Double stranded DNA-binding studies of potential Rhodium(ll) antitumor complexes

In 1952, Dwyer and coworkers began testing a series of metal complexes for potential inhibition of cancer cell proliferation in animals.[l] The complexes tested were unsuitable for such studies due to their high toxicity. Therefore, no further work was done on the project. However, in 1965, Rosenberg and coworkers revisited the possibility of potential metal-based drugs. Serendipitously, they discovered that cis-diamminedichloroplatinum(lI) (cisplatin) inhibits cell division in E. coli.[2] Further studies of this and other platinum compounds revealed inhibition of tumor cell lines sarcoma 180 and leukemia LI2l0 in mice.[l] Cisplatin was approved by the Food and Drug Administration in 1970 as a chemical chemotherapeutic agent in the treatment of cancer. The drug has primarily been used in the treatment of testicular and ovarian cancers, although the powerful chemotherapeutic properties of the compound indicate use against a variety of other cancers.[3] The toxicity of this compound, however, warrants the development of other metal-based potential antitumor agents. The success of cisplatin, a transition-metal-based chemotherapeutic, opened the doors to a host of research on the antitumor effects of other transition-metal complexes. Beginning in the 1970s, researchers looked to rhodium for potential use in antitumor complexes. Dirhodium complexes with bridging equatorial ligands (Figure I) were the primary focus for this research. The overwhelming majority of these complexes were dirhodium(II) carboxylate complexes, containing two rhodium(II) centers, four equatorial ligands in a lantero formation around the metal center, and an axial ligand on either end. The family of complexes in Figure 1 will be referred to as dirhodium(II) carboxylate complexes. The dirhodium centers are each d? with a metal-metal bond between them. Although d? atoms are paramagnetic, the two unpaired electrons pair to make the complex diamagnetic. The basic formula of the dirhodium(lI) carboxylate complexes is Rh?(RCOO)?(L)? with R being methyl, ethyl, propyl, or butyl groups and L being water or the solvent in which the complex was crystalized. Of these dirbodium(II) carboxylate complexes, our research focuses on Rb la and two other similar complexes Rh2 and Rh3 (Figure 2). Rh2 is an activated form of Rhla, with four acetonitrile groups in place of two of the bidentate acetate ligands. Rh3 is similar to Rhla, with trifluoromethyl groups in place of the methyl groups on the acetate ligands.

Investigation of Iron (III) desferrioxamine B oxalate ligand exchange by UV-vis spectroscopy: the next step in developing a quantitative analytical method for measuring bioavailable iron in marine ecosystems

To date there are no analytical techniques designed to exclusively measure bioavailable iron in marine environments. The goal of this research is to develop such a technique by isolating the bioavailable iron using the terrestrial siderophore desferrioxamine B (DFB). This project contained many challenging aspects, but the specific goal of this study was to develop a robust analytical technique for quantification of Fe(III)-DFB complexes at nanomolar concentrations. Past work showed that oxalate (Ox) promotes photodissociation of Fe(III)-DFB to Fe(Il), and we are specifically interested in the mechanism of this process. A model was developed using known thermodynamic constants for Fe(III)-DFB and Fe(III) oxalato complexes and adjusting for ionic strength. The model was confirmed by monitoring the UV-VIS absorbance of the system at a variety of oxalate concentrations and pH. The model did not include ternary complexes. Next., the rate of Fe(1I) production during UV irradiation was examined. The results showed that the rate of Fe(II) production was based entirely on the [Fe(Ox)?]3- speciation, and that reoxidation of Fe(II) occurred via reactive oxygen intermediates. This reoxidation could be avoided by either decreasing the oxygen concentration or by adding a Fe(II) stabilizing reagent, such as ferrozine. Further studies need to be done to confirm that these results apply at sub nanomolar concentrations, and the issue of Fe(II) reoxidation at lower Fe concentrations needs to be addressed.

