competes with FLS2 for AvrPto binding. The results suggest that the mechanism by which AvrPto recognizes virulence targets is linked to the evolution of Pto, which, in association with Prf, recognizes the bacterium and triggers strong resistance. PMID:18158241

Xiang, Tingting; Zong, Na; Zou, Yan; Wu, Yong; Zhang, Jie; Xing, Weiman; Li, Yan; Tang, Xiaoyan; Zhu, Lihuang; Chai, Jijie; Zhou, Jian-Min

2008-01-01

115

Fc gamma receptor IIB on dendritic cells enforces peripheral tolerance by inhibiting effector T cell responses.  

PubMed

The uptake of immune complexes by FcRs on APCs augments humoral and cellular responses to exogenous Ag. In this study, CD11c+ dendritic cells are shown to be responsible in vivo for immune complex-triggered priming of T cells. We examine the consequence of Ab-mediated uptake of self Ag by dendritic cells in the rat insulin promoter-membrane OVA model and identify a role for the inhibitory FcgammaRIIB in the maintenance of peripheral CD8 T cell tolerance. Effector differentiation of diabetogenic OT-I CD8+ T cells is enhanced in rat insulin promoter-membrane OVA mice lacking FcgammaRIIB, resulting in a high incidence of diabetes. FcgammaRIIB-mediated inhibition of CD8 T cell priming results from suppression of both DC activation and cross-presentation through activating FcgammaRs. Further FcgammaRIIB on DCs inhibited the induction of OVA-specific Th1 effectors, limiting Th1-type differentiation and memory T cell accumulation. In these MHC II-restricted responses, the presence of FcgammaRIIB only modestly affected initial CD4 T cell proliferative responses, suggesting that FcgammaRIIB limited effector cell differentiation primarily by inhibiting DC activation. Thus, FcgammaRIIB can contribute to peripheral tolerance maintenance by inhibiting DC activation alone or by also limiting processing of exogenously acquired Ag. PMID:17475849

Desai, Dharmesh D; Harbers, Stephanie O; Flores, Marcella; Colonna, Lucrezia; Downie, Matthew P; Bergtold, Amy; Jung, Steffen; Clynes, Raphael

2007-05-15

116

The necrotrophic effector SnToxA induces the synthesis of a novel phytoalexin in wheat.  

PubMed

Stagonospora nodorum and Pyrenophora tritici-repentis produce the effector ToxA that interacts with the dominant susceptibility gene in wheat, Tsn1. However, the way in which ToxA induces cell death and causes disease is unclear. Here, we performed comprehensive metabolite profiling of ToxA-infiltrated wheat (Triticum aestivum) to observe the secondary metabolite response to this effector. A strong induction of secondary metabolism subsequent to SnToxA infiltration was observed, including the monoamine serotonin. We established a novel role for serotonin as a phytoalexin in wheat and demonstrated that serotonin strongly inhibited sporulation of S. nodorum. Microscopy revealed that serotonin interferes with spore formation and maturation within pycnidial structures of the fungus. Subsequent analysis of S. nodorum exposed to serotonin revealed metabolites changes previously associated with sporulation, including trehalose and alternariol. Furthermore, we identified significantly lower concentrations of serotonin during infection compared with infiltration with ToxA, providing evidence that S. nodorum may suppress plant defence. This is the first study demonstrating induction of plant secondary metabolites in response to a necrotrophic effector that have significant antifungal potential against the pathogen. While it is generally accepted that necrotrophs exploit host cell responses, the current research strengthens the notion that necrotrophs require mechanisms to overcome plant defence to survive initial stages of infection. PMID:23782173

Du Fall, Lauren A; Solomon, Peter S

2013-10-01

117

Autophagy as an immune effector against tuberculosis  

PubMed Central

Summary The now well-accepted innate immunity paradigm that autophagy acts as a cell-autonomous defense against intracellular bacteria has its key origins in studies with Mycobacterium tuberculosis, an important human pathogen and a model microorganism infecting macrophages. A number of different factors have been identified that play into the anti-mycobacterial functions of autophagy, and recent in vivo studies in the mouse model of tuberculosis have uncovered additional anti-inflammatory and tissue-sparing functions of autophagy. Complementing these observations, genome wide association studies indicate a considerable overlap between autophagy, human susceptibility to mycobacterial infections, and predisposition loci for inflammatory bowel disease. Finally, recent studies show that autophagy is an important regulator and effector of IL-1 responses, and that autophagy intersects with type I interferon pathology-modulating responses.

Bradfute, Steven B.; Castillo, Eliseo F.; Arko-Mensah, John; Chauhan, Santosh; Jiang, Shanya; Mandell, Michael; Deretic, Vojo

2013-01-01

118

Rack Insertion End Effector (RIEE) automation  

NASA Technical Reports Server (NTRS)

NASA is developing a mechanism to manipulate and insert Racks into the Space Station Logistic modules. The mechanism consists of the following: a base with three motorized degrees of freedom, a 3 section motorized boom that goes from 15 to 44 feet in length, and a Rack Insertion End Effector (RIEE) with 5 hand wheels for precise alignment. The robotics section was tasked with the automation of the RIEE unit. In this report, for the automation of the RIEE unit, application of the Perceptics Vision System was conceptually developed to determine the position and orientation of the RIEE relative to the logistic module, and a MathCad program is written to display the needed displacements for precise alignment and final insertion of the Rack. The uniqueness of this report is that the whole report is in fact a MathCad program including text, derivations, and executable equations with example inputs and outputs.

Malladi, Narasimha

1993-01-01

119

Plant immunity: a lesson from pathogenic bacterial effector proteins  

Microsoft Academic Search

Summary Phytopathogenic bacteria inject an array of effec- tor proteins into host cells to alter host physiology and assist the infection process. Some of these effectors can also trigger disease resistance as a result of recognition in the plant cell by cyto- plasmic immune receptors. In addition to effector- triggered immunity, plants immunity can be triggered upon the detection of

Haitao Cui; Tingting Xiang; Jian-Min Zhou

2009-01-01

120

Tissue-tropic effector T cells: generation and targeting opportunities  

Microsoft Academic Search

The localization of effector T cells to extralymphoid tissues is crucial for the generation of an effective immune response, but it also underlies many autoimmune and inflammatory disorders. Recent studies have highlighted a central role for draining lymph nodes and environmentally imprinted dendritic cells in the generation of tissue-tropic effector T cells. Here, I outline our current understanding of the

William W. Agace

2006-01-01

121

Double lead spiral platen parallel jaw end effector  

NASA Technical Reports Server (NTRS)

The double lead spiral platen parallel jaw end effector is an extremely powerful, compact, and highly controllable end effector that represents a significant improvement in gripping force and efficiency over the LaRC Puma (LP) end effector. The spiral end effector is very simple in its design and has relatively few parts. The jaw openings are highly predictable and linear, making it an ideal candidate for remote control. The finger speed is within acceptable working limits and can be modified to meet the user needs; for instance, greater finger speed could be obtained by increasing the pitch of the spiral. The force relaxation is comparable to the other tested units. Optimization of the end effector design would involve a compromise of force and speed for a given application.

Beals, David C.

1989-01-01

122

Tissue Specific Heterogeneity in Effector Immune Cell Response  

PubMed Central

Post pathogen invasion, migration of effector T-cell subsets to specific tissue locations is of prime importance for generation of robust immune response. Effector T cells are imprinted with distinct “homing codes” (adhesion molecules and chemokine receptors) during activation which regulate their targeted trafficking to specific tissues. Internal cues in the lymph node microenvironment along with external stimuli from food (vitamin A) and sunlight (vitamin D3) prime dendritic cells, imprinting them to play centre stage in the induction of tissue tropism in effector T cells. B cells as well, in a manner similar to effector T cells, exhibit tissue-tropic migration. In this review, we have focused on the factors regulating the generation and migration of effector T cells to various tissues along with giving an overview of tissue tropism in B cells.

Tufail, Saba; Badrealam, Khan Farheen; Sherwani, Asif; Gupta, Umesh D.; Owais, Mohammad

2013-01-01

123

Advanced Aerodynamic Design of Passive Porosity Control Effectors  

NASA Technical Reports Server (NTRS)

This paper describes aerodynamic design work aimed at developing a passive porosity control effector system for a generic tailless fighter aircraft. As part of this work, a computational design tool was developed and used to layout passive porosity effector systems for longitudinal and lateral-directional control at a low-speed, high angle of attack condition. Aerodynamic analysis was conducted using the NASA Langley computational fluid dynamics code USM3D, in conjunction with a newly formulated surface boundary condition for passive porosity. Results indicate that passive porosity effectors can provide maneuver control increments that equal and exceed those of conventional aerodynamic effectors for low-speed, high-alpha flight, with control levels that are a linear function of porous area. This work demonstrates the tremendous potential of passive porosity to yield simple control effector systems that have no external moving parts and will preserve an aircraft's fixed outer mold line.

Hunter, Craig A.; Viken, Sally A.; Wood, Richard M.; Bauer, Steven X. S.

2001-01-01

124

Action selection in multi-effector decision making  

PubMed Central

Decision making and reinforcement learning over movements suffer from the curse of dimensionality: the space of possible movements is too vast to search or even represent in its entirety. When actions involve only a single effector, this problem can be ameliorated by considering that effector separately; accordingly, the brain’s sensorimotor systems can subdivide choice by representing values and actions separately for each effector. However, for many actions, such as playing the piano, the value of an action by an effector (e.g., a hand) depends inseparably on the actions of other effectors. By definition, the values of such coordinated multi-effector actions cannot be represented by effector-specific action values, such as those that have been most extensively investigated in parietal and premotor regions. For such actions, one possible solution is to choose according to more abstract valuations over different goods or options, which can then be mapped onto the necessary motor actions. Such an approach separates the learning and decision problem, which will often be lower-dimensional than the space of possible movements, from the multi-effector movement planning problem. The ventromedial prefrontal cortex (vmPFC) is thought to contain goods-based value signals, so we hypothesized that this region might preferentially drive multi-effector action selection. To examine how the brain solves this problem, we used fMRI to compare patterns of BOLD activity in humans during reward learning tasks in which options were selected through either unimanual or bimanual actions, and in which the response requirements in the latter condition inseparably coupled valuation across both hands. We found value signals in the bilateral medial motor cortex and vmPFC, and consistent with previous studies, the medial motor value signals contained contra-lateral biases indicating effector-specificity, while the vmPFC value signals did not exhibit detectable effector specificity. Although neither region’s value signaling differed significantly between bimanual and unimanual conditions, the vmPFC value region showed enhanced connectivity with the medial motor cortex during bimanual than during unimanual choices. The specific region implicated, the anterior mid-cingulate cortex, is thought to act as a hub that links subjective value signals to motor control centers. These results are consistent with the idea that while valuation for unilateral actions may be subserved by an effector-specific network, complex multi-effector actions preferentially implicate communication between motor regions and prefrontal regions, which may reflect increased top-down input into motor regions to guide action selection.

Madlon-Kay, Seth; Pesaran, Bijan; Daw, Nathaniel D.

2012-01-01

125

T-regulatory cells and programmed death 1(+) T cells contribute to effector T-cell dysfunction in patients with chronic obstructive pulmonary disease.  

PubMed

Rationale: Previous studies from our laboratory have shown that peripheral blood mononuclear cells (PBMCs) from patients with chronic obstructive pulmonary disease (COPD) prone to exacerbations with nontypeable Haemophilus influenzae have impaired responses to lipoprotein P6. We hypothesized that an underlying immunosuppressive network could be responsible for the defective antibacterial immunity observed in these patients. We evaluated T regulatory cells (Tregs), myeloid-derived suppressor cells (MDSC), and exhausted T effector cells (programmed death 1 [PD-1](+)) in patients with COPD, because these cells are known to play a pivotal role in suppressing immune responses. Objectives: We performed an in-depth characterization of Tregs, T effector cells, and MDSC in COPD and correlated their levels and function with disease severity. Methods: Treg, effector T cell, and MDSC frequency from patients with COPD and healthy subjects' PBMCs were analyzed by flow cytometry. Treg immunosuppressive capacity was measured by in vitro suppression assay. The frequency of interferon-? producing T cells and T-cell proliferation were measured after blocking CTLA-4 and PD-1. Plasma proinflammatory and immunosuppressive cytokine levels were measured. Measurements and Main Results: Significantly increased levels of Tregs, MDSC, and PD-1(+) exhausted effector T cells were present in patients with COPD compared with healthy subjects. Tregs from patients with COPD suppressed P6-specific T-cell proliferation to a greater extent than Tregs from healthy subjects. Plasma levels of Treg-generated cytokines, IL-10, and transforming growth factor-? were elevated. Blockade of CTLA-4 resulted in significant augmentation of T-cell IFN-? production in patients with COPD. Conclusions: Functionally suppressive Tregs, MDSCs, and exhausted PD-1(+) T cells contribute to effector T-cell dysfunction in COPD. PMID:24825462

Kalathil, Suresh Gopi; Lugade, Amit Anand; Pradhan, Vandana; Miller, Austin; Parameswaran, Ganapathi Iyer; Sethi, Sanjay; Thanavala, Yasmin

2014-07-01

126

System for exchanging tools and end effectors on a robot  

SciTech Connect

A system and method for exchanging tools and end effectors on a robot permits exchange during a programmed task. The exchange mechanism is located off the robot, thus reducing the mass of the robot arm and permitting smaller robots to perform designated tasks. A simple spring/collet mechanism mounted on the robot is used which permits the engagement and disengagement of the tool or end effector without the need for a rotational orientation of the tool to the end effector/collet interface. As the tool changing system is not located on the robot arm no umbilical cords are located on robot.

Burry, David B. (Westminster, CO); Williams, Paul M. (Lafayette, CO)

1991-02-19

127

System for exchanging tools and end effectors on a robot  

DOEpatents

A system and method for exchanging tools and end effectors on a robot permits exchange during a programmed task. The exchange mechanism is located off the robot, thus reducing the mass of the robot arm and permitting smaller robots to perform designated tasks. A simple spring/collet mechanism mounted on the robot is used which permits the engagement and disengagement of the tool or end effector without the need for a rotational orientation of the tool to the end effector/collet interface. As the tool changing system is not located on the robot arm no umbilical cords are located on robot. 12 figures.

Burry, D.B.; Williams, P.M.

1991-02-19

128

Rack Insertion End Effector (RIEE) guidance  

NASA Astrophysics Data System (ADS)

NASA-KSC has developed a mechanism to handle and insert Racks into the Space Station Logistic Modules. This mechanism consists of a Base with 3 motorized degrees of freedom, a 3 section motorized Boom that goes from 15 to 44 feet in length, and a Rack Insertion End Effector (RIEE) with 5 hand wheels for precise alignment. During the 1993 NASA-ASEE Summer Faculty Fellowship Program at KSC, I designed an Active Vision (Camera) Arrangement and developed an algorithm to determine (1) the displacements required by the Room for its initial positioning and (2) the rotations required at the five hand-wheels of the RIEE, for the insertion of the Rack, using the centroids fo the Camera Images of the Location Targets in the Logistic Module. Presently, during the summer of '94, I completed the preliminary design of an easily portable measuring instrument using encoders to obtain the 3-Dimensional Coordinates of Location Targets in the Logistics Module relative to the RIEE mechanism frame. The algorithm developed in '93 can use the output of this instrument also. Simplification of the '93 work and suggestions for the future work are discussed.

Malladi, Narasimha S.

1994-10-01

129

Bioprospecting open reading frames for peptide effectors.  

PubMed

Recent successes in the development of small-molecule antagonists of protein-protein interactions designed based on co-crystal structures of peptides bound to their biological targets confirm that short peptides derived from interacting proteins can be high-value ligands for pharmacologic validation of targets and for identification of druggable sites. Evolved sequence space is likely to be enriched for interacting peptides, but identifying minimal peptide effectors within genomic sequence can be labor intensive. Here we describe the use of incremental truncation to diversify genetic material on the scale of open reading frames into comprehensive libraries of constituent peptides. The approach is capable of generating peptides derived from both continuous and discontinuous sequence elements, and is compatible with the expression of free linear or backbone cyclic peptides, with peptides tethered to amino- or carboxyl-terminal fusion partners or with the expression of peptides displayed within protein scaffolds (peptide aptamers). Incremental truncation affords a valuable source of molecular diversity to interrogate the druggable genome or evaluate the therapeutic potential of candidate genes. PMID:24146398

Xiong, Ling; Scott, Charles

2014-01-01

130

Rack Insertion End Effector (RIEE) guidance  

NASA Technical Reports Server (NTRS)

NASA-KSC has developed a mechanism to handle and insert Racks into the Space Station Logistic Modules. This mechanism consists of a Base with 3 motorized degrees of freedom, a 3 section motorized Boom that goes from 15 to 44 feet in length, and a Rack Insertion End Effector (RIEE) with 5 hand wheels for precise alignment. During the 1993 NASA-ASEE Summer Faculty Fellowship Program at KSC, I designed an Active Vision (Camera) Arrangement and developed an algorithm to determine (1) the displacements required by the Room for its initial positioning and (2) the rotations required at the five hand-wheels of the RIEE, for the insertion of the Rack, using the centroids fo the Camera Images of the Location Targets in the Logistic Module. Presently, during the summer of '94, I completed the preliminary design of an easily portable measuring instrument using encoders to obtain the 3-Dimensional Coordinates of Location Targets in the Logistics Module relative to the RIEE mechanism frame. The algorithm developed in '93 can use the output of this instrument also. Simplification of the '93 work and suggestions for the future work are discussed.

Malladi, Narasimha S.

1994-01-01

131

Hippo pathway effector Yap promotes cardiac regeneration.  

PubMed

The adult mammalian heart has limited potential for regeneration. Thus, after injury, cardiomyocytes are permanently lost, and contractility is diminished. In contrast, the neonatal heart can regenerate owing to sustained cardiomyocyte proliferation. Identification of critical regulators of cardiomyocyte proliferation and quiescence represents an important step toward potential regenerative therapies. Yes-associated protein (Yap), a transcriptional cofactor in the Hippo signaling pathway, promotes proliferation of embryonic cardiomyocytes by activating the insulin-like growth factor and Wnt signaling pathways. Here we report that mice bearing mutant alleles of Yap and its paralog WW domain containing transcription regulator 1 (Taz) exhibit gene dosage-dependent cardiac phenotypes, suggesting redundant roles of these Hippo pathway effectors in establishing proper myocyte number and maintaining cardiac function. Cardiac-specific deletion of Yap impedes neonatal heart regeneration, resulting in a default fibrotic response. Conversely, forced expression of a constitutively active form of Yap in the adult heart stimulates cardiac regeneration and improves contractility after myocardial infarction. The regenerative activity of Yap is correlated with its activation of embryonic and proliferative gene programs in cardiomyocytes. These findings identify Yap as an important regulator of cardiac regeneration and provide an experimental entry point to enhance this process. PMID:23918388

Xin, Mei; Kim, Yuri; Sutherland, Lillian B; Murakami, Masao; Qi, Xiaoxia; McAnally, John; Porrello, Enzo R; Mahmoud, Ahmed I; Tan, Wei; Shelton, John M; Richardson, James A; Sadek, Hesham A; Bassel-Duby, Rhonda; Olson, Eric N

2013-08-20

132

Expressing the Erwinia amylovora type III effector DspA/E in the yeast Saccharomyces cerevisiae strongly alters cellular trafficking.  

PubMed

Erwinia amylovora is responsible for fire blight, a necrotic disease of apples and pears. E. amylovora relies on a type III secretion system (T3SS) to induce disease on host plants. DspA/E belongs to the AvrE family of type III effector. Effectors of the AvrE family are injected via the T3SS in plant cell and are important to promote bacterial growth following infection and to suppress plant defense responses. Their mode of action in the plant cells is unknown. Here we study the physiological effects induced by dspA/E expression in the yeast Saccharomyces cerevisiae. Expression of dspA/E in the yeast inhibits cell growth. This growth inhibition is associated with perturbations of the actin cytoskeleton and endocytosis. PMID:23650572

Siamer, Sabrina; Patrit, Oriane; Fagard, Mathilde; Belgareh-Touzé, Naïma; Barny, Marie-Anne

2011-12-01

133

Vision-based end-effector position error compensation  

NASA Technical Reports Server (NTRS)

This paper describes a computationally efficient algorithm that provides the ability to accurately place an arm end-effector on a target designated in an image using low speed feed back from a fixed stero camera.

Bajracharya, Max; Backes, Paul; DiCicco, Matthew

2006-01-01

134

Programmer's Guide to the Sensory-Effector Interface.  

National Technical Information Service (NTIS)

A Sensory-effector interface performs three major functions: maintaining its own copy of the world data structures, selecting information from these structures appropriate to the perception capabilities of a particular organism, and translating actions ta...

K. Barnett

1987-01-01

135

Design, testing and evaluation of latching end effector  

NASA Technical Reports Server (NTRS)

The Latching End Effector (LEE) forms part of the Space Station Remote Manipulator System (SSRMS) for which Spar Aerospace Ltd, Space Systems Division is the prime contractor. The design, testing and performance evaluation of the Latching End Effector mechanisms is the subject of this paper focusing on: (1) ambient, thermal and vibration testing; (2) snare/rigidize performance testing and interaction during payload acquisition; and (3) latch/umbilical test results and performance.

Walker, B.; Vandersluis, R.

1995-01-01

136

Functional heterogeneity of human effector CD8+ T cells.  

PubMed

Effector CD8(+) T cells are believed to be terminally differentiated cells having cytotoxic activity and the ability to produce effector cytokines such as INF-? and TNF-?. We investigated the difference between CXCR1(+) and CXCR1(-) subsets of human effector CD27(-)CD28(-)CD8(+) T cells. The subsets expressed cytolytic molecules similarly and exerted substantial cytolytic activity, whereas only the CXCR1(-) subset had IL-2 productivity and self-proliferative activity and was more resistant to cell death than the CXCR1(+) subset. These differences were explained by the specific up-regulation of CAMK4, SPRY2, and IL-7R in the CXCR1(-) subset and that of pro-apoptotic death-associated protein kinase 1 (DAPK1) in the CXCR1(+) subset. The IL-2 producers were more frequently found in the IL-7R(+) subset of the CXCR1(-) effector CD8(+) T cells than in the IL-7R(-) subset. IL-7/IL-7R signaling promoted cell survival only in the CXCR1(-) subset. The present study has highlighted a novel subset of effector CD8(+) T cells producing IL-2 and suggests the importance of this subset in the homeostasis of effector CD8(+) T cells. PMID:22174157

Takata, Hiroshi; Naruto, Takuya; Takiguchi, Masafumi

2012-02-01

137

Diverse type VI secretion phospholipases are functionally plastic antibacterial effectors.  

PubMed

Membranes allow the compartmentalization of biochemical processes and are therefore fundamental to life. The conservation of the cellular membrane, combined with its accessibility to secreted proteins, has made it a common target of factors mediating antagonistic interactions between diverse organisms. Here we report the discovery of a diverse superfamily of bacterial phospholipase enzymes. Within this superfamily, we defined enzymes with phospholipase A1 and A2 activity, which are common in host-cell-targeting bacterial toxins and the venoms of certain insects and reptiles. However, we find that the fundamental role of the superfamily is to mediate antagonistic bacterial interactions as effectors of the type VI secretion system (T6SS) translocation apparatus; accordingly, we name these proteins type VI lipase effectors. Our analyses indicate that PldA of Pseudomonas aeruginosa, a eukaryotic-like phospholipase D, is a member of the type VI lipase effector superfamily and the founding substrate of the haemolysin co-regulated protein secretion island II T6SS (H2-T6SS). Although previous studies have specifically implicated PldA and the H2-T6SS in pathogenesis, we uncovered a specific role for the effector and its secretory machinery in intra- and interspecies bacterial interactions. Furthermore, we find that this effector achieves its antibacterial activity by degrading phosphatidylethanolamine, the major component of bacterial membranes. The surprising finding that virulence-associated phospholipases can serve as specific antibacterial effectors suggests that interbacterial interactions are a relevant factor driving the continuing evolution of pathogenesis. PMID:23552891

Russell, Alistair B; LeRoux, Michele; Hathazi, Krisztina; Agnello, Danielle M; Ishikawa, Takahiko; Wiggins, Paul A; Wai, Sun Nyunt; Mougous, Joseph D

2013-04-25

138

Characterization of the Largest Effector Gene Cluster of Ustilago maydis  

PubMed Central

In the genome of the biotrophic plant pathogen Ustilago maydis, many of the genes coding for secreted protein effectors modulating virulence are arranged in gene clusters. The vast majority of these genes encode novel proteins whose expression is coupled to plant colonization. The largest of these gene clusters, cluster 19A, encodes 24 secreted effectors. Deletion of the entire cluster results in severe attenuation of virulence. Here we present the functional analysis of this genomic region. We show that a 19A deletion mutant behaves like an endophyte, i.e. is still able to colonize plants and complete the infection cycle. However, tumors, the most conspicuous symptoms of maize smut disease, are only rarely formed and fungal biomass in infected tissue is significantly reduced. The generation and analysis of strains carrying sub-deletions identified several genes significantly contributing to tumor formation after seedling infection. Another of the effectors could be linked specifically to anthocyanin induction in the infected tissue. As the individual contributions of these genes to tumor formation were small, we studied the response of maize plants to the whole cluster mutant as well as to several individual mutants by array analysis. This revealed distinct plant responses, demonstrating that the respective effectors have discrete plant targets. We propose that the analysis of plant responses to effector mutant strains that lack a strong virulence phenotype may be a general way to visualize differences in effector function.

Vincon, Volker; Kahmann, Regine

2014-01-01

139

The RalGEF-Ral Effector Signaling Network  

PubMed Central

The high frequency of RAS mutations in human cancers (33%) has stimulated intense interest in the development of anti-Ras inhibitors for cancer therapy. Currently, the major focus of these efforts is centered on inhibitors of components involved in Ras downstream effector signaling. In particular, more than 40 inhibitors of the Raf-MEK-ERK mitogen-activated protein kinase cascade and phosphoinositide 3-kinase-AKT-mTOR effector signaling networks are currently under clinical evaluation. However, these efforts are complicated by the fact that Ras can utilize at least 9 additional functionally distinct effectors, with at least 3 additional effectors with validated roles in Ras-mediated oncogenesis. Of these, the guanine nucleotide exchange factors of the Ras-like (Ral) small GTPases (RalGEFs) have emerged as important effectors of mutant Ras in pancreatic, colon, and other cancers. In this review, we summarize the evidence for the importance of this effector pathway in cancer and discuss possible directions for therapeutic inhibition of aberrant Ral activation and signaling.

Neel, Nicole F.; Martin, Timothy D.; Stratford, Jeran K.; Zand, Tanya P.; Reiner, David J.; Der, Channing J.

2011-01-01

140

A Pathogen Type III Effector with a Novel E3 Ubiquitin Ligase Architecture  

PubMed Central

Type III effectors are virulence factors of Gram-negative bacterial pathogens delivered directly into host cells by the type III secretion nanomachine where they manipulate host cell processes such as the innate immunity and gene expression. Here, we show that the novel type III effector XopL from the model plant pathogen Xanthomonas campestris pv. vesicatoria exhibits E3 ubiquitin ligase activity in vitro and in planta, induces plant cell death and subverts plant immunity. E3 ligase activity is associated with the C-terminal region of XopL, which specifically interacts with plant E2 ubiquitin conjugating enzymes and mediates formation of predominantly K11-linked polyubiquitin chains. The crystal structure of the XopL C-terminal domain revealed a single domain with a novel fold, termed XL-box, not present in any previously characterized E3 ligase. Mutation of amino acids in the central cavity of the XL-box disrupts E3 ligase activity and prevents XopL-induced plant cell death. The lack of cysteine residues in the XL-box suggests the absence of thioester-linked ubiquitin-E3 ligase intermediates and a non-catalytic mechanism for XopL-mediated ubiquitination. The crystal structure of the N-terminal region of XopL confirmed the presence of a leucine-rich repeat (LRR) domain, which may serve as a protein-protein interaction module for ubiquitination target recognition. While the E3 ligase activity is required to provoke plant cell death, suppression of PAMP responses solely depends on the N-terminal LRR domain. Taken together, the unique structural fold of the E3 ubiquitin ligase domain within the Xanthomonas XopL is unprecedented and highlights the variation in bacterial pathogen effectors mimicking this eukaryote-specific activity.

Skarina, Tatiana; Xu, Xiaohui; Cui, Hong; Eschen-Lippold, Lennart; Egler, Monique; Srikumar, Tharan; Raught, Brian; Lee, Justin; Scheel, Dierk; Savchenko, Alexei; Bonas, Ulla

2013-01-01

141

Multiple Activities of the Plant Pathogen Type III Effector Proteins WtsE and AvrE1 require WxxxE Motifs  

PubMed Central

The broadly conserved AvrE-family of type III effectors from Gram-negative plant pathogenic bacteria includes important virulence factors, yet little is known about the mechanisms by which these effectors function inside plant cells to promote disease. We have identified two conserved motifs in AvrE-family effectors: a WxxxE motif and a putative C-terminal endoplasmic reticulum membrane retention/retrieval signal (ERMRS). The WxxxE and ERMRS motifs are both required for the virulence activities of WtsE and AvrE1, which are major virulence factors of the corn pathogen Pantoea stewartii subsp. stewartii and the tomato/Arabidopsis pathogen Pseudomonas syringae pv. tomato, respectively. The WxxxE and the predicted ERMRS motifs are also required for other biological activities of WtsE, including elicitation of the hypersensitive response in nonhost plants and suppression of defense responses in Arabidopsis. A family of type III effectors from mammalian bacterial pathogens requires WxxxE and sub-cellular targeting motifs for virulence functions that involve their ability to mimic activated G-proteins. The conservation of related motifs and their necessity for the function of type III effectors from plant pathogens indicates that disturbing host pathways by mimicking activated host G-proteins may be a virulence mechanism employed by plant pathogens as well.

Ham, Jong Hyun; Majerczak, Doris R.; Nomura, Kinya; Mecey, Christy; Uribe, Francisco; He, Sheng-Yang; Mackey, David; Coplin, David L.

2009-01-01

142

'Drugs from bugs': bacterial effector proteins as promising biological (immune-) therapeutics.  

PubMed

Immune system malfunctions cause many of the most severe human diseases. The immune system has evolved primarily to control bacterial, viral, fungal, and parasitic infections. In turn, over millions of years of coevolution, microbial pathogens have evolved various mechanisms to control and modulate the host immune system for their own benefit and survival. For example, many bacterial pathogens use virulence proteins to modulate and exploit target cell mechanisms. Our understanding of these bacterial strategies opens novel possibilities to exploit 'microbial knowledge' to control excessive immune reactions. Gaining access to strategies of microbial pathogens could lead to potentially huge benefits for the therapy of inflammatory diseases. Most work on bacterial pathogen effector proteins has the long-term aim of neutralizing the infectious capabilities of the pathogen. However, attenuated pathogens and microbial products have been used for over a century with overwhelming success in the form of vaccines to induce specific immune responses that protect against the respective infectious diseases. In this review, we focus on bacterial effector and virulence proteins capable of modulating and suppressing distinct signaling pathways with potentially desirable immune-modulating effects for treating unrelated inflammatory diseases. PMID:24261744

Rüter, Christian; Hardwidge, Philip R

2014-02-01

143

Effector and suppressor circuits of the immune response are activated in vivo by different mechanisms  

SciTech Connect

The application of fluorescein isothiocyanate (FITC) onto the skin of mice induces a contact hypersensitivity immune response. Lymph nodes draining the skin painted with FITC contain fluorescent cells that induce contact hypersensitivity to FITC when injected into normal mice. The antigen-presenting cells responsible for activating the effector pathway of the contact hypersensitivity response express Ia histocompatibility determinants and are resistant to inactivation with gamma-radiation. Exposing the skin to low doses of UV radiation (280-320 nm) before the application of FITC suppresses the contact hypersensitivity response to FITC. Cells present in the draining lymph nodes of these mice induce suppressor T lymphocytes when injected into normal recipients. The inducer cells in the draining lymph nodes are Thy 1+, Ia- and are inactivated by gamma-radiation. These studies demonstrate that different mechanisms are involved in the in vivo activation of effector and suppressor immune responses, and they suggest that the mode of initial antigen presentation determines which immunologic circuit will be activated in response to a contact-sensitizing antigen.

Okamoto, H.; Kripke, M.L.

1987-06-01

144

Genghis Khan (Gek) as a Putative Effector for Drosophila Cdc42 and Regulator of Actin Polymerization  

Microsoft Academic Search

The small GTPases Cdc42 and Rac regulate a variety of biological processes, including actin polymerization, cell proliferation, and JNK\\/mitogen-activated protein kinase activation, conceivably via distinct effectors. Whereas the effector for mitogen-activated protein kinase activation appears to be p65PAK, the identity of effector(s) for actin polymerization remains unclear. We have found a putative effector for Drosophila Cdc42, Genghis Khan (Gek), which

Liqun Luo; Tzumin Lee; Linus Tsai; Gale Tang; Lily Y. Jan; Yuh Nung Jan

1997-01-01

145

Immunologic effector mechanisms in animal models of occupational asthma.  

PubMed

Occupational asthma is a form of immunotoxicity resulting from an exaggerated immune response to substances encountered in the workplace. Symptoms include reversible airway obstruction, airway hyperresponsiveness, airway remodeling, mucus production and cellular infiltration into the lung, particularly eosinophilia. The asthmatic response is divided into the induction phase, occurring after initial exposure to allergen, followed by the effector phase where a subsequent exposure to the allergen results in the respiratory symptoms. Animal models have been used to investigate the asthmatic response and this review will focus on mechanistic studies of the effector phase. Variables that may impact the effector phase include strain and species of animal, dose of allergen, route of exposure, and developmental stage of the animal. Both trimellitic anhydride (TMA) and ovalbumin are known causes of occupational asthma. Ovalbumin is also a reference protein allergen in immunology, and TMA is used as a prototype of a low molecular weight respiratory allergen. Differences in effector mechanisms for TMA and ovalbumin have been noted in different animal models. Studies in the guinea pig provide the most direct comparisons of effector mechanisms of TMA and ovalbumin, with differences in the role of the complement system and arachidonate metabolites being noted. Besides the guinea pig, the Brown Norway rat, and various mouse strains provide useful asthma models for TMA and ovalbumin. However, studies of effector mechanisms are somewhat lacking in either of these species using TMA as the allergen. Continued studies are indicated to determine if unique effector mechanisms can be identified for the many different causes of occupational asthma. PMID:18958638

Regal, Jean F

2004-01-01

146

Target-Specific and Global Effectors in Gene Regulation by MicroRNA  

PubMed Central

MicroRNAs are responsible for post-transcriptional gene silencing as part of critical cellular pathways and intercellular coordination, for example during embryonic development. Yet, the basic mechanism by which this silencing is accomplished is still not understood. For example, it is not known to what extent and through what process does the suppression of protein accumulation accompany a reduction in mRNA level. Here we present a simple quantitative modeling approach to microRNA mediated silencing. We show how differential responses of the mRNA- and protein levels may be tuned by target-specific parameters and how global effectors may alter this behavior for some—but not all—miRNA targets in the cell.

Levine, Erel; Ben Jacob, Eshel; Levine, Herbert

2007-01-01

147

Innate Immunity in Plants: An Arms Race Between Pattern Recognition Receptors in Plants and Effectors in Microbial Pathogens  

NSDL National Science Digital Library

Access to the article is free, however registration and sign-in are required. Plant defense responses known as PAMP-triggered immunity (PTI) begin when the plant is exposed to microbial elicitors named pathogen- or microbe-associated molecular patterns (PAMPs or MAMPs). Recent studies provide an elegant explanation for the difficulty of demonstrating the role of PTI in plant disease resistance. It turns out that the important contribution of PTI to disease resistance is masked by pathogen virulence effectors that have evolved to suppress it.

Thomas Boller (University of Basel;Zurich-Basel Plant Science Center, Botanical Institute); Sheng Yang He (Michigan State University;Department of Energy Plant Research Laboratory, Department of Plant Biology)

2009-05-08

148

Detection and Functional Characterization of a 215 Amino Acid N-Terminal Extension in the Xanthomonas Type III Effector XopD  

Microsoft Academic Search

During evolution, pathogens have developed a variety of strategies to suppress plant-triggered immunity and promote successful infection. In Gram-negative phytopathogenic bacteria, the so-called type III protein secretion system works as a molecular syringe to inject type III effectors (T3Es) into plant cells. The XopD T3E from the strain 85-10 of Xanthomonas campestris pathovar vesicatoria (Xcv) delays the onset of symptom

Joanne Canonne; Daniel Marino; Laurent D. Noël; Ignacio Arechaga; Carole Pichereaux; Michel Rossignol; Dominique Roby; Susana Rivas; Mohammed Bendahmane

2010-01-01

149

Salmonella Effectors: Important players modulating host cell function during infection  

PubMed Central

Summary Salmonella enterica serovar Typhimurium (S. Typhimurium) is a Gram-negative facultative foodborne pathogen that causes gastroenteritis in humans. This bacterium has evolved a sophisticated machinery to alter host cell function critical to its virulence capabilities. Central to S. Typhimurium pathogenesis are two Type three secretion systems (T3SS) encoded within pathogenicity islands SPI-1 and SPI-2 that are responsible for the secretion and translocation of a set of bacterial proteins termed effectors into host cells with the intention of altering host cell physiology for bacterial entry and survival. Thus, once delivered by the T3SS, the secreted effectors play critical roles in manipulating the host cell to allow for bacteria invasion, induction of inflammatory responses, and the assembly of an intracellular protective niche created for bacterial survival and replication. Emerging evidence indicates that these effectors are modular proteins consisting of distinct functional domains/motifs that are utilized by the bacteria to activate intracellular signaling pathways modifying host cell function. Also, recently reported are the dual functionality of secreted effectors and the concept of “terminal reassortment”. Herein, we highlight some of the nascent concepts regarding Salmonella effectors in the context infection.

Agbor, Terence A.; McCormick, Beth A.

2012-01-01

150

Suppression and dissociation  

Microsoft Academic Search

The present study examined the connection between susppression and dissociation. Fifty-four normal subjects completed the White Bear Suppression Inventory and the Dissociative Experiences Scale. Results showed that suppression and dissociation were significantly correlated. Furthermore, both suppression and dissociation correlated positively with less adaptive defense categories as indexed by the Defense Style Questionnaire: suppression was found to be related to immature

Peter Muris; Harald Merckelbach

1997-01-01

151

Differences in TCR-V? Repertoire and Effector Phenotype between Tumor Infiltrating Lymphocytes and Peripheral Blood Lymphocytes Increase with Age  

PubMed Central

Tumor infiltrating lymphocytes (TIL) reflect the host's anti-tumor immune response, and can be a valuable predictor of prognosis. However, many properties of TIL are not fully understood. In the present study, TCR-V? repertoires of cancer patients were primarily analyzed by flow cytometry. Abnormally expressed TCR-V? subfamilies were generally found in both TIL and peripheral blood lymphocytes (PBL) of each patient. Of note, increased patient age was associated with increasingly biased TCR-V? repertoire in TIL but not in PBL, and the dispersion degree of the differences of TCR-V? subfamilies between TIL and PBL correlated positively with age (P?=?0.007). Utilizing immunoscope analysis, we identified the age-related reduction in TCR-V? diversity, but polyclonal pattern was predominant in significantly expanded TCR-V? subfamilies. In addition, we found that older patients possessed a decreased ratio of CD8+CD62L+ non-effector cells in TIL compared to PBL, implying age-related increase of CD8+CD62L? effector cells in TIL. The colocalization analysis of CD8 and CD3, however, suggested the suppressed activity of these effector cells in tumor microenvironment. These findings further elucidate the properties of TIL, showing an increasing difference between TIL and PBL with age, which may provide insight for the development of effective immunotherapies for cancer patients of different ages.

Wang, Teng; Shen, Han; Wu, Fenglin; Zhang, Wenfeng; Tao, Changli; Yuan, Yin; Bo, Huaben; Wang, Hui; Huang, Shulin

2014-01-01

152

Functional diversification of the GALA type III effector family contributes to Ralstonia solanacearum adaptation on different plant hosts  

PubMed Central

Type III effectors from phytopathogenic bacteria exhibit a high degree of functional redundancy, hampering the evaluation of their precise contribution to pathogenicity. This is illustrated by the GALA type III effectors from Ralstonia solanacearum, which have been shown to be collectively, but not individually, required for disease on Arabidopsis thaliana and tomato. We investigated evolution, redundancy and diversification of this family in order to understand the individual contribution of the GALA effectors to pathogenicity. From sequences available, we reconstructed GALA phylogeny and performed selection studies. We then focused on the GALAs from the reference strain GMI1000 to examine their ability to suppress plant defense responses and contribution to pathogenicity on three different host plants: A. thaliana, tomato (Lycopersicum esculentum) and eggplant (Solanum melongena). The GALA family is well conserved within R. solanacearum species. Patterns of selection detected on some GALA family members, together with experimental results, show that GALAs underwent functional diversification. We conclude that functional divergence of the GALA family likely accounts for its remarkable conservation during R. solanacearum evolution and could contribute to R. solanacearum’s adaptation on several host plants.

Remigi, Philippe; Anisimova, Maria; Guidot, Alice; Genin, Stephane; Peeters, Nemo

2011-01-01

153

Functional diversification of the GALA type III effector family contributes to Ralstonia solanacearum adaptation on different plant hosts.  

