VictorJuiz/thesis huggingface dataset:
Stress characterization in isostatic granular materials [electronic resource]
Keywords: Energy Resources Engineering.

Stress propagation in granular media is an interesting and relatively open research problem. Compared to liquids or elastic solids, stress patterns in granular media show unusual features. For example, the nonuniform stress fields that have been observed in many experimental and numerical studies of granular systems cannot be readily explained with conventional models. The primary challenge in understanding of the nonuniform stress patterns in granular systems lies in the development of a continuum stress model. Central to the development of such a model is the derivation of a constitutive equation that would close the system of balance equations. Isostatic granular systems play a key role in the understanding of nonuniform stress fields. Modeling of stress fields at the macroscopic level for isostatic granular systems requires introduction of stress-structure constitutive relations instead of conventional stress-strain relations. In particular, we focus on the constitutive relation proposed by Ball and Blumenfeld for two-dimensional granular systems, which couples the local geometry and the continuum stress tensor at the grain level. The resulting continuum model cannot be readily applied macroscopically since geometric averaging, such as area averaging, for coarse-graining the parameters of the constitutive equation, also known as the fabric tensor, leads to a zero fabric tensor. To address the issue Blumenfeld suggests to upscale on a specific subset of the grains in the domain. Our analytical evaluations, as well as numerical experiments, show that the suggested upscaling approach can be applied to a specific family of granular materials. To evaluate the accuracy of the proposed continuum model we compare the stress behavior, as predicted by the continuum model, with discrete force solutions. We argue that solving for the discrete forces under isostatic conditions is different from the common practice used in Discrete Element Modeling, in the sense that isostatic structures must remain intact during the process. Despite the conventional assumption in the field, we demonstrate that an arbitrary structure of dry cohensionless grains with proper average number of contacts per grain may not comprise a physical isostatic system. Consequently, we present an algorithm to check if there exists a boundary load under which a given structure can remain static. We also develop an algorithm for computation of intergranular forces of an isostatic system under an under-determined boundary load, which resembles the boundary load of the continuum simulation. We observe minor discrepancies between the discrete force solution, assumed to reflect the actual physical processes, and the predictions of the continuum model. Utilizing the discrete force solution, we propose an alternative model-fitting based technique for estimation of the fabric tensor, which enables us to obtain a non-zero fabric tensor for the constitutive equation at the macroscopic level.
Structural Changes in the Primary Visual Cortex of Alzheimer's Disease Model Mice As A Correlate to Diminished Plasticity
Keywords:  Department of Biology
Alzheimer's
APP/PS1
Neurodevelopment
Neurobiology
Stanford University
Department of Biology
Thesis

Amyloid-β (Aβ) accumulation has been implicated in Alzheimer’s disease pathogenesis. Mice with transgenic expression of mutant amyloid precursor protein (APP) and presenilin-1 (PS1) accumulate Aβ and have therefore been used as models of the disease. Previous research has shown that critical period ocular dominance (OD) plasticity is defective in these mice, which indicate an early effect of Alzheimer’s on neural plasticity, even before the typical Aβ plaques accumulate. In an attempt to determine the mechanism responsible for this defect, I investigated layer 5 apical dendritic spine density and morphology in the primary visual cortex of juvenile (P30) and adult (P74) APP/PS1 mice. We found that wildtype and APP/PS1 transgenic juvenile and adult mice both displayed comparable spine densities and initially concluded that the critical period ocular dominance plasticity defect observed in APP/PS1 transgenic mice is not associated with a decrease in spine density in layer 5 apical dendrites. However, recent discoveries within the lab have led us to believe that the APP/PS1;YFP-H+ mouse line used in these experiments may have epigenetic or other modifications that would inhibit transcription of YFP and/or APP/PS1. Further experiments should be conducted to verify the presence of Aβ accumulation in this mouse line before continuing research.
Structural determinants of Smoothened regulation in the Hedgehog pathway
Keywords:  Department of Biology
Biology
Hedgehog
Smoothened
Thesis

The seven-transmembrane oncoprotein Smoothened (Smo) is a key activator in the Hedgehog (Hh) signaling pathway, and thus a driver of many processes in tissue patterning and postembryonic stem cell regulation. In normal pathway activity, Smo is repressed by the tumor suppressor protein Patched (Ptch), and this repression is relieved when the Hh morphogen binds to and inactivates Ptch. However, the mechanism of Ptch action on Smo is poorly understood. In this study, the approaches of cyclopamine pocket mutagenesis and functional phylogenetic comparisons of five Smo orthologs (urchin, tunicate, lamprey, skate, and coelacanth) were used to identify key determinants of the regulatory interaction between Ptch and Smo. Mouse-lamprey Smo chimeras provided evidence for a role of the cysteine-rich domain in restraining signaling activity, and suggested a two-site model of Ptch regulation. To address the difficulty of measuring pathway activity of basal orthologs in vertebrate cells, a new FRET assay was developed that provides a more direct readout of Smo activity state. This assay, based on Smo coupling to a G protein alpha subunit, has broad applications in the Hedgehog field. The regulatory mechanism of Smo is an open question in developmental and oncogenic signaling, and a better understanding of the Ptch-Smo interaction will lay the groundwork for more effective cancer therapies.
Structure, mechanism, and electronic properties of organic molecular n-dopants and n-doped materials [electronic resource]
Keywords: Chemistry.

