401 research outputs found
Molecular-Detailed Computational Tools to Study HIV Pathogenesis and Design Anti-HIV Stem Cell Therapies
No full textCombination antiretroviral therapy (cART) ensures that millions of people with HIV lead normal lives. However, cART is not a cure and if stopped, even after decades, HIV hidden in the latent reservoir can activate and lead to viral rebound. Given the drawbacks of cART particularly cost and difficulties of adherence to chronic treatment, HIV cures could significantly reduce the burden on patients while reducing the healthcare cost.
In 2008, the “Berlin Patient” was treated with myeloablative irradiation and hematopoietic stem cell transplant (HSCT) from a donor with a CCR5Δ32 mutation conferring resistance to HIV. Since then, the recipient has been “functionally cured”, i.e. has shown no signs of active HIV-1 replication in the absence of cART. This success renewed hope that replacing HIV-susceptible cells with more resistant cells by inserting genes or gene networks into patients’ or matched donors’ stem cells before transplantation could provide HIV-resistance to progeny target cells and lead to cure. This approach was recently shown in macaques to reduce viral load and return T cell counts to normal levels. Key questions remain: (a) given that donor chimerism occurs, what percentage of the cells must be HIV-resistant in order to block HIV; (b) what is the minimal level of anti-HIV activity needed in these cells; (c) which anti-HIV genes will work best, and for which patients; and (d) will combinations of anti-HIV genes synergize?
As few patients have undergone transplants, we built novel molecular-detailed mechanistic models of HIV infection to answer these questions. The models are validated against independent in vitro and in vivo experimental data. Using the models, we study the complex pathogenesis of HIV, design gene-augmented stem cell therapies, and calculate the probability of cure for each therapy. We focus on HSCTs that include knocking out CCR5 and/or inserting anti-HIV genes or gene circuits such as the APOBEC3 family, SAMHD1, and on-demand apoptosis-inducing circuits. Instead of studying a single average course of HIV infection in a typical patient, we apply our models, parameterized using real patient data, to simulate a population of HIV-infected patients. Using this population of models, we run virtual clinical trials of different treatments. We validate the model by predicting recent clinical data from CCR5-modified T-cell therapy. The model has the ability to help design stem cell-based therapies and predict the results in clinical studies
Evandro Affonso Ferreira: vidas desengraçadas e o arquivo debilitado
No full textDissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Comunicação e Expressão. Programa de Pós-graduação em LiteraturaEsta dissertação investiga procedimentos da escritura de Evandro Affonso Ferreira, autor brasileiro contemporâneo com cinco livros publicados até o momento. Estes procedimentos são estudados a partir de como suas personagens se movem. O trabalho se divide em duas partes: a primeira é um jogo entre uma galeria (possível e falhada) de estúpidos e suas "vidas infames", acerca da experiência e da existência precárias dessas personagens. O jogo se dá num contágio com as artes visuais (Marcelo Coutinho, Elida Tessler e León Ferrari) e com alguns outros textos ficcionais de autores como Gusmán, Kafka, Melville, Walser etc. A segunda é como o autor trabalha com seus textos, seus livros e o léxico que usa - as palavras sonoras -, como se tudo isso formasse um só livro, livre numa biblioteca de babel da língua, da imaginação, da memória, da literatura. O livro como objeto que compõe a trajetória de um autor-leitor, a sua coleção babélica. Para isso faço uso de teóricos como Agamben, Benjamin, Blanchot, Derrida, Deleuze, Foucault entre outros. This dissertation investigates writing procedures by Evandro Affonso Ferreira, a contemporary Brazilian author with five books published so far. These procedures are studied according to the movement of the characters. The work is divided in two parts: the first one is a game for a galery (possible and failed) of stupids and its "infamous lives" regarding the precarious experience and existence of these characters. The game happens in an involvement with the visual arts (Marcelo Coutinho, Elida Tessler and León Ferrari) and with some other fictional texts from authors like Gusmán, Kafka, Melville, Walser etc. The second one is how the author works with his texts, books and the lexicon he uses - the sonorous words -, as all this would form a single (an unique) book, free in a Babel library of the language, of the imagination, of the memory, of the literature. The book as an object that compounds the trajectory of an author-reader, his Babelic collection. For this I use the theories of Agamben, Benjamin, Blanchot, Derrida, Deleuze, Foucault and others
Characterization of a Membrane-Associated Protein Implicated in Visna Virus Binding and Infection
