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MicroRNAs 155 and 125b Physiologically and Pathologically Regulate Hematopoiesis and Immunity
Get PDFMicroRNAs are a class of ~22 nucleotide RNA molecules with roles in diverse biological processes. Here I focus on two microRNAs, miR-155 and miR-125b, and reveal pathways by which their dysregulation leads to myeloproliferative disorder (MPD) and leukemia, respectively. I begin by searching for miR-155 target genes relevant to MPD. By writing an algorithm to search microarray data for predicted microRNA target genes, I identified 89 candidate target genes for miR-155 in myeloid cells. Literature search whittled this list down to 11, and one gene among them, SHIP1, turned out to be largely responsible for miR-155’s ability to cause MPD. My focus shifted to miR-125b when I noticed that miR-125b was enriched in macrophages and thus might play important roles in that cell type. Indeed, gain- and loss-of-function experiments indicated that miR-125b is a potent activator of macrophage activation, and I identified IRF4 as the primary target gene in this process. Finally I asked whether miR-125b plays pathophysiological roles in the development of the hematopoietic system. Thus I overexpressed miR-125b in the hematopoietic system and, to my surprise, observed a very aggressive myeloid leukemia capable of infiltrating peripheral organs including the lungs, liver, kidneys and brain. To determine whether miR-125b is physiologically necessary for normal hematopoietic development, I designed a loss-of-function sponge vector that acts as a decoy, attracting the microRNA away from its normal targets. Use of the sponge in the mouse hematopoietic system led to significantly decreased overall hematopoietic ouput, indicating that miR-125b is physiologically required for normal hematopoiesis. Next, I assayed in vitro a panel of miR-125b target genes and saw that one, Lin28, was superior to the rest. Indeed, Lin28 gain- and loss-of-function in vivo recapitulated major aspects of miR-125b loss- and gain-of-function, respectively. Thus I identified Lin28 as a primary target of miR-125b in the hematopoietic system. In summary, my work shows that two microRNAs, miR-155 and miR-125b, physiologically and pathologically control hematopoietic development. I also identify important target genes for each of these microRNAs in their respective disease processes. Indeed, therapeutic targeting of these pathways may prove useful in the treatment of cancer
Dynamical Paleoclimatology of Mars
Get PDFWe investigated the dynamical paleoclimatology of Mars with a focus on three areas: large scale dynamics, atmospheric collapse, and controls on precipitation and aridity of a warm, wet Mars. We explored the changes, and lack of changes, in the large scale circulation over a range of atmospheric masses. We present the results here, with an emphasis on the response of the winds and the meridional transport.
The conditions for continuous condensation of the CO2 atmospheres in the polar regions, often called 'atmospheric collapse', were explored by simulating the Martian atmosphere over a wide range of obliquities for a wide range of atmospheric thicknesses. As expected, atmospheric collapse occurs at low obliquities, but surprisingly, collapse occurs for high obliquities (up to 40◦) for moderate atmospheric thicknesses (100's of millibars up to 1000 millibars). Using the MarsWRF model, we show that a competition between atmospheric heating feedbacks, including the greenhouse feedback and the heat transport feedback, and the condensation temperature feedback determines whether atmosphere collapse occurs.
Finally, we explored the precipitation and aridity of a warm, wet Mars with an active hydrological system. Even an extremely wet climate with a northern hemisphere ocean produces an extremely dry, desert climate in the southern hemisphere, with an equatorial band of rain and run off. Cross-equatorial flows deliver moist air from the northern ocean into the southern region, but topography and the distribution of land versus ocean limit the extent of the rainfall.</p
The Multistrand Simulator: Stochastic Simulation of the Kinetics of Multiple Interacting DNA Strands
Get PDFDNA has been used in vitro as a computational substrate due to programmable base-pairing interactions. This allows the construction of logic gates, self-assembled shapes, motors, walkers and other nanoscale devices comprised of DNA strands. These strands must be carefully designed in order to correctly perform their function, which requires effective models of the DNA system. The thermodynamics of multiple interacting DNA strands is a well-studied model which can make equilibrium predictions on these systems, but many devices operate far from equilibrium. The prediction of large non-equilibrium systems requires the simulation of a kinetics model, as these are both stochastic and computationally difficult to solve in an exact form. We developed the Multistrand kinetics simulator, which extends the previous work by expanding the kinetics model to handle multiple nucleic acid strands, as well as using optimized algorithms in order to speed up the simulations
Robust Dynamic Mechanisms
Get PDFThis thesis presents and solves two dynamic problems. The first problem comes from online display advertising. In display advertising, a publisher displays an ad for an advertiser when a targeted user visits a webpage related to the advertiser's products or services. However, the publisher cannot control the supply of display opportunities, and hence the actual supply of ads that it can sell is stochastic. I consider the problem of optimal ad delivery, where the advertiser demands a certain number of impressions to be displayed over a certain time horizon. Time is divided into periods, and in the beginning of each period the publisher chooses a fraction of the still unrealized supply to allocate towards fulfilling the publisher's demand. The goal is to be able to fulfill the demand at the end of the horizon with minimal costs incurred from penalties associated with shortage or overdelivery of impressions. For a special case of this problem I describe an optimal policy that is very easy to implement. The general version of the problem is more computationally demanding, but I describe policies that are both implementable and arbitrarily close to the optimal solution.
