VictorJuiz/thesis huggingface dataset:
Characterization of Deuteron-Deuteron Neutron Generators

A facility based on a next-generation, high-flux D-D neutron generator (HFNG) was commissioned at the University of California Berkeley. The characterization of the HFNG is presented in the following study. The current generator design produces near mono-energetic 2.45 MeV neutrons at outputs of 10^8 n/s. Calculations provided show that future conditioning at higher currents and voltages will allow for a production rate over 10^10 n/s./nCharacteristics that affect the operational stability include the suppression of the target-emitted back streaming electrons, target sputtering and cooling, and ion beam optics. Suppression of secondary electrons resulting from the deuterium beam striking the target was achieved via the implementation of an electrostatic shroud with a voltage offset of greater than -400 V relative to the target. Ion beam optics analysis resulted in the creation of a defocussing extraction nozzle, allowing for cooler target temperatures and a more compact design. To calculate the target temperatures, a finite difference method (FDM) solver incorporating the additional heat removal effects of subcooled boiling was developed. Validation of the energy balance results from the finite difference method calculations showed the iterative solver converged to heat removal results within about 3% of the expected value. Testing of the extraction nozzle at 1.43 mA and 100 kV determined that overheating of the target did not occur as the measured neutron flux of the generator was near predicted values./nMany factors, including the target stopping power, deuterium atomic species, and target loading ratio, affect the flux distribution of the HFNG neutron generator. A detailed analysis to understand these factors effects is presented. Comparison of the calculated flux of the neutron generator using deuteron depth implantation data, neutron flux distribution data, and deuterium atomic species data matched the experimentally calculated flux determined from indium foil irradiations. An overview of experiments using the HFNG, including medical isotope cross section measurements, geochronology, delayed gamma measurements from uranium fission, and single event upset of cpu's is discussed. Future work should focus on the reduction of beam induced arcing between the shroud and the vacuum chamber. Investigation of insulator charge build-up, as well as electrical flash-over of insulators should be explored. The reduction of beam induced arcing will allow for larger beam currents and acceleration voltages, therefore increasing the neutron flux.

Advisor: Van Bibber, Karl A
Genetic variation as a tool for identifying novel transducers of itch

The mammalian somatosensory system mediates itch, the irritating sensation that elicits a desire to scratch. Millions of people worldwide suffer from chronic itch that fails to respond to current drugs and therapies. Even though recent studies have begun to elucidate the basic characteristics of the itch circuitry, we have little understanding about the molecules and signaling mechanisms that underlie detection and transduction of itch sensation, especially during chronic itch conditions. We have taken a genomic approach by harnessing natural variation in itch-evoked scratching behaviors in mice to identify novel molecular players that are involved in itch signal transduction at the level of primary sensory neurons. From our analysis, we identified numerous candidate itch genes, and further identified a serotonin receptor, HTR7 as a key transducer that is required for both development and maintenance of chronic itch. We further investigated the genetic basis of variation in itch, and identified a set of genes and regulatory pathways that may be involved in controlling itch behaviors. Our work illustrates the power of genomic studies in identifying genes and regulatory pathways involved in somatosensory behaviors, further providing resources and molecular insights into possible treatment options for chronic itch conditions.

Advisor: Bautista, Diana M
Brem, Rachel B
Modeling of natural stimulus representation in the human brain using canonical correlation analysis

Understanding the representation of natural stimuli in the human brain is one of the fundamental goals of neuroscience. In this dissertation, I describe an unsupervised learning approach for investigating BOLD (blood oxygen level dependent) responses throughout the cortex to natural movies and speech. This approach for data-driven learning of representational features is particularly useful for regions of the brain where the features aren't well understood./nFirst, I describe Python software for canonical correlation analysis called Pyrcca, developed for implementing this approach. Then, I introduce a method called FISCA (functional inter-subject component analysis). FISCA uses canonical correlation analysis to estimate components of BOLD responses based on cross-subject similarity. FISCA can be used for combining data across subjects according to functional and not anatomical similarity. FISCA predictively models BOLD responses to novel stimuli across subjects and allows accurate identification of stimulus timepoints based on these predictions./nFISCA components are interpretable. For both natural movie and natural story experiments, I visualize the components on the cortical surface to characterize the role of each component in explaining representation in different brain areas. I also compute the tuning of each component for low-level visual and semantic features. FISCA components are stimulus-agnostic. I demonstrate how FISCA can be used to identify amodal regions by combining data between natural movie and speech experiments./nFISCA is an accurate, flexible, and extensible unsupervised method for modeling brain responses to natural stimuli. Using this approach, I uncover representation of natural visual and speech stimuli throughout the cortex. I hope that in the future, this approach will be used for creating more accurate models and improving our understanding of cortical processing.