PubMed

Type III effectors from phytopathogenic bacteria exhibit a high degree of functional redundancy, hampering the evaluation of their precise contribution to pathogenicity. This is illustrated by the GALA type III effectors from Ralstonia solanacearum, which have been shown to be collectively, but not individually, required for disease on Arabidopsis thaliana and tomato. We investigated evolution, redundancy and diversification of this family in order to understand the individual contribution of the GALA effectors to pathogenicity. From sequences available, we reconstructed GALA phylogeny and performed selection studies. We then focused on the GALAs from the reference strain GMI1000 to examine their ability to suppress plant defense responses and contribution to pathogenicity on three different host plants: A. thaliana, tomato (Lycopersicum esculentum) and eggplant (Solanum melongena). The GALA family is well conserved within R. solanacearum species. Patterns of selection detected on some GALA family members, together with experimental results, show that GALAs underwent functional diversification. We conclude that functional divergence of the GALA family likely accounts for its remarkable conservation during R. solanacearum evolution and could contribute to R. solanacearum's adaptation on several host plants. PMID:21902695

Remigi, Philippe; Anisimova, Maria; Guidot, Alice; Genin, Stéphane; Peeters, Nemo

2011-12-01

154

Graft rejection by cytolytic T cells. Specificity of the effector mechanism in the rejection of allogeneic marrow  

SciTech Connect

Cellular effector mechanisms of allograft rejection remain incompletely described. Characterizing the rejection of foreign-marrow allografts rather than solid-organ grafts has the advantage that the cellular composition of the marrow graft, as a single cell suspension, can be altered to include cellular components with differing antigen expression. Rejection of marrow grafts is sensitive to lethal doses of radiation in the mouse but resistant to sublethal levels of radiation. In an effort to identify cells mediating host resistance, lymphocytes were isolated and cloned from spleens of mice 7 days after sublethal TBI (650 cGy) and inoculation with allogeneic marrow. All clones isolated were cytolytic with specificity for MHC encoded gene products of the allogeneic marrow donor. When cloned cells were transferred in vivo into lethally irradiated (1025 cGy) recipients unable to reject allogeneic marrow, results utilizing splenic 125IUdR uptake indicated that these MHC-specific cytotoxic clones could suppress marrow proliferation. In order to characterize the effector mechanism and the ability of the clones to affect final engraftment, double donor chimeras were constructed so that 2 target cell populations differing at the MHC from each other and from the host were present in the same marrow allograft. Results directly demonstrated an ability of CTL of host MHC type to mediate graft rejection and characterized the effector mechanism as one with specificity for MHC gene products.

Nakamura, H.; Gress, R.E. (National Cancer Institute, Bethesda, MD (USA))

1990-02-01

155

Type VI secretion delivers bacteriolytic effectors to target cells.  

PubMed

Peptidoglycan is the major structural constituent of the bacterial cell wall, forming a meshwork outside the cytoplasmic membrane that maintains cell shape and prevents lysis. In Gram-negative bacteria, peptidoglycan is located in the periplasm, where it is protected from exogenous lytic enzymes by the outer membrane. Here we show that the type VI secretion system of Pseudomonas aeruginosa breaches this barrier to deliver two effector proteins, Tse1 and Tse3, to the periplasm of recipient cells. In this compartment, the effectors hydrolyse peptidoglycan, thereby providing a fitness advantage for P. aeruginosa cells in competition with other bacteria. To protect itself from lysis by Tse1 and Tse3, P. aeruginosa uses specific periplasmically localized immunity proteins. The requirement for these immunity proteins depends on intercellular self-intoxication through an active type VI secretion system, indicating a mechanism for export whereby effectors do not access donor cell periplasm in transit. PMID:21776080

Russell, Alistair B; Hood, Rachel D; Bui, Nhat Khai; LeRoux, Michele; Vollmer, Waldemar; Mougous, Joseph D

2011-07-21

156

Salmonella pathogenesis and processing of secreted effectors by caspase-3  

PubMed Central

The enteric pathogen, Salmonella enterica serovar Typhimurium, causes food poisoning resulting in gastroenteritis. The S. Typhimurium effector protein, SipA, promotes gastroenteritis by functional motifs that either trigger mechanisms of inflammation or bacterial entry. During infection of intestinal epithelial cells, SipA was found to be responsible for the early activation of caspase-3, an enzyme that is required for SipA cleavage at a specific recognition motif that divided the protein into its two functional domains, and activated SipA in a manner necessary for pathogenicity. Other caspase-3 cleavage sites identified in S. Typhimurium appeared to be restricted to secreted effector proteins, indicating this may be a general strategy employed by this pathogen for processing of its secreted effectors.

Maldonado-Contreras, Ana; Shi, Haining; Zhou, Daoguo; Demma, Zachary; Mumy, Karen L.; McCormick, Beth A.

2014-01-01

157

Interferon-induced NK augmentation in humans. An analysis of target recognition, effector cell recruitment and effector cell recycling.  

PubMed

By combining a single-cell cytotoxicity assay in agarose with estimations of the maximal natural killer (NK) cell potential (Vmax) by 51Cr release, the mechanism behind interferon augmentation of human NK cells were analysed. The number of target-binding cells (TBCs) the fraction of active TBCs and NK cell recycling were studied after short-term interferon treatment. The results demonstrate a dual effect of interferon on human NK cells: effector cell recruitment and increased effector cell recycling. Both of these variables were increased when NK cells were tested against the standard target K-562 and against Daudi and BJAB cells, derived from B-type lymphomas. However, when T cell lines derived from acute lymphocytic leukaemia (Molt-4 and 1310) were used as targets, a larger fraction of active NK cells were found among untreated TBCs, whereas interferon treatment only resulted in increased effector cell recycling and not in effector cell recruitment. No increase in TBCs after interferon treatment could be detected with any cell line tested. The difference seen between T and non-T cell lines with regard to interferon-induced effector cell recruitment is discussed in relation to known characteristics of the human NK system. PMID:6173918

Ullberg, M; Merrill, J; Jondal, M

1981-09-01

158

Visual End-Effector Position Error Compensation for Planetary Robotics  

NASA Technical Reports Server (NTRS)

This paper describes a vision-guided manipulation algorithm that improves arm end-effector positioning to subpixel accuracy and meets the highly restrictive imaging and computational constraints of a planetary robotic flight system. Analytical, simulation-based, and experimental analyses of the algorithm's effectiveness and sensitivity to camera and arm model error is presented along with results on several prototype research systems and 'ground-in-the-loop' technology experiments on the Mars Exploration Rover (MER) vehicles. A computationally efficient and robust subpixel end-effector fiducial detector that is instrumental to the algorithm's ability to achieve high accuracy is also described along with its validation results on MER data.

Bajracharya, Max; DiCicco, Matthew; Backes, Paul; Nickels, Kevin

2007-01-01

159

Blockade of Programmed Death-1 Pathway Rescues the Effector Function of Tumor-Infiltrating T Cells and Enhances the Antitumor Efficacy of Lentivector Immunization  

PubMed Central

Despite intensive effort, the antitumor efficacy of tumor vaccines remains limited in treating established tumors regardless of the potent systemic tumor-specific immune response and the increases of tumor infiltration of T effector cells. In the current study, we demonstrated that although lentivector (lv) immunization markedly increased Ag-dependent tumor infiltration of CD8 and CD4 T cells and generated Ag-specific antitumor effect, it simultaneously increased the absolute number of myeloid-derived suppressor cells and regulatory T cells in the tumor lesions. In addition, lv immunization induced expression of programmed death-ligand 1 in the tumor lesions. Furthermore, the tumor-infiltrating CD8 T cells expressed high levels of programmed death-1 and were partially dysfunctional, producing lower amounts of effector cytokines and possessing a reduced cytotoxicity. Together, these immune-suppression mechanisms in the tumor microenvironment pose a major obstacle to effective tumor immunotherapy and may explain the limited antitumor efficacy of lv immunization. The loss of effector function in the tumor microenvironment is reversible, and the effector function of CD8 T cells in the tumor could be partially rescued by blocking programmed death-1 and programmed death-ligand 1 pathway in vitro and in vivo, resulting in enhanced antitumor efficacy of lv immunization. These data suggest that immunization alone may exacerbate immune suppression in the tumor lesions and that methods to improve the tumor microenvironment and to rescue the effector functions of tumor-infiltrating T cells should be incorporated into immunization strategies to achieve enhanced antitumor efficacy.

Zhou, Qifeng; Xiao, Haiyan; Liu, Yanjun; Peng, Yibing; Hong, Yuan; Yagita, Hideo; Chandler, Phillip; Munn, David H.; Mellor, Andrew; Fu, Ning; He, Yukai

2011-01-01

160

Ralstonia solanacearum Requires PopS, an Ancient AvrE-Family Effector, for Virulence and To Overcome Salicylic Acid-Mediated Defenses during Tomato Pathogenesis  

PubMed Central

ABSTRACT During bacterial wilt of tomato, the plant pathogen Ralstonia solanacearum upregulates expression of popS, which encodes a type III-secreted effector in the AvrE family. PopS is a core effector present in all sequenced strains in the R. solanacearum species complex. The phylogeny of popS mirrors that of the species complex as a whole, suggesting that this is an ancient, vertically inherited effector needed for association with plants. A popS mutant of R. solanacearum UW551 had reduced virulence on agriculturally important Solanum spp., including potato and tomato plants. However, the popS mutant had wild-type virulence on a weed host, Solanum dulcamara, suggesting that some species can avoid the effects of PopS. The popS mutant was also significantly delayed in colonization of tomato stems compared to the wild type. Some AvrE-type effectors from gammaproteobacteria suppress salicylic acid (SA)-mediated plant defenses, suggesting that PopS, a betaproteobacterial ortholog, has a similar function. Indeed, the popS mutant induced significantly higher expression of tomato SA-triggered pathogenesis-related (PR) genes than the wild type. Further, pretreatment of roots with SA exacerbated the popS mutant virulence defect. Finally, the popS mutant had no colonization defect on SA-deficient NahG transgenic tomato plants. Together, these results indicate that this conserved effector suppresses SA-mediated defenses in tomato roots and stems, which are R. solanacearum’s natural infection sites. Interestingly, PopS did not trigger necrosis when heterologously expressed in Nicotiana leaf tissue, unlike the AvrE homolog DspEPcc from the necrotroph Pectobacterium carotovorum subsp. carotovorum. This is consistent with the differing pathogenesis modes of necrosis-causing gammaproteobacteria and biotrophic R. solanacearum.

Jacobs, Jonathan M.; Milling, Annett; Mitra, Raka M.; Hogan, Clifford S.; Ailloud, Florent; Prior, Philippe; Allen, Caitilyn

2013-01-01

161

CD8+ IL-17 producing T cells are important in effector functions for the elicitation of contact hypersensitivity responses1  

PubMed Central

Allergen induced contact hypersensitivity (CHS) is a T cell mediated delayed type immune response which has been considered to be primarily mediated by CD8+ Tc1 cells. IFN-?, the prototype Tc1 (Th1) cytokine, has been implicated as the primary inflammatory cytokine for CHS. In this report, we demonstrate that neutralization of IL-17 rather than IFN-? suppresses the elicitation of CHS. The suppression does not result from inhibition of the proliferation of allergen-activated T cells. Allergen sensitization induces the development of distinct CD8+ T cell subpopulations that produce IFN-? or IL-17. While CD8+ IL-17 producing cells are stimulated by IL-23, they are inhibited by IL-12, a prototypical stimulator of IFN-? producing Tc1 cells. This indicates that CD8+ IL-17 producing cells are distinct from Tc1 cells and are important in effector functions at the elicitation of CHS. The studies provide insights into a novel mechanism for CHS.

He, Donggou; Wu, Lizhi; Kim, Hee Kyung; Li, Hui; Elmets, Craig A.; Xu, Hui

2011-01-01

162

Robotic End Effectors for Hard-Rock Climbing  

NASA Technical Reports Server (NTRS)

Special-purpose robot hands (end effectors) now under development are intended to enable robots to traverse cliffs much as human climbers do. Potential applications for robots having this capability include scientific exploration (both on Earth and other rocky bodies in space), military reconnaissance, and outdoor search and rescue operations. Until now, enabling robots to traverse cliffs has been considered too difficult a task because of the perceived need of prohibitively sophisticated planning algorithms as well as end effectors as dexterous as human hands. The present end effectors are being designed to enable robots to attach themselves to typical rock-face features with less planning and simpler end effectors. This advance is based on the emulation of the equipment used by human climbers rather than the emulation of the human hand. Climbing-aid equipment, specifically cams, aid hooks, and cam hooks, are used by sport climbers when a quick ascent of a cliff is desired (see Figure 1). Currently two different end-effector designs have been created. The first, denoted the simple hook emulator, consists of three "fingers" arranged around a central "palm." Each finger emulates the function of a particular type of climbing hook (aid hook, wide cam hook, and a narrow cam hook). These fingers are connected to the palm via a mechanical linkage actuated with a leadscrew/nut. This mechanism allows the fingers to be extended or retracted. The second design, denoted the advanced hook emulator (see Figure 2), shares these features, but it incorporates an aid hook and a cam hook into each finger. The spring-loading of the aid hook allows the passive selection of the type of hook used. The end effectors can be used in several different modes. In the aid-hook mode, the aid hook on one of the fingers locks onto a horizontal ledge while the other two fingers act to stabilize the end effector against the cliff face. In the cam-hook mode, the broad, flat tip of the cam hook is inserted into a non-horizontal crack in the cliff face. A subsequent transfer of weight onto the end effector causes the tip to rotate within the crack, creating a passive, self-locking action of the hook relative to the crack. In the advanced hook emulator, the aid hook is pushed into its retracted position by contact with the cliff face as the cam hook tip is inserted into the crack. When a cliff face contains relatively large pockets or cracks, another type of passive self-locking can be used. Emulating the function of the piece of climbing equipment called a "cam" (note: not the same as a "cam hook"; see Figure 1), the fingers can be fully retracted and the entire end effector inserted into the feature. The fingers are then extended as far as the feature allows. Any weight then transferred to the end effector will tend to extend the fingers further due to frictional force, passively increasing the grip on the feature. In addition to the climbing modes, these end effectors can be used to walk on (either on the palm or the fingertips) and to grasp objects by fully extending the fingers.

Kennedy, Brett; Leger, Patrick

2004-01-01

163

Understanding effector selectivity in human posterior parietal cortex by combining information patterns and activation measures.  

PubMed

The posterior parietal cortex (PPC) has traditionally been viewed as containing separate regions for the planning of eye and limb movements, but recent neurophysiological and neuroimaging observations show that the degree of effector specificity is limited. This has led to the hypothesis that effector specificity in PPC is part of a more efficient than strictly modular organization, characterized by both distinct and common activations for different effectors. It is unclear, however, what differentiates the distinctions and commonalities in effector representations. Here, we used fMRI in humans to study the cortical representations involved in the planning of eye, hand, and foot movements. We used a novel combination of fMRI measures to assess the effector-related representational content of the PPC: a multivariate information measure, reflecting whether representations were distinct or common across effectors and a univariate activation measure, indicating which representations were actively involved in movement preparation. Active distinct representations were evident in areas previously reported to be effector specific: eye specificity in the posterior intraparietal sulcus (IPS), hand tuning in anterior IPS, and a foot bias in the anterior precuneus. Crucially, PPC regions responding to a particular effector also contained an active representation common across the other two effectors. We infer that rostral PPC areas do not code single effectors, but rather dichotomies of effectors. Such combinations of representations could be well suited for active effector selection, efficiently coding both a selected effector and its alternatives. PMID:24849346

Leoné, Frank T M; Heed, Tobias; Toni, Ivan; Medendorp, W Pieter

2014-05-21

164

Concurrent simulation of a parallel jaw end effector  

NASA Technical Reports Server (NTRS)

A system of programs developed to aid in the design and development of the command/response protocol between a parallel jaw end effector and the strategic planner program controlling it are presented. The system executes concurrently with the LISP controlling program to generate a graphical image of the end effector that moves in approximately real time in response to commands sent from the controlling program. Concurrent execution of the simulation program is useful for revealing flaws in the communication command structure arising from the asynchronous nature of the message traffic between the end effector and the strategic planner. Software simulation helps to minimize the number of hardware changes necessary to the microprocessor driving the end effector because of changes in the communication protocol. The simulation of other actuator devices can be easily incorporated into the system of programs by using the underlying support that was developed for the concurrent execution of the simulation process and the communication between it and the controlling program.

Bynum, Bill

1985-01-01

165

Protein kinase C and other diacylglycerol effectors in cancer  

Microsoft Academic Search

Almost three decades after the discovery of protein kinase C (PKC), we still have only a partial understanding of how this family of serine\\/threonine kinases is involved in tumour promotion. PKC isozymes — effectors of diacylglycerol (DAG) and the main targets of phorbol-ester tumour promoters — have important roles in cell-cycle regulation, cellular survival, malignant transformation and apoptosis. How do

Erin M. Griner; Marcelo G. Kazanietz

2007-01-01

166

Competition for IL-2 between Regulatory and Effector T Cells to Chisel Immune Responses  

PubMed Central

In this review we discuss how the competition for cytokines between different cells of the immune system can shape the system wide immune response. We focus on interleukin-2 (IL-2) secretion by activated effector T cells (Teff) and on the competition for IL-2 consumption between Teff and regulatory T cells (Treg). We discuss the evidence for the mechanism in which the depletion of IL-2 by Treg cells would be sufficient to suppress an autoimmune response, yet not strong enough to prevent an immune response. We present quantitative estimations and summarize our modeling effort to show that the tug-of-war between Treg and Teff cells for IL-2 molecules can be won by Treg cells in the case of weak activation of Teff leading to the suppression of the immune response. Or, for strongly activated Teff cells, it can be won by Teff cells bringing about the activation of the whole adaptive immune system. Finally, we discuss some recent applications attempting to achieve clinical effects through the modulation of IL-2 consumption by Treg compartment.

Hofer, Thomas; Krichevsky, Oleg; Altan-Bonnet, Gregoire

2012-01-01

167

Diverse type VI secretion phospholipases are functionally plastic antibacterial effectors  

PubMed Central

Membranes allow the compartmentalization of biochemical processes and are therefore fundamental to life. The conservation of the cellular membrane, combined with its accessibility to secreted proteins, has made it a common target of factors mediating antagonistic interactions between diverse organisms. Here we report the discovery of a diverse superfamily of bacterial phospholipase enzymes. Within this superfamily, we defined enzymes with phospholipase A1 (PLA1) and A2 (PLA2) activity, which are common in host cell-targeting bacterial toxins and the venoms of certain insects and reptiles1,2. However, we find that the fundamental role of the superfamily is to mediate antagonistic bacterial interactions as effectors of the type VI secretion system (T6SS) translocation apparatus; accordingly, we name these proteins type VI lipase effectors (Tle). Our analyses indicate that PldA of Pseudomonas aeruginosa, a eukaryotic-like phospholipase D (PLD)3, is a member of the Tle superfamily and the founding substrate of the haemolysin co-regulated protein secretion island II T6SS (H2-T6SS). While prior studies have specifically implicated PldA and the H2-T6SS in pathogenesis3–5, we uncovered a specific role for the effector and its secretory machinery in intra- and inter-species bacterial interactions. Furthermore we find that this effector achieves its antibacterial activity by degrading phosphatidylethanolamine (PE), the major component of bacterial membranes. The surprising finding that virulence-associated phospholipases can serve as specific antibacterial effectors suggests that interbacterial interactions are a relevant factor driving the ongoing evolution of pathogenesis.

Russell, Alistair B.; LeRoux, Michele; Hathazi, Kristina; Agnello, Danielle M.; Ishikawa, Takahiko; Wiggins, Paul A.; Wai, Sun Nyunt; Mougous, Joseph D.

2013-01-01

168

Active Flow Effectors for Noise and Separation Control  

NASA Technical Reports Server (NTRS)

New flow effector technology for separation control and enhanced mixing is based upon shape memory alloy hybrid composite (SMAHC) technology. The technology allows for variable shape control of aircraft structures through actively deformable surfaces. The flow effectors are made by embedding shape memory alloy actuator material in a composite structure. When thermally actuated, the flow effector def1ects into or out of the flow in a prescribed manner to enhance mixing or induce separation for a variety of applications, including aeroacoustic noise reduction, drag reduction, and f1ight control. The active flow effectors were developed for noise reduction as an alternative to fixed-configuration effectors, such as static chevrons, that cannot be optimized for airframe installation effects or variable operating conditions and cannot be retracted for off-design or fail-safe conditions. Benefits include: Increased vehicle control, overall efficiency, and reduced noise throughout all f1ight regimes, Reduced flow noise, Reduced drag, Simplicity of design and fabrication, Simplicity of control through direct current stimulation, autonomous re sponse to environmental heating, fast re sponse, and a high degree of geometric stability. The concept involves embedding prestrained SMA actuators on one side of the chevron neutral axis in order to generate a thermal moment and def1ect the structure out of plane when heated. The force developed in the host structure during def1ection and the aerodynamic load is used for returning the structure to the retracted position. The chevron design is highly scalable and versatile, and easily affords active and/or autonomous (environmental) control. The technology offers wide-ranging market applications, including aerospace, automotive, and any application that requires flow separation or noise control.

Turner, Travis L.

2011-01-01

169

Dexamethasone suppression test  

MedlinePLUS

DST; ACTH suppression test; Cortisol suppression test ... During this test, you will receive dexamethasone. This is a strong man-made (synthetic) glucocorticoid medication. Afterward, your blood is drawn ...

170

The HrpN effector of Erwinia amylovora, which is involved in type III translocation, contributes directly or indirectly to callose elicitation on apple leaves.  

PubMed

Erwinia amylovora is responsible for fire blight of apple and pear trees. Its pathogenicity depends on a type III secretion system (T3SS) mediating the translocation of effectors into the plant cell. The DspA/E effector suppresses callose deposition on apple leaves. We found that E. amylovora and Pseudomonas syringae DC3000 tts mutants or peptide flg22 do not trigger callose deposition as strongly as the dspA/E mutant on apple leaves. This suggests that, on apple leaves, callose deposition is poorly elicited by pathogen-associated molecular patterns (PAMPs) such as flg22 or other PAMPs harbored by tts mutants and is mainly elicited by injected effectors or by the T3SS itself. Callose elicitation partly depends on HrpW because an hrpW-dspA/E mutant elicits lower callose deposition than a dspA/E mutant. Furthermore, an hrpN-dspA/E mutant does not trigger callose deposition, indicating that HrpN is required to trigger this plant defense reaction. We showed that HrpN plays a general role in the translocation process. Thus, the HrpN requirement for callose deposition may be explained by its role in translocation: HrpN could be involved in the translocation of other effectors inducing callose deposition. Furthermore, HrpN may also directly contribute to the elicitation process because we showed that purified HrpN induces callose deposition. PMID:21463207

Boureau, Tristan; Siamer, Sabrina; Perino, Claude; Gaubert, Stéphane; Patrit, Oriane; Degrave, Alexandre; Fagard, Mathilde; Chevreau, Elisabeth; Barny, Marie-Anne

2011-05-01

171

N-Glycosylation of Effector Proteins by an ?-1,3-Mannosyltransferase Is Required for the Rice Blast Fungus to Evade Host Innate Immunity[W][OPEN  

PubMed Central

Plant pathogenic fungi deploy secreted effectors to suppress plant immunity responses. These effectors operate either in the apoplast or within host cells, so they are putatively glycosylated, but the posttranslational regulation of their activities has not been explored. In this study, the ASPARAGINE-LINKED GLYCOSYLATION3 (ALG3)-mediated N-glycosylation of the effector, Secreted LysM Protein1 (Slp1), was found to be essential for its activity in the rice blast fungus Magnaporthe oryzae. ALG3 encodes an ?-1,3-mannosyltransferase for protein N-glycosylation. Deletion of ALG3 resulted in the arrest of secondary infection hyphae and a significant reduction in virulence. We observed that ?alg3 mutants induced massive production of reactive oxygen species in host cells, in a similar manner to ?slp1 mutants, which is a key factor responsible for arresting infection hyphae of the mutants. Slp1 sequesters chitin oligosaccharides to avoid their recognition by the rice (Oryza sativa) chitin elicitor binding protein CEBiP and the induction of innate immune responses, including reactive oxygen species production. We demonstrate that Slp1 has three N-glycosylation sites and that simultaneous Alg3-mediated N-glycosylation of each site is required to maintain protein stability and the chitin binding activity of Slp1, which are essential for its effector function. These results indicate that Alg3-mediated N-glycosylation of Slp1 is required to evade host innate immunity.

Chen, Xiao-Lin; Shi, Tao; Yang, Jun; Shi, Wei; Gao, Xusheng; Chen, Deng; Xu, Xiaowen; Xu, Jin-Rong; Talbot, Nicholas J.; Peng, You-Liang

2014-01-01

172

Dysfunctional Blood and Target Tissue CD4+CD25high Regulatory T Cells in Psoriasis: Mechanism Underlying Unrestrained Pathogenic Effector T Cell Proliferation1  

PubMed Central

The balance between regulatory and effector functions is important for maintaining efficient immune responses, while avoiding autoimmunity. The inflammatory skin disease psoriasis is sustained by the ongoing activation of pathogenic effector T cells. We found that a CD4+ T lymphocyte subpopulation in peripheral blood, phenotypically CD25high, CTLA-4+, Foxp3high (regulatory T (Treg) cells), is deficient in its suppressor activity in psoriasis. This was associated with accelerated proliferation of CD4+ responder T cells in psoriasis, the majority of which expressed CXCR3. Nevertheless, criss-cross experiments isolated the defect to psoriatic Treg cells. To examine Treg cells in a nonlymphoid tissue of a human T cell-mediated disease, Treg cells were also analyzed and isolated from the site of inflammation, psoriatic lesional skin. At the regulatory vs effector T cells ratios calculated to be present in skin, however, the psoriatic Treg cell population demonstrated decreased suppression of effector T cells. Thus, dysfunctional blood and target tissue CD4+CD25high Treg cell activity may lead to reduced restraint and consequent hyperproliferation of psoriatic pathogenic T cells in vivo. These findings represent a critical component of human organ-specific autoimmune disease and may have important implications with regard to the possible therapeutic manipulation of Treg cells in vivo.

Sugiyama, Hideaki; Gyulai, Rolland; Toichi, Eiko; Garaczi, Edina; Shimada, Shinji; Stevens, Seth R.; McCormick, Thomas S.; Cooper, Kevin D.

2010-01-01

173

Dysfunctional blood and target tissue CD4+CD25high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation.  

PubMed

The balance between regulatory and effector functions is important for maintaining efficient immune responses, while avoiding autoimmunity. The inflammatory skin disease psoriasis is sustained by the ongoing activation of pathogenic effector T cells. We found that a CD4(+) T lymphocyte subpopulation in peripheral blood, phenotypically CD25(high), CTLA-4(+), Foxp3(high) (regulatory T (Treg) cells), is deficient in its suppressor activity in psoriasis. This was associated with accelerated proliferation of CD4(+) responder T cells in psoriasis, the majority of which expressed CXCR3. Nevertheless, criss-cross experiments isolated the defect to psoriatic Treg cells. To examine Treg cells in a nonlymphoid tissue of a human T cell-mediated disease, Treg cells were also analyzed and isolated from the site of inflammation, psoriatic lesional skin. At the regulatory vs effector T cells ratios calculated to be present in skin, however, the psoriatic Treg cell population demonstrated decreased suppression of effector T cells. Thus, dysfunctional blood and target tissue CD4(+)CD25(high) Treg cell activity may lead to reduced restraint and consequent hyperproliferation of psoriatic pathogenic T cells in vivo. These findings represent a critical component of human organ-specific autoimmune disease and may have important implications with regard to the possible therapeutic manipulation of Treg cells in vivo. PMID:15611238

Sugiyama, Hideaki; Gyulai, Rolland; Toichi, Eiko; Garaczi, Edina; Shimada, Shinji; Stevens, Seth R; McCormick, Thomas S; Cooper, Kevin D

2005-01-01

174

Critical role for all-trans retinoic acid for optimal effector and effector memory CD8 T cell differentiation.  

PubMed

A plethora of work implicates important effects of the vitamin A derivative retinoic acid (RA) in myeloid differentiation, whereas fewer studies explore the role of RA in lymphoid cells. Most work on lymphoid cells has focused on the influence of RA on CD4 T cells. Little information about the role of RA in CD8 T cell differentiation is available, and even less on cell-intrinsic effects in the CD8 T cell. This study explores the role of RA in effector and memory differentiation in a cell-intrinsic manner in the context of vaccinia virus infection. We observed the loss of the short-lived effector cell phenotype (reduced KLRG1(+), T-bet(hi), granzyme B(hi)), accompanied by an enhanced memory precursor phenotype at the effector (increased CD127(hi), IL-2(+)) and contraction phases (increased CD127(hi), IL-2(+), eomesodermin(hi)) of the CD8 response in the absence of RA signaling. The lack of RA also increased the proportion of central memory CD8s. Collectively, these results introduce a new role for RA in CD8 T cell activation and differentiation. This new role may have significant implications for optimal vaccine design in which vitamin A supplementation is used to augment effector responses, but it may be to the detriment of the long-term central memory response. PMID:23338237

Allie, S Rameeza; Zhang, Weijun; Tsai, Ching-Yi; Noelle, Randolph J; Usherwood, Edward J

2013-03-01

175

Towards understanding the virulence functions of RXLR effectors of the oomycete plant pathogen Phytophthora infestans  

Microsoft Academic Search

Plant pathogens establish infection by secretion of effector proteins that may be delivered inside host cells to manipulate innate immunity. It is increasingly apparent that the ubiquitin proteasome system (UPS) contributes significantly to the regulation of plant defences and, as such, is a target for pathogen effectors. Bacterial effectors delivered by the type III and IV secretion systems have been

Paul R. J. Birch; Miles Armstrong; Jorunn Bos; Petra Boevink; Eleanor M. Gilroy; Rosalind M. Taylor; Stephan Wawra; Leighton Pritchard; Lucio Conti; Richard Ewan; Stephen C. Whisson; Pieter van West; Ari Sadanandom; Sophien Kamoun

2009-01-01

176

Tim-3 Pathway Controls Regulatory and Effector T cell Balance during HCV Infection  

PubMed Central

Hepatitis C virus (HCV) is remarkable at disrupting human immunity to establish chronic infection. Up-regulation of inhibitory signaling pathways (such as Tim-3) and accumulation of regulatory T cells (Tregs) play pivotal roles in suppressing antiviral effector T cell (Teff) responses that are essential for viral clearance. While the Tim-3 pathway has been shown to negatively regulate Teffs, its role in regulating Foxp3+ Tregs is poorly explored. In this pilot study, we investigated whether and how the Tim-3 pathway alters Foxp3+ Treg development and function in patients with chronic HCV infection. We found that Tim-3 was up-regulated, not only on IL-2-producing CD4+CD25+Foxp3? Teffs, but also on CD4+CD25+Foxp3+ Tregs, which accumulate in the peripheral blood of chronically HCV-infected individuals when compared to healthy subjects. Tim-3 expression on Foxp3+ Tregs positively correlated with expression of the proliferation marker Ki67 on Tregs, but inversely associated with proliferation of IL-2-producing Teffs. Moreover, Foxp3+ Tregs were found to be more resistant to, and Foxp3? Teffs more sensitive to, TCR-activation-induced cell apoptosis, which was reversible by blocking Tim-3 signaling. Consistent with its role in T cell proliferation and apoptosis, blockade of Tim-3 on CD4+CD25+ T cells promoted expansion of Teffs more substantially than Tregs through improving STAT-5 signaling, thus correcting the imbalance of Foxp3+ Tregs/Foxp3? Teffs that was induced by HCV infection. Taken together, the Tim-3 pathway appears to control regulatory and effector T cell balance through altering cell proliferation and apoptosis during HCV infection.

Moorman, Jonathan P.; Wang, Jia M.; Zhang, Ying; Ji, Xiao J.; Ma, Cheng J.; Wu, Xiao Y.; Jia, Zhan S.; Wang, Ke S.; Yao, Zhi Q.

2012-01-01

177

Effector and central memory T helper 2 cells respond differently to peptide immunotherapy.  

PubMed

Peptide immunotherapy (PIT) offers realistic prospects for the treatment of allergic diseases, including allergic asthma. Much is understood of the behavior of naive T cells in response to PIT. However, treatment of patients with ongoing allergic disease requires detailed understanding of the responses of allergen-experienced T cells. CD62L expression by allergen-experienced T cells corresponds to effector/effector memory (CD62L(lo)) and central memory (CD62L(hi)) subsets, which vary with allergen exposure (e.g., during, or out with, pollen season). The efficacy of PIT on different T helper 2 (Th2) cell memory populations is unknown. We developed a murine model of PIT in allergic airway inflammation (AAI) driven by adoptively transferred, traceable ovalbumin-experienced Th2 cells. PIT effectively suppressed AAI driven by unfractionated Th2 cells. Selective transfer of CD62L(hi) and CD62L(lo) Th2 cells revealed that these two populations behaved differently from one another and from previously characterized (early deletional) responses of naive CD4(+) T cells to PIT. Most notably, allergen-reactive CD62L(lo) Th2 cells were long-lived within the lung after PIT, before allergen challenge, in contrast to CD62L(hi) Th2 cells. Despite this, PIT was most potent against CD62L(lo) Th2 cells in protecting from AAI, impairing their ability to produce Th2 cytokines, whereas this capacity was heightened in PIT-treated CD62L(hi) Th2 cells. We conclude that Th2 cells do not undergo an early deletional form of tolerance after PIT. Moreover, memory Th2 subsets respond differently to PIT. These findings have implications for the clinical translation of PIT in different allergic scenarios. PMID:24516158

Mackenzie, Karen J; Nowakowska, Dominika J; Leech, Melanie D; McFarlane, Amanda J; Wilson, Claire; Fitch, Paul M; O'Connor, Richard A; Howie, Sarah E M; Schwarze, Jürgen; Anderton, Stephen M

2014-02-25

178

The effect of chitin metabolic effectors on the population increase of stored product mites.  

PubMed

The study tested the effect of the chitin metabolic effectors, teflubenzuron, diflubenzuron, and calcofluor, and a combination of a chitinase and soybean trypsin inhibitor (STI) on the population growth of eight species of stored product mites under laboratory conditions. The compounds were incorporated into the diets of the mites in concentrations ranging from 0.01 to 50 mg g(-1). The final populations of mites were observed after 21 days of growth in controlled conditions. Diflubenzuron and calcofluor suppressed the growth of all the tested species more effectively than the other compounds. The doses required to suppress the mite populations to 50% (rc(50)) in comparison to the control ranged from 0.29 to 12.68 mg g(-1) for diflubenzuron and from 1.75 to 37.7 mg g(-1) for calcofluor, depending on the mite species. When tested at the highest concentration (10 mg g(-1)), teflubenzuron also suppressed all of the tested mite species in comparison to the control. The addition of chitinase/STI into the diet influenced population growth in several ways. When the highest concentration of chitinase in a cocktail of chitinase and STI (12.5 mg g(-1) of diet) was compared to the control, populations of Acarus siro, Aleuroglyphus ovatus and Aëroglyphus robustus decreased significantly, whereas populations of Tyroborus lini and Sancassania rodionovi increased significantly. The sensitivity of species to the tested compounds differed among species. The most tolerant species was S. rodionovi, the most sensitive was A. ovatus. The results confirmed that calcofluor and diflubenzuron have a toxic effect on stored product mites. PMID:20229097

Stara, Jitka; Erban, Tomas; Hubert, Jan

2010-10-01

179

End-Effector Development for the PIP Puck Handling Robot  

SciTech Connect

It has been decided that excess, weapons-grade plutonium shall be immobilized to prevent nuclear proliferation. The method of immobilization is to encapsulate the plutonium in a ceramic puck, roughly the size of a hockey puck, using a sintering process. This method has been officially identified as the Plutonium Immobilization Process (PIP). A Can-in-Canister storage method will be used to further immobilize the plutonium. The Can-in-Canister method uses the existing design of a Defense Waste Processing Facility (DWPF) canister to house the plutonium pucks. the process begins with several pucks being stacked in a stainless steel can. Several of the stainless steel cans are stacked in a cage-like magazine. Several of the magazines are then placed in a DWPF canister. The DWPF canister is then filled with molten glass containing high-level, radioactive waste from the DWPF vitrification process. The Can-in-Canister method makes reclamation of plutonium from the pucks technically difficult and highly undesirable. The mechanical requirements of the Can-in-Canister process, in conjunction with the amount of time required to immobilize the vast quantities of weapons-grade plutonium, will expose personnel to unnecessarily high levels of radiation if the processes were completed manually, in glove boxes. Therefore, automated equipment is designed into the process to reduce or eliminate personnel exposure. Robots are used whenever the automated handling operations become complicated. There are two such operations in the initial stages of the Can-in-Canister process, which required a six-axis robot. The first operation is a press unloading process. The second operation is a tray transfer process. To successfully accomplish the operational tasks described in the two operations, the end-effector of the robot must be versatile, lightweight, and rugged. As a result of these demands, an extensive development process was undertaken to design the optimum end-effector for these puck-handling operations. As an overall requirement, it was desired to keep the design of the robot end-effector as simple as possible. There were pros and cons for either type of actuation method (pneumatic or electric). But, pneumatic actuation was chosen for its simplicity and durability in a radioactive environment. It was determined early in the design process that at least two different types of end-effectors would be required for each of the operations. Therefore, a tool changer was incorporated into the end-effector design. The tool changer would also provide for simple end-effector maintenance when used in the PIP process.

Fowley, M.D.

2001-01-31

180

End-Effector Development for the PIP Puck Handling Robot  

SciTech Connect

It has been decided that excess, weapons-grade plutonium shall be immobilized to prevent nuclear proliferation. The method of immobilization is to encapsulate the plutonium in a ceramic puck, roughly the size of a hockey puck, using a sintering process. This method has been officially identified as the Plutonium Immobilization Process (PIP). A Can-in-Canister storage method will be used to further immobilize the plutonium. The Can-in-Canister method uses the existing design of a Defense Waste Processing Facility (DWPF) canister to house the plutonium pucks. the process begins with several pucks being stacked in a stainless steel can. Several of the stainless steel cans are stacked in a cage-like magazine. Several of the magazines are then placed in a DWPF canister. The DWPF canister is then filled with molten glass containing high-level, radioactive waste from the DWPF vitrification process. The Can-in-Canister method makes reclamation of plutonium from the pucks technically difficult and highly undesirable. The mechanical requirements of the Can-in-Canister process, in conjunction with the amount of time required to immobilize the vast quantities of weapons-grade plutonium, will expose personnel to unnecessarily high levels of radiation if the processes were completed manually, in glove boxes. Therefore, automated equipment is designed into the process to reduce or eliminate personnel exposure. Robots are used whenever the automated handling operations become complicated. There are two such operations in the initial stages of the Can-in-Canister process, which required a six-axis robot. The first operation is a press unloading process. The second operation is a tray transfer process. To successfully accomplish the operational tasks described in the two operations, the end-effector of the robot must be versatile, lightweight, and rugged. As a result of these demands, an extensive development process was undertaken to design the optimum end-effector for these puck-handling operations. As an overall requirement, it was desired to keep the design of the robot end-effector as simple as possible. There were pros and cons for either type of actuation method (pneumatic or electric). But, pneumatic actuation was chosen for its simplicity and durability in a radioactive environment. It was determined early in the design process that at least two different types of end-effectors would be required for each of the operations. Therefore, a tool changer was incorporated into the end-effector design. The tool changer would also provide for simple end-effector maintenance when used in the PIP process.

Fowley, M.D.

2001-01-03

181

Evidence for acquisition of virulence effectors in pathogenic chytrids  

PubMed Central

Background The decline in amphibian populations across the world is frequently linked to the infection of the chytrid fungus Batrachochytrium dendrobatidis (Bd). This is particularly perplexing because Bd was only recently discovered in 1999 and no chytrid fungus had previously been identified as a vertebrate pathogen. Results In this study, we show that two large families of known virulence effector genes, crinkler (CRN) proteins and serine peptidases, were acquired by Bd from oomycete pathogens and bacteria, respectively. These two families have been duplicated after their acquisition by Bd. Additional selection analyses indicate that both families evolved under strong positive selection, suggesting that they are involved in the adaptation of Bd to its hosts. Conclusions We propose that the acquisition of virulence effectors, in combination with habitat disruption and climate change, may have driven the Bd epidemics and the decline in amphibian populations. This finding provides a starting point for biochemical investigations of chytridiomycosis.

2011-01-01

182

[Involvement of G protein in receptor-effector coupling].  

PubMed

G proteins consist of three subunits, alpha, beta and gamma, and bind with GTP or GDP to mediate the transformation and amplification of the signals between receptor on the cell membrane and the intracellular effector system (enzymes or ion channels), which produces various types of messenger. Bacterial toxins such as cholera and pertussis are widely used for research of signal transduction, owing to their ability for ADP-ribosylation of some types of G proteins to modify their functions. Network of signal transduction involving G proteins expands in cells of various organs, and relationship between G protein and receptors, or effectors, has been revealed day by day. Recent information of them are reviewed here. PMID:8320830

Takahashi, K; Katada, T

1993-06-01

183

Posttranscriptional Control of T Cell Effector Function by Aerobic Glycolysis  

PubMed Central

SUMMARY A “switch” from oxidative phosphorylation (OXPHOS) to aerobic glycolysis is a hallmark of T cell activation and is thought to be required to meet the metabolic demands of proliferation. However, why proliferating cells adopt this less efficient metabolism, especially in an oxygen-replete environment, remains incompletely understood. We show here that aerobic glycolysis is specifically required for effector function in T cells but that this pathway is not necessary for proliferation or survival. When activated T cells are provided with costimulation and growth factors but are blocked from engaging glycolysis, their ability to produce IFN-? is markedly compromised. This defect is translational and is regulated by the binding of the glycolysis enzyme GAPDH to AU-rich elements within the 3? UTR of IFN-? mRNA. GAPDH, by engaging/disengaging glycolysis and through fluctuations in its expression, controls effector cytokine production. Thus, aerobic glycolysis is a metabolically regulated signaling mechanism needed to control cellular function.

