The effects of estrogen on carrageenan-induced nociceptive behaviors and inflammatory mediators in ovariectomized female mice
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Epidemiological studies have shown that pain perception is sexually dimorphic; females tend to experience greater sensitivity to painful stimuli and more chronic pain compared to males. Researchers believe that this dichotomy is caused by the distinct endocrinological profile of females. 17beta -estradiol has been shown to attenuate inflammatory behaviors in both the formalin and carrageenan (Cg) models of inflammation. Research also shows that estrogen affects many inflammatory mediators, including proinflammatory cytokines and prostaglandins (PG). Estrogen plays an important, yet complicated role, in inflammation, and little is known about the specific biochemical mechanisms involved. The objective of this study is to determine if, similar to rats, estrogen attenuates Cg-induced thermal hyperalgesia by altering cytokine or PG release. To that end, female OVX mice were pretreated with various doses of estradiol and injected with 1% Cg. Paw withdrawal latency was recorded prior to, 1 hour, and 5 hours after Cg-treatment in response to a low, medium, and high heat stimuli. Additional animals were treated with indomethacin, a COX blocker. High doses of estradiol caused an increase in nociceptive responses prior to and subsequent to Cg administration. This increase in these pain behaviors was not directly caused by an increase in proinflammatory cytokine levels or a decrease in anti-inflammatory cytokines levels. However, estradiol caused increases in cytokine levels in the untreated paw. Furthermore, treatment with indomethacin caused an attenuation of hyperalgesia. Additionally, indomethacin negated the difference between estradiol- and vehicle-treated mice, indicating that estrogen may interact with prostanoid synthesis. This effect, however, was not seen in the Cg-treated paw, suggesting that estradiol may be increasing hyperalgesia via another pathway as well. Taken together, our results suggest that estrogen's hyperalgesic effects are partly mediated through cytokine up-regulation and prostanoid synthesis, but the main mechanism of action still needs further investigation.
Registered Sex Offenders in the Community: A Test of Agnew's General Strain Theory
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Over the past two decades, sexual offending and offenders have become a topic of interest among researchers, policymakers, and the public. Since the inception of Registration and Community Notification Laws (RCNLS), researchers have assessed the negative consequences associated with the laws and how they affect sex offenders in the community; however, no study has utilized a criminological framework to do so. Agnew's General Strain Theory, which should be able to account for all crime, suggests that when individuals do not achieve desired goals, have negative stimuli placed on them or positive stimuli taken away, they are more likely to engage in crime. These are conditioned by certain factors, such as coping strategies and self-esteem. This study will synthesize these two distinct fields of research to determine whether the negative consequences of RCNLSs lead to recidivism. In all, surveys were mailed to 4,500 sex offenders with (N=997) in Nebraska, (N=2086) and (N=1417) sex and violent offenders in Kansas and Montana, respectively. These states are similar in population and demographic aspects, though they differ in RCNLSs. Findings lend partial support to GST and suggest that, consistently, anger influences recidivism.
Building the New American Nation: The U.S. Army and Economic Development, 1787-1860
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This dissertation examines the Army's integral role in the early American political economy. Notwithstanding its small size, the Army proved to be a powerful instrument for promoting economic expansion and guiding the pattern and direction of development. The Army spurred development through two lines of activity: first, the traditional application of coercion and, second, by providing public goods that neither private actors nor state governments could supply. Considering the Army leads me to reconceptualize the early American state as a bifurcated entity: a state of the periphery, dominated by the Army, and a state of the center, in which the Army still influenced economic development but other public institutions also performed key development functions.
