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MAG does not Require NgR1, PirB or Sialic Acid Binding to Inhibit Neurite Outgrowth
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The Role of Gangliosides, NgR1, NgR2 and PirB Receptors in MAG Inhibition of Neurite Outgrowth by Najat Al-bashir Thesis Advisor: Dr. Marie T. Filbin Following injury, axons in the central nervous system (CNS) do not spontaneously regenerate, and this is due to several factors, one of which is the presence of myelin- associated inhibitors. There are three major myelin-associated inhibitors that have been identified, Nogo-66, myelin associated glycoprotein (MAG), and Oligodendrocyte myelin glycoprotein (OMgp). MAG is a member of immunoglobulin (IgG) super-family and contains 5 Ig-like domains in its extracellular domain. Like Nogo-66 and OMgp, MAG binds to a receptor complex consisting of NgR1- p75NTR-Lingo-1 to inhibit neurite outgrowth. MAG is also a sialic acid binding protein and specifically binds to gangliosides GT1b and GD1a. Recently, NgR2 was also shown to be a sialic acid- dependent binding receptor for MAG. Recently, paired immunoglobulin B (PirB) was also identified as a novel receptor for MAG, Nogo-66 and OMgp. Previously, we showed that the sialic acid binding activity of MAG is not necessary for its inhibitory effects. We mapped the sialic acid binding site on MAG to Arg 118 in the first Ig-domain. When this site is mutated, sialic acid binding is lost but MAG, when expressed by CHO cells, still retains its ability to inhibit neurite outgrowth. Also, we showed that a soluble form of MAG consisting of the MAG extracellular domain fused to the Fc portion of human IgG (MAG-Fc), and a truncated soluble form of MAG consisting iii only of the first three Ig-like domains (MAG (d1-3)-Fc), both bind to neurons in a sialic acid-dependent manner; however, only MAG-Fc inhibits neurite outgrowth. In addition, MAG mutated at Arg118 (MAG (R118A)-Fc), does not bind to neurons and could not inhibit neurite outgrowth. Recently, we mapped the inhibition site on MAG to Ig-domain 5, which is distinct from the sialic acid binding site. Others have reported that gangliosides are functional binding partners for MAG and are necessary for inhibition by MAG when expressed in immobilized membranes. They reported that neurons from mice deficient in the B1, 4-N-actylgalactosaminyltransferase (GalNAcT) gene, which lack all complex gangliosides including GT1b and GD1a, are not inhibited by MAG in immobilized membrane. Others have also shown that clustering gangliosides with antibodies in the absence of MAG is sufficient to inhibit neurite outgrowth via a mechanism engaging p75 NTR receptor. Here we show that clustering MAG (d1-3)-Fc can inhibit neurite outgrowth in neurons from wild type mice but not from GalNAcT deficient mice. We also show that MAG can inhibit neurite outgrowth independent of NgR1, PirB, and sialic acid binding. We show that neurons from GalNAcT deficient mice are inhibited by MAG as effectively as neurons from wild type mice. Also, we show that neurons from NgR1 deficient mice are inhibited by full length MAG and mutated MAG (MAG R118A) that cannot bind sialic acid residues. In addition, in the presence of PirB antibodies, both MAG- and mutated MAG (R118A)-expressing CHO were able to inhibit neurite outgrowth of neurons from NgR1 deficient mice and wild type mice. Taking all these results together, MAG interacts with another as yet unknown receptor(s), in addition to NgR's, PirB and sialic acid to inhibit neurite outgrowth.
