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Search Results: 1 - 10 of 464271 matches for " Michelle A. Dunstone "
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A New Model for Pore Formation by Cholesterol-Dependent Cytolysins
Cyril F. Reboul,James C. Whisstock,Michelle A. Dunstone
PLOS Computational Biology , 2014, DOI: doi/10.1371/journal.pcbi.1003791
Abstract: Cholesterol Dependent Cytolysins (CDCs) are important bacterial virulence factors that form large (200–300 ?) membrane embedded pores in target cells. Currently, insights from X-ray crystallography, biophysical and single particle cryo-Electron Microscopy (cryo-EM) experiments suggest that soluble monomers first interact with the membrane surface via a C-terminal Immunoglobulin-like domain (Ig; Domain 4). Membrane bound oligomers then assemble into a prepore oligomeric form, following which the prepore assembly collapses towards the membrane surface, with concomitant release and insertion of the membrane spanning subunits. During this rearrangement it is proposed that Domain 2, a region comprising three β-strands that links the pore forming region (Domains 1 and 3) and the Ig domain, must undergo a significant yet currently undetermined, conformational change. Here we address this problem through a systematic molecular modeling and structural bioinformatics approach. Our work shows that simple rigid body rotations may account for the observed collapse of the prepore towards the membrane surface. Support for this idea comes from analysis of published cryo-EM maps of the pneumolysin pore, available crystal structures and molecular dynamics simulations. The latter data in particular reveal that Domains 1, 2 and 4 are able to undergo significant rotational movements with respect to each other. Together, our data provide new and testable insights into the mechanism of pore formation by CDCs.
Perforin evolved from a gene duplication of MPEG1, followed by a complex pattern of gene gain and loss within Euteleostomi
Michael E D'Angelo, Michelle A Dunstone, James C Whisstock, Joseph A Trapani, Phillip I Bird
BMC Evolutionary Biology , 2012, DOI: 10.1186/1471-2148-12-59
Abstract: We identified orthologs and homologs of human perforin in all but one species analysed from Euteleostomi, and present evidence for an earlier ortholog in Gnathostomata but not in more primitive chordates. In placental mammals perforin is a single copy gene, but there are multiple perforin genes in all lineages predating marsupials, except birds. Our comparisons of these many-to-one homologs of human perforin show that they mainly arose from lineage-specific gene duplications in multiple taxa, suggesting acquisition of new roles or different modes of regulation. We also present evidence that perforin arose from duplication of the ancient MPEG1 gene, and that it shares a common ancestor with the functionally related complement proteins.The evolution of perforin in vertebrates involved a complex pattern of gene, as well as intron, gain and loss. The primordial perforin gene arose at least 500 million years ago, at around the time that the major histocompatibility complex-T cell receptor antigen recognition system was established. As it is absent from primitive chordates and invertebrates, cytotoxic cells from these lineages must possess a different effector molecule or cytotoxic mechanism.
Screening of 71 P. multocida Proteins for Protective Efficacy in a Fowl Cholera Infection Model and Characterization of the Protective Antigen PlpE
Tamás Hatfaludi, Keith Al-Hasani, Lan Gong, John D. Boyce, Mark Ford, Ian W. Wilkie, Noelene Quinsey, Michelle A. Dunstone, David E. Hoke, Ben Adler
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0039973
Abstract: Background There is a strong need for a recombinant subunit vaccine against fowl cholera. We used a reverse vaccinology approach to identify putative secreted or cell surface associated P. multocida proteins that may represent potential vaccine candidate antigens. Principal Findings A high-throughput cloning and expression protocol was used to express and purify 71 recombinant proteins for vaccine trials. Of the 71 proteins tested, only one, PlpE in denatured insoluble form, protected chickens against fowl cholera challenge. PlpE also elicited comparable levels of protection in mice. PlpE was localized by immunofluorescence to the bacterial cell surface, consistent with its ability to elicit a protective immune response. To explore the role of PlpE during infection and immunity, a plpE mutant was generated. The plpE mutant strain retained full virulence for mice. Conclusion These studies show that PlpE is a surface exposed protein and was the only protein of 71 tested that was able to elicit a protective immune response. However, PlpE is not an essential virulence factor. This is the first report of a denatured recombinant protein stimulating protection against fowl cholera.
