VictorJuiz/thesis huggingface dataset:
Discovery and synthesis of novel chloride transport protein inhibitors [electronic resource]

CLC chloride channels and transporters play diverse physiological roles in processes ranging from regulating bone-density, muscle excitability, and blood pressure, to facilitating extreme-acid survival of pathogenic bacteria. Defects in CLC proteins cause human disorders in these processes. Small-molecule inhibitors of the CLCs would be useful as drugs for treating a variety of CLC-related human diseases and also to investigate CLC physiology. In addition, inhibitors are powerful tools for studying molecular mechanisms of Cl-- gating. Trapping channels or transporters in particular conformational states with high-affinity ligands could potentially advance our understanding of the structural basis for CLC activity. Despite their usefulness, specific small-molecule inhibitors for CLC proteins are scarce. To address this shortfall, we have exploited the 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) scaffold to develop two novel classes of CLC inhibitors. DIDS has been used as an anion-transport inhibitor for decades and was first used to inhibit CLCs over 30 years ago. However, experiments to determine the compound's mode of inhibition led us to discover that minor contaminants in the DIDS solutions inhibit CLC proteins more effectively than DIDS itself. The contaminants were found to derive from hydrolysis of the labile isothiocyanate moieties. The structures of five major hydrolysis products were determined by 1H NMR, HRMS analysis, and chemical synthesis to be DIDS-based polythioureas. These compounds bind directly to the CLC proteins, as evidenced by the fact that they inhibit purified, reconstituted ClC-ec1 and that inhibition of ClC-Ka can be prevented by the point mutation N68D. These polythioureas are the highest affinity inhibitors known for the CLCs and provide a new class of chemical probes for dissecting the molecular mechanisms of chloride transport. The second class of identified CLC inhibitors combines the DIDS core structure with alkyl chain carboxylic acids. The most potent inhibitor identified, 4,4'-octanamidostilbene-2,2'-disulfonic acid (OADS), inhibits ClC-ec1 with an apparent affinity of 29 [Mu]M. As a means to identify the inhibitor-binding site, we synthesized photo-reactive diazirine derivatives of OADS and showed that these photo-affinity reagents specifically inhibit ClC-ec1. Experiments to identify the binding site using 'top-down' mass spectrometry, in which the protein is cleaved into peptide fragments via electron-capture dissociation, have identified an intracellular binding region encompassing 76 amino acids, or 16% of the protein. Current efforts using protease digestion procedures are focused on further refinement of the binding region. Once located, protein/inhibitor interactions gleaned from the labeling of ClC-ec1 could allow us to rationally design more potent inhibitors of CLC transporters and channels.

Keywords: Chemistry
Advisor: Du Bois Justin primary advisor. Thesis advisor
Khosla Chaitan
Wender Paul A. advisor. Thesis advisor
Discovery of the two-neutrino double-beta decay of xenon-136 with EXO-200 [electronic resource]

Recent neutrino oscillation measurements provide definitive evidence for non-zero neutrino masses. Oscillation measurements, however, only measure mass differences, not the absolute mass scale. Neutrinoless double-beta decay, a hypothetical nuclear transition, can probe the absolute neutrino mass scale. This process, if observed, would also imply that neutrinos are their own anti-particles and that lepton number is not a conserved quantity. The 200 kg Enriched Xenon Observatory (EXO-200) detector is currently taking data to search for the neutrinoless double-beta decay of Xe-136, with an expected half-life in excess of 10^25 years. Located at the Waste Isolation Pilot Plant (WIPP) near Carlsbad, New Mexico, the detector is filled with 200 kg of isotopically enriched liquid xenon. The analysis presented here describes the recent observation with EXO-200 of the two-neutrino double beta-decay of Xe-136. This is the rarest process ever directly observed with a half-life of 2.11+-0.21 x 10^21 years and provides important input to the measurement of the neutrinoless decay.