Performance Effects of Computer-Based Multitasking Behavior
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This research examines multitasking from the perspective of human-computer interaction (HCI). Multitasking is defined as the performance of multiple tasks concurrently. In a computer-based environment, users generally switch between multiple computer-based tasks either due to a personal decision to break from the current task or due to an external interruption, such as an electronic notification. This dissertation describes an in-depth empirical study, using a laboratory setting with different numeric, verbal, and visual computer-based tasks. Six hundred and thirty six subjects were randomly assigned into three conditions: discretionary multitasking, where participants were allowed to decide when and how often to switch tasks, forced multitasking, where participants were forced to switch tasks at certain allotted times, and non-multitasking, where participants performed the tasks sequentially and were not allowed to multitask. In order to investigate performance effectiveness (accuracy) and performance efficiency (productivity), participants' overall accuracy and productivity scores were compared across conditions. The results suggest that during difficult tasks, subjects who were forced to multitask had the lowest accuracy. In addition, those subjects in the forced multitasking condition who felt the primary task was difficult had lower accuracy than those who felt the task was easy. This was not true in the other two conditions. Receiving interruptions during a difficult task impacted not only their primary task, but their secondary tasks as well. In the discretionary multitasking condition, the more subjects decided to multitask, the lower their accuracy scores. In fact, an additional analysis revealed that high multitaskers not only performed worse than low and medium multitaskers in the discretionary condition, but actually had the worst performance than subjects in any other condition. Medium multitaskers, however, had the highest productivity scores. While multitasking in that case was considered the best in terms of efficiency, it was not true in terms of effectiveness. Therefore, discretionary multitasking gives the illusion of high performance. Furthermore, this study also explored why people chose to multitask and the impact that had on performance. The results of this study can assist HCI researchers in developing a more comprehensive understanding of user multitasking which can lead to better interface designs.
The Role of Striatal Neuropeptides on Glutamate and Methamphetamine-Induced Neurotoxicity in the Murine Brain
ABSTRACT THE ROLE OF STRIATAL NEUROPEPTIDES ON GLUTAMATE AND METHAMPHETAMINE-INDUCED NEUROTOXICITY IN THE MURINE BRAIN by Lauriaselle Afanador Adviser: Dr. Jesus A. Angulo
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The rising worldwide epidemic in addiction to methamphetamine (METH) and the well-documented neurological detriments it causes emphasizes the importance of elucidating the mechanisms by which METH causes widespread and prolonged damage. Also, METH's pathophysiology resembles a number of neurodegenerative diseases. Therefore a better understanding of the mechanisms involved would provide more effective therapeutic targets for the treatment of these neurological disorders.
METH toxicity is a complex interplay of various factors however a number of necessary components have been identified such as dopamine overflow (DA), glutamate signaling, and oxidative stress. Although METH-induced DA overflow is the initiating event, it is not the direct cause of damage. Oxidative stress is thought to be the mediator of METH toxicity and nitric oxide (NO) as a contributor.
We have found that substance P (SP) exacerbates METH-induced NO. Inhibition of SP signaling mitigated NO synthesis and conferred protection. Considering the role SP is playing in METH toxicity we wanted to investigate the role that other striatal neuropeptides play in these events, notably the inhibitory peptides neuropeptide Y (NPY) and somatostatin (SST).
We hypothesized that SP is augmenting NMDA signaling and thus magnifying NO production. Whereas NPY and SST would serve as a counteracting force thus dampening oxidative stress and conferring protection. Overall, our data demonstrated that SP does augment NMDA signaling as inhibition of the neurokinin-1 receptor (NK-1R) decreased NMDA-induced striatal cell loss. We found that SP was potentiating NMDA-induced NO production. Although the predominant source of NO was the inducible form of nitric oxide synthase (NOS).
In support of our hypothesis, NPY and SST proved to attenuate NO. Also, they were protective from METH-induced cell death although SST failed to protect DA terminals. However, an agonist for the NPY-Y2 receptor was successful in maintaining DA terminal viability. Of interest is that neither NPY nor SST modulated NMDA-induced NO or cell loss suggesting that their protective mechanism does not include modulation glutamate signaling within the striatum.
