VictorJuiz/thesis huggingface dataset:
Intertwined orders and their dynamical properties in strongly correlated systems
Keywords: Physics.

Strongly correlated quantum materials are of interest for both their exotic phases, often harboring multiple intertwined orders, and their unconventional normal states. This thesis investigates these topics from the perspective of numerical simulations of strongly correlated toy model Hamiltonians. First, I present large scale determinantal quantum Monte Carlo calculations demonstrating fluctuating spin stripes in both the Emery and Hubbard models on a 2d square lattice. These results suggest the pervasiveness and importance of density wave ordering in the phase diagram of high-Tc cuprate superconductors. Furthermore, they shed new light on interpreting previous numerical results for the Hubbard model. Second, I discuss transport properties of the 2d Hubbard model evaluated by analytic continuation of DQMC data. Our data, extending to temperatures around an order of magnitude below the Fermi temperature, show features reminiscent of the strange metal phase observed in unconventional superconductors, including resistivity with linear-T dependence and in violation of the Mott-Ioffe-Regel limit. I conclude with a survey of possible ideas that might enable one to go beyond the results in this thesis.
Intestinal enteroids as a novel model system for studying MHC class II regulation and function in intestinal epithelial cells
Keywords: Immunology.

The intestinal epithelium is a vast surface where dietary antigens, enteric microbes, and the mucosal immune system interact. The intestinal immune system faces a considerable challenge: mediating the timely clearance of pathogens while maintaining tolerance to harmless commensals and dietary antigens. Dysregulation of tolerance leads to disorders such as celiac disease and inflammatory bowel disease. Major Histocompatibility Complex II (MHC-II) plays a critical role in regulating adaptive immunity through the presentation of fragment fragments to CD4 T cells. Small intestinal epithelial cells (IECs) constitutively express MHC-II, though the precise role of epithelial MHC-II in tolerance and immunity is poorly understood. A major obstacle to elucidating the role of IEC MHC-II is the lack of a tractable, physiologically relevant model system. We present a method for inducing MHC class II (MHC-II) in human enteroids, "mini-guts" derived from small intestinal crypt stem cells. The cytokine interferon gamma, typically found at low levels in healthy epithelium, induces MHC-II when provided to IECs along their basolateral surface. We analyzed the intracellular MHC-II peptide-pathway and show that MHC-II molecules in IECs undergo peptide editing before trafficking to the cell surface. We then used a novel polarity reversal approach to demonstrate that MHC-II-expressing enteroids could be reversed such that their apical surface faces outward. This allows for apical antigens and microbes to be added to enteroids in a physiological manner. Our method enables human enteroids to be used for novel in vitro studies into IEC MHC-II regulation and function during health and disease.
Investigating contrary phenotypes in TSO/SOL mutants of Arabidopsis and Brachypodium
Keywords:  Department of Biology
Biology
Plant Biology
Molecular Genetics
Thesis

Stomata, gas-exchange valves in the epidermis of plants, provide a useful developmental model for regulation of cell division and differentiation. The TSO/SOL protein family members play key roles in certain division steps and fate transitions within the stomatal lineage, which can drastically affect plant physiological fitness via stomatal shape and patterning. Recent work in the dicot plant Arabidopsis thaliana found that mutants with SOL1 and SOL2 deletions display increased small cells and instances of stomatal clustering, which both indicate extra cell divisions in stomatal precursor cells. However, deletion of SOL2 in the monocot species Brachypodium distachyon leads to incomplete divisions in stomatal guard cells. To determine the functional similarity between these homologous proteins, we cloned the Brachypodium SOL2 gene into Arabidopsis sol1;sol2 double mutants expressed under Arabidopsis SOL, TSO1, and overexpression promoters. The transformed Arabidopsis sol1;sol2 mutants displayed a lack of expression of Brachypodium SOL2 protein despite confirmed presence of the BdSOL2 gene. If the expression of BdSOL2 in Arabidopsis is substantially different from AtSOL1 and AtSOL2 expression, this result could imply a diversification of roles within the TSO/SOL gene family. The specialization of homologous proteins could contribute to the developmental differences of the stomatal lineage between the two species. These findings are a start towards further understanding of the stomatal lineage as a model for species-specific cellular development and of functional roles for TSO/SOL proteins in general cell cycle control.
Investigating distributed brain circuits in vivo with multi-axis calcium imaging
Keywords: Electrical Engineering.

