VictorJuiz/thesis huggingface dataset:
Mechanism of an epigenetic switch that mediates neural development [electronic resource]
Keywords: Developmental Biology.

During the development of the vertebrate nervous system neural progenitors divide, generate progeny that exit mitosis and then migrate to sites where they elaborate specific morphologies and synaptic connections. Mitotic exit in neurons is accompanied by an essential switch in the Mammalian SWI/SNF (also called BAF) ATP-dependent chromatin regulatory complexes from the neural progenitor npBAF to neuron-specific nBAF complexes. We elucidated the mechanism of a microRNA/chromatin switch underlying the switch of the npBAF subunit, BAF53a for the nBAF subunit BAF53b. Recapitulating this microRNA/chromatin switch in fibroblasts leads to their direct conversion to neurons. We have defined the kinetics of nBAF complex assembly in the formation of induced neurons from ES cells or fibroblasts as well as normal neural differentiation and using proteomic analysis find that this switch also includes the removal of SS18 and its replacement by CREST at mitotic exit. We find that switching of chromatin remodeling mechanisms is highly correlated with a broad switch in the use of neurogenic transcription factors. Knockdown of SS18 in neural stem cells causes cell-cycle exit and failure to self-renew, while continued expression of SS18 in neurons blocks dendritic outgrowth underlining the importance of subunit switching. Recent whole genome sequencing studies show that dominant mutations in BAF subunits underlie widely different human neurologic diseases including mental retardation, microcephally, schizophrenia, sporadic mutations in autism as well as the neurodegenerative disease, amyotrophic lateral sclerosis (ALS) also known as Lou Gehrig's disease. Using whole exome analysis of ALS trios (trio=two unaffected parents and affected child), we identified and functionally characterized two de novo mutations in CREST that function in a dominant negative mode to inhibit dendrite outgrowth in cortical and motor neurons. As the aforementioned neurological diseases arise in different neuronal types, our studies suggest that the characteristics of these diseases must be interpreted in the context of the different BAF assemblies in neurons rather than a singular mSWI/SNF complex.
Mechanochemical coupling and structural dynamics in DNA gyrase [electronic resource]
Keywords: Applied Physics.

DNA gyrase is a molecular motor that directionally introduces negative supercoils into DNA, serving a function that is critical to most bacterial life. This thesis addresses the question of how gyrase transduces chemical energy stored in ATP into mechanical energy stored in supercoiled DNA. I have investigated how substeps in the ATPase cycle -- ATP binding, hydrolysis and product release -- coordinate structural transitions of the nucleoprotein complex during the course of the supercoiling reaction. Using single-molecule real-time tracking of DNA compaction and rotation, I have characterized the geometry and interconversion dynamics of DNA configurations under different nucleotide conditions. A critical step in the reaction cycle of DNA gyrase involves the formation and manipulation of a chiral wrap in the path of DNA on a scale of ~ 150 base pairs. I show that chiral wrapping is a multistep process that dominates the overall kinetics and is modulated by ATP. My results identify new roles for ATP binding, hydrolysis and product release, and show that nucleotide states in gyrase cannot be uniquely identified with structural intermediates. The work reveals a sophisticated molecular motor in which a conformational landscape of loosely coupled transitions funnels the enzyme toward productive energy transduction.
Methods for high dimensional uncertainty quantification [electronic resource] : regularization, sensitivity analysis, and derivative enhancement
Keywords: Aeronautics and Astronautics.

Surrogates are used to mitigate the aggregate cost of simulation needed to perform a comprehensive uncertainty quantification (UQ) analysis. A realistic uncertainty analysis of any engineering system involves a large number of uncertainties, and as a result, the surrogates take inputs in a high dimensional space. We investigate surrogates that take the form of a truncated Legendre polynomial series, from which the coefficients associated to each polynomial basis function must be estimated. High dimensional estimation is a known instance of the curse of dimensionality, and for sufficiently "complex'" functions, an unsolved problem. In order to break the curse, we assume the function to be approximated is sparse in the Legendre polynomials and employ the machinery of l-1-regularized regression. We make three contributions under this theme. Firstly, we present a novel approach to choosing sample (design) points and show that it yields lower estimation error over a broad range of functions compared to existing sampling approaches. Secondly, we give a novel sparse estimator that effectively uses (partial) derivative information for estimation and show empirically that estimation using derivatives can be more efficient than function values if the derivatives are sparser than the function. Thirdly, we show that by exploiting the best k-term approximation} property of l-1-methods, we can quickly identify the most signfiicant uncertainties and reduce the dimensionality of the input space accordingly. We conclude by demonstrating the efficacy of these methods in a UQ analysis of a notional vertical axis wind turbine design.
Microbial biogeochemistry of ammonia oxidation in coastal environments [electronic resource]
Keywords: Environmental Earth System Science.

