Unique Cardiovascular Risk Profiles in US South Asians: From Epidemiology to Epigenetic Biomarker Discovery

Flowers, Elena University of California, San Francisco 2012 해외박사(DDOD)

Gene-environment interactions are increasingly understood to be a primary contributing factor in the etiology of cardiovascular disease. Environmental factors include person and societal-level variables. Genome factors include sequence variation and mechanisms controlling genome expression. These regulatory mechanisms are the nexus of gene-environment interactions, and can be transient or adaptive; the latter are termed epigenetics. Some genetic characteristics are highly homogeneous within ethnic groups, due to a combination of geographically derived natural selection and environmental factors. South Asians are a population with disproportionately high cardiovascular disease burden. A prevalence study of cardiovascular risk factors in this population provides evidence that common risk factors are alterations in cholesterol metabolism; specifically low high-density lipoprotein cholesterol with elevated triglycerides. These initial observations led to a second study yielding evidence that abdominal adiposity is not a necessary precursor to the development of this dyslipidemia, challenging previous assumptions. A third study found pro-atherogenic risk profiles in South Asians are present decades earlier than in other populations. While these risk factors have genetic underpinnings, the added effects of a changing environment (i.e., Westernization of South Asians) are not known. MicroRNA are an epigenetic post-transcriptional regulatory mechanism of messenger RNA translation, and are potential biomarkers of pathophysiology and response to interventions. MicroRNA in human blood are differentially expressed in numerous disease conditions, and in vitro studies indicate that microRNA play a role in regulation of cholesterol metabolism in response to the extracellular environment. Methods to quantify microRNA include microarray, in which a large number of microRNA targets are screened. Microarray results are then validated with the more sensitive quantitative polymerase chain reaction method. Using microRNA arrays and a case-control design of pooled bio-specimens, a fourth study identified 16 candidate microRNA biomarkers of this atherogenic profile, which were then verified by quantitative polymerase chain reaction. Several of these are known to target messenger RNA involved in cholesterol metabolism. These results are promising evidence for translational application of microRNA as clinical biomarkers elucidating underlying genetic determinants of atherogenic risk in South Asians. Further research is needed to determine whether microRNA expression in blood is sensitive to cardiovascular risk reduction interventions.

The atomic point contact as a detector of nanomechanical motion

Flowers-Jacobs, Nathan Edward University of Colorado at Boulder 2010 해외박사(DDOD)

I experimentally demonstrate that an atomic point contact (APC) is a sensitive detector of nanomechanical motion. With a microwave technique, I increase the measurement speed of APCs by a factor of 500. This measurement is fast enough to detect the resonant motion of nanomechanical structures at frequencies up to 150 MHz. I measure displacement with a shot-noise limited imprecision of Sx = 0.29 fm/ Hz and simultaneously observe a SF = 61 aN/ Hz backaction force. A quantum limited detector would operate at the limit imposed by the Heisenberg uncertainty principle, SxSF ≥ h; for this APC detector SxSF = 168h. Because the measurement noise is dominated by the shot noise of tunneling electrons, the non-ideality of the APC detector is likely due to a backaction force in excess of that required by quantum mechanics. Although I cannot unambiguously determine the origin of this excess backaction force, I am able to eliminate certain possible origins. For example, the observed linear dependence of the backaction force SF on APC current is inconsistent with a noisy electrostatic attraction mediated by the mutual capacitance between the APC electrodes. In contrast, a model of the backaction force that invokes a momentum impulse delivered by each tunneling electron correctly accounts for the observed scaling. However, each electron would have to deliver a momentum impulse greater than 20 times the Fermi momentum which seems implausibly large. I also observe the signs of molecular vibrations in the APC using inelastic electron tunneling spectroscopy. At the bias energy associated with vibrations I measure a resonant increase in the backaction force. This observation suggests that the excess backaction may arise from the interaction of tunneling electrons and molecular vibrations.