Chang, Chih-Hao; Curtis, Jonathan D.; Maggi, Leonard B.; Faubert, Brandon; Villarino, Alejandro V.; O'Sullivan, David; Huang, Stanley Ching-Cheng; van der Windt, Gerritje J.W.; Blagih, Julianna; Qiu, Jing; Weber, Jason D.; Pearce, Edward J.; Jones, Russell G.; Pearce, Erika L.

2013-01-01

184

Identification of Novel Type III Effectors Using Latent Dirichlet Allocation  

PubMed Central

Among the six secretion systems identified in Gram-negative bacteria, the type III secretion system (T3SS) plays important roles in the disease development of pathogens. T3SS has attracted a great deal of research interests. However, the secretion mechanism has not been fully understood yet. Especially, the identification of effectors (secreted proteins) is an important and challenging task. This paper adopts machine learning methods to identify type III secreted effectors (T3SEs). We extract features from amino acid sequences and conduct feature reduction based on latent semantic information by using latent Dirichlet allocation model. The experimental results on Pseudomonas syringae data set demonstrate the good performance of the new methods.

Yang, Yang

2012-01-01

185

Scleroderma pathogenesis: a pivotal role for fibroblasts as effector cells  

PubMed Central

Scleroderma (systemic sclerosis; SSc) is characterised by fibrosis of the skin and internal organs in the context of autoimmunity and vascular perturbation. Overproduction of extracellular matrix components and loss of specialised epithelial structures are analogous to the process of scar formation after tissue injury. Fibroblasts are the resident cells of connective tissue that become activated at sites of damage and are likely to be important effector cells in SSc. Differentiation into myofibroblasts is a hallmark process, although the mechanisms and cellular origins of this important fibroblastic cell are still unclear. This article reviews fibroblast biology in the context of SSc and highlights the potentially important place of fibroblast effector cells in fibrosis. Moreover, the heterogeneity of fibroblast properties, multiplicity of regulatory pathways and diversity of origin for myofibroblasts may underpin clinical diversity in SSc, and provide novel avenues for targeted therapy.

2013-01-01

186

Interchangeable end effector tools utilized on the protoflight manipulator arm  

NASA Technical Reports Server (NTRS)

A subset of teleoperator and effector tools was designed, fabricated, delivered and successfully demonstrated on the Marshall Space Flight Center (MSFC) protoflight manipulator arm (PFMA). The tools delivered included a rotary power tool with interchangeable collets and two fluid coupling mate/demate tools; one for a Fairchild coupling and the other for a Purolator coupling. An electrical interface connector was also provided for the rotary power tool. A tool set, from which the subset was selected, for performing on-orbit satellite maintenance was identified and conceptionally designed. Maintenance requirements were synthesized, evaluated and prioritized to develop design requirements for a set of end effector tools representative of those needed to provide on-orbit maintenance of satellites to be flown in the 1986 to 2000 timeframe.

1987-01-01

187

Pseudomonas aeruginosa Suppresses Host Immunity by Activating the DAF-2 Insulin-Like Signaling Pathway in Caenorhabditis elegans  

Microsoft Academic Search

Some pathogens have evolved mechanisms to overcome host immune defenses by inhibiting host defense signaling pathways and suppressing the expression of host defense effectors. We present evidence that Pseudomonas aeruginosa is able to suppress the expression of a subset of immune defense genes in the animal host Caenorhabditis elegans by activating the DAF-2\\/DAF-16 insulin-like signaling pathway. The DAF-2\\/DAF-16 pathway is

Eric A. Evans; Trupti Kawli; Man-Wah Tan

2008-01-01

188

A smart end-effector for assembly of space truss structures  

NASA Technical Reports Server (NTRS)

A unique facility, the Automated Structures Research Laboratory, is being used to investigate robotic assembly of truss structures. A special-purpose end-effector is used to assemble structural elements into an eight meter diameter structure. To expand the capabilities of the facility to include construction of structures with curved surfaces from straight structural elements of different lengths, a new end-effector has been designed and fabricated. This end-effector contains an integrated microprocessor to monitor actuator operations through sensor feedback. This paper provides an overview of the automated assembly tasks required by this end-effector and a description of the new end-effector's hardware and control software.

Doggett, William R.; Rhodes, Marvin D.; Wise, Marion A.; Armistead, Maurice F.

1992-01-01

189

Platelets as Cellular Effectors of Inflammation in Vascular Diseases  

PubMed Central

Platelets are chief effector cells in hemostasis. In addition, they are multifaceted inflammatory cells with functions that span the continuum from innate immune responses to adaptive immunity. Activated platelets have key “thromboinflammatory” activities in a variety of vascular disorders and vasculopathies. Recently-identified inflammatory and immune activities provide insights into the biology of these versatile blood cells that are directly relevant to human vascular diseases.

Rondina, Matthew T.; Weyrich, Andrew S.; Zimmerman, Guy A.

2013-01-01

190

Correlation between segmental flexibility and effector function of antibodies  

Microsoft Academic Search

Mouse monoclonal anti-dansyl antibodies with the same antigen-binding sites but different heavy chain constant regions were generated. The extent of segmental flexibility in times of nanoseconds and the capacity to fix complement were greatest for IgG2b, intermediate for IgG2a, and least for IgG1 and IgE. Hence, the effector functions of immunoglobulin isotypes may be controlled in part by the freedom

V. T. Oi; T. M. Vuong; R. Hardy; J. Reidler; J. Dangl; L. A. Herzenberg; L. Stryer

1984-01-01

191

Mesenchymal stem cell effects on T-cell effector pathways  

Microsoft Academic Search

Mesenchymal stem (stromal) cells (MSCs) are rare, multipotent progenitor cells that can be isolated and expanded from bone\\u000a marrow and other tissues. Strikingly, MSCs modulate the functions of immune cells, including T cells, B cells, natural killer\\u000a cells, monocyte\\/macrophages, dendritic cells, and neutrophils. T cells, activated to perform a range of different effector\\u000a functions, are the primary mediators of many

Michelle M Duffy; Thomas Ritter; Rhodri Ceredig; Matthew D Griffin

2011-01-01

192

Interplay Between Effector Th17 and Regulatory T Cells  

Microsoft Academic Search

Introduction  Over two decades ago, T helper cells were classified into its functional subsets. Soon after the classical observation of\\u000a Mosmann et al., immunologists agreed to accept the Th1\\/Th2 paradigm of the T helper subsets. Each subset is not only characterized\\u000a by its specific cytokines pattern and effector functions but also by their properties to counter regulate each other’s functions.\\u000a This

Amit Awasthi; Gopal Murugaiyan; Vijay K. Kuchroo

2008-01-01

193

On modeling two immune effectors two strain antigen interaction  

PubMed Central

In this paper we consider the fractional order model with two immune effectors interacting with two strain antigen. The systems may explain the recurrence of some diseases e.g. tuberculosis (TB). The stability of equilibrium points are studied. Numerical solutions of this model are given. Using integer order system the system oscillates. Using fractional order system the system converges to a stable internal equilibrium. Ulam-Hyers stability of the system has been studied.

2010-01-01

194

Inactivation of the apoptosis effector Apaf1 in malignant melanoma  

Microsoft Academic Search

Metastatic melanoma is a deadly cancer that fails to respond to conventional chemotherapy and is poorly understood at the molecular level. p53 mutations often occur in aggressive and chemoresistant cancers but are rarely observed in melanoma. Here we show that metastatic melanomas often lose Apaf-1, a cell-death effector that acts with cytochrome c and caspase-9 to mediate p53-dependent apoptosis. Loss

Jose L Pablos; P Capodieci; D Polsky; J Mora; M Esteller; X Opitz-Araya; R McCombie; JG Herman; WL Gerald; YA Lazebnik; C Cordon-Cardo; SW Lowe

2001-01-01

195

Rac3-Mediated Transformation Requires Multiple Effector Pathways  

Microsoft Academic Search

Ourinitial characterizationof Rac3, aclose relative ofthesmall GTPase Rac1, established its ability to promote membrane ruffling, transformation, and activation of c-jun transcription- al activity. The finding that Rac3 is transforming, and its similarity to Rac1, a protein that has a well-established connection to many processes important for cancer progres- sion, prompted further investigation into Rac3 transformation. We used effector domain mutants

Patricia J. Keller; Michele R. Wing

2005-01-01

196

A nematode effector protein similar to annexins in host plants  

PubMed Central

Nematode parasitism genes encode secreted effector proteins that play a role in host infection. A homologue of the expressed Hg4F01 gene of the root-parasitic soybean cyst nematode, Heterodera glycines, encoding an annexin-like effector, was isolated in the related Heterodera schachtii to facilitate use of Arabidopsis thaliana as a model host. Hs4F01 and its protein product were exclusively expressed within the dorsal oesophageal gland secretory cell in the parasitic stages of H. schachtii. Hs4F01 had a 41% predicted amino acid sequence identity to the nex-1 annexin of C. elegans and 33% identity to annexin-1 (annAt1) of Arabidopsis, it contained four conserved domains typical of the annexin family of calcium and phospholipid binding proteins, and it had a predicted signal peptide for secretion that was present in nematode annexins of only Heterodera spp. Constitutive expression of Hs4F01 in wild-type Arabidopsis promoted hyper-susceptibility to H. schachtii infection. Complementation of an AnnAt1 mutant by constitutive expression of Hs4F01 reverted mutant sensitivity to 75mM NaCl, suggesting a similar function of the Hs4F01 annexin-like effector in the stress response by plant cells. Yeast two-hybrid assays confirmed a specific interaction between Hs4F01 and an Arabidopsis oxidoreductase member of the 2OG-Fe(II) oxygenase family, a type of plant enzyme demonstrated to promote susceptibility to oomycete pathogens. RNA interference assays that expressed double-stranded RNA complementary to Hs4F01 in transgenic Arabidopsis specifically decreased parasitic nematode Hs4F01 transcript levels and significantly reduced nematode infection levels. The combined data suggest that nematode secretion of an Hs4F01 annexin-like effector into host root cells may mimic plant annexin function during the parasitic interaction.

Patel, Nrupali; Hamamouch, Noureddine; Li, Chunying; Hewezi, Tarek; Hussey, Richard S.; Baum, Thomas J.; Mitchum, Melissa G.; Davis, Eric L.

2010-01-01

197

TNFR2 Expression on CD25(hi)FOXP3(+) T Cells Induced upon TCR Stimulation of CD4 T Cells Identifies Maximal Cytokine-Producing Effectors.  

PubMed

In this study, we show that CD25(hi)TNFR2(+) cells can be rapidly generated in vitro from circulating CD4 lymphocytes by polyclonal stimuli anti-CD3 in the presence of anti-CD28. The in vitro induced CD25(hi)TNFR2(+) T cells express a conventional regulatory T cells phenotype FOXP3(+)CTLA4(+)CD127(lo/-), but produce effector and immunoregulatory cytokines including IL-2, IL-10, and IFN-g. These induced CD25(hi)TNFR2(+) T cells do not suppress target cell proliferation, but enhance it instead. Thus the CD25(hi)TNFR2(+) phenotype induced rapidly following CD3/28 cross linking of CD4 T cells identifies cells with maximal proliferative and effector cytokine-producing capability. The in vivo counterpart of this cell population may play an important role in immune response initiation. PMID:23964278

Govindaraj, Chindu; Scalzo-Inguanti, Karen; Scholzen, Anja; Li, Shuo; Plebanski, Magdalena

2013-01-01

198

TNFR2 Expression on CD25hiFOXP3+ T Cells Induced upon TCR Stimulation of CD4 T Cells Identifies Maximal Cytokine-Producing Effectors  

PubMed Central

In this study, we show that CD25hiTNFR2+ cells can be rapidly generated in vitro from circulating CD4 lymphocytes by polyclonal stimuli anti-CD3 in the presence of anti-CD28. The in vitro induced CD25hiTNFR2+ T cells express a conventional regulatory T cells phenotype FOXP3+CTLA4+CD127lo/?, but produce effector and immunoregulatory cytokines including IL-2, IL-10, and IFN-g. These induced CD25hiTNFR2+ T cells do not suppress target cell proliferation, but enhance it instead. Thus the CD25hiTNFR2+ phenotype induced rapidly following CD3/28 cross linking of CD4 T cells identifies cells with maximal proliferative and effector cytokine-producing capability. The in vivo counterpart of this cell population may play an important role in immune response initiation.

Govindaraj, Chindu; Scalzo-Inguanti, Karen; Scholzen, Anja; Li, Shuo; Plebanski, Magdalena

2013-01-01

199

Heterogeneity of human effector CD4+ T cells  

PubMed Central

For many years the heterogeneity of CD4+ T-helper (Th) cells has been limited to Th1 and Th2 cells, which have been considered not only to be responsible for different types of protective responses, but also for the pathogenesis of many disorders. Th1 cells are indeed protective against intracellular microbes and they are thought to play a pathogenic role in organ-specific autoimmune and other chronic inflammatory disorders. Th2 cells provide protection against helminths, but are also responsible for the pathogenesis of allergic diseases. The identification and cloning of new cytokines has allowed one to enlarge the series of functional subsets of CD4+ Th effector cells. In particular, CD4+ Th cells producing IL-17 and IL-22, named Th17, have been initially implicated in the pathogenesis of many chronic inflammatory disorders instead of Th1 cells. However, the more recent studies in both humans and mice suggest that Th17 cells exhibit a high plasticity toward Th1 cells and that both Th17 and Th1 cells may be pathogenic. More recently, another two subsets of effector CD4+ Th cells, named Th9 and Th22 cells, have been described, even if their pathophysiological meaning is still unclear. Despite the heterogeneity of CD4+ effector Th cells being higher than previously thought and some of their subsets exhibiting high plasticity, the Th1/Th2 paradigm still maintains a strong validity.

2009-01-01

200

Chlamydial Effector Proteins Localized to the Host Cell Cytoplasmic Compartment?  

PubMed Central

Disease-causing microbes utilize various strategies to modify their environment in order to create a favorable location for growth and survival. Gram-negative bacterial pathogens often use specialized secretion systems to translocate effector proteins directly into the cytosol of the eukaryotic cells they infect. These bacterial proteins are responsible for modulating eukaryotic cell functions. Identification of the bacterial effectors has been a critical step toward understanding the molecular basis for the pathogenesis of the bacteria that use them. Chlamydiae are obligate intracellular bacterial pathogens that have a type III secretion system believed to translocate virulence effector proteins into the cytosol of their host cells. Selective permeabilization of the eukaryotic cell membrane was used in conjunction with metabolic labeling of bacterial proteins to identify chlamydial proteins that localize within the cytosol of infected cells. More than 20 Chlamydia trachomatis and C. pneumoniae proteins were detected within the cytoplasmic compartment of infected cells. While a number of cytosolic proteins were shared, others were unique to each species, suggesting that variation among cytosolic chlamydial proteins contributes to the differences in the pathogenesis of the chlamydial species. The spectrum of chlamydial proteins exported differed concomitant with the progress of the developmental cycle. These data confirm that a dynamic relationship exists between Chlamydia and its host and that translocation of bacterial proteins into the cytosol is developmentally dependent.

Kleba, Betsy; Stephens, Richard S.

2008-01-01

201

Multiple Regulatory and Effector Roles of Autophagy in Immunity  

PubMed Central

Summary Autophagy is a cytoplasmic homeostasis pathway, enabling cells to digest their own cytosol, remove toxic protein aggregates, and eliminate deffective or surplus organelles. A plenitude of studies have now expanded roles of autophagy to both effector and regulatory functions in innate and adaptive immunity. In its role of an immunological effector, autophagy plays many parts: (i) In its most primeval manifestation, autophagy captures and digests intracellular microbes; (ii) it is an anti-microbial output of Toll-like receptor (TLR) response to pathogen associated molecular patterns (PAMP); and (iii) autophagy is an effector of Th1-Th2 polarization in resistance or susceptibility to intracellular pathogens. As a regulator of immunity, autophagy plays a multitude of functions: (i) It acts as a topological inversion device servicing both innate and adaptive immunity by delivering cytosolic antigens to the lumen of MHC II compartments and cytosolic PAMPs to endosomal TLRs; (ii) autophagy is critical in T cell repertoire selection in the thymus and control of central tolerance; (iii) it plays a role in T and B cell homeostasis; and (iv) autophagy is of significance for inflammatory pathology. A properly functioning autophagy helps prevent autoimmunity and assists in clearing pathogens. When aberrant, it contributes to human inflammatory disorders such as Crohn’s disease.

Deretic, Vojo

2009-01-01

202

Compact effector optics for processing in limited physical access situations  

NASA Astrophysics Data System (ADS)

A major advantage of fiber-optic beam delivery in laser materials processing is the ability to guide the laser power to the location where it is needed, leaving the laser itself remote and protected from the process. This is of special importance if the processing is to be performed in a hazardous environment. Particular problems are faced by the nuclear industry where weld repair and surface treatment work are required inside radioactive installations. By use of fiber beam delivery, only part of the delivery system and effector optics become contaminated, but the expensive laser system does not. However, in many cases the region where repair is required is not only radioactive but has only limited physical access, e.g., inside tubes or into corners, which prevents use of standard effector optics. We present a new design to deal with such constraints of a 2-mm outer diameter employing a hollow waveguide and gas shielding. This design is optically characterized and its performance assessed in welding and surface treatment applications. The potential of this compact effector optics in limited physical access situations is clearly demonstrated.

Kuhn, Andreas; Fox, Mahlen D. T.; French, Paul W.; Hettrick, Simon; Hand, Duncan P.; Shi, Yi-Wei; Matsuura, Yuji; Miyagi, Mitsunobu; Watkins, Kenneth G.; Ireland, Clive L. M.; Jones, Julian D. C.

2003-09-01

203

Rapamycin-resistant effector T-cell therapy.  

PubMed

Pharmacologic inhibition of the mechanistic target of rapamycin (mTOR) represents a stress test for tumor cells and T cells. Mechanisms exist that allow cells to survive this stress, including suboptimal target block, alternative signaling pathways, and autophagy. Rapamycin-resistant effector T (T-Rapa) cells have an altered phenotype that associates with increased function. Ex vivo rapamycin, when used in combination with polarizing cytokines and antigen-presenting-cell free costimulation, is a flexible therapeutic approach as polarization to T-helper 1 (Th1)- or Th2-type effectors is possible. Murine T-Rapa cells skewed toward a Th2-type prevented graft rejection and graft-versus-host disease (GVHD) more potently than control Th2 cells and effectively balanced GVHD and graft-versus-tumor (GVT) effects. A phase II clinical trial using low-intensity allogeneic hematopoietic cell transplantation demonstrated that interleukin-4 polarized human T-Rapa cells had a mixed Th2/Th1 phenotype; T-Rapa cell recipients had a balanced Th2/Th1 cytokine profile, conversion of mixed chimerism toward full donor chimerism, and a potentially favorable balance between GVHD and GVT effects. In addition, a phase I clinical trial evaluating autologous T-Rapa cells skewed toward a Th1- and Tc1-type is underway. Use of ex vivo rapamycin to modulate effector T-cell function represents a promising new approach to transplantation therapy. PMID:24329799

Fowler, Daniel H

2014-01-01

204

Multiple recognition of RXLR effectors is associated with nonhost resistance of pepper against Phytophthora infestans.  

PubMed

Nonhost resistance (NHR) is a plant immune response to resist most pathogens. The molecular basis of NHR is poorly understood, but recognition of pathogen effectors by immune receptors, a response known as effector-triggered immunity, has been proposed as a component of NHR. We performed transient expression of 54 Phytophthora infestansRXLR effectors in pepper (Capsicum annuum) accessions. We used optimized heterologous expression methods and analyzed the inheritance of effector-induced cell death in an F2 population derived from a cross between two pepper accessions. Pepper showed a localized cell death response upon inoculation with P. infestans, suggesting that recognition of effectors may contribute to NHR in this system. Pepper accessions recognized as many as 36 effectors. Among the effectors, PexRD8 and Avrblb2 induced cell death in a broad range of pepper accessions. Segregation of effector-induced cell death in an F2 population derived from a cross between two pepper accessions fit 15 : 1, 9 : 7 or 3 : 1 ratios, depending on the effector. Our genetic data suggest that a single or two independent/complementary dominant genes are involved in the recognition of RXLR effectors. Multiple loci recognizing a series of effectors may underpin NHR of pepper to P. infestans and confer resistance durability. PMID:24889686

Lee, Hyun-Ah; Kim, Shin-Young; Oh, Sang-Keun; Yeom, Seon-In; Kim, Saet-Byul; Kim, Myung-Shin; Kamoun, Sophien; Choi, Doil

2014-08-01

205

Herbivore exploits orally secreted bacteria to suppress plant defenses  

PubMed Central

Induced plant defenses in response to herbivore attack are modulated by cross-talk between jasmonic acid (JA)- and salicylic acid (SA)-signaling pathways. Oral secretions from some insect herbivores contain effectors that overcome these antiherbivore defenses. Herbivores possess diverse microbes in their digestive systems and these microbial symbionts can modify plant–insect interactions; however, the specific role of herbivore-associated microbes in manipulating plant defenses remains unclear. Here, we demonstrate that Colorado potato beetle (Leptinotarsa decemlineata) larvae exploit bacteria in their oral secretions to suppress antiherbivore defenses in tomato (Solanum lycopersicum). We found that antibiotic-untreated larvae decreased production of JA and JA-responsive antiherbivore defenses, but increased SA accumulation and SA-responsive gene expression. Beetles benefit from down-regulating plant defenses by exhibiting enhanced larval growth. In SA-deficient plants, suppression was not observed, indicating that suppression of JA-regulated defenses depends on the SA-signaling pathway. Applying bacteria isolated from larval oral secretions to wounded plants confirmed that three microbial symbionts belonging to the genera Stenotrophomonas, Pseudomonas, and Enterobacter are responsible for defense suppression. Additionally, reinoculation of these bacteria to antibiotic-treated larvae restored their ability to suppress defenses. Flagellin isolated from Pseudomonas sp. was associated with defense suppression. Our findings show that the herbivore exploits symbiotic bacteria as a decoy to deceive plants into incorrectly perceiving the threat as microbial. By interfering with the normal perception of herbivory, beetles can evade antiherbivore defenses of its host.

Chung, Seung Ho; Rosa, Cristina; Scully, Erin D.; Peiffer, Michelle; Tooker, John F.; Hoover, Kelli; Luthe, Dawn S.; Felton, Gary W.

2013-01-01

206

In vivo inhibition of human CD19 targeted effector T cells by natural T regulatory cells in a xenotransplant murine model of B cell malignancy  

PubMed Central

Human T cells genetically modified to express chimeric antigen receptors (CARs) specific to the B cell tumor antigen CD19 can successfully eradicate systemic human CD19+ tumors in immunocompromised SCID-Beige mice. However, in the clinical setting, CD4+ CD25hi T regulatory cells (Tregs) present within the tumor microenvironment are potent suppressors of tumor-targeted effector T cells. In order to assess the impact of Tregs on CAR-modified T cells in the SCID-Beige xenotransplant model, we isolated, genetically targeted and expanded natural T regulatory cells (nTregs). In vitro, nTregs, modified to express CD19 targeted CARs efficiently inhibited the proliferation of activated human T cells, as well as the capacity of CD19-targeted 19-28z+ effector T cells to lyse CD19+ Raji tumor cells. Intravenous infusion of CD19-targeted nTregs into SCID-Beige mice with systemic Raji tumors traffic to sites of tumor and recapitulate a clinically relevant hostile tumor microenvironment. Anti-tumor efficacy of subsequently infused 19-28z+ effector T cells was fully abrogated as assessed by long-term survival of treated mice. Optimal suppression by genetically targeted nTregs was dependent on nTreg to effector T cell ratios and in vivo nTreg activation. Prior infusion of cyclophosphamide in the setting of this nTreg-mediated hostile microenvironment was able to restore the anti-tumor activity of subsequently infused 19-28z+ effector T cells through the eradication of tumor targeted nTregs. These findings have significant implications on the design of future clinical trials utilizing CAR-based adoptive T cell therapies of cancer.

Lee, James; Hayman, Erik; Pegram, Hollie; Santos, Elmer; Heller, Glen; Sadelain, Michel; Brentjens, Renier J.

2011-01-01

207

The Yersinia enterocolitica type 3 secretion system (T3SS) as toolbox for studying the cell biological effects of bacterial Rho GTPase modulating T3SS effector proteins.  

PubMed

The bacterial effector proteins IpgB(1) and IpgB(2) of Shigella and Map of Escherichia coli activate the Rho GTPases Rac1, RhoA and Cdc42, respectively, whereas YopE and YopT of Yersinia inhibit these Rho family GTPases. We established a Yersinia toolbox which allows to study the cellular effects of these effectors in different combinations in the context of Yersinia type 3 secretion system (Ysc)-T3SS-mediated injection into HeLa cells. For this purpose hybrid proteins were constructed by fusion of YopE with the effector protein of interest. As expected, injected hybrid proteins induced membrane ruffles and Yersinia uptake for IpgB(1) , stress fibres for IpgB(2) and microspikes for Map. By co-infection experiments we could demonstrate (i) IpgB(2) -mediated and ROCK-dependent inhibition of IpgB(1) -mediated Rac1 effects, (ii) YopT-mediated suppression of IpgB(1) -induced Yersinia invasion and (iii) failure of YopE-mediated suppression of IpgB(1) -induced Yersinia invasion, presumably due to preferential inhibition of RhoG by YopE GAP function. By infecting polarized MDCK cells we could demonstrate that Map or IpgB(1) but not IpgB(2) affects cell monolayer integrity. In summary, the Yersinia toolbox is suitable to study cellular effects of effector proteins of diverse bacterial species separately or in combination in the context of bacterial T3SS-mediated injection. PMID:21718421

Wölke, Stefan; Ackermann, Nikolaus; Heesemann, Jürgen

2011-09-01

208

Effective suppressibility of chaos.  

PubMed

Suppression of chaos is a relevant phenomenon that can take place in nonlinear dynamical systems when a parameter is varied. Here, we investigate the possibilities of effectively suppressing the chaotic motion of a dynamical system by a specific time independent variation of a parameter of our system. In realistic situations, we need to be very careful with the experimental conditions and the accuracy of the parameter measurements. We define the suppressibility, a new measure taking values in the parameter space, that allows us to detect which chaotic motions can be suppressed, what possible new choices of the parameter guarantee their suppression, and how small the parameter variations from the initial chaotic state to the final periodic one are. We apply this measure to a Duffing oscillator and a system consisting on ten globally coupled He?non maps. We offer as our main result tool sets that can be used as guides to suppress chaotic dynamics. PMID:23822472

López, Álvaro G; Seoane, Jesús M; Sanjuán, Miguel A F

2013-06-01

209

Effective suppressibility of chaos  

NASA Astrophysics Data System (ADS)

Suppression of chaos is a relevant phenomenon that can take place in nonlinear dynamical systems when a parameter is varied. Here, we investigate the possibilities of effectively suppressing the chaotic motion of a dynamical system by a specific time independent variation of a parameter of our system. In realistic situations, we need to be very careful with the experimental conditions and the accuracy of the parameter measurements. We define the suppressibility, a new measure taking values in the parameter space, that allows us to detect which chaotic motions can be suppressed, what possible new choices of the parameter guarantee their suppression, and how small the parameter variations from the initial chaotic state to the final periodic one are. We apply this measure to a Duffing oscillator and a system consisting on ten globally coupled Hénon maps. We offer as our main result tool sets that can be used as guides to suppress chaotic dynamics.

López, Álvaro G.; Seoane, Jesús M.; Sanjuán, Miguel A. F.

2013-06-01

210

Fire Suppression and Response  

NASA Technical Reports Server (NTRS)

This report is concerned with the following topics regarding fire suppression:What is the relative effectiveness of candidate suppressants to extinguish a representative fire in reduced gravity, including high-O2 mole fraction, low -pressure environments? What are the relative advantages and disadvantages of physically acting and chemically-acting agents in spacecraft fire suppression? What are the O2 mole fraction and absolute pressure below which a fire cannot exist? What effect does gas-phase radiation play in the overall fire and post-fire environments? Are the candidate suppressants effective to extinguish fires on practical solid fuels? What is required to suppress non-flaming fires (smoldering and deep seated fires) in reduced gravity? How can idealized space experiment results be applied to a practical fire scenario? What is the optimal agent deployment strategy for space fire suppression?

Ruff, Gary A.

2004-01-01

211

Deconstructing continuous flash suppression.  

PubMed

In this paper, we asked to what extent the depth of interocular suppression engendered by continuous flash suppression (CFS) varies depending on spatiotemporal properties of the suppressed stimulus and CFS suppressor. An answer to this question could have implications for interpreting the results in which CFS influences the processing of different categories of stimuli to different extents. In a series of experiments, we measured the selectivity and depth of suppression (i.e., elevation in contrast detection thresholds) as a function of the visual features of the stimulus being suppressed and the stimulus evoking suppression, namely, the popular "Mondrian" CFS stimulus (N. Tsuchiya & C. Koch, 2005). First, we found that CFS differentially suppresses the spatial components of the suppressed stimulus: Observers' sensitivity for stimuli of relatively low spatial frequency or cardinally oriented features was more strongly impaired in comparison to high spatial frequency or obliquely oriented stimuli. Second, we discovered that this feature-selective bias primarily arises from the spatiotemporal structure of the CFS stimulus, particularly within information residing in the low spatial frequency range and within the smooth rather than abrupt luminance changes over time. These results imply that this CFS stimulus operates by selectively attenuating certain classes of low-level signals while leaving others to be potentially encoded during suppression. These findings underscore the importance of considering the contribution of low-level features in stimulus-driven effects that are reported under CFS. PMID:22408039

Yang, Eunice; Blake, Randolph

2012-01-01

212

Deconstructing continuous flash suppression  

PubMed Central

In this paper, we asked to what extent the depth of interocular suppression engendered by continuous flash suppression (CFS) varies depending on spatiotemporal properties of the suppressed stimulus and CFS suppressor. An answer to this question could have implications for interpreting the results in which CFS influences the processing of different categories of stimuli to different extents. In a series of experiments, we measured the selectivity and depth of suppression (i.e., elevation in contrast detection thresholds) as a function of the visual features of the stimulus being suppressed and the stimulus evoking suppression, namely, the popular “Mondrian” CFS stimulus (N. Tsuchiya & C. Koch, 2005). First, we found that CFS differentially suppresses the spatial components of the suppressed stimulus: Observers' sensitivity for stimuli of relatively low spatial frequency or cardinally oriented features was more strongly impaired in comparison to high spatial frequency or obliquely oriented stimuli. Second, we discovered that this feature-selective bias primarily arises from the spatiotemporal structure of the CFS stimulus, particularly within information residing in the low spatial frequency range and within the smooth rather than abrupt luminance changes over time. These results imply that this CFS stimulus operates by selectively attenuating certain classes of low-level signals while leaving others to be potentially encoded during suppression. These findings underscore the importance of considering the contribution of low-level features in stimulus-driven effects that are reported under CFS.

Yang, Eunice; Blake, Randolph

2012-01-01

213

Phytophthora sojae Avirulence Effector Avr3b is a Secreted NADH and ADP-ribose Pyrophosphorylase that Modulates Plant Immunity  

PubMed Central

Plants have evolved pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) and effector-triggered immunity (ETI) to protect themselves from infection by diverse pathogens. Avirulence (Avr) effectors that trigger plant ETI as a result of recognition by plant resistance (R) gene products have been identified in many plant pathogenic oomycetes and fungi. However, the virulence functions of oomycete and fungal Avr effectors remain largely unknown. Here, we combined bioinformatics and genetics to identify Avr3b, a new Avr gene from Phytophthora sojae, an oomycete pathogen that causes soybean root rot. Avr3b encodes a secreted protein with the RXLR host-targeting motif and C-terminal W and Nudix hydrolase motifs. Some isolates of P. sojae evade perception by the soybean R gene Rps3b through sequence mutation in Avr3b and lowered transcript accumulation. Transient expression of Avr3b in Nicotiana benthamiana increased susceptibility to P. capsici and P. parasitica, with significantly reduced accumulation of reactive oxygen species (ROS) around invasion sites. Biochemical assays confirmed that Avr3b is an ADP-ribose/NADH pyrophosphorylase, as predicted from the Nudix motif. Deletion of the Nudix motif of Avr3b abolished enzyme activity. Mutation of key residues in Nudix motif significantly impaired Avr3b virulence function but not the avirulence activity. Some Nudix hydrolases act as negative regulators of plant immunity, and thus Avr3b might be delivered into host cells as a Nudix hydrolase to impair host immunity. Avr3b homologues are present in several sequenced Phytophthora genomes, suggesting that Phytophthora pathogens might share similar strategies to suppress plant immunity.

Dong, Suomeng; Yin, Weixiao; Kong, Guanghui; Yang, Xinyu; Qutob, Dinah; Chen, Qinghe; Kale, Shiv D.; Sui, Yangyang; Zhang, Zhengguang; Dou, Daolong; Zheng, Xiaobo; Gijzen, Mark; M. Tyler, Brett; Wang, Yuanchao

2011-01-01

214

Peroxisome proliferator-activated receptor-? agonist pioglitazone suppresses experimental autoimmune uveitis.  

PubMed

Peroxisome proliferator-activated receptor (PPAR)-? agonists are clinically used as anti-diabetes agents. Recent research has discovered that an anti-inflammatory effect of PPAR agonist may have the potential to treat autoimmune disease. In the present study, we investigated the anti-inflammatory effects of PPAR-? agonist, pioglitazone, on murine model of endogenous uveitis. Experimental autoimmune uveoretinitis (EAU) was induced by immunizing C57BL/6 mice with human interphotoreceptor retinoid binding protein-derived peptide (1-20). Pioglitazone or vehicle was injected intravenously from day -1 (whole phase treatment) or day 8 (effector phase study) until day 20. Severity of EAU was assessed clinically and pathologically on day 21. Immunological status was assessed by measuring intraocular inflammatory factors, and activation and regulatory markers of CD4(+) T cells in draining lymph nodes (LNs). Treatment with pioglitazone suppressed both whole-phase and effector-phase of EAU. In effector-phase treatment, intraocular concentrations of TNF-? and IL-6 were significantly suppressed, and CD4(+)Foxp3(+) regulatory T cells and CD4(+)CD62L(high) naïve T cells increased in draining LNs, although there were no differences in CD4(+)CD44(high) effector T cells and IL-17 producing CD4(+) T cells between pioglitazone- and vehicle-treated mice. Administration of pioglitazone before and after the onset of EAU significantly reduced disease severity. The present results suggest that pioglitazone may be a novel therapeutic agent for endogenous uveitis. PMID:24107513

Okunuki, Yoko; Usui, Yoshihiko; Nakagawa, Hayate; Tajima, Kazuki; Matsuda, Ryusaku; Ueda, Shunichiro; Hattori, Takaaki; Kezuka, Takeshi; Goto, Hiroshi

2013-11-01

215

Identification and Characterisation CRN Effectors in Phytophthora capsici Shows Modularity and Functional Diversity  

PubMed Central

Phytophthora species secrete a large array of effectors during infection of their host plants. The Crinkler (CRN) gene family encodes a ubiquitous but understudied class of effectors with possible but as of yet unknown roles in infection. To appreciate CRN effector function in Phytophthora, we devised a simple Crn gene identification and annotation pipeline to improve effector prediction rates. We predicted 84 full-length CRN coding genes and assessed CRN effector domain diversity in sequenced Oomycete genomes. These analyses revealed evidence of CRN domain innovation in Phytophthora and expansion in the Peronosporales. We performed gene expression analyses to validate and define two classes of CRN effectors, each possibly contributing to infection at different stages. CRN localisation studies revealed that P. capsici CRN effector domains target the nucleus and accumulate in specific sub-nuclear compartments. Phenotypic analyses showed that few CRN domains induce necrosis when expressed in planta and that one cell death inducing effector, enhances P. capsici virulence on Nicotiana benthamiana. These results suggest that the CRN protein family form an important class of intracellular effectors that target the host nucleus during infection. These results combined with domain expansion in hemi-biotrophic and necrotrophic pathogens, suggests specific contributions to pathogen lifestyles. This work will bolster CRN identification efforts in other sequenced oomycete species and set the stage for future functional studies towards understanding CRN effector functions.

Stam, Remco; Jupe, Julietta; Howden, Andrew J. M.; Morris, Jenny A.; Boevink, Petra C.; Hedley, Pete E.; Huitema, Edgar

2013-01-01

216

Identification of novel type III secretion effectors in Xanthomonas oryzae pv. oryzae.  

PubMed

Many gram-negative bacteria secrete so-called effector proteins via a type III secretion (T3S) system. Through genome screening for genes encoding potential T3S effectors, 60 candidates were selected from rice pathogen Xanthomonas oryzae pv. oryzae MAFF311018 using these criteria: i) homologs of known T3S effectors in plant-pathogenic bacteria, ii) genes with expression regulated by hrp regulatory protein HrpX, or iii) proteins with N-terminal amino acid patterns associated with T3S substrates of Pseudomonas syringae. Of effector candidates tested with the Bordetella pertussis calmodulin-dependent adenylate cyclase reporter for translocation into plant cells, 16 proteins were translocated in a T3S system-dependent manner. Of these 16 proteins, nine were homologs of known effectors in other plant-pathogenic bacteria and seven were not. Most of the effectors were widely conserved in Xanthomonas spp.; however, some were specific to X. oryzae. Interestingly, all these effectors were expressed in an HrpX-dependent manner, suggesting coregulation of effectors and the T3S system. In X. campestris pv. vesicatoria, HpaB and HpaC (HpaP in X. oryzae pv. oryzae) have a central role in recruiting T3S substrates to the secretion apparatus. Secretion of all but one effector was reduced in both HpaB() and HpaP() mutant strains, indicating that HpaB and HpaP are widely involved in efficient secretion of the effectors. PMID:19061406

Furutani, Ayako; Takaoka, Minako; Sanada, Harumi; Noguchi, Yukari; Oku, Takashi; Tsuno, Kazunori; Ochiai, Hirokazu; Tsuge, Seiji

2009-01-01

217

Flavonols modulate the effector functions of healthy individuals' immune complex-stimulated neutrophils: A therapeutic perspective for rheumatoid arthritis.  

PubMed

Rheumatoid arthritis (RA) patients usually exhibit immune complex (IC) deposition and increased neutrophil activation in the joint. In this study, we assessed how four flavonols (galangin, kaempferol, quercetin, and myricetin) modulate the effector functions of healthy individuals' and active RA patients' IC-stimulated neutrophils. We measured superoxide anion and total reactive oxygen species production using lucigenin (CL-luc)- and luminol (CL-lum)-enhanced chemiluminescence assays, respectively. Galangin, kaempferol, and quercetin inhibited CL-lum to the same degree (mean IC50=2.5?M). At 2.5?M, quercetin and galangin suppressed nearly 65% CL-lum of active RA patients' neutrophils. Quercetin inhibited CL-luc the most effectively (IC50=1.71±0.36?M). The four flavonols diminished myeloperoxidase activity, but they did not decrease NADPH oxidase activity, phagocytosis, microbial killing, or cell viability of neutrophils. The ability of the flavonols to scavenge hypochlorous acid and chloramines, but not H2O2, depended on the hydroxylation degree of the flavonol B-ring. Therefore, at physiologically relevant concentrations, the flavonols partially inhibited the oxidative metabolism of IC-stimulated neutrophils without affecting the other investigated effector functions. Using these compounds to modulate IC-mediated neutrophil activation is a promising safe therapeutic strategy to control inflammation in active RA patients. PMID:24797916

Santos, Everton O L; Kabeya, Luciana M; Figueiredo-Rinhel, Andréa S G; Marchi, Larissa F; Andrade, Micássio F; Piatesi, Fabiana; Paoliello-Paschoalato, Adriana B; Azzolini, Ana Elisa C S; Lucisano-Valim, Yara M

2014-07-01

218

Rotating stall suppression  

NASA Technical Reports Server (NTRS)

Rotating stall in an axial-flow compressor is suppressed by the positioning of a fixed inlet flow divider in the annular inlet flow passage upstream of the compressor. The inlet flow divider is aligned with the flow of fluid through the duct and acts to block or interfere with any rotating wave in the inlet and thereby suppresses rotating stall in the compressor.

Moore, Franklin K. (Inventor)

1994-01-01

219

Decoder based noise suppression  

Microsoft Academic Search

Abstract Acoustic background noise in mobile speech communication systems, while largely inevitable, can have a severely detrimental efiect on speech intelligibility. Noise suppression is highly desirable in these systems. However, the process of reducing noise in a speech signal is associated with distortion of the processed signal, the severity of which is generally proportional to the amount of noise suppression

Erik Hennix

2006-01-01

220

Interferon-alpha regulates the dynamic balance between human activated regulatory and effector T cells: implications for antiviral and autoimmune responses.  