The processes responsible for the fixation and removal of nitrogen (N) from the ocean are ultimately linked by nitrification, the sequential oxidation of ammonia (NH3) to nitrite (NO2 ) and then nitrate (NO3-). It is estimated that almost all of the approximately 4x1011 kg of N that cycles through the ocean annually is nitrified at least one time. The degree to which nitrification occurs within a given environment alters the distribution of inorganic nitrogen available to support the growth of phytoplankton in surface waters of the ocean. In coastal environments, the process plays another critical part in N cycling, by linking the decomposition of organic matter to N loss via denitrification. It has been nearly a decade since the discovery of the ammonia oxidizing archaea expanded our perspective of N cycling in terrestrial and marine environments. Initial reports of their widespread abundance in all major biomes called for a reexamination of nitrification, and the role the archaea (and the ammonia oxidizing bacteria, AOB) play in the global N cycle. At present there is insurmountable support for nitrification being a largely archaeal-mediated process both on land and at sea. Estuaries remain a grey zone, where either the AOA or the AOB may be the primary organisms responsible for ammonia oxidation. This dissertation focuses on microbial N transformations through field studies of the distribution and activity of ammonia oxidizing microorganisms in sediments and water columns of the coastal environment, using an approach that includes molecular biology, microbial ecology and biogeochemistry.The broad objective of my thesis research was to investigate the roles of the AOA and AOB in the cycling of inorganic N, and how specific environmental conditions select for their activity in two important parts of the coastal environment: the upper ocean, where N plays a key role in supporting phytoplankton growth, and intertidal sediments, responsible for removing vast amounts of anthropogenic N pollution from coastal waters.
Microfabricated tools for functional assessment of developing cardiomyocytes [electronic resource]
Keywords: Mechanical Engineering.

Cardiomyocytes cultured from stem cells offer potential for use in regenerative tissue grafts, however the difficulty in manipulating and culturing these cells necessitates novel tools for both stimulating their development and assessing their mechanical and electrical function. Herein I introduce the tools for performing biomechanical investigations of cells and describe the challenges in working with cardiomyocytes and the development of two microfabricated sensors for quantifying the electricomechanical properties of immature cardiomyocytes throughout their development.
Microlocal analysis of lagrangian submanifolds of radial points [electronic resource]
Keywords: Mathematics.

Microlocal analysis relies on correspondences between quantum physics and classical physics to give information about certain PDEs -- for instance, linear variable-coefficient PDEs on manifolds. PDEs are interpreted as quantum systems. The corresponding classical systems tell us, for example, function spaces on which problems are solvable or almost solvable, existence and uniqueness results, and the structure of solution operators. Landmark papers of Hörmander and Duistermaat and Hörmander establish key results for the standard calculus of microlocal analysis, which gives a broad framework for dealing with variable-coefficient PDEs on manifolds. Their work is well-suited for dealing with PDEs which, in a generalized sense, are hyperbolic, with corresponding classical dynamics looking like wave propagation of geometric optics. In this thesis, we aim to extend many of their results to situations in which the corresponding classical dynamics are less well-behaved: those with a Lagrangian submanifold of radial points.
Micromachined temperature compensated pressure sensor implemented using a multi-sensor integration platform [electronic resource]
Keywords: Mechanical Engineering.