Stranger in a Strange Land: The struggle for cultural and personal identity in Haruki Murakami's Hard-Boiled Wonderland and the End of the World

In order to explicate Murakami's version of the official culture, I have analyzed the novel with the works of several different theorists. Primarily, I drew my own understanding of the official culture from Raymond Williams's examination of culture in Marxism and Literature. His terminology became helpful in writing about the operation of the System and the Town, though it did not define that operation precisely. Williams's work also introduced me to the theory behind the official culture's manipulation and exclusion of historical aspects in order to create their "official" version of history, from which the official culture draws its identity. For further analysis of the treatment of history, I turned to Friedrich Nietzsche's On the Advantage and Disadvantage of History for Life. Though it examines the official culture's manipulation of history in a much more in-depth manner, it seems to have influenced Murakami's treatment of individual memories and cultural histories. For instance, the herd ofunicoms in the End of the World resembles Nietzsche's description of the ''unhistorical herd," or has the potential to resemble it. With these theories I was able to access the mechanisms of cultural control that Murakami depicts in the form of the System and the Town, and from there I was able to develop a model for how the narrator struggles to subvert that control. Both sides of that struggle are depicted and re-imagined many times throughout Hard-Boiled Wonderland and the End of the World.

Avoiding the Fog of Crisis: A Protocol for the Proper Domestic Use of the Military

Failure to contemplate and define an appropriate role for the armed forces of the national government in domestic crises of this sort is a serious problem. It is all the more serious now as these potential crises seem to multiply in character and scope. This thesis will explore the history of this problem and its recent implications. It will argue the need for a comprehensive, operational framework, codified in law, which defines the various alternative uses of all emergency services, both civilian and military, and is applicable to “all hazards.” I will attempt to provide a blue-print for what such a framework should look like.

Scriptural Archeology: Excavating the Presence of Women in the Torah

Women's roles in religious history have been traditionally described in terms of their relation and value to men. The normative religious texts provide an androcentric perspective on the gender relationships within the early community, the growth of Judaism in "Jacob's House" and the monotheistic worship of God. Yet these literary representations omit an entire half of the experience of the Jewish community: the perspective and participation of women. As Judith Plaskow argues extensively in Standing Again at Sinai, women are defined not in her own terms or in her own voice, but by her relationship and value to men through the androcentric vocabulary of the Torah. This statement is textually illustrated by the authorial and editorial presentation of women and their place in ancient Israelite society in the Torah. As Judaism grew increasingly androcentric in its leadership, women were increasingly reduced to marginal figures in the community by authorial and editorial revisions. Yet the participation of women of ancient Israel is not lost. Instead, the presence of women is buried beneath the androcentric presentation of the early Judaic community, waiting to be excavated by historical and scriptural examination. The retelling of the past is influenced by the present; memory is not static but takes on different shapes depending on the focus of concentration. However, tradition greatly influences the interpretation of religious history as well. In the book of Genesis, the literature emphasizes the divine appointment of male figures such as Abraham the father of the covenant and Jacob who is renamed and claimed by God as "Israel," placing them at the center of Jewish history. As a result, the other figures in these biblical narratives are described in relation to the patriarchs, those male bearers of the covenant, by their service or their value to him. Women are at the bottom of this hierarchy. Although female figures of exceptional quality are noted in later chronicles, such as Ruth, Deborah and Miriam, it is the very nature of their exception that highlights the androcentric editorial focus of the Torah. I agree with Peggy Day, whose own scriptural examination in Gender and Difference in Ancient Israel, makes the important distinction between the literary representation and the reality of ancient Israelite culture: they are not coextensive nor equivalent. Although the text represents the culture of ancient Israel as male dominated from the time of Abraham, this presentation omits the perspective of half of the population-the women. By beginning at the point of realization that women did exist and were active in their culture, and placing aside the androcentric perspective of the text and its editors, the reality of women's place in ancient Israel may be determined. Through this new perspective, the women of the Torah will emerge as the archetypes of strength, leadership and spiritual insight to provide Jewish women of the present with female, ancestral role models and a foundation for their gender's heritage, a more complete understanding of the partial record of Jewish history recorded in the Torah. Those stories that appear as the exception of women's presence will unveil an exceptional presence. As Tamar Frankiel eloquently states in The Voice of Sarah, "the women we call our 'Mothers'-Sarah, Rivkah (Rebekah), Rachel, and Leah-are not merely mothers, any more than the 'Fathers'-Abraham, Isaac and Jacob-are merely fathers "(Frankiel 5).