PubMed

An adequate effector response against pathogens and its subsequent inactivation after pathogen clearance are critical for the maintenance of immune homeostasis. This process involves an initial phase of T-cell effector (Teff) activation followed by the expansion of regulatory T cells (Tregs), a unique cell population that limits Teff functions. However, significant questions remain unanswered about the mechanisms that regulate the balance between these cell populations. Using an in vitro system to mimic T-cell activation in human peripheral blood mononuclear cells (PBMC), we analysed the patterns of Treg and Teff activation, with special attention to the role of type I interferon (IFN-I). Interestingly, we found that IFN-alpha, either exogenously added or endogenously induced, suppressed the generation of CD4(+) FoxP3(HI )IFN-gamma(Neg) activated Tregs (aTregs) while simultaneously promoting propagation of CD4(+) FoxP3(Low/Neg )IFN-gamma(Pos) activated Teffs (aTeffs). We also showed that IFN-alpha-mediated inhibition of interleukin (IL)-2 production may play an essential role in IFN-alpha-induced suppression of aTregs. In order to test our findings in a disease state with chronically elevated IFN-alpha, we investigated systemic lupus erythematosus (SLE). Plasma from patients with SLE was found to contain IFN-I activity that suppressed aTreg generation. Furthermore, anti-CD3 activated SLE PBMCs exhibited preferential expansion of aTeffs with a very limited increase in aTreg numbers. Together, these observations support a model whereby a transient production of IFN-alpha (such as is seen in an early antiviral response) may promote CD4 effector functions by delaying aTreg generation, but a chronic elevation of IFN-alpha may tip the aTeff:aTreg balance towards aTeffs and autoimmunity. PMID:20465564

Golding, Amit; Rosen, Antony; Petri, Michelle; Akhter, Ehtisham; Andrade, Felipe

2010-09-01

221

TSC1 regulates the balance between effector and regulatory T cells  

PubMed Central

Mammalian target of rapamycin (mTOR) plays a crucial role in the control of T cell fate determination; however, the precise regulatory mechanism of the mTOR pathway is not fully understood. We found that T cell–specific deletion of the gene encoding tuberous sclerosis 1 (TSC1), an upstream negative regulator of mTOR, resulted in augmented Th1 and Th17 differentiation and led to severe intestinal inflammation in a colitis model. Conditional Tsc1 deletion in Tregs impaired their suppressive activity and expression of the Treg marker Foxp3 and resulted in increased IL-17 production under inflammatory conditions. A fate-mapping study revealed that Tsc1-null Tregs that lost Foxp3 expression gained a stronger effector-like phenotype compared with Tsc1–/– Foxp3+ Tregs. Elevated IL-17 production in Tsc1–/– Treg cells was reversed by in vivo knockdown of the mTOR target S6K1. Moreover, IL-17 production was enhanced by Treg-specific double deletion of Tsc1 and Foxo3a. Collectively, these studies suggest that TSC1 acts as an important checkpoint for maintaining immune homeostasis by regulating cell fate determination.

Park, Yoon; Jin, Hyung-Seung; Lopez, Justine; Elly, Chris; Kim, Gisen; Murai, Masako; Kronenberg, Mitchell; Liu, Yun-Cai

2013-01-01

222

TSC1 regulates the balance between effector and regulatory T cells.  

PubMed

Mammalian target of rapamycin (mTOR) plays a crucial role in the control of T cell fate determination; however, the precise regulatory mechanism of the mTOR pathway is not fully understood. We found that T cell-specific deletion of the gene encoding tuberous sclerosis 1 (TSC1), an upstream negative regulator of mTOR, resulted in augmented Th1 and Th17 differentiation and led to severe intestinal inflammation in a colitis model. Conditional Tsc1 deletion in Tregs impaired their suppressive activity and expression of the Treg marker Foxp3 and resulted in increased IL-17 production under inflammatory conditions. A fate-mapping study revealed that Tsc1-null Tregs that lost Foxp3 expression gained a stronger effector-like phenotype compared with Tsc1-/- Foxp3+ Tregs. Elevated IL-17 production in Tsc1-/- Treg cells was reversed by in vivo knockdown of the mTOR target S6K1. Moreover, IL-17 production was enhanced by Treg-specific double deletion of Tsc1 and Foxo3a. Collectively, these studies suggest that TSC1 acts as an important checkpoint for maintaining immune homeostasis by regulating cell fate determination. PMID:24270422

Park, Yoon; Jin, Hyung-Seung; Lopez, Justine; Elly, Chris; Kim, Gisen; Murai, Masako; Kronenberg, Mitchell; Liu, Yun-Cai

2013-12-01

223

IL-7 receptor blockade reverses autoimmune diabetes by promoting inhibition of effector/memory T cells  

PubMed Central

To protect the organism against autoimmunity, self-reactive effector/memory T cells (TE/M) are controlled by cell-intrinsic and -extrinsic regulatory mechanisms. However, how some TE/M cells escape regulation and cause autoimmune disease is currently not understood. Here we show that blocking IL-7 receptor-? (IL-7R?) with monoclonal antibodies in nonobese diabetic (NOD) mice prevented autoimmune diabetes and, importantly, reversed disease in new-onset diabetic mice. Surprisingly, IL-7–deprived diabetogenic TE/M cells remained present in the treated animals but showed increased expression of the inhibitory receptor Programmed Death 1 (PD-1) and reduced IFN-? production. Conversely, IL-7 suppressed PD-1 expression on activated T cells in vitro. Adoptive transfer experiments revealed that TE/M cells from anti–IL-7R?–treated mice had lost their pathogenic potential, indicating that absence of IL-7 signals induces cell-intrinsic tolerance. In addition to this mechanism, IL-7R? blockade altered the balance of regulatory T cells and TE/M cells, hence promoting cell-extrinsic regulation and further increasing the threshold for diabetogenic T-cell activation. Our data demonstrate that IL-7 contributes to the pathogenesis of autoimmune diabetes by enabling TE/M cells to remain in a functionally competent state and suggest IL-7R? blockade as a therapy for established T-cell–dependent autoimmune diseases.

Penaranda, Cristina; Kuswanto, Wilson; Hofmann, Jerry; Kenefeck, Rupert; Narendran, Parth; Walker, Lucy S. K.; Bluestone, Jeffrey A.; Abbas, Abul K.; Dooms, Hans

2012-01-01

224

Type III chaperones & Co in bacterial plant pathogens: a set of specialized bodyguards mediating effector delivery  

PubMed Central

Gram-negative plant pathogenic bacteria possess a type III secretion system (T3SS) to inject bacterial proteins, called type III effectors (T3Es), into host cells through a specialized syringe structure. T3Es are virulence factors that can suppress plant immunity but they can also conversely be recognized by the plant and trigger specific resistance mechanisms. The T3SS and injected T3Es play a central role in determining the outcome of a host-pathogen interaction. Still little is known in plant pathogens on the assembly of the T3SS and the regulatory mechanisms involved in the temporal control of its biosynthesis and T3E translocation. However, recent insights point out the role of several proteins as prime candidates in the role of regulators of the type III secretion (T3S) process. In this review we report on the most recent advances on the regulation of the T3S by focusing on protein players involved in secretion/translocation regulations, including type III chaperones (T3Cs), type III secretion substrate specificity switch (T3S4) proteins and other T3S orchestrators.

Lohou, David; Lonjon, Fabien; Genin, Stephane; Vailleau, Fabienne

2013-01-01

225

Stability and loss of a virus resistance phenotype over time in transgenic mosquitoes harbouring an antiviral effector gene.  

PubMed

Transgenic Aedes aegypti were engineered to express a virus-derived, inverted repeat (IR) RNA in the mosquito midgut to trigger RNA interference (RNAi) and generate resistance to dengue virus type 2 (DENV2) in the vector. Here we characterize genotypic and phenotypic stabilities of one line, Carb77, between generations G(9) and G(17). The anti-DENV2 transgene was integrated at a single site within a noncoding region of the mosquito genome. The virus resistance phenotype was strong until G(13) and suppressed replication of different DENV2 genotypes. From G(14)-G(17) the resistance phenotype to DENV2 became weaker and eventually was lost. Although the sequence of the transgene was not mutated, expression of the IR effector RNA was not detected and the Carb77 G(17) mosquitoes lost their ability to silence the DENV2 genome. PMID:19754743

Franz, A W E; Sanchez-Vargas, I; Piper, J; Smith, M R; Khoo, C C H; James, A A; Olson, K E

2009-10-01

226

Effectors of animal and plant pathogens use a common domain to bind host phosphoinositides.  

PubMed

Bacterial Type III Secretion Systems deliver effectors into host cells to manipulate cellular processes to the advantage of the pathogen. Many host targets of these effectors are found on membranes. Therefore, to identify their targets, effectors often use specialized membrane-localization domains to localize to appropriate host membranes. However, the molecular mechanisms used by many domains are unknown. Here we identify a conserved bacterial phosphoinositide-binding domain (BPD) that is found in functionally diverse Type III effectors of both plant and animal pathogens. We show that members of the BPD family functionally bind phosphoinositides and mediate localization to host membranes. Moreover, NMR studies reveal that the BPD of the newly identified Vibrio parahaemolyticus Type III effector VopR is unfolded in solution, but folds into a specific structure upon binding its ligand phosphatidylinositol-(4,5)-bisphosphate. Thus, our findings suggest a possible mechanism for promoting refolding of Type III effectors after delivery into host cells. PMID:24346350

Salomon, Dor; Guo, Yirui; Kinch, Lisa N; Grishin, Nick V; Gardner, Kevin H; Orth, Kim

2013-01-01

227

Effector candidates in the secretome of Piriformospora indica, a ubiquitous plant-associated fungus  

PubMed Central

One of the emerging systems in plant–microbe interaction is the study of proteins, referred to as effectors, secreted by microbes in order to modulate host cells function and structure and to promote microbial growth on plant tissue. Current knowledge on fungal effectors derives mainly from biotrophic and hemibiotrophic plant fungal pathogens that have a limited host range. Here, we focus on effectors of Piriformospora indica, a soil borne endophyte forming intimate associations with roots of a wide range of plant species. Complete genome sequencing provides an opportunity to investigate the role of effectors during the interaction of this mutualistic fungus with plants. We describe in silico analyses to predict effectors of P. indica and we explore effector features considered here to mine a high priority protein list for functional analysis.

Rafiqi, Maryam; Jelonek, Lukas; Akum, Ndifor F.; Zhang, Feng; Kogel, Karl-Heinz

2013-01-01

228

Secreted fungal effector lipase releases free fatty acids to inhibit innate immunity-related callose formation during wheat head infection.  

PubMed

The deposition of the (1,3)-?-glucan cell wall polymer callose at sites of attempted penetration is a common plant defense response to intruding pathogens and part of the plant's innate immunity. Infection of the Fusarium graminearum disruption mutant ?fgl1, which lacks the effector lipase FGL1, is restricted to inoculated wheat (Triticum aestivum) spikelets, whereas the wild-type strain colonized the whole wheat spike. Our studies here were aimed at analyzing the role of FGL1 in establishing full F. graminearum virulence. Confocal laser-scanning microscopy revealed that the ?fgl1 mutant strongly induced the deposition of spot-like callose patches in vascular bundles of directly inoculated spikelets, while these callose deposits were not observed in infections by the wild type. Elevated concentrations of the polyunsaturated free fatty acids (FFAs) linoleic and ?-linolenic acid, which we detected in F. graminearum wild type-infected wheat spike tissue compared with ?fgl1-infected tissue, provided clear evidence for a suggested function of FGL1 in suppressing callose biosynthesis. These FFAs not only inhibited plant callose biosynthesis in vitro and in planta but also partially restored virulence to the ?fgl1 mutant when applied during infection of wheat spikelets. Additional FFA analysis confirmed that the purified effector lipase FGL1 was sufficient to release linoleic and ?-linolenic acids from wheat spike tissue. We concluded that these two FFAs have a major function in the suppression of the innate immunity-related callose biosynthesis and, hence, the progress of F. graminearum wheat infection. PMID:24686113

Blümke, Antje; Falter, Christian; Herrfurth, Cornelia; Sode, Björn; Bode, Rainer; Schäfer, Wilhelm; Feussner, Ivo; Voigt, Christian A

2014-05-01

229

Sphingosine-kinase 1 and 2 contribute to oral sensitization and effector phase in a mouse model of food allergy  

PubMed Central

Background Sphingosine-1-phosphate (S1P) influences activation, migration and death of immune cells. Further, S1P was proposed to play a major role in the induction and promotion of allergic diseases. However, to date only limited information is available on the role of S1P in food allergy. Objective We aimed to investigate the role of sphingosine-kinase (SphK) 1 and 2, the enzymes responsible for endogenous S1P production, on the induction of food allergy. Methods and results Human epithelial colorectal Caco2 cells stimulated in vitro with S1P revealed a decrease of transepithelial resistance and enhanced transport of FITC labeled OVA. We studied the effect of genetic deletion of the enzymes involved in S1P production on food allergy induction using a mouse model of food allergy based on intragastrically (ig.) administered ovalbumin (OVA) with concomitant acid-suppression. Wild-type (WT), SphK1?/? and SphK2?/? mice immunized with OVA alone ig. or intraperitoneally (ip.) were used as negative or positive controls, respectively. SphK1- and SphK2- deficient mice fed with OVA under acid-suppression showed reduced induction of OVA specific IgE and IgG compared to WT mice, but had normal responses when immunized by the intraperitoneal route. Flow cytometric analysis of spleen cells, revealed a significantly reduced proportion of CD4+ effector T-cells in both SphK deficient animals after oral sensitization. This was accompanied by a reduced accumulation of mast cells in the gastric mucosa in SphK-deficient animals compared to WT mice. Furthermore, mouse mast cell protease-1 (mMCP-1) levels, an IgE-mediated anaphylaxis marker, were reliably elevated in allergic WT animals. Conclusion Modulation of the S1P homeostasis by deletion of either SphK1 or SphK2 alters the sensitization and effector phase of food allergy.

Diesner, Susanne C.; Olivera, Ana; Dillahunt, Sandra; Schultz, Cornelia; Watzlawek, Thomas; Forster-Waldl, Elisabeth; Pollak, Arnold; Jensen-Jarolim, Erika; Untersmayr, Eva; Rivera, Juan

2011-01-01

230

Functions and requirements for the INEL light duty utility arm gripper end effector  

SciTech Connect

This gripper end effector system functions and requirements document defines the system functions that the end effector must perform as well as the requirements the design must meet. Safety, quality assurance, operations, environmental conditions, and regulatory requirements have been considered. The main purpose of this document is to provide a basis for the end effector engineering, design, and fabrication activities. The document shall be the living reference document to initiate the development activities and will be updated as system technologies are finalized.

Pace, D.P.; Barnes, G.E.

1995-02-01

231

Induction and suppression of PEN3 focal accumulation during Pseudomonas syringae pv. tomato DC3000 infection of Arabidopsis.  

PubMed

The pleiotropic drug resistance (PDR) proteins belong to the super-family of ATP-binding cassette (ABC) transporters. AtPDR8, also called PEN3, is required for penetration resistance of Arabidopsis to nonadapted powdery mildew fungi. During fungal infection, plasma-membrane-localized PEN3 is concentrated at fungal entry sites, as part of the plant's focal immune response. Here, we show that the pen3 mutant is compromised in resistance to the bacterial pathogen Pseudomonas syringae pv. tomato DC3000. P. syringae pv. tomato DC3000 infection or treatment with a flagellin-derived peptide, flg22, induced strong focal accumulation of PEN3-green fluorescent protein. Interestingly, after an initial induction of PEN3 accumulation, P. syringae pv. tomato DC3000 but not the type-III-secretion-deficient mutant hrcC could suppress PEN3 accumulation. Moreover, transgenic overexpression of the P. syringae pv. tomato DC3000 effector AvrPto was sufficient to suppress PEN3 focal accumulation in response to flg22. Analyses of P. syringae pv. tomato DC3000 effector deletion mutants showed that individual effectors, including AvrPto, appear to be insufficient to suppress PEN3 accumulation when delivered by bacteria, suggesting a requirement for a combined action of multiple effectors. Collectively, our results indicate that PEN3 plays a positive role in plant resistance to a bacterial pathogen and show that focal accumulation of PEN3 protein may be a useful cellular response marker for the Arabidopsis-P. syringae interaction. PMID:23815470

Xin, Xiu-Fang; Nomura, Kinya; Underwood, William; He, Sheng Yang

2013-08-01

232

Multiplicity of effectors of the cardioprotective agent, diazoxide.  

PubMed

Diazoxide has been identified over the past 50years to have a number of physiological effects, including lowering the blood pressure and rectifying hypoglycemia. Today it is used clinically to treat these conditions. More recently, another important mode of action emerged: diazoxide has powerful protective properties against cardiac ischemia. The heart has intrinsic protective mechanisms against ischemia injury; one of which is ischemic preconditioning. Diazoxide mimics ischemic preconditioning. The purpose of this treatise is to review the literature in an attempt to identify the many effectors of diazoxide and discuss how they may contribute to diazoxide's cardioprotective properties. Particular emphasis is placed on the concentration ranges in which diazoxide affects its different targets and how this compares with the concentrations commonly used to study cardioprotection. It is concluded that diazoxide may have several potential effectors that may potentially contribute to cardioprotection, including KATP channels in the pancreas, smooth muscle, endothelium, neurons and the mitochondrial inner membrane. Diazoxide may also affect other ion channels and ATPases and may directly regulate mitochondrial energetics. It is possible that the success of diazoxide lies in this promiscuity and that the compound acts to rebalance multiple physiological processes during cardiac ischemia. PMID:23792087

Coetzee, William A

2013-11-01

233

Flight Control Using Distributed Shape-Change Effector Arrays  

NASA Technical Reports Server (NTRS)

Recent discoveries in material science and fluidics have been used to create a variety of novel effector devices that offer great potential to enable new approaches to aerospace vehicle flight control. Examples include small inflatable blisters, shape-memory alloy diaphragms, and piezoelectric patches that may be used to produce distortions or bumps on the surface of an airfoil to generate control moments. Small jets have also been used to produce a virtual shape-change through fluidic means by creating a recirculation bubble on the surface of an airfoil. An advanced aerospace vehicle might use distributed arrays of hundreds of such devices to generate moments for stabilization and maneuver control, either augmenting or replacing conventional ailerons, flaps or rudders. This research demonstrates the design and use of shape-change device arrays for a tailless aircraft in a low-rate maneuvering application. A methodology for assessing the control authority of the device arrays is described, and a suite of arrays is used in a dynamic simulation to illustrate allocation and deployment methodologies. Although the authority of the preliminary shape-change array designs studied in this paper appeared quite low, the simulation results indicate that the effector suite possessed sufficient authority to stabilize and maneuver the vehicle in mild turbulence.

Raney, David L.; Montgomery, Raymond C.; Green, Lawrence I.; Park, Michael A.

2000-01-01

234

Heat shock proteins, end effectors of myocardium ischemic preconditioning?  

PubMed Central

The purpose of this study was to investigate (1) whether ischemia-reperfusion increased the content of heat shock protein 72 (Hsp72) transcripts and (2) whether myocardial content of Hsp72 is increased by ischemic preconditioning so that they can be considered as end effectors of preconditioning. Twelve male minipigs (8 protocol, 4 sham) were used, with the following ischemic preconditioning protocol: 3 ischemia and reperfusion 5-minute alternative cycles and last reperfusion cycle of 3 hours. Initial and final transmural biopsies (both in healthy and ischemic areas) were taken in all animals. Heat shock protein 72 messenger ribonucleic acid (mRNA) expression was measured by a semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method using complementary DNA normalized against the housekeeping gene cyclophilin. The identification of heat shock protein 72 was performed by immunoblot. In our “classic” preconditioning model, we found no changes in mRNA hsp72 levels or heat shock protein 72 content in the myocardium after 3 hours of reperfusion. Our experimental model is valid and the experimental techniques are appropriate, but the induction of heat shock proteins 72 as end effectors of cardioprotection in ischemic preconditioning does not occur in the first hours after ischemia, but probably at least 24 hours after it, in the so-called “second protection window.”

Guisasola, Maria Concepcion; Desco, Maria del Mar; Gonzalez, Fernanda Silvana; Asensio, Fernando; Dulin, Elena; Suarez, Antonio; Garcia Barreno, Pedro

2006-01-01

235

Innovative technology summary report: Confined sluicing end effector  

SciTech Connect

A Confined Sluicing End-Effector (CSEE) was field tested during the summer of 1997 in Tank W-3, one of the Gunite and Associated Tanks (GAAT) at the Oak Ridge Reservation (ORR). It should be noted that the specific device used at the Oak Ridge Reservation demonstration was the Sludge Retrieval End-Effector (SREE), although in common usage it is referred to as the CSEE. Deployed by the Modified Light-Duty Utility Arm (MLDUA) and the Houdini remotely operated vehicle (ROV), the CSEE was used to mobilize and retrieve waste from the tank. After removing the waste, the CSEE was used to scarify the gunite walls of Tank W-3, removing approximately 0.1 in of material. The CSEE uses three rotating water-jets to direct a short-range pressurized jet of water to effectively mobilize the waste. Simultaneously, the water and dislodged tank waste, or scarified materials, are aspirated using a water-jet pump-driven conveyance system. The material is then pumped outside of the tank, where it can be stored for treatment. The technology, its performance, uses, cost, and regulatory issues are discussed.

NONE

1998-09-01

236

Method and apparatus for positioning a robotic end effector  

NASA Technical Reports Server (NTRS)

A robotic end effector and operation protocol for a reliable grasp of a target object irrespective of the target's contours is disclosed. A robotic hand includes a plurality of jointed fingers, one of which, like a thumb, is in opposed relation to the other. Each finger is comprised of at least two jointed sections, and provided with reflective proximity sensors, one on the inner surface of each finger section. Each proximity sensor comprises a transmitter of a beam of radiant energy and means for receiving reflections of the transmitted energy when reflected by a target object and for generating electrical signals responsive thereto. On the fingers opposed to the thumb, the proximity sensors on the outermost finger sections are aligned in an outer sensor array and the sensors on the intermediate finger sections and sensors on the innermost finger sections are similarly arranged to form an intermediate sensor array and an inner sensor array, respectively. The invention includes a computer system with software and/or circuitry for a protocol comprising the steps in sequence of: (1) approach axis alignment to maximize the number of outer layer sensors which detect the target; (2) non-contact contour following the target by the robot fingers to minimize target escape potential; and (3) closing to rigidize the target including dynamically re-adjusting the end effector finger alignment to compensate for target motion. A signal conditioning circuit and gain adjustment means are included to maintain the dynamic range of low power reflection signals.

Hess, Clifford W. (inventor); Li, Larry C. H. (inventor)

1990-01-01

237

Local sensory control of a dexterous end effector  

NASA Technical Reports Server (NTRS)

A numerical scheme was developed to solve the inverse kinematics for a user-defined manipulator. The scheme was based on a nonlinear least-squares technique which determines the joint variables by minimizing the difference between the target end effector pose and the actual end effector pose. The scheme was adapted to a dexterous hand in which the joints are either prismatic or revolute and the fingers are considered open kinematic chains. Feasible solutions were obtained using a three-fingered dexterous hand. An algorithm to estimate the position and orientation of a pre-grasped object was also developed. The algorithm was based on triangulation using an ideal sensor and a spherical object model. By choosing the object to be a sphere, only the position of the object frame was important. Based on these simplifications, a minimum of three sensors are needed to find the position of a sphere. A two dimensional example to determine the position of a circle coordinate frame using a two-fingered dexterous hand was presented.

Pinto, Victor H.; Everett, Louis J.; Driels, Morris

1990-01-01

238

Regulation of Cell Wall-Bound Invertase in Pepper Leaves by Xanthomonas campestris pv. vesicatoria Type Three Effectors  

PubMed Central

Xanthomonas campestris pv. vesicatoria (Xcv) possess a type 3 secretion system (T3SS) to deliver effector proteins into its Solanaceous host plants. These proteins are involved in suppression of plant defense and in reprogramming of plant metabolism to favour bacterial propagation. There is increasing evidence that hexoses contribute to defense responses. They act as substrates for metabolic processes and as metabolic semaphores to regulate gene expression. Especially an increase in the apoplastic hexose-to-sucrose ratio has been suggested to strengthen plant defense. This shift is brought about by the activity of cell wall-bound invertase (cw-Inv). We examined the possibility that Xcv may employ type 3 effector (T3E) proteins to suppress cw-Inv activity during infection. Indeed, pepper leaves infected with a T3SS-deficient Xcv strain showed a higher level of cw-Inv mRNA and enzyme activity relative to Xcv wild type infected leaves. Higher cw-Inv activity was paralleled by an increase in hexoses and mRNA abundance for the pathogenesis-related gene PRQ. These results suggest that Xcv suppresses cw-Inv activity in a T3SS-dependent manner, most likely to prevent sugar-mediated defense signals. To identify Xcv T3Es that regulate cw-Inv activity, a screen was performed with eighteen Xcv strains, each deficient in an individual T3E. Seven Xcv T3E deletion strains caused a significant change in cw-Inv activity compared to Xcv wild type. Among them, Xcv lacking the xopB gene (Xcv ?xopB) caused the most prominent increase in cw-Inv activity. Deletion of xopB increased the mRNA abundance of PRQ in Xcv ?xopB-infected pepper leaves, but not of Pti5 and Acre31, two PAMP-triggered immunity markers. Inducible expression of XopB in transgenic tobacco inhibited Xcv-mediated induction of cw-Inv activity observed in wild type plants and resulted in severe developmental phenotypes. Together, these data suggest that XopB interferes with cw-Inv activity in planta to suppress sugar-enhanced defense responses during Xcv infection.

Sonnewald, Sophia; Priller, Johannes P. R.; Schuster, Julia; Glickmann, Eric; Hajirezaei, Mohammed-Reza; Siebig, Stefan; Mudgett, Mary Beth; Sonnewald, Uwe

2012-01-01

239

A Plethora of Virulence Strategies Hidden Behind Nuclear Targeting of Microbial Effectors  

PubMed Central

Plant immune responses depend on the ability to couple rapid recognition of the invading microbe to an efficient response. During evolution, plant pathogens have acquired the ability to deliver effector molecules inside host cells in order to manipulate cellular and molecular processes and establish pathogenicity. Following translocation into plant cells, microbial effectors may be addressed to different subcellular compartments. Intriguingly, a significant number of effector proteins from different pathogenic microorganisms, including viruses, oomycetes, fungi, nematodes, and bacteria, is targeted to the nucleus of host cells. In agreement with this observation, increasing evidence highlights the crucial role played by nuclear dynamics, and nucleocytoplasmic protein trafficking during a great variety of analyzed plant–pathogen interactions. Once in the nucleus, effector proteins are able to manipulate host transcription or directly subvert essential host components to promote virulence. Along these lines, it has been suggested that some effectors may affect histone packing and, thereby, chromatin configuration. In addition, microbial effectors may either directly activate transcription or target host transcription factors to alter their regular molecular functions. Alternatively, nuclear translocation of effectors may affect subcellular localization of their cognate resistance proteins in a process that is essential for resistance protein-mediated plant immunity. Here, we review recent progress in our field on the identification of microbial effectors that are targeted to the nucleus of host plant cells. In addition, we discuss different virulence strategies deployed by microbes, which have been uncovered through examination of the mechanisms that guide nuclear localization of effector proteins.

Rivas, Susana; Genin, Stephane

2011-01-01

240

Interleukin 4 inhibits TGF-?-induced-Foxp3+T cells and generates, in combination with TGF-?, Foxp3? effector T cells that produce interleukins 9 and 10  

PubMed Central

Foxp3 is a key transcription factor involved in the generation and function of regulatory T (Treg) cells. Transforming growth factor ? (TGF-?) induces Foxp3, which generates inducible Foxp3+ Treg cells from naïve T cells, and interleukin 6 (IL-6) inhibits the generation of inducible Treg cells and induces T helper cells that produce IL-17 (TH-17 cells). However, a role for IL-4 in the generation of TGF-?-induced Treg cells and/or the generation of effector CD4+ T helper cells has not been studied. Here, we show that IL-4 blocked the generation of TGF-?-induced Foxp3+ Treg cells. Instead, IL-4 induced a population of T helper cells that predominantly produce IL-9 and IL-10. The IL-9+IL-10+ T cells did not exhibit any regulatory properties in spite of producing large quantities of IL-10. Adoptive transfer of IL-9+IL-10+producing T cells into RAG-1-deficient mice induced colitis and peripheral neuritis. Interestingly, the severity of tissue inflammation was aggravated when IL-9+IL-10+ T cells were co-transferred with CD45RBhi CD4+ effector T cells into RAG-1-deficient mice, which indicated that IL-9+IL-10+ T cells do not display any suppressive function and therefore constitute a unique population of IL-10-producing helper-effector T cells that promote tissue inflammation.

Dardalhon, Valerie; Awasthi, Amit; Kwon, Hyoung; Galileos, George; Gao, Wenda; Sobel, Raymond A.; Mitsdoerffer, Meike; Strom, Terry B.; Elyaman, Wassim; Ho, I-Cheng; Khoury, Samia; Oukka, Mohamed; Kuchroo, Vijay K

2010-01-01

241

Cough suppression disorders spectrum.  

PubMed

Volitional cough suppression, identified exclusively in females, is an unusual causal mechanism for instances of lobar atalectasis and bronchiectasis. It is a postulated mechanism for the genesis of Lady Windermere Syndrome. PMID:24462261

Reich, Jerome M

2014-02-01

242

Cable Strumming Suppression.  

National Technical Information Service (NTIS)

This report presents a consolidation of existing data on various devices used to suppress vortex-induced motions of cables and circular cylinders in the ocean. The types of devices discussed herein include 'fringe,' 'hair,' and ribbon flexible fairings an...

B. E. Hafen D. J. Meggitt

1977-01-01

243

Cochannel Talker Interference Suppression.  

National Technical Information Service (NTIS)

Cochannel talker interference suppression is defined as the processing of a waveform containing two simultaneous speech signals, referred to as the target and the jammer, to produce a signal containing an estimate of the target speech signal alone. The fi...

M. A. Zissman

1991-01-01

244

STAT5 IS CRITICAL TO MAINTAIN EFFECTOR CD8+ T CELL RESPONSES  

PubMed Central

During an immune response, most effector T cells die, while some are maintained and become memory T cells. Factors controlling the survival of effector CD4+ and CD8+ T cells remain unclear. Here, we assessed the role of IL-7, IL-15, and their common signal transducer, STAT5, in maintaining effector CD4+ and CD8+ T cell responses. Following viral infection, IL-15 was required to maintain a subpopulation of effector CD8+ T cells expressing high levels of killer cell lectin-like receptor subfamily G, member 1 (KLRG1) and lower levels of CD127, while IL-7 and IL-15 acted together to maintain KLRG1loCD127hi CD8+ effector T cells. In contrast, effector CD4+ T cell numbers were not affected by the individual or combined loss of IL-15 and IL-7. Both IL-7 and IL-15 drove phosphorylation of STAT5 (pSTAT5) within effector CD4+ and CD8+ T cells. When STAT5 was deleted during the course of infection, both KLRG1hiCD127lo and KLRG1loCD127hi CD8+ T cells were lost, while effector CD4+ T cell populations were maintained. Further, STAT5 was required to maintain expression of Bcl-2 in effector CD8+, but not CD4+, T cells. Finally, IL-7 and IL-15 required STAT5 to induce Bcl-2 expression and to maintain effector CD8+ T cells. Together, these data demonstrate that IL-7 and IL-15 signaling converge on STAT5 to maintain effector CD8+ T cell responses.

Tripathi, Pulak; Kurtulus, Sema; Wojciechowski, Sara; Sholl, Allyson; Hoebe, Kasper; Morris, Suzanne C.; Finkelman, Fred D.; Grimes, H. Leighton; Hildeman, David A.

2010-01-01

245

Histone/protein deacetylase inhibitors increase suppressive functions of human FOXP3+ Tregs1  

PubMed Central

Histone/protein deacetylases (HDACs) decrease histone and protein acetylation, typically leading to suppression of gene transcription and modulation of various protein functions. We found significant differences in expression of HDAC before and after stimulation of human T regulatory (Treg) and T effector cells, suggesting the potential for future selective targeting of Tregs with HDAC inhibitors (HDACi). Use of various HDACi small molecules enhanced, by up to 4.5-fold (average 2-fold), the suppressive functions of both freshly isolated and expanded human Tregs, consistent with our previous murine data. HDACi use increased Treg expression of CTLA-4, a key negative regulator of immune response, and we found a direct and significant correlation between CTLA-4 expression and Treg suppression. Hence, HDACi compounds are promising pharmacologic tools to increase Treg suppressive functions, and this action may potentially be of use in patients with autoimmunity or post-transplantation.

Akimova, Tatiana; Ge, Guanghui; Golovina, Tatiana; Mikheeva, Tatiana; Wang, Liqing; Riley, James L.; Hancock, Wayne W.

2010-01-01

246

Deletions in the Repertoire of Pseudomonas syringae pv. tomato DC3000 Type III Secretion Effector Genes Reveal Functional Overlap among Effectors  

Microsoft Academic Search

The ?-proteobacterial plant pathogen Pseudomonas syringae pv. tomato DC3000 uses the type III secretion system to inject ca. 28 Avr\\/Hop effector proteins into plants, which enables the bacterium to grow from low inoculum levels to produce bacterial speck symptoms in tomato, Arabidopsis thaliana, and (when lacking hopQ1-1) Nicotiana benthamiana. The effectors are collectively essential but individually dispensable for the ability

Brian H. Kvitko; Duck Hwan Park; André C. Velásquez; Chia-Fong Wei; Alistair B. Russell; Gregory B. Martin; David J. Schneider; Alan Collmer

2009-01-01

247

Immune Effector Mechanisms Implicated in Atherosclerosis: From Mice to Humans  

PubMed Central

According to the traditional view, atherosclerosis results from a passive buildup of cholesterol in the artery wall. Yet, burgeoning evidence implicates inflammation and immune effector mechanisms in the pathogenesis of this disease. Both innate and adaptive immunity operate during atherogenesis and link many traditional risk factors to altered arterial functions. Inflammatory pathways have become targets in the quest for novel preventive and therapeutic strategies against cardiovascular disease, a growing contributor to morbidity and mortality worldwide. Here we review current experimental and clinical knowledge of the pathogenesis of atherosclerosis through an immunological lens and how host defense mechanisms essential for survival of the species actually contribute to this chronic disease but also present new opportunities for its mitigation.

Libby, Peter; Lichtman, Andrew H.; Hansson, Goran K.

2013-01-01

248

Using nanotopography and metabolomics to identify biochemical effectors of multipotency.  

PubMed

It is emerging that mesenchymal stem cell (MSC) metabolic activity may be a key regulator of multipotency. The metabolome represents a "snapshot" of the stem cell phenotype, and therefore metabolic profiling could, through a systems biology approach, offer and highlight critical biochemical pathways for investigation. To date, however, it has remained difficult to undertake unbiased experiments to study MSC multipotency in the absence of strategies to retain multipotency without recourse to soluble factors that can add artifact to experiments. Here we apply a nanotopographical systems approach linked to metabolomics to regulate plasticity and demonstrate rapid metabolite reorganization, allowing rational selection of key biochemical targets of self-renewal (ERK1/2, LDL, and Jnk). We then show that these signaling effectors regulate functional multipotency. PMID:23072705

Tsimbouri, P Monica; McMurray, Rebecca J; Burgess, Karl V; Alakpa, Enateri V; Reynolds, Paul M; Murawski, Kate; Kingham, Emmajayne; Oreffo, Richard O C; Gadegaard, Nikolaj; Dalby, Matthew J

2012-11-27

249

Type VI secretion system effectors: poisons with a purpose.  

PubMed

The type VI secretion system (T6SS) mediates interactions between a broad range of Gram-negative bacterial species. Recent studies have led to a substantial increase in the number of characterized T6SS effector proteins and a more complete and nuanced view of the adaptive importance of the system. Although the T6SS is most often implicated in antagonism, in this Review, we consider the case for its involvement in both antagonistic and non-antagonistic behaviours. Clarifying the roles that type VI secretion has in microbial communities will contribute to broader efforts to understand the importance of microbial interactions in maintaining human and environmental health, and will inform efforts to manipulate these interactions for therapeutic or environmental benefit. PMID:24384601

Russell, Alistair B; Peterson, S Brook; Mougous, Joseph D

2014-02-01

250

Effector and Memory T cell Responses to Commensal Bacteria  

PubMed Central

Barrier surfaces are home to a vast population of commensal organisms that together encode millions of proteins, each of them possessing several potential foreign antigens. Regulation of immune responses to this enormous antigenic load represents a tremendous challenge for the immune system. Tissues exposed to commensals have developed elaborate systems of regulation including specialized populations of resident lymphocytes that maintain barrier function and limit potential responses to commensal antigens. However, in settings of infection and inflammation these regulatory mechanisms are compromised and specific effector responses against commensal bacteria can develop. This review discusses the circumstances controlling the fate of commensal specific T cells and how dysregulation of these responses could lead to severe pathological outcomes.

Belkaid, Yasmine; Bouladoux, Nicolas; Hand, Timothy W.

2013-01-01

251

The role of protein effectors in plant-aphid interactions.  

PubMed

Aphid salivary proteins, which are injected into the phloem sieve elements during feeding, play a central role in plant-aphid interactions. Among the dozens of known salivary proteins, many have no homology to proteins from other organisms. These aphid-specific proteins likely have evolved as effectors that inhibit plant defenses, prevent phloem sieve-element occlusion, and otherwise promote the unique phloem feeding style. However, aphid salivary proteins also are recognized by plants to mount defense responses and are likely a major factor in limiting the host range of particular aphid species and biotypes. Newly developed research tools provide excellent opportunities for analyzing the mostly unknown functions of aphid salivary proteins and elucidating their contribution to the complex interactions between aphids and their host plants. PMID:23850072

Elzinga, Dezi A; Jander, Georg

2013-08-01

252

Gibberellin Perception by the Gibberellin Receptor and its Effector Recognition  

NASA Astrophysics Data System (ADS)

Gibberellins control a diverse range of growth and developmental processes in higher plants and have been widely utilized in the agricultural industry. By binding to a nuclear receptor GIBBERELLIN INSENSITIVE DWARF1 (GID1), gibberellins regulate gene expression by promoting degradation of the transcriptional regulator DELLA proteins. The precise manner in which GID1 discriminates and becomes activated by bioactive gibberellins for specific binding to DELLA proteins remains unclear. We present the crystal structure of a ternary complex of Arabidopsis thaliana GID1A, a bioactive gibberellin and the N-terminal DELLA domain of GAI. In this complex, GID1a occludes gibberellin in a deep binding pocket covered by its N-terminal helical switch region, which in turn interacts with the DELLA domain containing DELLA, VHYNP and LExLE motifs. Our results establish a structural model of a plant hormone receptor which is distinct from the hormone-perception mechanism and effector recognition of the known auxin receptors.

Hakoshima, Toshio; Murase, Kohji; Hirano, Yoshinori; Sun, Tai-Ping

253

Thrombin A-Chain: Activation Remnant or Allosteric Effector?  

PubMed Central

Although prothrombin is one of the most widely studied enzymes in biology, the role of the thrombin A-chain has been neglected in comparison to the other domains. This paper summarizes the current data on the prothrombin catalytic domain A-chain region and the subsequent thrombin A-chain. Attention is given to biochemical characterization of naturally occurring prothrombin A-chain mutations and alanine scanning mutants in this region. While originally considered to be simply an activation remnant with little physiologic function, the thrombin A-chain is now thought to play a role as an allosteric effector in enzymatic reactions and may also be a structural scaffold to stabilize the protease domain.

Carter, Isis S. R.; Vanden Hoek, Amanda L.; Pryzdial, Edward L. G.; MacGillivray, Ross T. A.

2010-01-01

254

Intervention of Phytohormone Pathways by Pathogen Effectors[OPEN  

PubMed Central

The constant struggle between plants and microbes has driven the evolution of multiple defense strategies in the host as well as offense strategies in the pathogen. To defend themselves from pathogen attack, plants often rely on elaborate signaling networks regulated by phytohormones. In turn, pathogens have adopted innovative strategies to manipulate phytohormone-regulated defenses. Tactics frequently employed by plant pathogens involve hijacking, evading, or disrupting hormone signaling pathways and/or crosstalk. As reviewed here, this is achieved mechanistically via pathogen-derived molecules known as effectors, which target phytohormone receptors, transcriptional activators and repressors, and other components of phytohormone signaling in the host plant. Herbivores and sap-sucking insects employ obligate pathogens such as viruses, phytoplasma, or symbiotic bacteria to intervene with phytohormone-regulated defenses. Overall, an improved understanding of phytohormone intervention strategies employed by pests and pathogens during their interactions with plants will ultimately lead to the development of new crop protection strategies.

Kazan, Kemal; Lyons, Rebecca

2014-01-01

255

[Transcription activator-like effectors(TALEs)based genome engineering].  

PubMed

Systematic reverse-engineering of functional genome architecture requires precise modifications of gene sequences and transcription levels. The development and application of transcription activator-like effectors(TALEs) has created a wealth of genome engineering possibilities. TALEs are a class of naturally occurring DNA-binding proteins found in the plant pathogen Xanthomonas species. The DNA-binding domain of each TALE typically consists of tandem 34-amino acid repeat modules rearranged according to a simple cipher to target new DNA sequences. Customized TALEs can be used for a wide variety of genome engineering applications, including transcriptional modulation and genome editing. Such "genome engineering" has now been established in human cells and a number of model organisms, thus opening the door to better understanding gene function in model organisms, improving traits in crop plants and treating human genetic disorders. PMID:24115666

Zhao, Mei-Wei; Duan, Cheng-Li; Liu, Jiang

2013-10-01

256

The Pseudomonas syringae type III effector AvrRpt2 functions downstream or independently of SA to promote virulence on Arabidopsis thaliana.  