In the second part of the thesis, I develop a framework in which a principal can exploit myopic social learning in a population of agents in order to implement social or selfish outcomes that would not be possible under the traditional fully-rational agent model. Learning in this framework takes a simple form of imitation, or replicator dynamics, a class of learning dynamics that often leads the population to converge to a Nash equilibrium of the underlying game. To illustrate the approach, I give a wide class of games for which the principal can obtain strictly better outcomes than the corresponding Nash solution and show how such outcomes can be implemented. The framework is general enough to accommodate many scenarios, and powerful enough to generate predictions that agree with empirically-observed behavior. The last part of the thesis considers two more learning models, best response and fictitious play, and derives the principal's optimal policies theoretically and computationally for the same class of games considered in the social learning model.</p
Particle-Based Modeling of Ni-YSZ Anodes
Get PDFIn this work we examine the performance of particle-based models with respect to the Ni-YSZ composite anode system. The conductivity and triple-phase boundary (tpb) of particle-based systems is estimated. The systems considered have mono-dispersed particle size distributions, bi-modal particle size distributions with a YSZ:Ni particle size ratio of 1:0.781, and particle size distributions based on experimental measurements. All three types of systems show qualitative behavioral agreement in terms of conductivity, with clear transition from non-conducting behavior to high conducting behavior over a small transition regime which varied from a nickel phase fraction of .22-.28 for the mono- dispersed cases, 0.19-.0.25 for the bimodal cases, and 0.19-0.30 for the experimentally based cases. Mono-dispersed and simple-polydispersed particle size distribution show very low variation from case to case, with σ/μ ≤ 0.04. Cases based on empirical particle size distribution data demonstrated significantly higher variances which varied over a very large range, 0.3 ≤ σ/μ ≤ 1.1. With respect to the calculations of the TPB length, we find that the same pattern of variance in the measure of the triple-phase boundary length. The TPB length for the mono-dispersed and simple poly-dispersed systems was in the range of 3 × 1012 –4 × 1013 m/m3 . For empirical particle size distribution data the TPB length density was in the range of 8×109–2×1011 m/m3. The variance of the TPB length density follows the same pattern as the conductivity measurements with very low variance for the mono-dispersed and simple poly-dispersed systems and much larger variance for the empirically-based systems. We also examine the association between the TPB length and the availability of conducting pathways for the participating particles xv of individual TPBs. The probability of a TPB having a conducting pathway in the gas phase is essentially 100% in all cases. The probability of an individual tpb section having conducting pathways in either of the solid phases is directly related to percolation condition of that phase.
We also considered a particle-based composite electrode realization based on a three- dimensional reconstruction of an actual Ni-YSZ composite electrode. For this model we used particles which vary in nominal size from 85–465 nm, with size increments of 42.5 nm. We paid particular attention to the coordination numbers between particles and the distribution of particle size interconnections. We found that homogeneous inter-particle connections were far more common than would occur using a random distribution of particles. In particular we found that for a random collection of particles of similar composition the likelihood Ni-Ni particle connections was between 0.18–0.30. For the reconstruction we found the likelihood of Ni-Ni particle connections to be greater than 0.56 in all cases. Similarly, the distribution of connections between particles, with respect to particle size of the participating particles, deviated from what would be expected using a random distribution of particles. Particles in the range of 85–169 nm showed the highest coordination with particles of the same size. Particles in the range of 211–338 nm have the highest coordination with particles of radius 169 nm with very similar distributions. Particles with radius greater than 338 nm represented only 7.2 × 10−3 % of the particles within the reconstruction, and showed the highest coordination with particles of radius of 211 nm, but the distributions vary widely.
