Investigating novel immunomodulatory roles of prostate-specific antigen

Manning, Michael L The Johns Hopkins University 2012 해외박사(DDOD)

Prostate-specific antigen (PSA) is a serine protease expressed almost exclusively by normal and malignant prostate epithelial cells. Remarkably high levels of enzymatically active PSA are present in the extracellular fluid surrounding the normal prostate. This high level expression of PSA continues in prostate cancer (PCa) cells even as they become increasingly less differentiated and lose the morphological characteristics of the normal prostate gland. On this basis PSA is best known for its use as a biomarker for the screening of PCa, or to detect recurrence after therapy. The continued high-level expression of PSA throughout the stages of PCa suggests it may have a role in the pathogenesis and/or progression of disease, but surprisingly there has been relatively little interest in understanding the role of PSA in the pathobiology of PCa. The studies described herein suggest a previously uncharacterized function of PSA as an immunoregulatory protease that may help to create an environment hospitable to malignancy through the inactivation of the complement system. I also propose the hypothesis that PCa cells have assimilated this immunoregulatory role from healthy cells as this activity may exist under normal circumstances to aid in fertility. The American Cancer Society estimates that in 2012 in the United States alone there will be 241,740 new diagnoses of PCa and 28,170 men will die from the disease. This places prostate cancer at #2 on the unenviable list of leading causes of cancer death in American men. Hormone therapy, discovered in the 1940's, is the first line of treatment for metastatic PCa and is accepted to be largely palliative in nature. Accordingly, there is an unmet need for novel targeted therapeutics to offer men an increased survival benefit. A therapeutic approach championed by our laboratory yet not fully exploited is the use of PSA-activated prodrugs and protoxins for the targeted therapy of PCa. In this thesis I describe two attempts at applying PSA-activation technology to create new therapeutic options for PCa patients. The first therapeutic is an innovative humanized pore-forming immunotoxin while the second utilizes cell penetrating peptides to deliver cytotoxins in a controlled manner.

An investigation into measuring the multiple components of the pain experience

Manning, Erika Lyn The University of North Carolina at Chapel Hill 2001 해외박사(DDOD)

To examine the relationship between the intensity and unpleasantness of a pain experience, a series of studies were conducted. The first study assessed the meanings assigned to commonly employed numerical rating scales. I asked participants to provide events that they had experienced, were familiar with, or had knowledge of, that would fit each level of 2 11 point numerical rating scales, one for the intensity of a pain experience, the other for unpleasantness. Participants provided strikingly different events for these scales, indicating that the anchors of these scales have different meanings for different participants. To determine if these common pain events might prove to be better anchors for a pain rating scale, the second study employed 13 of the most common pain events derived from Study 1, and asked participants to place those events in rank order based on three different criteria: (a) the intensity of the pain, (b) the unpleasantness of the pain, and (c) the aversiveness of the pain. Only limited ordinal qualities were found for those events, indicating that they would not be appropriate as anchors for pain rating scales. The third study employed the same 13 pain events—however, participants were asked to rate each event for three different criteria, on 11 point scales: (a) intensity of the pain, (b) unpleasantness of the pain, and (c) aversiveness of the pain experience. Correlation analyses found a high degree of relationship for intensity and unpleasantness in predicting the aversiveness of a pain experience. In the final study, experimental pain stimuli were used instead of imagined pain events. Five different levels of pressure pain stimuli and five different levels of cold pain stimuli were employed within subjects. Participants were asked to rate each stimulus based on three different factors, using 11 point scales: (a) intensity, (b) unpleasantness, and (c) aversiveness. Heart rate was also monitored. Similar to the above studies, no clear pattern of intensity and unpleasantness was found in predicting aversiveness across all stimuli. However, as the unpleasantness of stimuli increased, the intensity of a pain stimulus became more of a factor in predicting aversiveness ratings.