PubMed

AvrRpt2, a Pseudomonas syringae type III effector protein, functions from inside plant cells to promote the virulence of P. syringae pv. tomato strain DC3000 (PstDC3000) on Arabidopsis thaliana plants lacking a functional copy of the corresponding RPS2 resistance gene. In this study, we extended our understanding of AvrRpt2 virulence activity by exploring the hypothesis that AvrRpt2 promotes PstDC3000 virulence by suppressing plant defenses. When delivered by PstDC3000, AvrRpt2 suppresses pathogen-related (PR) gene expression during infection, suggesting that AvrRpt2 suppresses defenses mediated by salicylic acid (SA). However, AvrRpt2 promotes PstDC3000 growth on transgenic plants expressing the SA-degrading enzyme NahG, indicating that AvrRpt2 does not promote bacterial virulence by modulating SA levels during infection. AvrRpt2 general virulence activity does not depend on the RPM1 resistance gene, as mutations in RPM1 had no effect on AvrRpt2-induced phenotypes. Transgenic plants expressing AvrRpt2 displayed enhanced susceptibility to PstDC3000 strains defective in type III secretion, indicating that enhanced susceptibility of these plants is not because of suppression of defense responses elicited by other type III effectors. Additionally, avrRpt2 transgenic plants did not exhibit increased susceptibility to Peronospora parasitica and Erysiphe cichoracearum, suggesting that AvrRpt2 virulence activity is specific to P. syringae. PMID:14756766

Chen, Zhongying; Kloek, Andrew P; Cuzick, Alayne; Moeder, Wolfgang; Tang, Dingzhong; Innes, Roger W; Klessig, Daniel F; McDowell, John M; Kunkel, Barbara N

2004-02-01

257

Immune effectors required for hepatitis B virus clearance  

PubMed Central

To better define the mechanism(s) likely responsible for viral clearance during hepatitis B virus (HBV) infection, viral clearance was studied in a panel of immunodeficient mouse strains that were hydrodynamically transfected with a plasmid containing a replication-competent copy of the HBV genome. Neither B cells nor perforin were required to clear the viral DNA transcriptional template from the liver. In contrast, the template persisted for at least 60 days at high levels in NOD/Scid mice and at lower levels in the absence of CD4+ and CD8+ T cells, NK cells, Fas, IFN-gamma (IFN-?), IFN-alpha/beta receptor (IFN-?/?R1), and TNF receptor 1 (TNFR1), indicating that each of these effectors was required to eliminate the transcriptional template from the liver. Interestingly, viral replication was ultimately terminated in all lineages except the NOD/Scid mice, suggesting the existence of redundant pathways that inhibit HBV replication. Finally, induction of a CD8+ T cell response in these animals depended on the presence of CD4+ T cells. These results are consistent with a model in which CD4+ T cells serve as master regulators of the adaptive immune response to HBV; CD8+ T cells are the key cellular effectors mediating HBV clearance from the liver, apparently by a Fas-dependent, perforin-independent process in which NK cells, IFN-?, TNFR1, and IFN-?/?R play supporting roles. These results provide insight into the complexity of the systems involved in HBV clearance, and they suggest unique directions for analysis of the mechanism(s) responsible for HBV persistence.

Yang, Priscilla L.; Althage, Alana; Chung, Josan; Maier, Holly; Wieland, Stefan; Isogawa, Masanori; Chisari, Francis V.

2009-01-01

258

The structural basis for activation of plant immunity by bacterial effector protein AvrPto  

Microsoft Academic Search

Pathogenic microbes use effectors to enhance susceptibility in host plants. However, plants have evolved a sophisticated immune system to detect these effectors using cognate disease resistance proteins, a recognition that is highly specific, often elicits rapid and localized cell death, known as a hypersensitive response, and thus potentially limits pathogen growth. Despite numerous genetic and biochemical studies on the interactions

Weiman Xing; Yan Zou; Qun Liu; Jianing Liu; Xi Luo; Qingqiu Huang; She Chen; Lihuang Zhu; Ruchang Bi; Quan Hao; Jia-Wei Wu; Jian-Min Zhou; Jijie Chai

2007-01-01

259

Spatial and effector processing in the human parietofrontal network for reaches and saccades.  

PubMed

It is generally accepted that interactions between parietal and frontal cortices subserve the visuomotor processing for eye and hand movements. Here, we used a sequential-instruction paradigm in 3-T functional MRI to test the processing of effector and spatial signals, as well as their interaction, as a movement is composed and executed in different stages. Subjects prepared either a saccade or a reach following two successive visual instruction cues, presented in either order. One cue instructed which effector to use (eyes, right hand); the other signaled the spatial goal (leftward vs. rightward target location) of the movement. During the first phase of the prepared movement, after cueing of either goal or effector information, we found significant spatial goal selectivity but no effector specificity along the parietofrontal network. During the second phase of the prepared movement, when both goal and effector information were available, we found a large overlap in the neural circuitry involved in the planning of eye and hand movements. Gradually distributed along this network, we observed clear spatial goal selectivity and limited, but significant, effector specificity. Regions in the intraparietal sulcus and the dorsal premotor cortex were selective to both goal location and motor effector. Taken together, our results suggest that the relative weight of spatial goal and effector selectivity changes along the parietofrontal network, depending on the status of the movement plan. PMID:19321636

Beurze, S M; de Lange, F P; Toni, I; Medendorp, W P

2009-06-01

260

Autogeneic but Not Allogeneic Earthworm Effector Coelomocytes Kill the Mammalian Tumor Cell Target K562  

Microsoft Academic Search

Earthworm coelomocytes have been used as effector cells against the human tumor target, K562. To first assess the viability of effectors, incorporation of [3H]thymidine was tested and was higher in autogeneic (A ? A, self) than in allogeneic (A ? B, nonself) coelomocytes. A ? A showed significantly greater numbers in S, G2, or M phases than A ? B

EDWIN L. COOPER; ANDREA COSSARIZZA; MICHAEL M. SUZUKI; STEFANO SALVIOLI; MIRIAM CAPRI; DANIELA QUAGLINO; CLAUDIO FRANCESCHI

1995-01-01

261

Bacterial EPIYA effectors--where do they come from? What are they? Where are they going?  

PubMed

Recent studies have revealed a distinct class of bacterial effectors defined by the presence of EPIYA or EPIYA-related motif. These bacterial EPIYA effectors are delivered into host cells via type III or IV secretion, where they undergo tyrosine phosphorylation at the EPIYA motif and thereby manipulate host signalling by promiscuously interacting with multiple SH2 domain-containing proteins. Up to now, nine EPIYA effectors have been identified from various bacteria. These effectors do not share sequence homology outside the EPIYA motif, arguing against the idea that they have common ancestors. A search of mammalian proteomes revealed the presence of a mammalian EPIYA-containing protein, Pragmin, which potentiates Src family kinase (SFK) activity by binding and sequestrating the SFK inhibitor Csk upon EPIYA phosphorylation. As several bacterial EPIYA effectors also target Csk, they may have evolved through generation of sequences that mimic the Pragmin EPIYA motif. EPIYA motifs are often diverged through multiple duplications in each bacterial effector. Such a structural plasticity appears to be due to intrinsic disorder of the EPIYA-containing region, which enables the bacterial effectors to undergo efficient phosphorylation and mediate promiscuous interaction with multiple host proteins. Given the functional versatility of the EPIYA motif, many more bacterial EPIYA effectors will soon be emerging. PMID:23051602

Hayashi, Takeru; Morohashi, Hiroko; Hatakeyama, Masanori

2013-03-01

262

A widespread bacterial type VI secretion effector superfamily identified using a heuristic approach.  

PubMed

Sophisticated mechanisms are employed to facilitate information exchange between interfacing bacteria. A type VI secretion system (T6SS) of Pseudomonas aeruginosa was shown to deliver cell wall-targeting effectors to neighboring cells. However, the generality of bacteriolytic effectors and, moreover, of antibacterial T6S remained unknown. Using parameters derived from experimentally validated bacterial T6SS effectors we identified a phylogenetically disperse superfamily of T6SS-associated peptidoglycan-degrading effectors. The effectors separate into four families composed of peptidoglycan amidase enzymes of differing specificities. Effectors strictly co-occur with cognate immunity proteins, indicating that self-intoxication is a general property of antibacterial T6SSs and effector delivery by the system exerts a strong selective pressure in nature. The presence of antibacterial effectors in a plethora of organisms, including many that inhabit or infect polymicrobial niches in the human body, suggests that the system could mediate interbacterial interactions of both environmental and clinical significance. PMID:22607806

Russell, Alistair B; Singh, Pragya; Brittnacher, Mitchell; Bui, Nhat Khai; Hood, Rachel D; Carl, Mike A; Agnello, Danielle M; Schwarz, Sandra; Goodlett, David R; Vollmer, Waldemar; Mougous, Joseph D

2012-05-17

263

A widespread bacterial type VI secretion effector superfamily identified using a heuristic approach  

PubMed Central

Summary Sophisticated mechanisms are employed to facilitate information exchange between interfacing bacteria. A type VI secretion system (T6SS) of Pseudomonas aeruginosa was shown to deliver cell wall-targeting effectors to neighboring cells. However, the generality of bacteriolytic effectors, and moreover, of antibacterial T6S, remained unknown. Using parameters derived from experimentally validated bacterial T6SS effectors and informatics, we identified a phylogenetically disperse superfamily of T6SS-associated peptidoglycan-degrading effectors. The effectors separate into four families composed of peptidoglycan amidase enzymes of differing specificities. Effectors strictly co-occur with cognate immunity proteins, indicating that self-intoxication is a general property of antibacterial T6SSs and effector delivery by the system exerts a strong selective pressure in nature. The presence of antibacterial effectors in a plethora of organisms, including many that inhabit or infect polymicrobial niches in the human body, suggests that the system could mediate interbacterial interactions of both environmental and clinical significance.

Russell, Alistair B.; Singh, Pragya; Brittnacher, Mitchell; Bui, Nhat Khai; Hood, Rachel D.; Carl, Mike A.; Agnello, Danielle M.; Schwarz, Sandra; Goodlett, David R.; Vollmer, Waldemar; Mougous, Joseph D.

2012-01-01

264

The 5HT receptor — G-protein — effector system complex in depression I. Effect of glucocorticoids  

Microsoft Academic Search

Summary Hormonal modulation of neurotransmission emerged as a concept from the recognition that adrenocortical steroids exert profound effects at the level of receptors, G-proteins and effector units. G-proteins, a family of guanine nucleotide binding regulatory components that couple neurotransmitter receptors to various types of intracellular effector systems, appear to be a key target of glucocorticoid (GC) action in the CNS.

K. P. Lesch; B. Lerer

1991-01-01

265

Verticillium dahliae Sge1 differentially regulates expression of candidate effector genes.  

PubMed

The ascomycete fungus Verticillium dahliae causes vascular wilt diseases in hundreds of dicotyledonous plant species. However, thus far, only few V. dahliae effectors have been identified, and regulators of pathogenicity remain unknown. In this study, we investigated the role of the V. dahliae homolog of Sge1, a transcriptional regulator that was previously implicated in pathogenicity and effector gene expression in Fusarium oxysporum. We show that V. dahliae Sge1 (VdSge1) is required for radial growth and production of asexual conidiospores, because VdSge1 deletion strains display reduced radial growth and reduced conidia production. Furthermore, we show that VdSge1 deletion strains have lost pathogenicity on tomato. Remarkably, VdSge1 is not required for induction of Ave1, the recently identified V. dahliae effector that activates resistance mediated by the Ve1 immune receptor in tomato. Further assessment of the role of VdSge1 in the induction of the nine most highly in-planta-induced genes that encode putative effectors revealed differential activity. Although the expression of one putative effector gene in addition to Ave1 was not affected by VdSge1 deletion, VdSge1 appeared to be required for the expression of six putative effector genes, whereas two of the putative effectors genes were found to be negatively regulated by VdSge1. In conclusion, our data suggest that VdSge1 differentially regulates V. dahliae effector gene expression. PMID:22970788

Santhanam, Parthasarathy; Thomma, Bart P H J

2013-02-01

266

Blockade of PD-1/B7-H1 Interaction Restores Effector CD8+ T Cell Responses in a Hepatitis C Virus Core Murine Model1  

PubMed Central

The impaired function of CD8+ T cells is characteristic of hepatitis C virus (HCV) persistent infection. HCV core protein has been reported to inhibit CD8+ T cell responses. To determine the mechanism of the HCV core in suppressing Ag-specific CD8+ T cell responses, we generated a transgenic mouse, core(+) mice, where the expression of core protein is directed to the liver using the albumin promoter. Using a recombinant adenovirus to deliver Ag, we demonstrated that core(+) mice failed to clear adenovirus-LacZ (Ad-LacZ) infection in the liver. The effector function of LacZ-specific CD8+ T cells was particularly impaired in the livers of core(+) mice, with suppression of IFN-?, TNF-?, and granzyme B production by CD8+ T cells. In addition, the impaired CD8+ T cell responses in core(+) mice were accompanied by the enhanced expression of the inhibitory receptor programmed death-1 (PD-1) by LacZ-specific CD8+ T cells and its ligand B7-H1 on liver dendritic cells following Ad-LacZ infection. Importantly, blockade of the PD-1/B7-H1 inhibitory pathway (using a B7-H1 blocking antibody) in core(+) mice enhanced effector function of CD8+ T cells and cleared Ad-LacZ-infection as compared with that in mice treated with control Ab. This suggests that the regulation of the PD-1/B7-H1 inhibitory pathway is crucial for HCV core-mediated impaired T cell responses and viral persistence in the liver. This also suggests that manipulation of the PD-1/B7-H1 pathway may be a potential immunotherapy to enhance effector T cell responses during persistent HCV infection.

Lukens, John R.; Cruise, Michael W.; Lassen, Matthew G.; Hahn, Young S.

2010-01-01

267

Suppression of developmental anomalies by maternal macrophages in mice  

SciTech Connect

We tested whether nonspecific tumoricidal immune cells can suppress congenital malformations by killing precursor cells destined to cause such defects. Pretreatment of pregnant ICR mice with synthetic (Pyran copolymer) and biological (Bacillus Calmette-Guerin) agents significantly suppressed radiation- and chemical-induced congenital malformations (cleft palate, digit anomalies, tail anomalies, etc.). Such suppressive effects were associated with the activation of maternal macrophages by these agents, but were lost either after the disruption of activated macrophages by supersonic waves or by inhibition of their lysosomal enzyme activity with trypan blue. These results indicate that a live activated macrophage with active lysosomal enzymes can be an effector cell to suppress maldevelopment. A similar reduction by activated macrophages was observed in strain CL/Fr, which has a high spontaneous frequency of cleft lips and palates. Furthermore, Pyran-activated maternal macrophages could pass through the placenta, and enhanced urethane-induced cell killing (but not somatic mutation) in the embryo. It is likely that a maternal immunosurveillance system eliminating preteratogenic cells allows for the replacement with normal totipotent blast cells during the pregnancy to protect abnormal development.

Nomura, T.; Hata, S.; Kusafuka, T. (Osaka Univ. (Japan))

1990-11-01

268

TAL effectors: highly adaptable phytobacterial virulence factors and readily engineered DNA-targeting proteins.  

PubMed

Transcription activator-like (TAL) effectors are transcription factors injected into plant cells by pathogenic bacteria of the genus Xanthomonas. They function as virulence factors by activating host genes important for disease, or as avirulence factors by turning on genes that provide resistance. DNA-binding specificity is encoded by polymorphic repeats in each protein that correspond one-to-one with different nucleotides. This code has facilitated target identification and opened new avenues for engineering disease resistance. It has also enabled TAL effector customization for targeted gene control, genome editing, and other applications. This article reviews the structural basis for TAL effector-DNA specificity, the impact of the TAL effector-DNA code on plant pathology and engineered resistance, and recent accomplishments and future challenges in TAL effector-based DNA targeting. PMID:23707478

Doyle, Erin L; Stoddard, Barry L; Voytas, Daniel F; Bogdanove, Adam J

2013-08-01

269

Apparatus for adapting an end effector device remotely controlled manipulator arm  

NASA Technical Reports Server (NTRS)

Apparatus for adapting a general purpose and effector device to a special purpose and effector is disclosed which includes an adapter bracket assembly which provides a mechanical and electrical interface between the end effector devices. The adapter bracket assembly includes an adapter connector post which interlocks with a diamond shaped gripping channel formed in closed jaws of the general purpose end effector. The angularly intersecting surfaces of the connector post and gripping channel prevent any relative movement there between. Containment webs constrain the outer finger plates of the general purpose jaws to prevent pitch motion. Electrical interface is provided by conical, self aligning electrical connector components carried by respective ones of said end effectors.

Clark, K. H. (inventor)

1985-01-01

270

Characterization of the human peripheral effector cells mediating antibody dependent cellular cytotoxicity against allogenic cells.  

PubMed Central

The effector cell populations in human peripheral blood responsible for antibody-dependent cellular cytotoxicity against allogenic cells coated with HLA polyspecific antibodies were investigated using several separation techniques including preparative electrophoresis. Electrophoresis produced a marked effector cells enrichment in a range of 2--5 fractions which exhibited an intermediary electrophoretic mobility. Monocytic cells do not contribute an effector mechanism but minor subsets of polymorphonuclear cells and nylon wool non-adherent non-phagocytic lymphocytes displayed ADCC. Both effector cell populations were found to exhibit a similar electrical charge of cell surface centered around -1.05 micrometer . sec-1 V-1 cm. These observations provided a precise biophysical basis for the identification of effector cells in ADCC. Images FIG. 7

Donner, M; Raffoux, C; Streiff, F

1979-01-01

271

The Vibrio cholerae type VI secretion system employs diverse effector modules for intraspecific competition  

PubMed Central

Vibrio cholerae is a Gram-negative bacterial pathogen that consists of over 200 serogroups with differing pathogenic potential. Only strains that express the virulence factors cholera toxin (CT) and toxin-coregulated pilus (TCP) are capable of pandemic spread of cholera diarrhoea. Regardless, all V. cholerae strains sequenced to date harbour genes for the type VI secretion system (T6SS) that translocates effectors into neighbouring eukaryotic and prokaryotic cells. Here we report that the effectors encoded within these conserved gene clusters differ widely among V. cholerae strains, and that immunity proteins encoded immediately downstream from the effector genes protect their host from neighbouring bacteria producing corresponding effectors. As a consequence, strains with matching effector-immunity gene sets can coexist, while strains with different sets compete against each other. Thus, the V. cholerae T6SS contributes to the competitive behaviour of this species.

Unterweger, Daniel; Miyata, Sarah T.; Bachmann, Verena; Brooks, Teresa M.; Mullins, Travis; Kostiuk, Benjamin; Provenzano, Daniele; Pukatzki, Stefan

2014-01-01

272

Independently evolved virulence effectors converge onto hubs in a plant immune system network.  

PubMed

Plants generate effective responses to infection by recognizing both conserved and variable pathogen-encoded molecules. Pathogens deploy virulence effector proteins into host cells, where they interact physically with host proteins to modulate defense. We generated an interaction network of plant-pathogen effectors from two pathogens spanning the eukaryote-eubacteria divergence, three classes of Arabidopsis immune system proteins, and ~8000 other Arabidopsis proteins. We noted convergence of effectors onto highly interconnected host proteins and indirect, rather than direct, connections between effectors and plant immune receptors. We demonstrated plant immune system functions for 15 of 17 tested host proteins that interact with effectors from both pathogens. Thus, pathogens from different kingdoms deploy independently evolved virulence proteins that interact with a limited set of highly connected cellular hubs to facilitate their diverse life-cycle strategies. PMID:21798943

Mukhtar, M Shahid; Carvunis, Anne-Ruxandra; Dreze, Matija; Epple, Petra; Steinbrenner, Jens; Moore, Jonathan; Tasan, Murat; Galli, Mary; Hao, Tong; Nishimura, Marc T; Pevzner, Samuel J; Donovan, Susan E; Ghamsari, Lila; Santhanam, Balaji; Romero, Viviana; Poulin, Matthew M; Gebreab, Fana; Gutierrez, Bryan J; Tam, Stanley; Monachello, Dario; Boxem, Mike; Harbort, Christopher J; McDonald, Nathan; Gai, Lantian; Chen, Huaming; He, Yijian; Vandenhaute, Jean; Roth, Frederick P; Hill, David E; Ecker, Joseph R; Vidal, Marc; Beynon, Jim; Braun, Pascal; Dangl, Jeffery L

2011-07-29

273

Independently Evolved Virulence Effectors Converge onto Hubs in a Plant Immune System Network  

PubMed Central

Plants generate effective responses to infection by recognizing both conserved and variable pathogen-encoded molecules. Pathogens deploy virulence effector proteins into host cells, where they interact physically with host proteins to modulate defense. We generated a plant-pathogen immune system protein interaction network using effectors from two pathogens spanning the eukaryote-eubacteria divergence, three classes of Arabidopsis immune system proteins and ~8,000 other Arabidopsis proteins. We noted convergence of effectors onto highly interconnected host proteins, and indirect, rather than direct, connections between effectors and plant immune receptors. We demonstrated plant immune system functions for 15 of 17 tested host proteins that interact with effectors from both pathogens. Thus, pathogens from different kingdoms deploy independently evolved virulence proteins that interact with a limited set of highly connected cellular hubs to facilitate their diverse life cycle strategies.

Mukhtar, M. Shahid; Carvunis, Anne-Ruxandra; Dreze, Matija; Epple, Petra; Steinbrenner, Jens; Moore, Jonathan; Tasan, Murat; Galli, Mary; Hao, Tong; Nishimura, Marc T.; Pevzner, Samuel J.; Donovan, Susan E.; Ghamsari, Lila; Santhanam, Balaji; Romero, Viviana; Poulin, Matthew M.; Gebreab, Fana; Gutierrez, Bryan J.; Tam, Stanley; Monachello, Dario; Boxem, Mike; Harbort, Christopher J.; McDonald, Nathan; Gai, Lantian; Chen, Huaming; He, Yijian; Vandenhaute, Jean; Roth, Frederick P.; Hill, David E.; Ecker, Joseph R.; Vidal, Marc; Beynon, Jim; Braun, Pascal; Dangl, Jeffery L.

2011-01-01

274

The novel GrCEP12 peptide from the plant-parasitic nematode Globodera rostochiensis suppresses flg22-mediated PTI  

PubMed Central

The potato cyst nematode Globodera rostochiensis is a biotrophic pathogen that secretes effector proteins into host root cells to promote successful plant parasitism. In addition to the role in generating within root tissue the feeding cells essential for nematode development,1 nematode secreted effectors are becoming recognized as suppressors of plant immunity.2-4 Recently we reported that the effector ubiquitin carboxyl extension protein (GrUBCEP12) from G. rostochiensis is processed into free ubiquitin and a 12-amino acid GrCEP12 peptide in planta. Transgenic potato lines overexpressing the derived GrCEP12 peptide showed increased susceptibility to G. rostochiensis and to an unrelated bacterial pathogen Streptomyces scabies, suggesting that GrCEP12 has a role in suppressing host basal defense or possibly pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) during the parasitic interaction.3 To determine if GrCEP12 functions as a PTI suppressor we evaluated whether GrCEP12 suppresses flg22-induced PTI responses in Nicotiana benthamiana. Interestingly, we found that transient expression of GrCEP12 in N. benthamiana leaves suppressed reactive oxygen species (ROS) production and the induction of two PTI marker genes triggered by the bacterial PAMP flg22, providing direct evidence that GrCEP12 indeed has an activity in PTI suppression.

Chen, Shiyan; Chronis, Demosthenis; Wang, Xiaohong

2013-01-01

275

The novel GrCEP12 peptide from the plant-parasitic nematode Globodera rostochiensis suppresses flg22-mediated PTI.  

PubMed

The potato cyst nematode Globodera rostochiensis is a biotrophic pathogen that secretes effector proteins into host root cells to promote successful plant parasitism. In addition to the role in generating within root tissue the feeding cells essential for nematode development, (1) nematode secreted effectors are becoming recognized as suppressors of plant immunity. (2)(-) (4) Recently we reported that the effector ubiquitin carboxyl extension protein (GrUBCEP12) from G. rostochiensis is processed into free ubiquitin and a 12-amino acid GrCEP12 peptide in planta. Transgenic potato lines overexpressing the derived GrCEP12 peptide showed increased susceptibility to G. rostochiensis and to an unrelated bacterial pathogen Streptomyces scabies, suggesting that GrCEP12 has a role in suppressing host basal defense or possibly pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) during the parasitic interaction. (3) To determine if GrCEP12 functions as a PTI suppressor we evaluated whether GrCEP12 suppresses flg22-induced PTI responses in Nicotiana benthamiana. Interestingly, we found that transient expression of GrCEP12 in N. benthamiana leaves suppressed reactive oxygen species (ROS) production and the induction of two PTI marker genes triggered by the bacterial PAMP flg22, providing direct evidence that GrCEP12 indeed has an activity in PTI suppression. PMID:23803745

Chen, Shiyan; Chronis, Demosthenis; Wang, Xiaohong

2013-09-01

276

Innate pro-B-cell progenitors protect against type 1 diabetes by regulating autoimmune effector T cells  

PubMed Central

Diverse hematopoietic progenitors, including myeloid populations arising in inflammatory and tumoral conditions and multipotent cells, mobilized by hematopoietic growth factors or emerging during parasitic infections, display tolerogenic properties. Innate immune stimuli confer regulatory functions to various mature B-cell subsets but immature B-cell progenitors endowed with suppressive properties per se or after differentiating into more mature regulatory B cells remain to be characterized. Herein we provide evidence for innate pro-B cells (CpG-proBs) that emerged within the bone marrow both in vitro and in vivo upon Toll-like receptor-9 activation and whose adoptive transfer protected nonobese diabetic mice against type 1 diabetes (T1D). These cells responded to IFN-? released by activated effector T cells (Teffs), by up-regulating their Fas ligand (FasL) expression, which enabled them to kill Teffs through apoptosis. In turn, IFN-? derived from CpG-proBs enhanced IFN-? while dramatically reducing IL-21 production by Teffs. In keeping with the crucial pathogenic role played by IL-21 in T1D, adoptively transferred IFN-?–deficient CpG-proBs did not prevent T1D development. Additionally, CpG-proBs matured in vivo into diverse pancreatic and splenic suppressive FasLhigh B-cell subsets. CpG-proBs may become instrumental in cell therapy of autoimmune diseases either on their own or as graft complement in autologous stem cell transplantation.

Montandon, Ruddy; Korniotis, Sarantis; Layseca-Espinosa, Esther; Gras, Christophe; Megret, Jerome; Ezine, Sophie; Dy, Michel; Zavala, Flora

2013-01-01

277

NleB, a bacterial effector with glycosyltransferase activity targets GADPH function to inhibit NF-?B activation  

PubMed Central

Summary Modulation of NF-?B-dependent responses is critical to the success of attaching/effacing (A/E) human pathogenic E. coli (EPEC and EHEC) and the natural mouse pathogen Citrobacter rodentium. NleB, a highly conserved type III secretion system effector of A/E pathogens, suppresses NF-?B activation, but the underlying mechanisms are unknown. We identified the mammalian glycolysis enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as an NleB interacting protein. Further, we discovered that GAPDH interacts with the TNF receptor associated factor 2 (TRAF2), a protein required for TNF-?-mediated NF-?B activation, and regulates TRAF2 polyubiquitination. During infection, NleB functions as a translocated N-acetyl-D-glucosamine (O-GlcNAc) transferase that modifies GAPDH. NleB-mediated GAPDH O-GlcNAcylation disrupts the TRAF2-GAPDH interaction to suppress TRAF2 polyubiquitination and NF-?B activation. Eliminating NleB O-GlcNAcylation activity attenuates C. rodentium colonization of mice. These data identify GAPDH as a TRAF2 signaling cofactor and reveal a virulence strategy employed by A/E pathogens to inhibit NF-?B dependent host innate immune responses.

Gao, Xiaofei; Wang, Xiaogang; Pham, Thanh H.; Feuerbacher, Leigh Ann; Lubos, Marie-Luise; Huang, Minzhao; Olsen, Rachel; Mushegian, Arcady; Slawson, Chad; Hardwidge, Philip R.

2013-01-01

278

Innate pro-B-cell progenitors protect against type 1 diabetes by regulating autoimmune effector T cells.  

PubMed

Diverse hematopoietic progenitors, including myeloid populations arising in inflammatory and tumoral conditions and multipotent cells, mobilized by hematopoietic growth factors or emerging during parasitic infections, display tolerogenic properties. Innate immune stimuli confer regulatory functions to various mature B-cell subsets but immature B-cell progenitors endowed with suppressive properties per se or after differentiating into more mature regulatory B cells remain to be characterized. Herein we provide evidence for innate pro-B cells (CpG-proBs) that emerged within the bone marrow both in vitro and in vivo upon Toll-like receptor-9 activation and whose adoptive transfer protected nonobese diabetic mice against type 1 diabetes (T1D). These cells responded to IFN-? released by activated effector T cells (Teffs), by up-regulating their Fas ligand (FasL) expression, which enabled them to kill Teffs through apoptosis. In turn, IFN-? derived from CpG-proBs enhanced IFN-? while dramatically reducing IL-21 production by Teffs. In keeping with the crucial pathogenic role played by IL-21 in T1D, adoptively transferred IFN-?-deficient CpG-proBs did not prevent T1D development. Additionally, CpG-proBs matured in vivo into diverse pancreatic and splenic suppressive FasL(high) B-cell subsets. CpG-proBs may become instrumental in cell therapy of autoimmune diseases either on their own or as graft complement in autologous stem cell transplantation. PMID:23716674

Montandon, Ruddy; Korniotis, Sarantis; Layseca-Espinosa, Esther; Gras, Christophe; Mégret, Jérôme; Ezine, Sophie; Dy, Michel; Zavala, Flora

2013-06-11

279

Diverse Secreted Effectors Are Required for Salmonella Persistence in a Mouse Infection Model  

SciTech Connect

Salmonella enterica serovar Typhimurium causes typhoid-like disease in mice and is a model of typhoid fever in humans. One of the hallmarks of typhoid is persistence, the ability of the bacteria to survive in the host weeks after infection. Virulence factors called effectors facilitate this process by direct transfer to the cytoplasm of infected cells thereby subverting cellular processes. Secretion of effectors to the cell cytoplasm takes place through multiple routes, including two separate type III secretion (T3SS) apparati as well as outer membrane vesicles. The two T3SS are encoded on separate pathogenicity islands, SPI-1 and -2, with SPI-1 more strongly associated with the intestinal phase of infection, and SPI-2 with the systemic phase. Both T3SS are required for persistence, but the effectors required have not been systematically evaluated. In this study, mutations in 48 described effectors were tested for persistence. We replaced each effector with a specific DNA barcode sequence by allelic exchange and co-infected with a wild-type reference to calculate the ratio of wild-type parent to mutant at different times after infection. The competitive index (CI) was determined by quantitative PCR in which primers that correspond to the barcode were used for amplification. Mutations in all but seven effectors reduced persistence demonstrating that most effectors were required. One exception was CigR, a recently discovered effector that is widely conserved throughout enteric bacteria. Deletion of cigR increased lethality, suggesting that it may be an anti-virulence factor. The fact that almost all Salmonella effectors are required for persistence argues against redundant functions. This is different from effector repertoires in other intracellular pathogens such as Legionella.

Kidwai, Afshan S.; Mushamiri, Ivy T.; Niemann, George; Brown, Roslyn N.; Adkins, Joshua N.; Heffron, Fred

2013-08-12

280

The genome sequence and effector complement of the flax rust pathogen Melampsora lini  

PubMed Central

Rust fungi cause serious yield reductions on crops, including wheat, barley, soybean, coffee, and represent real threats to global food security. Of these fungi, the flax rust pathogen Melampsora lini has been developed most extensively over the past 80 years as a model to understand the molecular mechanisms that underpin pathogenesis. During infection, M. lini secretes virulence effectors to promote disease. The number of these effectors, their function and their degree of conservation across rust fungal species is unknown. To assess this, we sequenced and assembled de novo the genome of M. lini isolate CH5 into 21,130 scaffolds spanning 189 Mbp (scaffold N50 of 31 kbp). Global analysis of the DNA sequence revealed that repetitive elements, primarily retrotransposons, make up at least 45% of the genome. Using ab initio predictions, transcriptome data and homology searches, we identified 16,271 putative protein-coding genes. An analysis pipeline was then implemented to predict the effector complement of M. lini and compare it to that of the poplar rust, wheat stem rust and wheat stripe rust pathogens to identify conserved and species-specific effector candidates. Previous knowledge of four cloned M. lini avirulence effector proteins and two basidiomycete effectors was used to optimize parameters of the effector prediction pipeline. Markov clustering based on sequence similarity was performed to group effector candidates from all four rust pathogens. Clusters containing at least one member from M. lini were further analyzed and prioritized based on features including expression in isolated haustoria and infected leaf tissue and conservation across rust species. Herein, we describe 200 of 940 clusters that ranked highest on our priority list, representing 725 flax rust candidate effectors. Our findings on this important model rust species provide insight into how effectors of rust fungi are conserved across species and how they may act to promote infection on their hosts.

Nemri, Adnane; Saunders, Diane G. O.; Anderson, Claire; Upadhyaya, Narayana M.; Win, Joe; Lawrence, Gregory J.; Jones, David A.; Kamoun, Sophien; Ellis, Jeffrey G.; Dodds, Peter N.

2014-01-01

281

At the Frontier; RXLR Effectors Crossing the Phytophthora-Host Interface  

PubMed Central

Plants are constantly beset by pathogenic organisms. To successfully infect their hosts, plant pathogens secrete effector proteins, many of which are translocated to the inside of the host cell where they manipulate normal physiological processes and undermine host defense. The way by which effectors cross the frontier to reach the inside of the host cell varies among different classes of pathogens. For oomycete plant pathogens – like the potato late blight pathogen Phytophthora infestans – it has been shown that effector translocation to the host cell cytoplasm is dependent on conserved amino acid motifs that are present in the N-terminal part of effector proteins. One of these motifs, known as the RXLR motif, has a strong resemblance with a host translocation motif found in effectors secreted by Plasmodium species. These malaria parasites, that reside inside specialized vacuoles in red blood cells, make use of a specific protein translocation complex to export effectors from the vacuole into the red blood cell. Whether or not also oomycete RXLR effectors require a translocation complex to cross the frontier is still under investigation. For one P. infestans RXLR effector named IPI-O we have found a potential host target that could play a role in establishing the first contact between this effector and the host cell. This membrane spanning lectin receptor kinase, LecRK-I.9, interacts with IPI-O via the tripeptide RGD that overlaps with the RXLR motif. In animals, RGD is a well-known cell adhesion motif; it binds to integrins, which are membrane receptors that regulate many cellular processes and which can be hijacked by pathogens for either effector translocation or pathogen entry into host cells.

Bouwmeester, Klaas; Meijer, Harold J. G.; Govers, Francine

2011-01-01

282

Computational Prediction and Molecular Characterization of an Oomycete Effector and the Cognate Arabidopsis Resistance Gene  

PubMed Central

Hyaloperonospora arabidopsidis (Hpa) is an obligate biotroph oomycete pathogen of the model plant Arabidopsis thaliana and contains a large set of effector proteins that are translocated to the host to exert virulence functions or trigger immune responses. These effectors are characterized by conserved amino-terminal translocation sequences and highly divergent carboxyl-terminal functional domains. The availability of the Hpa genome sequence allowed the computational prediction of effectors and the development of effector delivery systems enabled validation of the predicted effectors in Arabidopsis. In this study, we identified a novel effector ATR39-1 by computational methods, which was found to trigger a resistance response in the Arabidopsis ecotype Weiningen (Wei-0). The allelic variant of this effector, ATR39-2, is not recognized, and two amino acid residues were identified and shown to be critical for this loss of recognition. The resistance protein responsible for recognition of the ATR39-1 effector in Arabidopsis is RPP39 and was identified by map-based cloning. RPP39 is a member of the CC-NBS-LRR family of resistance proteins and requires the signaling gene NDR1 for full activity. Recognition of ATR39-1 in Wei-0 does not inhibit growth of Hpa strains expressing the effector, suggesting complex mechanisms of pathogen evasion of recognition, and is similar to what has been shown in several other cases of plant-oomycete interactions. Identification of this resistance gene/effector pair adds to our knowledge of plant resistance mechanisms and provides the basis for further functional analyses.

Goritschnig, Sandra; Krasileva, Ksenia V.; Dahlbeck, Douglas; Staskawicz, Brian J.

2012-01-01

283

The genome sequence and effector complement of the flax rust pathogen Melampsora lini.  

PubMed

Rust fungi cause serious yield reductions on crops, including wheat, barley, soybean, coffee, and represent real threats to global food security. Of these fungi, the flax rust pathogen Melampsora lini has been developed most extensively over the past 80 years as a model to understand the molecular mechanisms that underpin pathogenesis. During infection, M. lini secretes virulence effectors to promote disease. The number of these effectors, their function and their degree of conservation across rust fungal species is unknown. To assess this, we sequenced and assembled de novo the genome of M. lini isolate CH5 into 21,130 scaffolds spanning 189 Mbp (scaffold N50 of 31 kbp). Global analysis of the DNA sequence revealed that repetitive elements, primarily retrotransposons, make up at least 45% of the genome. Using ab initio predictions, transcriptome data and homology searches, we identified 16,271 putative protein-coding genes. An analysis pipeline was then implemented to predict the effector complement of M. lini and compare it to that of the poplar rust, wheat stem rust and wheat stripe rust pathogens to identify conserved and species-specific effector candidates. Previous knowledge of four cloned M. lini avirulence effector proteins and two basidiomycete effectors was used to optimize parameters of the effector prediction pipeline. Markov clustering based on sequence similarity was performed to group effector candidates from all four rust pathogens. Clusters containing at least one member from M. lini were further analyzed and prioritized based on features including expression in isolated haustoria and infected leaf tissue and conservation across rust species. Herein, we describe 200 of 940 clusters that ranked highest on our priority list, representing 725 flax rust candidate effectors. Our findings on this important model rust species provide insight into how effectors of rust fungi are conserved across species and how they may act to promote infection on their hosts. PMID:24715894

Nemri, Adnane; Saunders, Diane G O; Anderson, Claire; Upadhyaya, Narayana M; Win, Joe; Lawrence, Gregory J; Jones, David A; Kamoun, Sophien; Ellis, Jeffrey G; Dodds, Peter N

2014-01-01

284

MITEs in the promoters of effector genes allow prediction of novel virulence genes in Fusarium oxysporum  

PubMed Central

Background The plant-pathogenic fungus Fusarium oxysporum f.sp.lycopersici (Fol) has accessory, lineage-specific (LS) chromosomes that can be transferred horizontally between strains. A single LS chromosome in the Fol4287 reference strain harbors all known Fol effector genes. Transfer of this pathogenicity chromosome confers virulence to a previously non-pathogenic recipient strain. We hypothesize that expression and evolution of effector genes is influenced by their genomic context. Results To gain a better understanding of the genomic context of the effector genes, we manually curated the annotated genes on the pathogenicity chromosome and identified and classified transposable elements. Both retro- and DNA transposons are present with no particular overrepresented class. Retrotransposons appear evenly distributed over the chromosome, while DNA transposons tend to concentrate in large chromosomal subregions. In general, genes on the pathogenicity chromosome are dispersed within the repeat landscape. Effector genes are present within subregions enriched for DNA transposons. A miniature Impala (mimp) is always present in their promoters. Although promoter deletion studies of two effector gene loci did not reveal a direct function of the mimp for gene expression, we were able to use proximity to a mimp as a criterion to identify new effector gene candidates. Through xylem sap proteomics we confirmed that several of these candidates encode proteins secreted during plant infection. Conclusions Effector genes in Fol reside in characteristic subregions on a pathogenicity chromosome. Their genomic context allowed us to develop a method for the successful identification of novel effector genes. Since our approach is not based on effector gene similarity, but on unique genomic features, it can easily be extended to identify effector genes in Fo strains with different host specificities.

2013-01-01

285

Characterization of plant-fungal interactions involving necrotrophic effector-producing plant pathogens.  

PubMed

Recently, great strides have been made in the area of host-pathogen interactions involving necrotrophic fungi. In this article we describe a method to identify, produce, and characterize effectors that are important in host-necrotrophic fungal pathogen interactions, and to genetically characterize the interactions. The main strength of this method is the combined use of pathogen inoculation, a pathogen culture filtrate bioassay, and genetic analysis of susceptibility and sensitivity in segregating host-mapping populations. These methods have been successfully used to identify several Stagonospora nodorum necrotrophic effectors and to characterize the genetic and phenotypic effects of individual host-effector interactions in the wheat-S. nodorum system. S. nodorum isolates that induce a differential response on two lines are used to produce culture filtrates that contain necrotrophic effectors while the wheat lines differing in reaction to the pathogen are used to develop a mapping population. The wheat population is used to develop DNA marker-based genetic linkage maps and culture filtrates are infiltrated across the mapping population. Linkage and quantitative trait loci (QTL) analysis is used to identify regions of the wheat genome harboring genes that govern sensitivity to necrotrophic effectors. The same populations are inoculated with the effector-producing isolate to determine the significance and proportion of disease explained by individual host gene-effector interactions. Additionally, from this information, differential lines that are sensitive to single effectors are developed for further purification and characterization of the effectors, eventually resulting in the identification, molecular cloning, and characterization of the effector genes. PMID:22183655

Friesen, Timothy L; Faris, Justin D

2012-01-01

286

Explosion suppression system  

DOEpatents

An explosion suppression system and triggering apparatus therefor are provided for quenching gas and dust explosions. An electrically actuated suppression mechanism which dispenses an extinguishing agent into the path ahead of the propagating flame is actuated by a triggering device which is light powered. This triggering device is located upstream of the propagating flame and converts light from the flame to an electrical actuation signal. A pressure arming device electrically connects the triggering device to the suppression device only when the explosion is sensed by a further characteristic thereof beside the flame such as the pioneer pressure wave. The light powered triggering device includes a solar panel which is disposed in the path of the explosion and oriented between horizontally downward and vertical. Testing mechanisms are also preferably provided to test the operation of the solar panel and detonator as well as the pressure arming mechanism.