Keywords: Physics
Advisor: Gratta Giorgio primary advisor. Thesis advisor
Cabrera Blas advisor. Thesis advisor
Peskin Michael Edward
Disorder, defects, and their effect on charge transport in organic semiconductors [electronic resource]

Understanding the nature of charge transport and its limitations on device performance has guided the rational design of organic semiconductors for over a decade. This understanding has led to the development of high performance small molecule and polymeric semiconductors for applications in low-cost complementary logic circuits, displays, lighting, and solar cells. Unfortunately, the large catalog of available materials and processing variables make it difficult to outline general design rules. Specifically, in polycrystalline and semicrystalline organic semiconductors, little is understood about the structural order within a grain and between grains, and even less is known about how this structure affects the material's performance. In this thesis, characterization methods are introduced to address these issues. To understand the structural source of electronic defects, a multi-step Fourier transform X-ray line shape analysis with thorough error analysis is adapted to determine crystallite size and intra-grain cumulative disorder. For the first time, the intra-crystalline disorder in transport-relevant directions is quantitatively determined for a variety of high performing organic semiconductors. These van der Waals bonded crystallites exhibit a wide range of disorder (from < 1% to 10% fluctuations from the mean lattice spacing) depending on the packing geometry and chemistry. The degree of lattice disorder is found to be a useful tool for ranking materials quantitatively on a continuous scale, from perfectly ordered to completely disordered. High levels of lattice disorder, evident in many polymeric semiconductors are found to introduce a tail of localized trap states that limit charge transport. At the low-disorder end of the scale, transport-limiting disorder is not significant and grain boundaries are found to limit charge transport. Finally, we suggest that, from the charge transport perspective, the transition from small molecule/oligomer- to polymer-like behavior may be demarcated by the onset of strong, transport-limiting lattice disorder. Thus, understanding the effect of disorder on transport promises to further aid in determining the structural origins of charge trapping, guiding future materials design.

Keywords: Materials Science and Engineering
Advisor: Salleo Alberto
McGehee Michael
Toney Michael Folsom advisor. Thesis advisor
Dissecting the cellular and molecular mechanisms underpinning two aspects of photoreceptor morphology [electronic resource]

Neurons are morphologically diverse, with many anatomical specializations that are crucial for their functions. Photoreceptors represent a specialized class of neurons whose elaborated apical structures, the rhabdomeres, and specific axonal projections collect visual stimuli and transmit them to the appropriate synaptic partners, forming the basis for vision. Through genetic analyses in the Drosophila visual system, we have studied the molecular mechanisms that control these two aspects of photoreceptor morphology. A forward genetic screen identified the GTPase effector Genghis khan (Gek) as mediating the ability of a subset of photoreceptor neurons to target to their appropriate postsynaptic columns. Gek was not required for the layer targeting of a different subset of photoreceptors; however ectopic expression in these cells was sufficient to affect their targeting choices. Regulation of Gek's responses to targeting cues may underlie differences in target choices among photoreceptors. The specification of photoreceptor apical structures depends on genes of the apical -- basal polarity family. Mutants in the genes Crumbs (Crb) and Stardust (Sdt) are required for rhabdomere development in distinct but overlapping subsets of photoreceptors. In addition, both genes are required in all cell types for the formation of the adherens junctions contacts between cells, suggesting that Crb and Sdt have both overlapping and unique functions in photoreceptor morphogenesis. Thus, these experiments provide insight into how two aspects of photoreceptor morphology are determined, and suggest mechanisms by which cell type specific morphologies may be produced.

Advisor: Clandinin Thomas R. (Thomas Robert)
Fuller Margaret
Luo Liqun
Shen Kang
Dissecting the interactions between Francisella tularensis and its murine host [electronic resource]