The low ionization potentials of highly reducing organic n-dopants and host radical anions makes n-doping a much greater challenge than p-doping. However, many modern electronics such as transistors, complementary circuits, light-emitting diodes, photovoltaics, and thermoelectrics either require or benefit from both n- and p-type conduction. It is a long-standing and partially realized goal of the organic electronics community to mass produce devices by exploiting modern printing processes. To accomplish this will require new materials, device architectures, and processing methods. The goal of this thesis was to advance the state of solution-processable conductive n-type organic materials for use in printed organic solar cells, transistors, and thermoelectric devices. In this thesis, a bottom-up mechanistic approach was used to design new organic n-dopants and n-dopable host semiconductors. First, the n-doping mechanism of 1,3-dimethylbenzimidazole (DMBI) derived dopants was studied in solution, and it was discovered that DMBI dopants react with fullerenes by hydride transfer. Following this study, a new class of dimeric dopants ((DMBI)2) were developed to eliminate the dependence of the doping reaction on the hydrogenation thermodynamics of the host. The (DMBI)2 dopants were employed in a thorough synthetic, spectroscopic, and electrical study of new n-dopable conjugated polymers. Ultimately, several polymers with higher conductivities when n-doped than current state-of-the-art materials were identified. The results of this study indicate that the polaron delocalization length is the most relevant parameter to optimize to achieve high conductivity n-doped polymer films. Building upon this work, a class of self-n-doped polymers with remarkable stability in air were developed. Finally, as a demonstration of the utility of the new materials reported in this thesis, fully solution-processed logic gates and organic solar cells with n-doped layers were fabricated.
Structured estimation in healthcare and quantized matrix recovery [electronic resource]
Keywords: Electrical Engineering.

We find ourselves in the era of modern data, where new collection technologies provide us with vast amounts of data at an unprecedented speed. While this data provides us with ample opportunities for advancing research efforts in a variety of areas, we must understand how we can use it to achieve our objectives. Structured estimation gives researchers the tools to take advantage of this data, to help overcome the challenges associated with it, and help shape it to be more suitable for our application needs. As a result, we are able to use this data to, for example, enhance patient outcomes, provide recommendations to users of online music or movie streaming services, and predict reliability and identify power tampering of electricity meters. In the first part of this thesis, we use structured estimation to help us design a model for assessing a patients' risk for multiple diseases. While combining models used for individual disease prediction presents one solution, this approach can be improved upon in complexity as well as accuracy. We use methods from machine learning and dimensionality reduction to allow us to select a small set of biomarkers which are accurate predictors of multiple diseases. We validate our methods on real patient data. In the second part of this thesis, we investigate the problem of recovering a matrix from a subset of its entries. We focus on low rank matrices whose entries are from a finite set, especially those whose observations result from quantization of a noisy real-valued matrix. We present a performance guarantee for our approach, which is formulated as a rank-constrained maximum likelihood parameter estimation problem. We develop an algorithm for this approach, based on matrix factorization techniques, for which we provide convergence guarantees. Our proposed method provides a solution to many practical problems, such as collaborative filtering, network localization, and image denoising.
Structure-function studies of drosophila Mip120 [electronic resource]
Keywords: Genetics.