Sapko, Michael J. (Finleyville, PA); Cortese, Robert A. (Pittsburgh, PA)

1992-01-01

287

Piezoelectric Pushers Suppress Vibrations  

NASA Technical Reports Server (NTRS)

Vibration-suppressing control systems including piezoelectric actuators undergoing development. Small, lightweight, and rugged. Requires simpler electronic control subsystems and does not require large electromagnet coils. Continues to provide support and some passive damping even when electronic control subsystems or power supplies fail. Intended primarily to enhance safety and prevent damage in rotating machinery by sensing and counteracting vibrations. Useful in suppressing unpredictable vibrations caused by changes in loads, losses of rotating components and consequent imbalances in rotors, and ingestion of foreign objects into turbines.

Kascak, Albert F.

1990-01-01

288

Lysophosphatidylcholine as an effector of fatty acid-induced insulin resistance[S  

PubMed Central

The mechanism of FFA-induced insulin resistance is not fully understood. We have searched for effector molecules(s) in FFA-induced insulin resistance. Palmitic acid (PA) but not oleic acid (OA) induced insulin resistance in L6 myotubes through C-Jun N-terminal kinase (JNK) and insulin receptor substrate 1 (IRS-1) Ser307 phosphorylation. Inhibitors of ceramide synthesis did not block insulin resistance by PA. However, inhibition of the conversion of PA to lysophosphatidylcholine (LPC) by calcium-independent phospholipase A2 (iPLA2) inhibitors, such as bromoenol lactone (BEL) or palmitoyl trifluoromethyl ketone (PACOCF3), prevented insulin resistance by PA. iPLA2 inhibitors or iPLA2 small interfering RNA (siRNA) attenuated JNK or IRS-1 Ser307 phosphorylation by PA. PA treatment increased LPC content, which was reversed by iPLA2 inhibitors or iPLA2 siRNA. The intracellular DAG level was increased by iPLA2 inhibitors, despite ameliorated insulin resistance. Pertussis toxin (PTX), which inhibits LPC action through the G-protein coupled receptor (GPCR)/G?i, reversed insulin resistance by PA. BEL administration ameliorated insulin resistance and diabetes in db/db mice. JNK and IRS-1Ser307 phosphorylation in the liver and muscle of db/db mice was attenuated by BEL. LPC content was increased in the liver and muscle of db/db mice, which was suppressed by BEL. These findings implicate LPC as an important lipid intermediate that links saturated fatty acids to insulin resistance.

Han, Myoung Sook; Lim, Yu-Mi; Quan, Wenying; Kim, Jung Ran; Chung, Kun Wook; Kang, Mira; Kim, Sunshin; Park, Sun Young; Han, Joong-Soo; Park, Shin-Young; Cheon, Hyae Gyeong; Dal Rhee, Sang; Park, Tae-Sik; Lee, Myung-Shik

2011-01-01

289

Design schemes and comparison research of the end-effector of large space manipulator  

NASA Astrophysics Data System (ADS)

The end-effector of the large space manipulator is employed to assist the manipulator in handling and manipulating large payloads on orbit. Currently, there are few researches about the end-effector, and the existing end-effectors have some disadvantages, such as poor misalignment tolerance capability and complex mechanical components. According to the end positioning errors and the residual vibration characters of the large space manipulators, two basic performance requirements of the end-effector which include the capabilities of misalignment tolerance and soft capture are proposed. And the end-effector should accommodate the following misalignments of the mechanical interface. The translation misalignments in axial and radial directions and the angular misalignments in roll, pitch and yaw are ±100 mm, 100 mm, ±10o, ±15o, ±15o, respectively. Seven end-effector schemes are presented and the capabilities of misalignment tolerance and soft capture are analyzed elementarily. The three fingers-three petals end-effector and the steel cable-snared end-effector are the most feasible schemes among the seven schemes, and they are designed in detail. The capabilities of misalignment tolerance and soft capture are validated and evaluated, through the experiment on the micro-gravity simulating device and the dynamic analysis in ADAMS software. The results show that the misalignment tolerance capabilities of these two schemes could satisfy the requirement. And the translation misalignment tolerances in axial and radial directions and the angular misalignment tolerances in roll, pitch and yaw of the steel cable-snared end-effector are 30mm, 15mm, 6o, 3o and 3o larger than those of the three fingers-three petals end-effector, respectively. And the contact force of the steel cable-snared end-effector is smaller and smoother than that of the three fingers-three petals end-effector. The end-effector schemes and research methods are beneficial to the developments of the large space manipulator end-effctor and the space docking mechanism.

Feng, Fei; Liu, Yiwei; Liu, Hong; Cai, Hegao

2012-07-01

290

Tim-3-Expressing CD4+ and CD8+ T Cells in Human Tuberculosis (TB) Exhibit Polarized Effector Memory Phenotypes and Stronger Anti-TB Effector Functions  

PubMed Central

T-cell immune responses modulated by T-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) during Mycobacterium tuberculosis (Mtb) infection in humans remain poorly understood. Here, we found that active TB patients exhibited increases in numbers of Tim-3-expressing CD4+ and CD8+ T cells, which preferentially displayed polarized effector memory phenotypes. Consistent with effector phenotypes, Tim-3+CD4+ and Tim-3+CD8+ T-cell subsets showed greater effector functions for producing Th1/Th22 cytokines and CTL effector molecules than Tim-3? counterparts, and Tim-3-expressing T cells more apparently limited intracellular Mtb replication in macrophages. The increased effector functions for Tim-3-expressing T cells consisted with cellular activation signaling as Tim-3+CD4+ and Tim-3+CD8+ T-cell subsets expressed much higher levels of phosphorylated signaling molecules p38, stat3, stat5, and Erk1/2 than Tim-3- controls. Mechanistic experiments showed that siRNA silencing of Tim-3 or soluble Tim-3 treatment interfering with membrane Tim-3-ligand interaction reduced de novo production of IFN-? and TNF-? by Tim-3-expressing T cells. Furthermore, stimulation of Tim-3 signaling pathways by antibody cross-linking of membrane Tim-3 augmented effector function of IFN-? production by CD4+ and CD8+ T cells, suggesting that Tim-3 signaling helped to drive stronger effector functions in active TB patients. This study therefore uncovered a previously unknown mechanism for T-cell immune responses regulated by Tim-3, and findings may have implications for potential immune intervention in TB.

Liao, Hongying; Zhang, Yan; Wang, Hua; Li, Shaoyuan; Luo, Yanfen; Fang, Danyun; Li, Guobao; Zhou, Boping; Shen, Ling; Chen, Crystal Y.; Huang, Dan; Cai, Jiye; Cao, Kaiyuan; Jiang, Lifang; Zeng, Gucheng; Chen, Zheng W.

2012-01-01

291

?? T Cells Acquire Effector Fates in the Thymus and Differentiate into Cytokine-Producing Effectors in a Listeria Model of Infection Independently of CD28 Costimulation  

PubMed Central

Both antigen recognition and CD28 costimulation are required for the activation of naïve ?? T cells and their subsequent differentiation into cytokine-producing or cytotoxic effectors. Notably, this two-signal paradigm holds true for all ?? T cell subsets, regardless of whether they acquire their effector function in the periphery or the thymus. Because of contradictory results, however, it remains unresolved as to whether CD28 costimulation is necessary for ?? T cell activation and differentiation. Given that ?? T cells have been recently shown to acquire their effector fates in the thymus, it is conceivable that the contradictory results may be explained, in part, by a differential requirement for CD28 costimulation in the development or differentiation of each ?? T cell effector subset. To test this, we examined the role of CD28 in ?? T cell effector fate determination and function. We report that, although IFN?-producing ?? T (??-IFN?) cells express higher levels of CD28 than IL-17-producing ?? T (??-17) cells, CD28-deficiency had no effect on the thymic development of either subset. Also, following Listeria infection, we found that the expansion and differentiation of ??-17 and ??-IFN? effectors were comparable between CD28+/+ and CD28?/? mice. To understand why CD28 costimulation is dispensable for ?? T cell activation and differentiation, we assessed glucose uptake and utilization by ?? T cells, as CD28 costimulation is known to promote glycolysis in ?? T cells. Importantly, we found that ?? T cells express higher surface levels of glucose transporters than ?? T cells and, when activated, exhibit effector functions over a broader range of glucose concentrations than activated ?? T cells. Together, these data not only demonstrate an enhanced glucose metabolism in ?? T cells but also provide an explanation for why ?? T cells are less dependent on CD28 costimulation than ?? T cells.

Laird, Renee M.; Wolf, Benjamin J.

2013-01-01

292

Effector prediction in host-pathogen interaction based on a Markov model of a ubiquitous EPIYA motif  

Microsoft Academic Search

BACKGROUND: Effector secretion is a common strategy of pathogen in mediating host-pathogen interaction. Eight EPIYA-motif containing effectors have recently been discovered in six pathogens. Once these effectors enter host cells through type III\\/IV secretion systems (T3SS\\/T4SS), tyrosine in the EPIYA motif is phosphorylated, which triggers effectors binding other proteins to manipulate host-cell functions. The objectives of this study are to

Shunfu Xu; Chao Zhang; Yi Miao; Jianjiong Gao; Dong Xu

2010-01-01

293

Harnessing Regulatory T cells to Suppress Asthma  

PubMed Central

Regulatory T cells (Tregs) play an essential role in maintaining the homeostatic balance of immune responses. Asthma is an inflammatory condition of the airways that is driven by dysregulated immune responses toward normally innocuous antigens. Individuals with asthma have fewer and less functional Tregs, which may lead to uncontrolled effector cell responses and promote proasthmatic responses of T helper type 2, T helper 17, natural killer T, antigen-presenting, and B cells. Tregs have the capacity to either directly or indirectly suppress these responses. Hence, the induced expansion of functional Tregs in predisposed or individuals with asthma is a potential approach for the prevention and treatment of asthma. Infection by a number of micro-organisms has been associated with reduced prevalence of asthma, and many infectious agents have been shown to induce Tregs and reduce allergic airways disease in mouse models. The translation of the regulatory and therapeutic properties of infectious agents for use in asthma requires the identification of key modulatory components and the development and trial of effective immunoregulatory therapies. Further translational and clinical research is required for the induction of Tregs to be harnessed as a therapeutic strategy for asthma.

Thorburn, Alison N.; Hansbro, Philip M.

2010-01-01

294

Specific suppression of lupus-like graft-versus-host disease using extracorporeal photochemical attenuation of effector lymphocytes.  

PubMed

(C57BL/6 x DBA/2)F1 (B6D2F1) mice inoculated with parental DBA/2 (D2) splenocytes develop chronic stimulatory graft-versus-host reaction with many of the clinical manifestations of systemic lupus erythematosus. This investigation tested the ability of 8-methoxypsoralen (8-MOP) and ultraviolet A (UVA) light-treated D2 cells, primed to contain an expanded population of T cells specific for B6D2F1 major histocompatability complex antigens, to treat and/or prevent such systemic lupus erythematosus-like disease. 8-MOP/UVA-treated cells from B6D2F1-primed D2 donors were inoculated into B6D2F1 recipients weekly six to ten times, either before or after initiating graft-versus-host disease with normal D2 cells. A third group of B6D2F1 recipients were vaccinated weekly six times before disease initiation using 8-MOP/UVA-attenuated, B6D2F1-primed D2 cells that had been secondarily stimulated and expanded in vitro in the presence of irradiated B6D2F1 targets and interleukin-2. Control B6D2F1 mice were vaccinated with 8-MOP/UVA-treated D2 cells stimulated in vitro and/or in vivo with (C3H/HeJ x DBA/2)F1 cells. Only mice vaccinated with 8-MOP/UVA-attenuated D2-anti-B6D2F1 cells that were secondarily stimulated and expanded in vitro exhibited differences from controls when measured by the clinical parameters of ascites formation, and mean survival (p < 0.025). These groups also differed significantly in mean antinuclear antibody titer measured 14 weeks after disease initiation (p < 0.05). At 28 weeks, histologic evidence of systemic lupus erythematosus-like kidney disease was found only in the control group. These results indicate that photochemically attenuated D2-anti-B6D2F1 cells primed in vivo and secondarily stimulated and expanded in vitro are capable of vaccinating recipients against progression of graft-versus-host reaction-initiated systemic lupus erythematosus-like disease. PMID:7829872

Girardi, M; Herreid, P; Tigelaar, R E

1995-02-01

295

Specific Suppression of Lupus-Like Graft-Versus-Host Disease Using Extracorporeal Photochemical Attenuation of Effector Lymphocytes  

Microsoft Academic Search

(CS7BL\\/6 × DBA\\/2)F1 (B6D2F1) mice inoculated with parental DBA\\/2 (D2) splenocytes develop chronic stimulatory graft-versus-host reaction with many of the clinical manifestations of systemic lupus erythematosus. This Investigation tested the ability of 8-methoxypsoralen (8-MOP) and ultraviolet A (UVA) light-treated D2 cells, primed to contain an expanded population of T cells specific for B6D2F1 major histocompatability complex antigens, to treat and\\/or

Michael Girardi; Peter Herreid; Robert E. Tigelaar

1995-01-01

296

Ignition Suppression Device.  

National Technical Information Service (NTIS)

An ignition detection and suppression system was developed under the scope of this contract. The objective of this machine mounted system was to detect flames caused by frictional sparking from the cutting bits of a continuous-mining machine and to suppre...

W. B. Jamison H. Hadi

1976-01-01

297

Suppressing the Zs.  

ERIC Educational Resources Information Center

In the frameword of generalized phrase-structure grammar, possessive clitics (POSS), bound words (BWs), and phrasal affixes (PAs) are analyzed. It is argued that English POSS should be treated as an edge-located inflectional affix, since POSS is suppressed in the presence of other Z affixes (plural, other possessives). (Author/LMO)

Zwicky, A. M.

1987-01-01

298

Deregulation of Rab and Rab Effector Genes in Bladder Cancer  

PubMed Central

Growing evidence indicates that Rab GTPases, key regulators of intracellular transport in eukaryotic cells, play an important role in cancer. We analysed the deregulation at the transcriptional level of the genes encoding Rab proteins and Rab-interacting proteins in bladder cancer pathogenesis, distinguishing between the two main progression pathways so far identified in bladder cancer: the Ta pathway characterized by a high frequency of FGFR3 mutation and the carcinoma in situ pathway where no or infrequent FGFR3 mutations have been identified. A systematic literature search identified 61 genes encoding Rab proteins and 223 genes encoding Rab-interacting proteins. Transcriptomic data were obtained for normal urothelium samples and for two independent bladder cancer data sets corresponding to 152 and 75 tumors. Gene deregulation was analysed with the SAM (significant analysis of microarray) test or the binomial test. Overall, 30 genes were down-regulated, and 13 were up-regulated in the tumor samples. Five of these deregulated genes (LEPRE1, MICAL2, RAB23, STXBP1, SYTL1) were specifically deregulated in FGFR3-non-mutated muscle-invasive tumors. No gene encoding a Rab or Rab-interacting protein was found to be specifically deregulated in FGFR3-mutated tumors. Cluster analysis showed that the RAB27 gene cluster (comprising the genes encoding RAB27 and its interacting partners) was deregulated and that this deregulation was associated with both pathways of bladder cancer pathogenesis. Finally, we found that the expression of KIF20A and ZWINT was associated with that of proliferation markers and that the expression of MLPH, MYO5B, RAB11A, RAB11FIP1, RAB20 and SYTL2 was associated with that of urothelial cell differentiation markers. This systematic analysis of Rab and Rab effector gene deregulation in bladder cancer, taking relevant tumor subgroups into account, provides insight into the possible roles of Rab proteins and their effectors in bladder cancer pathogenesis. This approach is applicable to other group of genes and types of cancer.

Ho, Joel R.; Chapeaublanc, Elodie; Kirkwood, Lisa; Nicolle, Remy; Benhamou, Simone; Lebret, Thierry; Allory, Yves; Southgate, Jennifer; Radvanyi, Francois; Goud, Bruno

2012-01-01

299

The effector T cell response to ryegrass pollen is counterregulated by simultaneous induction of regulatory T cells.  

PubMed

Allergy is associated with pathological Th2 responses to otherwise harmless environmental Ags. In contrast, nonallergic individuals mount nonpathological immune responses to allergens, partly attributed to regulatory T cell (Treg) activity. Although thymus-derived natural Tregs have been shown to maintain tolerance to self-Ags and prevent autoimmunity, the generation of Tregs specific to non-self-Ags is less well understood. We investigated the potential for induction of Tregs from PBMCs of ryegrass pollen-allergic or healthy subjects by stimulation in vitro with ryegrass pollen extract in the absence of additional exogenous stimuli. We found that two subsets of proliferating CD4(+) T cells were induced, one expressing intermediate levels of Foxp3 (and IFN-gamma, IL-4, IL-17, or IL-2) and the other expressing high levels of Foxp3 (and no effector cytokines). After enrichment based on CD39 expression, the Foxp3(hi) subset suppressed CD4(+) T cell proliferation and IFN-gamma production. The Foxp3(hi) Treg originated from both conversion of dividing non-Tregs (CD4(+)CD25(-)CD127(hi)) and expansion of natural Tregs (CD4(+)CD25(+)CD127(lo)). Stable functional Tregs expressing high levels of Foxp3 were induced simultaneously with effector T cells by allergen stimulation. Induction of Foxp3(hi) Tregs was reduced in allergic subjects. These results indicate that the cogeneration of Foxp3(hi) Tregs in response to allergen may be a mechanism for controlling allergic reactions in healthy individuals, which is impaired in those with allergies. PMID:20308632

Mittag, Diana; Scholzen, Anja; Varese, Nirupama; Baxter, Lorraine; Paukovics, Geza; Harrison, Leonard C; Rolland, Jennifer M; O'Hehir, Robyn E

2010-05-01

300

Tumor-infiltrating programmed death receptor-1+ dendritic cells mediate immune suppression in ovarian cancer.  

PubMed

Within the ovarian cancer microenvironment, there are several mechanisms that suppress the actions of antitumor immune effectors. Delineating the complex immune microenvironment is an important goal toward developing effective immune-based therapies. A dominant pathway of immune suppression in ovarian cancer involves tumor-associated and dendritic cell (DC)-associated B7-H1. The interaction of B7-H1 with PD-1 on tumor-infiltrating T cells is a widely cited theory of immune suppression involving B7-H1 in ovarian cancer. Recent studies suggest that the B7-H1 ligand, programmed death receptor-1 (PD-1), is also expressed on myeloid cells, complicating interpretations of how B7-H1 regulates DC function in the tumor. In this study, we found that ovarian cancer-infiltrating DCs progressively expressed increased levels of PD-1 over time in addition to B7-H1. These dual-positive PD-1(+) B7-H1(+) DCs have a classical DC phenotype (i.e., CD11c(+)CD11b(+)CD8(-)), but are immature, suppressive, and respond poorly to danger signals. Accumulation of PD-1(+)B7-H1(+) DCs in the tumor was associated with suppression of T cell activity and decreased infiltrating T cells in advancing tumors. T cell suppressor function of these DCs appeared to be mediated by T cell-associated PD-1. In contrast, ligation of PD-1 expressed on the tumor-associated DCs suppressed NF-?B activation, release of immune regulatory cytokines, and upregulation of costimulatory molecules. PD-1 blockade in mice bearing ovarian cancer substantially reduced tumor burden and increased effector Ag-specific T cell responses. Our results reveal a novel role of tumor infiltrating PD-1(+)B7-H1(+) DCs in mediating immune suppression in ovarian cancer. PMID:21551365

Krempski, James; Karyampudi, Lavakumar; Behrens, Marshall D; Erskine, Courtney L; Hartmann, Lynn; Dong, Haidong; Goode, Ellen L; Kalli, Kimberly R; Knutson, Keith L

2011-06-15

301

Tumor infiltrating PD-1+ dendritic cells mediate immune suppression in ovarian cancer  

PubMed Central

Within the ovarian cancer microenvironment there are several mechanisms that suppress the actions of anti-tumor immune effectors. Delineating the complex immune microenvironment is an important goal towards developing effective immune-based therapies. A dominant pathway of immune suppression in ovarian cancer involves tumor-associated and dendritic cell-associated, B7-H1. The interaction of B7-H1 with PD-1 on tumor-infiltrating T cells is a widely cited theory of immune suppression involving B7-H1 in ovarian cancer. Recent studies suggest that the B7-H1 ligand, PD-1, is also expressed on myeloid cells complicating interpretations of how B7-H1 regulates dendritic cell (DC) function in the tumor. In this study we found that ovarian cancer-infiltrating DCs progressively expressed increased levels of PD-1 over time in addition to B7-H1. These dual-positive PD-1+B7-H1+ DCs have a classical DC phenotype (i.e. CD11c+CD11b+CD8?) but are immature, suppressive and respond poorly to danger signals. Accumulation of PD-1+B7-H1+ DC in the tumor was associated with suppression of T cell activity and decreased infiltrating T cells in advancing tumors. T cell suppressor function of these DCs appeared to be mediated by T cell associated PD-1. In contrast, ligation of PD-1 expressed on the tumor-associated DC suppressed NF?B activation, release of immune regulatory cytokines, and upregulation of co-stimulatory molecules. PD-1 blockade in mice bearing ovarian cancer substantially reduced tumor burden and increased effector antigen-specific T cell responses. Our results reveal a novel role of tumor infiltrating PD-1+B7-H1+ DCs in mediating immune suppression in ovarian cancer.

Krempski, James; Karyampudi, Lavakumar; Behrens, Marshall D.; Erskine, Courtney L.; Hartmann, Lynn; Dong, Haidong; Goode, Ellen L.; Kalli, Kimberly R.; Knutson, Keith L.

2011-01-01

302

Immune modulation of effector CD4+ and regulatory T cell function by sorafenib in patients with hepatocellular carcinoma  

PubMed Central

Hepatocellular carcinoma (HCC) is a difficult to treat cancer characterized by poor tumor immunity with only one approved systemic drug, sorafenib. If novel combination treatments are to be developed with immunological agents, the effects of sorafenib on tumor immunity are important to understand. In this study, we investigate the impact of sorafenib on the CD4+CD25? effector T cells (Teff) and CD4+CD25+ regulatory T cells (Tregs) from patients with HCC. We isolated Teff and Treg from peripheral mononuclear cells of HCC patients to determineimmune reactivity by thymidine incorporation, ELISA and flow cytometry. Teff cultured alone or with Treg were supplemented with different concentrations of sorafenib. The effects of sorafenib on Teff responses were dose-dependent. Pharmacologic doses of sorafenib decreased Teff activation by down regulating CD25 surface expression. In contrast, sub-pharmacologic concentrations of sorafenib resulted in Teff activation. These low doses of sorafenib in the Teff cultures led to a significant increase in Teff proliferation, IL2 secretion and up-regulation of CD25 expression on the cell surface. In addition, low doses of sorafenib in the suppression Teff/Treg cocultures restored Teff responses by eliminating Treg suppression. The loss of Treg suppressive function correlated with an increase in IL2 and IL6 secretion. Our findings showthat sub-pharmacologic doses of sorafenib impact subsets of T cells differently, selectively increasing Teff activation while blocking Treg function. In conclusion, this study describes novel immune activating properties of low doses of sorafenib by promoting immune responsiveness in patients with HCC.

Ararat, Miguel; Xu, Yiling; Brusko, Todd; Wasserfall, Clive; Atkinson, Mark A.; Chang, Lung Ji; Liu, Chen; Nelson, David R.

2013-01-01

303

Immune modulation of effector CD4+ and regulatory T cell function by sorafenib in patients with hepatocellular carcinoma.  

PubMed

Hepatocellular carcinoma (HCC) is a difficult to treat cancer characterized by poor tumor immunity with only one approved systemic drug, sorafenib. If novel combination treatments are to be developed with immunological agents, the effects of sorafenib on tumor immunity are important to understand. In this study, we investigate the impact of sorafenib on the CD4+CD25- effector T cells (Teff) and CD4+CD25+ regulatory T cells (Tregs) from patients with HCC. We isolated Teff and Treg from peripheral mononuclear cells of HCC patients to determine immune reactivity by thymidine incorporation, ELISA and flow cytometry. Teff cultured alone or with Treg were supplemented with different concentrations of sorafenib. The effects of sorafenib on Teff responses were dose-dependent. Pharmacologic doses of sorafenib decreased Teff activation by down regulating CD25 surface expression. In contrast, sub-pharmacologic concentrations of sorafenib resulted in Teff activation. These low doses of sorafenib in the Teff cultures led to a significant increase in Teff proliferation, IL2 secretion and up-regulation of CD25 expression on the cell surface. In addition, low doses of sorafenib in the suppression Teff/Treg cocultures restored Teff responses by eliminating Treg suppression. The loss of Treg suppressive function correlated with an increase in IL2 and IL6 secretion. Our findings show that sub-pharmacologic doses of sorafenib impact subsets of T cells differently, selectively increasing Teff activation while blocking Treg function. In conclusion, this study describes novel immune activating properties of low doses of sorafenib by promoting immune responsiveness in patients with HCC. PMID:23223899

Cabrera, Roniel; Ararat, Miguel; Xu, Yiling; Brusko, Todd; Wasserfall, Clive; Atkinson, Mark A; Chang, Lung Ji; Liu, Chen; Nelson, David R

2013-04-01

304

Murine autoimmune cholangitis requires two hits: Cytotoxic KLRG1(+) CD8 effector cells and defective T regulatory cells.  

PubMed

Primary biliary cirrhosis (PBC) is an enigmatic disease mediated by autoimmune destruction of cholangiocytes in hepatic bile ducts. The early immunological events leading to PBC are poorly understood; clinical signs of disease occur very late in the pathological process. We have used our unique murine model of PBC in dominant-negative TGF-? receptor type II transgenic mice to delineate critical early immunopathological pathways, and previously showed that dnTGF?RII CD8 T cells transfer biliary disease. Herein we report significantly increased numbers of hepatic dnTGF?RII terminally differentiated (KLRG1(+)) CD8 T cells, a CD8 subset previously shown to be enriched in antigen specific cells during hepatic immune response to viral infections. We performed bone marrow chimera studies to assess whether dnTGF?RII CD8 mediated disease was cell intrinsic or extrinsic. Unexpectedly, mixed (dnTGF?RII and B6) bone marrow chimeric (BMC) mice were protected from biliary disease compared to dnTGF?RII single bone marrow chimerics. To define the protective B6 cell subset, we performed adoptive transfer studies, which showed that co-transfer of B6 Tregs prevented dnTGF?RII CD8 T cell mediated cholangitis. Treg mediated disease protection was associated with significantly decreased numbers of hepatic KLRG1(+) CD8 T cells. In contrast, co-transfer of dnTGF?RII Tregs offered no protection, and dnTGF?RII Treg cells were functionally defective in suppressing effector CD8 T cells in vitro compared to wild type B6 Tregs. In vitro cholangiocyte cytotoxicity assays demonstrated significantly increased numbers of cytotoxic hepatic dnTGF?RII KLRG1(+) CD8 cells compared to B6. Protection from disease by B6 Tregs was associated with elimination of hepatic dnTGF?RII CD8 mediated cholangiocyte cytotoxicity. These results emphasize that autoimmune cholangitis requires defects in both the T effector and regulatory compartments, and that an intrinsic T cell effector defect is not sufficient to mediate autoimmune biliary disease in the setting of intact immune regulation. These results have important implications for understanding the early pathogenesis of human PBC. PMID:24556277

Huang, Wenting; Kachapati, Kritika; Adams, David; Wu, Yuehong; Leung, Patrick S C; Yang, Guo-Xiang; Zhang, Weici; Ansari, Aftab A; Flavell, Richard A; Gershwin, M Eric; Ridgway, William M

2014-05-01

305

Motor resonance in left- and right-handers: evidence for effector-independent motor representations.  

PubMed

The idea of motor resonance was born at the time that it was demonstrated that cortical and spinal pathways of the motor system are specifically activated during both action-observation and execution. What is not known is if the human action observation-execution matching system simulates actions through motor representations specifically attuned to the laterality of the observed effectors (i.e., effector-dependent representations) or through abstract motor representations unconnected to the observed effector (i.e., effector-independent representations). To answer that question we need to know how the information necessary for motor resonance is represented or integrated within the representation of an effector. Transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEPs) were thus recorded from the dominant and non-dominant hands of left- and right-handed participants while they observed a left- or a right-handed model grasping an object. The anatomical correspondence between the effector being observed and the observer's effector classically reported in the literature was confirmed by the MEP response in the dominant hand of participants observing models with their same hand preference. This effect was found in both left- as well as in right-handers. When a broader spectrum of options, such as actions performed by a model with a different hand preference, was instead considered, that correspondence disappeared. Motor resonance was noted in the observer's dominant effector regardless of the laterality of the hand being observed. This would indicate that there is a more sophisticated mechanism which works to convert someone else's pattern of movement into the observer's optimal motor commands and that effector-independent representations specifically modulate motor resonance. PMID:23408666

Sartori, Luisa; Begliomini, Chiara; Castiello, Umberto

2013-01-01

306

Divergent antibody subclass and specificity profiles but not protective HLA-B alleles are associated with variable antibody effector function among HIV-1 controllers.  

PubMed

Understanding the coordination between humoral and cellular immune responses may be the key to developing protective vaccines, and because genetic studies of long-term HIV-1 nonprogressors have associated specific HLA-B alleles with spontaneous control of viral replication, this subject group presents an opportunity to investigate relationships between arms of the adaptive immune system. Given evidence suggesting that cellular immunity may play a role in viral suppression, we sought to determine whether and how the humoral immune response might vary among controllers. Significantly, Fc-mediated antibody effector functions have likewise been associated with durable viral control. In this study, we compared the effector function and biophysical features of HIV-specific antibodies in a cohort of controllers with and without protective HLA-B alleles in order to investigate whether there was evidence for multiple paths to HIV-1 control, or whether cellular and humoral arms of immunity might exhibit coordinated profiles. However, with the exception of IgG2 antibodies to gp41, HLA status was not associated with divergent humoral responses. This finding did not result from uniform antibody responses across subjects, as controllers could be regrouped according to strong differences in their HIV-specific antibody subclass specificity profiles. These divergent antibody profiles were further associated with significant differences in nonneutralizing antibody effector function, with levels of HIV-specific IgG1 acting as the major distinguishing factor. Thus, while HLA background among controllers was associated with minimal differences in humoral function, antibody subclass and specificity profiles were associated with divergent effector function, suggesting that these features could be used to make functional predictions. Because these nonneutralizing antibody activities have been associated with spontaneous viral control, reduced viral load, and nonprogression in infected subjects and protection in vaccinated subjects, understanding the specific features of IgGs with potentiated effector function may be critical to vaccine and therapeutic antibody development. Importance: In this study, we investigated whether the humoral and cellular arms of adaptive immunity exhibit coordinated or compensatory activity by studying the antibody response among HIV-1 controllers with different genetic backgrounds. PMID:24352471

Lai, Jennifer I; Licht, Anna F; Dugast, Anne-Sophie; Suscovich, Todd; Choi, Ickwon; Bailey-Kellogg, Chris; Alter, Galit; Ackerman, Margaret E

2014-03-01

307

Engineering synthetic TAL effectors with orthogonal target sites  

PubMed Central

The ability to engineer biological circuits that process and respond to complex cellular signals has the potential to impact many areas of biology and medicine. Transcriptional activator-like effectors (TALEs) have emerged as an attractive component for engineering these circuits, as TALEs can be designed de novo to target a given DNA sequence. Currently, however, the use of TALEs is limited by degeneracy in the site-specific manner by which they recognize DNA. Here, we propose an algorithm to computationally address this problem. We apply our algorithm to design 180 TALEs targeting 20?bp cognate binding sites that are at least 3?nt mismatches away from all 20?bp sequences in putative 2 kb human promoter regions. We generated eight of these synthetic TALE activators and showed that each is able to activate transcription from a targeted reporter. Importantly, we show that these proteins do not activate synthetic reporters containing mismatches similar to those present in the genome nor a set of endogenous genes predicted to be the most likely targets in vivo. Finally, we generated and characterized TALE repressors comprised of our orthogonal DNA binding domains and further combined them with shRNAs to accomplish near complete repression of target gene expression.

Garg, Abhishek; Lohmueller, Jason J.; Silver, Pamela A.; Armel, Thomas Z.

2012-01-01

308

Evaluation of Nod-Like Receptor (NLR) Effector Domain Interactions  

PubMed Central

Members of the Nod-like receptor (NLR) family recognize intracellular pathogens and recruit a variety of effector molecules, including pro-caspases and kinases, which in turn are implicated in cytokine processing and NF-?B activation. In order to elucidate the intricate network of NLR signaling, which is still fragmentary in molecular terms, we applied comprehensive yeast two-hybrid analysis for unbiased evaluation of physical interactions between NLRs and their adaptors (ASC, CARD8) as well as kinase RIPK2 and inflammatory caspases (C1, C2, C4, C5) under identical conditions. Our results confirmed the interaction of NOD1 and NOD2 with RIPK2, and between NLRP3 and ASC, but most importantly, our studies revealed hitherto unrecognized interactions of NOD2 with members of the NLRP subfamily. We found that NOD2 specifically and directly interacts with NLRP1, NLRP3 and NLRP12. Furthermore, we observed homodimerization of the RIPK2 CARD domains and identified residues in NOD2 critical for interaction with RIPK2. In conclusion, our work provides further evidence for the complex network of protein-protein interactions underlying NLR function.

Kufer, Thomas A.; Schwarzenbacher, Robert

2009-01-01

309

Lessons from Anaplasma phagocytophilum: chromatin remodeling by bacterial effectors.  

PubMed

Bacterial pathogens can alter global host gene expression via histone modifications and chromatin remodeling in order to subvert host responses, including those involved with innate immunity, allowing for bacterial survival. Shigella flexneri, Listeria monocytogenes, Chlamydia trachomatis, and Anaplasma phagocytophilum express effector proteins that modify host histones and chromatin structure. A. phagocytophilum modulates granulocyte respiratory burst in part by dampening transcription of several key phagocyte oxidase genes. The A. phagocytophilum protein AnkA localizes to the myeloid cell nucleus where it binds AT-rich regions in the CYBB promoter and decreases its transcription. AT-rich regions of DNA are characteristic of matrix attachment regions (MARs) which are critical for chromatin structure and transcription. MAR-binding proteins, such as SATB1, interact with histone modifying enzymes resulting in altered gene expression. With A. phagocytophilum infection, histone deacetylase 1 (HDAC1) expression is increased and histone H3 acetylation is decreased at the CYBB promoter, suggesting a role for AnkA in altering host epigenetics and modulating gene transcription, at this, and perhaps other loci. This review will focus on how bacterial pathogens alter host epigenetics, by specifically examining A. phagocytophilum AnkA cis-regulation of CYBB transcription and epigenetic changes associated with infection. PMID:23082961

Rennoll-Bankert, Kristen E; Dumler, J Stephen

2012-10-01

310

Membrane flickering of the human erythrocyte: physical and chemical effectors.  

PubMed

Recent studies suggest a link between adenosine triphosphate (ATP) concentration and the amplitude of cell membrane flickering (CMF) in the human erythrocyte (red blood cell; RBC). Potentially, the origin of this phenomenon and the unique discocyte shape could be active processes that account for some of the ATP turnover in the RBC. Active flickering could depend on several factors, including pH, osmolality, enzymatic rates and metabolic fluxes. In the present work, we applied the data analysis described in the previous article to study time courses of flickering RBCs acquired using differential interference contrast light microscopy in the presence of selected effectors. We also recorded images of air bubbles in aqueous detergent solutions and oil droplets in water, both of which showed rapid fluctuations in image intensity, the former showing the same type of spectral envelope (relative frequency composition) to RBCs. We conclude that CMF is not directly an active process, but that ATP affects the elastic properties of the membrane that flickers in response to molecular bombardment in a manner that is described mathematically by a constrained random walk. PMID:24668224

Puckeridge, Max; Chapman, Bogdan E; Conigrave, Arthur D; Kuchel, Philip W

2014-05-01

311

Cytokines are systemic effectors of lymphatic function in acute inflammation.  

PubMed

The response of the lymphatic system to inflammatory insult and infection is not completely understood. Using a near-infrared fluorescence (NIRF) imaging system to noninvasively document propulsive function, we noted the short-term cessation of murine lymphatic propulsion as early as 4h following LPS injection. Notably, the effects were systemic, displaying bilateral lymphatic pumping cessation after a unilateral insult. Furthermore, IL-1?, TNF-?, and IL-6, cytokines that were found to be elevated in serum during lymphatic pumping cessation, were shown separately to acutely and systemically decrease lymphatic pulsing frequency and velocity following intradermal administration. Surprisingly, marked lymphatic vessel dilation and leakiness were noted in limbs contralateral to IL-1? intradermal administration, but not in ipsilateral limbs. The effects of IL-1? on lymphatic pumping were abated by pre-treatment with an inhibitor of inducible nitric oxide synthase, L-NIL (N-iminoethyl-L-lysine). The results suggest that lymphatic propulsion is systemically impaired within 4h of acute inflammatory insult, and that some cytokines are major effectors of lymphatic pumping cessation through nitric oxide-mediated mechanisms. These findings may help in understanding the actions of cytokines as mediators of lymphatic function in inflammatory and infectious states. PMID:23764549

Aldrich, Melissa B; Sevick-Muraca, Eva M

2013-10-01

312

Receptor-coupled effector systems and their interactions  

SciTech Connect

We investigated the modulation of intracellular signal generation by receptor-coupled effector systems in B lymphocytes, and whether these alterations are consistent with the effects of prostaglandins. TPA (12-O-tetradecanoyl phorbol-13-acetate) and sn-1,2,-dioctanoylglycerol (diC{sub 8}) substitute for lipid derived signals which activate protein kinase C. Pretreating splenocytes from athymic nude mice with 100nM TPA or 5 {mu}M diC{sub 8} potentiated the forskolin-induced increased in cAMP (measured by radioimmunoassay) 2.5 and 3.0 times (respectively), but they decreased the PGE{sub 1}-induced cAMP rise 48% and 35% (respectively). Goat anti-mouse IgM, which activates diacylglycerol production, potentiated the forskolin-induced cAMP increase by 76%, but reduced that of PGE{sub 1} by 30%. Rabbit anti-mouse IgG, its F(ab{prime}){sub 2} fragment, or goat anti-mouse IGM induced increases in the cytosolic free (Ca{sup 2+}), (Ca{sup 2+}){sub i}, which TPA inhibited. In contrast, TPA potential antibody-induced {sup 3}H-thymidine (85x) and {sup 3}H-uridine (30x) uptake in B lymphocytes.

Wiener, E.C.

1988-01-01

313

Bidirectional effectors of a group I intron ribozyme.  

PubMed

The group I self-splicing introns found in many organisms are competitively inhibited by L-arginine. We have found that L-arginine acts stereoselectively on the Pc1. LSU nuclear group I intron of Pneumocystis carinii, competitively inhibiting the first (cleavage) step of the splicing reaction and stimulating the second (ligation) step. Stimulation of the second step is most clearly demonstrated in reactions whose first step is blocked after 15 min by addition of pentamidine. The guanidine moiety of arginine is required for both effects. L-Canavanine is a more potent inhibitor than L-arginine yet it fails to stimulate. L-Arginine derivatized on its carboxyl group as an amide, ester or peptide is more potent than L-arginine as a stimulator and inhibitor, with di-arginine amide and tri-arginine being the most potent effectors tested. The most potent peptides tested are 10,000 times as effective as L-arginine in inhibiting ribozyme activity, and nearly 400 times as effective as stimulators. Arginine and some of its derivatives apparently bind to site(s) on the ribozyme to alter its conformation to one more active in the second step of splicing while competing with guanosine substrate in the first step. This phenomenon indicates that ribozymes, like protein enzymes, can be inhibited or stimulated by non-substrate low molecular weight compounds, which suggests that such compounds may be developed as pharmacological agents acting on RNA targets. PMID:7753618

Liu, Y; Leibowitz, M J

1995-04-25

314

Molecular diversity of antimicrobial effectors in the oyster Crassostrea gigas  

PubMed Central

Background To gain insight into the molecular diversity of antimicrobial peptides and proteins in the oyster Crassostrea gigas, we characterized and compared the sequence polymorphism of the antimicrobial peptides (AMPs), Cg-Defensins (Cg-Defs) and Cg-Proline Rich peptide (Cg-Prp), and of the bactericidal permeability increasing protein, Cg-BPI. For that, we analyzed genomic and transcript sequences obtained by specific PCR amplification and in silico searches. Results High diversification among the three antimicrobial effectors was evidenced by this polymorphism survey. On the basis of sequence phylogenies, each AMP aggregates into clearly defined groups of variants and is the product of a multigenic family displaying a variety of gene structures. In contrast, Cg-bpi forms a single group and is encoded by a single gene copy. Moreover, we identified for both AMPs several genetic mechanisms of diversification such as recombination, parallel mutations leading to phylogenetic homoplasy and indel events. In addition, the non synonymous to synonymous substitutions ratio by codon (dN/dS) revealed several negatively and positively selected sites for both AMPs, suggesting that directional selection pressures have shaped their sequence variations. Conclusions This study shows for the first time in a mollusc that antimicrobial peptides and proteins have been subject to distinct patterns of diversification and we evidence the existence of different evolutionary routes leading to such sequence variability.

