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Recent documents in ScholarlyCommons

Last Build Date: Wed, 07 Dec 2016 03:08:23 PST

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Marketing America: Public Culture and Public Diplomacy in the Marshall Plan Era, 1947–1954

Tue, 06 Dec 2016 13:54:40 PST

Between 1947 and into the mid 1950s, the foreign assistance agencies of the United States developed an ambitious information program intended to support its foreign policy mission by shaping the every day behavior of average European citizens. This dissertation argues that the rationale behind this program was based on a corporatist vision of a productive political economy driven by consumption that became popular in American leadership circles as the means to combat global communism and support US foreign policy goals in Western Europe. Behind this world view lay a rhetoric of economic abundance its proponents advanced as a non-divisive, universally appealing language they believed would cut across class boundaries to neutralize the draw of socialist arrangements without alienating left-leaning groups whose support the US needed to secure stable European governments. This rhetoric thus dominated the American information efforts that accompanied US assistance to Europe in an effort to encourage the foreign audiences to restructure certain aspects of their economies to secure the abundance US diplomats felt was needed to maintain social peace and political stability. This work also argues that European response to this American project was complicated and was determined not by communist sympathies or level of support for the US as the American diplomats anticipated, but instead by native European issues. In focusing on advertising the merits of increasing productivity and consumption to secure abundance in Europe, American officials, rather than smoothing potential social divisions, inadvertently stirred deep-seated concerns among certain segments of the European public who feared US suggestions might marginalize their traditional roles and instigate disruptive social and economic change. For example, US efforts to encourage consumption by promoting self-service shopping arrangements to European housewives raised the ire of more traditional male retailers who felt threatened by such US supported market reform. These European responses help reveal the inherent contradictions in US policy and propaganda efforts and contribute to a better understanding of the complex European view of the US in the post WWII era.

School violence in China: A multi-level analysis of student victimization in rural middle schools

Mon, 05 Dec 2016 20:08:08 PST

Motivation: Physical victimization at school is little studied in impoverished developing country contexts. Moreover, the role of school and classroom contexts as risk factors remains poorly understood.

Purpose: The aim of the study is to investigate the prevalence of physical victimization in rural Chinese middle schools as well as the individual, teacher/classroom, and school level risk factors associated with experiencing physical victimization.

Design: We use two waves of longitudinal, representative survey data to perform a multi-level logistic regression analysis of physical victimization among middle school students from 100 villages in one of China’s poorest provinces. We focus on a subset of questionnaire items that were gathered from students when the sampled children were 13-16 years old. We also utilize student data from the first wave of the survey to control for prior internalizing problems and academic achievement. Finally, we link matched data collected from principal and teacher questionnaires to examine the risk factors for physical victimization associated with students’ microclimates and the wider school environment.

Findings: A substantial proportion of middle school students (40%) reported having been beaten by classmates. Elevated risk was found among males; students with prior poor performance in language; students with past internalizing problems; students of female teachers and teachers evaluated as low performing; students in disruptive classrooms; and students in classrooms undergoing mandated reforms.

Implications: These findings suggest that efforts to reduce school violence should not focus on the deficits of individual students, but rather should target practices to alter the within school risk factors associated with micro-climates.

Ischemia Induces P-Selectin-Mediated Selective Progenitor Cell Engraftment in the Isolated-Perfused Heart

Mon, 05 Dec 2016 18:26:51 PST

Clinical trials infusing Bone Marrow Cells (BMCs) into injured hearts have produced measureable improvements in cardiac performance, but were insufficient to improve patient outcomes. Low engraftment rates are cited as probable contributor to limited improvements. To understand the mechanisms that control myocardial engraftment of BMCs following ischemia-reperfusion injury, in isolated–perfused mouse hearts, stop-flow ischemia was followed by variable-duration reperfusion (0–60 min) before addition of labeled syngenic BMCs to the perfusate. After a buffer-only wash, the heart was disaggregated. Retained BMCs (digest) and infused BMCs (aliquot) were compared by flow cytometry for c-kit and CD45 expression to determine the proportion of cell subtypes engrafted versus delivered (selectivity ratio). In these studies, a time-dependent selective retention of c-kit+ cells was apparent starting at 30 min of reperfusion, at which time c-kit+/CD45+ BMCs showed a selectivity ratio of 18 ± 2 (versus 2 ± 1 in sham-ischemic controls). To study the underlying mechanism for this selective retention, neutralizing antibodies for P-selectin or L-selectin were infused into the heart preparation and incubated with BMCs prior to BMC infusion. Blocking P-selectin in ischemic hearts ablated selectivity for c-kit+/CD45+ BMCs at 30 min reperfusion (selectivity ratio of 3 ± 1) while selectivity persisted in the presence of L-selectin neutralization (selectivity ratio of 17 ± 2). To corroborate this finding, a parallel plate flow chamber was used to study capture and rolling dynamics of purified c-kit+ versus c-kit- BMCs on various selectin molecules. C-kit+ BMCs interacted weakly with L-selectin substrates (0.03 ± 0.01% adhered) but adhered strongly to P-selectin (0.28 ± 0.04% adhered). C-kit- BMCs showed intermediate binding regardless of substrate (0.18 ± 0.04% adhered on L-selectin versus 0.17 ± 0.04% adhered on P-selectin). Myocardial ischemia–reperfusion stress induces selective engraftment of c-kit+ bone marrow progenitor cells via P-selectin activation.

A Study on Educational Production Function in Western Regions of China

Fri, 02 Dec 2016 13:20:55 PST

This paper uses the method of educational production function and hierarchical linear model to analyze the determinant factors of education quality in rural secondary schools in the Gansu province with the data of "The Gansu Survey of Children and Families in 2004".Results show that education quality in rural secondary schools in the Gansu province varies significantly among the student-level,the class-level and the school-level.The socio-economic status of student family and school peers put significantly effects on education quality.Teacher quality makes an important effect on education quality.The class size has a significantly negative effect on education quality.The decentralization of administrative power in school has a significantly positive effect on education quality.Based on the above findings,four aspects of policy suggestions are put forward to improve the education quality for the rural secondary school in the west of China: reducing the class size,improving teacher quality,setting up a system for protecting rights and interests of unauthorized teachers,promoting the decentralization of administrative power in school.

Weaponizing Principles: Clinical Ethics Consultations & the Plight of the Morally Vulnerable

Fri, 02 Dec 2016 08:46:15 PST

Internationally, there is an on-going dialogue about how to professionalize ethics consultation services (ECSs). Despite these efforts, one aspect of ECS-competence that has received scant attention is the liability of failing to adequately capture all of the relevant moral considerations in an ethics conflict. This failure carries a high price for the least powerful stakeholders in the dispute. When an ECS does not possess a sophisticated dexterity at translating what stakeholders say in a conflict into ethical concepts or principles, it runs the risk of naming one side’s claims as morally legitimate and decrying the other’s as merely self-serving. The result of this failure is that one side in a dispute is granted significantly more moral weight and authority than the other. The remedy to this problem is that ECSs learn how to expand the diagnostic moral lens they employ in clinical ethics conflicts.

What Mediators Can Teach Physicians about Managing 'Difficult' Patients

Fri, 02 Dec 2016 07:56:49 PST

Between 10% and 12% of patients are considered difficult by their treating physicians,1 indicating a widespread problem. Many physicians report feeling at a loss to know how to effectively manage challenging patient interactions.2 In extreme cases, physicians resort to refusing to treat hostile patients or dismissing them from their clinical practice.

Neglected Ends: Clinical Ethics Consultation and the Prospects for Closure

Fri, 02 Dec 2016 07:56:45 PST

Clinical ethics consultations (CECs) are sometimes deemed complete at the moment when the consultants make a recommendation. In CECs that involve actual ethical conflict, this view of a consult’s endpoint runs the risk of overemphasizing the conflict’s resolution at the expense of the consult’s process, which can have deleterious effects on the various parties in the conflict. This overly narrow focus on reaching a decision or recommendation in consults that involve profound moral disagreement can result in two types of adverse, lingering sequelae: moral distress or negative moral emotions. The problem, succinctly named, is that such consults have insufficient “closure” for patients, families, and providers. To promote closure, and avoid the ills of moral distress and the moral emotions, I argue that CECs need to prioritize assisted conversation between the different stakeholders in these conflicts, what is often referred to as “bioethics mediation.”

The "Difficult" Patient Reconceived: An Expanded Moral Mandate for Clinical Ethics

Fri, 02 Dec 2016 07:56:42 PST

Between 15%-60% of patients are considered “difficult” by their treating physicians. Patient psychiatric pathology is the conventional explanation for why patients are deemed “difficult.” But the prevalence of the problem suggests the possibility of a less pathological cause. I argue that the phenomenon can be better explained as responses to problematic interactions related to healthcare delivery. If there are grounds to reconceive the “difficult” patient as reacting to the perception of ill treatment, then there is an ethical obligation to address this perception of harm. Resolution of such conflicts currently lies with the provider and patient. But the ethical stakes place these conflicts into the province of the ethics consult service. As the resource for addressing ethical dilemmas, there is a moral mandate to offer assistance in the resolution of these ethically charged conflicts that is no less pressing than the more familiar terrain of clinical ethics consultation.

When It Hurts to Ask: Avoiding Moral Injury in Requests to Forgo Treatment

Fri, 02 Dec 2016 07:56:38 PST

Clinicians commonly believe that "there is no harm in asking" patients with life-threatening illnesses if they would like to forgo aggressive therapy. In fact, many clinicians believe that the question is not only appropriate, but obligatory on grounds of patient empowerment and autonomy: Patients should be given all options, including the option to stop treatment. But in this piece, I argue that there is, indeed, serious -- and even traumatic -- harm in asking patients to forgo treatment if that request is perceived by the patient as evidence that the clinician devalues or questions the integrity of that patient's life. When such requests are perceived to imply: "Your life is not worth saving," the effect of the "ask" is insult and offense, not empowerment. I then argue how clinicians can avoid moral injury in conversations about withholding or withdrawing treatment.

'Quality Attestation' and the Risk of the False Positive

Fri, 02 Dec 2016 07:56:34 PST

The Quality Attestation Presidential Task Force’s recent proposal for “quality attestation” (QA) of clinical ethics consultants was advanced on the premise that, “[g]iven the importance of clinical ethics consultation, the people doing it should be asked to show that they do it well.” To this end, the task force attempted to develop “a standardized system for proactively assessing the knowledge, skills, and practice of clinical ethicists.” But can this proposed method deliver? If the proposed QA process is flawed, it will label clinical ethicists as qualified to do clinical ethics consultations (CECs) when they are not. The result will be the creation of a new, likely intractable, problem of CEC “false positives:” consultants who have passed QA without actually possessing the requisite knowledge and skills to perform CECs.

To avoid the risk of false positives, the QAPTF needs to conduct a rigorous analysis of the skills that the QA process will be positioned to judge and those that are simply beyond the scope of its current metrics. Rather than “attesting” to overall CEC “quality,” QA needs to be precise about the skill inventory it can confirm yet honest about the skills it has no basis to assess. I will argue here that QA has strong prospects for accurately assessing consultants’ competence in ethical analysis but very weak prospects for determining competence in two other skills listed as essential by the QAPTF: value-neutrality and conflict resolution.

Teaching Nonauthoritarian Clinical Ethics: Using an Inventory of Values and Positions

Fri, 02 Dec 2016 07:56:30 PST

One area of bioethics education with direct impact on the lives of patients, families, and providers is the training of clinical ethics consultants who practice in hospital-based settings. There is a universal call for increased skills and knowledge among practicing consultants, broad recognition that many are woefully undertrained, and a clear consensus that CECs must avoid an “authoritarian approach” to consultation—an approach, that is, in which the consultant imposes his or her values, ethical priorities, or religious convictions on the stakeholders in an ethics conflict. Yet little work has been done on how to teach CECs not to impose their values in an ethics consultation, or even on the dimensions of this problem. In this essay, I propose a tool for bioethical instruction that targets this question: how can CECs be taught a nonauthoritarian mode of ethical analysis and consultation that can avert the problem of values imposition?

Commentary: The Questions We Shouldn't Ask

Fri, 02 Dec 2016 07:56:27 PST

What "Patient-Centered Care" Requires in Serious Cultural Conflict

Fri, 02 Dec 2016 07:56:23 PST

The recent movement to provide “patient-centered care” has been hailed as a progressive step forward in meeting the needs of the very diverse patient population of the United States. The focus on patient-centered care has been embraced at all levels of American medicine: professional organizations, public advocacy groups, hospital administrators, medical school leadership, insurance carriers, and nursing schools. But while the ideal of patient-centered care is universally endorsed, the ethical obligations it entails have only begun to be explored. One of the most difficult circumstances in which to provide patient-centered care is in deep cultural conflict, where the values and priorities of the patient are in direct opposition to those of the clinical team. Given the mandate to provide care that is “culturally and linguistically appropriate,” the author asks what obligations providers have to meet patient demands when it is inconvenient, challenging, or, at the extreme, offensive and antithetical to mainstream values. Bariers are examined that patient-centered care in such cases is disruptive to the work-flow of the service, requires acknowledgement of illegitimate values, or entails discriminatory practices that constitute a personal insult or affront to the provider. The strategy invoked for this analysis is a search for common values that might provide a bridge between patients and providers in deep cultural conflict. The author concludes by responding to these important barriers to providing patient-centered care.

Mediation and Advocacy

Fri, 02 Dec 2016 07:56:19 PST

Mediation and Recommendations

Fri, 02 Dec 2016 07:56:11 PST

Physiological and Histopathological Responses Following Closed Rotational Head Injury Depend on Direction of Head Motion

Fri, 02 Dec 2016 07:53:06 PST

Rotational inertial forces are thought to be the underlying mechanism for most severe brain injuries. However, little is known about the effect of head rotation direction on injury outcomes, particularly in the pediatric population. Neonatal piglets were subjected to a single non-impact head rotation in the horizontal, coronal, or sagittal direction, and physiological and histopathological responses were observed. Sagittal rotation produced the longest duration of unconsciousness, highest incidence of apnea, and largest intracranial pressure increase, while coronal rotation produced little change, and horizontal rotation produced intermediate and variable derangements. Significant cerebral blood flow reductions were observed following sagittal but not coronal or horizontal injury compared to sham. Subarachnoid hemorrhage, ischemia, and brainstem pathology were observed in the sagittal and horizontal groups but not in a single coronal animal. Significant axonal injury occurred following both horizontal and sagittal rotations. For both groups, the distribution of injury was greater in the frontal and parietotemporal lobes than in the occipital lobes, frequently occurred in the absence of ischemia, and did not correlate with regional cerebral blood flow reductions. We postulate that these direction-dependent differences in injury outcomes are due to differences in tissue mechanical loading produced during head rotation.

Stretch Magnitude and Frequency-Dependent Actin Cytoskeleton Remodeling in Alveolar Epithelia

Fri, 02 Dec 2016 07:53:03 PST

Alveolar epithelial cells (AEC) maintain integrity of the blood-gas barrier with gasket-like intercellular tight junctions (TJ) that are anchored internally to the actin cytoskeleton. We hypothesize that stretch rapidly reorganizes actin (<10 >min) into a perijunctional actin ring (PJAR) in a manner that is dependent on magnitude and frequency of the stretch, accompanied by spontaneous movement of actin-anchored receptors at the plasma membrane. Primary AEC monolayers were stretched biaxially to create a change in surface area (ΔSA) of 12%, 25%, or 37% in a cyclic manner at 0.25 Hz for up to 60 min, or held tonic at 25% ΔSA for up to 60 min, or left unstretched. By 10 min of stretch PJARs were evident in 25% and 37% ΔSA at 0.25 Hz, but not for 12% ΔSA at 0.25 Hz, or at tonic 25% ΔSA, or with no stretch. Treatment with 1 μM jasplakinolide abolished stretch-induced PJAR formation, however. As a rough index of remodeling rate, we measured spontaneous motions of 5-μm microbeads bound to actin focal adhesion complexes on the apical membrane surfaces; within 1 min of exposure to ΔSA of 25% and 37%, these motions increased substantially, increased with increasing stretch frequency, and were consistent with our mechanistic hypothesis. With a tonic stretch, however, the spontaneous motion of microbeads attenuated back to unstretched levels, whereas PJAR remained unchanged. Stretch did not increase spontaneous microbead motion in human alveolar epithelial adenocarcinoma A549 monolayers, confirming that this actin remodeling response to stretch was a cell-type specific response. In summary, stretch of primary rat AEC monolayers forms PJARs and rapidly reorganized actin binding sites at the plasma membrane in a manner dependent on stretch magnitude and frequency.