Micromachined pressure sensors are widely used in our everyday lives; they are used in automobiles for tire pressure monitor, in medical devices for blood pressure track, and in indoor navigation for altitude measurement. While the requirements for a pressure sensor vary depending upon the specific application, a common requirement is accurate sensing over a wide operating temperature range. This dissertation begins by introducing our capacitive pressure sensor design and demonstrating how it outperforms a commercially available piezoresistive pressure sensor with respect to temperature insensitivity. The capacitive pressure sensors were designed to use a central subset of the entire circular diaphragm as the electrode to improve fractional capacitance change. The capacitive pressure sensors show an order of magnitude smaller temperature coefficient of sensitivity (TCS) compared to the piezoresistive reference pressure sensor. To further reduce temperature dependence, a resonant thermometer with resolution of 1 m°C was cofabricated with the capacitive pressure sensor, enabling the tracking of temperature fluctuations on the die to correct the associated pressure error. Experimental results indicate that the temperature-induced errors are successfully suppressed, and the sensors have remaining errors within ±0.15 kPa over the tested temperature range. In the second part of the dissertation, the design and performance of our resonant pressure sensors are discussed. The development of the resonant sensors was motivated by the emerging demand of altimeters which require high resolution in pressure sensing (a one-meter elevation change corresponds to a ten-Pascal pressure change, i.e., 10 Pa/meter). As the design is coupled to the die strain, the accuracy of the resonant pressure sensors is strongly influenced by errors induced by both temperature and package stress. We addressed this limitation with a multiple sensor solution whereby temperature and strain sensors were cofabricated to reduce the pressure sensor's temperature and package stress dependence, thus improving accuracy. The devices show sensitivity to pressure ranging between 50 and 150 ppm/kPa with a minimum detectable signal of approximately 7 Pa in a one-kHz bandwidth. After temperature is compensated for, the sensors have remaining offset errors within ±0.3 kPa. Throughout this work, a multiple sensor integration platform was used to fabricate the sensors. Key innovations include time insensitive vapor etching of silicon dioxide with hydrofluoric acid to release structures as well as the fabrication of structures that can be driven and sensed in both in-plane (x, y) and out-of-plane (z) directions on either bulk silicon or SOI wafer substrates. Such a multi-sensor integration platform is suitable for a variety of MEMS devices, such as accelerometers, gyroscopes, switches, and resonators.
Microprobing mechanical and fracture behavior in complex structures [electronic resource]
Keywords: Materials Science and Engineering.

As the feature size of device technologies scales to ever-smaller dimensions, they become more susceptible to mechanical damage. This is particularly true in microelectronics, where high temperatures are required for solder reflow during packaging of semiconductor dies. A mismatch in coefficient of thermal expansion between the silicon chip and the package causes mechanical stresses to be exerted on interconnect structures. Such chip-package interactions (CPI) cause damage and delamination of metals and dielectrics found in interconnects and other die structures. This damage occurs at the micron length scale and has been exacerbated by the integration of fragile ultra low-K (ULK) layers, stiffer lead-free solder and elevated reflow temperatures. To explore mechanics at the micron length scale, a microprobe system was designed and built. The system consists of custom-made micron-scale probe tips and a piezoelectric actuator mounted on a high-stiffness steel chassis for the accurate characterization of a range of mechanical properties under compressive, tensile or shear loading. These loading modes can also be performed cyclically, which allows for the study of fatigue phenomena. The system includes integrated heating and active cooling, allowing measurements at temperatures up to 300oC. The microprobe system is used to exert stresses on complex stacked structures consisting of Cu bumps or solder bumps and several layers of passivation and copper/low-K dielectrics. The interconnect architecture, dielectric porosity, loading mode mixity, temperature and the direction of shear loading were found to have a significant effect on damage processes. It was shown that the interconnect stack structures weaken dramatically with temperature and that fracture behavior is sensitive to the presence of high porosity dielectric films with sub-micron thickness. Failure analysis of the test structures was conducted using FIB milling and SEM imaging, revealing that rather than always occurring in the weakest layer, the location of ultimate failure depends on the damage initiation site as well as the overall stack mechanics dictated by both geometry and material properties. This study allows for a quantitative understanding of the mechanics of complex structures, particularly damage initiation and evolution processes. This information is useful for optimizing the manufacturing process of devices with micron-scale features.
Microstructure and charge transport in conjugated polymers [electronic resource]
Keywords: Applied Physics.

Conjugated polymers have attracted broad interest in the past few decades due to their potential applications in organic light emitting diodes, low-cost flexible circuits, biosensors and photovoltaics. Because of their semicrystalline nature, the spatial arrangement of the crystallites and the disordered regions would have strong impact on the charge transport properties of conjugated polymer thin films. Therefore, in this presentation, I will focus on understanding the relationship between the film's morphology, microstructure and electronic properties, and how to fabricate desired structure to achieve devices with novel electronic performance. In the first part of the presentation, I will show that the device's electronic performance can be greatly improved by engineering its structure in solution based fabrication process. The binary blends of regioregular (rr) and regiorandom (RRa) P3HT are used to form desired FET structures. X-ray diffraction of the blended films is consistent with a vertically-separated structure, with rr-P3HT preferentially crystallizing at the semiconductor/dielectric interface. Because of the ultra-thin rr-P3HT active layer at the interface, these devices not only preserve high mobility in rr-P3HT, but also eliminate the short channel effects due to bulk currents, suggesting a new route to fabricate high performance, short-channel and reliable organic electronic devices. After that, I will discuss the microstructural origin of high mobility in poly(2,5-bis(3-alkylthiophen-2-yl)thieno[3,2-b]thiophenes) (PBTTT) thin-film transistors (TFTs). Charge transport in PBTTT TFTs is analyzed with a mobility edge (ME) model and compared to these in poly(3-hexylthiophene) (P3HT) TFTs. With TEM characterization of delaminated films, we conclude that the improved performance of PBTTT compared to P3HT is not due to a low trap density but rather to a high mobility in the crystallites. Finally, the third part of the presentation will focus on optical characterization of doping in conjugated polymers. UV-vis and IR absorption spectra of 2,3,5,6-Tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F4TCNQ) doped P3HT at different doping concentration are measured and analyzed. Absorption peaks from P3HT, F4TCNQ, F4TCNQ anion and P3HT polaron/bipolarons are identified and decomposed. The P3HT polaron/bipolarons cross sections in UV-vis region are estimated, which can be used to evaluate doping efficiency in this material.
Microsystems for studying single heart cell mechanobiology [electronic resource]
Keywords: Mechanical Engineering.