Prevention of Cytotoxic T Cell Escape Using a Heteroclitic Subdominant Viral T Cell Determinant
Noah S. Butler equal contributor,Alex Theodossis equal contributor,Andrew I. Webb,Roza Nastovska,Sri Harsha Ramarathinam,Michelle A. Dunstone,Jamie Rossjohn,Anthony W. Purcell ,Stanley Perlman
PLOS Pathogens , 2008, DOI: 10.1371/journal.ppat.1000186
Abstract: High affinity antigen-specific T cells play a critical role during protective immune responses. Epitope enhancement can elicit more potent T cell responses and can subsequently lead to a stronger memory pool; however, the molecular basis of such enhancement is unclear. We used the consensus peptide-binding motif for the Major Histocompatibility Complex molecule H-2Kb to design a heteroclitic version of the mouse hepatitis virus-specific subdominant S598 determinant. We demonstrate that a single amino acid substitution at a secondary anchor residue (Q to Y at position 3) increased the stability of the engineered determinant in complex with H-2Kb. The structural basis for this enhanced stability was associated with local alterations in the pMHC conformation as a result of the Q to Y substitution. Recombinant viruses encoding this engineered determinant primed CTL responses that also reacted to the wildtype epitope with significantly higher functional avidity, and protected against selection of virus mutated at a second CTL determinant and consequent disease progression in persistently infected mice. Collectively, our findings provide a basis for the enhanced immunogenicity of an engineered determinant that will serve as a template for guiding the development of heteroclitic T cell determinants with applications in prevention of CTL escape in chronic viral infections as well as in tumor immunity.
The Type III Effectors NleE and NleB from Enteropathogenic E. coli and OspZ from Shigella Block Nuclear Translocation of NF-κB p65
Hayley J. Newton equal contributor,Jaclyn S. Pearson equal contributor,Luminita Badea,Michelle Kelly,Mark Lucas,Gavan Holloway,Kylie M. Wagstaff,Michelle A. Dunstone,Joan Sloan,James C. Whisstock,James B. Kaper,Roy M. Robins-Browne,David A. Jans,Gad Frankel,Alan D. Phillips,Barbara S. Coulson,Elizabeth L. Hartland
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1000898
Abstract: Many bacterial pathogens utilize a type III secretion system to deliver multiple effector proteins into host cells. Here we found that the type III effectors, NleE from enteropathogenic E. coli (EPEC) and OspZ from Shigella, blocked translocation of the p65 subunit of the transcription factor, NF-κB, to the host cell nucleus. NF-κB inhibition by NleE was associated with decreased IL-8 expression in EPEC-infected intestinal epithelial cells. Ectopically expressed NleE also blocked nuclear translocation of p65 and c-Rel, but not p50 or STAT1/2. NleE homologues from other attaching and effacing pathogens as well OspZ from Shigella flexneri 6 and Shigella boydii, also inhibited NF-κB activation and p65 nuclear import; however, a truncated form of OspZ from S. flexneri 2a that carries a 36 amino acid deletion at the C-terminus had no inhibitory activity. We determined that the C-termini of NleE and full length OspZ were functionally interchangeable and identified a six amino acid motif, IDSY(M/I)K, that was important for both NleE- and OspZ-mediated inhibition of NF-κB activity. We also established that NleB, encoded directly upstream from NleE, suppressed NF-κB activation. Whereas NleE inhibited both TNFα and IL-1β stimulated p65 nuclear translocation and IκB degradation, NleB inhibited the TNFα pathway only. Neither NleE nor NleB inhibited AP-1 activation, suggesting that the modulatory activity of the effectors was specific for NF-κB signaling. Overall our data show that EPEC and Shigella have evolved similar T3SS-dependent means to manipulate host inflammatory pathways by interfering with the activation of selected host transcriptional regulators.
Metapopulation approach to assess survival of Oncifelis guigna in fragmented forests of central Chile: A theoretical model
Gerardo Acosta-Jamett,Javier A. Simonetti,Ramiro O. Bustamante,Nigel Dunstone
Mastozoolog?-a neotropical , 2003,
Abstract: Aproximación metapoblacional para determinar la sobrevivencia de Oncifelis guigna en bosques frragmentados de Chile central: un modelo teórico. La pérdida y fragmentación de hábitat han sido identificados como las principales amenazas para la sobrevivencia de Oncifelis guigna, felino endémico de los bosques templados del sur de Chile y Argentina. Esta especie ha sido descrita como restringida a estos bosques nativos. La creciente reducción y fragmentación de este hábitat, especialmente en la cordillera de la costa en Chile central, constituye una amenaza a su sobrevivencia. Actualmente, O. guigna es considerado en peligro de extinción en Chile. En un ejercicio teórico utilizamos una aproximación metapoblacional para inferir la probabilidad de extinción de las poblaciones protegidas en parques y reservas de la zona costera de Chile central entre los 35o 30 y 38o S. Empleamos la tipificación de S. Harrison para determinar el tipo de metapoblación dependiendo del tama o y grado de aislamiento de las poblaciones existentes en los fragmentos de bosques. De este modo, identificamos que existirían 11 potenciales metapoblaciones, de las cuales ocho serían metapoblaciones en no-equilibrio (extintas o cercanas a la extinción), una del tipo continente-isla y dos no serían clasificables según la metodología empleada. La única metapoblación viable en la actualidad correspondería a la del Parque Nacional Nahuelbuta, la cual incluye los fragmentos remanentes vecinos al parque. Por otra parte, la otra metapoblación compuesta por las Reservas Nacionales Los Queules y Los Ruiles podría mantenerse si se instalara un activo plan de protección de los fragmentos aleda os a éstas. Sin ellos, ambas poblaciones tenderían a la extinción tarde o temprano. Mediante este modelo, podemos inferir que las poblaciones de O. guigna en la zona central requerirían de la mantención de los peque os fragmentos de bosque nativo ubicados fuera de las áreas silvestres protegidas. Finalmente hacemos hincapié en la necesidad de obtener más datos de la biología de esta especie para calibrar nuestro modelo.