Rho Kinase Signaling Pathways During Stretch in Primary Alveolar Epithelia

Fri, 02 Dec 2016 07:52:59 PST

Alveolar epithelial cells (AECs) maintain integrity of the blood-gas barrier with actin-anchored intercellular tight junctions. Stretched type I-like AECs undergo magnitude- and frequency-dependent actin cytoskeletal remodeling into perijunctional actin rings. On the basis of published studies in human pulmonary artery endothelial cells (HPAECs), we hypothesize that RhoA activity, Rho kinase (ROCK) activity, and phosphorylation of myosin light chain II (MLC2) increase in stretched type I-like AECs in a manner that is dependent on stretch magnitude, and that RhoA, ROCK, or MLC2 activity inhibition will attenuate stretch-induced actin remodeling and preserve barrier properties. Primary type I-like AEC monolayers were stretched biaxially to create a change in surface area (ΔSA) of 12%, 25%, or 37% in a cyclic manner at 0.25 Hz for up to 60 min or left unstretched. Type I-like AECs were also treated with Rho pathway inhibitors (ML-7, Y-27632, or blebbistatin) and stained for F-actin or treated with the myosin phosphatase inhibitor calyculin-A and quantified for monolayer permeability. Counter to our hypothesis, ROCK activity and MLC2 phosphorylation decreased in type I-like AECs stretched to 25% and 37% ΔSA and did not change in monolayers stretched to 12% ΔSA. Furthermore, RhoA activity decreased in type I-like AECs stretched to 37% ΔSA. In contrast, MLC2 phosphorylation in HPAECs increased when HPAECs were stretched to 12% ΔSA but then decreased when they were stretched to 37% ΔSA, similar to type I-like AECs. Perijunctional actin rings were observed in unstretched type I-like AECs treated with the Rho pathway inhibitor blebbistatin. Myosin phosphatase inhibition increased MLC2 phosphorylation in stretched type I-like AECs but had no effect on monolayer permeability. In summary, stretch alters RhoA activity, ROCK activity, and MLC2 phosphorylation in a manner dependent on stretch magnitude and cell type.

The Anesthetic Effects on Vasopressor Modulation of Cerebral Blood Flow in an Immature Swine Model

Fri, 02 Dec 2016 07:52:56 PST

BACKGROUND: The effect of various sedatives and anesthetics on vasopressor modulation of cerebral blood flow (CBF) in children is unclear. In adults, isoflurane has been described to decrease CBF to a lesser extent than fentanyl and midazolam. Most large-animal models of neurocritical care use inhaled anesthetics for anesthesia. Investigations involving modulations of CBF would have improved translatability within a model that more closely approximates the current practice in the pediatric intensive care unit.

METHODS: Fifteen 4-week-old piglets were given 1 of 2 anesthetic protocols: total IV anesthesia (TIVA) (midazolam 1 mg/kg/h and fentanyl 100 μg/kg/h, n = 8) or ISO (isoflurane 1.5%–2% and fentanyl 100 μg/kg/h, n = 7). Mean arterial blood pressure, intracranial pressure (ICP), CBF, and brain tissue oxygen tension were measured continuously as piglets were exposed to escalating doses of arginine vasopressin, norepinephrine (NE), and phenylephrine (PE).

RESULTS: Baseline CBF was similar in the 2 groups (ISO 38 ± 10 vs TIVA 35 ± 26 mL/100 g/min) despite lower baseline cerebral perfusion pressure in the ISO group (45 ± 11 vs 71 ± 11 mm Hg; P < 0.0005). Piglets in the ISO group displayed increases in ICP with PE and NE (11 ± 4 vs 16 ± 4 mm Hg and 11 ± 8 vs 18 ± 5 mm Hg; P < 0.05), but in the TIVA group, only exposure to PE resulted in increases in ICP when comparing maximal dose values with baseline data (11 ± 4 vs 15 ± 5 mm Hg; P < 0.05). Normalized CBF displayed statistically significant increases regarding anesthetic group and vasopressor dose when piglets were exposed to NE and PE (P < 0.05), suggesting an impairment of autoregulation within ISO, but not TIVA.

CONCLUSION: The vasopressor effect on CBF was limited when using a narcotic-benzodiazepine–based anesthetic protocol compared with volatile anesthetics, consistent with a preservation of autoregulation. Selection of anesthetic drugs is critical to investigate mechanisms of cerebrovascular hemodynamics, and in translating critical care investigations between the laboratory and bedside.

Establishing a Clinically Relevant Large Animal Model Platform for TBI Therapy Development: Using Cyclosporin A as a Case Study

Fri, 02 Dec 2016 07:52:52 PST

We have developed the first immature large animal translational treatment trial of a pharmacologic intervention for traumatic brain injury (TBI) in children. The preclinical trial design includes multiple doses of the intervention in two different injury types (focal and diffuse) to bracket the range seen in clinical injury and uses two post-TBI delays to drug administration. Cyclosporin A (CsA) was used as a case study in our first implementation of the platform because of its success in multiple preclinical adult rodent TBI models and its current use in children for other indications. Tier 1 of the therapy development platform assessed the short-term treatment efficacy after 24 h of agent administration. Positive responses to treatment were compared with injured controls using an objective effect threshold established prior to the study. Effective CsA doses were identified to study in Tier 2. In the Tier 2 paradigm, agent is administered in a porcine intensive care unit utilizing neurological monitoring and clinically relevant management strategies, and intervention efficacy is defined as improvement in longer term behavioral endpoints above untreated injured animals. In summary, this innovative large animal preclinical study design can be applied to future evaluations of other agents that promote recovery or repair after TBI.

Stretch Increases Alveolar Epithelial Permeability to Uncharged Micromolecules

Fri, 02 Dec 2016 07:52:48 PST

We measured stretch-induced changes in transepithelial permeability in vitro to uncharged tracers 1.5–5.5 Å in radius to identify a critical stretch threshold associated with failure of the alveolar epithelial transport barrier. Cultured alveolar epithelial cells were subjected to a uniform cyclic (0.25 Hz) biaxial 12, 25, or 37% change in surface area (ΔSA) for 1 h. Additional cells served as unstretched controls. Only 37% ΔSA (100% total lung capacity) produced a significant increase in transepithelial tracer permeability, with the largest increases for bigger tracers. Using the permeability data, we modeled the epithelial permeability in each group as a population of small pores punctuated by occasional large pores. After 37% ΔSA, increases in paracellular transport were correlated with increases in the radii of both pore populations. Inhibition of protein kinase C and tyrosine kinase activity during stretch did not affect the permeability of stretched cells. In contrast, chelating intracellular calcium and/or stabilizing F-actin during 37% ΔSA stretch reduced but did not eliminate the stretch-induced increase in paracellular permeability. These results provide the first in vitro evidence that large magnitudes of stretch increase paracellular transport of micromolecules across the alveolar epithelium, partially mediated by intracellular signaling pathways. Our monolayer data are supported by whole lung permeability results, which also show an increase in alveolar permeability at high inflation volumes (20 ml/kg) at the same rate for both healthy and septic lungs.

Neurocritical Care Monitoring Correlates with Neuropathology in a Swine Model of Pediatric Traumatic Brain Injury

Fri, 02 Dec 2016 07:52:44 PST

BACKGROUND—Small animal models have been used in traumatic brain injury (TBI) research to investigate the basic mechanisms and pathology of TBI. Unfortunately, successful TBI investigations in small animal models have not resulted in marked improvements in clinical outcomes of TBI patients.

OBJECTIVE—To develop a clinically relevant immature large animal model of pediatric neurocritical care following TBI. METHODS—Eleven 4 week old piglets were randomized to either rapid axial head rotation without impact (N=6) or instrumented sham (N=5). All animals had an intracranial pressure monitor, brain tissue oxygen (PbtO2) probe, and cerebral microdialysis probe placed in the frontal lobe and data collected for 6 h following injury.

RESULTS—Injured animals had sustained elevations in intracranial pressure and lactatepyruvate ratio (LPR), and decreased PbtO2 compared to sham. PbtO2 and LPR from separate frontal lobes had strong linear correlation in both sham and injured animals. Neuropathologic examination demonstrated significant axonal injury and infarct volumes in injured animals compared to sham at 6 hours post-injury. Averaged over time, PbtO2 in both injured and sham animals had a strong inverse correlation with total injury volume. Average LPR had a strong correlation with total injury volume.

CONCLUSION—LPR and PbtO2 can be utilized as serial non-terminal secondary markers in our injury model for neuropathology, and as evaluation metrics for novel interventions and therapeutics in the acute post-injury period. This translational model bridges a vital gap in knowledge between TBI studies in small animal models and clinical trials in the pediatric TBI population.

Experiences and Utilization of Certified Peer Support Specialists Employed on Dialectical Behavior Therapy Teams

Thu, 01 Dec 2016 08:43:34 PST

The purpose of this dissertation is to explore the experiences and utilization of Certified Peer Support Specialists employed on Dialectical Behavior Therapy teams. Trends in the literature regarding peer support include the challenges faced by Peer Support Specialists, the benefits peers gained by employment, and solutions for ongoing peer program development. There is also an abundance of studies supporting the use of Dialectical Behavior Therapy (DBT) for treating Borderline Personality Disorder and other DBT adaptations for specific populations. Currently, there is limited literature available that discusses the training of line staff in DBT and no published studies that discuss the use of Certified Peer Support Specialists (CPSS’s) on DBT teams specifically. The State of Michigan mandates that DBT teams include a CPSS. Data were collected through the use of in-depth key informant interviews with thirteen CPSS’s working on DBT teams throughout Michigan. A thematic analysis was completed on the resultant transcripts. The analysis identified four salient themes that include: 1) the benefits of CPSS’s employment on themselves and their clients, 2) the challenges CPSS’s face, 3) the responsibilities and functions of those roles being filled by the CPSS’s, and 4) the supervision and support provided to CPSS’s. Further research on this topic is encouraged and this study recommends how CPSS’s can be used on DBT teams.

Rationality and Indeterminacy

Thu, 01 Dec 2016 07:10:19 PST

Much of the history of game theory has been dominated by the problem of indeterminacy. The very search for better versions of rationality, as well as the long list of attempts to refine Nash equilibrium, can be seen as answers to the indeterminacy that has accompanied game theory through its history. More recently, the experimental approach to game theory has attempted a more radical solution: by directly generating a stream of behavioral observations, one hopes that behavioral hypotheses will be sharper, and predictions more accurate. This article looks at several attempts to address indeterminacy, including the shift to evolutionary models. However, because its goal is to establish whether rational choice models are inescapably doomed to produce indeterminate outcomes, it pays much more attention to the experimental turn in game theory, the difficulty it encounters, and the promising results obtained by more realistic models of rationality that include a social component.

Intuitive and Reflective Inferences

Thu, 01 Dec 2016 07:10:16 PST

Much evidence has accumulated in favor of such a dual view of reasoning (Evans, 2003, in press; for arguments against, see Osman, 2004). There is however some vagueness in the way the two systems are characterized. Instead of a principled distinction, we are presented with a bundle of contrasting features - slow/fast, automatic/controlled, explicit/implicit, associationist/rule based, modular/central - that, depending on the specific dual process theory, are attributed more or less exclusively to one of the two systems. As Evans states in a recent review, “it would then be helpful to have some clear basis for this distinction”; he also suggests that “we might be better off talking about type 1 and type 2 processes” rather than systems (Evans, in press). We share the intuitions that drove the development of dual system theories. Our goal here is to propose in the same spirit a principled distinction between two types of inferences: ‘intuitive inference’ and ‘reflective inference’ (or reasoning proper). We ground this distinction in a massively modular view of the human mind where metarepresentational modules play an important role in explaining the peculiarities of human psychological evolution. We defend the hypothesis that the main function of reflective inference is to produce and evaluate arguments occurring in interpersonal communication (rather than to help individual ratiocination). This function, we claim, helps explain important aspects of reasoning. We review some of the existing evidence and argue that it gives support to this approach.

Third-Party Sanctioning and Compensation Behavior: Findings From the Ultimatum Game

Thu, 01 Dec 2016 07:10:13 PST

We measured the beliefs and behavior of third parties who were given the opportunity to add to or deduct from the payoffs of individuals who engaged in an economic bargaining game under different social contexts. Third parties rewarded bargaining outcomes that were equal and compensated victims of unfair bargaining outcomes rather than punishing perpetrators, but were willing to punish when compensation was not an available option. Beliefs of whether unequal bargaining outcomes were fair differed based on the normative context, but actual punishment, compensation, and rewarding behavior did not. This paper makes a contribution to the literature on informal mechanisms of social norm enforcement by comparing negative sanctions, positive sanctions, and compensation behavior by third parties.

Norm Manipulation, Norm Evasion: Experimental Evidence

Thu, 01 Dec 2016 07:10:10 PST

Using an economic bargaining game, we tested for the existence of two phenomena related to social norms, namely norm manipulation – the selection of an interpretation of the norm that best suits an individual – and norm evasion – the deliberate, private violation of a social norm. We found that the manipulation of a norm of fairness was characterized by a self-serving bias in beliefs about what constituted normatively acceptable behaviour, so that an individual who made an uneven bargaining offer not only genuinely believed it was fair, but also believed that recipients found it fair, even though recipients of the offer considered it to be unfair. In contrast, norm evasion operated as a highly explicit process. When they could do so without the recipient's knowledge, individuals made uneven offers despite knowing that their behaviour was unfair.

Seminar on "The Emergence of Roles in Large-Scale Networks of Communication"

Thu, 01 Dec 2016 06:56:47 PST

Communication through social media is becoming more prevalent in dynamics of coordination and information diffusion. However, online networks are so large and complex that we require new methods to summarize their structure and identify nodes holding relevant positions. We propose a method that generalizes the sociological theory of brokerage, originally devised on the basis of local transitivity and paths of length two, to make it applicable to larger, more complex structures. Our method makes use of the modular structure of networks to define brokerage at the local and global levels. The findings show that the method is better able to capture differences in communication dynamics than alternative approaches that only consider local or global network features.

Journalism’s Deep Memory: Cold War Mindedness and Coverage of Islamic State

Thu, 01 Dec 2016 06:56:43 PST

This article considers the coverage of and by Islamic State in conjunction with a mindset established during the Cold War. It illustrates the degree to which U.S. journalism shapes coverage of Islamic State via interpretive tenets from the Cold War era as well as Islamic State’s use of the same tenets in coverage of itself. The article raises questions about the deep memory structures that undergird U.S. news and about their [memory structures] travel to distant, unexpected, and often dissonant locations.

Image vs. Reality in Korean-American's Responses to Mass-Mediated Depictions of the United States

Thu, 01 Dec 2016 06:56:39 PST

This paper presents findings from a series interviews with Korean-American residents of Philadelphia. These interviews dealt with the informants pre-immigration experiences with images of the United States in movies, television programs, and magazines. The interviewees were asked to evaluate the role of these images in their decisions to immigrate and about their post-immigration responses to the relationship between these images and the reality of life in the United States. The analysis presented here focuses on ways in which reactions to the images might have been shaped by economic constraints and by values developed through formal education.

Family Conversations About Television

Thu, 01 Dec 2016 06:56:35 PST

This is an examination of two kinds of conversations that parents and children sometimes have about television programs: first, conversations in which parents and children seek and/or exchange information about some aspect of reality portrayed or referred to on television; second, conversations in which family members discuss the appropriateness or inappropriateness of behavior shown or mentioned on television as a model for their own or other people's conduct. Examples taken from an observational study of families watching television in their homes are used to illustrate some of the forms these conversations can take, and, on the basis of these illustrations and of some previous research, speculations are offered about the role such conversations might play in family members' developing relationships to one another and to the “outside” world.

The Film Audience's Awareness of the Production Process

Thu, 01 Dec 2016 06:56:32 PST

Christian Metz once argued that, of all the arts, film is the most capable of creating an illusion of reality in the audience's mind.l It is certainly true that any movie whose chief aim is to provide vicarious experience whether of romance, adventure, horror or whatever-depends precisely on the medium's ability to make the viewer forget about scripts, directors, production crews, and all other elements of "behind-the-scenes" manipulation. On the other hand, there are many circumstances in which a viewer's obliviousness to these aspects of a film probably contradicts the intentions of the film's creators. For example, a director who lavishes special attention on visual composition would no doubt be disappointed if viewers treated the images on the screen as random slices of reality. More seriously, perhaps, a viewer who loses sight of the deliberate ordering behind a movie's sequence of events is also likely to have an incomplete understanding of the implications of that movie. For these reasons, it is important to know what kind of interpretive frame of mind viewers typically bring to movies. To what extent can the filmmaker assume that audiences will be aware of his or her presence, and what kinds of circumstances are likely to heighten or diminish this awareness?

TV-Related Mother-Child Interaction and Children's Perceptions of TV Characters

Thu, 01 Dec 2016 06:56:28 PST

How does a parent’s or other adult’s involvement in a child’s TV viewing influence that child's responses to television? Much of the evidence on this question comes from experimental research. It has been shown that adult commentary can inhibit or intensify children’s imitative responses to a visual medium; that mothers’ comments can counteract children’s tendencies to follow the dictates of a TV commercial; and that adult commentary can enhance children’s comprehension of a TV program, as well as their retention of information and values presented on TV. Furthermore, studies in which mothers were merely encouraged to sit with their children (with no specific instructions as to what to say to them) while they were watching television have indicated that children learn more from the medium under such circumstances.

