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Redundanz von Signalbahnen für die Aktivierung von C0X-2
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Complete dissertationCandida albicans is a pathogenic yeast responsible for causing infection in
patients under immunosuppressive therapy, and is responsible for recurrent
vulvovaginal candidiasis. Although, number of C. albicans derived intrinsic
factors and the host factors have been found responsible for virulence and
favouring the disease process, there is no antimycotic drug which proves out
to be completely fungicidal, suppressing recurrent infections. This work deals
with the study of Candida albicans-host cell interaction, to give an insight
of the disease process, which could lead to new therapeutic interventions.
Earlier studies on D. uninucleata revealed presence of a biologically active
3-HETE derived from exogenously fed Arachidonic acid. It was found, that it is
not only important for its own life cycle, but also shows biological activity
in human cells. We tried to find if a similar mechanism occurs in pathogenic
fungi. It was found that although C. albicans does not contain arachidonic
acid, it is able to grow on arachidonic acid as a sole carbon source as
efficiently as it can utilise linoleic acid. Metabolism of arachidonic acid by
C. albicans occurs both by mitochondrial dependent and independent pathways as
shown by inhibitor studies. Arachidonic acid was shown to block the
alternative oxidase pathway of energy generation in Candida albicans, and was
efficiently metabolised to other fatty acids, carbohydrates, and proteins.
Arachidonic acid metabolism by Candida albicans produced a novel compound
3,18-diHETE, which was closely related to previously discovered 3-HETE by Dr.
S. Nigam's group. It was also observed that 3,18-diHETE was mainly associated
with the cells bearing germ-tube and hyphael forms. This production was found
to be aspirin sensitive. We found that C. albicans grown in aspirin showed
diminished immunofluorescence with anti-3-OH-oxylipins antibody, indicating
decreased amounts of 3,18 diHETE. Apart from this, there was diminished germ-
tube formation, which is essential for infection, in C. albicans in presence
of aspirin. Aspirin suppressed not only cell growth, but it also reduced the
adhesion of C. albicans to the host cells. These observations prompted us to
explore a therapeutic role for aspirin. When given along with clotrimazole,
aspirin was found to reduce minimum inhibitory concentration (MIC) of
clotrimazole against C. albicans. The action of aspirin was directed towards
inhibiting 3-hydroxylation mechanism in C. albicans and of clotrimazole
towards 18-hydroxylation mechanism and ergosterol synthesis, which occurs via
cytochrome p450. This demonstrates a novel approach to potentiate the action
of antimycotic drug clotrimazole. Moreover, aspirin is a cyclooxygenase-2
inhibitor, which inhibits formation of PGE2, and thus the infectivity of C.
albicans. Our results thus showed that aspirin may be a suitable drug for the
therapy of recurrent Candidiasis. It is known that host factors are also
responsible for the establishment of infection. HDL, which is lowered in
sepsis patients, and therefore substituted, was found to further increase
virulence by inducing germtube formation in C. albicans. The first step of
infection includes adhesion of pathogen to host cells. C. albicans which
adheres to host cells rapidly is found to be more virulent, and is able to
proceeds further to establish the infection process. Our results demonstrate
that aspirin is able to decrease the adhesion of C. albicans to HeLa cell,
thus decreasing its virulence. Upon infection with C. albicans signal
transduction pathways are triggered in host cells (HeLa cells). We found
upregulation of COX-2 in HeLa cells upon infection with C. albicans as well as
increase in PGE2 production. Not only C. albicans but also 3-HETE, upregulated
COX-2, showing that 3-HETE was important compound which mediated cell
signaling during infection. Using specific chemical inhibitors to various
signal transduction pathways, it was established that Protein Kinase C (PKC)
and p38 MAP kinase pathway were primarily involved in the COX-2 upregulation.
In other systems, involving cytokines and LPS, control of COX-2 transcription
involved ERK1/2 and JNK MAP kinase pathways. Further studies were performed to
evaluate the exact sequence of activation of kinases involved. GF 203190X (PKC
inhibitor) prevented the phosphorylation of p38 MAP kinase, while other
inhibitors failed to have any effect. Thus, PKC acts as an upstream factor
phosphorylating p38 MAP kinase. C. albicans induced p38 MAP kinase was also
observed to be involved in modulating cytoskeletol changes host cell. This
effect involved the activation, of phosphorylated HSP27, a factor involved in
the modulation of actin, which was abrogated by p38 MAP kinase inhibitor SB
202190.We find that inhibition of free radicals, NAC inhibits COX-2 and PGE2
upregulation suggesting involvement of reactive oxygen species and NFkB during
the infection of HeLa cells with C. albicans. The control of transcription
occur by the various transcription factors binding to the concerned gene
promoter. NFkB is one of the important transcription factors implicated in the
COX-2 transcription. The role of NFkB was studied using a NFkB-dependent
reporter plasmid and a dominant negative plasmid for IkB (prevents the release
of active NFkB). NFkB-dependent transcription was triggered upon infection
with C albicans. However, this could be only partially abrogated by the IkB
dominant negative plasmid, moreover PI3-kinase pathway is involved in COX-2
upregulation via NFkB pathway. Thus C. albicans brings about redundant
signalling for the upregulation and control of COX-2 transcription. Extensive
programmed cell death (apoptosis) was observed after 24 h in Hela cells
infected with C. albicans as shown by genomic DNA laddering and TUNEL assay.
After 6 h postinfection, upregulation of caspase-3 activity was observed.