A genetic dissection of left-right neuronal asymmetry in Caenorhabditis elegans

Flowers, Eileen Barbara Columbia University 2009 해외박사(DDOD)

Asymmetry is a feature of the body plans of most organisms. While asymmetric organs as well as a nervous system are generally important for diversities of function, asymmetry of the nervous system is not well understood. An important and yet unanswered question is: How is asymmetric neuronal function imposed upon a symmetric structure? This work describes the results of a large-scale genetic screen to reveal factors required for the asymmetric fate of the bilateral gustatory neurons ASEL/R. In this screen, we uncovered a total of 123 alleles, including 10 novel genes found to act in the ASE system. In this thesis, I describe the cloning and characterization of two of these novel genes, lsy-15 and lsy-22, as well as describe an interesting allele of a gene previously known to act in ASE. The genetic screen and the mutants described here shed light on new genes specifying asymmetric neuronal fate and are instrumental in furthering our understanding of the mechanisms underlying neuronal development.

A moment for metaphor on the Elizabethan stage (William Shakespeare)

Flowers, William Baker, Jr The University of North Carolina at Chapel Hill 2002 해외박사(DDOD)

Motivated by claims that Richard of Shakespeare's <italic> 3 Henry VI</italic> and <italic>Richard III</italic> represents a Vice figure only, this dissertation examines the configuration of early-English play personae en route to showing how Richard's metaphorical language encourages an interpretation of the persona that exceeds the meanings of the Vice alone. The first two chapters address the problems in the categorization and definition of plays and play personae, focusing on the material, experiential activities of medieval like all play personae, function as flexible tools of the playmaking craft, not as forms defined within classical categories, which is a post-Enlightenment conceptualization ill suited to the study of medieval, Tudor, or late-Elizabethan plays. The next three chapters begin with a review of some of the research-supporting cognitive linguistics, the major claims of which include the notions that basic-level concepts are grounded in our bodily experiences, that language and thought are fundamentally integrated, and that cognitive activities such as metaphor, metonymy, and blending create mental spaces structured in a manner that is motivated selectively but not determined by the structure of basic-level concepts. Other research supports the claim that Elizabethan grammar-school students engaged in certain cognitive-experiential activities that profoundly enhanced their ability to deploy metaphors. The late-Elizabethan playwrights' skills in metaphor use developed as well in response to their experiential activities within the urban subculture of commercial playmakers that formed in London by the 1580s. Analysis of metaphor use in English-language plays between 1300 and 1595 indicates a significant increase in use in the 1580s, at which time personae came to be configured through metaphorically elaborate dialogue and monologue. Rather than relating to a free play of meanings in a self-referential system of arbitrary signs and signifiers, the speech of a persona such as Shakespeare's Richard creates complex cognitive-linguistic domains that can be interpreted as a space of self that is meaningful to the reader or auditor.

Evolutionary genetics of the tidepool copepod Tigriopus californicus

Flowers, Jonathan M University of California, San Diego 2005 해외박사(DDOD)

This work examines the molecular population genetics of hybrid breakdown in the harpacticoid copepod Tigriopus californicus. The aim of this work was to use classical population genetic analysis of natural populations together with molecular genetics to characterize the genetic basis of reduced F2 hybrid fitness. Each of the chapters of this dissertation makes a unique contribution to our understanding of the genetic consequences of hybridization. In Chapter II, I combine time series data from natural populations with DNA sequence polymorphism data to characterize the extent of population exchange among local T. californicus populations. A primary result from this work is that gene flow among local populations is likely higher than previous data suggested. This has implications for our understanding of local population differentiation and the consequences of hybridization between T. californicus populations. In Chapters III and IV, I investigated two transcription systems, RNA polymerase I and mitochondrial RNA polymerase. Our interest in these systems primarily comes from their unusual mode of evolution. We hypothesized that rapid evolution of these transcription systems may be detrimental to the fitness of hybrid organisms. The data presented in Chapter III provide evidence of large-scale alterations in regulation of ribosomal RNA by the RNA polymerase I system in hybrids. Although the consequences of this for hybrid fitness are not clear, our results have significant implications for the molecular mechanisms responsible for the hybrid phenomenon of nucleolar dominance. In Chapter IV, results are presented on population differentiation of mitochondrial RNA polymerase, mtRPOL, and a mitochondrial transcription factor, mtTFBI. We hypothesized that elevated rates of genome evolution in T. californicus mitochondrial DNA would select for accelerated changes in the region of the polymerase responsible for promoter recognition. T. californicus populations have diverged substantially at this locus, but we found no evidence of rapid divergence in the region responsible for promoter recognition. In a separate study, I found that the mtRPOL and mtTFBI are tightly linked. A segregation study of the linkage group marked by these genes found a large viability effect of the mtRPOL/mtTFB1 locus on hybrid fitness. This effect is attributable to viability effects that are dependent on the cytoplasmic background. Finally, Appendix A presents work on variance in reproductive success in sea urchins that is unrelated to the main body of work. This was the product of research I conducted during the first two years of my dissertation and is included here as a supplement to the work conducted on T. californicus.