PUBLIC EDUCATION IN THE UNITED STATES: THE PRODUCTION OF A NORMATIVE CULTURAL LOGIC OF INEQUALITY THROUGH CHOICE
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"Public Education in the United States: The Production of a Normative Cultural Logic of Inequality Through Choice" is a historically informed ethnography that examines how choice emerged in the post-Brown v. Board of Education era as a key principle of reform and management in public education and became central to how rights, freedom, and citizenship were structured, constrained, and imagined. Scholarship within education studies has identified choice as a predicament of neoliberalism as privatization. Yet as my research examines, the inequalities associated with privatization mechanisms like charter schools are an exaggerated indexical representation of a much deeper and older problem. My research extends the historical trajectory through which we understand neoliberal restructuring and traces the ideological and material contours of a post-Brown realignment between the state, the structuring of rights, and the market--a realignment that extends beyond the realm of the private. This dissertation is based on eighteen months of ethnographic fieldwork in New York City's Community School District (CSD) 3, one of the most racially and economically diverse districts in the nation's largest school system. CSD 3 is also one of the most segregated districts in New York City and one of the districts that provides the most choice-based programs and policies. In my ethnography, I examine the ways that low-income and middle-income parents navigate and negotiate selecting a public non-charter elementary school for their child. I trace how situated claims to universal rights as choices facilitate the continuance of a tiered citizenship and the production of what I term a "normative cultural logic of inequality." My research interrogates how this logic narrates inequality in education as resulting from "bad" yet "fair" choices that are qualified by a lack of individual initiative, informed decisions, and capacities of parental care. My findings suggest that rather than these explanations, the differential accumulation of living in what Ruth Wilson Gilmore has termed the "forgotten" or "abandoned places" of a racial state are central to understanding how similar desires---of wanting the very best for one's child---result in very different outcomes.
PHOTOPHYSICS AND CATALYSIS OF PORPHYRINOIDS
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Organic nanoparticles (ONP) of metalloporphyrins can be versatile catalysts for the selective oxidation of alkenes and other hydrocarbons. Herein, we report the catalytic activity of ONP of 5,10,15,20-tetrakis-[4-(1'H,1'H,2'H,2'H-heptadecafluorodecane-1-thiol)-2,3,5,6-tetrafluorophenyl] porphyrinato iron(III), Fe(III)TPPF84, and 5,10,15,20-tetakis-(2,3,4,5,6-pentafluorophenyl) porphyrinato manganese(III), Mn(III)TPPF20, for cyclohexene oxidation using molecular oxygen as an oxidant in water under ambient conditions. While the solvated metalloporphyrins catalytically oxidize alkenes to the corresponding epoxide in halogenated solvent with a modest turn-over numbers (TON), 10-30 nm ONP of these metalloporphyrins have enhanced catalytic activity with up to a 4-fold greater TON and yields only allylic oxidation products. These ONP catalytic systems facilitate a greener reaction since ca. 89% of the reaction medium is water, molecular oxygen is used in place of man-made oxidants, and the ambient reaction conditions require less energy. The enhanced catalytic activity of these ONP is unexpected because the metalloporphyrins in the nanoaggregates are in the close proximity and the TON should diminish by self-oxidative degradation. The fluorous alkanes in Fe(III)TPPF84 stabilize the ONP towards self-oxidative degradation. Sequential dipping of indium-tin-oxide electrodes into solutions of tetra cationic porphyrins and tetra anionic polyoxometalates results in the controlled formation of nm thick films. The potential applications of these robust films on electrodes range from catalysts to sensors. This chapter focuses on the electrochemistry of the multilayered films where it is found that the oxidation and reduction potentials of each species remain largely the same as found in solution. Photophysical properties of Porphyrinoids bearing four rigid hydrogen bonding motifs on the meso positions, self-assembled into a cofacial cage with four complementary bis(decyl)melamine units in dry solvents are presented here. Self-assembly was investigated by NMR spectroscopy, dynamic light scattering, and atomic force microscopy. The phototphysical properties of the cage formation involve the measurement of their absorption and emission spectra and the fluorescence life time in dry THF. The hydrocarbon chains on the bis(decyl)melamine mediate the formation of nanofilms on surfaces as the solvent slowly evaporates. A systematic study of the photophysical properties of a series of porphyrinoids is presented. The role of the location of a heavy atom in shunting the excited state from the singlet to the triplet manifolds is compared for three cases. It is well known that Pt(II) metalloporphyrins do not fluoresce. For meso pyridyl porphyrins, the fluorescence quantum yield decreases as the number of coordinatively attached Pt(II) complexes increase from 0-4, but the tetracoordinated species