A major technological goal in neuroscience is to enable the interrogation of neural populations throughout the living brain. Calcium imaging allows monitoring of neural activity at sub-cellular resolution, but has typically been restricted to single fields-of-views per subject and hence limited to studies of local neural dynamics in isolated brain regions. Here, by combining computer-aided surgical planning for rodents, custom miniaturized optics, and specialized imaging instrumentation, we expand the capability of optical physiology to address distributed brain circuits in individual subjects. We first present the "Crystal Skull", a curved glass replacement to the dorsal mouse cranium yielding an estimated > 1 million neurons (albeit not concurrently) over > 30 neocortical areas. Next, we introduce the "multi-axis" approach for optically accessing multiple brain regions---deep or superficial---by way of a dual-axis two-photon microscope. With this apparatus, we performed, for the first time, chronic studies of the corticocerebellar pathway at single-cell resolution as mice learned a forelimb movement planning task. Concurrent optogenetic manipulation demonstrated the necessity of specific anatomical pathways for the observed corticocerebellar dynamics. This study highlights the potency of the multi-axis approach for discovering new insights for how distributed brain networks communicate and interact. From the initial dual area experiments, we identify the key optomechanical principles necessary to extend our approach to four or more regions in a single subject. Namely, scaling of the multi-axis concept requires: (1) an efficient use of the space above the animal's head by optimizing the surgical placement of optical ports (e.g. microendoscopes) on the animal itself; (2) miniaturization of each optical instrument using elements such as millimeter-scale gradient index lenses and specialized micro-prisms; and, (3) enhanced instrument maneuverability, attained by incorporating concepts such as remote center of motion from the field of surgical robotics. We design and implement a novel two-photon microscope based on these principles, which will enable the optical investigation of 4--8 brain areas simultaneously from behaving mice.
Investigating molybdenum disulfide as a protective catalyst for solar-water splitting devices
Keywords: Chemical Engineering.

Generating hydrogen by using solar energy to split water molecules is an appealing idea due to the renewable and sustainable nature of the inputs: sunlight and water. This idea can be achieved with photoelectrochemical hydrogen evolution in which a photoactive semiconductor is paired with an electrocatalyst. The field of unassisted, solar-driven water-splitting for hydrogen production has made remarkable progress in the past few decades. Solar to hydrogen (STH) efficiencies have increased from low single digits in the 1970s to 19% in 2018 -- rivaling the typical efficiencies of "off the shelf" solar cells. While efficiencies have become competitive, durabilities have not. The average commercial solar panel comes with a 25 year "lifetime guarantee", but the longest an unassisted water-splitting device of any efficiency has lasted to date is only 100 hours. This stability gap has remained largely unchanged these past few decades primarily due to the complex challenge of preventing semiconductor corrosion in aqueous environments. In this dissertation, we explore whether Molybdenum Disulfide nanomaterials can serve as protection layers and catalysts for solar water-splitting devices. We found that a very thin, conformal coating of MoS2 can improve the stability of GaInP2 by over 500 times as measured by light-limited current density. Furthermore, we found that our MoS2 protection layers were excellent catalysts for hydrogen evolution, rivaling a state-of-the-art Pt-based catalyst, and our MoS2 protected device was among the most active and stable single-absorber photocathodes to date. We further probed the interfacial energetics with transient photon reflectance and revealed that a conformal MoS2 catalyst interface imparts improved electron transfer in addition to catalytic activity compared to a nonconformal PtRu catalyst. This insight into the semiconductor-catalyst interface is potentially relevant to catalytically protected photoectrodes across the field. We also found that our Molybdenum Disulfide nanomaterials can be used to stabilize high-efficiency GaAs/GaInAsP tandem water-splitting devices and demonstrated the first-ever unassisted water splitting device that uses Molybdenum Disulfide protective catalysts. We compared these devices to the best unassisted water-splitting devices to date and revealed a two orders of magnitude "stability gap" between where the field currently is and where the field needs to be for feasible commercialization. This dissertation explores the field of photoelectrochemical water-splitting at multiple levels. We dive into the stability challenges facing the field and present detailed and novel strategies for overcoming them. We also put our results into a greater context, revealing important field-wide trends, and discussing the challenges that must be solved to enable this sustainable technology to change how we produce and consume energy.
Investigating neural stem cell function in an Alzheimer's disease model
Keywords: Stem Cell Biology and Regenerative Medicine.

Alzheimer's disease is a progressive neurodegenerative disease characterized by dementia and amyloid plaques. In a mouse model of Alzheimer's disease harboring mutant amyloid precursor protein, we show elevated expression of Cdkn2a, a gene linked to brain aging, apoptosis, and neural precursor cell long-term proliferation defects. Genetic reduction of USP16, a critical up-regulator of Cdkn2a, led to decreased astrogliosis and neuronal apoptosis, reduced neural precursor cell proliferation defects, and improved memory. In combination with agents targeting classical Alzheimer's disease pathologies, we identify USP16 as a potential therapeutic target that may help to ameliorate the cognitive deficits in some cases of Alzheimer's disease.
Investigating Pain Modulation by the Descending Pathway from the Locus Coeruleus To the Spinal Cord
Keywords:  Department of Biology
Biology
neurobiology
nociception
locus coeruleus
central nervous system
DREADD
cTRIO
Thesis