Advisor: Gallant, Jack L
Estimating the size of unobserved populations in human rights: Problems in Syria and El Salvador

In this dissertation, I examine two human right estimation problems./nFirst, I assess data on child abductions from El Salvador's civil war. Between 1979 and 1992, El Salvador was wracked by conflict between leftist guerrilla groups and right-wing nationalist governments. One feature of the conflict was the abduction of children by government military forces, or the forced surrender of children to those same forces. Since 1994, La Asociación Pro-Búsqueda de Niñas y Niños Desaparecidos has investigated cases of these child abductions. To date, they have opened more than 950 cases and located nearly 400 abducted children (now, young adults). The organization remains active, and new cases come to light each year. In Chapter 2, I examine Pro Busqueda's data, assessing what can be said to date about the total as yet unknown number of abductions that occurred. I demonstrate that more abductions occurred than the number of currently known cases discuss capture-recapture estimates under a range of assumptions about the data available today. I then lay out a plan for updating estimates as new data becomes available./nThen, I examine current data on deaths from the ongoing conflict in Syria. Early in the conflict, the United Nations Office of the High Commissioner for Refugees (UNOHCR) contracted with statisticians at the Human Rights Data Analysis Group (HRDAG) to analyze data from multiple human rights groups that were documenting deaths from the conflict there. HRDAG produced three reports from the United Nations and has maintained ongoing relationships with the local human rights groups that are collecting the raw data. HRDAG is now in the unusual position of possessing a series of multiple ``snapshots'' of each group's data, collected at a number of points between 2012 and 2016. Using those snapshots, I examine how each group's data is changing over time, and discuss how those changes can impact resulting estimates of unreported deaths, showing that the changes can result in estimates for a single governorate that vary by nearly 100,000. In addition, I take advantage of the large number of processed cases to assess the performance of a variety of classification algorithms in determining whether two records refer to the same individual.

Advisor: Jewell, Nicholas P
A Search for Long-Lived, Charged, Supersymmetric Particles using Ionization with the ATLAS Detector

Several extensions of the Standard Model predict the existence of charged, very/nmassive, and long-lived particles. Because of their high masses these particles/nwould propagate non-relativistically through the ATLAS pixel detector and would/ntherefore be identifiable through a measurement of large specific energy loss./nMeasuring heavy, long-lived particles through their track parameters in the pixel/ndetector allows sensitivity to particles with lifetimes in the nanosecond range/nand above. This dissertation presents an inner detector driven method for identifying/nsuch particles in proton-proton collisions at 13 TeV with the 2015 LHC/ndataset corresponding to an integrated luminosity of 3.5 pb−1.

Advisor: Heinemann, Beate
Proximity-Enhanced Reactivity for Chemical Biotechnology

Chemoselective reactions are powerful tools for the progression of basic science and biochemical technologies. Bond-forming reactions are routinely used for monitoring the status of cellular activity and in the production of precision therapeutics and diagnostics. However, the development of such reactions is a challenging feat, as one must account for the broad swathes of interfering chemical entities present within the biological milieu. One way to address this complicating factor is through the use of “bioorthogonal” chemistry. These reactions involve two reactive groups with xenochemical properties, i.e., reactivity preferences that are inert to biological moieties yet exquisitely reactive with one another. By necessity, bioorthogonal reactions are forged from deep chemical insight. A complementary strategy to achieve reaction selectivity in biological settings seeks to use proximity enhancement. Positioning two groups in close proximity to one another raises the higher effective local concentration of the desired partners, increasing the rate by which they react to afford highly selective conjugation, even amidst complex systems. In this dissertation, I explore several applications of this concept to develop a variety of tools for basic bioscience and clinical diagnostics./nIn Chapter 1, I provide a brief overview of several landmark papers that employ proximity-enhanced reactions in chemical biotechnology./nIn Chapter 2, I describe the use of proximity-enhanced reactivity to direct ligation and detection of protein-specific glycosylation on live cells./nIn Chapter 3, I describe the application of proximity enhancement to selectively accelerate the ligation of DNA strands that have been chemically attached to different antibodies. In this particular project, we used paired antibodies that bind either to biotin or a protein of interest, driving the ligation and formation of a DNA amplicon in the presence of a biotinylated protein. In combination with chemistries that selectively attach biotin to glycans, this technology allows the use of qPCR to detect very low levels of glycosylated proteins./n/nIn Chapter 4, I describe the development of a new technology, termed Antibody Detection by Agglutination-PCR (ADAP), which uses PCR to detect antibodies with a high degree of multiplexing and sensitivity./nIn Chapter 5, I describe a method for re-purposing cyclooctynes to selectively ligate to thiols present on serum albumin as a strategy to improve the serum-half lives of therapeutic molecules./nIn Chapter 6, I describe the computational modeling and synthesis of dendrimer-based glycan mimetics.