Quantum information processing with trapped ion chains

Manning, Timothy Andrew University of Maryland, College Park 2014 해외박사(DDOD)

Trapped atomic ion systems are currently the most advanced platform for quantum information processing. Their long coherence times, pristine state initialization and detection, and precisely controllable and versatile interactions make them excellent quantum systems for experiments in quantum computation and quantum simulation. One of the more promising schemes for quantum computing consists of performing single and multi-qubit quantum gates on qubits in a linear ion crystal. Some of the key challenges of scaling such a system are the individual addressing of arbitrary subsets of ions and controlling the growing complexity of motional mode interactions as the number of qubits increases or when the gates are performed faster. Traditional entangling quantum gates between ion qubits use laser pulses to couple the qubit states to the collective motion of the crystal, thereby generating a spin-spin interaction that can produce entanglement between selected qubits. The intrinsic limitations on the performance of gates using this method can be alleviated by applying optimally shaped pulses instead of pulses with constant amplitude. This thesis explains the theory behind this pulse shaping scheme and how it is implemented on a chain of Yb ions held in a linear radiofrequency 'Paul' trap. Several experiments demonstrate the technique in chains of two, three, and five ions using various types of pulse shapes. A tightly focused individual addressing beam allows us to apply the entangling gates to a target pair of ions, and technical issues related to such tight focusing are discussed. Other advantages to the pulse shaping scheme include a robustness against detuning errors and the possibility of suppressing undesirable coupling due to optical spillover on neighboring ions. Combined with ion shuttling, we harness these features to perform sequential gates to different qubit pairs in order to create genuine tripartite entangled states and demonstrate the programmable quantum information processing capability of our system.

Temporal variability of atmospheric oxygen from both continuous measurements and a flask sampling network: Tools for studying the global carbon cycle

Manning, Andrew C University of California, San Diego 2001 해외박사(DDOD)

Atmospheric oxygen (O₂) measurements, together with carbon dioxide (CO₂), are useful tools for elucidating mechanisms that influence the global carbon cycle. This dissertation presents a synthesis of data from eleven years of measurements from a global network of flask sampling stations, describes a new method for achieving continuous atmospheric O₂ measurements, and presents one year of data from a field station deployment of this continuous measurement technique. The eleven-year record shows atmospheric O₂ decreasing, but slower than expected from fossil fuel combustion owing to the influence of land biota. From these data a global carbon budget is calculated for the period from January 1990 to January 2000: fossil fuel combustion produced an average of 6.33 ± 0.38 Gt C/y of CO₂, of which 3.21 ± 0.13 Gt C/y remained in the atmosphere, 1.44 ± 0.66 Gt C/y were taken up by land biota, and 1.68 ± 0.52 Gt C/y were taken up by oceans. The rate of decrease in atmospheric O₂ and increase in CO₂ vary from year to year. Analysis of these covariations suggests that exchanges with land biota can account for most of the variation in the CO₂ growth rate. The amplitudes of the seasonal cycles of atmospheric O₂ also show interannual variations, suggesting that oceanic marine productivity rates vary interannually. Observations such as these highlight the value of long records and the need for higher temporal resolution atmospheric O₂ time series that together can capture variability on time-scales ranging from hours to decades. The new continuous measurement technique employs an analyzer that utilizes the paramagnetic properties of molecular O₂. The design and development of the analyzer system is discussed, and it is shown to achieve a precision of 1 per meg (≈0.2 ppm) from repeated measurements over a one-hour interval. This system was deployed at Baring Head, New Zealand, where it has collected data since June 1999. These data show high resolution features in the seasonal cycle, and high frequency variability that the land biota and oceans can induce in atmospheric O₂ and CO₂ concentrations. This dissertation also discusses gas handling issues that are important to consider for accurate determination of precise atmospheric O₂ concentrations.

Acquisition, storage, and retrieval in digital and biological brains

Manning, Jeremy R University of Pennsylvania 2011 해외박사(DDOD)

My work examines how the brain acquires, stores, and retrieves information. I first present a theoretical model of the retina, and use the model to explore how the design of sensory systems affects our ability to make inferences about the physical world. I next present three analyses of electrocorticographic recordings taken as human neurosurgical patients participated in experimental cognitive tasks. In the first analysis, I measure the relation between single-neuron spiking and local field potentials, which reflect the aggregate activity of large populations of neurons. In the second analysis, I ask how the brain represents the meanings of individual words as they are studied and remembered. In the third electrocorticographic analysis, I address the question of how our brains retrieve memories of past experiences.