Nanoacoustic Effects in Type-II Superconductors and Decoherence of Two-state Systems
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In this thesis we focus on two areas of research: nanoacoustic effects in superconductors, and decoherence of two-state systems due to radiation of acoustic phonons. In the first part of this thesis we propose two new nanoacoustic effects: induction of voltage by mechanical stress, and nucleation of a superconducting vortex by an acoustic standing wave. Both of these effects take place in type-II superconductors. In the second part we study relaxation processes via acoustic phonons of a particle in a double-well potential and of a flux qubit. Part 1: Mechanical stress causes motion of dislocations in solids. In a type-II superconductor a moving dislocation generates a pattern of current that exerts a force on the surrounding vortex lattice capable of depinning it. We show that the concentration and the speed of dislocations needed to produce depinning currents are within practical range. When external magnetic field and transport current are present, this effect generates voltage across the superconductor. In this manner, a type-II superconductor can serve as an electrical sensor of the mechanical stress. Nucleation of vortices in a superconductor below the first critical field can be assisted by transverse sound in the GHz frequency range. We work out from energy considerations that, in the presence of a sound wave, vortices enter and exit the superconductor at the frequency of the sound. The computed threshold parameters of the sound are shown to be within experimental reach. Part 2: We propose a method of computing phonon-induced relaxation of two-state systems that is based on symmetry arguments. This allows one to express the rates in terms of independently measurable parameters. For translationally and rotationally invariant systems the conservation of linear and angular momenta must be taken into account when formulating the interaction Hamiltonian. For a particle (e.g., electron or proton) in a rigid double-well potential embedded in a solid the rate is proportional to the seventh power of temperature. For a flux qubit the two-phonon relaxation is important only if the size of the qubit is much smaller than the phonon wavelength. Due to symmetry the two-phonon rate of both systems is proportional to the square of the bias. This allows for additional control of the relaxation rate.
Images of Chopin in the New World: Performances of Chopin's Music in New York City, 1839-1876
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This dissertation examines the reception history of the music of Fryderyk Chopin (1810-1849) in the city of New York from the first documented performance of his works, in 1839, until 1876, the year of the historic American tour of Hans von Bülow (1830-1894). The dynamics of those responses correspond with the growth of New York, which, during that time, experienced a dramatic transformation from a provincial city into a vibrant cultural metropolis. In addition, I aim to explore the evolution of musical aesthetics and taste within a larger scope that includes social, political, and cultural issues. That evolution is illustrated by the ways the music of Chopin was performed, disseminated, and criticized demonstrating the presence of points of intersection with other important artistic centers in Europe. My broader goal is to contribute to a better understanding of the dynamics of the musical life of the city in the thirty-seven years covered in this study. A meticulous work of documentation of hundreds of performances provides a valuable tool for scholars who wish to keep exploring that fascinating period in New York history, and the circumstances that paved the way for the future conditions of the musical life in the city and in the nation.
Jealousy Comprehension during Middle Childhood: The Roles of Perspective Taking, Gender, and Maternal Reminiscing within Narrative Construction
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The aim of the current study was to provide an extensive assessment of the socio-cognitive development of children's jealousy understanding during middle childhood within the context of narrative construction. In doing so, influences of perspective-taking ability, gender, and maternal reminiscing on children's ability to understand -and talk about- jealousy (a complex emotion) between the ages of 5 and 11 were examined. In total, 40 girls (M age = 8y;2m, SD = 2y;1m), 40 boys (M age = 8y;7m, SD = 2y;0m), and their mothers participated. Children completed a series of narrative tasks that were coded for emotion understanding: a fictional narrative about a frog experiencing jealousy, post-story probe questions, an individual autobiographical narrative about their own experience of jealousy, and a co-constructed personal narrative in which children and their mothers were asked to talk about a time their child experienced jealousy. Additionally, mothers completed the fictional narrative task for an adult comparison to children's abilities. Children were also administered measures of socio-cognitive development (Test of Emotion Comprehension, Test of Perspective-Taking Ability) and intellectual development (Verbal Intelligence - PPVT, Nonverbal Intelligence - TONI), and mothers were administered a measure of Verbal Intelligence (PPVT). Overall, findings from the current study provide evidence that (1) children exhibit an increased understanding of jealousy across multiple measures of emotion understanding between the ages of 5 and 11, (2) there is considerable overlap in the feelings of jealousy and envy during middle childhood, (3) perspective taking is linked to children's abilities to talk about another's feelings during middle childhood, and (4) girls' emotion understanding is displayed and acquired in a more interpersonal context than boys'. Furthermore, the present study extends the literature on maternal-guided reminiscing to include assessment during middle childhood, examining the roles of both style and content, and through evaluating both parties' discourse. In doing so, maternal elaboration was found to be beneficial for children's autobiographical narrative abilities during middle childhood. Results are discussed in relation to socialization practices behind children's expression of jealousy -a negative emotion associated with interpersonal rivalry- that is frequently experienced, but that American culture says should not be expressed.
