1,721,000 research outputs found
Analyzing the Candida albicans Transcriptional Program Shortly After Hypha Induction
No full textThe author has granted permission for their work to be available to the general public.Candida albicans is an opportunistic fungal pathogen that is part of the human microbiota, growing mainly on the mucosal surfaces of the gastrointestinal and genitourinary tracts. Its ability to change from yeast to hyphae plays a critical role in its virulence. This change in cellular morphology is negatively regulated by the transcriptional repressor Nrg1 and induced to varying degrees by an assortment of transcription factors, including Brg1, Ume6, Efg1, Cph1, Flo8 and others. Upon hyphal induction, BRG1 expression is rapidly upregulated and simultaneously, NRG1 transcript levels decline. Previous work in our lab uncovered a novel feedback circuit in which Brg1 is required for the induction of an NRG1 antisense transcript that enables filamentation. Currently it is not known whether BRG1 acts directly or indirectly to produce the NRG1 antisense transcript. In order to identify transcription factors that function downstream of Brg1 (since they may play a role in the production of the antisense transcript), we performed RNA-Seq on wild-type (SC5314) and brg1 mutant strains, 15 minutes after hyphal induction. We discovered that the transcription factors Cph1 and Ume6 were differentially upregulated in the wild-type strain. By introducing a regulatable tet-BRG1 allele into cph1Δ and ume6Δ mutant strains, we were able to determine that, while Cph1 plays little if any role in mediating hypha formation downstream of Brg1, Ume6 seems to be heavily involved in this process and therefore its interaction with Brg1 and the induction of the NRG1 antisense transcript warrants further examination.Integrative Biolog
Repurposing for Antifungal Drug Development: Large-scale Screening of the Library of Pharmacologically Active Compounds (LOPAC®1280) for Identification of Candida Albicans Biofilm Inhibitors
No full textThis item is available only to currently enrolled UTSA students, faculty or staff. To download, navigate to Log In in the top right-hand corner of this screen, then select Log in with my UTSA ID.Fungal infections represent an increasing threat to an expanding population of immune- and medically-compromised patients. Candida albicans is the major human fungal pathogen that causes candidiasis, now the third most common nosocomial infection in US hospitals with high mortality rates. The existing arsenal of antifungal drugs is very limited and better therapeutic strategies are urgently needed, particularly for the treatment of biofilm associated infections which are intrinsically resistant to most clinically-used antifungal agents.
We have screened the Library of Pharmacologically Active Compounds (LOPAC®1280), which includes 1,280 FDA-approved drugs and other pharmaceutically relevant structures, in search for inhibitors of C. albicans biofilm formation. Importantly, drug-like molecules in this library impact most signaling pathways and cover all major known drug targets. Using a 96-well micro titer plate-based large-scale screening assay developed in our laboratory, our initial screen identified 37 pharmacologically active agents that inhibit C. albicans biofilm formation. Secondary experiments included dose-response assays to confirm the activity and determine the potency of initial hits and evaluating the activity of confirmed compounds against preformed biofilms. Since the process of developing a brand-new medication is long (about 15 years) and expensive (over 1 billion dollars), this strategy of repurposing or repositioning already existing drugs opens a new, rapid and cost-effective avenue for antifungal drug development. This project has identified 3 leading candidates that show promising activity against biofilm formation.Integrative Biolog
Properties of silver and copper nanoparticle-containing aqueous solutions and evaluation of their in vitro activity against Candida albicans and Staphylococcus aureus biofilms
No full textThis item is available only to currently enrolled UTSA students, faculty or staff. To download, navigate to Log In in the top right-hand corner of this screen, then select Log in with my UTSA ID.Most microorganisms grow on surfaces as biofilms rather than as individual planktonic cells, and cells within biofilms show high levels of resistance against antimicrobial drugs. Thereby biofilm formation complicates treatment and contributes to high morbidity and mortality rates associated with infections. This study explores the physical, optical, and nano-structural properties of selected nanoparticles dispersed in aqueous solutions (nanoparticulate colloidal water or nanofluids) and examines their in vitro activity against microbial biofilms. Silver and copper nanofluids of various concentrations were prepared and studied. Their surface energies, surface charge and surface plasmonic resonance properties were obtained using contact angle measurement, zeta potential and optical spectrometer, respectively. The temperature dependence of the surface plasmon resonance behavior was also determined for the selected nanoparticulate aqueous solutions. A model of biofilm formation on the wells of microtiter plates was used to determine the in vitro activity of the nanoparticle preparations against both fungal (Candida albicans) and bacterial (Staphylococcus aureus) biofilms. Scanning electron microscopy (SEM) was used to observe the nanoparticle interactions with microbial cells. Results show that silver nanofluid has higher surface energy than that of the copper, the surface energy increases as the concentration of silver nanoparticles increases; and both nanoparticles in liquid are positively charged. The interaction between silver nanoparticles and water molecules produces notable changes on the usual temperature properties of water. Altogether, effectiveness of silver nanoparticle-containing liquids in controlling biofilm formation is observed and reported. For a given size of silver nanoparticles studied, it is found that the effective concentrations of silver nanoparticles against microbial biofilms are far lower than their cytotoxic concentrations, indicating an overall safety and a good therapeutic index thus substantial application potential.Electrical and Computer Engineerin
An in vitro study of sequential fluconazole / caspofungin treatment against Candida albicans biofilms