Using azahetercyclic electrophiles to synthesize novel Bicyclooxacalixarenes and Oxacalix[2]N-hexylnaphthalimide[2]naphthyridines

Various bicyclooxacalixarenes, tricyclooxacalixarenes and oxacalix[2]N-hexylnapthalimide[2]naphthyridines are synthesized via SnAr condensation. This research has involved synthesis optimization. The oxacalix[2]N-hexylnaphthalimide[2]naphthyridines have exhibited host-guest binding in fluorescence experiments. These compounds have been characterized by NMR spectroscopy as well as single crystal X-ray diffraction.

Theological Voices. PAC Politics and the Abortion Debate: Abortion Politics and the Reagan Era

This investigation shall focus upon the issue of legalized abortion. I believe the complex controversy surrounding the issue of abortion, demonstrates more clearly than any other single contemporary issue the social, political, moral and religious forces working for change in a post-Reagan America. I shall examine in depth the theology, writings, strategies and activities of those Americans who seek to express themselves and their beliefs in religious, or religiously supported interest groups. The current debate surrounding abortion legislation lends itself to several forms of analysis: religious, political, sociological, etc. I will write from the perspective of a student of religion. I shall focus more upon the religious, moral and theological conviction-s of the abortion activists than upon their constitutional right to free speech or assembly. I shall give more attention to denominational structures and church/state relations than to the structuring of representative districts and democratic theory.

Too Many Bad Cooks Spoiling the Broth? Effectiveness of NGOs in Addressing Child Labour in El Salvador

The reaction of the first world to the persevering plight of a large part of the third world varies. In response to the sometimes glaring disparities, many international organizations and multinational corporations have recently adopted a pro-development rhetoric with relation to the problem of global poverty. However, the rhetoric rarely translates into action. As David Bacon discusses, leaders of corporations and organizations now tend to conclude their speeches by expressing a desire to reduce the suffering of the third world. However, when it comes to agreeing on specific concessions that could indeed improve the world-wide economic situation, first world countries are reluctant to act. A good example of this type of behavior is the current negotiation of the WTO, the “development round of Doha,” in which the United States along with the European Union pressure countries of the developing South to open up their markets, while at the same time refusing to remove or even decrease their own agricultural subsidies. The first world civil society observes the behavior of international organizations and western based multinational corporations as ineffectual. Taking the matter in its own hands, especially in the past couple of decades, this civil society has created a countless number of development-oriented nongovernmental organizations. These are supposed to compensate for the lack of action by international organizations. Development NGOs are believed to be more locally responsive as well as free of business or political considerations in choosing their strategies, and thus generally more efficient than IOs. However, if they really were how they are alleged to be, the problems of the third world would already be ameliorated by a significant amount, if not completely eradicated. Do development-NGOs indeed possess the characteristics that they claim to possess? What is their real affect on human rights? And how effective are they in their work?

Opening the Windows of the Church to the World: The Creation of Nostra Aetate and Its Impact on the Christian-Jewish relationship

It is important to assert that this study is not a work to inflict guilt on the Catholics or Catholicism for their silence and indifference during the Holocaust. Instead, this study is about the process of moving on from the Catholic Church's past to where the Jewish community's theological existence was finally recognized and the Jewish people were no longer seen as the Others who killed Christ. This was, achieved through a church declaration titled Nostra Aetate (In Our Time). This study records the journey traversed by this declaration, the insurmountable odds it faced in its creation until its promulgation and the impact it has on the Jewish-Christian relationship.

