A major problem with breast cancer treatment is the prevalence of antiestrogen resistance, be it de novo or acquired after continued use. Many of the underlying mechanisms of antiestrogen resistance are not clear, although estrogen receptor-mediated actions have been identified as a pathway that is blocked by antiestrogens. Selective estrogen receptor modulators (SERMs), such as tamoxifen, are capable of producing reactive oxygen species (ROS) through metabolic activation, and these ROS, at high levels, can induce irreversible growth arrest that is similar to the growth arrest incurred by SERMs. This suggests that SERM-mediated growth arrest may also be through ROS accumulation. Breast cancer receiving long-term antiestrogen treatment appears to adapt to this increased, persistent level of ROS. This, in turn, leads to the disruption of reversible redox signaling that involves redox-sensitive phosphatases and protein kinases and transcription factors. This has downstream consequences for apoptosis, cell cycle progression, and cell metabolism. For this dissertation, we explored if altering the ROS formed by tamoxifen also alters sensitivity of the drug in resistant cells. We explored an association with a thioredoxin/Jab1/p27 pathway, and a possible role of dysregulation of thioredoxin-mediated redox regulation contributing to the development of antiestrogen resistance in breast cancer. We used standard laboratory techniques to perform proteomic assays that showed cell proliferation, protein concentrations, redox states, and protein-protein interactions. We found that increasing thioredoxin reductase levels, and thus increasing the amount of reduced thioredoxin, increased tamoxifen sensitivity in previously resistant cells, as well as altered estrogen and tamoxifen-induced ROS. We also found that decreasing levels of Jab1 protein also increased tamoxifen sensitivity, and that the downstream effects showed a decrease p27 phosphorylation in both cases. We conclude that the chronic use of tamoxifen can lead to an increase in ROS that alters cell signaling and causing cell growth in the presence of tamoxifen, and that this resistant cell growth can be reversed with an alteration to the thioredoxin/Jab1 pathway.

Invasive range expansion is correlated to life- history variation, boldness and dispersal behavior. The invasion of the African Jewelfish in Everglades National Park provides an opportunity to test life-history trait variation, boldness and dispersal behavior in the invasion success of this species. My study examined variation in somatic traits, boldness, and dispersal of jewelfish across their invaded range. Life histories were examined on wild individuals. Boldness and dispersal were tested in outdoor experimental tanks. Tested populations from the invasion front have higher somatic traits, but they were not bolder than longer established populations. Understanding the underlying mechanisms of invasions are key for the development of strategies looking to contain invaders and prevent their spread.

The presences of heavy metals, organic contaminants and natural toxins in natural water bodies pose a serious threat to the environment and the health of living organisms. Therefore, there is a critical need to identify sustainable and environmentally friendly water treatment processes. In this dissertation, I focus on the fundamental studies of advanced oxidation processes and magnetic nano-materials as promising new technologies for water treatments. Advanced oxidation processes employ reactive oxygen species (ROS) which can lead to the mineralization of a number of pollutants and toxins. The rates of formation, steady-state concentrations, and kinetic parameters of hydroxyl radical and singlet oxygen produced by various TiO2 photocatalysts under UV or visible irradiations were measured using selective chemical probes. Hydroxyl radical is the dominant ROS, and its generation is dependent on experimental conditions. The optimal condition for generation of hydroxyl radical by of TiO2 coated glass microspheres is studied by response surface methodology, and the optimal conditions are applied for the degradation of dimethyl phthalate. Singlet oxygen (1O2) also plays an important role for advanced processes, so the degradation of microcystin-LR by rose bengal, an 1O2 sensitizer was studied. The measured bimolecular reaction rate constant between MC-LR and 1O2 is ~ 106 M-1 s-1 based on competition kinetics with furfuryl alcohol. The typical adsorbent needs separation after the treatment, while magnetic iron oxides can be easily removed by a magnetic field. Maghemite and humic acid coated magnetite (HA-Fe3O4) were synthesized, characterized and applied for chromium(VI) removal. The adsorption of chromium(VI) by maghemite and HA-Fe3O4 follow a pseudo-second-order kinetic process. The adsorption of chromium(VI) by maghemite is accurately modeled using adsorption isotherms, and solution pH and presence of humic acid influence adsorption. Humic acid coated magnetite can adsorb and reduce chromium(VI) to non-toxic chromium (III), and the reaction is not highly dependent on solution pH. The functional groups associated with humic acid act as ligands lead to the Cr(III) complex via a coupled reduction-complexation mechanism. Extended X-ray absorption fine structure spectroscopy demonstrates the Cr(III) in the Cr-loaded HA-Fe3O4 materials has six neighboring oxygen atoms in an octahedral geometry with average bond lengths of 1.98 Å.

