Global ETD Search

1	The mechanism of waterborne lead uptake and toxicity in <i>Daphnia magna</i> Roy, Sayanty 05 June 2009 Lead is an omnipresent pollutant, and its contamination in natural waters is an issue of current regulatory concern throughout the world including Canada. The free divalent ion of lead (Pb2+) is considered to be the most bioavailable and toxic form of lead. Pb2+ is known to be a calcium antagonist in vertebrates including fish. It is believed that lead causes toxicity to freshwater fish primarily by disrupting ionic homeostasis both during acute and chronic waterborne exposure. Lead can also potentially act as a respiratory toxicant since it is known to impair hemoglobin synthesis in both vertebrates. To date, the mechanistic underpinnings of lead accumulation and toxicity in aquatic invertebrates are not well understood, particularly during acute exposure. Therefore, the main objectives of the present study were in two folds: (i) to investigate the mechanisms of waterborne lead uptake, and (ii) to understand the physiological basis of lead toxicity during acute exposure. I used freshwater crustacean, <i>Daphnia magna</i>, as a model freshwater invertebrate species for my study. <i>Daphnia</i> are known to be quite sensitive to metals and widely used as a model species for toxicity assessments. The results of my study suggest that lead inhibits waterborne Ca2+ uptake in <i>Daphnia</i> in a concentration dependent manner, and this inhibition occurs predominantly through a direct competitive interaction. The entry of waterborne Pb2+ in <i>Daphnia</i> likely occurs via both lanthanum-sensitive and verapamil-sensitive epithelial calcium channels. Moreover, my results also indicate that acute waterborne lead exposure severely disrupts both Ca2+ and Na+ uptake from water, which are concomitant with the increase in the lead body burden in <i>Daphnia</i>. Interestingly however, acute exposure to lead does not affect the rate of oxygen consumption in <i>Daphnia</i>, indicating no acute respiratory toxicity of lead. Overall, it appears that lead acts as an ionoregulatory toxicant to <i>Daphnia</i> during acute waterborne exposure. Lead. Daphnia magna ion uptake and ion homeostasis
2	The mechanism of waterborne lead uptake and toxicity in <i>Daphnia magna</i> Roy, Sayanty 05 June 2009 (has links) Lead is an omnipresent pollutant, and its contamination in natural waters is an issue of current regulatory concern throughout the world including Canada. The free divalent ion of lead (Pb2+) is considered to be the most bioavailable and toxic form of lead. Pb2+ is known to be a calcium antagonist in vertebrates including fish. It is believed that lead causes toxicity to freshwater fish primarily by disrupting ionic homeostasis both during acute and chronic waterborne exposure. Lead can also potentially act as a respiratory toxicant since it is known to impair hemoglobin synthesis in both vertebrates. To date, the mechanistic underpinnings of lead accumulation and toxicity in aquatic invertebrates are not well understood, particularly during acute exposure. Therefore, the main objectives of the present study were in two folds: (i) to investigate the mechanisms of waterborne lead uptake, and (ii) to understand the physiological basis of lead toxicity during acute exposure. I used freshwater crustacean, <i>Daphnia magna</i>, as a model freshwater invertebrate species for my study. <i>Daphnia</i> are known to be quite sensitive to metals and widely used as a model species for toxicity assessments. The results of my study suggest that lead inhibits waterborne Ca2+ uptake in <i>Daphnia</i> in a concentration dependent manner, and this inhibition occurs predominantly through a direct competitive interaction. The entry of waterborne Pb2+ in <i>Daphnia</i> likely occurs via both lanthanum-sensitive and verapamil-sensitive epithelial calcium channels. Moreover, my results also indicate that acute waterborne lead exposure severely disrupts both Ca2+ and Na+ uptake from water, which are concomitant with the increase in the lead body burden in <i>Daphnia</i>. Interestingly however, acute exposure to lead does not affect the rate of oxygen consumption in <i>Daphnia</i>, indicating no acute respiratory toxicity of lead. Overall, it appears that lead acts as an ionoregulatory toxicant to <i>Daphnia</i> during acute waterborne exposure. Lead. Daphnia magna ion uptake and ion homeostasis
3	Roles for zebrafish trpm7 in growth, skeletogenesis, kidney function and physiological ion homeostasis Elizondo, Michael Reuben 20 August 2010 (has links) Development of the adult form requires coordinated growth and patterning of multiple traits in response to local gene activity as well as global endocrine and physiological effectors. In recent years the zebrafish has been utilized as a favorable animal model as a step towards dissecting and better understanding these postembryonic developmental processes. One of the more powerful methods utilized in zebrafish has been the identification of new gene functions through the use of mutant screens. The nutria mutant was recovered from one such screen to identify postembryonic defects in pigment pattern, growth and metamorphosis. These mutants exhibited a pigment cell defect, touch unresponsiveness and severe growth retardation. Here I will discuss my work towards dissecting the underlying developmental processes governing the phenotypic changes in nutria mutants. I characterize gross alterations in skeletal development in nutria mutants that lead to accelerated endochondral ossification but delayed intramembranous ossification. I show that