The Pollination Biology and Mating System of a Peripheral Population of Witheringia solanacea (Solanaceae)

Pollinator visitation rates over the life of a flower are determined by pollinator abundance and floral longevity. If flowers are not visited frequently enough, pollen limitation may occur, favoring the evolution of self-compatibility (SC). In plant species with varying SC levels, central populations often are self-incompatible (SI) and peripheral populations are SC. Witheringia solanacea (Solanaceae) is a species that follows this trend with the exception of one population in the Monteverde Cloud Forest Reserve, which is peripheral yet SI. I investigated this population using multiple techniques including floral bagging, pollinator observations, microsatellite analysis, and floral longevity manipulations. My results confirmed the self-incompatibility of the Monteverde population and indicated low but perhaps adequate rates of pollinator visitation per flower per hour. I found reduced genetic diversity at Monteverde and gene flow occurring unidirectionally from San Luis (a central population) to Monteverde. In the greenhouse, there was more of an effect of male than female function on floral longevity, but the largest differences were environmental. Flowers stayed open substantially longer when cool, cloudy weather was simulated and shorter when conditions were hot and sunny. The results indicate that the Monteverde population of W. solanacea is SI because 1) it is unable to maximize its fitness due to gene flow from San Luis and its relatively recent colonization of the area and 2) pollen limitation may not be severe because of supplemental pollinator availability from other Witheringia species in the area and increased floral longevities due to cool and cloudy conditions.

Cytotoxicity of Diepoxybutane and Epichlorohydrin in Relation to Stages of the Cell Cycle

Work conducted in the Millard Biochemistry Research Laboratory examines the dual nature of molecules as carcinogens and anti-tumor agents through the molecular mechanisms of duplex DNA damage by bifunctional alkylating agents. Diepoxybutane (DEB) and epichlorohydrin (ECH) are polar molecules that form covalent DNA interstrand lesions by cross-linking the N7 position of deoxyguanosine residues. A recent experiment indicated that ECH preferentially targets nuclear DNA over mitochondrial DNA, whereas DEB shows similar rates of lesion formation for both loci. It was concluded that preferential targeting of nuclear DNA results from relatively poor uptake of ECH across the mitochondrial membrane. The objective of my honors research was to determine if the cytotoxicities of DEB and ECH vary according to the presence of the nuclear envelope in 6C2 chicken erythro-progenitor cells. The cytotoxicity of DEB and ECH was compared between cells randomly distributed throughout the cell cycle (Go/G, and S » G2/M) and cells enriched in G2/M stages. Results indicated that ECH is more cytotoxic than DEB in both unsynchronized control 6C2 cells and synchronized 6C2 cells enriched in G2/M stages of the cell cycle. Treatment with either bifunctional alkylating agent induced greater cytotoxicity in 6C2 cells enriched in G2/M stages than in unsynchronized control 6C2 cells, suggesting that the presence of the nuclear envelope-or any plasma membrane-may inhibit the reactivity of DEB and ECH.

Syntheses of Cross-Linking Agents, Molecular Modeling of Oligonucleotides and Polypeptide-Ion Complexes

Each section of this thesis will be subdivided into three parts encompassing all of the research in which I have been involved during the past three years. These will be referred to under the headings "Syntheses:' "Molecular Modeling," and "Cross-linking Efficiencies." Each of these subdivisions may have divisions within them when necessary in order to fully detail the research.