With the recent emergence of candidemia as a significant cause of mortality in our health care system, clinicians must identify methods to minimize the sequelae of infection of this type in patients already burdened with serious underlying conditions. While well established as a major cause of blood stream infection (BSI), candidemia has been shown to have some of the highest rates of inappropriate therapy when compared to infections from all other sources. Rates of inappropriate therapy may be even higher for some of the less common and antifungal resistant non-albicans candidemia. Identifying those patients at risk for the development of these types of infections will help improve clinical outcomes. Antifungal activity is dependent both on species and agent, describing the unique susceptibility patterns between Candida species can help identify the appropriate therapy. We performed a case-case-control study to identify clinical risk factors for the development of Candida glabrata candidemia compared to Candida albicans candidemia and an uninfected control using multivariate and logistic regression analysis. We observed that patients in the C. glabrata cohort were more likely to have gastrointestinal disorders and peripheral vascular disease than patients suffering from C. albicans BSIs. We also determined that when compared to the uninfected control group, patients with C. glabrata BSIs were more likely to have been prior colonized with C. glabrata, undergone dialysis, and have been catheterized with both arterial and urinary catheters. We concluded that patient exposure to unique clinical risk factors may be predictive of the development of future candidemia and may help distinguish between albicans versus non-albicans candidemia. We performed a drug susceptibility study using time-kill methods with the echinocandin antifungal agents on Candida parapsilosis and two newly identified species of Candida, C. orthopsilosis and C. metapsilosis. The echinocandins as a group displayed primarily fungistatic activity against the clinical isolates tested. However, we observed substantial variability in antifungal activity that varied by both the echinocandin used and Candida species analyzed. We concluded that this variability in activity that is both species and drug dependent should be considered when selecting the treatment of candidemia resulting from these non-albicans species.

Cancer cells are believed to exist in a condition of metabolic oxidative stress compared to normal cells because of inherent mitochondrial dysfunction. Cancer cells up regulate antioxidant defense mechanisms to combat the toxic effect of reactive oxygen species (ROS). Many anticancer agents block ROS detoxification mechanisms and utilize oxidative stress to cause cytotoxicity to cancer cells. However, ROS also up-regulate many pro-survival signaling pathways that may mediate resistance to chemotherapy. I hypothesize that ROS induces both cytotoxicity and pro-survival mechanisms in cells treated with chemotherapeutic agents such as the EGFR inhibitor erlotinib. This thesis explores how oxidative stress may induce both pro-survival and pro-death mechanisms in HNSCC cells and how this can be exploited to increase the cytotoxicity of erlotinib. The combined use of buthionine-[S,R]-sulfoximine, an inhibitor of glutathione and auranofin, an inhibitor of thioredoxin metabolism enhanced human head and neck cancer cell killing by a mechanism involving oxidative stress both in vitro and in vivo and sensitized cells to erlotinib in vitro. However, in other studies erlotinib as a single agent induced oxidative stress and this was mediated by NADPH oxidase 4 (NOX4). NOX4 mediated oxidative stress activated a process called autophagy which protected cancer cells from cytotoxic effect of erlotinib and inhibition of autophagy sensitized cells to erlotinib in vitro. These studies show that oxidative stress may have a dual role in cancer chemotherapy. ROS generated from various drug treatments can cause oxidative damage of cells culminating in cell death. However, it may also activate autophagy protecting cells against the stress and leading to decreased efficacy of the treatment. Hence inhibiting autophagy and hydroperoxide metabolism can be effective treatment modalities to enhance the cytotoxicity of erlotinib and achieve maximum therapeutic efficacy.