Identifying genetic modifiers of obesity and insulin sensitivity

Flowers, Jessica Byers The University of Wisconsin - Madison 2006 해외박사(DDOD)

Insulin resistance is widely considered to be a pre-diabetic syndrome. Over 40 million Americans are estimated to be insulin resistant. Diabetes is averted by the ability of the pancreas to compensate for insulin resistance by secreting more insulin. Not all individuals with impaired insulin sensitivity will go on to develop type 2 diabetes; however increased morbidity and mortality already exist in insulin resistant individuals. Obesity is a significant risk factor for the development of insulin resistance, yet it is estimated that 13-18% of individuals with normal body mass index have significant risk factors for diabetes and cardiovascular disease. The distribution of excess fat may be the most important determinant of overall risk for complications of insulin resistance such as cardiovascular disease. Excess fat in the abdominal region is associated with a much greater risk of morbidity and mortality than is excess subcutaneous fat. The mechanisms regulating fat localization and pathogenicity remain poorly understood. Finding models to adequately represent the spectrum of weight distribution and associated risks will help us to understand this complex process. Inbred mouse models represent as much, or more, total genetic diversity as the human population, and are therefore a valuable resource for discovering genes that contribute to complex human diseases. We have focused on the BTBR strain, which replicates many features of insulin resistance found in humans with excess visceral adiposity. In this dissertation, I describe studies focused on identifying genetic modifiers of insulin sensitivity. Chapter two details the tissues involved in mediating the insulin resistance phenotype observed in BTBR mice. In chapter three, I describe the paradoxical improvement of insulin resistance in lean SCD1-deficient mice, yet worsening of diabetes in SCD1-deficient obese mice. Chapter four identifies a small genetic region on mouse chromosome 2 that confers increased adiposity to BTBR mice. In chapter five, I review several obesity, diabetes, and cardiovascular disease QTL that localize to mouse chromosome 2, and I use gene expression analysis to nominate candidate genes that are related to body weight and plasma insulin.

Brine transport in the subsurface: Analysis of mechanisms and implications for groundwater contamination

Flowers, Tracey Clark University of California, Berkeley 2003 해외박사(DDOD)

Little is currently understood about the transport of brines in water saturated porous media. The ultimate objective of this research endeavor was to increase the understanding of brine fate by developing a comprehensive model describing the mixing behavior at stable and unstable brine/freshwater interfaces. The principle conclusions of this research effort are: (1) Stability. Gravitational and viscous forces do affect the stability of miscible displacements. A displacement is destabilized by gravitational forces if the heavier fluid overlies the lighter fluid and is stabilized otherwise. Also, a displacement is destabilized by viscous forces if the viscosity of the resident fluid is greater than the viscosity of the displacing fluid and is stabilized otherwise. Consequently, brine displacements are often destabilized by one force, yet stabilized by the other. The dominance of one force over the other is determined by the magnitude of the displacement velocity in relation to the magnitude of a parameter-dependent critical velocity: UC=kgrR -rD mR-mD where k is the permeability, g is gravitational acceleration, rho is the density, mu is the dynamic viscosity, and the subscripts R and D represent the resident and the displacing fluids, respectively. (2) Brine displacing freshwater. A series of one-dimensional displacements in which brine displaced ambient groundwater in the direction of gravity were conducted. These displacements were destabilized by gravitational forces, but stabilized by viscous forces. If the magnitude of the displacement velocity is greater than the magnitude of the critical velocity, then the stabilizing viscous force is dominant and mixing is suppressed. Conversely, if the magnitude of the displacement velocity is less than the magnitude of the critical velocity, then the destabilizing gravitational force is dominant and mixing is enhanced. (3) Freshwater displacing brine. A series of one-dimensional displacements in which ambient groundwater displaced brine in the direction of gravity were conducted. These displacements were stabilized by gravitational forces, but destabilized by viscous forces. If the magnitude of the displacement velocity is less than the magnitude of the critical velocity, then the stabilizing gravitational force is dominant and mixing is suppressed. Conversely, if the magnitude of the displacement velocity is greater than the magnitude of the critical velocity, then the destabilizing viscous force is dominant and mixing is enhanced. (Abstract shortened by UMI.).