Francisella is a gram-negative bacterium that causes tularemia. It is capable of infecting a remarkably broad host range including humans, mammals, birds and fish via multiple different routes of infection, establishing a successful colonization event within the various organs. This facultative, intracellular pathogen is also capable of invading a broad range of host cell types ranging from macrophages to fibroblasts. This is an extremely fascinating facet of the bacterium. The ability of Francisella to infect such a wide range of hosts and cell types suggests that the bacterium either co-opts cellular mechanisms common to all hosts and cell types or has the requisite bacterial genes to adapt to many different intraorganismal environments, or both. We were interested in studying the diverse repertoire of interactions that may occur between the bacterium and its murine host. In this thesis, the transposon site hybridization (TraSH) negative selection strategy was applied in a range of in vivo and in vitro systems to identify novel host-pathogen interactions in Francisella. We subsequently demonstrated that Francisella require tryptophan for virulence specifically in the lungs due to lung-specific induction of a host innate immune molecule indoleamine 2,3-dioxygenase 1. Alveolar macrophages may also deplete intracellular trytophan via a novel mechanism and microbial lung-specific requirement of tryptophan for virulence may be widely applicable to all bacterial species. We also demonstrate that Francisella hypercytotoxic mutants, unlike previously suggested, induce macrophage hypercytotoxicity due to increased bacteriolysis in the intracellular milieu. Identification and characterization of bacterial mutants that are attenuated under different in vitro and in vivo conditions have led to further insights into the interactions that occur between Francisella and its murine host.

Keywords: Microbiology and Immunology
Advisor: Monack Denise M. primary advisor. Thesis advisor
Falkow Stanley advisor. Thesis advisor
Lewis David advisor. Thesis advisor
Schneider David (David Samuel)
Distributional impacts of energy policies in India [electronic resource] : implications for equity in international climate change agreements [electronic resource]

While there is much agreement in the climate policy literature that climate change mitigation should not interfere with humans' ability to enjoy a minimal standard of living, there is little scholarship on how to carve out such an "exemption" for poor subpopulations within large developing economies. Further, there is little analysis in developing countries of how the burdens of specific mitigation policies would be distributed. This dissertation begins to fill these gaps. This work consists of three studies, the first two of which are positive studies of the income distributional impacts of two energy policies that have climate mitigation benefits in Maharashtra, India: electricity pricing to recover low-carbon electric supply; and removal of the kerosene subsidy. In the first study I use an economic simulation model of the electricity sector and household welfare to assess the impacts of economy-wide electricity price increases under different political and institutional constraints. The analysis reveals that regulators can insulate low-income households from welfare losses without trading off aggregate welfare losses as long as they can raise prices to industry and high-income households. Mitigation may also have a co-benefit of reducing supply interruptions to the poor. In the second study, the kerosene subsidy is found to be progressive and material in urban areas, but regressive and less material in rural areas. One reason is that households' allocated quotas far exceed kerosene demand in rural areas, but fall short of many urban households' needs. A better targeted subsidy in urban areas alone would avoid high costs of the current subsidy, yet avoid the impoverishment of urban users from their complete removal. These results emphasize that protecting the interests of the poor in international climate change mitigation agreements requires some accountability from the institutions that implement mitigation policies within states. The third study questions the adequacy of burden-sharing proposals for climate mitigation that advocate an exemption for the poor without accounting for states' agency over the costs and outcomes of such an exemption. Participating states face moral hazards over the choice of future baselines of the poor's emissions. I show - using India for illustration - that the financial stakes for parties in how future growth is distributed in India can be up to tens of billions of dollars. Getting agreement on the terms of exemption may be easier if benefiting states adopt comparative benchmarks of accountability for the poor's emissions, but which do not infringe on particular policy choices. Furthermore, participating states should have shared duties to ensure that the poor receive the benefits of an awarded exemption.

Advisor: Goulder Lawrence H. (Lawrence Herbert) primary advisor. Thesis advisor
Satz Debra primary advisor. Thesis advisor
Cohen Joshua
Victor David
DNA methylation profiling reveals novel biomarkers and important roles for DNA methyltransferases in prostate cancer [electronic resource]