2010-01-01

315

Measles virus-induced immunosuppression: from effectors to mechanisms  

Microsoft Academic Search

Immunosuppression is the major cause of infant death associated with acute measles. Hallmarks of this generalized modulation\\u000a of immune functions include: (1) lymphopenia, (2) a prolonged cytokine imbalance consistent with suppression of cellular immunity\\u000a to secondary infections and (3) silencing of peripheral blood lymphocytes that fail to expand in response to ex vivo stimulation. Lymphopenia results from depletion of T

Elita Avota; Evelyn Gassert; Sibylle Schneider-Schaulies

2010-01-01

316

Pressure suppression containment system  

DOEpatents

A pressure suppression containment system includes a containment vessel surrounding a reactor pressure vessel and defining a drywell therein containing a non-condensable gas. An enclosed wetwell pool is disposed inside the containment vessel, and a gravity driven cooling system (GDCS) pool is disposed above the wetwell pool in the containment vessel. The wetwell pool includes a plenum for receiving the non-condensable gas carried with steam from the drywell following a loss-of-coolant-accident (LOCA). The wetwell plenum is vented to a plenum above the GDCS pool following the LOCA for suppressing pressure rise within the containment vessel. A method of operation includes channeling steam released into the drywell following the LOCA into the wetwell pool for cooling along with the non-condensable gas carried therewith. The GDCS pool is then drained by gravity, and the wetwell plenum is vented into the GDCS plenum for channeling the non-condensable gas thereto. 6 figures.

Gluntz, D.M.; Townsend, H.E.

1994-03-15

317

Pressure suppression containment system  

DOEpatents

A pressure suppression containment system includes a containment vessel surrounding a reactor pressure vessel and defining a drywell therein containing a non-condensable gas. An enclosed wetwell pool is disposed inside the containment vessel, and a gravity driven cooling system (GDCS) pool is disposed above the wetwell pool in the containment vessel. The wetwell pool includes a plenum for receiving the non-condensable gas carried with steam from the drywell following a loss-of coolant-accident (LOCA). The wetwell plenum is vented to a plenum above the GDCS pool following the LOCA for suppressing pressure rise within the containment vessel. A method of operation includes channeling steam released into the drywell following the LOCA into the wetwell pool for cooling along with the non-condensable gas carried therewith. The GDCS pool is then drained by gravity, and the wetwell plenum is vented into the GDCS plenum for channeling the non-condensable gas thereto.

Gluntz, Douglas M. (San Jose, CA); Townsend, Harold E. (San Jose, CA)

1994-03-15

318

Suppressed Charmed B Decay  

Microsoft Academic Search

This thesis describes the measurement of the branching fractions of the suppressed charmed B° D{sup (*)-} a{sup +} decays and the non-resonant B° D{sup (*)-} {sup +} decays in approximately 230 million (4S) B{bar B} events. The data have been collected with the BABAR detector at the PEP-II B factory at the Stanford Linear Accelerator Center in California. Theoretical predictions

Hella Leonie Snoek

2011-01-01

319

Menstrual suppression: current perspectives  

PubMed Central

Menstrual suppression to provide relief of menstrual-related symptoms or to manage medical conditions associated with menstrual morbidity or menstrual exacerbation has been used clinically since the development of steroid hormonal therapies. Options range from the extended or continuous use of combined hormonal oral contraceptives, to the use of combined hormonal patches and rings, progestins given in a variety of formulations from intramuscular injection to oral therapies to intrauterine devices, and other agents such as gonadotropin-releasing hormone (GnRH) antagonists. The agents used for menstrual suppression have variable rates of success in inducing amenorrhea, but typically have increasing rates of amenorrhea over time. Therapy may be limited by side effects, most commonly irregular, unscheduled bleeding. These therapies can benefit women’s quality of life, and by stabilizing the hormonal milieu, potentially improve the course of underlying medical conditions such as diabetes or a seizure disorder. This review addresses situations in which menstrual suppression may be of benefit, and lists options which have been successful in inducing medical amenorrhea.

Hillard, Paula Adams

2014-01-01

320

Glioma associated cancer-initiating cells induce immune suppression  

PubMed Central

Purpose Glioblastoma multiforme (GBM) is a lethal cancer that responds poorly to therapy. GBM cancer-initiating cells have been shown to mediate resistance to both chemotherapy and radiation; however, it is unknown to what extent these cells contribute to the profound immune suppression in GBM patients and if strategies that alter their differentiation state can reduce this immune suppression. Experimental Design We isolated a subpopulation of cells from GBMs that possessed the capacity for self-renewal, formed neurospheres in vitro, were capable of pluripotent differentiation and could initiate tumors in vivo. These cells immune phenotype was characterized including the elaboration of immunosuppressive cytokines and chemokines by enzyme-linked immunosorbent assay. Functional immunosuppressive properties were characterized based on the inhibition of T cell proliferation and effector responses, triggering of T cell apoptosis and the induction FoxP3+ regulatory T cells. Upon altering their differentiation state, the immune suppressive phenotype and functional assays were reevaluated. Results We found that the cancer-initiating cells markedly inhibited T cell proliferation and activation, induced regulatory T cells and triggered T cell apoptosis that were mediated by B7-H1 and soluble Galectin-3. These immunosuppressive properties were diminished upon altering the differentiation of the cancer-initiating cells. Conclusion Cancer-initiating cells contribute to tumor evasion of the immune surveillance and approaches that alter the differentiation state may have immune therapeutic potential.

Wei, Jun; Barr, Jason; Kong, Ling-Yuan; Wang, Yongtao; Wu, Adam; Sharma, Amit K.; Gumin, Joy; Henry, Verlene; Colman, Howard; Sawaya, Raymond; Lang, Frederick F.; Heimberger, Amy B.

2010-01-01

321

Plant parasitic nematode effectors target host defense and nuclear functions to establish feeding cells  

PubMed Central

Plant parasitic nematodes are microscopic worms, the most damaging species of which have adopted a sedentary lifestyle within their hosts. These obligate endoparasites have a biotrophic relationship with plants, in which they induce the differentiation of root cells into hypertrophied, multinucleate feeding cells (FCs). Effectors synthesized in the esophageal glands of the nematode are injected into the plant cells via the syringe-like stylet and play a key role in manipulating the host machinery. The establishment of specialized FCs requires these effectors to modulate many aspects of plant cell morphogenesis and physiology, including defense responses. This cell reprogramming requires changes to host nuclear processes. Some proteins encoded by parasitism genes target host nuclei. Several of these proteins were immunolocalized within FC nuclei or shown to interact with host nuclear proteins. Comparative genomics and functional analyses are gradually revealing the roles of nematode effectors. We describe here these effectors and their hypothesized roles in the unique feeding behavior of these pests.

Quentin, Michaeel; Abad, Pierre; Favery, Bruno

2013-01-01

322

Effectors as tools in disease resistance breeding against biotrophic, hemibiotrophic, and necrotrophic plant pathogens.  

PubMed

One of most important challenges in plant breeding is improving resistance to the plethora of pathogens that threaten our crops. The ever-growing world population, changing pathogen populations, and fungicide resistance issues have increased the urgency of this task. In addition to a vital inflow of novel resistance sources into breeding programs, the functional characterization and deployment of resistance also needs improvement. Therefore, plant breeders need to adopt new strategies and techniques. In modern resistance breeding, effectors are emerging as tools to accelerate and improve the identification, functional characterization, and deployment of resistance genes. Since genome-wide catalogues of effectors have become available for various pathogens, including biotrophs as well as necrotrophs, effector-assisted breeding has been shown to be successful for various crops. "Effectoromics" has contributed to classical resistance breeding as well as for genetically modified approaches. Here, we present an overview of how effector-assisted breeding and deployment is being exploited for various pathosystems. PMID:24405032

Vleeshouwers, Vivianne G A A; Oliver, Richard P

2014-03-01

323

Effector diversification within compartments of the Leptosphaeria maculans genome affected by Repeat-Induced Point mutations  

PubMed Central

Fungi are of primary ecological, biotechnological and economic importance. Many fundamental biological processes that are shared by animals and fungi are studied in fungi due to their experimental tractability. Many fungi are pathogens or mutualists and are model systems to analyse effector genes and their mechanisms of diversification. In this study, we report the genome sequence of the phytopathogenic ascomycete Leptosphaeria maculans and characterize its repertoire of protein effectors. The L. maculans genome has an unusual bipartite structure with alternating distinct guanine and cytosine-equilibrated and adenine and thymine (AT)-rich blocks of homogenous nucleotide composition. The AT-rich blocks comprise one-third of the genome and contain effector genes and families of transposable elements, both of which are affected by repeat-induced point mutation, a fungal-specific genome defence mechanism. This genomic environment for effectors promotes rapid sequence diversification and underpins the evolutionary potential of the fungus to adapt rapidly to novel host-derived constraints.

Rouxel, Thierry; Grandaubert, Jonathan; Hane, James K.; Hoede, Claire; van de Wouw, Angela P.; Couloux, Arnaud; Dominguez, Victoria; Anthouard, Veronique; Bally, Pascal; Bourras, Salim; Cozijnsen, Anton J.; Ciuffetti, Lynda M.; Degrave, Alexandre; Dilmaghani, Azita; Duret, Laurent; Fudal, Isabelle; Goodwin, Stephen B.; Gout, Lilian; Glaser, Nicolas; Linglin, Juliette; Kema, Gert H. J.; Lapalu, Nicolas; Lawrence, Christopher B.; May, Kim; Meyer, Michel; Ollivier, Benedicte; Poulain, Julie; Schoch, Conrad L.; Simon, Adeline; Spatafora, Joseph W.; Stachowiak, Anna; Turgeon, B. Gillian; Tyler, Brett M.; Vincent, Delphine; Weissenbach, Jean; Amselem, Joelle; Quesneville, Hadi; Oliver, Richard P.; Wincker, Patrick; Balesdent, Marie-Helene; Howlett, Barbara J.

2011-01-01

324

Proximal signaling control of human effector CD4 T cell function  

PubMed Central

The functional coupling of T cell receptor (TCR)-mediated signaling events in primary human T cells remains undefined. We demonstrate here that alterations in the expression of proximal TCR-coupled signaling subunits are associated with distinct effector capacities in differentiated human CD4 T cells. Analysis of proximal signaling profiles using biochemical and single cell approaches reveals decreased CD3? and ZAP-70 expression correlating with functional anergy, with increased CD3?/ZAP-70 expression and phosphorylation connoting acquisition of effector capacity. By contrast, the FcR? signaling subunit known to be expressed in human effector cells and in T cells from the autoimmune disease SLE, is up-regulated upon activation, yet does not correlate with functional capacity in effector cells, and does not alter signaling or function in primary FcR? transfectants. Our results have implications for targeting signaling molecules in immunotherapy and evaluating the functional consequence of signaling alterations associated with autoimmunity and chronic diseases.

Okoye, Francesca I.; Krishnan, Sandeep; Chandok, Meena R.; Tsokos, George C.; Farber, Donna L.

2007-01-01

325

End-effector: Joint conjugates for robotic assembly of large truss structures in space: Extended concepts  

NASA Technical Reports Server (NTRS)

Results from NASA/HBCU Grant No. NAG-1-1125 are summarized. Designs developed for model fabrication, exploratory concepts drafted, interface of computer with robot and end-effector, and capability enhancement are discussed.

Brewer, W. V.; Rasis, E. P.; Shih, H. R.

1993-01-01

326

The death of smart sensors and effectors for future combat aircraft  

Microsoft Academic Search

This paper presents the view that the combination of performance, availability and affordability requirements for future combat aircraft demands a concept for low-bandwidth sensor\\/effector interfacing which removes the need for smart sensors and effectors. This contrasts sharply with current trends for civil aircraft.The paper discusses the reasons for the above, then describes a concept which extends modular avionics into the

R. A. Edwards; B. Gleaves

1997-01-01

327

Expanded roles for multicargo and class 1B effector chaperones in type III secretion.  

PubMed

Bacterial type III secretion systems (T3SS) are complex protein assemblies that mediate the secretion of protein substrates outside the cell. Type III secretion chaperones (T3SC) are always found associated with T3SS, and they serve in multiple roles to ensure that protein substrates are efficiently targeted for secretion. Bacterial pathogens with T3SS express T3SC proteins that bind effectors, a process important for effector protein delivery into eukaryotic cells during infection. In this minireview, we focus on multicargo and class 1B T3SC that associate with effectors within significant pathogens of animals and plants. As a primary role, multicargo and class 1B T3SC form homodimers and specifically bind different effectors within the cytoplasm, maintaining the effectors in a secretion-competent state. This role makes T3SC initial and central contributors to effector-mediated pathogenesis. Recent findings have greatly expanded our understanding of cellular events linked to multicargo T3SC function. New binding interactions with T3SS components have been reported in different systems, thereby implicating multicargo T3SC in critical roles beyond effector binding. Three notable interactions with the YscN, YscV, and YscQ family members are well represented in the literature. Similar T3SC interactions are reported in the putative related flagellar T3SS, suggesting that secretion mechanisms may be more similar than previously thought. The evidence implicates multicargo and class 1B T3SC in effector binding and stabilization, in addition to T3SS recruitment and docking events. PMID:22636784

Thomas, Nikhil A; Ma, Irene; Prasad, Madhulika E; Rafuse, Cheryl

2012-08-01

328

Effector T cells control lung inflammation during acute influenza virus infection by producing IL10  

Microsoft Academic Search

Activated antigen-specific T cells produce a variety of effector molecules for clearing infection but also contribute to inflammation and tissue injury. Here we report an anti-inflammatory property of antiviral CD8+ and CD4+ effector T cells (Teff cells) in the infected periphery during acute virus infection. We find that, during acute influenza infection, interleukin-10 (IL-10) is produced in the infected lungs

Jie Sun; Rajat Madan; Christopher L Karp; Thomas J Braciale

2009-01-01

329

Characterization of novel store-operated calcium entry effectors.  

PubMed

2-Aminoethyl diphenylborinate (2-APB) is a well-known effector of the store-operated Ca(2+) entry of several cell types such as immune cells, platelets and smooth muscle cells. 2-APB has a dual effect: potentiation at 1-5?M and inhibition at >30?M. Unfortunately, it is also able to modify the activity of other Ca(2+) transporters and, thus, cannot be used as a therapeutic tool to control the leukocyte activity in diseases like inflammation. Previously, we have shown that SOCE potentiation by 2-APB depends on the presence of the central boron-oxygen core (BOC) and that the phenyl groups determine the sensitivity of the molecule to inhibit and/or potentiate the SOCE. We hypothesized that by modifying the two phenyl groups of 2-APB, we could identify more efficient and specific analogues. In fact, the addition of methoxyl groups to one phenyl group greatly decreased the potentiation ability without any significant effect on the inhibition. Surprisingly, when the free rotation of the two phenyl groups was blocked by a new hydrocarbon bridge, the BOC was no longer able to potentiate. Furthermore, larger aryl groups than phenyl also impaired the activity of the BOC. Thus, the potentiation site in the Ca(2+) channel is not accessible by the BOC when the lateral groups are too large or unable to freely rotate. However, these molecules are potent inhibitors of store-operated calcium entry with affinities below 1?M, and they can block the activation of the Jurkat T cells. Thus, it is possible to characterize 2-APB analogues with different properties that could be the first step in the discovery of new immunomodulators. This article is part of a special issue entitled "Calcium Signaling in Health and Disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau. PMID:24657813

Djillani, Alaeddine; Nüße, Oliver; Dellis, Olivier

2014-10-01

330

Pattern-Triggered Immunity Suppresses Programmed Cell Death Triggered by Fumonisin B1  

PubMed Central

Programmed cell death (PCD) is a crucial process for plant innate immunity and development. In plant innate immunity, PCD is believed to prevent the spread of pathogens from the infection site. Although proper control of PCD is important for plant fitness, we have limited understanding of the molecular mechanisms regulating plant PCD. Plant innate immunity triggered by recognition of effectors (effector-triggered immunity, ETI) is often associated with PCD. However pattern-triggered immunity (PTI), which is triggered by recognition of elicitors called microbe-associated molecular patterns (MAMPs), is not. Therefore we hypothesized that PTI might suppress PCD. Here we report that PCD triggered by the mycotoxin fumonisin B1 (FB1) can be suppressed by PTI in Arabidopsis. FB1-triggered cell death was suppressed by treatment with the MAMPs flg22 (a part of bacterial flagellin) or elf18 (a part of the bacterial elongation factor EF-Tu) but not chitin (a component of fungal cell walls). Although plant hormone signaling is associated with PCD and PTI, both FB1-triggered cell death and suppression of cell death by flg22 treatment were still observed in mutants deficient in jasmonic acid (JA), ethylene (ET) and salicylic acid (SA) signaling. The MAP kinases MPK3 and MPK6 are transiently activated and inactivated within one hour during PTI. We found that FB1 activated MPK3 and MPK6 about 36–48 hours after treatment. Interestingly, this late activation was attenuated by flg22 treatment. These results suggest that PTI suppression of FB1-triggered cell death may involve suppression of MPK3/MPK6 signaling but does not require JA/ET/SA signaling.

Igarashi, Daisuke; Bethke, Gerit; Xu, Yuan; Tsuda, Kenichi; Glazebrook, Jane; Katagiri, Fumiaki

2013-01-01

331

The tomato Prf complex is a molecular trap for bacterial effectors based on Pto transphosphorylation.  

PubMed

The major virulence strategy of phytopathogenic bacteria is to secrete effector proteins into the host cell to target the immune machinery. AvrPto and AvrPtoB are two such effectors from Pseudomonas syringae, which disable an overlapping range of kinases in Arabidopsis and Tomato. Both effectors target surface-localized receptor-kinases to avoid bacterial recognition. In turn, tomato has evolved an intracellular effector-recognition complex composed of the NB-LRR protein Prf and the Pto kinase. Structural analyses have shown that the most important interaction surface for AvrPto and AvrPtoB is the Pto P+1 loop. AvrPto is an inhibitor of Pto kinase activity, but paradoxically, this kinase activity is a prerequisite for defense activation by AvrPto. Here using biochemical approaches we show that disruption of Pto P+1 loop stimulates phosphorylation in trans, which is possible because the Pto/Prf complex is oligomeric. Both P+1 loop disruption and transphosphorylation are necessary for signalling. Thus, effector perturbation of one kinase molecule in the complex activates another. Hence, the Pto/Prf complex is a sophisticated molecular trap for effectors that target protein kinases, an essential aspect of the pathogen's virulence strategy. The data presented here give a clear view of why bacterial virulence and host recognition mechanisms are so often related and how the slowly evolving host is able to keep pace with the faster-evolving pathogen. PMID:23382672

Ntoukakis, Vardis; Balmuth, Alexi L; Mucyn, Tatiana S; Gutierrez, Jose R; Jones, Alexandra M E; Rathjen, John P

2013-01-01

332

New clues in the nucleus: transcriptional reprogramming in effector-triggered immunity  

PubMed Central

The robustness of plant effector-triggered immunity is correlated with massive alterations of the host transcriptome. Yet the molecular mechanisms that cause and underlie this reprogramming remain obscure. Here we will review recent advances in deciphering nuclear functions of plant immune receptors and of associated proteins. Important open questions remain, such as the identities of the primary transcription factors involved in control of effector-triggered immune responses, and indeed whether this can be generalized or whether particular effector-resistance protein interactions impinge on distinct sectors in the transcriptional response web. Multiple lines of evidence have implicated WRKY transcription factors at the core of responses to microbe-associated molecular patterns and in intersections with effector-triggered immunity. Recent findings from yeast two-hybrid studies suggest that members of the TCP transcription factor family are targets of several effectors from diverse pathogens. Additional transcription factor families that are directly or indirectly involved in effector-triggered immunity are likely to be identified.

Bhattacharjee, Saikat; Garner, Christopher M.; Gassmann, Walter

2013-01-01

333

In-flight adaptive performance optimization (APO) control using redundant control effectors of an aircraft  

NASA Technical Reports Server (NTRS)

Practical application of real-time (or near real-time) Adaptive Performance Optimization (APO) is provided for a transport aircraft in steady climb, cruise, turn descent or other flight conditions based on measurements and calculations of incremental drag from a forced response maneuver of one or more redundant control effectors defined as those in excess of the minimum set of control effectors required to maintain the steady flight condition in progress. The method comprises the steps of applying excitation in a raised-cosine form over an interval of from 100 to 500 sec. at the rate of 1 to 10 sets/sec of excitation, and data for analysis is gathered in sets of measurements made during the excitation to calculate lift and drag coefficients C.sub.L and C.sub.D from two equations, one for each coefficient. A third equation is an expansion of C.sub.D as a function of parasitic drag, induced drag, Mach and altitude drag effects, and control effector drag, and assumes a quadratic variation of drag with positions .delta..sub.i of redundant control effectors i=1 to n. The third equation is then solved for .delta..sub.iopt the optimal position of redundant control effector i, which is then used to set the control effector i for optimum performance during the remainder of said steady flight or until monitored flight conditions change by some predetermined amount as determined automatically or a predetermined minimum flight time has elapsed.

Gilyard, Glenn B. (Inventor)

1999-01-01

334

Autoacetylation of the Ralstonia solanacearum effector PopP2 targets a lysine residue essential for RRS1-R-mediated immunity in Arabidopsis.  

PubMed

Type III effector proteins from bacterial pathogens manipulate components of host immunity to suppress defence responses and promote pathogen development. In plants, host proteins targeted by some effectors called avirulence proteins are surveyed by plant disease resistance proteins referred to as "guards". The Ralstonia solanacearum effector protein PopP2 triggers immunity in Arabidopsis following its perception by the RRS1-R resistance protein. Here, we show that PopP2 interacts with RRS1-R in the nucleus of living plant cells. PopP2 belongs to the YopJ-like family of cysteine proteases, which share a conserved catalytic triad that includes a highly conserved cysteine residue. The catalytic cysteine mutant PopP2-C321A is impaired in its avirulence activity although it is still able to interact with RRS1-R. In addition, PopP2 prevents proteasomal degradation of RRS1-R, independent of the presence of an integral PopP2 catalytic core. A liquid chromatography/tandem mass spectrometry analysis showed that PopP2 displays acetyl-transferase activity leading to its autoacetylation on a particular lysine residue, which is well conserved among all members of the YopJ family. These data suggest that this lysine residue may correspond to a key binding site for acetyl-coenzyme A required for protein activity. Indeed, mutation of this lysine in PopP2 abolishes RRS1-R-mediated immunity. In agreement with the guard hypothesis, our results favour the idea that activation of the plant immune response by RRS1-R depends not only on the physical interaction between the two proteins but also on its perception of PopP2 enzymatic activity. PMID:21124938

Tasset, Céline; Bernoux, Maud; Jauneau, Alain; Pouzet, Cécile; Brière, Christian; Kieffer-Jacquinod, Sylvie; Rivas, Susana; Marco, Yves; Deslandes, Laurent

2010-01-01

335

Antigen-specific CD4+ effector T cells: analysis of factors regulating clonal expansion and cytokine production: clonal expansion and cytokine production by CD4+ effector T cells.  

PubMed

In order to fully understand T cell-mediated immunity, the mechanisms that regulate clonal expansion and cytokine production by CD4(+) antigen-specific effector T cells in response to a wide range of antigenic stimulation needs clarification. For this purpose, panels of antigen-specific CD4(+) T cell clones with different thresholds for antigen-induced proliferation were generated by repeated stimulation with high- or low-dose antigen. Differences in antigen sensitivities did not correlate with expression of TCR, CD4, adhesion or costimulatory molecules. There was no significant difference in antigen-dependent cytokine production by TG40 cells transfected with TCR obtained from either high- or low-dose-responding T cell clones, suggesting that the affinity of TCRs for their ligands is not primary determinant of T cell antigen reactivity. The proliferative responses of all T cell clones to both peptide stimulation and to TCRbeta crosslinking revealed parallel dose-response curves. These results suggest that the TCR signal strength of effector T cells and threshold of antigen reactivity is determined by an intrinsic property, such as the TCR signalosome and/or intracellular signaling machinery. Finally, the antigen responses of high- and low-peptide-responding T cell clones reveal that clonal expansion and cytokine production of effector T cells occur independently of antigen concentration. Based on these results, the mechanisms underlying selection of high "avidity" effector and memory T cells in response to pathogen are discussed. PMID:19338745

Ohnuki, Kazunobu; Watanabe, Yuri; Takahashi, Yusuke; Kobayashi, Sakiko; Watanabe, Shiho; Ogawa, Shuhei; Kotani, Motoko; Kozono, Haruo; Tanabe, Kazunari; Abe, Ryo

2009-03-20

336

Design of endoscopic micro-robotic end effectors: safety and performance evaluation based on physical intestinal tissue damage characteristics.  

PubMed

During the last several years, legged locomotive mechanism has been considered as one of the main self-propelling mechanisms for future endoscopic microrobots due to its superior propulsion efficiency of an endoscopic microrobot inside the intestinal track. Nevertheless, its clinical application has been largely limited since the legged locomotive mechanism utilizes an end effector which has a sharp tip to generate sufficient traction by physically penetrating and interlocking with the intestinal tissue. This can cause excessive physical tissue damage or even complete perforation of the intestinal wall that can lead to abdominal inflammation. Hence, in this work two types of new end effectors, penetration-limited end effector (PLEE) and bi-material structured end effector (BMEE) were specially designed to acquire high medical safety as well as effective traction generation performance. The microscopic end effector specimens were fabricated with micro-wire electric discharge machining process. Traction generation performance of the end effectors was evaluated by direct measurement of resistance forces during contact-sliding tests using a custom-built contact-sliding tester. The safety of the end effector design was evaluated by examination of microscopic intestinal tissue damage using a scanning electron microscope (SEM). Physical damage characteristics of the intestinal tissue and related contact physics of the end effectors were discussed. From the results, the end effectors were evaluated with respect to their prospects in future medical applications as safe end effectors as well as micro-surgical tools. PMID:24634056

Kim, Young-Tae; Kim, Dae-Eun; Yang, Sungwook; Yoon, Eui-Sung

2014-06-01

337

Ginkgo biloba extract EGb 761 has anti-inflammatory properties and ameliorates colitis in mice by driving effector T cell apoptosis  

PubMed Central

Ulcerative colitis is a dynamic, chronic inflammatory condition of the colon associated with an increased colon cancer risk. Ginkgo biloba is a putative antioxidant and has been used for thousands of years to treat a variety of ailments. The aim of this study was to test whether the standardized G.biloba extract, EGb 761, is an antioxidant that can be used to prevent and treat colitis in mice. Here, we show that EGb 761 suppresses the activation of macrophages and can be used to both prevent and treat mouse colitis. Markers of inflammation (iNOS, Cox-2 and tumor necrosis factor-?) and inflammatory stress (p53 and p53-phospho-serine 15) are also downregulated by EGb 761. Furthermore, we show that EGb 761 reduces the numbers of CD4+/CD25?/Foxp3? effector T cells in the colon. Interestingly, EGb 761 drives CD4+ effector T cell apoptosis in vitro and in vivo, providing a mechanistic explanation to the reduction in numbers of this cell type in the colon. This current study is in agreement with previous studies supporting a use of EGb 761 as a complementary and alternative strategy to abate colitis and associated colon cancer.

Kotakadi, Venkata S.; Jin, Yu; Hofseth, Anne B.; Ying, Lei; Cui, Xiangli; Volate, Suresh; Chumanevich, Alexander; Wood, Patricia A.; Price, Robert L.; McNeal, Anna; Singh, Udai P.; Singh, Narendra P.; Nagarkatti, Mitzi; Nagarkatti, Prakash S.; Matesic, Lydia E.; Auclair, Karine; Wargovich, Michael J.; Hofseth, Lorne J.

2008-01-01

338

The Salmonella Typhimurium effector SteC inhibits Cdc42-mediated signaling through binding to the exchange factor Cdc24 in Saccharomyces cerevisiae  

PubMed Central

Intracellular survival of Salmonella relies on the activity of proteins translocated into the host cell by type III secretion systems (T3SS). The protein kinase activity of the T3SS effector SteC is required for F-actin remodeling in host cells, although no SteC target has been identified so far. Here we show that expression of the N-terminal non-kinase domain of SteC down-regulates the mating and HOG pathways in Saccharomyces cerevisiae. Epistasis analyses using constitutively active components of these pathways indicate that SteC inhibits signaling at the level of the GTPase Cdc42. We demonstrate that SteC interacts through its N-terminal domain with the catalytic domain of Cdc24, the sole S. cerevisiae Cdc42 guanine nucleotide exchange factor (GEF). SteC also binds to the human Cdc24-like GEF protein Vav1. Moreover, expression of human Cdc42 suppresses growth inhibition caused by SteC. Of interest, the N-terminal SteC domain alters Cdc24 cellular localization, preventing its nuclear accumulation. These data reveal a novel functional domain within SteC, raising the possibility that this effector could also target GTPase function in mammalian cells. Our results also highlight the key role of the Cdc42 switch in yeast mating and HOG pathways and provide a new tool to study the functional consequences of Cdc24 localization.

Fernandez-Pinar, Pablo; Aleman, Ainel; Sondek, John; Dohlman, Henrik G.; Molina, Maria; Martin, Humberto

2012-01-01

339

Interleukin 35: a key mediator of suppression and the propagation of infectious tolerance.  

PubMed

The importance of regulatory T cells (Tregs) in balancing the effector arm of the immune system is well documented, playing a central role in preventing autoimmunity, facilitating graft tolerance following organ transplantation, and having a detrimental impact on the development of anti-tumor immunity. These regulatory responses use a variety of mechanisms to mediate suppression, including soluble factors. While IL-10 and TGF-? are the most commonly studied immunosuppressive cytokines, the recently identified IL-35 has been shown to have potent suppressive function in vitro and in vivo. Furthermore, not only does IL-35 have the ability to directly suppress effector T cell responses, it is also able to expand regulatory responses by propagating infectious tolerance and generating a potent population of IL-35-expressing inducible Tregs. In this review, we summarize research characterizing the structure and function of IL-35, examine its role in disease, and discuss how it can contribute to the induction of a distinct population of inducible Tregs. PMID:24151492

Olson, Brian M; Sullivan, Jeremy A; Burlingham, William J

2013-01-01

340

DEEP--a tool for differential expression effector prediction.  

PubMed

High-throughput methods for measuring transcript abundance, like SAGE or microarrays, are widely used for determining differences in gene expression between different tissue types, dignities (normal/malignant) or time points. Further analysis of such data frequently aims at the identification of gene interaction networks that form the causal basis for the observed properties of the systems under examination. To this end, it is usually not sufficient to rely on the measured gene expression levels alone; rather, additional biological knowledge has to be taken into account in order to generate useful hypotheses about the molecular mechanism leading to the realization of a certain phenotype. We present a method that combines gene expression data with biological expert knowledge on molecular interaction networks, as described by the TRANSPATH database on signal transduction, to predict additional--and not necessarily differentially expressed--genes or gene products which might participate in processes specific for either of the examined tissues or conditions. In a first step, significance values for over-expression in tissue/condition A or B are assigned to all genes in the expression data set. Genes with a significance value exceeding a certain threshold are used as starting points for the reconstruction of a graph with signaling components as nodes and signaling events as edges. In a subsequent graph traversal process, again starting from the previously identified differentially expressed genes, all encountered nodes 'inherit' all their starting nodes' significance values. In a final step, the graph is visualized, the nodes being colored according to a weighted average of their inherited significance values. Each node's, or sub-network's, predominant color, ranging from green (significant for tissue/condition A) over yellow (not significant for either tissue/condition) to red (significant for tissue/condition B), thus gives an immediate visual clue on which molecules--differentially expressed or not--may play pivotal roles in the tissues or conditions under examination. The described method has been implemented in Java as a client/server application and a web interface called DEEP (Differential Expression Effector Prediction). The client, which features an easy-to-use graphical interface, can freely be downloaded from the following URL: http://deep.bioinf.med.uni-goettingen.de. PMID:17584786

Degenhardt, Jost; Haubrock, Martin; Dönitz, Jürgen; Wingender, Edgar; Crass, Torsten

2007-07-01

341

Structure of the Type VI Effector-Immunity Complex (Tae4-Tai4) Provides Novel Insights into the Inhibition Mechanism of the Effector by Its Immunity Protein*  

PubMed Central

The type VI secretion system (T6SS), a multisubunit needle-like apparatus, has recently been found to play a role in interspecies interactions. The Gram-negative bacteria harboring T6SS (donor) deliver the effectors into their neighboring cells (recipient) to kill them. Meanwhile, the cognate immunity proteins were employed to protect the donor cells against the toxic effectors. Tae4 (type VI amidase effector 4) and Tai4 (type VI amidase immunity 4) are newly identified T6SS effector-immunity pairs. Here, we report the crystal structures of Tae4 from Enterobacter cloacae and Tae4-Tai4 complexes from both E. cloacae and Salmonella typhimurium. Tae4 acts as a dl-endopeptidase and displays a typical N1pC/P60 domain. Unlike Tsi1 (type VI secretion immunity 1), Tai4 is an all-helical protein and forms a dimer in solution. The small angle x-ray scattering study combined with the analytical ultracentrifugation reveal that the Tae4-Tai4 complex is a compact heterotetramer that consists of a Tai4 dimer and two Tae4 molecules in solution. Structure-based mutational analysis of the Tae4-Tai4 interface shows that a helix (?3) of one subunit in dimeric Tai4 plays a major role in binding of Tae4, whereas a protruding loop (L4) in the other subunit is mainly responsible for inhibiting Tae4 activity. The inhibition process requires collaboration between the Tai4 dimer. These results reveal a novel and unique inhibition mechanism in effector-immunity pairs and suggest a new strategy to develop antipathogen drugs.

Zhang, Heng; Zhang, Heng; Gao, Zeng-Qiang; Wang, Wen-Jia; Liu, Guang-Feng; Xu, Jian-Hua; Su, Xiao-Dong; Dong, Yu-Hui

2013-01-01

342

Structure of the type VI effector-immunity complex (Tae4-Tai4) provides novel insights into the inhibition mechanism of the effector by its immunity protein.  

PubMed

The type VI secretion system (T6SS), a multisubunit needle-like apparatus, has recently been found to play a role in interspecies interactions. The gram-negative bacteria harboring T6SS (donor) deliver the effectors into their neighboring cells (recipient) to kill them. Meanwhile, the cognate immunity proteins were employed to protect the donor cells against the toxic effectors. Tae4 (type VI amidase effector 4) and Tai4 (type VI amidase immunity 4) are newly identified T6SS effector-immunity pairs. Here, we report the crystal structures of Tae4 from Enterobacter cloacae and Tae4-Tai4 complexes from both E. cloacae and Salmonella typhimurium. Tae4 acts as a DL-endopeptidase and displays a typical N1pC/P60 domain. Unlike Tsi1 (type VI secretion immunity 1), Tai4 is an all-helical protein and forms a dimer in solution. The small angle x-ray scattering study combined with the analytical ultracentrifugation reveal that the Tae4-Tai4 complex is a compact heterotetramer that consists of a Tai4 dimer and two Tae4 molecules in solution. Structure-based mutational analysis of the Tae4-Tai4 interface shows that a helix (?3) of one subunit in dimeric Tai4 plays a major role in binding of Tae4, whereas a protruding loop (L4) in the other subunit is mainly responsible for inhibiting Tae4 activity. The inhibition process requires collaboration between the Tai4 dimer. These results reveal a novel and unique inhibition mechanism in effector-immunity pairs and suggest a new strategy to develop antipathogen drugs. PMID:23288853

Zhang, Heng; Zhang, Heng; Gao, Zeng-Qiang; Wang, Wen-Jia; Liu, Guang-Feng; Xu, Jian-Hua; Su, Xiao-Dong; Dong, Yu-Hui

2013-02-22

343

Structures of the flax-rust effector AvrM reveal insights into the molecular basis of plant-cell entry and effector-triggered immunity  

PubMed Central

Fungal and oomycete pathogens cause some of the most devastating diseases in crop plants, and facilitate infection by delivering a large number of effector molecules into the plant cell. AvrM is a secreted effector protein from flax rust (Melampsora lini) that can internalize into plant cells in the absence of the pathogen, binds to phosphoinositides (PIPs), and is recognized directly by the resistance protein M in flax (Linum usitatissimum), resulting in effector-triggered immunity. We determined the crystal structures of two naturally occurring variants of AvrM, AvrM-A and avrM, and both reveal an L-shaped fold consisting of a tandem duplicated four-helix motif, which displays similarity to the WY domain core in oomycete effectors. In the crystals, both AvrM variants form a dimer with an unusual nonglobular shape. Our functional analysis of AvrM reveals that a hydrophobic surface patch conserved between both variants is required for internalization into plant cells, whereas the C-terminal coiled-coil domain mediates interaction with M. AvrM binding to PIPs is dependent on positive surface charges, and mutations that abrogate PIP binding have no significant effect on internalization, suggesting that AvrM binding to PIPs is not essential for transport of AvrM across the plant membrane. The structure of AvrM and the identification of functionally important surface regions advance our understanding of the molecular mechanisms underlying how effectors enter plant cells and how they are detected by the plant immune system.

Ve, Thomas; Williams, Simon J.; Catanzariti, Ann-Maree; Rafiqi, Maryam; Rahman, Motiur; Ellis, Jeffrey G.; Hardham, Adrienne R.; Jones, David A.; Anderson, Peter A.; Dodds, Peter N.; Kobe, Bostjan

2013-01-01

344

The Ras effectors NORE1A and RASSF1A are frequently inactivated in pheochromocytoma and abdominal paraganglioma.  

PubMed

NORE1A (RASSF5) and RASSF1A are newly described Ras effectors with tumour suppressor functions. Both molecules are frequently inactivated in various cancers. In this study, we aimed to explore the potential involvement of NORE1A and RASSF1A in pheochromocytoma and abdominal paraganglioma tumorigenesis. A panel of 54 primary tumours was analysed for NORE1A and RASSF1A mRNA expression by TaqMan quantitative RT-PCR. Furthermore, NORE1A and RASSF1A promoter methylation was assessed by combined bisulphite restriction endonuclease assay and methylation-sensitive Pyrosequencing respectively. The anti-tumorigenic role of NORE1A was functionally investigated in Nore1A-transfected PC12 rat pheochromocytoma cells by fluorescent inhibition of caspase activity and soft agar assays. Significantly suppressed NORE1A and RASSF1A mRNA levels were detected in primary tumours compared with normal adrenal medulla (P<0.001). Methylation of the NORE1A promoter was not observed in primary tumours. On the other hand, 9% (5/54) of the primary tumours examined showed RASSF1A promoter methylation greater than 20% as detected by Pyrosequencing. Methylation of the RASSF1A promoter was significantly associated with malignant behaviour (P<0.05). Transient expression of Nore1a resulted in enhanced apoptosis and impaired colony formation in soft agar. Our study provides evidence that NORE1A and RASSF1A are frequently suppressed in pheochromocytoma and abdominal paraganglioma. Silencing of NORE1A contributes to the transformed phenotype in these tumours. PMID:17395981

Geli, Janos; Kiss, Nimrod; Lanner, Fredrik; Foukakis, Theodoros; Natalishvili, Natalia; Larsson, Olle; Kogner, Per; Höög, Anders; Clark, Geoffrey J; Ekström, Tomas J; Bäckdahl, Martin; Farnebo, Filip; Larsson, Catharina

2007-03-01

345

Green tea epigallocatechin-3-gallate modulates differentiation of naïve CD4? T cells into specific lineage effector cells.  

PubMed

CD4(+) T helper (Th) subsets Th1, Th9, and Th17 cells are implicated in inducing autoimmunity whereas regulatory T cells (Treg) have a protective effect. We and others have previously shown that epigallocatechin-3-gallate (EGCG) attenuates experimental autoimmune encephalomyelitis (EAE) and alters CD4(+) T cell subpopulations. In this study, we investigated how EGCG impacts differentiation of naïve CD4(+) T cells into different effector lineages and report that EGCG impeded Th1, Th9, and Th17 differentiation and prevented IL-6-induced suppression of Treg development. We further showed that EGCG inhibited T-bet, PU.1, and ROR?t, the specific transcription factors for Th1, Th9, and Th17 differentiation, respectively. These effects, in turn, may be mediated by EGCG-induced downregulation of transducers p-STAT1 and p-STAT4 for Th1, and p-STAT3 for Th17. EGCG-induced change in Th17/Treg balance may be mediated by its inhibition of IL-6 signaling because EGCG inhibited soluble IL-6R, membrane gp130, and IL-6-induced phosphorylation of STAT3. This notion was further supported by the in vivo results showing inhibited IL-6 and soluble IL-6R but increased soluble gp130 levels in plasma from EAE mice fed EGCG. Together, our results suggest that EGCG modulates development of CD4(+) T cell lineages through impacting their respective and interactive regulatory networks ultimately leading to an attenuated autoimmune response. PMID:23064699

Wang, Junpeng; Pae, Munkyong; Meydani, Simin Nikbin; Wu, Dayong

2013-04-01

346

Two linked genes encoding a secreted effector and a membrane protein are essential for Ustilago maydis-induced tumour formation.  