Search for supersymmetry at CMS in events with b-tagged jets and missing transverse energy at 8 TeV

Flowers, Kristen University of California, Santa Barbara 2015 해외박사(DDOD)

This dissertation presents results from a search for physics beyond the Standard Model, using 19.39 pb-1 of data collected by the CMS detector at the Large Hadron Collider, during its 2012 operation at √ s=8 TeV. It focuses on models of supersymmetry that lead to final states with multiple jets, especially those from b-quark decay, and a large amount of missing transverse momentum. The amounts of background from top-quark, W+jets, Z → nu[special character omitted], and multi-jet production are determined from data-driven techniques. In particular, this includes a novel estimation of the ETmiss spectrum from semi-leptonic tt¯ decay, which takes advantage of the precise knowledge of the W boson polarization. Predicted yields are consistent with simulated Standard Model processes and the observed data. Since no evidence of new physics is observed, limits are placed on the rate of gluino pair production to a final state with four b-quarks and two neutralinos. This process is excluded at 95% CL for a gluino with mass 1225 GeV and a neutralino with mass up to 350 GeV.

Rhythm in the Polyphonic Conductus: A Computational Model and Its Implications

Flowers, Andrew T University of Rochester 2013 해외박사(DDOD)

The two-part conductus in thirteenth-century manuscript sources employs notation in which the rhythm and alignment of the parts is often unclear. Modern attempts to root the rhythmic interpretation of this notation in poetic meter have been largely unsuccessful. Recent research indicates that the musical culture that created this music was largely oral and relied extensively on memory. Rather than being a primitive notational system, the rhythmically ambiguous notation may have been an efficient “shorthand” that relied on the unwritten, implicit knowledge shared by the musicians in the culture. This study demonstrates not only that this implicit knowledge existed, but also that it is at least partially recoverable 800 years later. Using a body of the repertory where the rhythm is clear alongside musical concepts that would have been familiar to a thirteenth-century musician, a machine learning algorithm (Bayesian network) is employed to learn implicit musical relationships through experience—much the same way a medieval musician would have. The resulting model indicates that the melodic contour of the voices communicates a large amount of implicit information about rhythm while, surprisingly, harmony does not. A reexamination of a previous study that relates harmony to rhythm in this same repertory confirms these results. Moreover, the structure of the learned model is in many ways analogous to the human way of dealing with the notation. The model is then applied to a piece of music where the notation is rhythmically ambiguous but in which we know the correct rhythms by other means. The model is successfully able to recover many of the correct rhythms in this piece, thus demonstrating that it was able to learn implicit musical relationships from the repertory much the same way a period musician would have.

Investigating teachers' beliefs about and self-reported practices in early literacy teaching

Flowers, Tiffany Armstead The University of Iowa 2015 해외박사(DDOD)

The purpose of this study was to examine the following: (a) What is the nature of Kindergarten and First grade teachers' beliefs and self-reported practices regarding early literacy learning and teaching?; (b) What is the relationship between Kindergarten and First grade teachers' beliefs and self-reported early literacy teaching practices?; and (c) How do teachers' educational backgrounds and professional development experiences explain the relationship between their beliefs and practices in early literacy learning and teaching? Three instruments were administered to the participants in this study. The Theoretical Orientation to Reading Profile (Deford, 1979), hereafter known as the TORP, was used to measure teachers' pedagogical beliefs about the teaching and learning of reading. The Preschool Literacy Practices Checklist (Burgess, Lundgren, Lloyd, & Pianta, 2001), hereafter known as the PLPC, was used to measure teachers' self-reported literacy instructional practices. A survey questionnaire I designed was used to obtain descriptive information about the participants in this study. Data were collected from forty-seven in-service Kindergarten and First grade teachers. The results of the TORP data from this study indicated that 6% of the participants represented the decoding perspective, 92% represented the skills perspective and 2% represented the wholistic perspective. Correlation scores from the PLPC regarding teachers' beliefs and practices show there was no significant correlation between teachers' beliefs and self-reported practices in the classroom. Additionally, the findings showed there is a relationship between teachers' educational backgrounds and the reading literacy practices teachers view as important or essential in the early grades such as understanding the meaning of words, recognizing basic sight words, understanding concepts of print, and identifying the elements of a story.