"I'm not trying to go back": Young women's strengths navigating their return from incarceration
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This is a qualitative, grounded-theory study of thirteen young women between the ages of 18 and 26 who were returning back to their lives in New York City after prison or an extended jail incarceration. The women spent anywhere from 8 months to 8 years incarcerated and were home between three months and three years from the time of their release. The study includes findings based on analysis and interpretations of the interviews, implications for future research and practice that center around the women's use of time while incarcerated, their connectedness to family, friends and staff, both while in prison and upon release, and the impact of both of those on their ability to stay free. The study includes implications for social work and correctional research and practice, and is grounded in women's relational theory and developmental frameworks.
Quantum dislocations in solid Helium-4
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In this thesis the following problems on properties of solid 4He are considered: i) the role of long-range interactions in suppression of dislocation roughening at T = 0; ii) the combined effect of 3He impurities and Peierls potential on shear modulus softening; iii) the dislocation superclimb and its connection to the phenomenon of “giant isochoric compressibility” ; iv) non-linear dislocation response to the applied stress and stress-induces dislocation roughening as a I-order phase transition in 1D at finite temperature. First we investigate the effect of long-range interactions on the state of edge dislocation at T = 0. Such interactions are induced by elastic forces of the solid. We found that quantum roughening transition of a dislocation at T = 0 is completely suppressed by arbitrarily small long-range interactions between kinks. A heuristic argument is presented and the result has been verified by numerical Monte-Carlo simulations using Worm Algorithm in J-current model. It was shown that the Peierls potential plays a crucial role in explaining the elastic properties of dislocations, namely shear modulus softening phenomenon. The crossover from T = 0 to finite temperatures leads to intrinsic softening of the shear modulus and is solely controlled by kink typical energy. It was demonstrated that the mechanism, involving only the binding of 3He impurities to the dislocations, requires an unrealistically high concentrations of defects (or impurities) in order to explain the shear modulus phenomenon and therefore an inclusion of Peierls potential in consideration is required. Superclimbing dislocations, that is the edge dislocations with the superfluidity along the core, were investigated. The theoretical prediction that superclimb is responsible for the phenomenon of “giant isochoric compressibility ” was confirmed by Monte-Carlo simulations. It was demonstrated that the isochoric compressibility is suppressed at low temperatures. The dependence of compressibility on the dislocation length was shown to be strongly dependent on long-range interaction. Non-linear behavior at high stresses was considered. The dislocation was observed to exhibit two types of behavior depending on the dislocation size: reversible and hysteretic. In the reversible regime responses of superclimbing dislocations exhibit sharp resonant peaks. We attribute this feature to the resonant creation of jog-antijog pairs. The peak in the compressibility results in the dip in the speed of sound which we believe was observed in “ UMASS-sandwich” mass-transport experiments. The hysteresis revealed an unusually strong sensitivity to the dislocation size signifying that the stress-induced roughening is a I-order phase transition in 1D at finite T.
Assessing Greenland Ice Sheet Albedo and Mass Balance Variability Using In-Situ Data, Spaceborne Observations and Regional Model Outputs
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Earth & Environmental Sciences
In this dissertation, I present a series of studies that further our understanding of processes responsible for variations in the mass balance of the Greenland ice sheet, and assess our ability to model them. The Greenland ice sheet will likely contribute to sea level rise in a future warmer climate, and it is important to be able to predict future changes in sea level. I perform assessments of (1) spatiotemporal variations in Greenland ice sheet albedo, a key parameter that modulates the mass and energy balance at the ice sheet surface, and (2) spatiotemporal variations in Greenland ice sheet mass balance. Both studies make use of model results, and spaceborne remote sensing estimates, and one makes use of in situ measurements, to assess the observed quantities. The first topic is addressed using satellite data, in situ observations, and results from the Modèle Atmosphérique Régionale (MAR), a regional climate model that simulates the ice sheet surface, and the atmosphere above. I find that MAR reproduces spatial variations in albedo captured by remote sensing and in situ observations, but overestimates albedo by up to 0.1 at low elevations, due to overestimated bare-ice albedo. This can significantly impact the simulated ice sheet surface mass balance. Declining trends in albedo over 2000-2012 are captured by MAR, satellite data, and in situ observations at low elevations. At high elevations, discrepancies between satellite data and in situ observations limit the ability to draw conclusions regarding albedo trends. Discrepancies between modeled and observed mean albedo and trends at low elevations may partially be accounted for by the presence of surface impurities, which are not accounted for by MAR. We also identify discrepancies between satellite albedo products in spatial variations in albedo north of 70°N, limiting our ability to draw conclusions for this region. In the second portion of this work I compare MAR surface mass balance estimates combined with dynamic mass changes from the Ice Sheet System Model (ISSM) with satellite-derived estimates of mass change from the Gravity Recovery and Climate Experiment (GRACE). I find that the models underestimate mass loss at low elevations, and capture the timing of the GRACE seasonal cycle. There are discrepancies between the modeled and observed seasonal cycles at smaller spatial scales, suggesting the need for further study of mass balance processes not fully captured by ISSM or MAR. The studies collectively provide information that will allow for improvement of models used to simulate future changes in Greenland ice sheet mass. I have also included a series of studies that I contributed to as part of my work for this dissertation. These include (1) a study investigating the processes responsible for trends in Greenland Ice Sheet albedo and predictions futurealbedo changes, (2) an investigation of processes responsible for record melting during the year 2012, and (3) a study of the role of surface lake drainage events in Greenland ice sheet motion.
