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Boronic Acids as Penicillinase Inhibitors
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Abstract Boronic Acids as Penicillinase Inhibitors by Juan F. Barquero Advisor: Dr. Manfred Philipp. £]-lactamases are enzymes produced by bacteria resistant to antibiotics. A common feature on beta lactam antibiotics is the beta-lactam ring. £]-lactamases hydrolyze the £]-lactam ring leaving the antibiotic inoperative. The advent of bacteria that are resistant to £]-lactams has impelled researchers to find inhibitors for £]-lactamases that mimic the lactam ring but do not get hydrolyzed. One group of these new antibiotics is the aryl boronic acids. The main reason the boronic acids have been chosen as potential drugs is their lack of toxicity and their easy excretion in the urine. One of the most important structural features of these compounds is their chemical and geometric fitness in the active site of £]-lactamases. Boronic acids mimic the tetrahedral intermediate formed in the half-acylation reaction that occurs during the hydrolysis of the fÒ-lactam ring. The major goal of the research presented here was to discover new aryl boronic acids inhibitors of penicillinases from the class A £]-lactamases. To accomplish this goal, commercially available boronic acids that are manufactured for the Suzuki reaction were used. These compounds included fluorinated, chlorinated, brominated, carboxylated, nitrophenylated, pinacol-esterified and thiophene-carboxylated aryl boronic acid derivatives. Kinetic evaluations of each class of compounds were performed under pseudo first-order enzymatic reaction conditions and the inhibitory constants (Ki) were reported using nitrocefin as substrate for two enzymes: the in-house expressed £]-lactamase BlaC and the £]-lactamase from Bacillus cereus 569/H9 (Calbiochem) identified as TEM-116. The structure-activity relationship (SAR) showed that the most potent inhibitors of BlaC £]-lactamase were 2-carboxythiophene-5-boronic acid; 3,4,5-trifluorophenylboronic acid; 3-nitrophenytlboronic acid and 2,3,4,5-tetrafluorophenylboronic acid, Ki values of 1.2, 175.7, 213.9 and 228.6 micromolar respectively. In addition, SAR revealed that the most potent inhibitors for Bacillus cereus £]-lactamase I were 2-carboxythiophen-5-boronic acid, 3-carboxyphenylboronic acid, 2-carboxythiophene-4-boronic acid, and 3-carboxy-4-fluorophenylboronic acid having Ki values of 1.1, 19.4, 46.5, and 47.1 micromolar respectively. To gain further insight into the molecular interactions between each class of inhibitors and their targeted enzymes docking experiments were performed using Autodock Vina program combined with Sculpt from MDL and followed by the molecular visualization of the protein-ligand complexes using Swiss-PdbViewer and DiscoveryStudio from Accelerys. The results conclusively show that some selective classes of aryl boronic acids are potent competitive inhibitors of BlaC and Bacillus cereus £]-lactamase I and that they should be further considered for advanced drug discovery and improvement of treatment against antibiotic resistant bacteria. Furthermore, the discovery that 4,4¡¦-DDT is an inhibitor of Mycobacterium tuberculosis £]-lactamase, combined with in silico studies, suggests that further elaboration of this molecule may be one route to new inhibitors.