retains about 30% of the fluorescence. Covalently attaching a heavy metal complex e.g.Pt(II) complex to the macrocycle by an organometalic bond at the peripheral meso position causes greater than a 20-fold decrease in fluorescence quantum yield and may enhance some internal conversion to the ground state. For comparison, the fluorescence quantum yield decreases somewhat as the number of pyridyl groups on the meso positions increase 0-4. We also evaluate the photophysical properties of a series of porphyrins with nitro groups on the β pyrrole position and on the meso phenyl group, which also quenches the fluorescence. These studies bear on the use of metal ions to enhance the photophysical properties of these dyes as photodynamic therapeutics and for supramolecular systems, while the nitrated macrocycles have potential application in non linear optics. The photophysical properties of non-hydrolysable tetra- thioglycosylated conjugates of chlorin (CGlc4), isobacteriochlorin (IGlc4) and bacteriochlorin (BGlc4) and core F20 platforms are reported here. These studies involve the measurement of absorption and emission spectra, fluorescence quantum yield, singlet oxygen quantum yield, and singlet state life time in three different solvents: phosphate buffer saline (PBS), ethanol, and ethylacetate. Compared to the porphyrin in PBS, CGlc4 has a markedly greater absorbance of red light near 650 nm and a 6-fold increase in fluorescence quantum yield; whereas IGlc4 has broad Q bands and a 12-fold increase in fluorescence quantum yield. Since IGlc4 CGlc4 very slowly bleach, these properties may enable their use as fluorescent tags to track biological processes. BGlc4 has a similar fluorescence quantum yield to PGlc4, (<10%), but the lowest energy absorption/emission peaks of BGlc4 are considerably red shifted to near 730 nm with a nearly 50-fold greater absorbance, which may allow this conjugate to be an effective PDT agent. The excited state life time of these conjugates ranges from 3-11 ns. The radiative time constant for IGlc4 is 20 fold less while non-radiative time constant is 2 fold more than BGlc4, indicates that IGlc4 has greater potential to form triplet state via inter system crossing, and so can serves as a better PDT agent. The uptake of CGlc4, IGlc4 and BGlc4 derivatives into cells such as human breast cancer cells MDA-MB-231 and K:Molv NIH 3T3 mouse fibroblast cells can be observed at nM concentrations. Photobleaching under these conditions is minimal.
An empirical re-evaluation of the effects of education in nonmarket production
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Abstract AN EMPIRICAL RE-EVALUATION OF THE EFFECTS OF EDUCATION IN NONMARKET PRODUCTION by CHRISTIE AGIOUTANTI Adviser: Distinguished Professor Michael Grossman This paper tests the empirical validity of the productive efficiency hypothesis effect of education in the nonmarket sector via consumption expenditure patterns, which is essentially the foundation in Michael's (1972) behavioral model. Under the assumption of factor and commodity neutrality, the education effect is expected to be positive for luxuries, negative for necessities and zero for market goods inputs whose income elasticity is equal to one. Much of the innovation of this paper primarily stems from a preliminary and broad attempt to update Michael's empirical work, while focusing on the demand for inputs in the production of "good health", the incorporation of both grouped and individual observations on consumer expenditures household data as an additional comparison tool, inclusion of all four geographical regions and allowing for zero value market good outlays. By and large, the empirical analysis of this study fails to support the predicted qualitative relationship between income and education elasticities, regardless of sample classification and item categorization. Consequently, it rejects the accuracy of productive efficiency hypothesis in the neutrality framework. Whether these findings are the byproduct of the limitations set by the theoretical model, the type and idiosyncratic nature of the dataset used or by the econometric approach employed, the effect of education on household productivity remains a puzzle and a topic that requires more rigorous investigation. "The most important of all capital is that invested in human beings." Alfred Marshall
Dopamine-glutamate interaction in the actions of typical antipsychotic drugs
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Typical antipsychotic drugs (APD) are currently the most effective psychoactive agents for the treatment of schizophrenia. Studies suggest that besides their conventional action of blocking dopamine (DA) D2 receptors, these drugs also interact with glutamatergic N-methyl-D-aspartate (NMDA) receptors. In addition, blockade of DA D2 receptors is believed to result in DA cell depolarization block (DB) and movement disorders (catalepsy) in animals. Since it has been hypothesized that drug's antipsychotic potency may be predicted by its ability to produce DB and catalepsy, using CD rats in behavioral, microdialysis and receptor binding studies we investigated whether typical APD induce DB and catalepsy though action on the dopaminergic system, glutamatergic system, or through the interaction between the two systems. Focus of this project was on striatum (STR) and frontal cortex (FC), two brain regions implicated in the DA-glutamate