Neural Effects of Exposure to the Environmental Chemical, Bisphenol A, During Development
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Exposure to Bisphenol A (BPA), an environmental chemical, has been linked to changes in physiology, neural development, and behavior. The focus of this study was to determine the effects of BPA exposure, during a short developmental window, on physiology, activity, anxiety, cognition, and neurochemistry. In prenatal study, dams were administered 100 mcg/kg/day orally, from gestational day 16 to parturition. Postnatal study pups received subcutaneous injection of 60 or 100 mcg/kg BPA from postnatal day 0 to 6. All pups were weighed, examined for evidence of vaginal opening, and, at adulthood, performed behavioral tasks measuring locomotor activity, anxiety, and visual and spatial memory. Brain monoamines were measured using high performance liquid chromatography in the postnatal group. Prenatal BPA contributed to low juvenile body weight in both sexes and adult overweight in male subjects. Hyperactivity and memory deficits were observed in both sexes of BPA treated subjects. Postnatal 100 mcg/kg BPA females experienced delayed vaginal opening, less anxiety behavior in elevated plus maze, and spatial memory impairments. BPA treated subjects of both sexes had increased norepinephrine and dopamine turnover in basolateral amygdala and hippocampus, areas which are implicated in anxiety and cognition, respectively. The data suggests that BPA exposure during perinatal life causes disruptions in physiology, behavior, memory and neurochemistry that persist to adulthood. In addition, postnatal effects of BPA may be mediated by alterations in central monoaminergic function.
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The primary aim of this project is to argue that empirical challenges to moral theories like virtue ethics should be co-opted rather than resisted. Virtue ethics has much to offer. Its vision of a flourishing life seems a better object of moral contemplation and evaluation than the sometimes dry rules of deontology and consequentialism; its focus on "thick" concepts like honesty and courage seems to bridge the is/ought gap; its weaving together of reasons and motivations obviates concerns about moral schizophrenia. Furthermore, the virtue ethical account of action paints a detailed picture of sensitivity to reasons, careful and correct construal of ambiguous information, and thoughtful deliberation. Recently, however, philosophers informed by the situationist tradition in social psychology have begun to question the empirical presuppositions of virtue ethics, and a cottage industry has grown up around attacking and defending their arguments. To move the debate forward, I develop a comprehensive list of the empirical presuppositions of virtue ethics, the most contentious items of which are consistency (if an agent possesses a virtue sensitive to reason r, then she responds to r whenever it is relevant), explanatory power (if an agent possesses a virtue, then reference to that virtue sometimes explains her behavior), predictive power (if an agent possesses a virtue, then reference to that virtue sometimes enables prediction of her behavior), and egalitarianism (almost anyone can be virtuous). The empirical challenge relates to the conjunction of these four claims. Nearly a century of studies in social psychology has shown that most people respond primarily not to the reasons there are for them to act on a given occasion but to situational factors like ambient sounds, ambient smells, moods and emotions, and presence of bystanders. These morally irrelevant but causally powerful factors can be unified under the heading of attentional focus: loud and annoying sounds, unpleasant smells, negative moods and emotions, and the presence of bystanders all lead to the focusing of attention on a small number of situational features, while their opposites lead to the dilation of attention. When their attention is focused, people exhibit inattentional blindness, which leads them to miss or misconstrue important moral features of their situations. Insensible to the reasons there are for them to act, they deliberate poorly (if at all) and act in violation of virtue. Situationist psychology does not just deny character traits. It also explains away the strongly felt intuition that there are character traits, invoking a virtual pantheon of gods of error and ignorance that includes the power of (mis)construal (misinterpreting ambiguous information as evidence for character traits), selection bias (using non-representative samples of behavior, thus overlook cases where people act in violation of traits), availability bias (assuming that first impressions are representative), and confirmation bias (seeking and using only evidence that confirms first impressions). These mechanisms guarantee that intuition would lead us to believe in traits even if traits did not