Contact-induced changes in word order and intonation in the Spanish of New York City bilinguals
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Hispanic & Luso Brazilian Literatures & Languages
This dissertation is a variationist sociolinguistic analysis of the variable word order and prosody of copular constructions (Nicolás es feliz versus Feliz es Nicolás, Es Nicolás feliz, Es feliz Nicolás, `Nicolas is happy') in the Spanish of first- and second-generation Spanish-English bilinguals in New York City. The data used for the study come from a spoken corpus of Spanish in New York City based on 140 sociolinguistic interviews (details of the corpus will be presented in Chapter Three). This dissertation addresses the question of whether second-generation bilinguals have a less flexible word order in Spanish as a result of their increased use of, and contact with, English, where a more fixed order prevails. We will show that the informants in the present study, like their peers in Los Angeles and other parts of the US, exhibit a more rigid word order compared to their first-generation peers. We have established that this increase in rigidity of word order among the second-generation can be attributed in large part to their increased use of and contact with English. The studies mentioned above have interpreted their results to mean that these speakers are losing or have lost the discourse pragmatic constraints that govern word order. However, the data here show that the first- and second-generation speakers in the present study share many of the same conditioning variables and constraints for word order, although these variables appear to account for a smaller amount of variance among the second-generation. In this way, we have established that the second-generation is not losing the discourse pragmatic constraints that govern word order, but that they are differently sensitive to these constraints. In fact, we show that second-generation speakers are very capable of communicating the pragmatic functions that the first-generation speakers do using word order because they maintain the prosodic details of their first-generation counterparts. In other words, the second-generation communicates these functions in ways that are slightly different from the first-generation, relying more on prosodic resources than syntactic ones. Furthermore, the data indicate that their prosodic patterns are not modeled after the prosody of English. In general terms we show that the second-generation does not have a different grammar from their first-generation counterparts, as is claimed by other researchers. Instead we show that these speakers favor certain first-generation strategies over others.
The Effects of Ethnic Matching on Abusive/Neglectful Minority Clients' Counseling Satisfaction, Engagement, Pre-mature Termination, and Outcome
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Georgiana Shick Tryon
This dissertation explored the relationship of ethnic matching between abusive and/or neglectful ethnic minority parents and minority counselors. Specifically, it examined these clients' satisfaction with and engagement in counseling as well as type of termination (unilateral or continuing) and outcome (client adjustment, meeting of agency goals, and re-abuse). This study also looked at the relationships of ethnic identity and acculturation discrepancies of clients who abused their children and their counselors, who were either ethnically matched or not matched, to client satisfaction, client engagement, client termination type, and client outcome. This dissertation sought to answer the following questions: (a) Are child-abusing clients who are ethnically matched with their counselors more satisfied with the intake counseling session than those who are not ethnically matched? (b) Are child-abusing clients who are ethnically matched with counselors more likely to become engaged in counseling than their non-matched counterparts? (c) Are child-abusing clients who are ethnically matched with their counselors less likely to terminate early than those who are not ethnically matched? ( d) Do child-abusing clients who are ethnically matched with their counselors have better outcomes than those who are not ethnically matched? (e) How do client-counselor differences in ethnic identity and acculturation relate to client satisfaction, engagement, termination, and outcome? I confirmed that abusive/neglectful clients who were ethnically matched with their counselors were significantly less likely to terminate prematurely after engagement than ethnically unmatched clients. Ethnic matching was not related to engagement, client satisfaction, or counseling outcome. Overall, results of this study suggested that ethnic matching per se may have little to do with client satisfaction, engagement, and outcome. Results also suggested that in contrast to ethnic matching, client-counselor ethnic identity discrepancy is important in client engagement, early-termination, and counseling outcome regardless of whether or not clients are ethnically matched. Although acculturation discrepancy was related to re-abuse, it had little relationship with the other variables in this study.
Components of Emotional Experience and Reaction Time: A study of Normal Aging and Parkinson's Disease
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We examined whether valence or arousal levels affect decision and movement times in Parkinson's disease (PD) and in healthy aging. For both decision and movement time, we were interested in differences in the speed and variability in responding. We also studied whether emotional experience is altered as a result of the aging process and PD pathology. Participants included 16 young healthy adults, 15 older healthy adults, and 15 non-demented individuals with mild PD. The PD participants were tested on medication. Participants viewed pictures from the International Affective Picture System (IAPS; Lang, Bradley, & Cuthbert, 2001) differing in emotional content and performed self-report valence and arousal ratings during picture presentation. Components of reaction time (i.e., decision time [DT] and movement time [MT]) were assessed during a forced-choice reaction time task. Results demonstrated that DT and MT were differentially affected by emotional stimuli. The PD group demonstrated significantly longer and more variable DTs than did the healthy controls for negative, positive, and neutral pictures; however, only the MTs for negative and neutral images were significantly different or more variable between groups. Although DTs were longer for the older control group relative to the younger control group, MTs were equivalent between the two control groups. Evidence of altered emotional experience in PD was found, as the PD participants rated negative pictures as less negative than did healthy older adults; however, this significant difference was reduced to a trend when individuals with more severe depressive symptomatology were excluded from the analysis. In addition, high arousal images were rated as more highly arousing among the PD group when depressed individuals were not included in the analyses. There was no evidence of impaired emotional experience as a function of aging, as valence and arousal ratings were not significantly different between younger and older adults. Better understanding of emotional processing deficits, which have been associated with poorer quality of life, in healthy aging and PD may lead to a better understanding of the neural bases of emotional processing, as well as offer treatment approaches.