interplay. Our behavioral results show that haloperidol, a potent APD and postsynaptic DA D2 receptor blocker is a strong catalepsy inducer. Receptor binding study showed that chronic administration of this drug caused a decrease in maximal binding at the NMDA receptors in STR and FC but no significant changes in the DA D2 receptor densities were seen in the two brain areas. In contrast, metoclopramide, another DA D2 receptor blocker but not an APD, within the therapeutic doses (5 mg/kg-10 mg/kg) did not produce catalepsy in experimental animals. The maximal binding parameters for DA D2 and NMDA receptors in STR and FC after repeated administration of metoclopramide were significantly elevated as compared to haloperidol. However, when animals were pre-treated with metoclopramide (10 mg/kg) it sensitized the brain to haloperidol and enhanced catalepsy. Additionally, our receptor binding studies showed that psychotomimetic agents, PCP and ketamine that cause schizophrenia-like symptoms have several-fold higher binding affinity at NMDA receptors as compared to DA D2 receptors, indicating that pharmacological effect of these drugs may be mainly mediated by blockade of NMDA receptors. Finally, studying the neurochemical mechanism for DA cell DB we saw a decrease in striatal DA release after chronic cocaine treatment compared to controls. In a series of follow-up experiments we compared the effect of low dose (0.5 mg/kg) haloperidol and high dose (3.0 mg/kg) haloperidol by acute injection to the chronic cocaine treated rats and to the control animals. Low dose haloperidol significantly increased straital DA release compared to respective controls, while the high dose haloperidol significantly reduced it compared to the low dose. On the other hand, high dose haloperidol drastically increased striatal DA release in chronic cocaine-treated rats compared to controls. These results suggest that the mechanism for catalepsy is based on the concurrent DA D2 receptor antagonism and activation of glutamatergic NMDA transmission. Similarly, the mechanism for DA cell DB is mediated through blockade of dopaminergic D2 receptors and stimulation of NMDA receptors. Thus, catalepsy as well as antipsychotic activity appears to be mediated through modifications of dopaminergic and glutamatergic transmissions.
Fabrication of Quantum Dot Encoded Silica Beads for High-throughput Screening Applications
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The focus of this research is on the development of optically barcoded silica gel microbeads, synthesized to be used in high throughput screening platforms, using suspension methods for bead synthesis developed specifically for rapid gelation. In suspension methods for particle manufacture, precursor droplets are first formed in a continuous phase immiscible with the droplet phase. The droplets are then solidified into particles. Silica is chosen as the bead material because it can very easily be functionalized to anchor probe molecules which is necessary to function as a capture element in high throughput screening applications. The optical code embedded into the microbeads consists of the spectral signature (the emission spectrum) of a collection of luminescent species. In particular, for this study, multicolor semiconductor nanocrystals or quantum dots (QDs) are used. Each type of QD emits electromagnetic waves at a set wavelength (color), and sets of QDs will be incorporated in differing quantities to form the code. The encoding QDs are dispersed in the pre-gel droplet phase, and are surface functionalized so as not to partition in the continuous phase. In this way, the QDs are effectively trapped in the droplets as they gel to microbeads, which allows for a quantitative loading necessary for optical coding. In this study, the suspension process for encoded silica bead production is implemented using a batch stirring method for forming the emulsion, and a flow-focusing microfluidic device. The later is used to generate uniformally sized droplets of the pre-gel phase, thus insuring a monodisperse size distribution that is useful for high throughput screening platforms. The gelation of the silica precursor droplets uses an amine catalyst as an accelerant, and thus eliminates the post-production necessary in existing methodologies for obtaining silica beads. Confocal laser scanning microscopy (CLSM) is used to record the spatial distribution of the nanocrystal fluorescence in the beads and the emission spectra (the barcode). Two colors of QDs were used to create a prototype barcode, and Forster Resonance Energy Transfer (FRET) between these colors was used in addition to the spatial distribution of the fluorescence to infer the aggregation of the nanocrystals in their new silica gel environment. A comparison of the photoluminescence (PL) profiles of the barcoded silica beads demonstrate that indeed resonant energy transfer is occurring, and the crystals do aggregate. FRET shifts in the PL profiles can be attributed to poor dispersability issues in the precursor solution and can in some instances- due to extent of unfavorable conditions for the surface molecules of QDs with the solvent- limit our ability to generate a full compliment of barcodes. Untimely ionization of catalyst, and degree of which, and poor solvability of hydrophylically surface functionalized nanocrystals leads to their poor performance as entrapped luminescing signals.