Visual Communication: Theory and Research

Thu, 01 Dec 2016 06:56:24 PST

As an organized subarea of academic communication scholarship, the study of visual communication is relatively new. For instance, at this writing, visual communication has not yet attained regular division status in either the International Communication Association or the National Communication Association. However, interest in visual issues appears to be growing among communication scholars, and the two books under review are part of a rapidly expanding literature (e.g., Barnard, 2001; Emmison & Smith, 2000; Evans & Hall, 1999; Helfand, 2001; Howells, 2002; Mirzoeff, 1999; Prosser, 1998; Rose, 2001; Thomas, 2000). As it seeks to differentiate itself from other scholarly areas with similar purviews (such as mass communication or cultural studies), the study of visual communication is increasingly confronted with two major issues. First, on a theoretical level, visually oriented scholars need to develop a sharper understanding of the distinctions among the major modes of communication (image, word, music, body display, etc.) and a clearer appreciation of the specific role that each plays in social processes. Second, on the research front, there is a need for more sophisticated ways of exploring visual meanings and investigating viewers' responses to images. Taken together, the two books reviewed here touch upon both of these features of visual scholarship and make productive contributions with respect to each of them.

Visual Aspects of Media Literacy

Thu, 01 Dec 2016 06:56:21 PST

A central component of media literacy should be an understanding of the representational conventions through which the users of media create and share meanings. This paper analyzes the representational conventions of visual communication. It distinguishes between semantic and syntactic conventions and focuses on those characteristics that most sharply differentiate visual language from other modes of communication. It examines the impact of visual literacy on viewers’ cognitive growth and on their development as informed consumers of visual media.

Video Ergo Cogito: Visual Education and Analogical Thinking

Thu, 01 Dec 2016 06:56:18 PST

For more than a decade, educators and media critics have been arguing that we are on the threshold of a new age of visual thinking (e.g., Pittman, 1990). Their reasoning: young people's minds are now being molded from the earliest years by intense exposure to television and other visual media; consequently, the young people of today are part of a new 'visual generation.' This is a widely accepted claim, and there are some data that seem to support it. For example, recent findings indicate that, over the past decade, young adults in the 18-24 age group have exhibited a pronounced increase in visual-arts involvement (Zill & Robinson, 1995). However, there is very little systematic theoretical work on the following basic question: if young people are indeed acquiring visually-oriented habits of thought from their encounters with visual media, what exactly do these habits of thought look like? To put this differently: if there is a visual intelligence, what mental skills does it consist of?

This study is an attempt to give a partial answer to this question. Specifically, the study takes a close look at one particular type of mental skill that seems to play a major role in people's uses of visual media—namely, analogical thinking. Consider, for example, a recent music video called Take a Bow, which portrays a sexual encounter between Madonna and a matador. This video contains a lengthy sequence in which the editing takes us back and forth between two scenes: on the one hand, Madonna and the matador having sex; on the other hand, the matador fighting a bull. This form of parallel editing is clearly intended as an analogy: the viewer is meant to see various strands of similarity between the passionate doings in one scene and the violent ritual in the other.

What’s Visual about “Visual Rhetoric”?

Thu, 01 Dec 2016 06:56:14 PST

Activation And Evasion Of The Inflammasome By Yersinia

Wed, 30 Nov 2016 15:19:03 PST

Multicellular organisms constantly encounter microbes, ranging from beneficial to pathogenic. In order to mount appropriate immune responses that allow the host to clear pathogens while maintaining a balance with nonpathogenic microbes, the innate immune system must discriminate between pathogens and commensals. Through the recognition of virulence structures and activities, innate immune cells can distinguish pathogens from commensals. One such virulence structure, the type III secretion system (T3SS), translocates effector proteins into target cells in order to disrupt or modulate host cell signaling pathways and establish replicative niches. Over 25 species of pathogenic gram-negative bacteria depend upon T3SSs to cause productive infection. However, recognition of T3SS activity by cytosolic Pattern Recognition Receptors (PRRs) of the Nucleotide-Binding Domain Leucine Rich Repeat (NLR) family, either through detection of translocated products or membrane disruption, induces assembly of multiprotein complexes known as inflammasomes. Yersinia pseudotuberculosis (Yptb) is an ideal model for inflammasome recognition of the T3SS as Yptb expresses an archetypal T3SS and is a genetically tractable, natural rodent pathogen. Investigation of the interaction between the inflammasomes and the T3SS could reveal important mechanistic and cell biological information about the inflammasomes themselves as well as a potential target for treating T3SS expressing bacteria. Although effectors of Yptb has been shown to actively inhibit inflammasome activation, until this work very little was known about what inflammasome is actually activated by the T3SS, what activity of the T3SS is recognized, and how Yersinia’s YopK protein inhibits inflammasome activation. Therefore, we investigated the bacterial and host interactions required for inflammasome activation and the mechanism by which YopK inhibits inflammasome activation. To dissect the contribution of the different consequences of T3SSs, pore-formation and translocation, to inflammasome activation, we took advantage of variants of YopD and LcrH that separate these functions. Our findings indicated that inflammasome activation required hyper-translocation of YopB/D. Using macrophages deficient in caspase-1, caspase-11, or certain guanylate binding proteins, we characterized the host pathways activated by hyper-translocation of YopD/B. Finally, using mutations in YopK, we characterized how YopK prevents inflammasome activation. Overall, our findings help define how bacterial virulence activities activate innate immune responses.

Monocular 3d Object Recognition

Wed, 30 Nov 2016 15:19:00 PST

Object recognition is one of the fundamental tasks of computer vision. Recent advances in the field enable reliable 2D detections from a single cluttered image. However, many challenges still remain. Object detection needs timely response for real world applications. Moreover, we are genuinely interested in estimating the 3D pose and shape of an object or human for the sake of robotic manipulation and human-robot interaction.

In this thesis, a suite of solutions to these challenges is presented. First, Active Deformable Part Models (ADPM) is proposed for fast part-based object detection. ADPM dramatically accelerates the detection by dynamically scheduling the part evaluations and efficiently pruning the image locations. Second, we unleash the power of marrying discriminative 2D parts with an explicit 3D geometric representation. Several methods of such scheme are proposed for recovering rich 3D information of both rigid and non-rigid objects from monocular RGB images. (1) The accurate 3D pose of an object instance is recovered from cluttered images using only the CAD model. (2) A global optimal solution for simultaneous 2D part localization, 3D pose and shape estimation is obtained by optimizing a unified convex objective function. Both appearance and geometric compatibility are jointly maximized. (3) 3D human pose estimation from an image sequence is realized via an Expectation-Maximization algorithm. The 2D joint location uncertainties are marginalized out during inference and 3D pose smoothness is enforced across frames.

By bridging the gap between 2D and 3D, our methods provide an end-to-end solution to 3D object recognition from images. We demonstrate a range of interesting applications using only a single image or a monocular video, including autonomous robotic grasping with a single image, 3D object image pop-up and a monocular human MoCap system. We also show empirical start-of-art results on a number of benchmarks on 2D detection and 3D pose and shape estimation.

Interplay Between P53 And Epigenetic Pathways In Cancer

Wed, 30 Nov 2016 15:18:57 PST

The human TP53 gene encodes the most potent tumor suppressor protein p53. More than half of all human cancers contain mutations in the TP53 gene, while the majority of the remaining cases involve other mechanisms to inactivate wild-type p53 function. In the first part of my dissertation research, I have explored the mechanism of suppressed wild-type p53 activity in teratocarcinoma. In the teratocarcinoma cell line NTera2, we show that wild-type p53 is mono-methylated at Lysine 370 and Lysine 382. These post-translational modifications contribute to the compromised tumor suppressive activity of p53 despite a high level of wild-type protein in NTera2 cells. This study provides evidence for an epigenetic mechanism that cancer cells can exploit to inactivate p53 wild-type function. The paradigm provides insight into understanding the modes of p53 regulation, and can likely be applied to other cancer types with wild-type p53 proteins. On the other hand, cancers with TP53 mutations are mostly found to contain missense substitutions of the TP53 gene, resulting in expression of full length, but mutant forms of p53 that confer tumor-promoting “gain-of-function” (GOF) to cancer. In the second section of my dissertation, I have investigated the mechanism of this GOF property by examining genome-wide p53 binding profiles in multiple cancer cell lines bearing p53 mutations. This reveals an epigenetic mechanism underlying mutant p53 GOF. Various GOF p53 mutants bind to and upregulate genes including MLL1, MLL2, and MOZ, leading to genome-wide changes of histone modifications. These studies also demonstrate a critical functional role of the MLL pathway in mediating mutant p53 GOF cancer phenotypes, and that genetic or pharmacological perturbation of MLL function can achieve specific inhibition of GOF p53 cell proliferation. Overall, studies described in this dissertation demonstrate the crosstalk between p53 signaling and chromatin regulatory pathways, contribute to our knowledge of p53 cancer biology with respect to epigenetic regulation, and in the long term suggest new therapeutic opportunities in targeting cancers according to their p53 mutational status.

Optomechanical Devices And Sensors Based On Plasmonic Metamaterial Absorbers

Wed, 30 Nov 2016 15:18:53 PST

Surface plasmon resonance is the resonant oscillations of the free electrons at the interface between two media with different signs in real permittivities, e.g. a metal and a dielectric, stimulated by light. Plasmonics is a promising field of study, because electron oscillations inside a subwavelength space at optical frequencies simultaneously overcome the limit of diffraction in conventional photonics and carrier mobilities in semiconductor electronics. Due to the subwavelength confinement, plasmonic resonances can strongly enhance local fields and, hence, magnify light-matter interactions. Optical absorbers based on plasmonic metamaterials can absorb light resonantly at the operating wavelengths with up to 100% efficiency. We have explored plasmonic absorbers at infrared wavelengths for thermal detectors, e.g. a gold nanostrip antenna absorber that can absorb 10-times light using only 2% of material consumption comparing to a uniform gold film.

In an optomechanical device, the optical mode and mechanical mode are mutually influenced, through the optical forces exerted on the mechanical oscillator and the detuning of optical resonance by the mechanical oscillator, so that the mechanical oscillations are either amplified or suppressed by light. We designed an optomechanical device integrated with plasmonic metamaterial absorber on a membrane mechanical oscillator, wherein a tunable Fano-resonant absorption in the absorber arises from the coupling between the plasmonic and Fabry-Perot reonsances. The absorber traps the incident light and heat up the membrane, causing an increase in thermal stress and a normal plasmomechanical force on it. This is a light-absorption-dependent elastic force arising from the opto-thermo-mechanical interactions. Due to the finite thermal response time in the membrane, the elastic plasmomechanical force is delayed and, consequently, generates a viscous component modifying the damping rate of the mechanical oscillator. We have observed optomechanical amplification and cooling in the device at designed detuning conditions. In particular, on the condition that the optomechanical gain beats the intrinsic mechanical damping, the oscillation becomes coherent, i.e. phonon lasing. We successfully demonstrated phonon lasing with a threshold power of 19 μW. This device is promising as an integration-ready coherent phonon source and may set the stage for applications in fundamental studies and ultrasonic imaging modalities.

Selective Forces That Shape The Vls Antigenic Variation System In Borrelia Burgdorferi

Wed, 30 Nov 2016 15:18:49 PST

Evolutionary success of microbial pathogens requires survival within hosts, despite the rapidly changing and lethal immune response. Pathogens such as the Lyme disease bacteria Borrelia burgdorferi have evolved antigenic variation systems that are necessary for survival within the adverse immune environment. Although antigenic variation systems are essential to both microbial pathogenesis and microbial evolution, it is largely unclear what selective forces have influenced the evolution of antigenic variation systems. In this thesis, we investigate evolution of the vls antigenic variation system in B. burgdorferi by asking two major questions: First, what traits relevant to the vls antigenic variation system have natural selection acted on? Second, how did the selective forces shape the genetic sequences of the vls antigenic variation systems? We characterize sources of natural selection using mathematical modeling, computational simulation and mutagenesis experiments. Our findings show that natural selection has promoted diversity among VlsE variants on both sequence and structure by organizing the variable sites in the vls unexpressed cassettes. We also show that the level of diversity among the VlsE variants may strongly influence the within-host dynamics of Bb, an important fitness component of B. burgdorferi. Finally, our results indicate that diversity among VlsE variants might be constrained by purifying or stabilizing selections on translational efficiency and structural stability of the VlsE variants.

Phase Boundary Propagation In Mass Spring Chains And Long Molecules

Wed, 30 Nov 2016 15:18:45 PST

Martensitic phase transitions in crystalline solids have been studied and utilized for many technological applications, including biomedical devices. These transitions typically proceed by the nucleation and propagation of interfaces, or phase boundaries. Over the last few decades, a continuum theory of phase transitions has emerged under the framework of thermoelasticity to study the propagation of these phase boundaries. It is now well-established that classical mechanical and thermodynamic principles are not sufficient to describe their motion within a continuum theory, and a kinetic relation must be supplied to complete the constitutive description. A few theoretical techniques that have been used to infer kinetic relations are phase-field models and viscosity-capillarity based methods, within both of which a phase boundary is sharp, but smeared over a short length. Here we use a different technique to infer a kinetic relation. We discrete a one-dimensional continuum into a chain of masses and springs with multi-well energy landscapes and numerically solve impact and Riemann problems in such systems. In our simulations we see propagating phase boundaries that satisfy all the jump conditions of continuum theories. By changing the boundary and initial conditions on the chains we can explore all possible phase boundary velocities and infer kinetic relations that when fed to the continuum theory give excellent agreement with our discrete mass-spring simulations. A physical system that shares many features with the mass-spring systems analyzed in this thesis is DNA in single molecule extension-rotation experiments. DNA is typically modeled as a one-dimensional continuum immersed in a heat bath. It is also known from fluorescence experiments that some of these transitions proceed by the motion of phase boundaries, just as in crystalline solids. Hence, we use a continuum theory to study these phase boundaries in DNA across which both the stretch and twist can jump. We show that experimental observations from many different labs on various DNA structural transitions can be quantitatively explained within our model.

Genomic, Evolutionary And Functional Analyses Of Diapause In Drosophila Melanogaster

Wed, 30 Nov 2016 15:18:42 PST

Understanding the genetic basis of adaptation has been and remains to be one major goal of ecological and evolutionary genetics. The variation in diapause propensity in the model organism Drosophila melanogaster represents different life-history strategies underlying adaptation to regular and widespread environmental heterogeneity, thus provides an ideal model to study the genetic control of ecologically important complex phenotype. This work employs global genomic and transcriptomic approaches to identify genetic polymorphisms co-segregating with diapause propensity, as well as genes that are differentially regulated at the transcriptional level as a function of the diapause phenotype. I show that genetic polymorphisms co-segregating with diapause propensity are found throughout all major chromosomes, demonstrating that diapause is a multi-genic trait. I show that diapause in D. melanogaster is an actively regulated phenotype at the transcriptional level, suggesting that diapause is not a simple physiological or reproductive quiescence. I also demonstrate that genetic polymorphisms co-segregating with diapause propensity, as well as genes differentially expressed as a function of diapause are enriched for clinally varying and seasonal oscillating SNPs, supporting the hypothesis that natural variation in diapause propensity underlies adaptation to spatially and temporally varying selective pressures. In addition to global genomic and transcriptomic screens, I also performed functional analysis of one candidate polymorphism on the gene Crystalllin, which represents an intersection of multiple global screens related to seasonal adaptation. I show that this polymorphism affects patterns of gene expression and a subset of fitness-related phenotypes including diapause, in an environment-specific manner. Taken together, this work provide a holistic view of the genetic basis of a complex trait underlying climatic adaptation in wild populations of D. melanogaster, linking genetic polymorphism, gene regulation, organismal phenotype, population dynamics and environmental parameters.

