College of Sciences
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Browsing College of Sciences by Department "Biology"
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Item Candida albicans Morphology-Dependent Host FGF-2 Response as a Potential Therapeutic Target(2019-03-05) Vellanki, Sandeep; Huh, Eun Young; Saville, Stephen P.; Lee, Soo ChanAngiogenesis mediated by proteins such as Fibroblast Growth Factor-2 (FGF-2) is a vital component of normal physiological processes and has also been implicated in contributing to the disease state associated with various microbial infections. Previous studies by our group and others have shown that Candida albicans, a common agent of candidiasis, induces FGF-2 secretion in vitro and angiogenesis in brains and kidneys during systemic infections. However, the underlying mechanism(s) via which the fungus increases FGF-2 production and the role(s) that FGF-2/angiogenesis plays in C. albicans disease remain unknown. Here we show, for the first time, that C. albicans hyphae (and not yeast cells) increase the FGF-2 response in human endothelial cells. Moreover, Candidalysin, a toxin secreted exclusively by C. albicans in the hyphal state, is required to induce this response. Our in vivo studies show that in the systemic C. albicans infection model, mice treated with FGF-2 exhibit significantly higher mortality rates when compared to untreated mice not given the angiogenic growth factor. Even treatment with fluconazole could not fully rescue infected animals that were administered FGF-2. Our data suggest that the increase of FGF-2 production/angiogenesis induced by Candidalysin contributes to the pathogenicity of C. albicans.Item Characterization of Local and Systemic Impact of Whitefly (Bemisia tabaci) Feeding and Whitefly-Transmitted Tomato Mottle Virus Infection on Tomato Leaves by Comprehensive Proteomics(2020-09-30) Ogden, Aaron J.; Boukari, Wardatou; Nava, Alba; Lucinda, Natalia; Sunter, Garry; Curtis, Wayne R.; Adkins, Joshua N.; Polston, Jane E.Tomato mottle virus (ToMoV) is a single-stranded DNA (ssDNA) begomovirus transmitted to solanaceous crops by the whitefly species complex (Bemisia tabaci), causing stunted growth, leaf mottling, and reduced yield. Using a genetic repertoire of seven genes, ToMoV pathogenesis includes the manipulation of multiple plant biological processes to circumvent antiviral defenses. To further understand the effects of whitefly feeding and whitefly-transmitted ToMoV infection on tomato plants (Solanum lycopersicum 'Florida Lanai'), we generated comprehensive protein profiles of leaves subjected to feeding by either viruliferous whiteflies harboring ToMoV, or non-viruliferous whiteflies, or a no-feeding control. The effects of whitefly feeding and ToMoV infection were measured both locally and systemically by sampling either a mature leaf directly from the site of clip-cage confined whitefly feeding, or from a newly formed leaf 10 days post feeding (dpf). At 3 dpf, tomato's response to ToMoV included proteins associated with translation initiation and elongation as well as plasmodesmata dynamics. In contrast, systemic impacts of ToMoV on younger leaves 10 dpf were more pronounced and included a virus-specific change in plant proteins associated with mRNA maturation and export, RNA-dependent DNA methylation, and other antiviral plant processes. Our analysis supports previous findings and provides novel insight into tomato's local and systemic response to whitefly feeding and ToMoV infection.Item Correlated Oxidative Stress and Mitochondrial Abnormalities in Aging are Discontinuous with Alzheimer’s Disease(Office of the Vice President for Research, 2018) Nguyen, Richard Q.; Bach, Stephan H.; Phelix, Clyde F.; Perry, GeorgeOxidative stress and mitochondrial damage precede Alzheimer’s disease (AD) hallmark pathologies, neurofibrillarytangles (NFT), and senile plaques.Mitochondria’s exact role in oxidation of pyruvate and NADH play a critical role in oxidative damage. We conducted this study to identify the relationship of oxidized RNA, 8--OHG biomarker, and mtDNA accumulation in AD and