Advisor: Bertozzi, Carolyn R
Strategies for Enantioselective Carbon-Heteroatom Bond Formation

Although the topics discussed in this dissertation each stand as unique areas of research in their respective fields, they are united under the common approach of using catalyst structure to control the selectivity of a particular reaction. For the majority of these transformations, use of a chiral counterion-based catalyst, a relatively new strategy in the field of asymmetric synthesis, proved essential for successful enantioinduction. An additional subtheme, design and application of electrophilic reaction components, provided an added dimension of control to the reaction outcome./nChapter 1 presents a brief perspective on the gold-catalyzed synthesis of heterocycles with an emphasis on previously published hydrofunctionalizations of allene substrates containing tethered nucleophiles, thus providing context for Chapter 2./nChapter 2 describes efforts toward the gold(I)-catalyzed enantioselective bromocyclization of allenes. The primary goal of this project was the synthesis of enantioenriched vinyl halide-containing products containing enantioenriched allylic stereocenters within a heterocyclic ring moiety. Efforts to synthesize these molecules were initially hindered if more traditional electrophilic halogen sources such as N-bromosuccinimide were used; however, employment of the relatively unexplored N-bromolactams resulted in high yields and selectivities of the desired products. Additionally, this methodology partially utilized chiral phosphate-based molecules as counterions as an additional source of chiral information./nChapter 3 takes inspiration from the previous use of chiral phosphate counterions to accomplish an enantioselective intermolecular α-amination reaction utilizing nucleophilic nitrogen sources. This project sought a reaction complementary to previously existing versions which utilized electrophilic sources of nitrogen. Choice of chiral phosphoric acid in addition to an appropriately activated azoalkene substrate was critical for the high levels of yield and enantioselectivity observed. While expanding the substrate scope, a serendipitous kinetic resolution was observed, which revealed an interesting mode of reactivity associated with α-arylamino hydrazones./nChapter 4, the final installment, is intended to be an initial survey of explorations into Pummerer-like reactivity again utilizing chiral phosphoric acids or phosphates as a source of chirality. Still in its infancy, this project has explored various carbon-heteroatom bond-forming reactions utilizing either sulfoxide or fluorosulfonium moieties as a source of oxidized sulfur to enable an enantioselective cross-dehydrogenative coupling using a Pummerer-like reaction mechanism. One eventual goal would be to expand the space of enantioenriched sulfur-containing heterocycles.

Advisor: Toste, F. Dean
Statistical Mechanics and Dynamics of Liquids in and out of Equilibrium

Liquids display an astonishing array of phenomena that, at first glance, seem to have little in common. In this thesis, we study two of these phenomena. The first is the hydrophobic effect, the well-known tendency of oil and water to demix and the driving force for biological assembly. The second is the glass transition, the process by which liquids cooled to very low temperatures become increasingly viscous until succumbing to structural arrest and displaying the rigidity of a solid with none of its microscopic ordering./nIn the first part of this thesis, we expand upon our prior understanding of the hydrophobic effect. We study the behavior of water in the confined volume created by a pair of RNA helices at the inter-subunit interface of the bacterial ribosome, which provides an opportunity to apply our contemporary understanding of the hydrophobic effect, first detailed by Lum, Chandler, and Weeks almost twenty years ago, to a context that is less idealized than previously studied. We also discuss and improve upon computational models of hydrophobic solvation, expanding their applicability to more complicated solute geometries./nIn the second part of this thesis, we study the glass transition from the perspective of the East model, a kinetically constrained lattice model of glass formers. We review and derive a number of results for East model glasses that we expect to emerge in more realistic, atomistic models of glass formers. We choose one such model and drive it out of equilibrium by cooling, forming a glass. We then check whether our East model predictions are correct. Of particular interest to us is whether inter-excitation correlations emerge out of equilibrium, a key prediction of the East model. Our atomistic results suggest that they do not, forcing us to reconsider our conceptual mapping between the highly abstract East model and more realistic models of glass formers./nThe common thread in these seemingly disparate parts of the thesis is the importance of collective fluctuations in liquid-state phenomena. The hydrophobic effect is a physical consequence of liquid-vapor interfacial fluctuations near extended hydrophobic surfaces, while dynamics in supercooled liquids, the precursors to glasses, are dominated by small, collective motions of particles in an otherwise jammed material. The importance of fluctuations in these and other liquid-state phenomena make the tools of statistical mechanics particularly suitable to their study. In this thesis, we employ these tools in the service of furthering our understanding of the liquid state.