Blocking Immunosuppressive Factors And Taking Advantage Of The Nutrient Supply Within The Tumor Microenvironment: Pathways To Achieve Improved Cancer Immunotherapeutic Efficacy For Patients With Metastatic Melanoma

Wed, 30 Nov 2016 15:18:39 PST

The incidence of melanoma is increasing. Immunotherapy commonly fails due to the immunosuppressive tumor microenvironment (TME). The aim of my dissertation is to develop strategies that dampen the TME’s immunosuppressive capacity and improve the antitumor performance of vaccine-induced melanoma-associated antigen (MAA)-specific CD8+T cells. I pursued this goal using three approaches. First, interactions between co-inhibitors on CD8+ tumor-infiltrating lymphocytes (TILs) with immunoinhibitory ligands within the TME impair T cells’ effector functions. I assessed whether blocking immunoinhibitory signaling during T cell priming augments their antitumor activity. I designed a melanoma vaccine expressing MAAs within herpes simplex virus (HSV) glycoprotein D (gD), which blocks the inhibitory BTLA/CD160-HVEM pathway. Compared to a non-gD vaccine, the gD-adjuvanted vaccine enhances CD8+T cells to low avidity epitopes and prolongs survival of tumor-bearing mice. gD renders MAA-specific CD8+TILs more resistant to functional impairment within TME, which increases their ability to limit tumor progression. Second, the stroma of solid tumors is crucial for tumorigenesis and suppresses the CD8+TILs’ effector functions. To determine whether destroying tumor stroma could improve the MAA-specific CD8+T cells’ tumoricidal capacity, I designed a vaccine targeting the fibroblast activation protein (FAP), which is expressed at high levels on tumor-stromal fibroblasts. Combining the vaccines to FAP and MAAs significantly improves the survival of tumor-bearing mice. This is caused by destruction of FAP+ cells, which reduces frequencies and inhibitory functions of immunosuppressive cells. It also decreases the MAA-specific CD8+TILs’ metabolic stress and delays their progression towards functional exhaustion. Finally, the TME commonly lacks nutrients and oxygen needed for the CD8+TILs’ energy production. My data demonstrate that these metabolic challenges profoundly contribute to the CD8+TILs' functional impairment. Using 13C-stable isotope tracing in vivo, I show that metabolically stressed CD8+TILs in late stage tumors increasingly depend on fatty acids (FAs) catabolism for energy production. Promoting FA catabolism by CD8+TILs improves their effector functions and capacity to delay tumor growth. Overall, my studies show that blocking inhibitory factors while taking advantage of the available nutrients within the TME could improve the performance of vaccine- or adoptive transfer-induced CD8+TILs. These strategies provide new avenues for cancer immunotherapy that may benefit cancer patients.

Networked Social Influence: Online Social Network Physical Activity Interventions For Young Adults

Wed, 30 Nov 2016 15:18:35 PST

Sedentary lifestyle significantly increases the risks of chronic disease and all-cause mortality. Nevertheless, low levels of physical activity among young adults remain a serious nationwide problem, with 69% of Americans 18 to 24 years of age failing to meet the federal guidelines for both aerobic and muscle-strengthening activity in 2014. Among all the social and environmental factors affecting physical activity levels, interpersonal social networks are one of the most prominent targets for cost-effective interventions. In particular, online social networks are a highly attractive resource for large scale health initiatives given their capacity to disseminate interventions easily while simultaneously facilitating social influence dynamics. This dissertation examines online social networks’ efficacy and mechanisms in increasing physical activity among young adults. The dissertation comprises three experiment studies. The first study employed a 3-arm randomized controlled trial (RCT) to examine the effects of basic website, promotional media messaging, and web-based anonymous online networks in increasing exercise class enrollment. The results showed among 217 university graduate students anonymous online networks were more effective than the basic website in increasing exercise class enrollment. The second study built upon the first study and employed a 2 by 2 factorial RCT to compare the effects of supportive versus competitive interactions and individual versus team incentives through web-based online networks in increasing exercise class attendance. The results showed among 790 university graduate students, social comparison was more effective in increasing exercise class attendance than social support. There was no significant difference between individual and team incentives in increasing class attendance. The third study shifted the technological platform and employed a mobile application. It tested the efficacy of an online network mobile app intervention in increasing daily active minutes objectively recorded by a fitness tracking device (Fitbit zip) in comparison with a control condition where individuals used the app by themselves without any connection with other people. Results showed among 91 young African American women, the online networks did not impact the primary outcome, daily active minutes. Self-reported physical activity significantly increased after the intervention program irrespective of intervention arms. Online networks were effective in increasing daily engagement with the fitness tracking device and the mobile app in comparison with the control condition. In addition, descriptive analyses on theoretical variables indicated that young African American women perceived low levels of peer norm and social support on physical activi[...]

Investigating The Role Of Innate Inflammatory Pathways During Infection With Murine Coronavirus

Wed, 30 Nov 2016 15:18:32 PST

Multicellular organisms are constantly exposed to microorganisms, such as viruses and bacteria, many of which are infectious pathogens. The immune system evolved to provide protection against these organisms, and includes numerous components to defend against a diverse, rapidly evolving pool of pathogens. The immune system is classically divided into two arms, the innate and adaptive systems. The time and metabolic cost of activating the T and B cell responses are considerable, and can also have deleterious side effects if the response is not properly controlled. Therefore, the adaptive immune system is carefully regulated so as to be activated only when necessary. The innate immune system serves to control most pathogens in a more rapid, less energetically expensive manner than the adaptive immune system, and to help regulate subsequent immune responses, guiding and controlling them in order to most efficiently clear pathogens with a minimum of pathological side effects. Among the first elements of the innate system that pathogens encounter are pattern recognition receptors, invariant receptors that detect conserved pathogen associated molecular patterns. Upon recognizing its binding ligand, a pattern recognition receptor will activate a signaling cascade that often triggers production and/or release of one or more pro- inflammatory cytokines. These in turn modulate additional elements of both the innate and adaptive immune responses, and are often critical lynchpins of host defense. Due to this central role in the immune system we investigated the roles of two distinct innate inflammatory pathways, the inflammasome and the MDA5-dependent portion of the type 1 interferon response, during infection with the murine coronavirus mouse hepatitis virus (MHV). Utilizing transgenic mice deficient in Caspase-1 and -11, which catalyze all inflammasome processing, the IL-1 receptor, the IL-18 receptor, or MDA5, we characterize the disease course and subsequent immune response following infection with MHV, a model murine coronavirus. We find that inflammasome signaling is protective during infection, and that much or all of this protection is mediated by IL-18 signaling driving production of interferon gamma by T cells. We also demonstrate that MDA5 signaling controls viral tropism and replication, and that in its absence the host immune response becomes over active, likely leading to lethal pathology. Overall, our studies help define how innate inflammatory pathways can have diverse influences on pathogenesis and the immune response.

Characterization Of Solid Lewis Acids In Biomass Conversion Reactions

Wed, 30 Nov 2016 15:18:29 PST

Solid Lewis acids can be very selective in many important biomass reactions. Unfortunately, our understanding of solid Lewis acidity is very poor, making it difficult to design and select specific catalysts for a particular reaction. In this dissertation, characterization and examination of solid Lewis acids were performed through home-built instruments including Temperature-Programmed Desorption (TPD)/Thermogravimetric Analysis (TGA), calorimetry, and a multiphase continuous flow reactor. A number of important catalyst families were examined in this work, including bulk metal oxides, ion-exchanged zeolites and framework substitution Lewis acid zeolites. In this work, it has been shown that the adsorption features obtained from TPD-TGA, calorimetry experiments are very helpful in understanding reaction results from reactor study. Adsorption studies are able to determine Lewis site density, relative adsorption strength and activation energy of monomolecular reactions which are extremely valuable information for catalysts. Biomass reactions over Lewis acid catalysts are through multiple and complicated steps. Works in my study provides a valuable method to understand solid Lewis acidity in biomass reactions through an adsorption feature investigation.

The Intended And Unintended Consequences Of Regulating For-Profit Colleges: A Model Of College Choice And Retention

Wed, 30 Nov 2016 15:18:25 PST

This dissertation investigates individuals' college choice and dropout behavior in the market for vocational training, specifically in response to a recently proposed financial aid regulation. Vocational training is an important component of the postsecondary education arena and has been promoted by political leaders as an option for high school graduates who do not wish to attend traditional 4 year colleges. The major players in this market are for-profit colleges and community colleges, both of which offer open admission and mainly confer certificates and associate degrees. This paper evaluates the implications of a regulation proposed by the Obama administration to restrict federal student financial aid to for-profit colleges. Specifically, I examine the effect of this policy change on students' college enrollment and college retention. To that end, I develop and estimate a two-period discrete choice model of differentiated products, where the products are vocational colleges. In the first period, forward-looking and risk-neutral individuals choose a vocational college to attend or the outside option of no college. In the second period, those who are enrolled in a college decide whether or not to drop out of school upon learning more about their postgraduation outcomes. I estimate this model using Generalized Methods of Moments with school-level data collected from the Department of Education. Model estimates reveal heterogeneous preference across demographic groups and several differentiating factors between for-profit colleges and community colleges. I find that for-profit college enrollment is highly responsive to federal student financial aid availability and that most of those who attend for-profit colleges would rather forgo college altogether than substitute to community colleges. Counterfactual simulations reveal that the proposed regulation would be successful at steering students away from for-profit colleges, as intended by policy makers, but an unintended consequence of the regulation is that 77% of those who would have otherwise gone to for-profit colleges would rather choose the no college option than the community college option. This would amount to a net decline of 15% in college enrollment in the market for vocational training. Furthermore, I find that for those who would substitute from for-profit colleges to community colleges in response to the proposed regulation, their dropout probabilities on average would increase by 24 percent points due to mismatch.

Synthesis And Characterization Of Transition Metal Based Metal Oxide And Metallic Nanocrystals For Ac Magnetic Devices And Catalysis

Wed, 30 Nov 2016 15:18:21 PST

The d-block elements are very important in magnetics, electronics, catalysis, and biological systems. The synthesis and characterization of nearly monodisperse d-block element based nanocrystals with a precise control over the size, composition, and shape are important to utilize the nanocrystals in such applications. The goals of my thesis are to synthesize d-block transition metal based nanocrystals and understand their magnetic and catalytic properties. I present the size- and composition-dependent AC magnetic permeability of superparamagnetic iron oxide nanocrystals for radio frequency applications. The nanocrystals are synthesized through high-temperature solvothermal decomposition, and their stoichiometry is determined by M�ssbauer spectroscopy. Size-dependent magnetic permeability is observed in maghemite nanocrystals, while as-synthesized, magnetite-rich, iron oxide nanocrystals do not show size dependence due to the inhomogeneous crystal structure of the as-synthesized nanocrystals. The saturation magnetization of iron oxide nanocrystals is increased by doping of non-magnetic Zn2+ into A site of ferrite, resulting the enhancement of the real part of the magnetic permeability of Zn0.25Fe2.75O4 nanocrystals by twofold compared to that of similarly sized ferrite nanocrystals. The integration of 12.3 nm Zn0.25Fe2.75O4 nanocrystals into a microfabricated toroidal inductor and a solenoid inductor yield higher quality factors than air core inductors with the same geometries. The ligand exchange with dendrimers reduces the blocking temperature of Mn0.08Zn0.33Fe2.59O4 nanocrystal, indicating the decrease of dipolar coupling between nanocrystals. The study on MnxFe3-xO4 and CoxFe3-xO4 nanocrystals shows a clear difference in DC and AC magnetic behaviors of soft and hard magnetic nanocrystals. The inductor with zinc ferrite nanocrystal core is embedded into a power converter and its temperature dependent energy efficiency is measured. The energy efficiency of a power converter with the nanocrystal core inductor rises as the temperature increases while that of the power converters with an air core inductor or commercial core inductor decreases. Finally, I describe the hydrodeoxygenation reaction of 5-hydroxymethylfurfural into 2,5-dimethylfuran by metallic nanocrystals such as Pt, PtMn, PtFe, PtCo, and PtNi. Both conversion ratio and selectivity for 2,5-dimethylfuran show clear composition dependent catalytic properties and, in particular, 3.7 nm Pt3Co2 nanocrystals achieve 98 % of selectivity for 2,5-dimethylfuran.

High-Level Abstractions For Programming Network Policies

Wed, 30 Nov 2016 15:18:19 PST

The emergence of network programmability enabled by innovations such as active network- ing, SDN and NFV offers tremendous flexibility to program network policies. However, it also poses a new demand to network operators on programming network policies. The motivation of this dissertation is to study the feasibility of using high-level abstractions to simplify the programming of network policies. First, we propose scenario-based programming, a framework that allows network operators to program stateful network policies by describing example behaviors in representative scenarios. Given these scenarios, our scenario-based programming tool NetEgg automatically infers the controller state that needs to be maintained along with the rules to process network events and update state. The NetEgg interpreter can execute the generated policy implementation on top of a centralized controller, but also automatically infers flow-table rules that can be pushed to switches to improve throughput. We study a range of policies considered in the literature and report our experience regarding specifying these policies using scenarios. We evaluate NetEgg based on the computational requirements of our synthesis algorithm as well as the overhead introduced by the generated policy implementation. Our results show that our synthesis algorithm can generate policy implementations in seconds, and the automatically generated policy implementations have performance comparable to their hand-crafted implementations. Our preliminary user study results show that NetEgg was able to reduce the programming time of the policies we studied. Second, we propose NetQRE, a high-level declarative language for programming quantitative network policies that require monitoring a stream of network packets. Based on a novel theoretical foundation of parameterized quantitative regular expressions, NetQRE integrates regular-expression-like pattern matching at flow-level as well as application-level payloads with aggregation operations such as sum and average counts. We describe a compiler for NetQRE that automatically generates an efficient implementation from the specification in NetQRE. Our evaluation results demonstrate that NetQRE is expressive to specify a wide range of quantitative network policies that cannot be naturally specified in other systems. The performance of the generated implementations is comparable with that of the manually-optimized low-level code. NetQRE can be deployed in different settings. Our proof-of-concept deployment shows that NetQRE can provide timely enforcement of quantitative network policies. [...]

Sex, Drugs, And Transgenerational Inheritance: Are The Kids Alright?

Wed, 30 Nov 2016 15:18:16 PST

The occurrence of neuropsychiatric disorders and substance abuse is subject to familial inheritance (nature) as well influence from the environment (nurture). In addition, familial patterns of behavior and disease are also mediated by transgenerational epigenetic inheritance. The dynamic nature of the epigenome allows for exposures to stress, drugs of abuse, environmental toxins, and even changes in diet to produce changes in gene expression. In addition these changes can be inherited by offspring. Therefore, offspring behavior and quality of life are shaped by their own experiences as well as the experiences of their parents and more distant relatives. The studies in this dissertation had two objectives: first to identify the transgenerational inheritance of adolescent stress exposure and its effects on offspring behavior including response to nicotine and second, to determine the cross-generational interaction of nicotine and stress exposures on offspring behavior. To address the first objective, we exposed male and female mice to adolescent stress exposure, determined the long-term effects of exposure on their behavior, and identified changes in phenotype in their F1 and F2 offspring. We found that adolescent stress exposure produced changes in anxiety, startle response, and gene expression in adulthood that was not found when the same stress exposure occurred in adult mice. In addition, we found that transgenerational inheritance of adolescent stress exposure promoted sex- and lineage-dependent changes in anxiety, depression, startle, and response to nicotine in F1 and F2 offspring. Furthermore, to determine if parental stress exposure influenced gene expression in the brains of offspring we analyzed the transcriptome of F1 males and found 240 differentially expressed genes in the amygdala of males whose fathers were exposed to stress. In our final study, we developed a novel multigenerational exposure paradigm and determined that F0 nicotine and F1 stress exposure interact across generations to produce unique phenotypes in F2 and F3 offspring. Together, research from this dissertation provides evidence of an adolescent chronic stress exposure that mediates anxiety in adulthood and is inherited in future generations by reprogramming the brain of offspring, and provides the first example of cross-generational interactions of two environmental exposures to influence offspring phenotype.

Information In Environmental Architecture: Ecological Network Analysis And New Indices Of Building Performance

Wed, 30 Nov 2016 15:18:13 PST

This dissertation suggests a new framework and indices of building performance evaluation based on an eco-systemic approach. The energy-efficient building construction and operation are important to achieve sustainability. Nevertheless, efficiency does not fully account for the building’s complex environmental phenomena in which nature, art, and human living are inseparably involved. In particular, increasing efficiency cannot clearly associate the robustness and stability of the building’s internal energetic organization (and trade-offs between energy efficiency and material use) with building form and occupant behavior. The purpose of this study is to argue that environmental information content is a substantial source to achieve building sustainability and to suggest that an emergy (spelled with an “m”)-coupled information measure is the most comprehensive and holistic index of building performance. Based on ecosystems theory, this dissertation defines building as a thermodynamic system that utilizes, transfers, and self-organizes the useful environmental resources―energy, material, and information―through networking processes. Definitions and formulas of information measures and ecological indicators from Shannon’s information theory, Ulanowicz’s ascendency principle, and Odum’s maximum empower principle are discussed and adopted to develop a new methodology of integrating building information and emergy and a model of building emergy-flow networking. A hypothetical generic building system is modeled and tested to characterize the building’s systematic behavior with the examination of information change. Results of the hypothetical tests show that the informational characteristics of building emergy-flow networking parallels the phenomenological evidences of ecosystems development and sustainability―increasing complexity, resilience, fitness, and useful energy (power). To verify the consistency between ecosystem development and building sustainability, experiments were conducted with two case study buildings: a net-zero energy building (NZEB) and a non-NZEB. Emergy-integrated information analyses according to the suggested governing equations and system models were carried out. Results show that the non-NZEB tends to be more resilient and adaptable and to have more “generative” empower (or total system information), even though the NZEB is more efficient. This indicates that high-performance (high-efficient) buildings may end up greater nonrenewable inputs. On the other hand, the investigation of the information content of building envelope [...]

