2,439 research outputs found
The biochemical basis of arsenical-diamidine crossresistance in African trypanosomes
No full textResistance to currently used drugs is a serious problem in most fields of antimicrobial chemotherapy. Crossresistance between two of the major classes of drug used in the treatment of African trypanosomiasis, the melaminophenyl arsenicals and diamidines is easily selected in the laboratory. Here, Mike Barrett and Alan Fairlamb outline the mechanism underlying this crossresistance, which appears to arise as a result of alterations in an unusual adenosine transporter involved in the uptake of these drugs.</p
Trypanothione metabolism:a chemotherapeutic target in trypanosomatids
No full textChemotherapy of trypanosomotid infections continues to present challenges. Treatment of Trypanosoma cruzi infections is virtually impossible, while treatment of Leishmaniasis and African tryponosomiasis is, at best, difficult - often involving toxic drugs based on heavy metals such as antimony and arsenic. As with several other parasites, much recent research has focused on defining metabolic differences between parasite and host that could represent good targets for chemotherapy. As Graeme Henderson and Alan Fairlamb explain, there is something strange about glutothione in trypanosomotids - which seems to offer a very promising chemotherapeutic target.</p
Alan Moore Comics as Performance, Fiction as Scalpel
No full textEclectic British author Alan Moore (b. 1953) is one of the most acclaimed and controversial comics writers to emerge since the late 1970s. He has produced a large number of well-regarded comic books and graphic novels while also making occasional forays into music, poetry, performance, and prose. In Alan Moore: Comics as Performance, Fiction as Scalpel , Annalisa Di Liddo argues that Moore employs the comics form to dissect the literary canon, the tradition of comics, contemporary society, and our understanding of history. The book considers Moore's narrative strategies and pinpoints the main thematic threads in his works: the subversion of genre and pulp fiction, the interrogation of superhero tropes, the manipulation of space and time, the uses of magic and mythology, the instability of gender and ethnic identity, and the accumulation of imagery to create satire that comments on politics and art history. Examining Moore's use of comics to scrutinize contemporary culture, Di Liddo analyzes his best-known works-- Swamp Thing, V for Vendetta, Watchmen, From Hell, Promethea , and Lost Girls . The study also highlights Moore?s lesser-known output, such as Halo Jones, Skizz , and Big Numbers , and his prose novel Voice of the Fire. Alan Moore: Comics as Performance, Fiction as Scalpel reveals Moore to be one of the most significant and distinctly postmodern comics creators of the last quarter-century.Intro -- Contents -- Preface and Acknowledgments -- Introduction -- CHAPTER 1. Formal Considerations on Alan Moore's Writing -- CHAPTER 2. Chronotopes: Outer Space, the Cityscape, and the Space of Comics -- CHAPTER 3. Moore and the Crisis of English Identity -- CHAPTER 4. Finding a Way into Lost Girls -- Conclusion -- Notes -- Bibliography -- Index -- A -- B -- C -- D -- E -- F -- G -- H -- I -- J -- K -- L -- M -- N -- O -- P -- Q -- R -- S -- T -- U -- V -- W -- Y -- ZEclectic British author Alan Moore (b. 1953) is one of the most acclaimed and controversial comics writers to emerge since the late 1970s. He has produced a large number of well-regarded comic books and graphic novels while also making occasional forays into music, poetry, performance, and prose. In Alan Moore: Comics as Performance, Fiction as Scalpel , Annalisa Di Liddo argues that Moore employs the comics form to dissect the literary canon, the tradition of comics, contemporary society, and our understanding of history. The book considers Moore's narrative strategies and pinpoints the main thematic threads in his works: the subversion of genre and pulp fiction, the interrogation of superhero tropes, the manipulation of space and time, the uses of magic and mythology, the instability of gender and ethnic identity, and the accumulation of imagery to create satire that comments on politics and art history. Examining Moore's use of comics to scrutinize contemporary culture, Di Liddo analyzes his best-known works-- Swamp Thing, V for Vendetta, Watchmen, From Hell, Promethea , and Lost Girls . The study also highlights Moore?s lesser-known output, such as Halo Jones, Skizz , and Big Numbers , and his prose novel Voice of the Fire. Alan Moore: Comics as Performance, Fiction as Scalpel reveals Moore to be one of the most significant and distinctly postmodern comics creators of the last quarter-century.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
Portrait of Senator Alan H. Bible.
