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Function of MicroRNA-146a and NF-κB in Physiologic and Pathologic Hematopoiesis
Get PDFDuring inflammation and infection, hematopoietic stem and progenitor cells (HSPCs) are stimulated to proliferate and differentiate into mature immune cells, especially of the myeloid lineage. MicroRNA-146a (miR-146a) is a critical negative regulator of inflammation. Deletion of the gene encoding miR-146a—expressed in all blood cell types—produces effects that appear as dysregulated inflammatory hematopoiesis, leading to a decline in the number and quality of hematopoietic stem cells (HSCs), excessive myeloproliferation, and, ultimately, to exhaustion of the HSCs and hematopoietic neoplasms. Six-week-old deleted mice are normal, with no effect on cell numbers, but by 4 months bone marrow hypercellularity can be seen, and by 8 months marrow exhaustion is becoming evident. The ability of HSCs to replenish the entire hematopoietic repertoire in a myelo-ablated mouse also declines precipitously as miR-146a-deficient mice age. In the absence of miR-146a, LPS-mediated serial inflammatory stimulation accelerates the effects of aging. This chronic inflammatory stress on HSCs in deleted mice involves a molecular axis consisting of upregulation of the signaling protein TRAF6 leading to excessive activity of the transcription factor NF-κB and overproduction of the cytokine IL-6. At the cellular level, transplant studies show that the defects are attributable to both an intrinsic problem in the miR-146a-deficient HSCs and extrinsic effects of miR-146a-deficient lymphocytes and non-hematopoietic cells. This study has identified a microRNA, miR-146a, to be a critical regulator of HSC homeostasis during chronic inflammatory challenge in mice and has provided a molecular connection between chronic inflammation and the development of bone marrow failure and myeloproliferative neoplasms. This may have implications for human hematopoietic malignancies, such as myelodysplastic syndrome, which frequently displays downregulated miR-146a expression
High-Coherence Hybrid Si/III-V Semiconductor Lasers
Get PDFThe relentlessly increasing demand for network bandwidth, driven primarily by Internet-based services such as mobile computing, cloud storage and video-on-demand, calls for more efficient utilization of the available communication spectrum, as that afforded by the resurging DSP-powered coherent optical communications. Encoding information in the phase of the optical carrier, using multilevel phase modulationformats, and employing coherent detection at the receiver allows for enhanced spectral efficiency and thus enables increased network capacity. The distributed feedback semiconductor laser (DFB) has served as the near exclusive light source powering the fiber optic, long-haul network for over 30 years. The transition to coherent communication systems is pushing the DFB laser to the limits of its abilities. This is due to its limited temporal coherence that directly translates into the number of different phases that can be imparted to a single optical pulse and thus to the data capacity. Temporal coherence, most commonly quantified in the spectral linewidth Δν, is limited by phase noise, result of quantum-mandated spontaneous emission of photons due to random recombination of carriers in the active region of the laser.