the nutria phenotype results from mutations in trpm7, which encodes a transient receptor potential (TRP) family member that functions as both a cation channel and a kinase. I find trpm7 expression in the fish-specific, ion homeostasis-regulating gland known as the corpuscles of Stannius (CS), and in the mesonephric kidney. I show that mutants also develop kidney stones. Together these results suggest a role for trpm7 activity in regulation of physiological ion homeostasis. Next I confirm that role by identifying late-embryonic and early larval defects in the CS and the kidney, two organs that regulate physiological ion homeostasis. I demonstrate the early larval detection of kidney stones in trpm7 mutants and show that their appearance is presaged by decreased levels of total calcium and magnesium. Furthermore I establish a link between trpm7 function in the CS and stanniocalcin1 (stc1), a potent molecular regulator of calcium homeostasis. Finally, using transgenic overexpression and morpholino-oligonucleotide knockdown, I demonstrate that stc1 modulates calcium and magnesium levels in trpm7 mutant and wild-type backgrounds. Together these analyses establish postembryonic roles for trpm7 function in growth, skeletogenesis, kidney function, and physiological ion homeostasis. / text trpm7 Zebrafish Danio Rerio Bone Kidney Growth Ion homeostasis Calcium Magnesium Kidney stone Stanniocalcin stc1 Skeletogenesis
4	Developing Tools towards Ion Homeostasis in Spatially Polarized Excitable Cells Liu, Ziyi 16 January 2024 (has links) In 1800, Volta, inspired by the electric organs of a genus of electric fish, the Electrophorus, invented the first electric batteries, which were termed "artificial electric organs." Since then, the far-reaching implications of the fishes’ electrogenesis have come under greater attention and interest. In these fishes, the electric organ resembles a series of batteries. The electric organs are formed by electrocytes (the "batteries") with a distinct cytomorphology for discharging and charging. Although the arrangements of electrocytes in the electric organ are well-understood, the mechanisms involved in generating electric discharges within equivalent circuits remain unclear. In this thesis, the first element consists of adapting spatially defined models that we use to investigate the process of electrocyte charging and recharging under the added assumption of ion homeostasis, the process by which a cell restores its internal milieu. The study focuses on Eigenmannia and Electrophorus, two genera of electric fish. Eigenmannia's steady high-frequency dipole oscillator-like electric organ discharges enables electro-sensing and electro-communication, whilst Electrophorus's brief taser-like electric bursts serve as tetanizing predatory assaults. In addition, the second section of this study proposes a one-dimensional charge difference model that focuses on the modification of endogenous electric fields resulting from the uneven distribution of ions in a homeostatic apparatus. Electric Organ Discharge Electric Fish Eigenmannia Electrophorus Ion Homeostasis Endogenous Electric Field Polarized Excitable Cell
5	Assessment of Cerebellar and Hippocampal Morphology and Biochemical Parameters in the Compound Heterozygous, Tottering/leaner Mouse Murawski, Emily M. 2009 December 1900 (has links) Due to two different mutations in the gene that encodes the a1A subunit of voltage-activated CaV 2.1 calcium ion channels, the compound heterozygous tottering/leaner (tg/tgla) mouse exhibits numerous neurological deficits. Human disorders that arise from mutations in this voltage dependent calcium channel are familial hemiplegic migraine, episodic ataxia-2, and spinocerebellar ataxia 6. The tg/tgla mouse exhibits ataxia, movement disorders and memory impairment, suggesting that both the cerebellum and hippocampus are affected. To gain greater understanding of the many neurological abnormalities that are exhibited by the 90-120 day old tg/tgla mouse the following aspects were investigated: 1) the morphology of the cerebellum and hippocampus, 2) proliferation and death in cells of the hippocampal dentate gyrus and 3) changes in basic biochemical parameters in granule cells of the cerebellum and hippocampus. This study revealed no volume abnormalities within the hippocampus of the mutant mice, but a decrease in cell density with the pyramidal layer of CA3 and the hilus of the dentate gyrus. Cell size in the CA3 region was unaffected, but cell size in the hilus of the dentate gyrus did not exhibit the gender difference seen in the wild type mouse. The cerebellum showed a decrease in volume without any decrease in cerebellar cellular density. Cell proliferation and differentiation in the subgranular zone of the hippocampal dentate gyrus remained normal. This region also revealed a decrease in cell death in the tg/tgla mice. Basal intracellular calcium levels in granule cells show no difference within the hippocampus, but an increase in the tg/tgla male cerebellum compared to the wild type male cerebellum. There was no significant difference in granule cell mitochondrial membrane potential within the wild type and mutant animals in either the hippocampus or cerebellum. The rate of reactive oxygen species (ROS) production in granule cells revealed no variation within the hippocampus or cerebellum. The amount of ROS was decreased in cerebellar granule cells, but not granule cells of the hippocampus. Inducing ROS showed no alteration in production or amount of ROS produced in the hippocampus, but did show a ceiling in the amount of ROS produced, but not rate of production, in the cerebellum. Cerebellum Hippocampal neurogenesis Voltage-gated calcium ion channels Mitochondrial membrane potential