exist. Since one does not know that p if one would believe p were it false, we cannot know on the basis of intuitions that character traits exist. Three primary responses to the situationist critique can be identified in the literature. The dodge: virtue is a rare ideal, so data showing that most people are not virtuous is moot. The counterattack: the data do not support the situationist critique. The retreat: although the situationist critique shows that global traits do not exist, a naturalistic theory of virtue can still be formulated in terms of actions or local traits. Unfortunately, most versions of these arguments are either unsound or give up the consistency, explanatory power, predictive power, or egalitarianism of virtue. The dodge, for instance, is an outright denial of egalitarianism. Most versions of the counterattack fail to individuate virtues by their characteristic reasons, and thus are morally inadequate; others appeal to unreliable intuitions. Two compatible tactics for dealing with the challenge, however, do emerge from this literature: an emphasis on what I call the portability of context and a shift from situation-consumerism to situation-producerism. By recognizing the power of situations and identifying the types of situations (not) conducive to behavior in accordance with virtue, one can strategically seek (avoid) situations likely to lead to (non-)virtuous actions. And by recognizing the causal dialectic between agents and situations, one can shift to thinking of agents as active producers rather than passive consumers of situations - a point of view that encourages the creation of situations conducive to action in accordance with virtue. Along these lines, I argue that virtue (though not vice) attributions of the right sort should be made regardless of their truth-value. Drawing on formal work in multi-agent epistemic logic and empirical studies in social psychology, consumer research, and behavioral economics, I show that the plausible, public attribution of virtuous traits induces both identification with those traits and belief that others expect one to act in trait-consonant ways, which in turn leads to trait-consonant behavior. The notions of placebo effects and self-fulfilling prophecies are instructive parallels to virtue-labeling. Thinking of virtue attributions merely as true or false is too limited. We must recognize in addition a third category: factitious attributions, which become true by being plausibly, publicly announced. In another example of the portability of context and situation-producerism, I present a novel theory of social distance in terms of potential for interaction, group identity, and information. This theory draws support from recent work by experimental psychologists and economists, as well as an experiment that I myself conducted. By manipulating heuristics that track social distance, agents can be led systematically to underestimate it, which in turn leads to elevated levels of behavior in accordance with virtue.
Does Discovery-Based Instruction Enhance Learning?
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Since Bruner's (1961) call for research into discovery-based learning, controversy has surrounded the efficacy of such a constructivist approach to instruction (e.g., Tobias & Duffy, 2009). For decades, research has investigated to what extent discovery-based instruction enhances learning tasks or conversely, detracts from them. Research has included wide varieties of domains and discovery-based instructional approaches. Samples have included both children and adults and both novices and experts within their specific domains. It seems that what the field needs is a definition of discovery learning from a practical perspective because a review of the literature reveals that although there might be an implied sense of what discovery learning is, the methodologies employed vary greatly. Furthermore, the characteristics of effective discovery methodology(s) need to be examined with careful consideration of the domain involved, the age of the sample, the comparison condition, and the outcome assessments. Therefore, two meta-analyses were conducted using a sample of 164 studies: the first examined the effects of unassisted discovery learning versus explicit instruction and the second examined the effects of enhanced and/or assisted discovery versus other types of instruction (e.g., explicit, unassisted discovery, etc.). Random effects analyses of 580 comparisons revealed that outcomes were favorable for explicit instruction when compared to unassisted discovery under most conditions, d = -.38 (95% CI = -.44/-.31). In contrast, analyses of 360 comparisons revealed that outcomes were favorable for enhanced discovery when compared to other forms of instruction, d = .30 (95% CI = .23/.36). The findings suggest that unassisted discovery does not benefit learners, whereas feedback, worked examples, scaffolding, and elicited explanations do.