Caspase-3 is an effector caspase which is involved in the cleavage of cellular
proteins during apoptosis. Further more, using DNA microarray technology, we
showed that C. albicans upregulated PI-3-kinase in HeLa cells. PI-3-kinase is
a prominent mediator of anti-apoptotic functions via AKT and p65 NFkB. Its
inhibition by wortmannin increased the caspase-3 activity in infected cells.
IkB dominant negative transfected cells showed no caspase-3 activity upon
infection. This result was surprising as p65 NFkB, whose release is prevented
by the dominant negative plasmid, is an anti-apoptotic molecule. This
paradoxical reaction was clarified by the observation of truncated forms of
p65 NFkB in C. albicans infected HeLa cells. Carboxy terminal truncation of
p65 NFkB by caspase-3 renders the molecule inactive thereby preventing its
anti-apoptotic function. The pro-apoptotic subunits of NFkB, p50 and c-REL,
however, were upregulated in C. albicans infected cells. Thus, the anti-
apoptotic pathway, from PI-3-kinase via AKT to p65 NFkB is rendered
ineffective by the cleavage of p65 NFkB by caspase-3.3(R)-Hydroxyoxylipine sind neue Oxygenierungsprodukte von Polyenfettsäuren,
die gemeinsam von den Arbeitsgruppen in Berlin (AG Nigam) und Bloemfontein,
Südafrika (AG Kock) in der Hefe Dipodascopsis uninucleata entdeckt wurden.
Darüber hinaus konnte mittelsImmunfluoreszenzmikroskopie gezeigt werden, daß
die entsprechenden Arachidonsäure- und Linolsäuremetaboliten auch in
denhumanpathogenen Pilzen, wie Candida albicans vorkommen. In C. albicans
wurden 3-Hydroxyoxylipine in den filamentären Strukturformen undKeimschläuchen
identifiziert, nicht aber in freien Blastosporen. Vorbehandlung der
Pilzkulturen mit Aspirin ließ die 3-Hydroxyoxylipineweitgehend verschwinden.
Aspirin bewirkte ebenfalls eine starke Hemmung des Pilzwachstum und zugleich
eine Verringerung des Anteilsfilamentärer Strukturelemente. In der
vorliegenden Arbeit sind Untersuchungen zur Struktur, Biosynthese und
biologischen Funktionen der 3(R)-Hydroxyoxylipine auf 3 verschiedenen Ebenen
durchgeführt: auf der Ebene des Pilzstoffwechsels, auf der Ebene der Pathogen-
Wirtszell-Interaktion sowie auf der Ebene biologischer Wirkung von C. albicans
auf intrazelluläre Signalkette. Desweiteren wurden biologische Wirkungen der
bereits von uns isolierten undidentifizierten 3-Hydroxyoxylipinen durch die
Transformation von Arachidonsäure auf mammaliäre Zellen und die Funktion
dieser Oxylipine für die Morphogenese und Pathogenität von Candida im Hinblick
auf ihre mögliche Rolle beim Infektionsprozess untersucht. Da Aspirin sowohl
über die Hemmung der Cyclooxygenase in den Wirtszellen als auch der
3-Hydroxyoxylipine beim Pathogen in die Pathogen-Wirtszell-Interaktion
eingreift,verspricht die Aspirintherapie auch Erfolg bei der Behandlung
resistenter Candida-Stämme.Hinsichtlich der Ergebnisse dieser Untersuchungen
sind einige Neuheiten hervorzuheben: (i) C. albicans kann allein auf
Arachidonsäure als Substrat gedeihen. Dabei werden primär über "Glyoxalat-
Shunt" Kohlenhydrate produziert. Dieser Mechanismus deutet auf die erhöhte
Virulenz beteiligter Gene hin. (ii) die Produktion von einem neuartigem,
dioxygeniertem Eikosanoid 3,18-DiHETE wurde für die Bildung von "germ-tube"
und Hyphen verantwortlich gemacht. (iii) Clomatrizol, das meist- benutzte
Mittel gegen vulvovaginale Kandidose, zusammen mit Aspirin wurde als das
wirkungsvollste Mittel gegen Kandidose nachgewiesen. (iv) C. albicans hat
selektiv COX-2 in HeLa Zellen hochreguliert. Diese Hochregulierung wurde mit
der erhöhten Synthese von Prostaglandin E2 begleitet. Prostaglandin E2 wird
u.a. für die morphogenetische Veränderung in C. albicans verantwortlich
gemacht, und somit für die Infektivität. (v) Die Hochregulierung von COX-2
erfolgt über verschiedene Signaltransduktionswege, wieTyrosinkinase,
Proteinkinase C, p38MAP Kinase oder via NFkappaB. NFkappaB und p38MAPK spielen
dabei Schlüsselrollen. Dagegen sind andere Stresskinasen, wie ERK1/2, JNK,
SAPK offensichtlich nicht beteiligt. (vi) C. albicans triggert auch Apoptose
via NFkappaB und/oderPI-3-Kinase in HeLa Zellen. Dabei wechselt NFkappaB ihre
anti-apoptotische Wirkung während der Reaktion in eine proapototische Wirkung.
Aus den Ergebnissen dieser Arbeit werden neue Aspekte der Regulation des
Wachstums und der Morphogenese von 3-hydroxyoxylipin-produzierenden Pilzen
sowie neue Ansatzpunkte zur Behandlung von Pilzerkrankungen bei Menschen und
Nutzpflanzen erwartet
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
Author Under Sail The Imagination of Jack London, 1893-1902
No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.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
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