Therapeutic Discourse and the American Public Philosophy: On American Liberalism's Troubled Relationship with Psychology

I explore the main currents of postwar American liberalism. One, sociological, emerged in response to the danger of mass movements. Articulated primarily by political sociologists and psychologists and ascendant from the mid-fifties till the mid-seventies, it heralded the "end of ideology." It emphasized stability, elitism, positive science and pluralism; it recast normatively sound politics as logrolling and hard bargaining. I argue that these normative features, attractive when considered in isolation, taken together led to a vicious ad hominem style in accounting for views outside the postwar consensus. It used pseudo-scientific literature in labeling populists, Progressives, Taft conservatives, Goldwaterites, the New Left and others "pathological," viz. mentally ill. Hence, "therapeutic discourse." I argue that philosophical liberalism, which reasserts the role of political theory in working out norms and adjudicating disagreement, is a more profitable way of thinking about and defending from critics liberalism. I take the philosopher John Rawls as the tradition's modern representative. This inquiry is important because the themes of sociological liberalism are making a comeback in American public discourse, and with them perhaps the baggage of therapeutic discourse. I present a cautionary tale.

Investigating the Effects of Mifepristone (RU486) in the Behavioral, Hormonal and Central Responses to Acute Stress

Depression is associated with glucocorticoid hypersecretion, due to dysfunction of the hypothalamo-pituitary-adrenocorticol axis (HPA-axis). Because excess glucocorticoids are associated with depressive-like features in humans, glucocorticoid receptor antagonists are currently being tested for antidepressant efficacy in clinical trials. In the current study the hypothesis that mifepristone (RU486), a glucocorticoid receptor antagonist, would decrease the neuroendocrine and central HPA-axis responses to an acute stressor and attentuate depressive like behavior in an animal model of behavioral helplessness (forced swim test) was tested. Adult male rats were treated with 10 mglkg RU486 (subcutaneous) for five days and then exposed to a IO-minute forced swim test (FST), conducted in Plexiglas cylinders. FST sessions were videotaped for later analysis of behavioral immobility. Plasma ACTH and corticosterone CORT were measured at 15min and 90min after FST cessation. Animals were perfused and brains were collected for immunocytochemical assessment of c-Fos expression in the medial prefrontal cortex (mPFC), a brain region implicated in both depression and central control of the HPA axis. RU486 significantly decreased peak ACTH and CORT concentrations following FST exposure. In addition, glucocorticoid negative feedback was at1enuated in RU486-treated animals exposed to the FST. Exposure to FST alone induced c-FOS expression in the mPFC, as measured by the number of c-Fos positive neurons. Treatment with RU486 significantly increased the number of rnPFC c-Fos positive cell following FST exposure. The behavioral data obtained from FST paradigm, demonstrated that RU486 decreased immobility in the FST illustrating the potential efficacy of this drug as an antidepressant. Collectively these data suggest that RU486 dampens HPA-axis responses to stress, possibly by enhancing the excitability of stress-inhibitory neurons in the mPFC. This is particularly exciting, given the fact that this neural region is associated with decreased neural activity during depression in humans.

The Effects of Eating Behaviors and Exercise Patterns on the Processing of Food and Exercise Related Stimuli

The effectiveness of Cognitive Behavioral Therapy (CBT) for eating disorders has established a link between cognitive processes and unhealthy eating behaviors. However, the relationship between individual differences in unhealthy eating behaviors that are not related to clinical eating disorders, such as overeating and restrained eating, and the processing of food related verbal stimuli remains undetermined. Furthermore, the cognitive processes that promote unhealthy and healthy exercise patterns remain virtually unexplored by previous research. The present study compared individual differences in attitudes and behaviors around eating and exercise to responses to food and exercise-related words using a Lexical Decision Task (LDT). Participants were recruited from Colby (n = 61) and the greater Waterville community (n = 16). The results indicate the following trends in the data: Individuals who scored high in “thin ideal” responded faster to food-related words than individuals with low “thin Ideal” scores did. Regarding the exercise-related data, individuals who engage in more “low intensity exercise” responded faster to exercise-related words than individuals who engage in less “low intensity exercise” did. These findings suggest that cognitive schemata about food and exercise might mediate individual’s eating and exercise patterns.