C−f→ln/an Interactions And Molecular Cerium(iii) Photochemistry

Wed, 30 Nov 2016 15:18:10 PST

Part I: Ligand design is at the crux of molecular f-block element chemistry where well-defined ligand frameworks allow rational coordination and reaction chemistry. In the first part of this work, the C−F→Ln/An interaction, a type of non-covalent interaction, was incorporated into amide complexes of f-block cations. Solid-state and solution evidence for the presence of C−F→Ln/An interactions was presented. Collective impacts of multiple C−F→Ln/An interactions on the molecular geometries and electronic structures were investigated through experimental and computational studies. The labile nature of C−F→Ln/An interactions allowed their displacement by donor molecules opening a venue toward unconventional coordination chemistry of f-block cations.

Part II: The replacement of the element samarium for cerium in one-electron reduction reactions is desirable for economic and sustainability reasons. Notably, cerium is comparable to base metals in terms of abundance. At the crux of such replacement is the capability of producing cerium(III) species with comparable or superior reduction potentials than samarium(II) iodides. In the second part of this work, this issue was tackled with photochemical methods taking advantage of energetically accessible 4f→5d absorptive transitions of cerium(III) cations. Luminescent cerium(III) complexes in their long-lived doublet d-orbital based excited states are more reducing than in ground states, allowing for their electron transfer to substrates. Significant insight is provided into the photophysics of cerium luminescence through the preparation and comparison of two complete mixed-ligand series of luminescent cerium(III) complexes. The photochemical reactivity of excited-state cerium(III) complexes were demonstrated in both stoichiometric and catalytic fashions.

The Regulation Of Psf Activity In T Cells By Trap150 And Gsk3

Wed, 30 Nov 2016 15:18:06 PST

PSF is a ubiquitously expressed and essential nuclear protein that influences many aspects of the genome maintenance and gene expression pathways. Although previous studies have identified numerous protein cofactors and nucleic acid targets of PSF, insufficient work has been done to understand how it is regulated to accomplish its various functions in a coordinated manner. Previous research in the Lynch laboratory demonstrated that, in T cells, PSF is a downstream target of the serine/threonine kinase GSK3. Phosphorylation of PSF T687 by GSK3 promotes interaction of PSF with another multifunctional nuclear factor, TRAP150. This interaction prevents PSF from binding RNA and regulating alternative splicing of CD45 exon 4, though the mechanism for TRAP150’s effect on PSF is unknown. In this dissertation, I probe this regulatory mechanism using several biochemical and biophysical tools. First, I use a combination of mammalian co-immunoprecipitation reactions and GST pull-downs to isolate the minimal domains of PSF and TRAP150 responsible for their interaction. Interestingly, TRAP150 binds the highly conserved DBHS core of PSF using a previously unannotated 70-residue region. Using electrophoretic mobility shift assays and UV-induced protein/RNA crosslinking, I next localize PSF’s mRNA-binding ability to noncanonical RRM2, and I show that TRAP150’s interaction with the PSF RRMs is sufficient to ablate PSF/mRNA interaction. Further, I provide evidence from RASL-Seq showing that PSF regulates ~40 alternative splicing events in T cells. Critically, TRAP150 has an antagonistic effect on PSF’s regulation of these events. Finally, I use limited proteolysis assays to provide evidence that PSF undergoes a phosphorylation-dependent conformational change in unstimulated versus stimulated T cells. Together, these data suggest that phosphorylation of PSF T687 by GSK3 induces a conformational shift in PSF that allows TRAP150 to bind its RRMs and, in turn, decrease its ability to bind RNA and regulate alternative splicing. Together, the results described here point to a generalizable model of PSF regulation predicated on selective posttranslational modification and induced conformational changes that influence its interactions with different cofactors and targets.

Genetic Diversity In Svaneti And Highland Western Georgia

Wed, 30 Nov 2016 15:18:01 PST

This study investigates the genetic diversity and ethnohistory of Svaneti and its neighboring highland Georgian and breakaway regions in order to better understand the complex population history of the South Caucasus. The objectives of this project are to (1) document the biological diversity in contemporary settlements in the region of Svaneti; (2) compare patterns of gene diversity with Svaneti’s western and eastern neighbors, Abkhazia and South Ossetia, respectively; and (3) determine whether gene frequencies in Svaneti are evently distributed across geographic space by characterizing any village-level structuring. We will contextualize the findings within broader studies that address major regional population settlement events during the Upper Paleolithic, Neolithic, and Metal Ages, as well as the putative ‘Alan migration’ in the 4th century AD. To accomplish these goals, biological samples were collected from participants in Svaneti for genetic analysis, providing a more thorough coverage of village districts in Svaneti than has been achieved in previous studies. In addition, local-level ethnohistorical interviews were conducted in an effort to distinguish patterns of diversity resulting from long-term inhabitation versus those arising from recent immigration into the region. These DNA samples were characterized for mitochondrial DNA and Y-chromosome variation, and the resulting data analyzed with statistical and phylogenetic methods to define the biological affinities of highland Georgian populations, and reconstruct the migration and settlement history of the region. Data from published and unpublished sources on the genetic diversity of the greater Near East and Caucasus, specifically Abkhaz and Ossete populations, were used for phylogeographic and statistical comparison. The results revealed reduced Y-chromosome haplogroup diversity in Svans, with a predominance of G2a, although their paternal lineages occurred at frequencies comparable to those of neighboring highland populations. By contrast, mtDNA haplogroup diversity in Svans was both very high and reasonably similar in terms of frequency to other regional populations, with W6 and X2 occurring at unusually high frequencies. Interestingly, there was no geographic patterning of Y-chromosome or mitochondrial DNA diversity within Svaneti at the village level. Nevertheless, strong Y-chromosome affinities with eastern and western populations (i.e., Ossete and Abkhaz, respectively) living adjacent to the Svans indicated a common[...]

Building Blocks Of Chinese Historiography: A Narratological Analysis Of Shi Ji

Wed, 30 Nov 2016 15:17:57 PST

In Shi ji studies, scholars from both the East and West have predominantly taken one particular approach: the psychological reading of its author, Sima Qian. Since the author suffered penal castration when he was writing the Shi ji, this approach has been summarized as “the theory of conveying one’s frustration.” Many scholars, modern and pre-modern alike, have inferred the author’s feelings and emotions from his biographical experiences and have interpreted the text accordingly. This narrow interpretation constrains our understanding by exclusively focusing on the author’s personal pains and purposes. Such analysis thus commits the intentional fallacy, which mistakenly equates the author with the text, unjustifiably simplifying the complicated interpretive process. I explore the features of the text itself, shifting the focus of research from the author’s intention to the effects produced by its narrative devices, which have determinative influence over the interpretive process but have long been overlooked. I explore the role of narrative as a medium in historical works, applying theories of narratology from the French Structualist G�rard Genette to analyze narratives in the Shi ji. By setting the text into this framework, I systematically examine the narrative sequences, such as anticipation and flashback, narrative duration and mood, and characterization. My investigation shows that these narrative devices produce literary effects, distinguishing Shi ji from both earlier and later histories, such as the Zuo zhuan and Han shu. Shi ji presents a highly complicated past by manipulating interrelations among historical events, regulating information, and emphasizing changes and their effects. It pays most attention to how the historical events happened, more than what happened and why, a significant issue has not been discussed in a context of Chinese historiography. My narratological approach provides an alternative perspective and explores new territory in Shi ji studies.

Bypassing Nk Cell Tuning By Targeting Diacylglycerol Kinase Zeta, A Distal Regulator Of Signaling

Wed, 30 Nov 2016 15:17:55 PST

NK cells are part of the innate immune system, and play an important role in viral and tumor defense. Improving natural killer (NK) cell function could be beneficial for enhancing anti-tumor or anti-viral responses. However, efforts to improve NK cell function by disrupting negative regulators that target proximal signaling pathways paradoxically results in less responsive NK cells. This is often attributed to their ability to tune their responsiveness. In this thesis, I found that NK cells are extremely sensitive to loss of inhibitory ligand or mediators of inhibitory signaling. Using adoptive transfer and mixed chimera models, I found that MHC class I expression is necessary both in cis and trans for NK cells to possess full functionality. Furthermore, using an acute model of genetic targeting, I found that temporal ablation of SHP-1 was sufficient to drive hyporesponsiveness, and the loss of even a single allele of SHP-1 had profound effects on NK cell responses. However, the data also showed that tuned NK cells could still be stimulated to respond via analogs of secondary messengers of signaling, suggesting that NK cell tuning targets proximal signaling pathways.

To improve NK cell function but avoid NK cell tuning, I targeted a distal negative regulator of signaling. I found that genetic deletion of diacylglycerol kinase zeta (DGKζ), a negative regulator of diacylglycerol-mediated signaling, enhances NK cell function due to its distal position in the signaling cascade. Upon activating receptor stimulation, NK cells from mice lacking DGKζ display increased cytokine production and cytotoxicity in an ERK-dependent manner. This enhancement of NK cell function is NK cell-intrinsic and developmentally independent. Importantly, DGKζ deficiency does not affect inhibitory NK cell receptor expression or function. Thus, DGKζ KO mice display enhanced clearance of a TAP-deficient tumor. I therefore propose that enzymes that negatively regulate distal signaling pathways such as DGKζ represent novel targets for augmenting the therapeutic potential of NK cells.

Forest Biomass And Soil Carbon Stock Changes In The Delaware River Basin

Wed, 30 Nov 2016 15:17:52 PST

Forests play an important role in the global carbon cycle. Quantifying forest biomass and soil carbon stocks and their change over time and space is important to understand forest dynamics and their feedbacks with climate change. This dissertation investigates the forest biomass and soil carbon stocks and their controlling factors in the Delaware River Basin (DRB) using a combination of field measurements and modeling. In 2001-2003, 77 forest plots in three research sites were established and their biomass was measured. In 2012-2014, 61 of these plots were revisited and forest biomass was re-measured using the same protocols. Two soil sampling methods, the Forest Inventory Analysis standard soil core method and the quantitative soil pit method, were also used to collect soil samples. Based on the results of field measurements, a process-based ecosystem model (PnET-CN) was parameterized and used to simulate the spatial distribution of forest carbon pool and fluxes in the three sites. We found that the mean biomass carbon stock in the three sites was 166.5 Mg C ha-1 and had increased by 2.35 Mg C ha-1 yr-1 and was thus a carbon sink over the past decade. The soil carbon stock to 40 cm depth was 76.6 Mg C ha-1. The accuracy of the soil core sampling method was questioned because in the surface mineral soil layer, lower bulk density, lower coarse fragment content and greater carbon concentration were measured using the core method compared to the pit method. By parameterizing the wood turnover rate, maximum photosynthesis rate and disturbance year based on field measurements, the performance of the PnET-CN model was improved in capturing the spatial variation of forest carbon dynamics. The modified model was also used in experimental scenarios, demonstrating 39% of forest carbon sequestered over the past decade could be attributed to the combined effects of elevated CO2 and nitrogen deposition. Large uncertainties in forest carbon stocks at regional scales are associated with the spatial heterogeneity of the forest. A long-term forest monitoring system combined with modelling can greatly reduce the uncertainties and increase the accuracy of our estimates of forest carbon stocks.

Liquid Crystal Anchoring Control And Its Applications In Responsive Materials

Wed, 30 Nov 2016 15:17:48 PST

Liquid crystals (LCs), owing to their anisotropy in molecular ordering, are of interests not only in the display industry, but also in the soft matter community, e.g., to direct colloidal assembly and phase separation of surfactants, and to actuate two-dimensional (2D) sheets into three-dimension (3D). The functionality and performance of LC materials extensively rely on the molecular ordering and alignment of LCs, which are dictated by LC anchoring at various boundaries. Therefore, this thesis focuses on the study of LC anchoring from both small molecule LCs and liquid crystal monomers (LCMs), which in turn guides my design of surface topography and surface chemistry to control formation of uniform LC defect structures over cm2 samples under complex boundary conditions. The ability to precisely embed defect structures in a LC material also allows me to exploit the responsiveness of LCs to create actuators and scaffolds to (dis)assemble nano- and micro-objects. Specifically, by exploiting the bulk disclinations formed in the nematic phase of 4-octyl-4’-cyanobiphenyl (8CB) surrounding the micropillar arrays, we demonstrate (dis)assembly of gold nano-rods (AuNRs) for dynamic tuning of surface plasmon resonance (SPR). Due to the highly temperature-sensitive elastic anisotropy of 8CB, the bulk disclinations and consequently the AuNR assemblies and SPR properties can be altered reversibly by heating and cooling the LC system. Then we design and synthesize a new type of nematic LCMs with a very large nematic window. Therefore, they can be faithfully aligned at various boundary conditions, analogous to that of small molecule LCs. After crosslinking LCMs into liquid crystal polymers (LCPs), we are able to study the LC assembly, director field, and topological defects using scanning electronic microscopy (SEM) at the 100 nm resolution. We then turn our attention to direct LCM alignment through controlling of surface chemistry and topography. We demonstrate the essential role of surface chemistry in the fabrication of liquid crystal elastomer (LCE) micropillar arrays during soft lithography. A monodomain LCM alignment is achieved in a poly(2-hydroxyethyl methacrylate) coated polydimethylsiloxane (PDMS) mold. After crosslinking, the resultant LCE micropillars display a large radial strain (~30%) when heated across the nematic-isotropic phase transition temperature (TNI). The understanding of [...]

Lifting Problems And Their Independence Of The Coefficient Field

Wed, 30 Nov 2016 15:17:44 PST

Our aim is to find out new things about lifting problems in general and Oort groups

in particular. We would like to know more about what kind of rings are needed to find

liftings to characteristic 0 of covers of curves in characteristic p. For this, we use explicit

parametrization of curves and model theory of algebraically closed fields and valued fields.

The geometric machinery we need includes local-global principle of lifting problems and

HKG-covers of ring extensions. We won’t use formal or rigid geometry directly, although

it is used to prove some of that machinery. Also we need some model theoretical results

such as AKE-principles and Keisler-Shelah ultrapower theorem. To be able to use model

theoretical tools we need to assume some bounds on the complexity of our curves. The

standard way to do this is to bound the genus. What we want is that for the finite group G,

the curves of a fixed genus can be lifted over a fixed ring extension. This kind of question —

where both the curve and the ring are bounded — is well suited for model theoretical tools.

For a fixed finite group G, we will show that for genus g and an algebraic integer π, the

statement “every G-cover Y → P 1 with genus g has a lifting over W (k)[π]” does not depend

on k. In other words, it is either true for all algebraically closed fields k or none of them.

This gives some reason to believe that being an Oort group does not depend on the field k.

Also it might help in finding explicit bounds on the ring extension needed.

Algorithms For Blind Equalization Based On Relative Gradient And Toeplitz Constraints

Wed, 30 Nov 2016 15:17:41 PST

Blind Equalization (BE) refers to the problem of recovering the source symbol sequence from a signal received through a channel in the presence of additive noise and channel distortion, when the channel response is unknown and a training sequence is not accessible. To achieve BE, statistical or constellation properties of the source symbols are exploited. In BE algorithms, two main concerns are convergence speed and computational complexity.

In this dissertation, we explore the application of relative gradient for equalizer adaptation with a structure constraint on the equalizer matrix, for fast convergence without excessive computational complexity. We model blind equalization with symbol-rate sampling as a blind source separation (BSS) problem and study two single-carrier transmission schemes, specifically block transmission with guard intervals and continuous transmission. Under either scheme, blind equalization can be achieved using independent component analysis (ICA) algorithms with a Toeplitz or circulant constraint on the structure of the separating matrix. We also develop relative gradient versions of the widely used Bussgang-type algorithms. Processing the equalizer outputs in sliding blocks, we are able to use the relative gradient for adaptation of the Toeplitz constrained equalizer matrix. The use of relative gradient makes the Bussgang condition appear explicitly in the matrix adaptation and speeds up convergence.

For the ICA-based and Bussgang-type algorithms with relative gradient and matrix structure constraints, we simplify the matrix adaptations to obtain equivalent equalizer vector adaptations for reduced computational cost. Efficient implementations with fast Fourier transform, and approximation schemes for the cross-correlation terms used in the adaptation, are shown to further reduce computational cost.

We also consider the use of a relative gradient algorithm for channel shortening in orthogonal frequency division multiplexing (OFDM) systems. The redundancy of the cyclic prefix symbols is used to shorten a channel with a long impulse response. We show interesting preliminary results for a shortening algorithm based on relative gradient.