The Drosophila dMyb-MuvB (MMB)/Drosophila RBF, dE2F2, and dMyb- interacting proteins (dREAM) is a multi-protein transcriptional regulator that regulates many biological processes including the cell cycle, development, and differentiation. MMB/dREAM contains multiple members that have DNA binding domains: dMyb, dE2F2-dDP, and Mip120. It is currently unclear which of these members can localize the rest of the complex to DNA. My studies focused on Mip120/LIN54. We wanted to determine which domains of Mip120 were necessary for its function, because previous studies of dMyb unexpectedly showed that the highly conserved dMyb DNA binding domain was not necessary to rescue Myb null lethality. In addition, we also wanted to determine which domains of Mip120 were sufficient for nuclear localization in different Drosophila cell types, including the egg chambers, wing discs, salivary glands, and eye discs. mip120 null females were sterile, had an ovary development phenotype, and did not lay eggs. Using the ovary development phenotype and egg laying defect as an assay for mip120 gene function, we conducted rescue experiments to determine which domains of Mip120 were necessary for its function. We found that multiple domains of Mip120, including the N-terminus, which contains two putative nuclear localization signals, and the C-terminus, which contains a highly conserved cysteine rich DNA binding domain (CXC) and a helix-coil-helix protein interaction domain (HCH) were necessary for mip120 function. From the nuclear localization experiments, we found that all of the Mip120 fragments were sufficient for nuclear localization. We found a previously unreported mip120 null phenotype. mip120 null nurse cell chromosomes were very condensed and had blobbier DNA than controls. The phenotype occurred very early in egg chamber development because even egg chambers as early as stage 2-4 chambers appeared blobbier in mip120 null mutants than controls. We attempted to determine the mechanism of mip120 null mutants. We found that global expression of many common epigenetic marks including H3K9me2/3, HP1, H3S10P, H3K4me3, and H4Ac remained similar in mip120 null mutants compared to controls. In mip120 null mutants, we also assayed which dREAM complex members still localized to DNA. Mip40 and dMyb no longer localized to DNA without Mip120, suggesting that Mip120 is necessary for dMyb and Mip40 nuclear and DNA localization. dE2F2 and p55 Caf1 still localized to DNA without Mip120, suggesting that dE2F2 and p55 Caf1 can localize to DNA independently of Mip120. Unexpectedly, Mip130 was also still able to localize to DNA without Mip120. Though Mip130 does not have a traditional DNA binding domain, it does have an AT hook, which may be able to localize Mip130 to the complex.
Structure-guided engineering of CD47 and stem cell factor for immunotherapeutic applications [electronic resource]
Keywords: Bioengineering.

Protein biologics have revolutionized the clinical landscape in recent decades. In particular, abundant attention and momentum has been generated in the immunotherapy space, which directs one's immune system to combat diseases. Protein immunotherapeutics are currently evolving at a rapid pace as a result of growing efforts into applying protein-engineering strategies to improve their therapeutic index. In this dissertation, two independent immunoregulatory ligands, CD47 and stem cell factor (SCF), were engineered using structure-guided approaches for immunotherapeutic applications. CD47/SIRPα (Signal regulatory protein α) immunoregulatory pathway is a key inhibitor of macrophage effector function (i.e. phagocytosis) in homeostatic cell clearance and in immune evasion by cancer cells. Due to ubiquitous CD47 expression, current CD47-targeted cancer therapies are handicapped by large antigen sinks in vivo that could reduce bioavailability and increase the risk of toxicity. We engineered a high-affinity variant of human CD47 (Velcro-CD47) as a competitive antagonist of SIRPα, which has restricted tissue expression compared to CD47. To do so, we developed a novel approach that we termed 'Velcro' engineering, which enhances protein-protein interaction by a 'molecular velcro'. Specifically targeting a subset of myeloid cells in human blood ex vivo, Velcro-CD47 enhances tumor-specific antibody mediated antibody-dependent cellular phagocytosis (ADCP) of tumor cells in vitro, demonstrating its potential therapeutic use as an adjuvant to antibody therapy for cancer. On the other hand, SCF is a homodimeric growth factor that dimerizes c-Kit receptors to elicit therapeutic expansion of hematopoietic progenitors, but is toxic in vivo because it concurrently activates mast cells. We modified the SCF ligand in order to 'cripple' c-Kit dimerization efficiency and truncate downstream signaling as a strategy to decouple SCF efficacy and toxicity. We engineered a high-affinity monomeric SCF variant that behaves as a partial agonist of c-Kit and shows selectivity for hematopoietic progenitors over mast cells in vitro. Tests in pre-clinical mouse models of SCF-mediated anaphylaxis, radioprotection, and cancer therapy revealed that our SCF variant exhibits therapeutic efficacy in vivo with virtually no anaphylactic effects, thus unlocking SCF's clinical potential. This approach has broad applications in dimeric receptor-ligand systems. Collectively, the work presented in this dissertation has generated two potential immunotherapeutic leads that encourage further preclinical and clinical investigations. In addition, it has expanded the repertoire of protein-engineering strategies to create novel protein biologics with potentially improved therapeutic value.
Studies of skeletal muscle satellite cell death and renewal [electronic resource]
Keywords: Developmental Biology.