In this work we develop a generically new type of semiconductor laser with the requisite coherence properties. We demonstrate electrically driven lasers characterized by a quantum noise-limited spectral linewidth as low as 18 kHz. This narrow linewidth is result of a fundamentally new laser design philosophy that separates the functions of photon generation and storage and is enabled by a hybrid Si/III-V integration platform. Photons generated in the active region of the III-V material are readily stored away in the low loss Si that hosts the bulk of the laser field, thereby enabling high-Q photon storage. The storage of a large number of coherent quanta acts as an optical flywheel, which by its inertia reduces the effect of the spontaneous emission-mandated phase perturbations on the laser field, while the enhanced photon lifetime effectively reduces the emission rate of incoherent quanta into the lasing mode. Narrow linewidths are obtained over a wavelength bandwidth spanning the entire optical communication C-band (1530-1575nm) at only a fraction of the input power required by conventional DFB lasers. The results presented in this thesis hold great promise for the large scale integration of lithographically tuned, high-coherence laser arrays for use in coherent communications, that will enable Tb/s-scale data capacities.</p
Sunyaev-Zel’dovich Observations Using Large-Format Millimeter Arrays
Get PDFGalaxy clusters are the largest gravitationally bound objects in the observable universe, and they are formed from the largest perturbations of the primordial matter power spectrum. During initial cluster collapse, matter is accelerated to supersonic velocities, and the baryonic component is heated as it passes through accretion shocks. This process stabilizes when the pressure of the bound matter prevents further gravitational collapse. Galaxy clusters are useful cosmological probes, because their formation progressively freezes out at the epoch when dark energy begins to dominate the expansion and energy density of the universe. A diverse set of observables, from radio through X-ray wavelengths, are sourced from galaxy clusters, and this is useful for self-calibration. The distributions of these observables trace a cluster's dark matter halo, which represents more than 80% of the cluster's gravitational potential. One such observable is the Sunyaev-Zel'dovich effect (SZE), which results when the ionized intercluster medium blueshifts the cosmic microwave background via Compton scattering. Great technical advances in the last several decades have made regular observation of the SZE possible. Resolved SZE science, such as is explored in this analysis, has benefitted from the construction of large-format camera arrays consisting of highly sensitive millimeter-wave detectors, such as Bolocam. Bolocam is a submillimeter camera, sensitive to 140 GHz and 268 GHz radiation, located at one of the best observing sites in the world: the Caltech Submillimeter Observatory on Mauna Kea in Hawaii. Bolocam fielded 144 of the original spider web NTD bolometers used in an entire generation of ground-based, balloon-borne, and satellite-borne millimeter wave instrumention. Over approximately six years, our group at Caltech has developed a mature galaxy cluster observational program with Bolocam. This thesis describes the construction of the instrument's full cluster catalog: BOXSZ. Using this catalog, I have scaled the Bolocam SZE measurements with X-ray mass approximations in an effort to characterize the SZE signal as a viable mass probe for cosmology. This work has confirmed the SZE to be a low-scatter tracer of cluster mass. The analysis has also revealed how sensitive the SZE-mass scaling is to small biases in the adopted mass approximation. Future Bolocam analysis efforts are set on resolving these discrepancies by approximating cluster mass jointly with different observational probes
Models of Turbulent Pipe Flow
Get PDFThe physics of turbulent pipe flow was investigated via the use of two models based on simplified versions of the Navier-Stokes equations. The first model was a streamwise-constant projection of these equations, and was used to study the change in mean flow that occurs during transition to turbulence. The second model was based on the analysis of the turbulent pipe flow resolvent, and provided a radial basis for the modal decomposition of turbulent pipe flow. The two models were tested numerically and validated against experimental and numerical data.
Analysis of the streamwise-constant model showed that both non-normal and nonlinear effects are required to capture the blunting of the velocity profile, which occurs during pipe flow transition. The model generated flow fields characterized by the presence of high- and low-speed streaks, whose distribution over the cross-section of the pipe was remarkably similar to the one observed in the velocity field near the trailing edge of the puff structures present in pipe flow transition.
A modal decomposition of turbulent pipe flow, in the three spatial directions and in time, was performed, and made possible by the significant reduction in data requirements achieved via the use of compressive sampling and model-based radial basis functions. The application and efficiency of compressive sampling in wall-bounded turbulence was demonstrated.
Approximately sparse representations of turbulent pipe flow by propagating waves with model-based radial basis functions, were derived. The basis functions, obtained by singular value decomposition of the resolvent, captured the wall-normal coherence of the flow; and provided a link between the propagating waves and the governing equations, allowing for the identification of the dominant mechanims sustaining the waves, as a function of their streamwise wavenumber.