PubMed

Ustilago maydis is a biotrophic fungal pathogen that colonizes living tissue of its host plant maize. Based on transcriptional upregulation during biotrophic development we identified the pit (proteins important for tumours) cluster, a novel gene cluster comprising four genes of which two are predicted to encode secreted effectors. Disruption of the gene cluster abolishes U. maydis-induced tumour formation and this phenotype can be caused by deleting either pit1 encoding a transmembrane protein or pit2 encoding a secreted protein. Pit1 localizes to the fungal plasma membrane at hyphal tips, endosomes and vacuoles while Pit2 is secreted to the biotrophic interface. Both ?pit1 and ?pit2 mutants are able to penetrate maize epidermis and grow intracellularly at sites of infection but fail to spread in the infected leaf. Microarray analysis shows an indistinguishable response of the plant to infection by ?pit1 and ?pit2 mutant strains. Transcriptional activation of maize defence genes in infections with ?pit1/2 mutant strains indicates that the mutants have a defect in suppressing plant immune responses. Our results suggest that the activity of Pit1 and Pit2 during tumour formation might be functionally linked and we discuss possibilities for a putative functional connection of the two proteins. PMID:21692877

Doehlemann, Gunther; Reissmann, Stefanie; Assmann, Daniela; Fleckenstein, Martin; Kahmann, Regine

2011-08-01

347

The Glucose Transporter Glut1 Is Selectively Essential for CD4 T Cell Activation and Effector Function.  

PubMed

CD4 T cell activation leads to proliferation and differentiation into effector (Teff) or regulatory (Treg) cells that mediate or control immunity. While each subset prefers distinct glycolytic or oxidative metabolic programs in vitro, requirements and mechanisms that control T cell glucose uptake and metabolism in vivo are uncertain. Despite expression of multiple glucose transporters, Glut1 deficiency selectively impaired metabolism and function of thymocytes and Teff. Resting T cells were normal until activated, when Glut1 deficiency prevented increased glucose uptake and glycolysis, growth, proliferation, and decreased Teff survival and differentiation. Importantly, Glut1 deficiency decreased Teff expansion and the ability to induce inflammatory disease in vivo. Treg cells, in contrast, were enriched in vivo and appeared functionally unaffected and able to suppress Teff, irrespective of Glut1 expression. These data show a selective in vivo requirement for Glut1 in metabolic reprogramming of CD4 T cell activation and Teff expansion and survival. PMID:24930970

Macintyre, Andrew N; Gerriets, Valerie A; Nichols, Amanda G; Michalek, Ryan D; Rudolph, Michael C; Deoliveira, Divino; Anderson, Steven M; Abel, E Dale; Chen, Benny J; Hale, Laura P; Rathmell, Jeffrey C

2014-07-01

348

How the TP53 Family Proteins TP63 and TP73 Contribute to Tumorigenesis: Regulators and Effectors.  

PubMed

In mammals, the p53 family comprises two additional members, p63 and p73 (hereafter referred to as TP53, TP63, and TP73, respectively). The usage of two alternative promoters produces protein variants either with (transactivating [TA] isoforms) or without (?N isoforms) the N-terminal transactivation domain (TAD). In general, the TA proteins exert TP53-like tumor-suppressive activities through their ability to activate a common set of target genes. The ?N proteins can act as dominant-negative inhibitors of the transcriptionally active family members. Additionally, they possess intrinsic-specific biological activities due to the presence of alternative TADs, and as a result of engaging a different set of regulators. This review summarizes the current understanding of upstream regulators and downstream effectors of the TP53 family proteins, with particular emphasis on those that are relevant for their role in tumorigenesis. Furthermore, we highlight the existence of networks and cross-talks among the TP53 family members, their modulators, as well as the transcriptional targets. PMID:24488880

Candi, Eleonora; Agostini, Massimiliano; Melino, Gerry; Bernassola, Francesca

2014-06-01

349

Compatibility in the Ustilago maydis-Maize Interaction Requires Inhibition of Host Cysteine Proteases by the Fungal Effector Pit2  

PubMed Central

The basidiomycete Ustilago maydis causes smut disease in maize, with large plant tumors being formed as the most prominent disease symptoms. During all steps of infection, U. maydis depends on a biotrophic interaction, which requires an efficient suppression of plant immunity. In a previous study, we identified the secreted effector protein Pit2, which is essential for maintenance of biotrophy and induction of tumors. Deletion mutants for pit2 successfully penetrate host cells but elicit various defense responses, which stops further fungal proliferation. We now show that Pit2 functions as an inhibitor of a set of apoplastic maize cysteine proteases, whose activity is directly linked with salicylic-acid-associated plant defenses. Consequently, protease inhibition by Pit2 is required for U. maydis virulence. Sequence comparisons with Pit2 orthologs from related smut fungi identified a conserved sequence motif. Mutation of this sequence caused loss of Pit2 function. Consequently, expression of the mutated protein in U. maydis could not restore virulence of the pit2 deletion mutant, indicating that the protease inhibition by Pit2 is essential for fungal virulence. Moreover, synthetic peptides of the conserved sequence motif showed full activity as protease inhibitor, which identifies this domain as a new, minimal protease inhibitor domain in plant-pathogenic fungi.

Mueller, Andre N.; Ziemann, Sebastian; Treitschke, Steffi; Assmann, Daniela; Doehlemann, Gunther

2013-01-01

350

Halofuginone-induced amino acid starvation regulates Stat3-dependent Th17 effector function and reduces established autoimmune inflammation.  

PubMed

The IL-23 pathway is genetically linked to autoimmune disease in humans and is required for pathogenic Th17 cell function in mice. However, because IL-23R-expressing mature Th17 cells are rare and poorly defined in mice at steady-state, little is known about IL-23 signaling. In this study, we show that the endogenous CCR6(+) memory T cell compartment present in peripheral lymphoid organs of unmanipulated mice expresses Il23r ex vivo, displays marked proinflammatory responses to IL-23 stimulation in vitro, and is capable of transferring experimental autoimmune encephalomyelitis. The prolyl-tRNA synthetase inhibitor halofuginone blocks IL-23-induced Stat3 phosphorylation and IL-23-dependent proinflammatory cytokine expression in endogenous CCR6(+) Th17 cells via activation of the amino acid starvation response (AAR) pathway. In vivo, halofuginone shows therapeutic efficacy in experimental autoimmune encephalomyelitis, reducing both established disease progression and local Th17 cell effector function within the CNS. Mechanistically, AAR activation impairs Stat3 responses downstream of multiple cytokine receptors via selective, posttranscriptional suppression of Stat3 protein levels. Thus, our study reveals latent pathogenic functions of endogenous Th17 cells that are regulated by both IL-23 and AAR pathways and identifies a novel regulatory pathway targeting Stat3 that may underlie selective immune regulation by the AAR. PMID:24489094

Carlson, Thaddeus J; Pellerin, Alex; Djuretic, Ivana M; Trivigno, Catherine; Koralov, Sergei B; Rao, Anjana; Sundrud, Mark S

2014-03-01

351

A bacterial type III secretion assay for delivery of fungal effector proteins into wheat.  

PubMed

Large numbers of candidate effectors from fungal pathogens are being identified through whole-genome sequencing and in planta expression studies. Although Agrobacterium-mediated transient expression has enabled high-throughput functional analysis of effectors in dicot plants, this assay is not effective in cereal leaves. Here, we show that a nonpathogenic Pseudomonas fluorescens engineered to express the type III secretion system (T3SS) of P. syringae and the wheat pathogen Xanthomonas translucens can deliver fusion proteins containing T3SS signals from P. syringae (AvrRpm1) and X. campestris (AvrBs2) avirulence (Avr) proteins, respectively, into wheat leaf cells. A calmodulin-dependent adenylate cyclase reporter protein was delivered effectively into wheat and barley by both bacteria. Absence of any disease symptoms with P. fluorescens makes it more suitable than X. translucens for detecting a hypersensitive response (HR) induced by an effector protein with avirulence activity. We further modified the delivery system by removal of the myristoylation site from the AvrRpm1 fusion to prevent its localization to the plasma membrane which could inhibit recognition of an Avr protein. Delivery of the flax rust AvrM protein by the modified delivery system into transgenic tobacco leaves expressing the corresponding M resistance protein induced a strong HR, indicating that the system is capable of delivering a functional rust Avr protein. In a preliminary screen of effectors from the stem rust fungus Puccinia graminis f. sp. tritici, we identified one effector that induced a host genotype-specific HR in wheat. Thus, the modified AvrRpm1:effector-Pseudomonas fluorescens system is an effective tool for large-scale screening of pathogen effectors for recognition in wheat. PMID:24156769

Upadhyaya, Narayana M; Mago, Rohit; Staskawicz, Brian J; Ayliffe, Michael A; Ellis, Jeffrey G; Dodds, Peter N

2014-03-01

352

Factors influencing dust suppressant effectiveness  

SciTech Connect

Water sprays are a common method used to reduce particulate matter (PM) emissions. Various factors such as wettability, surface area coverage, fine particle engulfment rates, interparticle adhesion forces, suppressant penetration and suppressant longevity have all been suggested as critical factors in achieving effective PM control. However, it has not been established which of these factors are the most important. Experimental work indicated that suppressant penetration is the most critical of these factors. The length of time after application that suppressants were effective was also improved by using hygroscopic reagents that retained moisture to prevent evaporation. Maximizing suppressant penetration and improving suppressant longevity led to an average 86% reduction in PM10 concentrations in laboratory dust tower tests.

Copeland, C.R.; Eisele, T.C.; Chesney, D.J.; Kawatra, S.K. [Michigan Technology University, Houghton, MI (United States). Dept. of Chemical Engineering

2008-11-15

353

Secreted Fungal Effector Lipase Releases Free Fatty Acids to Inhibit Innate Immunity-Related Callose Formation during Wheat Head Infection[W][OPEN  

PubMed Central

The deposition of the (1,3)-?-glucan cell wall polymer callose at sites of attempted penetration is a common plant defense response to intruding pathogens and part of the plant’s innate immunity. Infection of the Fusarium graminearum disruption mutant ?fgl1, which lacks the effector lipase FGL1, is restricted to inoculated wheat (Triticum aestivum) spikelets, whereas the wild-type strain colonized the whole wheat spike. Our studies here were aimed at analyzing the role of FGL1 in establishing full F. graminearum virulence. Confocal laser-scanning microscopy revealed that the ?fgl1 mutant strongly induced the deposition of spot-like callose patches in vascular bundles of directly inoculated spikelets, while these callose deposits were not observed in infections by the wild type. Elevated concentrations of the polyunsaturated free fatty acids (FFAs) linoleic and ?-linolenic acid, which we detected in F. graminearum wild type-infected wheat spike tissue compared with ?fgl1-infected tissue, provided clear evidence for a suggested function of FGL1 in suppressing callose biosynthesis. These FFAs not only inhibited plant callose biosynthesis in vitro and in planta but also partially restored virulence to the ?fgl1 mutant when applied during infection of wheat spikelets. Additional FFA analysis confirmed that the purified effector lipase FGL1 was sufficient to release linoleic and ?-linolenic acids from wheat spike tissue. We concluded that these two FFAs have a major function in the suppression of the innate immunity-related callose biosynthesis and, hence, the progress of F. graminearum wheat infection.

Blumke, Antje; Falter, Christian; Herrfurth, Cornelia; Sode, Bjorn; Bode, Rainer; Schafer, Wilhelm; Feussner, Ivo; Voigt, Christian A.

2014-01-01

354

Interference suppression of SRS  

SciTech Connect

The theory of three-wave SRS is developed, which takes into account nonlinear dispersion of a medium for arbitrary phases of the pump waves at the input to the medium. The effect of interference suppression of SRS is predicted for values of the total phase of the three-wave pump (2n+1){pi} (n=0, {+-}1, {+-}2...), the effect being caused by the destructive interference of polarisations of the nonresonant dipole-allowed transitions. The relation between the contributions of the linear and nonlinear dispersions to the SRS is found. It is shown that at a sufficiently large wave detuning, the anti-Stokes wave amplitude experiences spatial oscillations. (nonlinear-optics phenomena)

Kochanov, V P [V.E. Zuev Institute of Atmospheric Optics, Siberian Branch, Russian Academy of Sciences, Tomsk (Russian Federation)

2011-01-24

355

Pressure suppression system  

DOEpatents

A pressure suppression system includes a containment vessel surrounding a reactor pressure vessel and defining a drywell therein containing a non-condensable gas. An enclosed wetwell pool is disposed inside the containment vessel, and an enclosed gravity driven cooling system (GDCS) pool is disposed above the wetwell pool in the containment vessel. The GDCS pool includes a plenum for receiving through an inlet the non-condensable gas carried with steam from the drywell following a loss-of-coolant accident (LOCA). A condenser is disposed in the GDCS plenum for condensing the steam channeled therein and to trap the non-condensable gas therein. A method of operation includes draining the GDCS pool following the LOCA and channeling steam released into the drywell following the LOCA into the GDCS plenum for cooling along with the non-condensable gas carried therewith for trapping the gas therein. 3 figs.

Gluntz, D.M.

1994-10-04

356

Pressure suppression system  

DOEpatents

A pressure suppression system includes a containment vessel surrounding a reactor pressure vessel and defining a drywell therein containing a non-condensable gas. An enclosed wetwell pool is disposed inside the containment vessel, and an enclosed gravity driven cooling system (GDCS) pool is disposed above the wetwell pool in the containment vessel. The GDCS pool includes a plenum for receiving through an inlet the non-condensable gas carried with steam from the drywell following a loss-of-coolant accident (LOCA). A condenser is disposed in the GDCS plenum for condensing the steam channeled therein and to trap the non-condensable gas therein. A method of operation includes draining the GDCS pool following the LOCA and channeling steam released into the drywell following the LOCA into the GDCS plenum for cooling along with the non-condensable gas carried therewith for trapping the gas therein.

Gluntz, Douglas M. (San Jose, CA)

1994-01-01

357

Lipidation by the Host Prenyltransferase Machinery Facilitates Membrane Localization of Legionella pneumophila Effector Proteins*  

PubMed Central

The intracellular human pathogen Legionella pneumophila translocates multiple proteins in the host cytosol known as effectors, which subvert host cellular processes to create a membrane-bound organelle that supports bacterial replication. It was observed that several Legionella effectors encode a prototypical eukaryotic prenylation CAAX motif (where C represents a cysteine residue and A denotes an aliphatic amino acid). These bacterial motifs mediated posttranslational modification of effector proteins resulting in the addition of either a farnesyl or geranylgeranyl isoprenyl lipid moiety to the cysteine residue of the CAAX tetrapeptide. Lipidation enhanced membrane affinity for most Legionella CAAX motif proteins and facilitated the localization of these effector proteins to host organelles. Host farnesyltransferase and class I geranylgeranyltransferase were both involved in the lipidation of the Legionella CAAX motif proteins. Perturbation of the host prenylation machinery during infection adversely affected the remodeling of the Legionella-containing vacuole. Thus, these data indicate that Legionella utilize the host prenylation machinery to facilitate targeting of effector proteins to membrane-bound organelles during intracellular infection.

Ivanov, Stanimir S.; Charron, Guillaume; Hang, Howard C.; Roy, Craig R.

2010-01-01

358

A knockout approach to understanding CD8+ cell effector mechanisms in adaptive immunity to Listeria monocytogenes.  

PubMed

In the described experimental approach, we use an attenuated LM strain to evoke LM specific CD8+ T cell responses. In this fashion, we can immunize immunocompromised gene knockout mice, that would succumb to low level infection with virulent LM. We then generate antigen matched, LM-specific CD8+ T cell lines from wild-type and gene knockout mice, and compare their capacity to provide immunity to LM infection in vivo. To date, our results demonstrate that CD8+ T cell-derived IFN-gamma and TNF are not required effector functions. Perforin deficiency has an impact on CD8+ T cell immunity but our studies provide strong evidence for the existence of perforin independent pathways of CD8+ T cell immunity to LM. To assess the potential for redundancy in effector mechanisms, we have generated mice deficient in both perforin and IFN-gamma and are developing mice deficient in perforin and TNF. By removing the major CD8+ T cell effector mechanisms, singly and in combination, we will eventually determine whether immunity to LM can be provided by redundant effector pathways or if novel effector mechanisms exist beyond our current knowledge. The generation of MHC matched, single and double knockout mice, will also aid in continuing studies to analyze the role of these molecules in resistance to in vivo infection. PMID:10631568

Harty, J T; White, D

1999-12-01

359

RASSF4/AD037 is a potential ras effector/tumor suppressor of the RASSF family.  

PubMed

Activated Ras proteins interact with a broad range of effector proteins to induce a diverse series of biological consequences. Although typically associated with enhanced growth and transformation, activated Ras may also induce growth antagonistic effects such as senescence or apoptosis. It is now apparent that some of the growth-inhibitory properties of Ras are mediated via the RASSF family of Ras effector/tumor suppressors. To date, four members of this family have been identified (Nore1, RASSF1, RASSF2, and RASSF3). We now identify a fifth member of this group, RASSF4 (AD037). RASSF4 shows approximately 25% identity with RASSF1A and 60% identity with RASSF2. RASSF4 binds directly to activated K-Ras in a GTP-dependent manner via the effector domain, thus exhibiting the basic properties of a Ras effector. Overexpression of RASSF4 induces Ras-dependent apoptosis in 293-T cells and inhibits the growth of human tumor cell lines. Although broadly expressed in normal tissue, RASSF4 is frequently down-regulated by promoter methylation in human tumor cells. Thus, RASSF4 appears to be a new member of the RASSF family of potential Ras effector/tumor suppressors. PMID:15574778

Eckfeld, Kristin; Hesson, Luke; Vos, Michele D; Bieche, Ivan; Latif, Farida; Clark, Geoffrey J

2004-12-01

360

454 Genome sequencing of Pseudoperonospora cubensis reveals effector proteins with a QXLR translocation motif.  

PubMed

Pseudoperonospora cubensis is a biotrophic oomycete pathogen that causes downy mildew of cucurbits, a devastating foliar disease threatening cucurbit production worldwide. We sequenced P. cubensis genomic DNA using 454 pyrosequencing and obtained random genomic sequences covering approximately 14% of the genome, thus providing the first set of useful genomic sequence information for P. cubensis. Using bioinformatics approaches, we identified 32 putative RXLR effector proteins. Interestingly, we also identified 29 secreted peptides with high similarity to RXLR effectors at the N-terminal translocation domain, yet containing an R-to-Q substitution in the first residue of the translocation motif. Among these, a family of QXLR-containing proteins, designated as PcQNE, was confirmed to have a functional signal peptide and was further characterized as being localized in the plant nucleus. Internalization of secreted PcQNE into plant cells requires the QXLR-EER motif. This family has a large number of near-identical copies within the P. cubensis genome, is under diversifying selection at the C-terminal domain, and is upregulated during infection of plants, all of which are common characteristics of characterized oomycete effectors. Taken together, the data suggest that PcQNE are bona fide effector proteins with a QXLR translocation motif, and QXLR effectors are prevalent in P. cubensis. Furthermore, the massive duplication of PcQNE suggests that they might play pivotal roles in pathogen fitness and pathogenicity. PMID:21261462

Tian, Miaoying; Win, Joe; Savory, Elizabeth; Burkhardt, Alyssa; Held, Michael; Brandizzi, Federica; Day, Brad

2011-05-01

361

Coiled-coil domains enhance the membrane association of Salmonella type III effectors  

PubMed Central

Summary Coiled-coil domains in eukaryotic and prokaryotic proteins contribute to diverse structural and regulatory functions. Here we have used in silico analysis to predict which proteins in the proteome of the enteric pathogen, Salmonella enterica serovar Typhimurium, harbor coiled-coil domains. We found that coiled-coil domains are especially prevalent in virulence-associated proteins, including type III effectors. Using SopB as a model coiled-coil domain type III effector, we have investigated the role of this motif in various aspects of effector function including chaperone binding, secretion and translocation, protein stability, localization and biological activity. Compared to wild type SopB, SopB coiled-coil mutants were unstable, both inside bacteria and after translocation into host cells. In addition, the putative coiled-coil domain was required for the efficient membrane association of SopB in host cells. Since many other Salmonella effectors were predicted to contain coiled-coil domains, we also investigated the role of this motif in their intracellular targeting in mammalian cells. Mutation of the predicted coiled-coil domains in PipB2, SseJ and SopD2 also eliminated their membrane localization in mammalian cells. These findings suggest that coiled-coil domains may represent a common membrane-targeting determinant for Salmonella type III effectors.

Knodler, Leigh A.; Ibarra, J. Antonio; Perez-Rueda, Ernesto; Yip, Calvin K.; Steele-Mortimer, Olivia

2012-01-01

362

Myeloid cells as effector cells for monoclonal antibody therapy of cancer.  

PubMed

Monoclonal antibodies (mAbs) have become an important addition to chemo- and/or radiotherapy for the treatment of cancer. They have multiple effector functions that can lead to eradication of tumor, including induction of apoptosis, growth inhibition, and initiation of complement-dependent lysis. Furthermore, mAbs can recruit immune effector cells. Traditionally, natural killer cells have been considered as the main effector cell population in mAb-mediated tumor killing. Myeloid cells have potent cytotoxic ability, as well. Monocytes and macrophages have been shown to induce antibody-dependent cytotoxicity and phagocytosis of tumor cells in the presence of IgG anti-tumor mAb. Furthermore, neutrophils are the most abundant population of circulating white blood cells, and as such may constitute a formidable source of effector cells. However, when targeting neutrophils for tumor therapy, antibodies of the IgA subclass may be more effective. This article focuses on enlisting myeloid effector cells for mAb-based immunotherapy of cancer. Additionally, methods to study mAb-dependent phagocytosis of tumor cells by macrophages are compared. PMID:23811299

Braster, Rens; O'Toole, Tom; van Egmond, Marjolein

2014-01-01

363

Wind Tunnel Test of an RPV with Shape-Change Control Effector and Sensor Arrays  

NASA Technical Reports Server (NTRS)

A variety of novel control effector concepts have recently emerged that may enable new approaches to flight control. In particular, the potential exists to shift the composition of the typical aircraft control effector suite from a small number of high authority, specialized devices (rudder, aileron, elevator, flaps), toward larger numbers of smaller, less specialized, distributed device arrays. The concept envisions effector and sensor networks composed of relatively small high-bandwidth devices able to simultaneously perform a variety of control functions using feedback from disparate data sources. To investigate this concept, a remotely piloted flight vehicle has been equipped with an array of 24 trailing edge shape-change effectors and associated pressure measurements. The vehicle, called the Multifunctional Effector and Sensor Array (MESA) testbed, was recently tested in NASA Langley's 12-ft Low Speed wind tunnel to characterize its stability properties, control authorities, and distributed pressure sensitivities for use in a dynamic simulation prior to flight testing. Another objective was to implement and evaluate a scheme for actively controlling the spanwise pressure distribution using the shape-change array. This report describes the MESA testbed, design of the pressure distribution controller, and results of the wind tunnel test.

Raney, David L.; Cabell, Randolph H.; Sloan, Adam R.; Barnwell, William G.; Lion, S. Todd; Hautamaki, Bret A.

2004-01-01

364

The Legionella pneumophila IcmSW Complex Interacts with Multiple Dot/Icm Effectors to Facilitate Type IV Translocation  

PubMed Central

Many Gram-negative pathogens use a type IV secretion system (T4SS) to deliver effector proteins into eukaryotic host cells. The fidelity of protein translocation depends on the efficient recognition of effector proteins by the T4SS. Legionella pneumophila delivers a large number of effector proteins into eukaryotic cells using the Dot/Icm T4SS. How the Dot/Icm system is able to recognize and control the delivery of effectors is poorly understood. Recent studies suggest that the IcmS and IcmW proteins interact to form a stable complex that facilitates translocation of effector proteins by the Dot/Icm system by an unknown mechanism. Here we demonstrate that the IcmSW complex is necessary for the productive translocation of multiple Dot/Icm effector proteins. Effector proteins that were able to bind IcmSW in vitro required icmS and icmW for efficient translocation into eukaryotic cells during L. pneumophila infection. We identified regions in the effector protein SidG involved in icmSW-dependent translocation. Although the full-length SidG protein was translocated by an icmSW-dependent mechanism, deletion of amino terminal regions in the SidG protein resulted in icmSW-independent translocation, indicating that the IcmSW complex is not contributing directly to recognition of effector proteins by the Dot/Icm system. Biochemical and genetic studies showed that the IcmSW complex interacts with a central region of the SidG protein. The IcmSW interaction resulted in a conformational change in the SidG protein as determined by differences in protease sensitivity in vitro. These data suggest that IcmSW binding to effectors could enhance effector protein delivery by mediating a conformational change that facilitates T4SS recognition of a translocation domain located in the carboxyl region of the effector protein.

Cambronne, Eric D; Roy, Craig R

2007-01-01

365

Effector genes of Xanthomonas axonopodis pv. vesicatoria promote transmission and enhance other fitness traits in the field.  

PubMed Central

Establishing durable disease resistance in agricultural crops, where much of the plant defense is provided through effector-R gene interactions, is complicated by the ability of pathogens to overcome R gene resistance by losing the corresponding effector gene. Many proposed methods to maintain disease resistance in the field depend on the idea that effector gene loss results in a fitness cost to the pathogen. In this article we test for fitness costs of effector gene function loss. We created directed knockouts of up to four effector genes from the bacterial plant pathogen Xanthomonas axonopodis pv. vesicatoria (Xav) and examined the effect of the loss of a functional gene product on several important fitness parameters in the field. These traits included transmission, lesion development, and epiphytic survival. We found that the products of all four effector genes had significant and often additive effects on fitness traits. Additional greenhouse tests revealed costs of effector gene loss on in planta growth and further showed that the effects on lesion development were separable from the effects on growth. Observable fitness effects of the three plasmid-borne effector genes were dependent upon the loss of functional avrBs2, indicating that complex functional interactions exist among effector genes with Xav.

Wichmann, Gale; Bergelson, Joy

2004-01-01

366

Plasticity in programming of effector and memory CD8+ T-cell formation  

PubMed Central

Summary CD8+ T cells (also called cytotoxic T lymphocytes) play a major role in protective immunity against many infectious pathogens and can eradicate malignant cells. The path from naive precursor to effector and memory CD8+ T-cell development begins with interactions between matured antigen-bearing dendritic cells (DCs) and antigen-specific naive T-cell clonal precursors. By integrating differences in antigenic, costimulatory, and inflammatory signals, a developmental program is established that governs many key parameters associated with the ensuing response, including the extent and magnitude of clonal expansion, the functional capacities of the effector cells, and the size of the memory pool that survives after the contraction phase. In this review, we discuss the multitude of signals that drive effector and memory CD8+ T-cell differentiation and how the differences in the nature of these signals contribute to the diversity of CD8+ T-cell responses.

Arens, Ramon; Schoenberger, Stephen P.

2010-01-01

367

Effector recruitment method to study spatially regulated activation of Ras and Rho GTPases.  

PubMed

Ras and Rho family GTPases control a wide variety of cellular processes, and the signaling downstream of these GTPases is influenced by their subcellular localization when activated. Since only a minority of total cellular GTPases is active, observation of the total subcellular distribution of GTPases does not reveal where active GTPases are localized. In this chapter, we describe the use of effector recruitment assays to monitor the subcellular localization of active Ras and Rho family GTPases. The recruitment assay relies on preferential binding of downstream effectors to active GTPases versus inactive GTPases. Tagging the GTPase-binding-domain (GBD) of a downstream effector with a fluorescent protein produces a probe that is recruited to compartments where GTPases are active. We describe an example of a recruitment assay using the GBD of PAK1 to monitor Rac1 activity and explain how the assay can be expanded to determine the subcellular localization of activation of other GTPases. PMID:24470032

Huff, Lauren P; DeCristo, Molly J; Cox, Adrienne D

2014-01-01

368

Metalloprotease type III effectors that specifically cleave JNK and NF-?B  

PubMed Central

Two major arms of the inflammatory response are the NF-?B and c-Jun N-terminal kinase (JNK) pathways. Here, we show that enteropathogenic Escherichia coli (EPEC) employs the type III secretion system to target these two signalling arms by injecting host cells with two effector proteins, NleC and NleD. We provide evidence that NleC and NleD are Zn-dependent endopeptidases that specifically clip and inactivate RelA (p65) and JNK, respectively, thus blocking NF-?B and AP-1 activation. We show that NleC and NleD co-operate and complement other EPEC effectors in accomplishing maximal inhibition of IL-8 secretion. This is a remarkable example of a pathogen using multiple effectors to manipulate systematically the host inflammatory response signalling network.

Baruch, Kobi; Gur-Arie, Lihi; Nadler, Chen; Koby, Simi; Yerushalmi, Gal; Ben-Neriah, Yinon; Yogev, Orli; Shaulian, Eitan; Guttman, Chen; Zarivach, Raz; Rosenshine, Ilan

2011-01-01

369

Volumetric reach comparison of possible end-effectors for the articulated transporter and manipulator system  

SciTech Connect

The goal of this research was to investigate the performance of the Articulated Transporter and Manipulator System (ATMS) during various tasks relative to the choice of wrist/end-effector configuration. The approach taken was to generate computer graphics-aided three-dimensional interactive application (CATIA) system-based models of four wrist/end-effector combinations and consider the volumetric reach of each of these configurations based on the capacity of the ATMS. The results indicate that a simple, lightweight end-effector provides a greater volumetric reach. The greatest variation presented herein is {approximately}40% when comparing a 7-degree-of-freedom (DOF) dexterous arm with a simple 3-DOF arm; however, the benefit of increasing volumetric reach by only 40% by using a simple arm may be outweighed by the loss of dexterity. 10 refs., 5 figs., 3 tabs.

Kress, R.L.; Babcock, S.M.; Hamel, W.R. (Oak Ridge National Lab., TN (USA)); Bills, K.C. (Martin Marietta Energy Systems, Inc., Oak Ridge, TN (USA))

1990-01-01

370

Toluene 4-Monooxygenase and its Complex with Effector Protein T4moD  

SciTech Connect

Toluene 4-monooxygenase (T4MO) is a multiprotein diiron enzyme complex that catalyzes the regiospecific oxidation of toluene to p-cresol. Catalytic function requires the presence of a small protein, called the effector protein. Effector protein exerts substantial control on the diiron hydroxylase catalytic cycle through protein-protein interactions. High-resolution crystal structures of the stoichometric hydroxylase and effector protein complex described here reveal how protein-protein interactions and reduction of the diiron center produce an active site configuration poised for reaction with O{sub 2}. Further information from crystal structures of mutated isoforms of the hydroxylase and a peroxo adduct is combined with catalytic results to give a fuller picture of the geometry of the enzyme-substrate complex used for the high fidelity oxidation of hydrocarbon substrates.

Bailey, Lucas J.; Fox, Brian G. (UW)

2012-10-16

371

Suppression of Autoimmune Retinal Inflammation by an Antiangiogenic Drug  

PubMed Central

Chronic and recurrent uveitis account for approximately 10% of legal blindness in the western world. Autoimmune uveitis is driven by activated CD4+ T cells that differentiate into effector T helper cells (Th1, Th2, and Th17) which release proinflammatory cytokines that damage the retina. In this study we investigated the effect of the methionine aminopeptidase 2 (MetAP2) inhibitor, Lodamin, on T cell activation and differentiation. MetAp2 is an enzyme which regulates cellular protein synthesis and is highly expressed in T cells. Lodamin was found to suppress T cell receptor (TCR) mediated T cell proliferation and reduced the production of Th1 and Th17 cells. Further, Lodamin suppressed overall inflammation in the mouse model of experimental autoimmune uveitis (EAU) by a six fold. This effect was attributed in part to a reduction in retinal proinflammatory cytokines, down regulation of MetAP2 expression in purified lymph node CD4+ T cells, and a general normalization of the systemic immune reaction.

Bazinet, Lauren; D'Amato, Robert J.

2013-01-01

372

Regulatory role of suppressive motifs from commensal DNA  

PubMed Central

The microbiota contributes to the induction of both effector and regulatory responses in the gastrointestinal tract. However, the mechanisms controlling these distinct properties remain poorly understood. We previously showed that commensal DNA promotes intestinal immunity. Here, we find that the capacity of bacterial DNA to stimulate immune responses is species specific and correlated with the frequency of motifs known to exert immunosuppressive function. In particular, we show that the DNA of Lactobacillus species, including various probiotics, are enriched in suppressive motifs able to inhibit lamina propria DC activation. In addition, immunosuppressive oligonucleotides sustain Treg cell conversion during inflammation and limit pathogen-induced immunopathology and colitis. Altogether, our findings identify DNA suppressive motifs as a molecular ligand expressed by commensals and support the idea that a balance between stimulatory and regulatory DNA motifs contributes to the induction of controlled immune responses in the GI tract and gut immune homeostasis. Further, our findings suggest that the endogenous regulatory capacity of DNA motifs enriched in some commensal bacteria could be exploited for therapeutic purposes.

Bouladoux, N.; Hall, J.A.; Grainger, J. R.; dos Santos, L. M.; Kann, M.G.; Nagarajan, V.; Verthelyi, D.; Belkaid, Y.

2012-01-01

373

Genetically distinct pathways guide effector export through the type VI secretion system.  

PubMed

Bacterial secretion systems often employ molecular chaperones to recognize and facilitate export of their substrates. Recent work demonstrated that a secreted component of the type VI secretion system (T6SS), haemolysin co-regulated protein (Hcp), binds directly to effectors, enhancing their stability in the bacterial cytoplasm. Herein, we describe a quantitative cellular proteomics screen for T6S substrates that exploits this chaperone-like quality of Hcp. Application of this approach to the Hcp secretion island I-encoded T6SS (H1-T6SS) of Pseudomonas aeruginosa led to the identification of a novel effector protein, termed Tse4 (type VI secretion exported 4), subsequently shown to act as a potent intra-specific H1-T6SS-delivered antibacterial toxin. Interestingly, our screen failed to identify two predicted H1-T6SS effectors, Tse5 and Tse6, which differ from Hcp-stabilized substrates by the presence of toxin-associated PAAR-repeat motifs and genetic linkage to members of the valine-glycine repeat protein G (vgrG) genes. Genetic studies further distinguished these two groups of effectors: Hcp-stabilized effectors were found to display redundancy in interbacterial competition with respect to the requirement for the two H1-T6SS-exported VgrG proteins, whereas Tse5 and Tse6 delivery strictly required a cognate VgrG. Together, we propose that interaction with either VgrG or Hcp defines distinct pathways for T6S effector export. PMID:24589350

Whitney, John C; Beck, Christina M; Goo, Young Ah; Russell, Alistair B; Harding, Brittany N; De Leon, Justin A; Cunningham, David A; Tran, Bao Q; Low, David A; Goodlett, David R; Hayes, Christopher S; Mougous, Joseph D

2014-05-01

374

An Alternative to Thought Suppression?  

ERIC Educational Resources Information Center

Comments on the original article, "Setting free the bears: Escape from thought suppression," by D. M. Wegner (see record 2011-25622-008). While Wegner supposed that we might have to learn to live with bad thoughts, the present author discusses the use of imagination and guided imagery as an alternative to forced thought suppression.

Boice, Robert

2012-01-01

375

Paradoxical effects of thought suppression  

Microsoft Academic Search

In a first experiment, subjects verbalizing the stream of consciousness for a 5-min period were asked to try not to think of a white bear, but to ring a bell in case they did. As indicated both by mentions and by bell rings, they were unable to suppress the thought as instructed. On being asked after this suppression task to

Daniel M. Wegner; David J. Schneider; Samuel R. Carter III; Teri L. White

1987-01-01

376

Thought suppression in spider phobia  

Microsoft Academic Search

The current study examined the role of thought suppression in spider phobia. Spider phobic (n = 41) and non-phobic (n = 40) subjects were asked to monitor their thoughts for three 5 min periods. During the first period, all subjects were instructed to “think about anything”. During the second period, half of the subjects received suppression instructions (i.e., subjects were

Peter Muris; Harald Merckelbach; Robert Horselenberg; Madelon Sijsenaar; Ina Leeuw

1997-01-01

377

Diode recovery current suppression circuit  

Microsoft Academic Search

There are many known methods for diode recovery current suppression. Most of them have limited application-they can work only on certain types of power converters. Other known solutions work only in cases of certain input and\\/or output conditions. Many involve complex circuits and active devices. In this paper, a simple efficient way to suppress recovery diode current is shown. It

G. Mantov; K. Wallace

2000-01-01

378

STRV Cryocooler Tip Motion Suppression  

NASA Technical Reports Server (NTRS)

The Space Technology Research Vehicle (STRV-1b) scheduled to fly at the beginning of June 1994, has a cryocooler vibration suppression experiment aboard doing motion suppression of the tip of the coldfinger. STRV-1b is a bread box sized satellite to be launched on the next flight of the Ariane-4.

Glaser, R.; Ross, R. G., Jr.; Johnson, D. L.

1994-01-01

379

Searching algorithm for type IV secretion system effectors 1.0: a tool for predicting type IV effectors and exploring their genomic context  

PubMed Central

Type IV effectors (T4Es) are proteins produced by pathogenic bacteria to manipulate host cell gene expression and processes, divert the cell machinery for their own profit and circumvent the immune responses. T4Es have been characterized for some bacteria but many remain to be discovered. To help biologists identify putative T4Es from the complete genome of ?- and ?-proteobacteria, we developed a Perl-based command line bioinformatics tool called S4TE (searching algorithm for type-IV secretion system effectors). The tool predicts and ranks T4E candidates by using a combination of 13 sequence characteristics, including homology to known effectors, homology to eukaryotic domains, presence of subcellular localization signals or secretion signals, etc. S4TE software is modular, and specific motif searches are run independently before ultimate combination of the outputs to generate a score and sort the strongest T4Es candidates. The user keeps the possibility to adjust various searching parameters such as the weight of each module, the selection threshold or the input databases. The algorithm also provides a GC% and local gene density analysis, which strengthen the selection of T4E candidates. S4TE is a unique predicting tool for T4Es, finding its utility upstream from experimental biology.

Meyer, Damien F.; Noroy, Christophe; Moumene, Amal; Raffaele, Sylvain; Albina, Emmanuel; Vachiery, Nathalie

2013-01-01

380

Searching algorithm for type IV secretion system effectors 1.0: a tool for predicting type IV effectors and exploring their genomic context.  

PubMed

Type IV effectors (T4Es) are proteins produced by pathogenic bacteria to manipulate host cell gene expression and processes, divert the cell machinery for their own profit and circumvent the immune responses. T4Es have been characterized for some bacteria but many remain to be discovered. To help biologists identify putative T4Es from the complete genome of ?- and ?-proteobacteria, we developed a Perl-based command line bioinformatics tool called S4TE (searching algorithm for type-IV secretion system effectors). The tool predicts and ranks T4E candidates by using a combination of 13 sequence characteristics, including homology to known effectors, homology to eukaryotic domains, presence of subcellular localization signals or secretion signals, etc. S4TE software is modular, and specific motif searches are run independently before ultimate combination of the outputs to generate a score and sort the strongest T4Es candidates. The user keeps the possibility to adjust various searching parameters such as the weight of each module, the selection threshold or the input databases. The algorithm also provides a GC% and local gene density analysis, which strengthen the selection of T4E candidates. S4TE is a unique predicting tool for T4Es, finding its utility upstream from experimental biology. PMID:23945940

Meyer, Damien F; Noroy, Christophe; Moumène, Amal; Raffaele, Sylvain; Albina, Emmanuel; Vachiéry, Nathalie

2013-11-01

381

In active relapsing-remitting multiple sclerosis, effector T cell resistance to adaptive T(regs) involves IL-6-mediated signaling.  

PubMed

Patients with multiple sclerosis (MS) manifest demyelination and neurodegeneration mediated in part by CD4(+) T cells that have escaped regulation. Resistance of pathogenic effector T cells (T(effs)) to suppression by regulatory T cells (T(regs)) has been demonstrated in several autoimmune diseases. Although impairment in T(reg) number and function has been observed in relapsing-remitting MS (RRMS), T(eff) resistance has not been well studied in this disease. To determine whether T(eff) resistance contributes to failed tolerance in RRMS, we performed T(reg) suppression assays with T(effs) from either RRMS patients not on immunomodulatory therapy or healthy individuals. T(eff) resistance was present in the T(effs) of RRMS patients with active disease but not from patients with inactive disease. Interleukin-6 (IL-6) and phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) promote T(eff) resistance to T(regs), and we found an increase in IL-6 receptor ? (IL-6R?) expression and elevated IL-6 signaling as measured by pSTAT3 in our RRMS subjects. Further, the impaired suppression in RRMS subjects correlated with an increase in IL-6R? surface expression on CD4(+) T cells and an increase in pSTAT3 in response to IL-6. To address whether the enhanced pSTAT3 contributed to T(eff) resistance in active RRMS patients, we blocked STAT3 phosphorylation and found that impaired suppression was reversed. Therefore, enhanced IL-6R signaling through pSTAT3, in some cases through increased IL-6R? expression, contributed to T(eff) resistance in active RRMS. These markers may aid in determining disease activity and responsiveness to immunomodulatory therapies in RRMS. PMID:23363979

Schneider, Anya; Long, Sarah Alice; Cerosaletti, Karen; Ni, Chester T; Samuels, Peter; Kita, Mariko; Buckner, Jane Hoyt

2013-01-30