Pain sensation, also known as nociception, involves a complex system of neural connections that balance inhibition and excitation. Although the mechanisms that determine the level of nociception at the peripheral nervous system have been extensively studied, similar pathways in the central nervous system are not as well defined. Moreover, our understanding of how sustained inflammation, often found in chronic pain diseases, affects these pathways is not complete. Descending control circuits from the brainstem to the spinal cord are strong candidates for the modulation of nociception. The locus coeruleus (LC) is a nucleus in the pons of the brain stem that broadly innervates cortical areas involved in arousal, cognition, and memory. The LC descends down to the spinal cord and has been suggested to play an important role in modulating pain transmission in the spinal cord. In this study, we explored the possible influence of the noradrenergic descending projections from the LC to the dorsal horn on pain sensation. Combining a novel retrograde tracing strategy with Dbh-Cre mice, we achieved specific targeting of the spinal cord projecting neurons in the LC (LC→SC). This approach enabled us to use targeted chemogenetic manipulation to activate the LC→SC neurons and test the effect of this descending pathway on pain sensation. Our preliminary results indicated that activation of the LC→SC neurons decreased pain sensitivity, revealing an inhibitory role in nociception. We also found that LC inhibition of pain decreases in intensity in the presence of chronic inflammation, suggesting a possible connection between LC activity and chronic pain. Moreover, we employed a novel retrograde tracing method, named cTRIO, to identify brain wide monosynaptic inputs onto the LC→SC neurons. Together, results of this study advanced our understanding of the role of the locus coeruleus in nociception and may provide insights for developing novel pain treating strategies that do not have the addictive characteristics of currently used opiates.
Investigating Patient Quality of Life in San Francisco Homeless Health Facilities
Keywords:  Department of Civil and Environmental Engineering
healthcare
healthcare design
healthcare architecture
homeless
unhoused
design
architecture
staff
patient
health
human rights
Civil and Environmental Engineering
Architectural Design Program
Thesis

The Centers for Disease Control and Prevention, along with the American Psychological Association, emphasize that homelessness is a public health concern (CDC, 2017; Donovan & Shinseki, 2013). Concurrently, the U.S. Department of Housing and Urban Development (HUD) listed in its most recent report to Congress that San Francisco County has one of the highest rates of unhoused individuals in the nation, with roughly 6,211 people experiencing homelessness in 2018. HUD also estimates that roughly 65% of the unhoused population in the U.S. resides in physical shelters (Henry et al., 2018), many of which offer access to health services. Healthcare design research points to a number of factors that can influence patient wellbeing, one of which may be the size, in square feet, of healthcare facilities (Stichler, 2008). This qualitative thesis aims to summarize what staff members at facilities providing healthcare services to unhoused individuals in San Francisco County understand to be the salient healthcare needs of their clients, as well as to examine relationships between perceived quality of life of patients and characteristics of facilities. This research specifically seeks to assess whether the size of the facility as reflected in the square footage is associated with better or worse perceived quality of life, as reported by facility staff. Access to care was a central theme highlighted by facility staff, notably including addiction and psychological services; however, several aspects of the design of facilities were regarded as having the potential to be improved, with the availability of space particularly noted by staff at the smaller facility. The research findings emphasize that healthcare designs should aim to be both healing and efficient in order to enable patients to rapidly achieve their medical and social objectives.
Investigating Patient Quality of Life in San Francisco Homeless Health Facilities: An Architectural Exploration
Keywords: Architectural design
Homeless persons
Public health
Text
Report
Thesis

For her capstone project, Janet Coleman-Belin designed a healthcare facility that would provide critical resources to individuals experiencing homelessness in the Bay Area. Drawing upon her skills in Engineering and Architectural Design, Janet developed architectural plans, sections, and elevations; utilized a 3D computerized model in Revit (an industry standard building modeling program); and created a narrative explaining the spatial design decisions. Janet also consulted health design literature and first-hand accounts from various clinic staff as a way of fully creating a holistic architectural design. Her goal with this project is to envision a multi-level and multi-use community resource equipped with essential health, educational, and social resources dedicated to assisting homeless populations.
Investigating single-molecule interactions and photodynamics in solution by counteracting Brownian motion
Keywords: Chemistry.