Analysis of the resolvent showed that the long streamwise waves are amplified mainly via non-normality effects, and are also constrained to be tall in the wall-normal direction, which decreases the influence of viscous dissipation. The short streamwise waves were shown to be localized near the critical-layer (defined as the wall-normal location where the convection velocity of the wave equals the local mean velocity), and thus exhibit amplification with a large contribution from criticality. The work in this thesis allows the reconciliation of the well-known results concerning optimal disturbance amplification due to non-normal effects with recent resolvent analyses, which highlighted the importance of criticality effects.</p
Brownian Thermal Noise in Interferometric Gravitational Wave Detectors and Single Photon Optomechanics
Get PDFThe Laser Interferometric Gravitational-Wave Observatory (LIGO) is designed to detect the Gravitational Waves (GW) predicted by Albert Einstein’s general theory of relativity. The advanced LIGO project is ongoing an upgrade to increase the detection sensitivity by more than a factor of 10, which will make the events detection a routine occurrence. In addition to using higher power lasers, heavier test mass, and better isolation systems, several new designs and techniques are proposed in the long-term upgrade, such as modifying the optics configuration to reduce the quantum noise, active noise cancellation of the Newtonian noise, optimizing the coating structure, and employing non-Guassian laser beams etc.
In the first part of my thesis (Chapters 2 and 3), I apply statistical mechanics and elastostatics to the LIGO coated mirrors, and study the thermal fluctuations that dominate advanced LIGO’s most sensitive frequency band from 40 Hz to 200 Hz.
In particular, in Chapter 2, I study the so-called coating Brownian noise, fluctuations of mirrors coated with multiple layers of dielectrics due to internal friction. Assuming coating materials to be isotropic and homogeneous, I calculate the cross spectra of Brownian fluctuations in the bulk and shear strains of the coating layers, as well as fluctuations in the height of the coating-substrate interface. The additional phase shifting and back-scattering caused by photo elastic effects are also considered for the first time.
In Chapter 3, I study whether it is realistic to adopt higher-order Laguerre-Gauss modes in LIGO, in order to mitigate the effect of mirror thermal noise. We investigate the effect on the detector’s contrast defect caused by the mode degeneracy. With both analytical calculation and numerical simulation, we show that with this approach, the detector’s susceptibility to mirror figure errors is reduced greatly compared to using the nondegenerate modes, therefore making it unacceptable for LIGO requirements.
For the future GW detectors, with much lower noises and higher sensitivity, this might be used to investigate the quantum behaviors of macroscopic mechanical objects. In recent years the linear optomechanical systems with cavity modes coupling to a mechanical oscillator have been studied extensively. In the second part of my thesis (Chapter 4), I study the interaction between a single photon and a high-finesse cavity with a movable mirror, in the so-called strong coupling regime, where the recoil of the photon can cause significant change in the momentum of the mirror. The results are applied to analyze the case with a Fabry-Perot cavity. We also present that with engineering the photon wave function, it is possible to prepare the oscillator into an arbitrary quantum state.</p
Selectivity in Ruthenium Catalyzed Olefin Metathesis: Applications and Origins
Get PDFRuthenium-based catalysts for olefin metathesis display high activity in the presence of common functional groups and have been utilized in a variety of chemical disciplines. This thesis describes the development of new catalysts with superior properties and mechanistic studies directed at understanding the factors governing catalyst activity and selectivity.
Chapter 2 describes the preparation of acid-activated olefin metathesis catalysts containing acetylacetonate (acac)-type ligands. The effect of ligand structure and the exogenous acid on catalytic activity was examined. The acid-activated catalysts were also combined with a photoacid generator (PAG), which resulted in a highly active system for photo-activated olefin metathesis.
Chapter 3 details the incorporation of mesoionic carbenes (MICs) into ruthenium metathesis catalysts. The activity of these catalysts in several metathesis assays was measured and correlated to their initiation rates. The protonolysis of a Ru-MIC bond and the incorporation of this reaction into an acid-activated catalyst are also described.
Chapter 4 explores the relationship between catalyst structure and degenerate metathesis. A ring-closing metathesis assay was used to measure the preference of different catalysts for productive or degenerate metathesis. The relationship between degenerate metathesis and reactions such as ethenolysis is also discussed.