Macroeconomic And Fiscal Policy Implications Of Household Labor Supply

Wed, 30 Nov 2016 15:17:38 PST

This dissertation uses dynamic macroeconomic models with household heterogeneity to study the implications of household labor supply on household consumption dynamics and fiscal policy. Chapter 1 (joint work with Dirk Krueger) studies how the endogenous household labor supply channel affects the ability of households to smooth consumption against exogenous wage shocks. We show that a calibrated life-cycle two-earner household model with endogenous labor supply can rationalize the extent of consumption insurance against wage shocks estimated empirically by Blundell, Pistaferri, and Saporta-Eksten (2014) (BPS hereafter) in the U.S. data. With additive separable preferences, only 41% of male and 28% of female permanent wage shocks in the model pass through to household consumption. Most notably, the majority of the consumption insurance against permanent male wage shocks is provided through the endogenous labor supply response of the female earner. We also evaluate, using model-simulated data, the performance of the empirical approach of BPS on consumption responses to wage shocks and find only moderate biases. Chapter 2 studies the implications of changes in economic fundamentals such as increased female labor productivity, skill-biased technological change and aging population on the changes of the U.S. income tax code since the late 1970s. I first study these changes in economic fundamentals using an overlapping generations incomplete-markets life-cycle model with heterogeneous households. The model features both endogenous human capital accumulation and household labor supply and is calibrated to the U.S. economy in the 1970s and 2010s. Then I use this economic model to examine the income tax changes in a Ramsey optimal tax policy framework. I find that: (1) changes in economic fundamentals alone induce a less progressive optimal income tax and can account for 40% of the reduction in progressivity we observe; and (2) the change in Pareto weights required to explain the remaining part of tax policy change favors high-income households and also implies less valued government services. Finally, using a stylized political economy model, I discuss potential explanations for this change of Pareto weights such as the lower cost of conveying information to swing voters and the rising inequality of voter turnou[...]

Essays On The Interface Between Finance And Technology

Wed, 30 Nov 2016 15:17:34 PST

In the first chapter "Shock Spillover and Financial Response in Supply Chain Networks: Evidence from Firm-Level Data", using machine learning methods on firm-level textual disclosures, I construct a large-scale dataset featuring firm-specific shocks to production. I map these shocks into a unique, hand-built network of firm-level supply chain connections to empirically quantify how these localized shocks affect remote firms along the chains. Surprisingly, contrary to prediction by typical network theories, these firm-specific shocks impact the revenue of firms even up to 4 connections away from the origins. This pronounced spillover effect is explained by three features--uneven distribution of monopolistic power, variations in supplier substitutability, and different inventory levels--that are salient in the data but usually not present in existing models. In addition, firms seem to respond to these spillovers by increasing their working capital and financial leverage. Moreover, the stock market reacts to shock spillovers from distant connections with slower speeds: post-shock abnormal returns are persistently negative for up to 40 days.

In the second chapter "Deciphering Fedspeak: The Information Content of FOMC Meetings", we present a new approach to quantify the economic and policy content of Federal Reserve communications by dissecting the Federal Open Market Committee (FOMC) meeting minutes into distinct economic topics, and simultaneously extract the tone and uncertainty level of each topic. We use market reaction to objectively assess the relative informativeness of each topic, and we find significant incremental informational value from the topic contents, despite that the minutes are released several weeks after the original meetings. Furthermore, we find evidence consistent of the Fed possessing superior information, which is then transmitted to the market through the language of the minutes.

Organizational Resource Assembly In Technology Ventures

Wed, 30 Nov 2016 15:17:31 PST

This dissertation addresses the assembly of organizational resources by technology ventures. We study how innovative firms acquire human and financial capital and then organize those resources, and how public policy affects that capability. In the first chapter, we study the role of information in organizational decision-making for the financing of entrepreneurial ventures. We formally model a decentralized set of agents who vote strategically to allocate resources to a project with unknown outcome; they can each acquire costly information to improve their decision quality. We test our predictions in the setting of venture capital, where partners make their own angel investments outside of their employer. We find that the venture capital partners, acting independently, make riskier investments into younger firms with less educated and younger founding teams, but these investments perform better on some metrics even when controlling for investment size and stage. Geographic distance and liquidity constraints increase the probability the investment is taken up by a partner and not the VC. In the second chapter, we evaluate the impact of skilled immigration on U.S. innovation by exploiting a random lottery in the H-1B visa program. Proponents argue that immigration allows firms to access technical skills and promote innovation, while opponents argue that firms substitute domestic labor for cheaper but equally or less skilled foreign labor. We find that winning an H-1B immigrant does not significantly increase patent applications or grants at the firm level, and there is pervasive use of the program in industries where patenting is not the main value-appropriation strategy. In the third chapter, we study how a firm should organize the diversity of technical experience, contained within its pool of inventive human capital, for firm-level innovation. Using a sample of biotechnology start-ups, we examine the implications of alternate firm-level design regimes, drawing on both a firm-year panel structure and an inventor-year difference-in-differences empirical approach. Organizing a firm's human capital with greater across-team diversity yields increased firm-level innovation benefits as compared to organizing with greater within-team diversity. The benefit[...]

Diversity Of Receptor Tyrosine Kinase Signaling Mechanisms

Wed, 30 Nov 2016 15:17:28 PST

Receptor tyrosine kinases (RTKs) are a family of 58 transmembrane proteins in humans that play crucial roles in many biological processes and diseases. Different RTKs utilize subtly (but importantly) distinct molecular mechanisms for transmembrane signaling, and understanding these differences is crucial for devising new ways to intervene pharmacologically when aberrant RTK signaling causes cancer and other diseases. In this thesis, I focus on three RTK families: the ALK/LTK family, the Wnt-binding RTKs, and the EGF receptor – where I concentrate on efforts to understand its C-terminal regulatory region. My studies of ALK, for anaplastic lymphoma kinase, were motivated by the fact that this RTK sub-group has a unique domain architecture in its extracellular region. Little is known about the mechanisms of ligand binding to – and activation of – ALK, and the nature of its ligand(s) is(are) still not completely clear. Using biochemical, biophysical and structural biology approaches, I characterized the low-resolution structure of the ALK extracellular region. I further identified the binding mode of ALK binding to heparin, a recently discovered modulatory ligand for ALK. Based on a low-resolution structural analysis of ALK/heparin complex, I propose a model for ligand-induced ALK dimerization and activation. Ryk is one of the five RTKs that are now known to be Wnt receptors. In this thesis, I studied the Drosophila homolog of Ryk, Derailed (Drl), and its binding to ligand DWnt5. We were able to express and purify milligrams of active DWnt5 – thus overcoming a major obstacle in this field. We further characterized Drl/DWnt5 interactions. Using hydrogen/deuterium exchange approaches, I identified the DWnt5-binding interface on Drl. My efforts to understand the molecular mechanisms of Drl/DWnt5 binding using experimental and computational approaches suggest that DWnt5 may interact with Drl through a binding mode that differs from Wnt binding to other receptors. Across the RTK family, many receptors contain a long carboxy-terminal tail (C-tail) that harbors autophosphorylation sites for docking of downstream signaling molecules. This region is generally considered to be intrinsically disordered. I studied the dynamics of [...]

Insights Into Mbd2 Function Revealed By A Novel Genetic Tagging Approach

Wed, 30 Nov 2016 15:17:26 PST

Methylation of cytosine is an epigenetic mark essential for many cellular and

developmental processes. How methylation is interpreted into transcriptional regulation is not fully

understood, but previous studies have found that this process involves the methyl-CpG binding

domain (MBD) family of proteins. Three MBD proteins, MeCP2, MBD1 and MBD2, specifically

bind methylated cytosines and recruit different co-repressor complexes to regulate transcription

and chromatin states. Genetic studies also linked MeCP2 and MBD1 to neurodevelopmental

disorders in humans and mice. However, a role for MBD2 in the brain has not been described. In

this work, we characterized the phenotypes of mice lacking MBD2. We found that, unlike MeCP2

and MBD1, Mbd2 null mice behave similarly to wildtype littermates, with the exception of mildly

altered nesting and locomotor activity and reduced body weight. To investigate the underlying

cause of different functional requirements for the MBDs, we generated knockin mice in which

endogenous MBD2 and MBD1 are biotin-tagged. We systematically compared the spatiotemporal

expression patterns of the MBDs and found that MeCP2, MBD1 and MBD3 are primarily

expressed in the brain. In contrast, MBD2 is widely expressed throughout the body at young and

adult ages. In addition, the expression of MBD2 is upregulated in adult spleen and small intestine

compared to younger ages, while MBD1 and MBD3 are only enriched at early ages in the brain.

We also determined that MBD2 interacts with the NuRD complex ubiquitously across tissues. We

conclude that MBD2 is likely dispensable for brain function and instead may mediate NuRDrelated

functions primarily in peripheral tissues. Our study provides novel genetic tools and

reveals new directions to investigate MBD2 functions in vivo.

Romantic Periodicals And The Invention Of The Living Author

Wed, 30 Nov 2016 15:17:23 PST


Christine Marie Woody

Michael Gamer

This dissertation asks how the burgeoning market of magazines, book reviews, and newspapers shapes the practice and meaning of authorship during the Romantic period. Surveying the innovations in and conventions of British periodical culture between 1802 and 1830, this study emphasizes the importance of four main periodicals—the Edinburgh Review, Quarterly Review, London Magazine, and Blackwood’s Edinburgh Magazine—to the period’s understanding of what it means to be, or read, an author who is still living. In it, I argue that British periodicals undertook a project to theorize, narrativize, and regulate the deceptively simple concept of a living author. Periodicals confronted the inadequacy of their critical methods in dealing with the living and came to define the “living author” as a disturbing model for the everyday person—an encouragement to self-display and a burden on public attention. Through their engagement with this disruptive figure, periodical writers eventually found in it a potential model for their own contingent, anonymous work, and embraced the self-actualizing possibilities that this reviled figure unexpectedly offered. My chapters survey crises and scandals in the periodical sphere; from the famous attacks on John Keats and Leigh Hunt, to the dismissal of female novelists like Fanny Burney, to the uproar over the political apostasies of William Wordsworth, Samuel Taylor Coleridge, and Robert Southey. Through a critical look at the book-reviewing project and other responses to living authors, I argue that the Romantic periodical invented living authorship as practice rather than ontology, emphasizing the importance of body, habit, and iterative performance to its significance.

Pushback In The Jet Age: Investigating Neighborhood Change, Environmental Justice, And Planning Process In Airport-Adjacent Communities

Wed, 30 Nov 2016 15:17:20 PST

Beneath the shadow of the aircraft and beyond the airport fence, communities wrestle with the impacts of airport expansion and operations. This dissertation builds scholarly foundations to explore the tensions between local residents who want to maintain healthy and stable communities and airport owners who want to grow operations and promote regional economic growth. The literature review contributes an overview of existing scholarship that investigates airports in an urban planning context, a realm of study I term ‘aviation urbanism’. To address gaps in aviation urbanism scholarship, I derived and investigated three research questions pertaining to neighborhood change, environmental justice outcomes, and the airport infrastructure planning process for airport-adjacent communities. The dissertation first asks: How has the population of historically marginalized groups living near airports changed with the rise of the jet age? The spatial analysis and descriptive statistics show that airport-adjacent communities in multi-airport regions generally increased persons of color and increased renters more than their respective metropolitan regions. Additionally, the communities often underperformed socio-economically with respect to their region. The second research question asks: Were hub airports more likely to expand if historically marginalized groups surrounded them? The exact logistic regression model, which was designed to be suitable for binary outcomes and small sample sizes, did not offer statistical evidence that environmental injustice is a concern at a systemic, institutional level for major airport expansion decisions. Next, I investigated environmental injustice on a case-by-case basis during the planning process, asking: How did the Federal Aviation Administration and airport owners frame and evaluate environmental justice in the planning process for airport expansion projects? After investigating the methodological framing of environmental justice in Environmental Impact Statements, I found that the methodological variation in comparison geography prevented the FAA and airport owners from recognizing and mitigating disproportio[...]

Essays On Executive Search

Wed, 30 Nov 2016 15:17:17 PST

My dissertation focuses on how the market values different attributes of top managers and the role of market intermediaries in shaping firm and individual outcomes. I draw on a unique dataset from an executive search firm, which allows me to track the progress of nearly 1,700 top managers who emerged as candidates for around 400 executive roles spanning multiple industries. In Chapter 2, I explore the mixed signals sent by the frequency of moves between employers and tenure with their current employer at the time a candidate is being considered for a senior management job with a new employer. I argue that while frequently changing employer may decrease a candidate’s attractiveness to potential employers by signaling that the candidate is a serial job hopper, it may also increase attractiveness by signaling the accumulation of a breadth of experience typically valued in top managers. Also, while potential employers may view longer tenure with a current employer as a negative signal regarding a candidate’s level of cultural flexibility and adaptability, it may also provide opportunities for upward mobility with the firm, which is a visible signal of competence. I find empirical support for these relationships. In Chapter 3, I use the topic modeling technique to parse job descriptions to understand how clients’ preferences affect candidate selection and explore gender prejudice. I find evidence that is line with role congruity theory, as firms are more likely to select male candidates when agentic qualities are emphasized. In Chapter 4, I investigate how employee mobility affects the broker (the executive search firm) who has facilitated the process, specifically in its ability to work for the firm that lost its employee to the broker’s client. The effect I find is positive and is stronger for poached firms that are located outside the city where the search firm is located, suggesting that the poaching event may help the search firm increase its saliency towards its potential clients. These studies together provide a better understanding of the executive labor market and the role of market intermediary.

Harnessing Hollywood Hype: Film Marketing Meets The Challenges And Opportunities Of The 21st Century

Wed, 30 Nov 2016 15:17:12 PST

Marketing is a vital commercial activity and source of competitive advantage within the Hollywood film industry, serving to create, circulate and translate symbolic meaning around a film and its ancillary products, construct and target key audience segments, guide audience expectations and viewing choices, and mitigate financial risk. Marketers thus play an increasingly central role in all stages of the filmmaking process. To examine the often overlooked structures and practices of Hollywood’s marketing arm, this study adopts a media industry studies approach, employing interviews, fieldwork, and textual analysis to explore the social, technological, organizational, economic, and spatial forces that shape the contemporary context of Hollywood marketing materials’ creation. In the early 21st century, Hollywood studios face profound challenges and opportunities wrought by the dual forces of globalization and digitization. In response, marketers have developed a novel view of their audience: as increasingly global and empowered. Globalization and digitization are thus treated as centrifugal forces, diffusing production and meaning-making capabilities across geographic space and media platforms, and threatening the centralized control traditionally held by Hollywood studios. Marketers are incentivized to embrace these decentralizing forces and the cultural labor now provided by third party marketing agencies, international distributors, and audiences. However, Hollywood studios’ institutional inertia, risk aversion, and inclination to maintain firm control of their marketing messages and intellectual property preclude a whole-hearted embrace of these changes. Studio marketers thus act with deep ambivalence toward these outside players, attempting to capitalize on their cultural labor while simultaneously acting to circumscribe their power.

Cep290 And The Primary Cilium- Understanding The Protein's Role In Ciliary Health And Disease

Wed, 30 Nov 2016 15:17:09 PST

Mutations in CEP290 are associated with phenotypes ranging from early onset retinal degeneration to embryonic lethal, multisystem disease. The association of CEP290 with disease in multiple tissues is believed to be due to its role in stabilizing the primary cilium, an organelle found on almost every cell in the body whose involvement in human health and disease has only recently been identified. Like many ciliary proteins, CEP290’s exact function in this structure and how mutations affecting the protein lead to disease remains relatively unclear. Here, a proposed mechanism of CEP290-associated disease pathogenesis is explored, finding severity of CEP290-associated disease correlates with the amount of functional CEP290 protein predicted to result from a given patient’s genotype. In addition, a potential interaction between CEP290 and TTBK2, a kinase recently discovered to traffic to the base or the primary cilium before the onset of ciliogenesis, was observed, providing insight into a role of CEP290 in the early stages of cilium formation.

Specification And Morphogenesis Of The Drosophila Testis Niche

Wed, 30 Nov 2016 15:17:06 PST

Adult stem cells have the unique ability to either self-renew or differentiate, thus giving them tremendous therapeutic potential. These tissue-specific stem cells are directed to self-renew by signals from the local microenvironment termed the stem cell niche. While reconstitution assays have demonstrated the existence of stem cell niches in many adult organs, unambiguous identification of the resident stem cells and their niche cells continues to be a challenge. Accordingly, the mechanisms that direct specification and formation of a stem cell niche in vivo remain unclear. The Drosophila testis has emerged as a powerful system in which to study stem cell-niche interactions. The niche cells, called hub cells, form a small aggregate at the apical tip of the testis. Hub cells promote attachment and self-renewal in the germline stem cells and cyst stem cells, which are organized in a radial array around the hub. The signaling pathways that direct the maintenance and differentiation of these lineages have been well characterized; however, the initial specification and organization of the niche is still being elucidated. It was previously shown that Notch activation in a subset of somatic gonadal precursors specifies them as hub cells in the embryonic gonad. Here we use genetic analysis to show that Notch signaling activates a branched pathway for hub cell differentiation. Along one arm of the pathway, the Maf factor Traffic jam is downregulated to allow for niche signaling and adhesion. Along a separate arm, the transcription factor Bowl, promotes the assembly of hub cells at the anterior of the gonad where they recruit and organize stem cells. We also use live imaging to reveal two phases of niche morphogenesis; 1) a sorting and guidance phase in which hub cells are directed to the anterior by an extra-gonadal cue and 2) a compaction phase characterized by the formation of an acto-myosin cable around the compacting hub concomitant with the onset of oriented GSC divisions. These observations suggest a model in which the germ cells shape t[...]