In the final chapter, we build a model which can account for mass transfer, hetero- geneous chemistry, surface chemistry, and electrochemistry within a porous electrode. The electric potential is calculated on a particle basis using a network model; gas phase concentrations and surface coverages are calculated with a one-dimensional porous me- dia model. Properties of the porous media are calculated via a TPMC method. TPB electrochemistry is calculated at individual triple phase boundaries within the particle xvi model, based on local gas phase concentrations, surface coverages and particle poten- tials, and then added to the porous media model. Using this tool we are able to calculate the spatial distribution of the Faradaic current within the electrode, and variation in gas phase concentrations within the porous media.</p
Studies in Recombination and Dissociation Reactions for Collisional Energy Transfer and Electron Transfer of Nanocrystals and Dye Molecules
Get PDFThis dissertation consists of three parts. In the first part, the effect of the large impact parameter near-elastic peak of collisional energy transfer for unimolecular dissociation/bimolecular recombination reactions and deviation from equilibrium case is studied. To this end the conventional single exponential model, a bi-exponential model that fits the literature classical trajectory data better, a model with a singularity at zero energy transfer, and the most realistic model, a model with a near-singularity, are fitted to the trajectory data in the literature. A theory is developed for the population distribution as a function of the energy E of a dissociating model, and used to calculate the three-body low pressure recombination rate constant. In the second part, the electron transfer process in the single quantum dot fluorescence blinking phenomenon is studied. The DCET (diffusion controlled electron transfer) model has been modified to explain the exponential cutoff of the power law time distribution of the bright state and the quadratic dependence of the exponential tail on the excitation intensity. Based on ensemble measurements it is proposed that an exponential tail for the dark state time distribution for long time experiments exists for single trajectory experiments. In the last part, we develop a general MLE (maximum likelihood estimation) method to analyze experimental data with a potential distribution of power law form which can be extended to a power law with an exponential tail and more generally, many other distribution forms
Topics in Large-Scale Structure
Get PDFThis thesis presents my personal survey of topics and methods in large-scale structure, covering a range of cosmological probes and analytical, numerical, and observational techniques.
Chapters 2--4 present analytic calculations of systematic effects relevant for the interpretation of data from upcoming large-scale structure surveys: In chapter 2 we derive the relation between measured galaxy ellipticities and the cosmic shear power spectrum up to fourth order in the matter density field, accounting for multiple deflections along the light path, reduced shear, and magnification bias. In chapter 3 we develop a new third-order cosmic shear statistics, which separates shear three point correlation functions exactly into E- and B-mode correlations on a finite interval. Chapter 4 considers the effect of tidal galaxy alignments on the projected galaxy bispectrum, which are found to bias the inferred galaxy bias parameters.
Chapter 5 focusses on the halo-occupation distribution formalism, which constrains the relation between galaxy luminosities and the masses of their host halos through clustering measurements. We extend this method to model the cross-correlation functions between a galaxy sample of interest and multiple tracer populations simultaneously. This technique improves the accuracy of clustering analyses for sparse galaxy populations, and we apply it to constrain the environment of selected green valley galaxy samples. These galaxy samples are constructed by matching the Sloan Digital Sky Survey with the latest Galaxy Evolution Explorer source catalog which provides NUV photometry. We present cross-correlation function measurements and determine the halo occupation distribution of these transitional galaxies using the multiple tracer technique.
In chapter 6 we examine sources of scatter in scaling relations between galaxy cluster mass and thermal Sunyaev-Zeldovich (SZ) effect using cluster samples extracted from cosmological hydrodynamical simulations. This sample enables us to study for the first time the detailed evolution of merging clusters around the scaling relation for a cosmologically representative distribution of merger parameters. We find major mergers to cause an asymmetric scatter such that the inferred mass of merging systems is biased low. As the fraction of dynamically disturbed clusters increases with redshift, this analysis indicates that mergers cause a redshift-dependent bias in cluster mass scaling relations.</p
Cosmological Consequences of Gravitation: Structure Formation and Gravitational Waves
Get PDFThis thesis contains work on four topics which fit into two broad areas of research: the quest to understand structure formation and through it the properties of the dark matter, and the search for primordial gravitational radiation. The first project details the effect of an accretion shock on the colors of satellites in galaxy clusters. A new model of ram pressure stripping including an accretion shock with variable radius is developed and implemented in the Galform semi-analytic model of galaxy formation. A comparison of this model with previous models and with observations indicates that current data is unable to discriminate between models, though future observations will be able to place stronger constraints on the role of ram pressure stripping in and around clusters.