Chapter 5 describes the study of ruthenacyclobutanes formed from the degenerate metathesis selective catalysts presented in Chapter 4. The rates of various chemical exchange processes were measured and correlated to catalyst structure. Kinetic parameters for the rate-limiting step in ring-closing metathesis were also measured and used to rationalize the differences in productive/degenerate selectivity for various catalysts.
Chapter 6 details the preparation and study of C-H-activated ruthenium catalysts for Z-selective olefin metathesis. Ligand effects on catalyst activity and selectivity are explored along with the application of these catalysts in Z-selective cross-metathesis and ring-opening metathesis polymerization.</p
Search for a Standard Model Higgs Boson Decaying to Two Photons in CMS at the LHC
Get PDFIn part I of this thesis, I perform a search for the Standard Model Higgs boson decaying into two photons using 5.08 fb-1 of data collected by the Compact Muon Solenoid (CMS) detector in 2011 at a center-of-mass energy √(s)= 7 TeV.
The result of this search is interpreted as a local excess in the mass around 123 GeV/c2 with an significance of 3.3 standard deviation. This excess was later confirmed in the data in 2012, and was an important contribution to the CMS discovery paper published in 2012.
This search makes use of the excellent energy resolution of the CMS crystal electromagnetic calorimeter (ECAL). The energy intercalibration of approximately 76,000 crystals is crucial to improve the resolution performance. I describe in detail a novel intercalibration method using neutral π0(η) → γγ decays. This method was the first one in CMS to reach 0.5% calibration precision in the central part of ECAL with pseudorapidity less than 1. This calibration improved the Higgs to two photons search sensitivity by about 30%, compared to the precalibration performed before the installation of ECAL in CMS detector.
In part II of this thesis, I perform a search for an excited muon decaying into one muon and one photon using 36 pb-1 of data collected in 2010 at √(s)= 7 TeV. The result of this search indicates no evidence for excited muons. I report the first upper limits on single excited muon production cross section at this collision energy, and exclude a new region of the parameter space of compositeness scale and excited muon mass. Assume the compositness scale is the same as the excited muon mass, excited muons are excluded below 1090 GeV/c2 at the 95% confidence level, representing the most stringent limits, as of the date when the analysis was first published.</p
Silicon Microwire Arrays for Photoelectrochemical and Photovoltaic Applications
Get PDFSi microwire (Si MW) arrays grown by the vapor-liquid-solid (VLS) process are promising materials for next-generation solar energy devices. High-aspect-ratio semiconductor structures have attracted recent interest as solar absorber materials because their radial geometry decouples the direction of light absorption and carrier collection, enabling the use of materials with shorter minority-carrier diffusion lengths than would be acceptable in a planar geometry. The VLS growth process is a low-cost deposition technique, which can be used to fabricate flexible, high-performance semiconductor materials. Si MW arrays have been investigated as an inexpensive alternative to wafer-based solar photovoltaics for low- cost electricity generation. Another potential application is to use these vertically oriented wire arrays as photocathodes of a solar fuel conversion devices, where instead of producing electricity, sunlight is used to directly drive a fuel-forming reaction (e.g., splitting water to form O2 and H2). The high aspect ratio of the Si MW arrays provides a large surface area for the integration of fuel-forming catalysts, allowing for the development of a low-cost, scalable, energy storage technology.