No full textHandwritten inscription: \u27To an old and valued friend [with] deep affection - Alan Bible [V.S.] Senator, Nevada 1955\u27https://egrove.olemiss.edu/fmjohnston/1264/thumbnail.jp
Activation of Aryl C-H and C-X bonds by a pincer-ligated 'PCP' iridium complex
No full textThe activation of carbon-hydrogen (C-H) bonds mediated by transition metal complexes is a fundamental step in a vast array of chemical transformations and industrial processes. As such, research into the understanding of the factors governing both efficiency and selectivity of these reactions has been intense. The work presented in this thesis comprises results of experiments designed to evaluate the ability of a pincer-ligated iridium complex to activate the C-H bonds of several classes of aryl substrates. The pincer-ligated iridium fragment (PCP)Ir (PCP = {κ3-2,6-bis[(di-tert-butylphosphino)methyl]phenyl}) rapidly and reversibly adds the C-H bond of benzene, giving a kinetically labile addition product. The kinetics and thermodynamics of C-H activation of a series of halogen-, alkyl-, and trifluoromethyl-substituted arenes were studied with a particular focus on determining whether “directing” effects play a significant role. In regard to electronic effects, it was observed that electron withdrawing aryl substituents favor C-H activation. Products of C-H activation ortho to weakly or non-coordinating substituents (e.g., Cl, Br, CF3) are kinetically more stable than those of the meta- and para-substituted analogs, due to steric crowding in the transition state for addition and elimination. However, there is no thermodynamic preference for the ortho-substituted complexes. In addition to C-H activation, (PCP)Ir also activates C-X bonds (X = Cl, Br) under certain conditions, yielding product mixtures through a mechanism that remains unclear. Several series of polycyclic aromatic substrates (naphthalenes, biphenyls, bipyridines, and associated tricyclic analogs) were also studied, giving insight into the utility of aryl C-H activation and preferred binding modes of the (PCP)Ir fragment. Not surprisingly, steric effects play a significant role in the regioselectivity of polycyclic aromatic C-H bond activation by (PCP)Ir. Cyclometalation reactions resulting from single or double C-H activation processes yield particularly stable products. Additional results included an unexpected C-C activation, and several products stabilized by heteroatom (N, O) coordination to iridium. Activation of large polycycles like terpyridine yielded stable, κ2 chelates that may be of value in research on organic light emitting diodes (OLEDs). Finally, several congested (PCP)Ir dimers were synthesized by taking advantage of the remarkable stability of the products from cyclometalation to the (PCP)Ir complex.Ph. D.Includes bibliographical referencesIncludes vitaby David Alan Lavisk
Structural and mechanistic insights into type II trypanosomatid tryparedoxin-dependent peroxidases
No full textAlphey MS, König J, Fairlamb AH. Structural and mechanistic insights into type II trypanosomatid tryparedoxin-dependent peroxidases. The Biochemical Journal. 2008;414(3):375-381.TbTDPX (Trypanosoma brucei tryparedoxin-dependent peroxidase) is a genetically validated drug target in the fight against African sleeping sickness. Despite its similarity to members of the GPX (glutathione peroxidase) family, TbTDPX2 is functional as a monomer, lacks a selenocysteine residue and relies instead on peroxidatic and resolving cysteine residues for catalysis and uses tryparedoxin rather than glutathione as electron donor. Kinetic studies indicate a saturable Ping Pong mechanism, unlike selenium-dependent GPXs, which display infinite K(m) and V(max) values. The structure of the reduced enzyme at 2.1 A (0.21 nm) resolution reveals that the catalytic thiol groups are widely separated [19 A (0.19 nm)] and thus unable to form a disulphide bond without a large conformational change in the secondary-structure architecture, as reported for certain plant GPXs. A model of the oxidized enzyme structure is presented and the implications for small-molecule inhibition are discussed
Arsenic exposure and outcomes of antimonial treatment in visceral leishmaniasis patients in bihar, India:a retrospective cohort study
Full text linkBackground: In the late twentieth century, emergence of high rates of treatment failure with antimonial compounds (SSG) for visceral leishmaniasis (VL) caused a public health crisis in Bihar, India. We hypothesize that exposure to arsenic through drinking contaminated groundwater may be associated with SSG treatment failure due to the development of antimony-resistant parasites.Methods: A retrospective cohort design was employed, as antimony treatment is no longer in routine use. The study was performed on patients treated with SSG between 2006 and 2010. Outcomes of treatment were assessed through a field questionnaire and treatment failure used as a proxy for parasite resistance. Arsenic exposure was quantified through analysis of 5 water samples from within and surrounding the patient's home. A logistic regression model was used to evaluate the association between arsenic exposure and treatment failure. In a secondary analysis survival curves and Cox regression models were applied to assess the risk of mortality in VL patients exposed to arsenic.Results: One hundred and ten VL patients treated with SSG were analysed. The failure rate with SSG was 59%. Patients with high mean local arsenic level had a non-statistically significant higher risk of treatment failure (OR = 1.78, 95% CI: 0.7-4.6, p = 0.23) than patients using wells with arsenic concentration <10 μg/L. Twenty one patients died in our cohort, 16 directly as a result of VL. Arsenic levels ≥ 10 μg/L increased the risk of all-cause (HR 3.27; 95% CI: 1.4-8.1) and VL related (HR 2.65; 95% CI: 0.96-7.65) deaths. This was time dependent: 3 months post VL symptom development, elevated risks of all-cause mortality (HR 8.56; 95% CI: 2.5-29.1) and of VL related mortality (HR 9.27; 95% CI: 1.8-49.0) were detected.Discussion/Conclusion: This study indicates a trend towards increased treatment failure in arsenic exposed patients. The limitations of the retrospective study design may have masked a strong association between arsenic exposure and selection for antimonial resistance in the field. The unanticipated strong correlation between arsenic exposure and VL mortality warrants further investigation.</p