No full textThis item is available only to currently enrolled UTSA students, faculty or staff. To download, navigate to Log In in the top right-hand corner of this screen, then select Log in with my UTSA ID.Candida albicans is an opportunistic pathogenic fungus causing life threatening diseases in immunocompromised patients. Typically, these infections are associated with the formation of biofilms on both host tissues and implanted biomaterials. Biofilms are defined as complex microbial communities attached to a surface and encased in an exopolymeric matrix. The ability to form biofilms is important from a clinical perspective in that the biofilms show an increased resistance to antifungal therapy and the cells within the biofilms are able to withstand host immune defenses. C. albicans biofilms display intrinsic high levels of resistance to most major classes of antifungal drugs, including the azoles and polyenes. However, our group (and subsequently others) has demonstrated excellent activity of caspofungin, an antifungal drug belonging to the class echinocandins targeting cell wall biosynthesis, against C. albicans biofilms. Our present study indicates that, in a sequential antifungal drug therapy regimen, treatment of fluconazole first followed by caspofungin leads to a significant decrease of the in vitro efficacy of this echinocandin. Multiple clinical isolates of C. albicans demonstrated this antagonism to caspofungin after fluconazole pretreatment, and this effect was also specific only to C. albicans and not manifested by non-albicans Candida spp. Our studies pointed to the role of cell membrane stress response elements, such as calcineurin, in mediating this resistance process. Global gene expression analyses studies on drug treated biofilms revealed increasing levels of gene expression in genes associated with ergosterol and chitin biosynthetic pathways after fluconazole treatment. Expression levels of these genes were further elevated after subsequent caspofungin treatment. Other cell wall associated genes, such as several encoding GPI- anchored proteins were also found significantly regulated during the sequential drug treatment regimen. We hypothesize that treatment of C. albicans biofilms with fluconazole triggers a cell membrane stress response and also results in upregulation of the cell wall salvage pathway, which together render cells in biofilms resistant to caspofungin.Integrative Biolog
Characterization of the effects of new antifungal drug candidates against Candida albicans biofilms
No full textThis item is available only to currently enrolled UTSA students, faculty or staff. To download, navigate to Log In in the top right-hand corner of this screen, then select Log in with my UTSA ID.<italic>Candida</italic> spp. are commonly found among the microbiota of humans and are an increasing health threat to immunocompromised individuals. <italic>Candida albicans</italic> is the most common causative agent of candidiasis and these infections are commonly associated with the formation of biofilms on both biological surfaces and implanted medical devices. Biofilms are structured microbial communities attached to surfaces and encapsulated within a protective extracellular matrix. Previous studies in our laboratory identified four compounds from the Chembridge Corporation's NOVAcore<super>TM</super> and DIVERSet<super>TM</super> chemical libraries as initial "hits" against biofilm formation. Here we have screened a total of 72 analogs of these antifungal leads (60 from the NOVAcore<super>TM</super> library and 12 from the DIVERSet<super>TM</super> library) for their ability to inhibit <italic>C. albicans</italic> biofilm formation using a 96-well microtiter plate biofilm model. Results indicate that four "lead" compounds (NOVAcore<super>TM</super> compounds NCA and NCB; DIVERSet<super>TM</super> compounds DS1 and DS2) were the most effective inhibitors of biofilm formation. Follow-up characterization using light microscopy, scanning electron microscopy and confocal scanning laser microscopy has provided additional insight into the biofilm-inhibitory activity and mechanism of action for each of these "lead" compounds. This information will be valuable for the design of more potent and selective antifungal agents against <italic>C. albicans</italic> biofilms, which are urgently needed.Integrative Biolog
Characterizing the ability of novel, cytokine-producing Candida albicans strains to alter the course of a disseminated infection
No full textThis item is available only to currently enrolled UTSA students, faculty or staff. To download, navigate to Log In in the top right-hand corner of this screen, then select Log in with my UTSA ID.<italics>Candida albicans</italics> is a ubiquitous fungus that is found on the skin and mucosal surfaces of the human body; however, when the immune system is compromised, <italics>C. albicans</italics> can act as an opportunistic pathogen, causing a wide range of infections. Recent studies have suggested that IL-17A, produced as a result of Th17 cell differentiation, and TNF-alpha play critical roles in both the inflammatory and protective responses to <italics>C. albicans</italics> infections. In order to clarify the roles of TNF-alpha and IL-17A in candidiasis, this project was designed to construct genetically engineered strains of <italics>C. albicans</italics> that secrete either murine TNF-alpha or IL-17A cytokines. Codon modified TNF-alpha/IL-17A sequences were cloned in-frame with the <italics>C. albicans</italics> MFalpha1 secretion signal sequence and placed under the control of the tetracycline regulatable tetO promoter in a <italics>C. albicans</italics> integrating plasmid vector. Several tests and immunological assays were performed to confirm correct integration and determine if detectable levels of cytokines were produced. A mouse study was performed which corroborated recent findings with regards to the increased survival rates due to the increased production of IL-17A in disseminated <italics>C. albicans</italics> infections. Additional in vitro assays were performed which indicate the possibility that IL-17A binds directly to <italics>C. albicans</italics> hyphae, negatively affecting its viability.Integrative Biolog
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe 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
Full text link“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
Full text linkWe 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
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