This thesis discusses the fabrication and photoelectrochemical characterization of Si MWs grown by the VLS process, focusing on the use of these wire arrays as hydrogen- evolving photocathodes for solar water-splitting. To optimize such a device it is important to balance all of the factors that will affect performance: light absorption, band energetics, attainable open circuit voltage, and catalysis. First, we characterize the electrical performance of the wire arrays using regenerative photoelectrochemistry to understand the material quality and band energetics at the Si/water interface. We demonstrate the fabrication of H2-evolving photocathodes using p-n junction Si MW arrays and earth-abundant Ni–Mo alloy hydrogen evolution catalysts. We then investigate modifying the fabrication techniques for wire growth to lower the cost and processing time required to grow arrays of Si MWs. Finally, we study the band energetics of Si decorated with Pt to build a preliminary model of the heterogeneous catalyst/semiconductor/liquid interface.</p
Development of Targeted, Polymeric Delivery Vehicles for Camptothesin and siRNA Via Boronic Acid-Diol Complexation
Get PDFOur research lab has developed polymer-based nanoparticle delivery systems for the anticancer drug, camptothecin (CPT), CRLX101; and for the small interfering RNA (siRNA), CALAA-01. CRLX101 has shown great success in both animal studies and clinical trials. However, it is incapable of achieving targeted delivery. CALAA-01 has demonstrated effectiveness in a phase I clinical trial. However, it suffers from its rapid in vivo clearance. To address the issues of targeting in the anticancer drug delivery system and the short circulation time in the siRNA delivery system, we have created a new delivery platform involving the use of boronic acid-diol complexation. This thesis is divided into two parts to discuss CPT delivery and siRNA delivery separately.
In Part I, the targeted delivery of CPT via boronic acid-diol complexation is described. CPT was conjugated to a copolymer of mucic acid and PEG (MAP) and self-assembled into MAP-CPT nanoparticles. The targeting agent, Herceptin antibody was attached to boronic acid (BA), this was then complexed with the diol-containing MAP to form a targeted nanoparticle carrying ca. 60 CPT, with a 40 nm diameter and a slightly negative surface charge. The attachment of a single Herceptin per nanoparticle was sufficient to enhance cellular uptake of nanoparticles into BT-474, a HER2 overexpressing cell line by 70% compared to the non-targeted version. Nude mice bearing BT-474 xenograft tumors treated with targeted MAP-CPT nanoparticles resulted in all mice revealing complete tumor regression.
In Part II, the boronic acid-diol complexation delivery platform is applied for the delivery of siRNA. First, the CALAA-01 delivery system for siRNA was further characterized and optimized. Then, a copolymer of mucic acid and dimethylsuberimidate (MAD) was synthesized and used in condensing the anionic siRNA into nanoparticles. Nanoparticles were stabilized by placing a surface PEG layer through boronic acid-diol complexation. Targeting was achieved by conjugating the distal end of the BA-PEG with a targeting agent, Herceptin antibody. MAD/siRNA nanoparticles effectively entered cells and demonstrated low cellular toxicity. MAD/siRNA nanoparticles stabilized with nitroPBA-PEG resulted in a diameter of 130 nm with a slightly negative surface charge. Pharmacokinetic studies in mice demonstrated improved circulation compared to CALAA-01.</p
Studies of the Equation of State and Elasticity of Mantle Minerals
Get PDFBecause the Earth’s upper mantle is inaccessible to us, in order to understand the chemical and physical processes that occur in the Earth’s interior we must rely on both experimental work and computational modeling. This thesis addresses both of these geochemical methods. In the first chapter, I develop an internally consistent comprehensive molar volume model for spinels in the oxide system FeO-MgO-Fe2O3-Cr2O3-Al2O3-TiO2. The model is compared to the current MELTS spinel model with a demonstration of the impact of the model difference on the estimated spinel-garnet lherzolite transition pressure. In the second chapter, I calibrate a molar volume model for cubic garnets in the system SiO2-Al2O3-TiO2-Fe2O3-Cr2O3-FeO-MnO-MgO-CaO-Na2O. I use the method of singular value analysis to calibrate excess volume of mixing parameters for the garnet model. The implications the model has for the density of the lithospheric mantle are explored. In the third chapter, I discuss the nuclear inelastic X-ray scattering (NRIXS) method, and present analysis of three orthopyroxene samples with different Fe contents. Longitudinal and shear wave velocities, elastic parameters, and other thermodynamic information are extracted from the raw NRIXS data