The construction of Karen Karnak: The multi-author-function
No full textThis thesis is situated within the comparatively recent developments of Web 2.0 and the emergence of interactive WikiMedia, and explores the mode of authorship within a Read/Write culture compared to that of a Read/Only tradition. The hypothesis of this study is that the role of the audience has become merged with the author, and as such, represents new functions and attributes, distinct from a more conventional concept of authorship, in which the roles of audience and author are more separate. Read/Write and participatory culture, as defined by this study, is focused on collaboration, and includes the influences of D.I.Y. culture, Open-Source practices and the production of text by multiple authors. Multi-authorship presents a re-thinking of several concepts which support the notion of the individual author, since the focus of multi-authorship is not on attribution and ownership of a finished text, but on the continued malleability of a text. Modes of multi-authorship, demonstrated in the use of the pseudonyms Alan Smithee and Karen Eliot, represent declarative authors whose names signify multiple origins, whilst concurrently indicating a distinct body of work. The function of these names form an important context to this study, since primary research involves the construction of an experimental mode of multi-authorship utilising WikiMedia technology and the interaction of thirty nine participants, who are invited to create a body of work under the collective pseudonym Karen Karnak. The data generated by this experiment is analysed using aspects of Michel Foucault's author-function to identify and determine power structures inherent in the WikiMedia context. The interplay of power structures, including concepts such as identity, ownership and the body of work, affect the resulting mode of authorship and contribute to the construction of Karen Karnak, suggesting further areas of research into the emerging multi-author
Glutathione-like tripeptides as inhibitors of glutathionylspermidine synthetase: part 1: substitution of the glycine carboxylic acid group
Full text linkGlutathionylspermidine synthetase/amidase (GspS) is an essential enzyme in the biosynthesis and turnover of trypanothione and represents an attractive target for the design of selective anti-parasitic drugs. We synthesised a series of analogues of glutathione (L-γ-Glu-L-Leu-Gly-X) where the glycine carboxylic acid group (X) has been substituted for other acidic groups such as tetrazole, hydroxamic acid, acylsulphonamide and boronic acid. The boronic acid appears the most promising lead compound (IC50 of 17.2 μM).Fil: Amssoms, Katie. Universiteit Antwerp; BélgicaFil: Oza, Sandra L.. University of Dundee; Reino UnidoFil: Ravaschino, Esteban. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; ArgentinaFil: Yamani, Abdellah. Universiteit Antwerp; BélgicaFil: Lambeir, Anne Marie. Universiteit Antwerp; BélgicaFil: Rajan, Padinchare. Universiteit Antwerp; BélgicaFil: Bal, Gunther. Universiteit Antwerp; BélgicaFil: Rodriguez, Juan Bautista. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; ArgentinaFil: Fairlamb, Alan H.. University of Dundee; Reino UnidoFil: Augustyns, Koen. Universiteit Antwerp; BélgicaFil: Haemers, Achiel. Universiteit Antwerp; Bélgic
Diamine auxotrophy may be a universal feature of Trypanosoma cruzi epimastigotes
No full textPolyamines play an important and central role in normal cell growth and differentiation in many cells. In trypanosomatids, spermidine is also an essential precursor in the biosynthesis of the unique glutathione-spermidine conjugate, trypanothione. Our previous study has shown that the epimastigote stage of Trypanosoma cruzi (Silvio strain) is incapable of significant de novo synthesis of putrescine or cadaverine from their amino acid precursors [Hunter, Le Quesne and Fairlamb (1994) Eur. J. Biochem. 226, 1019-1027]. In this study we show that when grown to late log phase in medium containing trace amounts of putrescine (0.22 μM) and spermidine (0.63 μM), Y-strain epimastigotes contain low levels of polyamines with free glutathione as their principal low molecular mass thiol (> 97% of total glutathione). Following passage into fresh medium, trypanothione and glutathionylspermidine content increases to 46% of total glutathione by mid log phase but returns to less than 3% by late log phase. In contrast, when supplemented at inoculation with exogenous putrescine, glutathione-spermidine conjugates reach 80% of total glutathione by early log phase and remain elevated throughout growth. Supplementation with exogenous putrescine or spermidine during polyamine starvation (late log phase) results in increased conjugate levels (> 74% of total glutathione) and is associated with large increases in total putrescine and spermidine. Likewise, supplementation with exogenous cadaverine and aminopropylcadaverine results in similar increases in trypanothione analogues and total cadaverine and aminopropylcadaverine. In contrast, ornithine, arginine, lysine, agmatine and other amino acid precursors have no effect on polyamine or conjugate levels. No significant ornithine or arginine decarboxylase activities could be detected (< 0.8 pmol min-1 [mg protein]-1). Similar results were obtained for epimastigotes representing all the major zymodeme classes, providing evidence that diamine auxotrophy may be a universal feature of this stage of the life-cycle.</p
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