6	REPURPOSING FDA-APPROVED DRUGS FOR OVERCOMING AZOLE RESISTANCE IN CANDIDA SPECIES Hassan Elsayed Eldesouky (8715252) 21 June 2022 (has links) <p>In the past few decades, invasive mycosis has become a growing threat to global health, afflicting millions of people and claiming the lives of more than 1.5 million patients every year. Moreover, the economic burden of mycotic infections has become increasingly exhausting especially with the recent increases in the number of the high-risk population, the immunocompromised individuals. In the USA, the cost incurred by mycotic infections was estimated to be of more than $7.2 billion only in 2017. Of particular concern, <i>Candida</i> species are the most common fungal pathogens that infect humans, resulting in considerable morbidities and mortality rates that often exceed 50%. Unfortunately, the antifungal drug discovery is currently unable to keep pace with the urgent demand for more effective therapeutic options. Further complicating the situation is the recent emergence of multidrug-resistant species such as <i>Candida</i> <i>auris</i>, triggering outbreaks of deadly Candidemia across the globe. Given the risks inherent to the traditional de-novo drug discovery, combinatorial therapeutics stands out as a promising tool to hamper drug resistance and extend the clinical utility of the existing drugs. In this study, we assembled and screened ~3147 FDA-approved drugs and clinical molecules against fluconazole-resistant <i>C. albicans</i> and <i>C. auris</i> isolates, for the aim of restoring the antifungal activity of azole antifungals against drug-resistant <i>Candida </i>species. The screen revealed five promising hits: pitavastatin (antihyperlipidemic), ospemifene (estrogen receptor modulator), sulfa antibacterial drugs, lopinavir (antiviral), and aprepitant (antiemetic).</p> <p>All identified hits demonstrated variable azole chemosensitizing activities depending on the tested <i>Candida</i> species and the azole drug. Pitavastatin displayed broad-spectrum synergistic interactions with both fluconazole and voriconazole against isolates of <i>C. albicans</i>, <i>C. glabrata</i>, and <i>C. auris</i>. Ospemifene was able to interact synergistically with itraconazole against multiple fungal isolates including <i>Candida</i>, <i>Cryptococcus</i>, and <i>Aspergillus</i> species. Sulfa drugs displayed potent synergistic activities with different azoles against <i>C. albicans</i>, however, a limited efficacy was observed against efflux-hyperactive isolates such as <i>C. auris</i>. On the other hand, both lopinavir and aprepitant exerted potent and broad-spectrum synergistic activities with itraconazole and were effective against multiple <i>Candida</i> species including <i>C. albicans</i>, <i>C. auris</i>, <i>C. glabrata</i>, <i>C. krusie</i>, <i>C. tropicalis</i>, and <i>C. parapsilosis</i>. Furthermore, using <i>Caenorhabditis elegans</i> as an infection model, all drug combinations significantly reduced the fungal burden in the infected nematodes and significantly prolonged their survival as compared to single-drug treatments. Multiple phenotypic and molecular assays indicted that the identified hit compounds use distinct mechanisms to enhance the antifungal activity of azole drugs. These mechanisms include efflux pump inhibition, interference with the folate biosynthesis and disturbance of iron homeostasis. Taken together, this study reveals novel and potent azole chemosensitizing agents effective against multiple azole-resistant isolates and opens the door for more investigations to assess their clinical potential in human medicine as promising antifungal adjuvants.</p> Microbiology not elsewhere classified Azole resistance Candida auris Candida albicans Pitavastatin Ospemiphene Sulfa drugs Lopinavir Aprepitant Fungal Efflux Pumps Metal Ion Homeostasis Fungal Folate Pathway Caenorhabditis elegans Microbiology
7	Purification, functional characterization and crystallization of the PerR peroxide sensor from Saccharopolyspora erythraea Elison Kalman, Grim January 2019 (has links) This report summarizes the work on the cloning, expression, and purification of PerR, a metal sensing regulator from Saccharopolyspora erythraea and the subsequent characterization using small angle X-ray scattering and other biochemical methods. The report aims to provide an insight into prokaryotic metal homeostasis, provide a better understanding of how PerR works and provide valuable information for the continued work on the crystallization of PerR. structural biology cell culture protein expression genetic engineering spectroscopy X-ray crystallography small angle X-ray scattering SAXS transcription factor PerR metal binding antibiotics Saccharopolyspora erythraea S. erythraea soil bacterium actinobacteria actinomycetes oxidative stress peroxide stress structure determination characterization stabilization peroxide sensor iron sensor manganese sensor metalloprotein metal ion homeostasis metal ion prokaryotic strukturbiologi cellodling proteinuttryck genteknik spektroskopi röntgenkristallografi småvinkel-röntgenspridning SAXS transkriptionsfaktor PerR metallbindande antibiotika Saccharopolyspora erythraea S. erythraea jordartsbakterie Aktinobakterier Actinobacteria Actinomycetes oxidativ stress peroxid stress strukturbestämning karaktärisering stabilisering peroxidsensor järnsensor mangansensor metalljonshomeostas metalljoner prokaryot Structural Biology Strukturbiologi

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