No full textAbstractThe identity of the cellular receptor(s) for visna virus, an ovine lentivirus, is currently unknown; however, previous studies from our laboratory have identified membrane-associated proteins expressed selectively in susceptible cells which bind visna virus. Moreover, a polyclonal antibody (2-23), raised against a 45-kDa visna virus binding protein, bound specifically to the surface of susceptible cells in immunofluorescence assays and significantly reduced binding of visna virus to cells (S. E. Crane et al., 1991, J. Virol., 65, 6137–6143). In this report we extend our studies of this antibody (2-23), showing both that 2-23 significantly reduces visna virus infection of susceptible cells and that 2-23 immunoprecipitates a putative protein complex consisting of a prominent 30-kDa protein, as well as the 45-kDa immunogen, specifically from radiolabeled virus-susceptible sheep cells. Further, we demonstrate that the 30-kDa protein is a membrane-associated proteoglycan substituted with a chondroitin sulfate glycosaminoglycan (GAG) chain(s) and that treatment of susceptible cells with an inhibitor of GAG synthesis significantly reduces visna virus production. Collectively, these data support a role for a proteoglycan in visna virus cell binding and infection
Re-Enactment : Between Self and Other : Carl Beam, Panya Clark, Stan Douglas, Janice Gurney, Barbara Lounder, Lani Maestro
No full textFischer focuses on "the material means by which six contemporary Canadian artists attempt to renegotiate definitions of cultural identity, especially in the context of the art gallery and the museum." The author discusses and contextualizes the artists' work, touching on references ranging from Gounod, Barthes, Kristeva and Homi Bhabha to accounts of native and Inuit culture, and personal histories. Biographical notes. 7 bibl. ref
Janice Holt Giles: A Bio-Bibliography with Evaluations of the Kentucky Frontier Books as Historical Fiction
No full textThe purpose of this study was (1) to present a biographical sketch of the novelist Janice Holt Giles in terms of the influences upon her writing, (2) to evaluate the Kentucky historical novels written by Mrs. Giles in light of the requirements for historical fiction, and (3) to present a survey of the reviews of those books.
The life data on the author were obtained largely through two personal interviews with her and through her two autobiographical works: 40 Acres and No Mule and A Little Better Than Plumb. The Adair County Record Books on file at the Court House in Columbia, Kentucky, were consulted to determine the time the Giles ancestors made their first settlement in south-central Kentucky. For references to other biographical information, Biography Index, Reader\u27s Guide to Periodical Literature, Education Index, and Library Literature were searched. A scant amount of data on the author were found in Current Biography 1958, Wilson Library Bulletin, and Contemporary Authors 1962.
Certain criteria for evaluating historical fiction were specified in order to appraise the Kentucky frontier books by Mrs. Giles. The requirements of sound historical fiction: truth, graphic power, consistent character portrayal, sustained dramatic and human interest, are those cited by Helen E. Haines in her work Living with Books. Each requirement was discussed in evaluating all the books covered in this paper. Included in the discussion were details from the life influences of the author as they were thought to bear upon the novels.
In conclusion, each book met those requirements of sound historical fiction. Hannah Fowler and The Land Beyond the Mountains were the most highly praised in the survey of reviews
DESIGN AND DEVELOPMENT OF BISPECIFIC ANTIBODIES FOR HIV-1 RESERVOIR ELIMINATION
No full textCurrently, there are over 38.4 million people worldwide living human immunodeficiency virus type 1 (HIV-1), and despite advances in HIV-1 prevention, there are still 1.5 million new cases annually. Although antiretroviral therapy (ART) regimens suppress viral replication and prevent immunodeficiency, ART is not curative and cessation of treatment results in viral rebound within weeks. The inability of ART to cure HIV-1 stems from the persistence of a population of resting memory CD4+ T cells that contain integrated and transcriptionally silent HIV-1 proviral DNA. This CD4+ T cell population, referred to as the latent reservoir, eludes the immune system and can resume viral production and disease progression if ART is interrupted. Thus, the latent reservoir represents the major barrier to an HIV-1 cure and novel therapeutics are urgently needed to eliminate the latent reservoir.
Efforts to achieve a cure for HIV-1 infection have largely focused on the strategy known as ‘shock and kill’. In this approach, reversal of HIV latency (‘shock’) would be achieved through treatment with small molecule drugs capable of inducing HIV-1 gene expression without toxic global T cell activation. This latency reversing agent (LRA) would be administered while maintaining ART to prevent new infection events. Renewed expression of HIV-1 gene products would allow for clearance of infected cells (‘kill’) through viral cytopathic effects or immune-mediated clearance, resulting in a reduction in the size of the latent reservoir.
However, despite observations of transient increases in plasma and cell-associated viral RNA, indicative of latency reversal, in some LRA clinical trials, no significant reduction in reservoir size has been achieved to date. Several lines of evidence suggest the lack of reservoir size reduction observed may be partially explained by inefficient immune-mediated elimination of reactivated infected cells. To overcome limitations to CTL- and NK cell-mediated clearance of infected CD4+ T cells after reversal of latency in persons with HIV-1 (PWH), immunotherapies capable of augmenting cell-mediated cytolytic activity may be necessary. In this dissertation, we describe the development and preclinical characterization of bispecific antibodies capable of potently and specifically enhancing the elimination of HIV-1-infected CD4+ T cells by cytolytic CTLs and NK cells
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