VictorJuiz/thesis huggingface dataset:
Non-cell autonomous effects in diffuse intrinsic pontine glioma

Diffuse intrinsic pontine gliomas (DIPG) are highly aggressive tumors originating in the pons of the brainstem during childhood. With an average survival post-diagnosis of only 9 months, DIPG is the leading cause of pediatric brain tumor death. Because the unique biology underlying the disease is not well understood, little progress has been achieved in treating DIPG in the past thirty years. Here, we demonstrate that DIPG cells secrete soluble factors that promote abnormal proliferation of surrounding neural precursor cells. Using a combination of biochemical techniques, we identified SPARCL1 as a protein secreted by DIPG cells in vitro that is sufficient to increase both NPC and DIPG growth. Currently, therapeutic interventions mainly focus on targeting cancer cells themselves. However, we postulate that DIPG cells incorporate healthy neural precursor cells into the tumor mass. Thus, targeting interactions between DIPG cells and NPCs in the developing brain holds the potential to slow DIPG progression.

Keywords:  Department of Biology
pediatric high grade glioma
diffuse intrinsic pontine glioma
DIPG
SPARCL1
tumor microenvironment
Thesis
Advisor: Monje Michelle
McConnell Susan
Nonlinear optical devices as single-photon quantum frequency converters [electronic resource]

Appropriate interfaces between quantum nodes and low-loss quantum channels in long-distance quantum communication networks and upconversion-assisted SPDs are based on quantum frequency conversion (QFC) processes. QFC processes give us the ability to translate the qubit's carrier frequency while its quantum state is maintained. The primary interest of QFC has been upconversion single-photon detection. A process where a single-photon level signal in the telecommunications band is upconverted to a visible wavelength and use the well-developed single-photon detectors based on silicon avalanche photodiodes. The need for an interface between coherently controlled matter qubits (which typically have optical transitions in the visible or near-infrared spectral range) and low-loss photonic quantum channels (at the 1.3 or 1.5 m bands in silica optical fibers) is a primary challenge toward developing a long-distance hybrid quantum network. The possibility of making such an interface based on nonlinear interactions is another motivation to develop QFC processes. We can reach high conversion efficiency by using reverse-proton-exchange waveguides. A key issue in these devices is minimizing the generation of noise photons in the signal band by inelastic scattering of the pump. The two primary origins for this noise processes are known as spontaneous parametric down conversion (SPDC) and spontaneous Raman scattering (SRS). It has been shown that long-wavelength-pumping dramatically reduce the dark-count rate. This requirement limits the wavelength-translation range which can be achieved in a single conversion step. This constraint led to the development of integrated devices based on two cascaded parametric conversion processes. We discuss considerations in using cascaded frequency mixers for low-noise quantum frequency conversion between two widely disparate frequencies, such as long-wavelength-pumped down-conversion of visible single photons from a diamond nitrogen-vacancy center or trapped ion to 1550 nm. We have demonstrated an integrated architecture for low-noise, low power cascaded quantum frequency conversion from 649.7 nm to 1595 nm. The results presented in this dissertation represent a critical step toward low-power, low-noise quantum frequency conversion for long distance quantum communication networks.

Keywords: Electrical Engineering.
Advisor: Fejer Martin M. (Martin Michael) primary advisor. Thesis advisor
Harris J. S. (James Stewart)
Vuckovic Jelena advisor. Thesis advisor
Nonlinearities in bulk acoustic mode silicon micromechanical resonators [electronic resource]

Capacitive microelectromechanical (MEMS) oscillators represent a promising alternative to quartz-based systems as they provide benefits such as mass fabrication, size reduction, and compatibility with CMOS IC integration. However, one drawback that comes with size reduction is smaller induced currents, which leads to increased noise in the oscillator output. To overcome this challenge, resonators have to be driven to larger amplitudes of motion, and oftentimes operate in the nonlinear regime, where the resonator dynamics become much more complicated (e.g. Duffing-type nonlinearity, nonlinear damping, etc.). This work aims to characterize the nonlinear behavior in commonly used bulk acoustic mode resonators fabricated in a modified epi-seal process, where a variety of devices with reduced design limitations can be fabricated in this process while maintaining the core epi-seal process features (e.g. high stability, reliability, ultra-clean, etc.). Utilizing this process, high quality factor devices without release etch-hole in the device layer can be fabricated (e.g. Lamé resonator operated at 10.1 MHz with quality factor of 2.27e+13), which is beneficial towards characterization of nonlinear behavior in bulk mode devices. Frequency stability experiments have also been performed, with the measured stability of ± 18 ppb over one month of testing. Cavity pressure studies indicate a cavity pressure of less than 0.1Pa equivalent of air. These results justify that the modified process is comparable with the standard epi-seal process. The effect of doping on material nonlinearities is also analyzed, where three types of bulk acoustic mode resonators are used to characterize device nonlinearity with respect to doping type/concentration and orientation. Measurements on the effect of electrostatic nonlinearity are performed to justify that these devices are dominated by material nonlinearity. While recent studies have demonstrated the use of heavily p- or n-type doping for passive frequency-temperature compensation, this work demonstrates that device nonlinearity is also heavily influenced by the resonator mode shape, device crystal orientation, doping type and concentration. Lastly, a few modal coupling behaviors observed in commonly used bulk-mode resonators will be introduced, where we demonstrate that certain design parameters can be used to tune the modal coupling strength, thus directly affecting the resonator's frequency and quality factor.