Advisor: Chandler, David
Molecular basis for multimerization in the activation of the epidermal growth factor receptor

Abstract/nMolecular basis for multimerization in the activation of the epidermal growth factor receptor/nby/nYongjian Huang/nDoctor of Philosophy in Biophysics/nUniversity of California, Berkeley/nProfessor John Kuriyan, Chair/nThe epidermal growth factor receptor (EGFR), and its relatives HER2, HER3 and HER4, are receptor tyrosine kinases that couple the binding of extracellular ligands to the initiation of intracellular signaling pathways that control cell growth and proliferation. Aberrant signaling from EGFR family members underlies the onset of many human cancers. The canonical view of EGFR activation is that the receptor is activated by dimerization. It is known, however, that EGFR activation also generates higher-order multimers, whose structural details and functional consequences are poorly understood. Due to the incomplete understanding of the significance of multimerization for EGFR activity, the monomer/dimer model has remained the paradigm for EGFR activation mechanism. In collaboration with Shashank Bharill, a postdoc in Ehud Isacoff’s group, we now have characterized ligand-induced dimerization and multimerization of human EGFR using single-molecule based analysis, specifically, stepwise fluorescence photobleaching using EGFR transfected into Xenopus oocytes and fluorescence cross-correlation spectroscopy of EGFR expressed in mammalian cells. This single-molecule technique was first developed in Isacoff lab back in 2007, for counting subunits of membrane proteins in live-cell by observing photobleaching steps of GFP that is fused to a protein of interest. Without disrupting their membrane environment, we have now been able to determine the stoichiometry of EGFR complexes before and after activation. Using mutations identified in this study that are specifically important for multimerization of EGFR, I uncovered a functional role for multimerization in EGFR activation. These mutations reduce EGFR autophosphorylation in mammalian cells, particularly for sites in the C-terminal tail that are proximal to the kinase domain, and they also attenuate phosphorylation of phosphatidyl inositol 3-kinase, which binds to a proximal site on the EGFR C-terminal tail. In collaboration with Deepti Karandur, a postdoc in Kuriyan lab, we propose a structural model for EGFR multimerization that is consistent with our experimental observations, which might be applicable to other human EGFR family members as well. During the investigation of EGFR stoichiometry in the presence of EGF using Xenopus oocytes, we made an unexpected discovery. Upon binding to EGF, EGFR shows linear back-and-forth motion on the oocyte surface, which is dependent on EGFR kinase activity and the actin cytoskeleton. To fully uncover the mechanism behind the observed linear motion of EGFR, more extensive studies are needed.

Advisor: Kuriyan, John
Sustained neuronal activity in human prefrontal cortex links perception and action

The prefrontal cortex (PFC) is critical for organizing thought and behavior in accordance with internal goals. Patients with prefrontal lesions do not exhibit easily observable sensory deficits or simple behavioral deficits, but instead are unable to select appropriate responses based on internal representations. Neuroimaging in humans and single unit studies in non-human primates show PFC involvement across many task contexts requiring higher order control of behavior. However, despite converging evidence from neuroimaging and electrophysiology, the neuronal mechanism of flexible thought and behavior remains one of the most fundamental and elusive questions in neuroscience. One hypothesis posits that the PFC functionally bridges stimulus evaluation and response execution across time and cortical space, yet how this region implements the stimulus-to-response transformation is unknown. The first study described here defines how response selection is implemented during goal-directed behavior by examining the timing, magnitude, and spatial distribution of local cortical activation in humans. These results demonstrate that intrinsically sustained stimulus-to-response activation provides the foundation for binding stimulus processing with response execution on a single trial basis. Notably, this effect is seen across multiple tasks and sensory modalities. The second study introduces a novel method for probing how oscillations contribute to cognitive control by algorithmically extracting the center frequencies and bandwidths of oscillatory components in electrophysiological power spectra. The results demonstrate that the use of individualized frequency bands, which account for oscillatory heterogeneity, unmasks relationships between task and behavior that are hidden when using predefined, canonical frequency bands. Oscillatory dynamics support neuronal communication, and as such the method presented here is a critical step in understanding how the PFC exerts cognitive control over distributed cortical and subcortical regions supporting goal-directed behavior.

Advisor: Knight, Robert T