PRICING COLLATERALIZED DEBT OBLIGATIONS WITH PURE JUMP LÉVY PROCESSES: A DYNAMIC BOTTOM-UP APPROACH
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The Gaussian copula model is the industry standard in pricing CDO tranches because of its easy implementation and speedy calibration. However, it has several well-known shortcomings: It leads to the so-called correlation smile", generates symmetric and light-tailed asset return distributions and it is static. This dissertation proposes a dynamic bottom-up model based on a pure jump Lévy process, a path rarely taken in the credit pricing literature, and makes a comprehensive empirical analysis of bottom-up CDO pricing models. Owing to its ability to capture asymmetric heavy-tailed return distributions and to accommodate different degrees of dampening for positive and negative jumps, empirical evidence shows that the proposed model significantly outperforms the models commonly employed in the industry and frequently referenced in the literature in fitting CDX and iTraxx tranche spreads. As such, it constitutes an important addition to the credit pricing literature.
The Powerful Voice of Women Dramatists in the Arab American Theatre Movement
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The Powerful Voice of Women Dramatists in the Arab American Theatre Movement by Dalia Basiouny Advisor: Marvin Carlson This dissertation traces the recent emergance of the Arab American Theatre movement, focusing on plays by women dramatists. It presents an overview of contemporary theatre and performances by Arab American women, and explores their focus on political theatre and identity politics, through an examination of works by fifteen contemporary women playwrights and performers. The emergance of this relatively large group of women theatre writers of Arab descent is a significant cultural phenomenon because their productions not only help to create and solidify an Arab American identity for themselves, they also offer this constructed identity to their audiences. The political expression of this young theatre movement takes on different articulations, according to the different genres the dramatists use. The introduction presents Rania Khalil's silent performance piece and Suheir Hammad's collage performance . Chapter one examines three autobiographical solo performances. Leila Buck's ISite and Nora Armani's are theatrical presentations of the self through writing the story of lineage. Soha Al Jurf's documents her visits to the land of origin in the Arab world, connecting her search for identity to the killing of her Palestinian aunt. Chapter two explores the expansion from the individual search to the community. Heather Raffo's 9 Parts of Desire> is based on interviews conducted over a period of ten years with Iraqi women inside Iraq and in exile, while Nibras Group's presents verbatim responses to the question "What is Arab?" based on fifty interviews with Arab Americans and other Americans. Chapter three discusses how plays by Arab American women dramatists deal with the negotiation of identity by second-generation Arabs in America, looking at two plays by Betty Shamieh, and , and Laura Shamas' . Chapter four examines the comedy of Arab Americans, looking at the work of Maysoon Zayid and discussing the short plays presented at the Arab American Comedy Festival. The conclusion looks at the dominance of women's voice in this emerging theatre movement, and explores the aesthetic of this Arab American theatre.
Some Non-Classical Methods in Epistemic Logic and Games
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In this dissertation, we consider some non-classical methods in epistemic logic and games. We first consider, dynamic epistemic logics in topological and geometric semantics, and then extend such ideas to the cases where inconsistencies are allowed. Then, as a case example, we discuss a well known paradox in game theory which is essentially a two-person Russell's paradox. Finally, we conclude with considering an alternative approach to games where strategies are considered as the primitives of the theory, and advancing some results.