Keywords: Mechanical Engineering.
Advisor: Kenny Thomas William primary advisor. Thesis advisor
Pruitt Beth advisor. Thesis advisor
Senesky Debbie advisor. Thesis advisor
Not isolated, but still insulated [electronic resource] : switch-like transitions modularize biological networks

Cellular decisions are outputs of computations performed by complex genetic networks of interconnected protein, RNA, and DNA sequence elements that are difficult to comprehensively analyze. One way to study the principles underlying these computations has been to examine the dynamics of smaller sub-networks, known as network motifs. However, it is not clear whether this is valid because these motifs are embedded in complex larger networks. Here, we explore the conditions for modularity and the bounds of validity of motif analysis in the context of a feedforward motif in the S.cerevisiae network comprising G1/S cell cycle and pheromone pathways. Using modeling and single cell analysis, we find that the feedforward motif accurately predicts the dynamics of the cell cycle inhibitor Far1 because it is insulated from the effects of gradually increasing cell cycle inputs by a positive feedback-driven switch. Before the cell cycle switch, the cell cycle signal has no effect on Far1, so feedforward motif predicts the network behavior. Conversely, after the switch, the feedforward motif is dismantled and has no effect on cell cycle dynamics. When this insulation is broken, the network is no longer modular and the feedforward motif no longer predictive. Thus, switch-like elements can digitize analog signals to modularize complex networks so that smaller sub-networks function in effective isolation and can be analyzed using motif analysis. This work demonstrates how, despite the interconnectivity of networks, motifs can be insulated by switches that produce well-defined cellular states.

Keywords: Biology.
Advisor: Fisher Daniel
Skotheim Jan
Feldman Marcus W. advisor. Thesis advisor
[Not] lost in translation [electronic resource] : optogenetic and chemogenetic control of sensory circuits

This dissertation has two purposes: 1. To increase our ability to control the neural circuits that control pain perception, ideally in a way that can be applied to treat people with chronic pain disorders. 2. To improve our understanding of the spinal circuits required to process mechanical, thermal, and itch-related stimuli. Towards these ends, we performed three primary studies: 1. We initially asked whether optogenetic techniques (at the time used primarily in the brain) could be used to control peripheral pain circuits. We developed viral methods to specifically express stimulatory and inhibitory opsins in unmyelinated primary afferent neurons, and characterized the resulting transduction profile. We found that transdermal illumination could be used to non-invasively stimulate or inhibit pain perception. While blue light resulted in marked pain-related behavior in mice expressing channelrhodopsin-2 (ChR2), yellow light resulted in effective pain-suppression in mice expressing halorhodopsin (NpHR). Importantly pain inhibition could be maintained in mouse models of neuropathic pain --- pain thresholds under illumination could be restored to pre-injury levels. In a follow-up to this study, we found that optogenetically evoked pain-responses could be used to analyze analgesic drug efficacy. 2. In a second study, we addressed a major limitation of the first study --- that it enabled optogenetic inhibition of pain only through constant illumination, a major translational limitation. We devised two complementary strategies for sustained inhibition of pain perception over hour-long periods. In the first, we exploited innovations in opsin engineering to show that the step-function inhibitory channelrhodopsin (SwiChR), if expressed in primary afferent nociceptors, enabled long-term inhibition of pain perception with temporally sparse illumination. In the second, we expressed the inhibitory Gi coupled hM4D receptor in primary afferent neurons, and showed that activation of this designer receptor (DREADD) resulted in significant inhibition of pain thresholds. 3. Finally, we exploited innovations in light-delivery systems for optogenetic control of the spinal cord to examine the role of an excitatory interneuron population (somatostatin+ neurons) in mediating sensory perception. Using a combination of optogenetics, chemogenetics, and anatomical tracing, we examined the consequences of reversible bidirectional control over somatostatin+ interneurons, and identified a novel interaction between somatostatin+ neuron activity and itch-related behavior.