aging individuals. Abnormalities were examined by using densitometry of hippocampal pyramidal neurons: mtDNA accumulation as a marker of mitophagy and oxidative damage by 8-OHG. Among aging individuals, 8-OHG and mtDNA accumulation were highly correlated (R2=0.87,p=0.0007). While both 8-OHG and mtDNA were at higher levels in AD individuals, they were uncorrelated (R2=0.4418,p=0.07).In AD individuals, 8-OHG was inversely correlated with amyloid-β, while in aging, there was no significant correlation. These results suggest the discontinuity of similarities between aging and AD. These findings also indicate that the onset of AD is marked by a pleotrophic change in oxidative stress, one characterized by a change from mitochondria degeneration to amyloid-β independency.Item Host- and Age-Dependent Transcriptional Changes in Mycobacterium tuberculosis Cell Envelope Biosynthesis Genes after Exposure to Human Alveolar Lining Fluid(2022-01-17) Allué-Guardia, Anna; Garcia-Vilanova, Andreu; Olmo-Fontánez, Angélica M.; Peters, Jay; Maselli, Diego J.; Wang, Yufeng; Turner, Joanne; Schlesinger, Larry S.; Torrelles, Jordi B.Tuberculosis (TB) infection, caused by the airborne pathogen Mycobacterium tuberculosis (M.tb), resulted in almost 1.4 million deaths in 2019, and the number of deaths is predicted to increase by 20% over the next 5 years due to the COVID-19 pandemic. Upon reaching the alveolar space, M.tb comes into close contact with the lung mucosa before and after its encounter with host alveolar compartment cells. Our previous studies show that homeostatic, innate soluble components of the alveolar lining fluid (ALF) can quickly alter the cell envelope surface of M.tb upon contact, defining subsequent M.tb-host cell interactions and infection outcomes in vitro and in vivo. We also demonstrated that ALF from 60+ year old elders (E-ALF) vs. healthy 18- to 45-year-old adults (A-ALF) is dysfunctional, with loss of homeostatic capacity and impaired innate soluble responses linked to high local oxidative stress. In this study, a targeted transcriptional assay shows that M.tb exposure to human ALF alters the expression of its cell envelope genes. Specifically, our results indicate that A-ALF-exposed M.tb upregulates cell envelope genes associated with lipid, carbohydrate, and amino acid metabolism, as well as genes associated with redox homeostasis and transcriptional regulators. Conversely, M.tb exposure to E-ALF shows a lesser transcriptional response, with most of the M.tb genes unchanged or downregulated. Overall, this study indicates that M.tb responds and adapts to the lung alveolar environment upon contact, and that the host ALF status, determined by factors such as age, might play an important role in determining infection outcome.Item Increased Accumulation of Medium-Chain Fatty Acids by Dynamic Degradation of Long-Chain Fatty Acids in Mucor circinelloides(2020-08-05) Hussain, Syed Ammar; Garcia, Alexis; Khan, Md. Ahsanul Kabir; Nosheen, Shaista; Zhang, Yao; Koffas, Mattheos A. G.; Garre, Victoriano; Lee, Soo Chan; Song, YuandaConcerns about global warming, fossil-fuel depletion, food security, and human health have promoted metabolic engineers to develop tools/strategies to overproduce microbial functional oils directly from renewable resources. Medium-chain fatty acids (MCFAs, C8–C12) have been shown to be important sources due to their diverse biotechnological importance, providing benefits ranging from functional lipids to uses in bio-fuel production. However, oleaginous microbes do not carry native pathways for the production of MCFAs, and therefore, diverse approaches have been adapted to compensate for the requirements of industrial demand. Mucor circinelloides is a promising organism for lipid production (15–36% cell dry weight; CDW) and the investigation of mechanisms of lipid accumulation; however, it mostly produces long-chain fatty acids (LCFAs). To address this challenge, we genetically modified strain M. circinelloides MU758, first by integrating heterologous acyl-ACP thioesterase (TE) into fatty acid synthase (FAS) complex and subsequently by modifying