Skeletal muscle is an abundant tissue, accounting for 42% of the body mass of the average adult male human, and is required to generate the force necessary for movement and posture. The regeneration of skeletal muscle tissue in mammals is accomplished by a rare population of muscle-resident adult stem cells known as satellite cells. These satellite cells primarily reside in a dormant state and are prompted to carry-out their regenerative function by an injury to the neighboring muscle tissue. Atrophy and impaired regeneration of skeletal muscle are significant comorbidities of aging and chronic illness. This dissertation describes and interprets studies of skeletal muscle stem cell biology with particular attention paid to molecular mechanisms that influence stem cell-fate during regeneration in healthy and diseased contexts. The hypothesis that changes in stem cell regenerative potential underlie the poor tissue repair observed in aged animals is explored through comparisons of young and old cells. These studies identify a unique mitotic cell death phenomenon that occurs specifically within old cells as a consequence of age-associated changes in the satellite cell environment. In additional analyses, broad characterizations of gene expression in human satellite cells are leveraged to develop pharmacologic methods for controlling cell-fate to enhance the regenerative potential of purified cells. These analyses also provide insight into human-specific mechanisms of satellite cell-mediated myogenesis. The final series of studies uses satellite cells as a model system to examine cell-fate determination during stem cell divisions that give rise to daughter cells with divergent fates. These so-called asymmetric cell divisions are characterized specifically in terms of the unique patterns of chromosome segregation observed to coincide with regulation of muscle stem cell fate.
Studies toward improved RNA detection and isolation [electronic resource]
Keywords: Chemistry.

As our understanding of molecular biology continues to develop, both general improvements and specialized tools are needed for the progression of RNA detection and analysis. This thesis describes three distinct projects within the broad goal of expanding the techniques available for better interrogation of RNA. Chapter II illustrates the development of a new technique for microRNA detection. MicroRNAs are a class of small regulatory RNAs present in eukaryotes. MicroRNAs pose a challenge for detection because of their small size and sequence homology, but have drawn increasing interest due the predicted prevalence of their gene targets and links between their expression levels and cancer. The development of an isothermal detection strategy is described which incorporates two nucleic acid templated steps, two amplification steps, and fluorescent detection. Up to 3000-fold amplification can be obtained, and 200 pM quantities of let-7a microRNA and above can be detected reliably. In Chapter III, two distinct approaches are taken for the detection of N(6)-methyladenosine, the most common modification in RNA: harnessing base-pairing selectivity, and developing selective reactions. A successful method was developed that harnessed the inherently higher efficiency of a commercially-available polymerase, Tth DNA polymerase, when pairing T with adenosine as opposed to N(6)-methyladenosine. Kinetic analysis showed that the selectivity of the enzyme ranged from 4-18-fold, depending on sequence context. Detection of m6A in ribosomal RNA and in a highly-expressed messenger RNA are demonstrated. The final chapter focuses on a mechanistic approach for enhancing RNA recovery after formaldehyde treatment using an organocatalyst. Mass spectrometry and gel electrophoresis showed an enhanced rate of adduct reversal in the presence of the catalyst, and effects of temperature, buffer, and pH were also analyzed. The results from monomeric and oligomeric test systems have subsequently been applied to recovery of RNA from fixed samples, showing ~2-fold enhancement in recovered RNA due to the catalyst and up to 25-fold enhancement when the catalyst was used in conjunction with optimized time and temperature.
A study of input and output field quantification in heavy civil construction [electronic resource]
Keywords: Civil and Environmental Engineering.

When I began writing this thesis, it was two years after I had completed my time as a Laborer. Many of my ideas formed during my time as a field engineer at the Granite Heavy Construction Division when I was only a year out of the Laborers. The early drafts of this thesis read like it was written by someone that had never written more than three pages at any one time -- and nobody had ever read those three pages and provided feedback. After numerous revisions, while I may have improved the writing style I began to realize that the improvement is at the cost of losing the core knowledge the thesis contains. So, for the most part, this thesis contains an understanding of construction from the mind of a laborer. In this thesis, I convey the methods of measuring the status of a construction project. In the case of this thesis, I focus on the vertically integrated project style typical of heavy construction projects though the methods I present are general to other construction types such as buildings. The basic block of construction is the activity. The difference between two activity status points is equal to the project progress. The progress is a fundamental metric of success that is as old as the construction profession. Without knowing the progress of activities, it is not possible to predict the expected sequence and duration of future activities. This means it is not possible to assemble the activity aspects of workspace, labor, material, and equipment to converge at the right time and place to achieve a safe activity that has a low risk of neither damaging the environment nor impacting the surrounding community. The methodology I used as to study the methods of measuring status is a mixed approach. At the core, I used an ethnography to form my understanding from a first person perspective. I then compared my firsthand knowledge with publications to fill the gaps in my knowledge. The limitation is the small observation sample characteristic of the ethnography. I had remaining observations that I had not found in the published knowledge. To resolve these I used a questionnaire survey and interviews of experts to understand the relation of these outliers. I found that activity progress status is formed by two components -- these are the status and the context of the activity. The two are inseparable. Within those two topics, I found numerous approaches of estimating and measuring status and context. Further, I found sources of errors in the status and context measurements. The significance of my findings is rooted in first the lack of an existing unified source of this knowledge and second I provide a complete knowledge within the domain of heavy construction, particularly for the vertically integrated project organization.