Keywords: Bioengineering.
Advisor: Delp Scott primary advisor. Thesis advisor
Clark David
Deisseroth Karl advisor. Thesis advisor
Notch3 signaling and pericyte proliferation in coronary artery maturation

More than seven million people die from coronary artery disease each year, making it the leading cause of death worldwide. Investigating the developmental origins of coronary arteries can lead to a better understanding of and improved therapeutics for coronary artery disease. Many aspects of coronary artery angiogenesis, however, remain unclear. Pericytes, mural cells closely associated with small blood vessels, have recently been identified as progenitors for coronary artery smooth muscle cells (caSMCs) (Volz et al., 2015). This pathway is in part controlled by Platelet Derived Growth Factor Receptor β (PDGFRβ), an important receptor for smooth muscle development that diminishes caSMC maturation upon deletion (Mellgren et al., 2008). Similarly, studies of the Notch3 receptor have shown that notch3 is involved in pericyte development and maintenance and promotes vascular smooth muscle cell proliferation (Greenwald, 1998). Our study analyzes the effects of the Notch3 receptor on the development of coronary artery smooth muscle in a murine model. Coronary artery smooth muscle develops when blood flow induces vessels within the vascular plexus, an immature vessel bed permeating the entire ventricular heart muscle, to remodel into mature coronary arteries with smooth muscle cell coating in regions called remodeling zones (Red-Horse et al., 2010; Kattan et al., 2004). Here, we show that the deletion of Notch3 disrupts caSMC differentiation at the coronary artery remodeling zone. The defect in smooth muscle, however, is likely not due to differential proliferation of pericytes between wild type and Notch3-null mice. We additionally characterize pericyte biology at sites of arterial differentiation and show that the remodeling zone contains significantly more pericytes than the vascular plexus, but there is no difference in proliferation at the former site. These data collectively indicate that pericytes give rise to coronary artery smooth muscle through an integral Notch signaling mechanism and that smooth muscle differentiation involves pericytes migrating into the remodeling zone rather than increased proliferation at the remodeling zone. This reveals a new potential pathway that can be therapeutically targeted during coronary artery disease.

Keywords:  Department of Biology
Biology
Developmental Biology
Pericytes
Coronary Arteries
Notch3
Proliferation
Thesis
Advisor: Red-Horse Kristy
Morrison Ashby
Not-quite-optimal market design [electronic resource]

This thesis contains two self-contained essays on market design. The first essay considers a many-to-one matching setting in which students list a limited number of schools as acceptable, and matches are formed using the deferred acceptance algorithm. I provide exact asymptotic expressions for the number of students receiving a top-k choice as a function of factors such as the number of students, the number and capacities of schools, the length of student lists, the correlation in student preferences, and the procedure for generating school priorities. I then compare outcomes across priority rules, and find that there is a tradeoff between the goals of assigning many students to their top choice, and leaving few students unassigned. For example, when comparing district-wide and school-specific lotteries, the former assigns more students to their first choice, while the latter assigns more students overall. The second essay considers a setting in which several advertisers compete in an auction for the right to place an ad. Each advertiser has a value that is the product of the "common value" of the impression and an advertiser-specific idiosyncratic "match value." Although most advertisers observe their value for the impression, one advertiser is unable to do so. The first result is that holding a second price auction for the impression may lose up to half of the available match value. Meanwhile, the optimal auction induces adverse selection and is susceptible to shill bidding. I introduce Modified Second Bid auctions as the only deterministic anonymous mechanisms that are fully strategy-proof and eliminate adverse selection. Furthermore, when match values are independent draws from a power law distribution, a Modified Second Bid auction captures at least 94.8% of the value generated by the optimal mechanism.

Keywords: Management Science and Engineering.
Advisor: Johari Ramesh
Milgrom Paul R. (Paul Robert)
Roth Alvin E.
Novel Role of Wnt Target Receptors in Cartilage Development

Articular cartilage, a smooth white tissue composed of chondrocytes, cushions the ends of joints, yet possesses very poor regenerative potential. Identifying novel factors that govern cartilage development is an essential foundation for developing stem and progenitor cell-based therapies. Such therapies could include using cartilage regeneration to address focal cartilage injuries as well as osteoarthritis, a debilitating disease brought about by loss of cartilage tissue. Previous work has elucidated the role of the Wnt signaling pathway, a key regulator of gene transcription, in the process of chondrogenesis, or cartilage differentiation. We seek to address the specific role of one of the pathway’s non-canonical receptors: the leucine-rich repeat-containing G-protein coupled receptor (Lgr). The specific member Lgr5 was chosen as the focus of our study because of its previous implication as an adult stem cell marker. This trait is of particular interest to us in the field of progenitor cell-based therapies for cartilage tissue. We sought to investigate the expression and role of Lgr5 in cartilage in order to understand and identify tissue-resident stem or progenitor cells in the tissue. Surprisingly, we found that Lgr5 expression increased during chondrogenesis, and its knockdown significantly impaired this process. Using global microarray-based gene and protein expression assays to analyze the chondroprogenitor cell line ATDC5, we found that the Lgr5 knockdown led to decreased expression of the known chondrogenic markers Type II Collagen (Col2a1) and Aggrecan (Agc). Additionally, we observe that Wnt3a dependent β-catenin is activated during chondroprogenitor differentiation in parallel to Lgr5 upregulation. Further research towards understanding the molecular mechanisms underlying cartilage differentiation will aid in unlocking the tissue’s regenerative potential and help define future clinical strategies for enhancing cartilage regeneration.