Single-molecule fluorescence methods have become a mature and powerful tool to unravel the fundamental mechanisms of biological phenomena. These approaches enable researchers to investigate individual components on the nanoscale for heterogeneous mixtures and to monitor the dynamics of single biomolecules. Unfortunately, traditional burst-based methods are often limited by short observation time, and the immobilization of single biomolecules that enables long observation time is often undesirably perturbative. To address these limitations, a solution-based technique known as the Anti-Brownian ELectrokinetic (ABEL) trap has been developed. In the ABEL trap, high-speed feedback electronics sense position and compensate Brownian motion of a single molecule by applying electrokinetic forces, which keep the molecule in the trapping region for an extended period of time. This dissertation describes my work on the investigation of single-molecule interactions and photodynamics using the ABEL trap technology. First, I show how to measure and monitor single-molecule rotational diffusivity by combining the ABEL trap and maximum likelihood analysis of time-resolved fluorescence anisotropy based on the information inherent in each detected photon. The rotational diffusivity is extremely sensitive to the size of the molecule, and thus can be used to detect and monitor size-changing events, such as association and dissociation. We demonstrate this approach by resolving a mixture of single- and double-stranded fluorescently-labeled DNA molecules at equilibrium, freely rotating in a native solution environment. Next, we investigate photosynthetic photoprotection mechanisms at the level of individual antenna complexes (LHCII), the fundamental units which green plants use to harvest sunlight. We access the intrinsic conformational dynamics of individual LHCII complexes. In addition to an unquenched state, two partially quenched states of LHCII are observed. One of the quenched conformations significantly increases in relative population under environmental conditions mimicking high light. Our results suggest that there are at least two distinct quenching sites with different molecular compositions, meaning multiple dissipative pathways in the LHCII complex. Last, we describe the theoretical basis of a new method to measure the diffusion coefficient of diffusing objects on the surface of individual nanoscale lipid vesicles. We discuss how to probe diffusion in these highly confined environments using FRET pairs and fluorescence intensity correlation, and illustrate that this method is essentially a fluorescence correlation spectroscopy (FCS) experiment with a nanometer-sized probing volume.
Investigating the molecular effects of the 16P11.2 copy number variant using an induced pluripotent stem cell model
Keywords: Genetics.

The 16p11.2 copy number variant (CNV) locus is known to increase the risks of autism spectrum disorders (ASD), schizophrenia, and many other developmental problems in humans. However, it not understood as to how the CNVs at this locus, which occur as a heterozygous deletion or duplication of ~600 kbp in size, contribute to the development of these disorders. Previous studies have generated possible gene targets and pathways of interest for further investigation but due to the early onset nature of the phenotypes of the 16p11.2 CNVs, the studies were done using cell types that are not directly applicable (e.g. LCLs) or animal model systems. Here, we investigate the changes to gene expression and DNA methylation using a 16p11.2 CNV patient-derived induced pluripotent stem cell (iPSC) to induced neuron (iN) cell model system. This revealed global alterations to both gene expression and to DNA methylation patterns which further yielded new leads of genes potentially contributing to known patient phenotypes. Specifically, PCSK9 is identified as a possible contributing factor in the development of facial abnormalities in patients, along with also being involved with the reciprocal head circumference and body mass index (BMI) phenotypes seen in the deletion and duplication patients. Additionally, the protocadherin (PCDH) gene family is seen to have significantly altered methylation patterns in the CNV patient samples which could implicate these genes in the etiology of neuropsychiatric disorders.
Investigating the Spreading of Gene Silencing and Reactivation through the Chicken HS4 Insulator
Keywords:  Department of Bioengineering
chromatin
insulators
spreading
epigenetics
HS4
Department of Bioengineering
Thesis

Chromatin modifications help control gene expression in mammalian cells and spread through positive feedback mechanisms. This spreading can help coordinate gene expression programs, but can also lead to accidental silencing of transgenes. Insulators are genetic elements that can protect transgenes from background silencing. It is hypothesized that they act as barriers against heterochromatin spreading. However, the spreading of heterochromatin-induced gene silencing across insulators has not been directly tested. By engineering Chinese Hamster Ovary (CHO) cells with site-specifically integrated dual reporters, we developed a method to measure the spreading of gene silencing and reactivation across insulators. Each of the dual reporters contains two genes expressing fluorescent proteins separated by different insulator geometries containing the most widely used eukaryotic insulator, HS4, and its core region. Using a doxycycline-inducible system, chromatin regulators associated with histone methylation (KRAB, EED) and DNA methylation (DNMT3B) were recruited for five days at varying strengths to the upstream gene to induce gene silencing. The cells were monitored for their silencing and reactivation dynamics using flow cytometry. Surprisingly, neither the HS4 insulator nor its core region prevented spreading of silencing from the upstream target gene to the downstream gene. However, the presence of insulators hindered the ability to silence both genes when compared to spacer DNA. Moreover, after the end of EED and KRAB recruitment, the reactivation rates of both genes were 2-3x higher when the upstream gene was flanked by core insulators. This element also led to reactivation of both genes after DNMT3B silencing, despite previous reports that DNA methylation leads to permanent epigenetic memory. Therefore, rather than acting as a barrier to spreading, the HS4 insulator activates the entire gene locus.