Next, an analysis of the angular momentum evolution of dark matter particles in high-resolution N-body simulations of dark matter halos is presented. We find that individual particle angular momentum is not conserved, and also that the angular momentum of radial shells varies over the age of the Universe by up to factors of a few. These results have serious implications for the validity of current analytical models that assume angular momentum conservation.
Two methods for detecting the primordial gravitational wave (GW) background are then presented. Such a background, if detected, could greatly impact our understanding of the early universe. The first proposed method uses the apparent angular velocities of astrophysical objects induced by GWs, which may be detectable with upcoming astrometric missions such as the GAIA satellite. This work improves upon previous order-of-magnitude estimates, and presents a full calculation of the expected signal from a stochastic background of GWs.
The second method uses bipolar spherical harmonics decomposition, a formalism to characterize departures from statistical isotropy and Gaussianity, to quantify the expected lensing of the cosmic microwave background (CMB) and 21 cm radiation by GWs. The lensing of the CMB by GWs is found to not be detectable, but that of future 21 cm surveys could give a very high quality measurement of the primordial GW background.</p
Spatio-Temporal Analysis of the Turbulent Boundary Layer and An Investigation of the Effects of Periodic Disturbances
Get PDFThe purpose of this study was to investigate the turbulent boundary layer to learn more about the dynamics of the flow and how it might be controlled through the input of spatially and/or temporally periodic disturbances. The first part of this work studies the structure of a zero-pressure-gradient turbulent boundary layer using time-resolved particle image velocimetry in both wall-normal and wall-parallel planes. Using data from wall-parallel measurements, a 3D spectrum over streamwise, spanwise, and temporal wavelengths was constructed for the first time, a major focus of this work. Among several uses, this spectrum allows the calculation of a scale-based convection velocity, that is, a convection velocity for each streamwise-spanwise scale pair present in the flow. This data set also provided a method for investigating the temporal evolution of coherent structures in the flow, of which, swirling coherent structures (SCS), indicative of vortices, and low-momentum regions were investigated thoroughly. The convection velocity and lifetime of the SCS were measured; using histograms of the SCS convection velocity in multiple wall-parallel planes, it was possible to statistically infer different SCS structures that could be categorized as ``attached'' or ``detached'' from the wall.
A study was also performed on the response of the turbulent boundary layer to a stationary periodic roughness inspired by the scale pattern on the sailfish. The roughness was relatively sparse with element spacing on the order of the boundary layer thickness allowing the measurement of turbulent statistics at different points along the roughness as well as below the crests of the roughness elements, a region not commonly accessible in rough-wall boundary layer studies. The streamwise turbulent statistics were studied using hotwire anemometry from which it was found that while the outer part of the flow remained similar, the near-wall region was perturbed by structures of size similar to the roughness spacing.</p
Essays on Dynamic Political Economy
Get PDFThis dissertation comprises three essays that are linked by their focus on dynamic models of political economy, in which farsighted agents interact over an infinite number of periods, and the strategic environment evolves endogenously over time.
In Chapter 2, "Dynamic Legislative Bargaining with Veto Power", I analyze the consequences of veto power in an infinitely repeated divide-the-dollar bargaining game with an endogenous status quo policy. I show that a Markov equilibrium of this dynamic game exists, and that, irrespective of the discount factor of legislators, their recognition probabilities, and the initial division of the dollar, policy eventually gets arbitrarily close to full appropriation of the dollar by the veto player.
Chapters 3 and 4 -- coauthored with Thomas Palfrey and Marco Battaglini -- study free riding in a dynamic environment where a durable public good provides a stream of benefits over time and agents have opportunities to gradually build the stock. We consider economies with reversibility, where investments can be positive or negative, and economies with irreversibility, where investments are non-negative and the public good can only be reduced by depreciation. In Chapter 3, "The Free Rider Problem: A Dynamic Analysis", we study and compare the set of Markov equilibria of these models. With reversibility, there is a continuum of equilibrium steady states: the highest equilibrium steady state of the public good is increasing in the group size, and the lowest is decreasing. With irreversibility, the set of equilibrium steady states converges to a unique point as depreciation converges to zero: the highest steady state possible with reversibility. In Chapter 4, "The Dynamic Free Rider Problem: An Experimental Study", we test the results from this model with controlled laboratory experiments. The comparative static predictions for the treatments are supported by the data: irreversible investment leads to significantly higher public good production than reversible investment.</p