Screw-transform manifolds for camera self calibration

Manning, Russell Alan The University of Wisconsin - Madison 2003 해외박사(DDOD)

This dissertation concerns the mathematical theory of screw-transform manifolds and their use in camera self calibration. A camera's calibration is the function that maps 3D scene points to 2D image points, e.g., in photographs taken by the camera. Between every two photographs taken from different positions there exists a pairwise constraint called the "fundamental matrix," which can be computed directly from the images. When the two photographs are captured by the same camera, the fundamental matrix induces a surface in calibration space called a "screw-transform manifold." This manifold represents every possible internal calibration for the camera. By acquiring several different pairwise fundamental matrices, several different screw-transform manifolds can be computed; however, the internal calibration of the original camera must be a member of each manifold and hence, by finding the intersection point of all the manifolds, the camera's calibration can be determined. The process of determining calibration directly from images taken by a camera is called "self calibration.". The contributions of this dissertation include the theory of screw-transform manifolds and three original algorithms for determining the mutual intersection points of a collection of manifolds. While many papers have been written on self calibration, almost all previous methods posed their solutions as the global minima of an error function. However, performing global optimization is problematic; it is easy to locate a local minimum without finding the global minimum, and in some cases the attraction basin of the global minimum is so small that the algorithm must essentially "guess" the solution in order to find it. One of the new approaches created as part of this dissertation, called STM-SURFIT, avoids global optimization altogether and can effectively locate all global minima in a single pass, running in under 1 second on a modern home computer. The general approach used to avoid the problems of optimization may have wider applicability than simply camera calibration. A tutorial on multiview geometry that assumes only knowledge of linear algebra is included to provide the necessary mathematical background. The related history and previous work on self calibration and image-based rendering is also presented. As part of the theory of screw-transform manifolds, a theorem is introduced that partitions monocular view pairs into six categories based on the underlying screw motion of the camera and provides a simple test for determining category. In addition, some methods for self calibration and image-based rendering from dynamic scenes are presented. The image-based rendering techniques do not require camera calibration but are limited in applicability; this adds to the growing body of evidence that camera calibration is a necessity for most useful image-based rendering techniques.

How children think, feel, and hurt each other: An examination of the moral and emotional moderators and mediators of aggressive behavior

Manning, Maureen A University of Delaware 2005 해외박사(DDOD)

The purpose of the present study was three-fold: to determine whether moral reasoning predicts current and future aggression, to examine whether moral reasoning affects the stability of aggression over time, and to explore the moral and emotional processes involved in two specific functions of aggression (i.e., proactive and reactive). Gender differences in each of these relationships were also investigated. Students were initially assessed during the fall of first or second grade and were re-examined during the winter or spring of third, fourth, or fifth grade. Concurrent relationships between moral reasoning and aggression were expected at both time points. Early moral reasoning was expected to moderate the stability of overt aggression over time, such that hedonistic reasoning would be associated with increases in aggression and psychological needs-oriented reasoning with decreases. Emotions were expected to mediate the relationship of moral reasoning to proactive and reactive aggression. Hedonistic reasoning was expected to facilitate reactive aggression by promoting anger and/or shame, and to facilitate proactive aggression by inhibiting empathy and/or guilt. The opposite relationships were expected for psychological needs-oriented reasoning (i.e., it would promote empathy and/or guilt, inhibit anger and/or shame, and thus fail to facilitate either proactive or reactive aggression). Although results varied depending upon the specific variables examined, support was generally found for both concurrent and longitudinal relations between moral reasoning and aggression. Psychological needs-oriented reasoning in early elementary school predicted aggressive behavior in later elementary school but was not associated with different rates of aggression and thus did not moderate the stability of aggression over time. Contrary to predictions, emotions did not mediate the relationship between moral reasoning and aggression. In fact, with one important exception (i.e., a negative relationship between early imminent reasoning and later guilt), moral reasoning and moral emotions were largely unrelated. Guilt was also negatively related to peer-nominated proactive and reactive aggression and to teacher-reported overt aggression. Results have important implications for theory, research, and practice.