Student Athletes' Appraisals Of The Ncaa Amateurism Policies Governing College Sports

Wed, 30 Nov 2016 15:17:03 PST

The amateurism principle governing college sports prohibits student-athletes from receiving compensation beyond tuition, room, and board, despite them garnering publicity, bolstering school pride, providing entertainment, and generating billions of dollars in revenue for the Division I institutions they attend (Sylwester & Witosky, 2004). Purportedly a measure to protect players from exploitation by professional and commercial enterprises (NCAA, 2013a), the legitimacy of this claim has been called into question in recent years, as former college athletes have gone public about their basic needs not being met. From hungry nights with no food and inadequate insurance for sport-related injuries to comparatively lower graduation rates and “full” athletic scholarships that do not cover the cost of attending college, the concerns of college athletes have been captured in the press and media. Despite this, their voices have gone practically unheard in the published higher education research on student-athletes (Van Rheenen, 2012). This dissertation employed qualitative research methods to examine student- athletes’ appraisals of NCAA amateurism policies. Specifically, this phenomenological study used individual and group interviews with 40 college football players at 28 institutions across each of the power five conferences (PFCs) to answer the primary research question: How do student-athletes on revenue-generating athletic teams (hereinafter referred to as revenue-generating athletes) experience college and the amateurism policies governing college sports? Other research questions guiding this study include: (1) What do revenue-generating athletes perceive to be the costs and benefits of having participated in intercollegiate athletics? (2) How do revenue- generating athletes juxtapose the NCAA’s amateurism rhetoric with their own educational and professional expectations and experiences? (3) What are revenue- generating athletes’ appraisals of amateurism policies governing college sports? Criterion samp[...]

A Systems Approach To Hemostasis: How The Feedback Between Thrombus Structure And Molecular Transport Regulates The Hemostatic Response

Wed, 30 Nov 2016 15:17:00 PST

After vascular injury numerous chemical signals are released to induce platelet activation, coagulation, and post-hemostatic events. This thesis aims to investigate the interplay between thrombus structure and the spatiotemporal distribution and transport of biologically relevant solutes, and how this impacts thrombus formation in vivo. Using intravital microscopy we have previously described a characteristic architecture of thrombi formed in vivo. The architecture consists of a core of highly-activated and tightly packed platelets covered by a loose shell of less activated platelets. Initially, we developed a novel platelet-targeted sensor capable of reporting on thrombin activity, a potent platelet agonist, within thrombi formed ex vivo or in vivo. We found that thrombin activity was high in the core region, but restricted from the shell. We then designed another sensor capable of tracking soluble protein transport within thrombi formed in vivo, and found significant retention of soluble proteins within the platelets that would go on to form the core region. Using computational methods we found that the platelet packing density between the platelets restricted the diffusion of proteins within the core region, and allowed for rapid elution of proteins that made it to the shell. To test this in vivo we used mice with a defect in platelet retraction, but not platelet sensitivity to agonists. The mutant mice showed a much faster rate of solute elution using our transport sensor, and we also observed decreased platelet activation and thrombin activity within the thrombus. Next, we extended this model of thrombi as regulators of protein transport by examining how thrombus architecture altered the leakage of plasma proteins into the surrounding tissue. We found that extravascular solute gradients were sensitive to commonly used anti-platelet agents as well as small changes in platelet packing densities. Finally, we developed a new intravital imaging technique to visualize thrombus archi[...]

Good Character: Reality Television Production As Dirty Work

Wed, 30 Nov 2016 15:16:57 PST

Audiences, critics, and academics have raised significant moral concerns about reality television. The genre is commonly criticized for being exploitative, harmful, and fake. By extension, reality TV workers are morally tainted, seen as dirty workers of questionable character. This dissertation describes the sources of moral taint in reality television production and how production workers dispel this taint—making their work acceptable and even glorious to themselves and others—through everyday micro-level interaction. The data for this study comes from approximately 2 years of ethnographic observation at 2 reality TV production companies, attendance at 2 reality TV industry conferences, and interviews with 83 respondents, including reality TV production workers, television network executives, and people who auditioned to be on reality shows. Findings focus on the development process, during which production companies generate ideas for new television shows and pitch those ideas to television networks. First, I describe the development process and three significant moral dilemmas that workers face at this initial stage of production: creating negative representations (e.g. stereotypes), falsifying reality, and exploiting workers. Second, I discuss how even though some reality TV workers aspire to create “authentic” television and portray cast in a dignified manner, commercial demands sometimes pressure them into compromising their values. I find that workers justify making such creative compromises by distancing themselves from their actions or tweaking their standards of quality in their everyday shop floor talk. Third, I describe the significant creative contributions unpaid interns made at one production company and propose that supervisors dispel the moral taint of exploitation by framing their relationships with unpaid interns in terms of mentorship and friendship. Finally, I describe how people who audition for reality shows in development a[...]

Essays On Empirical Industrial Organization And Networks

Wed, 30 Nov 2016 15:16:54 PST

This dissertation is composed of two essays in the field of empirical industrial organization. They both examine how network structures arise in and affect markets. I focus on two industries. The first one is the airline industry, and the second one is the motion picture industry.

The first essay (chapter) studies airline networks. Airlines often match higher pas-

senger density with higher flight frequency. Meanwhile, a higher frequency reduces schedule delays, creating better service quality. This suggests that, on airline networks, the value of a link to passengers increases with the density on that link. I estimate a discrete choice model for U.S. airlines with endogenous link density. The model allows me to account for changes in frequencies in counterfactual experiments. I derive implications for airline pricing, market concentration and hub-and-spoke networks.

The second essay studies product entry in the presence of firm learning from the market outcomes of past products. Focusing on the U.S. motion picture industry, I construct a network capturing the similarity amongst the movies released in the last decades. I develop and estimate a model of how the network evolves. Risk averse firms make go/no go decisions on candidate products that arrive over time and can be either novel or similar to various previous products. I demonstrate that learning is an important factor in entry decisions and provide insights on the innovation vs. imitation tradeoff. In particular, I find that one firm benefits substantially from the learning by the other firms. I find that big-budget movies benefit more from imitation, but small-budget movies favor novelty. This leads to interesting market dynamics that cannot be produced by a model without learning.

Efficient Computation In The Brain

Wed, 30 Nov 2016 15:16:50 PST

It has been long proposed that the brain should perform computation efficiently to increase the fitness of the organism. However, the validity of this prominent hypothesis remains debated. In this thesis, I investigate how this idea of efficient computation can guide us to understand the operational regimes underlying various cognitive functions, in particular perception and spatial cognition. In the first study, I demonstrate that such idea leads to a well-constrained yet powerful model framework for human perceptual behaviors by assuming the system is efficient both in term of encoding and decoding. This framework, when applying to human visual perception, explains many reported perceptual biases, including the repulsive biases away from prior peak, which are counter-intuitive according to the traditional Bayesian view. This framework also offers a principle way to address the common criticisms of Bayesian models in perception, which argue that Bayesian models are lack of constraints. In the second study, I demonstrate that the idea of efficiency, coupled with a few assumptions, allows us to make quantitative predictions on the functional architecture of the grid cell system in rodents. One such prediction is that the spatial scales of grid modules should follow a geometric progression, importantly, with the scaling factor to be close to the square root of transcendental number e ~1.6. Such zero-parameter predictions closely match the data reported in recent neurophysiological experiments. The theory also makes several other predictions, some of which have been confirmed by the data. This study suggests that achieving efficiency computation may also apply to neural circuits involving a high-level cognition, i.e. representation of space. In the third study, I analytically derive a generic connection between mutual information and Fisher information. This clarifies an important theoretical issue which[...]

Empirical Bayes Estimation In Cross-Classified Gaussian Models With Unbalanced Design

Wed, 30 Nov 2016 15:16:46 PST

The James-Stein estimator and its Bayesian interpretation demonstrated the usefulness of empirical Bayes methods in facilitating competitive shrinkage estimators for multivariate problems consisting of nonrandom parameters.

When transitioning from homoscedastic to heteroscedastic Gaussian data, empirical ``linear Bayes" estimators typically lose attractive properties such as minimaxity, and are usually justified mainly from Bayesian viewpoints.

Nevertheless, by appealing to frequentist considerations, traditional empirical linear Bayes estimators can be modified to better accommodate the asymmetry in unequal variance cases.

This work develops empirical Bayes estimators for cross-classified (factorial) data with unbalanced design that are asymptotically optimal within classes of shrinkage estimators, and in particular asymptotically dominate traditional parametric empirical Bayes estimators as well the usual (unbiased) estimator.

No-Trespass Policies In Public Housing

Wed, 30 Nov 2016 15:16:44 PST

Increasingly, public housing authorities (PHAs) are implementing “no-trespass” policies designed to combat crime by non-residents in their developments. These policies allow PHAs to develop “ban lists” of unwanted non-residents who may be cited for criminal trespass if found on PHA property. Implementation of such policies may conflict with resident’s rights to have visitors, and invitees’ rights to visit. The effects of these policies on crime, perceptions of safety, and associational rights are unknown. Through legal analysis and case studies of three PHAs—Yonkers, NY; Chester, PA; and Annapolis, MD—I investigate the impact of these policies on residents, PHA officials, project managers, police, and people who are banned. My findings suggest that a no-trespass policy, narrowly targeted and as part of a larger security strategy, can promote perceptions of safety among public housing residents. Strong, stable PHA management and a collaborative relationship with residents are key to successful implementation. With due process protections and clear procedures for assuring that tenants’ rights to have visitors are not violated, it can pass constitutional muster. Whether it is an effective, or cost-effective, form of crime control is very much in debate. Implemented in isolation, however, a no-trespass policy is not likely to be effective in reducing crime and promoting perceptions of safety, and runs the risk of being used to police residents, rather than to protect them. If the policy is not narrowly tailored, it can divide families unnecessarily and discourage familial ties that create stability in a community. No-trespass policies can be blunt weapons against crime that cast very wide nets over a community, restrict movement, and interfere with family relationships. Applied arbitrarily and targeted indiscriminately, these policies[...]

Political Authority And Democracy

Wed, 30 Nov 2016 15:16:40 PST

Political institutions and actors have a moral responsibility to secure the equal freedom of those subject to their rule. It is in virtue of that responsibility that political authorities can possess certain moral rights to rule. Here, I argue that such political authorities can possess moral rights to create and employ the positive law to secure equal freedom. In doing so, I will address a number of common problems that theories of political authority face, including the subjection problem, the problem of consent, and the particularity problem, among other things. I also present an account of the role that democracy can play in an adequately framed theory of legitimate political authority.

Psukhai That Matter: The Psukhē In And Behind Clement Of Alexandria’s Paedagogus

Wed, 30 Nov 2016 15:16:37 PST

This dissertation aims to investigate the ideology and mechanics of the ancient soul’s materiality as witnessed in Clement of Alexandria’s late second- or early third-century work, the Paedagogus. I focus on four ways in which Clement refers to the soul: (1) as an entity in need of punishment and healing, (2) as vulnerable to substances and the activities of the body, (3) as made visible through the body’s appearance, and (4) as an internal moral-core. Through the lens of the Paedagogus, this dissertation introduces recent theoretical work on “materiality” and “the body,” especially as developed in gender studies, into the broad scholarly conversation about the ancient soul. In the process, it shows how Clement uses the interactions between the ancient soul and the ancient body in his attempt to produce and police Christian subjects.

Instrumental Variable And Propensity Score Methods For Bias Adjustment In Non-Linear Models

Wed, 30 Nov 2016 15:16:33 PST

Unmeasured confounding is a common concern when clinical and health services researchers attempt to estimate a treatment effect using observational data or randomized studies with non-perfect compliance. To address this concern, instrumental variable (IV) methods, such as two-stage predictor substitution (2SPS) and two-stage residual inclusion (2SRI), have been widely adopted. In many clinical studies of binary and survival outcomes, 2SRI has been accepted as the method of choice over 2SPS but a compelling theoretical rationale has not been postulated. First, We directly compare the bias in the causal hazard ratio estimated by these two IV methods. Under the potential outcome and principal stratification framework, we derive closed form solutions for asymptotic bias in estimating the causal hazard ratio among compliers for both the 2SPS and 2SRI methods by assuming survival time follows the Weibull distribution with random censoring. When there is no unmeasured confounding and no always takers, our analytic results show that 2SRI is generally asymptotically unbiased but 2SPS is not. However, when there is substantial unmeasured confounding, 2SPS performs better than 2SRI with respect to bias under certain scenarios. We use extensive simulation studies to confirm the analytic results from our closed-form solutions. We apply these two methods to prostate cancer treatment data from SEER-Medicare and compare these 2SRI and 2SPS estimates to results from two published randomized trials. Next, we propose a novel two-stage structural modeling framework to understanding the bias in estimating the conditional treatment effect for 2SPS and 2SRI when the outcome is binary, count or time to event. Under this framework, we demonstrate that the bias in 2SPS and 2SRI estimators can [...]

Optimal Neural Codes For Natural Stimuli

Wed, 30 Nov 2016 15:16:30 PST

The efficient coding hypothesis assumes that biological sensory systems use neural codes that are optimized to best possibly represent the stimuli that occur in their environment. When formulating such optimization problem of neural codes, two key components must be considered. The first is what types of constraints the neural codes must satisfy? The second is the objective function itself -- what is the goal of the neural codes? We seek to provide a systematic framework to address these types of problem. Previous work often assume one specific set of constraint and analytically or numerically solve the optimization problem. Here we want to put everything in a unified framework and show that these results can be understood from a much more generalized perspective. In particular, we provide analytical solutions for a variety of neural noise models and two types of constraint: a range constraint which specifies the max/min neural activity and a metabolic constraint which upper bounds the mean neural activity. In terms of objective functions, most common models rely on information theoretic measures, whereas alternative formulations propose incorporating downstream decoding performance. We systematically evaluate different optimality criteria based upon the $L_p$ reconstruction error of the maximum likelihood decoder. This parametric family of optimal criteria includes special cases such as the information maximization criterion and the mean squared loss minimization of decoding error. We analytically derive the optimal tuning curve of a single neuron in terms of the reconstruction error norm $p$ to encode natural stimuli with an arbitrary input distribution. Under our framework, we can try to answer questions such as what is the objective fun[...]

New Biosensing Strategies Using Hyperpolarized Xenon-129 Nmr Spectroscopy

Wed, 30 Nov 2016 15:16:27 PST

Molecular imaging holds considerable promise for elucidating biological processes in normal physiology as well as disease states, by determining the location and relative concentration of specific molecules of interest. Proton-based magnetic resonance imaging (1H MRI) is non-ionizing and provides good spatial resolution for clinical imaging, but lacks sensitivity for imaging low-abundance (i.e., submicromolar) molecular markers of disease, or environments with low proton densities. To address these limitations, hyperpolarized 129Xe NMR spectroscopy and MRI have emerged as attractive complementary methodologies. Beyond hyperpolarization, a 107-fold signal enhancement can be achieved by using novel indirect detection schemes (namely, Hyper-CEST), showing great potential to meet the sensitivity requirement in many applications. The concept of using 129Xe NMR for biosensing was first proposed by a Berkeley team in 2001 to realize targeted imaging and biological sensing at a molecular level. The development of xenon biosensors has since focused on modifying organic host molecules (e.g., cryptophanes) via diverse conjugation chemistries, and has brought about numerous sensing applications including detection of chemical modifications, oligonucleotide hybridization, enzyme active-site binding or enzyme-mediated proteolysis, and peptide binding events. Designs for new 129Xe NMR biosensors have recently extended beyond cryptophanes to new xenon-interacting scaffolds. The expanded palette of 129Xe NMR biosensors now includes synthetic cryptophane and cucurbit[6]uril constructs, as well as genetically-encoded gas vesicles and single proteins. In 2015 our lab first reported the Hyper-CEST capability of cucurbit[6]uril, and th[...]