Keywords:  Department of Biology
Biology
Chondrogenesis
Cartilage
Differentiation
Wnt Pathway
Thesis
Advisor: Bhutani Nidhi
Bergmann Dominique
Nozzle erosion in hybrid rocket motors [electronic resource]

Nozzle erosion in hybrid rocket motors is an unsolved and generally unstudied problem that poses a hurdle to small-scale and long-burning hybrid rocket motor development. While the nozzle erosion problem has been studied extensively in liquid rocket engines and solid rocket motors, it has remained largely untouched for the hybrid rocket configuration. In this research, nozzle erosion is measured in a small lab-scale motor utilizing gaseous oxygen and paraffin wax as propellants at various chamber pressures and oxidizer to fuel (O/F) ratios. Paraffin-based fuels are of particular interest as they are inert and have proven high-performance capabilities. An ultrasound sensor along with an array of thermocouple sensors are placed at the nozzle throat plane of the motor and the combination of the recorded data allows for the reconstruction of the time-varying wall thickness at the throat plane. This data is used to determine nozzle erosion, as well as a time varying estimate of the inner wall heat flux at the nozzle throat plane. While the nozzle erosion data is the primary interest for this study, other researchers may find the heat flux estimations useful as they can be used in the validation of CFD models. A dimensionless model is then proposed to capture the affects of O/F ratio, chamber pressure, nozzle material properties, flame temperature, efficiency, and mixing. This dimensionless model can be used to estimate nozzle erosion for any given hybrid rocket motor design, which should be useful to hybrid rocket motor designers.

Keywords: Aeronautics and Astronautics.
Advisor: Cantwell Brian primary advisor. Thesis advisor
Alonso Juan José
Close Sigrid
Nuclear magnetic resonance diffusion measurements for characterization of the near-surface [electronic resource]

Nuclear magnetic resonance (NMR) logging tools can be used to directly measure the response of hydrogen-bearing fluids in sediments surrounding a well or borehole. To date, applications of NMR in the near-surface have relied solely on relaxation time measurements to assess hydrogeological properties. The sensitivity of the NMR measurement to the diffusivity of pore fluids can provide additional information about properties of pore fluids and the geometry of the pore space. The goal of this thesis is to evaluate the application of NMR diffusion measurements to characterize properties of the near-surface that are relevant to groundwater problems. Internal gradients, caused by magnetic susceptibility contrasts between the solid matrix and the pore fluid, are a potential source of error in NMR measurements of the apparent diffusion coefficient (D). The results from a laboratory study show that internal gradients in sediments are often large enough to significantly impact NMR logging measurements of D. It is therefore important to consider possible effects from internal gradients when interpreting D measurements. To assess the link between D measurements and pore size, a numerical modeling study was conducted for model pores with a range of magnetic susceptibilities and surface relaxivities. We see that the expected relationship between D and pore size only applies in pores with low magnetic susceptibility and low to moderate surface relaxivity. In a complementary laboratory study, we find that D in natural sediments is largely controlled by internal gradients caused by grains with high magnetic susceptibility. We conclude that internal gradients will significantly limit the ability to estimate pore size from NMR logging measurements of D. In a subsequent pair of studies, we evaluate the use of NMR diffusion and relaxation time measurements to quantify organic contaminants in sediments. A laboratory study showed that the ability to quantify contaminant when water is also present depends on the properties of the contaminant and on the properties of the sediment. The addition of the diffusion measurement increased the range of conditions where NMR measurements could be used to quantify contaminant volumes compared to relaxation time measurements alone. In a field study, we show that NMR logging measurements can be used to detect and quantify in situ petroleum contamination. Diffusion and relaxation time measurements were used together to identify and estimate the volume of contaminant in the sediments surrounding existing monitoring wells. This research shows that diffusion measurements can enhance the ability of NMR logging measurements to quantify subsurface contamination, but that internal gradients limit the applicability of diffusion measurements for estimating pore size.

Keywords: Geophysics.
Advisor: Knight Rosemary (Rosemary Jane)
Mukerji Tapan
Vanorio Tiziana advisor. Thesis advisor