Status and Distribution of Otters In the Amboro National Park, Bolivia
Dunstone N.,Strachan R.
IUCN Otter Specialist Group Bulletin , 1988,
Abstract: Otters have not fared well in the presence of man, both species have been extensively hunted for their pelts. In recent years an even greater threat is posed by the dynamiting and poisoning of rivers and clearance of bankside vegetation. Amboro is a relatively new National Park and should be regarded as a showpiece for Bolivia. The foresight of the Government, C.D.F., Prodena Bolivia, and particularly Reginald Hardy and Robin Clarke in getting this venture off the ground and for their continuing support is commendable. Considerable problems remain however, paramount of which, is the hunting of animals for food, for live export or for skins. Ample evidence of this practise has been found on both visits to Amboro. Pteronura brasiliensis occurred commonly in the Park up until 10 years ago, and was hunted for its pelt until 15 years ago. The species of otter which was commonly encountered was the neotropical river otter (Lutra longicaudis). As far as the otter populations are concerned, direct persecution is now minimal since there is no market for their skins. However the practise of fishing using dynamite or poison should be actively discouraged if the good populations of these animals are to be maintained.
Endomycorrhizal Fungi and Opuntia ficus-indica Seed Germination on a Lunar Regolith Simulant  [PDF]
Gertrud Konings-Dudin, Michelle J. Butcher, Jesus A. Castor-Macías, Benjamin Kohanloo, Michelle Garcia
Advances in Microbiology (AiM) , 2014, DOI: 10.4236/aim.2014.410068

Endomycorrhizal fungi play an important role in the survival of plants on poor soils. Planting seeds into lunar soil at a lunar colony will be a challenge for seeds of any plant. The seeds will need a special microbial “tool kit” that will help them germinate and the young seedlings establish themselves. In this study, seeds of the prickly pear cactus, Opuntia ficus-indica, were chosen to examine the presence of fungus spores in the soil, inside the seeds and after germination in the rhizosphere, roots and other tissues of the young seedlings. The nutrient poor lunar regolith simulant JSC-1A was used as autoclaved or untreated growth medium. The mycorrhizal fungus Trichoderma viride was predominantly identified on the roots of new seedlings. This fungus also demonstrated the strongest effect on the germination rate of the seeds in comparison with other fungi isolated from the rhizosphere of Opuntia plants. T. viride was not detected within seeds and also not within seedlings, besides the root tips, whereas an arbuscular mycorrhizal Glomus species was seed-borne and present throughout most of the seedling. A close association between T. viride and a Glomus species associated with O. ficus-indica

Michelle Mojica Nore?a
El Agora USB , 2011,
Abstract: El presente artículo presenta resultados de una investigación que busca brindar elementos que den cuenta de la validez o sustento y justificación del apelativo de Terrrorista al grupo aramado de las FARC – EP. grupo insurgente alzado en Armas en Colombia y protagonista del conflicto interno en Colombia ya hace más de 45 a os No solo es importante ver cuál es el contexto en el que surgen estos calificativos, sino sentar las bases para un estudio riguroso del caso apoyándose en datos que confirmen las tesis aquí planteadas.Abstract:This article presents the research results whose aim is to provide elements that report the validity or the support and the justification of the nickname of Terrorist to the FARC - EP group. It is an armed insurgent group in Colombia and main figure of the internal conflict in Colombia for more than 45 years. Not only is it important to see the context in which these nicknames appear, but also to lay the foundations for a rigorous analysis of the case by relying on the data that confirm the theses raised in this study.
Pointing at the moon: teaching and learning without resistance
Michelle A. Massé
ETD : Educa??o Temática Digital , 2011,
Abstract: Teachers often embrace narratives in which students' resistance to our teaching marks repression of the truths delivered by our learned selves. In students' counter-narratives, the tale of resistance can morph into one about principled refusal of powerful figures trying to force them into stances not their own. Both stories have strong temporal dimensions in which closure, even if it comes decades later, reveals that one party or the other was indeed influenced and changed, whether or not that change was evident at semester's end. My interest here is in how to question premature closure and how to work instead within the suspended liminal time of knowing/not knowing for teacher and student.
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