Essays In Public Economics

Wed, 30 Nov 2016 15:16:24 PST

This dissertation consists of two essays. The common theme is Public Economics: to understand the effects of government policies in order to improve their design and to understand how special interest groups affect the local fiscal policies. In the first chapter, I study the impact of student debt on the education, career, and marriage choices of female lawyers. Law students quite often take on substantial amounts of debt to finance their graduate education. There has been much concern in the legal profession and among policy-makers that this debt burden distorts career choices. The empirical analysis is based on a novel, nationally representative, longitudinal data set. In contrast to the previous literature that has largely focused on males and finds only small effects, these new data suggest that debt has large and significant negative effects on female career and marriage outcomes. To explore the likely causes of these negative debt effects, I develop and estimate a dynamic model of education, labor, and marriage markets. My findings suggest that a large part of the debt effect on schooling and career choices comes from the diminished marriage prospects associated with the debt burden. I then focus on policies that aim to reduce the debt burden while also encouraging female lawyers to pursue careers in the public sector. My policy experiments show that subsidizing student debt repayment earlier in the career is more effective than doing so later. In the second chapter, I study the impact of unions on municipal elections and urban fiscal policies. The efficient decentralized provision of public goods requires that special interest groups, such as municipal unions, do not exercise undu[...]

Class I Histone Deacetylases In Lung Development And Regeneration

Wed, 30 Nov 2016 15:16:21 PST

The generation and development of the mammalian lung requires an elegantly regulated molecular program to control cell number, lineage specification, as well as morphogenetic remodeling. Histone deacetylases (HDACs) are a group of critical epigenetic factors that can mediate genome-wide transcriptional repression. However, the functional roles of HDACs in lung development and regeneration have not been previously characterized. In my dissertation, I utilized a series of mouse genetic models, ex vivo and in vitro assays to determine the functions of three members of class I HDAC family, HDAC1, HDAC2 and HDAC3 in lung epithelial development and regeneration. These studies reveal that HDAC1 and HDAC2 are redundantly required for the development and regeneration of Sox2+ proximal lung endoderm progenitors via regulation of Bmp4 and cell cycle inhibitors, while HDAC3 is critical for the alveolar epithelial remodeling and spreading during lung sacculation and alveologenesis. These findings demonstrate strong evidence for the crucial contributions of HDACs to lung development and regeneration, and provide novel insights into potential therapeutic directions for human lung diseases.

Chemical Modification Methods For Protein Misfolding Studies

Wed, 30 Nov 2016 15:16:18 PST

Protein misfolding is the basis of various human diseases, including Parkinson’s disease, Alzheimer’s disease and Type 2 diabetes. When a protein misfolds, it adopts the wrong three dimensional structures that are dysfunctional and sometime pathological. Little structural details are known about this misfolding phenomenon due to the lack of characterization tools. Our group previously demonstrated that a thioamide, a single atom substitution of the peptide bond, could serve as a minimalist fluorescence quencher. In the current study, we showed the development of protein semi-synthesis strategies for the incorporation of thioamides into full-length proteins for misfolding studies. We adopted the native chemical ligation (NCL) method between a C-terminal thioester fragment and an N-terminal Cys fragment. We first devised strategies for the synthesis of thioamide-containing peptide thioesters as NCL substrates, and demonstrated their applications in generating a thioamide/Trp-dually labeled α-synuclein (αS), which was subsequently used in a proof-of-concept misfolding study. To remove the constraint of a Cys at the ligation site, we explored traceless ligation methods that desulfurized Cys into Ala, or β- and γ- thiol analogs into native amino acids after ligation in the presence of thioamides. We further demonstrated that selective deselenization could be achieved in the presence of both Cys residues and thioamides, expanding the scope of thioamide incorporation through traceless ligation to proteins with native Cys. Finally, we showed that hemiselenide protected selenocysteines (Sec) can be incorporated onto the protein N-term[...]

Intimate Exegesis: Reading And Feeling In Early Modern Devotional Literature

Wed, 30 Nov 2016 15:16:15 PST

“Intimate Exegesis” proposes that early modern devotional literature offers feeling, and particularly bad feeling, as a productive matrix for interpretation. In this body of work, feeling – haptic, sensory, affective – generates an intimacy between reader and text in a reading practice that is also a means of coping with the tremendous gap between life in the fallen world and divine perfection. In an unlikely union that I argue involves a powerful shared approach to affect, embodiment, and interpretation, I bring patristic theology together with feminist and queer theory to address how Robert Southwell, Anne Lock, Aemilia Lanyer, and Katherine Philips develop sophisticated interpretive practices out of mourning, recalcitrance, despair, nostalgia, and failure, all grounded in the peculiar passions of embodied femininity. In their work, difficult or even destructive feeling is not an obstacle to reading and devotion, but rather enables the reader’s identification with and even desire for the text she reads. While recent debates in early modern studies have pitted historicism against queer temporality, devotional practice suggests that to read historically is – has always been – to read anachronically. The negative affects that Southwell, Lock, Lanyer, and Philips introduce to their scenes of leverage the properties of form and rhetoric to approach distant pasts, imagine radical futures, and above all to slow down the time of reading and the time of worldly politics, to stand still, to refuse to move on.

Engineering Extracellular Matrix Signals Into Fibrous Hyaluronic Acid Hydrogels

Wed, 30 Nov 2016 15:16:12 PST

Hydrogels have gained widespread use in biomedical applications for their ability to mimic certain features of the natural extracellular matrix (ECM) including tissue-like mechanics, water-swollen environments, and biodegradability. Despite these advantages, hydrogels typically do not present the fibrous architecture of natural ECM, even though this structure can guide cell behavior and tissue function. With this in mind, the overall goal of this dissertation is the translation of hydrogels from hyaluronic acid (HA) macromers into more complex, fibrous networks with spatiotemporal control. First, HA macromers that contain protease-cleavable and fluorescent peptides were synthesized and shown to form both isotropic hydrogels and electrospun fibrous hydrogels through a photoinitiated polymerization. These scaffolds were susceptible to protease-mediated cleavage in vitro in a protease dose dependent manner and in vivo in a subcutaneous mouse model using transdermal fluorescent imaging to monitor degradation. Importantly, materials containing an alternate and non-protease-cleavable peptide sequence were stable in both in vitro and in vivo settings. Next, the ability to spatially pattern fibrous hydrogels with biomolecules was investigated using thiol-ene reactions of thiolated molecules to electrospun norbornene modified HA (NorHA). This approach permitted pattern features as small as 50 μm and patterning of multiple molecules. Spatial control over cell adhesion and morphology was also demonstrated as cells responded to fiber organization and patterns of cell adhesive peptides. Final[...]

Religion And Son Preference In India And Bangladesh: Three Essays On Comparing Hindus And Muslims On Son Preference And Sex Differentials In Child Health

Wed, 30 Nov 2016 15:16:09 PST

While the existence of son preference in south Asia is well-known, a gap in our understanding of the determinants of son preference is potential differences between religious groups. In this dissertation, I examine whether Hindus and Muslims in India and Bangladesh differ in terms of son preference. I find low daughter discrimination among Muslims and significant son preference among Hindus. I first analyze preferences for the ideal number and sex of children in India, and compare them to actual fertility behaviors that serve as a measure of sex selective abortion. I find that Muslim women are less likely to report a preference for sons in their ideal fertility responses. Analysis of parity-specific births conditional on the sex composition of previous children reveals that the odds of male births are higher than female births for only Hindus and specifically when the previously born children are only girls. In Chapter 2, I extend the analysis to stunting and childhood immunization. I find that Hindu girls are worse off compared to Hindu boys in terms of stunting when their older siblings are also girls. However, there are no sex differentials in immunization, which suggests that while Hindu girls are disadvantaged in terms of long-term intra-household access to nutrition, girls are not discriminated against, in either Hindu or Muslim families, when it comes to availing health services through a fixed number of low-cost or free events. In Chapter 3, I examine whether a group’s majority/minority status influences son preferences by comparing Hindu-majo[...]

Power, Sexuality, And The Masochistic Aesthetic From Sacher-Masoch To Kharms

Wed, 30 Nov 2016 15:16:07 PST

This project centers on what I call the “masochistic aesthetic,” which emerged as literature dovetailed with medicine and law in German-speaking Europe and Russia around 1900. I argue that incipient totalitarian societies instrumentalized art and literature to produce citizens who enthusiastically consented to painful social discipline — that is, political masochists. Masochistic narratives like Leopold von Sacher-Masoch’s Venus in Furs (1870), Anton Chekhov’s The Duel (1891), or Andrei Platonov’s Happy Moscow (1933-6) reflect the ethnographic attention to borderlands, regulation of the body, and indefinite delay of pleasure inherent in the imperial or totalitarian settings that engendered them. After tracing the origins of the masochistic aesthetic to the synthesis of sexology and literature in Austria-Hungary, I track its passage into degeneration discourse in late-imperial Russia (Lev Tolstoy, Anton Chekhov) and the labor rationalization movements of interwar German-speaking Europe (Franz Kafka, Robert Walser). I conclude with an analysis of political masochism’s apotheosis in Stalinism (Andrei Platonov, Daniil Kharms), showing how the convergence of literature with bio-centric labor theory in the Soviet 1930s produced an ethos of joyful self-sacrifice and indefinitely delayed gratification. By casting masochism as a tool of political and ethnographic normalization, my work revises the traditionally psychoanalytic approach to the phenomenon in Russian culture. Mobilizing masochism’s understudied “Slavic”[...]

Mimetologies: Aesthetic Politics In Early Modern Opera

Wed, 30 Nov 2016 15:16:03 PST

In recent decades, mimesis has become a critical term for rethinking relationality, difference, and affect, reconsidered against the notions of artistic autonomy and representation. While music—and sound in general—seldom feature in these accounts, issues of musical autonomy and representation (aesthetic and political) in music studies have given way to a concern with immediacy, relationality, and vibration that bypass a revaluation of the discipline’s own accounts of mimesis, still understood largely as imitation. I propose a radical revision of mimesis away from its traditional understanding to bridge these various gaps and to reaffirm the necessity of thinking of alterity and difference in expanded conceptions of musical relationality. Music is more central in ancient Greek accounts of mimesis, especially in Plato’s Republic, than current musicology acknowledges. In close reading of these texts and drawing on the work of Philippe Lacoue-Labarthe and Jacques Derrida (1975), I elaborate a critical methodology to analyze the logics of mimesis—the mimetologies—as they are deployed in theoretical works and artistic performances. I propose to understand mimesis in music not as imitation but as (1) related to the ancient Greek mousikē—the collective performance of sung poetry and dance; (2) the production of originals out of copies (and not the reverse); (3) the inscription of the ethos and laws of the community through musical practice; (4) a general process involved in the production and[...]

Phenotypic Variation In The Dogwhelk. Nucella Lapillus: An Integration Of Ecology, Karyotype, And Phenotypic Plasticity

Wed, 30 Nov 2016 15:16:00 PST

The dogwhelk, Nucella lapillus, is an intertidal predator that displays classic ecotypic variation. Dogwhelks from exposed shores typically have small shells with large apertural openings while dogwhelks on protected shores have large, robust shells with thick apertural lips. The morphology of each ecotype is adaptive in its respective environment as the exposed shore morph minimizes the risk of dislodgement in heavy surf and the protected shore morph is more resistant to the shell-crushing predators common on protected shores This morphological variation has been attributed to wave exposure, site-specific and chromosomal factors and phenotypic plasticity. Through morphological analyses we have documented extensive site-specific variation in five morphological traits. Specifically, we found that site-specific factors rather than exposure explained a greater proportion of the variance across the five shell traits we examined. We have also documented the presence of a chromosomal polymorphism in Western Atlantic populations of the dogwhelk which were previously believed to be monomorphically of the 2n = 27 karyotype. We have found that chromosome number ranges from 2n = 26 to 2n = 32 in dogwhelk populations in Maine. Furthermore, we suggest that chromosome number is correlated with morphology and may explain the site-specific variation we observed in our morphological survey. Lastly, we transplanted snails of different karyotypes from exposed and protected shores to four dif[...]

The Effect Of Cell Contractility And Packing On Extracellular Matrix And Soft Tissue Rheology

Wed, 30 Nov 2016 15:15:56 PST

In the past decades it has become clear that the mechanical properties of tissues are important for healthy functioning. The mechanical properties of tissues and their load-bearing components found in the extracellular matrix (ECM) have been tested mechanically to provide more insight. However, there is a discrepancy between tissue and ECM mechanics. In this thesis this discrepancy is investigated with a novel multiaxial rheology method, which addresses a physiologically relevant combination of shear and axial strains. Blood clots are used to study the effect of cell traction and cell packing on ECM mechanics. The results show that ECM networks compression soften and extension stiffen in a typical asymmetric manner. The apparent Young’s moduli and shear moduli are decoupled, and are strongly influenced by a modest degree of axial strain. Cell traction induced pre-stress does not change the direction of this response but makes it more symmetrical and increases shear moduli. Close red cell packing in blood clots reverses the behavior of the clots from compression softening to stiffening, and from extension and shear strain stiffening to softening, resembling soft tissues. The same effects can be mimicked by embedding chemically inert beads into a fibrin network at densities approaching the jamming threshold for granular and colloidal materials. The overall conclusion is that cell jamming is likely to be the determining factor of soft tissue mecha[...]

Search For An Invisibly Decaying Higgs Boson Produced Via Vector Boson Fusion

Wed, 30 Nov 2016 15:15:53 PST

This thesis presents the first search of an invisibly decaying Higgs

boson produced via Vector Boson Fusion on ATLAS. The dataset used for

the analysis corresponds to 20.3fb$^{-1}$ of proton-proton collisions

at $\sqrt{s} = 8$ TeV recorded at the Large Hadron Collider in 2011

and 2012. An upper bound limit is set at 95\% confidence level on the

invisible branching fraction of the Higgs Boson. A limit of 28\% is

observed (34\% expected) and interpreted using the Higgs portal model

to set a limit on the dark matter-nucleon cross section. The unique

jet final state created by Vector Boson Fusion provides a stronger

signal to background ratio than other invisibly decaying Higgs

channels. The Vector Boson Fusion analysis presented resulted in the

strongest constraint on dark matter production set by a hadron


Palladium-Mediated Carbon-Carbon Bond Formation: Methodology And Mechanism. Part I: Palladium-Catalyzed Α-Arylation Of Aryl Nitromethanes, Phosphonoacetates, And Phosphine Oxides. Part Ii: Mechanistic Study Of The Palladium-Mediated Chemoselective Activation Of C(sp3)-H Bonds

Wed, 30 Nov 2016 15:15:50 PST

Part I: The catalytic α-arylation of aryl nitromethanes has been a longstanding challenge, due to the reported lack of reactivity of these compounds under cross-coupling conditions. Conditions for this transformation have been developed using mechanistically-driven high-throughput experimentation. The method efficiently provides access to a variety of isolable diaryl nitromethanes, which are useful synthetic intermediates, as well as diaryl ketones and diaryl methyl amines in sequential transformations. Additionally, a one-pot process has been developed for the differential di-arylation of nitromethane. The catalytic α-arylation of phosphonoacetates has also been achieved using mechanistically-driven high-throughput experimentation. α-Arylated phosphonoacetates are biologically active structural motifs, and are synthetically useful in the Horner-Wadsworth-Emmons olefination. The conditions developed provide a significant improvement to the range of accessible phosphonoacetates, as previously reported methods were limited in scope and/or required harsh reaction conditions. The method is useful for both aryl bromide and aryl chloride starting materials at low catalyst loadings, and has been shown to be robust on large scale. The challenging racemic quaternary α-arylation of phosphine oxides has been achieved as well, in 50% yield. Reaction conditions were thoroughly investigated using high-[...]

Role Of The Ebolavirus Glycoprotein In Countering Tetherin During Viral Budding

Wed, 30 Nov 2016 15:15:46 PST

Ebola virus (EBOV) is the causative agent of Ebola virus hemorrhagic fever and initiates sporadic outbreaks with very high mortality rates of up to 90%. The only viral surface protein on EBOV virions, the EBOV Glycoprotein (GP1,2), is a known antagonist of the intrinsic innate immune effector Tetherin, which prevents release of budded virions by “tethering” them to the cell. Unlike other Tetherin antagonists, GP1,2 does not degrade Tetherin, remove Tetherin from the cell surface, or sequester Tetherin in intracellular compartments. Thus, the mechanism of how GP1,2 counters Tetherin is not well understood. This study utilizes methods in molecular biology and microbiology to focus on the different domains of GP1,2 and understand their role in countering Tetherin. Using VP40 or HIV-1 Gag to produce virus-like particles (VLP), we show that the GP1,2 glycan cap and transmembrane domain are necessary for GP1,2 anti-Tetherin activity. Chimeric proteins containing alternative transmembrane domains in place of the GP1,2 transmembrane domain fail to counteract Tetherin and release VLP. Additionally, using widefield microscopy, alternative transmembrane domains do not change the surface localization of Tetherin and GP1,2, suggesting that surface interactions may not be important for understanding how GP1,2 counters Tetherin. Other observations and experiments suggest an ac[...]