the β-oxidation pathway by disrupting the acyl-CoA oxidase (ACOX) and/or acyl-CoA thioesterase (ACOT) genes with a preference for medium-chain acyl-CoAs, to elevate the yield of MCFAs. The resultant mutant strains (M-1, M-2, and M-3, respectively) showed a significant increase in lipid production in comparison to the wild-type strain (WT). MCFAs in M-1 (47.45%) was sharply increased compared to the wild type strain (2.25%), and it was further increased in M-2 (60.09%) suggesting a negative role of ACOX in MCFAs production. However, MCFAs in M-3 were much decreased compared to M-1, suggesting a positive role of ACOT in MCFAs production. The M-2 strain showed maximum lipid productivity (~1800 milligram per liter per day or mg/L.d) and MCFAs productivity (~1100 mg/L.d). Taken together, this study elaborates on how the combination of two multidimensional approaches, TE gene over-expression and modification of the ?-oxidation pathway via substantial knockout of specific ACOX gene, significantly increased the production of MCFAs. This synergistic approach ultimately offers a novel opportunity for synthetic/industrial biologists to increase the content of MCFAs.Item Molecular Effects of Silver Nanoparticles on Monogenean Parasites: Lessons from Caenorhabditis elegans(2020-08-16) Pimentel-Acosta, Citlalic A.; Ramírez-Salcedo, Jorge; Morales-Serna, Francisco Neptalí; Fajer-Ávila, Emma J.; Chávez-Sánchez, Cristina; Lara, Humberto H.; García-Gasca, AlejandraThe mechanisms of action of silver nanoparticles (AgNPs) in monogenean parasites of the genus Cichlidogyrus were investigated through a microarray hybridization approach using genomic information from the nematode Caenorhabditis elegans. The effects of two concentrations of AgNPs were explored, low (6 µg/L Ag) and high (36 µg/L Ag). Microarray analysis revealed that both concentrations of AgNPs activated similar biological processes, although by different mechanisms. Expression profiles included genes involved in detoxification, neurotoxicity, modulation of cell signaling, reproduction, embryonic development, and tegument organization as the main biological processes dysregulated by AgNPs. Two important processes (DNA damage and cell death) were mostly activated in parasites exposed to the lower concentration of AgNPs. To our knowledge, this is the first study providing information on the sub-cellular and molecular effects of exposure to AgNPs in metazoan parasites of fish.Item Repositionable Compounds with Antifungal Activity against Multidrug Resistant Candida auris Identified in the Medicines for Malaria Venture's Pathogen Box(2019-10-01) Wall, Gina; Herrera, Natalia; Lopez-Ribot, José L.Background. Candida auris has spread rapidly around the world as a causative agent of invasive candidiasis in health care facilities and there is an urgent need to find new options for treating this emerging, often multidrug-resistant pathogen. Methods. We screened the Pathogen Box® chemical library for inhibitors of C. auris strain 0390, both under planktonic and biofilm growing conditions. Results. The primary screen identified 12 compounds that inhibited at least 60% of biofilm formation or planktonic growth. After confirmatory dose-response assays, iodoquinol and miltefosine were selected as the two main leading repositionable compounds. Iodoquinol displayed potent in vitro inhibitory activity against planktonic C. auris but showed negligible inhibitory activity against biofilms; whereas miltefosine was able to inhibit the growth of C. auris under both planktonic and biofilm-growing conditions. Subsequent experiments confirmed their activity against nine other strains C. auris clinical isolates, irrespective of their susceptibility profiles against conventional antifungals. We extended our studies further to seven different species of Candida, also with similar findings. Conclusion. Both drugs possess broad spectrum of activity against Candida spp., including multiple strains of the emergent C. auris, and may constitute promising repositionable options for the development of novel therapeutics for the treatment of candidiasis.