With each heart contraction, blood rushes throughout the expansive circulatory system providing oxygen and other nutrients to the body. Cardiomyocytes are the contractile units responsible for these contractions. In the event of ischemia, the heart reduces its contractile output and loses a significant number of cardiomyocytes. In the ischemic region of the heart, the tissue remodels and the mechanical properties differ significantly from healthy tissue. Due to the limited regeneration capabilities of the heart, recent focus has been on understanding how the reintegration of pluripotent-derived cardiomyocytes can help restore contractile function. These pluripotent-derived cardiomyocytes will need to survive in mechanically active environments and contribute to the contractile output of the heart. However, even before these cardiomyocytes can be used, we need to develop an understanding for how primary immature cardiomyocytes should respond to mechanical forces in vitro. This work explores cardiomyocyte contractile ability in the presence of mechanical forces. For this work, we investigate neonatal murine cardiomyocytes. We begin by developing a protein patterning technique suitable for polyacrylamide. With this technique, we achieve repeatable arrays of neonatal cardiomyocytes and control their shape and size. We found this technique improves sarcomere distribution, making them look more mature and like adult cardiomyocytes. Using micro-tools, we then investigate cardiomyocyte contractility in the presence of mechanical forces. These findings suggest that the Frank-Starling law that governs the heart is also applicable to neonatal cardiomyocytes. Later in this work, we introduce the MEMS tool developed to better understand cardiomyocyte contractile forces. We describe the design goals and fabrication process of the micro-device. In addition, we present the calibration and testing results, and demonstrate that this device provides a reliable and alternative way to calibrate substrates used to study contractile forces. In the closing section of this work, we introduce ideas for future studies building on this work, and the work of others.
Mid-infrared laser diagnostics for chemical kinetics study of oxygenates [electronic resource]
Keywords: Mechanical Engineering.

Biofuels are classified as renewable because the carbon present in the vegetable oil or animal fat feedstocks originates from carbon dioxide already present in the atmosphere. One of the current focuses on biofuel-based combustion research is the design of advanced energy conversion devices using complex reaction mechanisms. The development of these mechanisms requires a large experimental database to ensure accuracy of computational predictions. Infrared laser-absorption diagnostics are widely used in combustion research for fast, sensitive, and non-intrusive measurements of species concentration, temperature, and pressure. This thesis explores three new areas of laser diagnostic research: (a) mid-infrared diagnostics, (b) sensing in multiphase flows, and (c) applications to shock tube chemical kinetics. A novel distributed-feedback quantum-cascade laser (DFB-QCL) near 4.7 um was investigated to develop a new mid-infrared absorption sensor for in situ measurements of carbon monoxide (CO) and temperature in combustion gases. The laser provides convenient access to the stronger vibrational bands of CO than was possible previously, enabling ppm-level detectivity with an optical path length of 10 cm at high temperatures between 1000-2000 K. Wavelength modulation spectroscopy with 1f-normalized 2f detection (WMS-2f/1f) of CO2 was developed for accurate temperature sensing in multiphase combustion flows. In this method, two tunable diode lasers with wavelengths near 2.7 um were used to measure time-varying gas temperature during the evaporation of shock-heated fuel aerosols. These recently developed mid-IR laser absorption diagnostics were then applied in studying the thermal decomposition of oxygenates (biofuel surrogates) by measuring species concentration time-histories behind reflected shock waves. In a particular study of methyl formate (the simplest biodiesel surrogate), the reaction rate constants of methyl formate unimolecular decomposition were measured using the mid-IR CO absorption behind reflected shock waves. Detailed comparisons of the measured methanol and CO time-histories with the model predictions were made. Sensitivity and reaction pathway analyses for these oxygenated fuel components were performed, leading to rate recommendations with improved model performance.