Don't Push Me Over the (Knowl)Edge: The Social Correlates of Latino High School Dropouts
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According to the forecast of the US Census Bureau, Latinos are the largest, fastest-growing ethnic group within the United States today and will comprise the majority of the US labor force sometime during the mid-21st century. Yet today, the youth of this diverse segment of the population are plagued by alarmingly high high school dropout rates, about double that of African-Americans youth and triple that of white youth. This yawning disparity prompts the examination of the social conditions contributing to this social crisis. How do demographic, aspirational, school-level, and socioeconomic variables affect the decision that so many Latino youth make to drop out of high school? Employing three waves from the Educational Longitudinal Study (2002, 2004 & 2006), this study seeks to add to the discussion of the causes of dropping out among Latinos by examining factors that influence high school persistence rates for a nationally representative sample of Latino youth. This dissertation's theoretical framework combines Bourdieu and Passeron's theory of societal reproduction, labeling theory, and social motivation theory. Variables from all three levels exerted some influence on dropout patterns among Latino youth. Attending a high school located in an urban center was especially significant in predicting the likelihood that a Latino in our sample would drop out of high school, despite the well-known personal costs.
THE ROLE OF SEXUAL SATISFACTION IN COUPLE RELATIONSHIP SATISFACTION, INDIVIDUAL STRESS, AND QUALITY OF LIFE
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One variable frequently found positively associated with relationship satisfaction is sexual satisfaction. In turn, relationship satisfaction is positively associated with both reduced individual stress of each partner and with subjective quality of life. However, little research has examined the relationship among all of these variables. This study examined the possible gender differences in the associations among relationship satisfaction, sexual satisfaction, individual stress, and quality of life. Additionally, this study explored whether the frequency of sex impacts the association among relationship satisfaction and well-being (individual stress and quality of life) for men, but not for women. There were some gender differences in the findings. Specifically, results showed that for men, sexual satisfaction and sexual conflicts were associated with their relationship satisfaction, stress, and quality of life. However, for women, sexual satisfaction and sexual conflicts were not associated with their relationship satisfaction, stress, and quality of life. The results also demonstrated that for both men and women, sexual frequency was not associated with their relationship satisfaction, quality of life, and stress.
Neverending Stories: Unauthorized Continuations, Fictional Realities, and the Long-Form Narrative from 1590 - 2011
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In reader-response theory, the open text demands that its readers collaborate in its construction. Such participation requires that these readers invest in the text's narrative universe, an investment made more possible when a fiction exhibits the properties of selvage: a firm, detailed, and consistent framework shot through with unfinished edges (termed fractures) that invite and support the reader's response in the form of continuation. These unauthorized extensions literally transform active reading into writing, while their presence recursively solidifies the fictional universe's imaginary space, further buttressing its autonomous existence. Such narrative reinforcement troubles many critics because an independent fictional reality not owned solely by a primary creator has disruptive implications for textual properties and copyrights. Nevertheless, these unauthorized continuations are the tangible artifacts of invested, pleasurable, and embodied reading, a type of reading and pleasure that is itself a revelatory form of literary criticism. Classifying texts in terms of their readers' desire to enter into and extend the narrative world encourages an understanding of these texts as evolving objects that must be categorized and described not just statically, but also dynamically, in terms of their capacity to generate. Three distinct (though occasionally intersecting) kinds of source-texts are identified here; the first locates the source's imaginary space as a narrative of place, the second as a narrative of society, character, and people, and the third as a narrative of interstices. Narratives of place such as Sir Philip Sidney's Arcadia evoke fantasies of exploration and colonization; narratives of society like Jane Austen's Pride and Prejudice call forth fantasies of unveiling; and narratives of interstices such as J.K. Rowling's Harry Potter series, as well as various long-running television programs, endorse fantasies of dimensionality and dialogue. An examination of these fantasies of continuation from 1590 to 2011 reveals a cyclical pattern in the reception of derivations and continuations. After the Romantic privileging of originality in the eighteenth and nineteenth centuries, the postmodern conception of creativity once more begins to resemble the more collaborative vision of the early modern period, a perspective which produces a queer, non-normative, multiplicitous, and post-canonical understanding of literature and fiction.