Multicultural organization development: Benchmarking progress towards diversity in higher education

Manning, Martin T Kent State University 2005 해외박사(DDOD)

The purpose of this multi-method study was to identify the perceived importance and prevalence of practices being utilized in higher education to achieve institutional diversity goals. In fulfilling this purpose, a survey was sent to Chief Diversity Officers at 200 institutions recognized for their work in diversity. In addition, semi-structured interviews were conducted with a sub-group of Chief Diversity Officers. Based on the analysis of the data, thirty of the thirty-six practices were considered important or very important by more than 75% of respondents. In particular, grievance procedures, presidential leadership, and institutional mission were considered to be very important by the largest percentage of respondents. The findings from the interviews further emphasized the importance of presidential leadership, institutional mission, curriculum, resource allocation, and positive campus climate. In contrast, only four of the thirty-six practices were reported as implementation underway or fully implemented by more than 70% of respondents. The only practice to be reported as fully implemented by more than 50% of respondents was the grievance process or complaint resolution process. The degree of implementation was further supported by the interviews in which practices had been fully implemented by only one of the seven campuses participating in the interviews. Furthermore, a comparison of the mean difference between importance and prevalence of practices indicated a statistically significant difference. The average importance of diversity practices was significantly greater than the average prevalence of diversity practices. Thus, many of the practices perceived to be important have yet to be fully implemented. Based on the results of this study, institutional leaders must turn their attention to narrowing the critical gaps between importance and prevalence of practices if progress is to be made towards diversity. A conceptual framework for assessing progress has been presented through the findings of this study. College and university leaders would be wise to utilize this framework to assess their progress regarding those practices perceived to be important and develop appropriate benchmarks that can help shape institutional policy for creating multicultural campus environments.

Suicide as social control: A theoretical and empirical study

Manning, Jason Philip University of Virginia 2011 해외박사(DDOD)

Suicide may be a way of handling conflict. It may be a desperate protest, a cry for help, an act of vengeance, or a means of escape. This dissertation examines suicide as a way of expressing grievances---that is, suicide which is also social control, or moralistic suicide. To this end I present data from the coroner's investigative files of a metropolitan area in the American South as well as evidence provided in the cross-cultural ethnographic literature. These data reveal that moralistic suicide is common and occurs across a wide variety of settings. Within these settings, however, moralistic suicide is concentrated in certain kinds of conflict, such as disputes between spouses. Drawing on Donald Black's theories of social control and paradigm of pure sociology, I explain moralistic suicide with the social structure of the conflicts in which it occurs. For example, suicide varies directly with social closeness, and suicide is greater in an upward direction than in a downward direction. My work addresses aspects of suicide ignored by previous studies and offers several formulations that help explain when and where this kind of suicide will occur.

Behavior of phosphorus in DRI/HBI during electric furnace steelmaking

Manning, Christopher Patrick Carnegie-Mellon University 2000 해외박사(DDOD)

In modern electric arc furnace (EAF) steelmaking, ore based scrap substitute materials are often used to control the chemistry of the steel produced and/or improve the efficiency of the process. Metallographic investigation of commercial direct reduced iron/hot briquetted iron, DRI/HBI materials indicates that before melting, phosphorus in DRI/HBI is contained as a calcium phosphate phase in the unreduced oxide “gangue” portion of the material. It was assumed that the kinetics of phosphorus transfer between slag and metal are limited by liquid phase mass transfer of phosphorus in the slag, metal, or both phases. An overall mass transfer coefficient, ko, was defined, which includes the effects of mass transfer in both the slag and the metal. Fundamental laboratory kinetic experiments indicate that either the slag-metal interfacial area, A, and/or the overall liquid phase mass transfer coefficient, ko, change during dephosphorization experiments. Because the contributions of the reaction area and the mass transfer coefficient to the overall rate are difficult to separate, experimental results were analyzed in terms of the mass transfer parameter, A*ko. The liquid phase mass transfer parameter for dephosphorization was found to range between 10<super>−7</super> to 1 × 10<super>−3</super> cm<super>3</super>/s for different experimental conditions. Plant trials were conducted to directly evaluate the conditions of mass transfer in the electric furnace. Controlled mass transfer experiments were conducted on a 150 ton DC electric arc furnace. The mass transfer parameter, A*ko, for this furnace was determined to be between 1.7*10<super>4</super> and 3.5*10<super>5</super> cm<super>3</super>/s. An additional series of plant trials were conducted on a 150 ton AC electric furnace to examine the effects of different scrap substitute materials upon the slag chemistry, the behavior of phosphorus in the steel, and upon furnace yield. The data from these trials were also used to develop empirical models for the slag chemistry and furnace temperature as functions of time during a single heat. A numerical process model was used to evaluate the influence of various EAF operating parameters upon phosphorus mass transfer between the slag and metal. (Abstract shortened by UMI.).