Thesis (MSc. (Plant production)) -- University of Limpopo, 2016 / Seriphium plumosum is a declared indicator of bush encroachment, and poses a serious threat to the management of sustainable utilization in all grasslands. The successful invasiveness of S. plumosum is attributed to its competitive ability and high allelopathic potential. A trial was established at the University of Limpopo to investigate the interference between S. plumosum and four plant species, namely: Eragrostis curvula, E. tef, Panicum maximum and Lactuca sativa. Plant material of S. plumosum were collected and used to make infusions which were used on the receiver species. The infusion inhibited the germination of all the receiver species, and it was highly significant (P ≤ 0.01), compared to control treatments where no inhibition occurred. All receiver species were sensitive to roots and shoots infusions, but the effect of shoots infusion differed significantly (P ≤ 0.01) from those of roots infusion. All receiver species were sensitive to both summer and winter collected materials, but plant material collected in winter had a bigger effect (P ≤ 0.01) than plant material from summer. All receiver species were sensitive to both fresh and stored plant material, but inhibition effects were not statistically significantly different (P ≥ 0.05). All receiver species were sensitive to both fresh and stored soils collected in infested areas, but effects were not significantly different (P ≥ 0.05), while the effects of infested and un-infested soils differed significantly (P ≤ 0.01). All receiver species were sensitive to soils collected during summer and winter. Where infested soils were concerned, all receiver species were sensitive to infested soils, compared to control treatments where no effects occurred. Where stored infested soils were concerned, all receiver species were sensitive to both fresh and stored infested soils. It was concluded that both plant material of S. plumosum and soils from areas encroached by S. plumosum have a negative effect on seed germination of the four receiver species. Should a farmer control this species by means of cutting, it should be quickly removed to allow the gass to recover. The farmer must not expect quick recovery of grasses due to the presence of allelopathic substances in the soil. / Agri-seta

Philosophiae Doctor - PhD / Searsia is the more recent name for the genus (Rhus) that contains over 250 individual species of flowering plants in the family Anacardiaceae. Research conducted on Searsia extracts to date indicates a promising potential for this plant group to provide renewable bioproducts with the following reported desirable bioactivities; antimicrobial, antifungal, antiviral, antimalarial, antioxidant, antifibrogenic, anti-inflammatory, antimutagenic, antithrombin, antitumorigenic, cytotoxic, hypoglycaemic, and leukopenic (Rayne and Mazza, 2007, Salimi et al., 2015). Searsia glauca, Searsia lucida and Searsia laevigata were selected for this study. The aim of this study was to isolate, elucidate and evaluate the biological activity of natural products occurring in the plants selected.

Philosophiae Doctor - PhD / The blood-brain barrier (BBB) is a critical interface between the blood circulation and brain tissue which performs critical selection of circulating molecules that gain access to the brain tissue. Its unique ability to adjust to changes in the constituents of the blood circulation confer in the BBB a dynamic nature enabling changes in its properties to suit the homeostatic needs of the brain. Dysfunction of the BBB has been established to be pivotal to the initiation and/or maintenance of an array of neurological disorders, most of which involve the production of excess reactive oxygen species (ROS) and oxidative stress in their pathophysiology. Thus, clinical trials of exogenous antioxidant agents have been proposed and initiated, with most results being inconclusive. Extensive studies of the impact, capacity and plasticity of endogenous antioxidants in the cells that constitute the blood-brain barrier, especially the brain endothelial cells, therefore, became necessary for the rational choice, timing, and the mode of application of antioxidants in the management of oxidative stress-mediated neurological diseases.

付記する学位プログラム名: 霊長類学・ワイルドライフサイエンス・リーディング大学院 / 京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第22635号 / 理博第4624号 / 新制||理||1664(附属図書館) / 京都大学大学院理学研究科生物科学専攻 / (主査)准教授 足立 幾磨, 准教授 後藤 幸織, 教授 濱田 穣 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

Up to 87% of the world’s wetlands have been destroyed, considerably reducing ecosystem services these wetlands once provided. More recently, many wetlands are being restored in an attempt to regain their ecosystem service. This study seeks to determine the effects of restored wetlands on local bat habitat use. Bat activity was found to be significantly higher around the wetlands when compared to distant grassy fields; however, no significant difference was found among the restored wetlands and a remote cattle farm containing multiple water features. Geospatial models of bat distribution and bat foraging were produced using machine learning that showed higher habitat suitability and foraging activity around restored wetlands than around distant grassy fields, suggesting that wetlands provide vital habitat for insectivorous bats. This study demonstrates that restored wetlands promote bat activity and bat foraging, and restoring wetlands may be a useful means of increasing natural pest control over nearby farmlands.