Candidate gene based studies have identified a handful of aberrant CpG DNA methylation events in prostate cancer (Brooks et al. 1998; Yegnasubramanian et al. 2004). However, large scale DNA methylation profiles have not been examined for normal prostates or prostate tumors. Additionally, the mechanisms behind these DNA methylation alterations are unknown. In this thesis, I describe the results of my efforts to better understand these previously unexplored areas of biology. For the study presented in this thesis, I quantitatively profiled 95 primary prostate tumors and 86 healthy prostate tissue samples for their DNA methylation levels at 26,333 CpGs representing 14,104 gene promoters by using the Illumina HumanMethylation27 platform. When the profiles of the prostate tissue samples were compared, I observed a substantial number of tumor-specific DNA methylation alterations. A 2-class Significance Analysis of this dataset revealed 5,912 CpG sites with increased DNA methylation and 2,151 CpG sites with decreased DNA methylation in tumors (FDR < 0.8%). Prediction Analysis of this dataset identified 87 CpGs that are the most predictive diagnostic methylation biomarkers of prostate cancer. By integrating available clinical follow-up data, I also identified 69 prognostic DNA methylation alterations that correlate with biochemical recurrence of the tumor. To identify the mechanisms responsible for these genome-wide DNA methylation alterations, I measured the gene expression levels of several DNA methyltransferases (DNMTs) and their interacting proteins by TaqMan qPCR and observed increased expression of DNMT3A2, DNMT3B, and EZH2 in tumors. Subsequent transient transfection assays in cultured primary prostate cells revealed that DNMT3B1 and DNMT3B2 overexpression resulted in increased methylation of a substantial subset of CpG sites that also showed tumor-specific increased methylation.

Keywords: Genetics
Advisor: Myers Richard (Richard M.)
Sherlock Gavin primary advisor. Thesis advisor
Brooks James (James D.) advisor. Thesis advisor
Lipsick Joseph Steven
Tang Hua (Geneticist) advisor. Thesis advisor
Does Court-Mandated School Finance Reform Affect Private School Enrollment?

Several court-mandated public school finance reforms, among them the Serrano cases in California, the Abbott cases in New Jersey, and the Edgewood cases in Texas, have drastically changed the way in which public schools are financed. Much of this litigation has led to more centralized financing mechanisms in an attempt to better equalize funds between richer and poorer school districts. However, while such policies may have equity advantages for students at the bottom, they can have some tricky ramifications for students at the top. I examine the proportion of students enrolled in private schools and how that proportion changes based on school finance litigation status, in an attempt to assess the role of public school finance on parents’ willingness to pay for private education. An increase in private school enrollment following court-mandated public school finance reform suggests that parents are willing to pay much more for schools if they have more control over how that money is spent, and that they are willing to pay less if their money is subsidizing the education of other children.

Keywords:  Department of Economics
Stanford Department of Economics
private schools
school finance litigation
Serrano
Proposition 13
equality
redistribution
Thesis
Advisor: Fitzpatrick Maria
Drift fields, a method for resource allocation in wireless networks [electronic resource]

This dissertation recommends system engineering designs that implement the latest technologies in OFDMA cellular and femtocellular networks, specifically in the area of resource allocation and interference coordination. These recommended designs guarantee good user experience for time-sensitive applications such as streaming video. While throughput is often the metric used to benchmark a system, field performance requires the system also guarantees a maximum service latency to satisfy users. This dissertation provides both intuitive and low-overhead schemes that are robust and practical for implementation. The novelty of this work is the application of stochastic control techniques that guarantee the Quality of Service (QoS) through proper buffer management. Guarantee of a non-empty user buffer for streaming applications prevents service interruption. The thesis considers both centralized and distributed topologies that result from either a single base-station serving many users, or many femtocell base-stations each serving a single user, respectively. This dissertation provides insight and solutions to the following question: Under the constraints of buffer management, how does a system engineer determine the transmission scheme, resource allocation algorithms, transmitter coordination, user feedback, and achievable QoS guarantees that maximize efficiency. A combination of theory, heuristics motivated in theory, and numerical simulations will justify the presented methods.

Keywords: Electrical Engineering
Advisor: Cioffi John M. primary advisor. Thesis advisor
Cox Donald C. primary advisor. Thesis advisor
O'Neill Daniel C. (Daniel Craig) advisor. Thesis advisor
A duality theorem for deligne-mumford stacks with respect to Morava K-theory [electronic resource]

In [7] Greenlees and Sadofsky used a transfer map to show that the classifying spaces of finite groups are self-dual with respect to Morava K-theory K(n). By regarding these classifying spaces as the homotopy types of certain differentiable stacks, their construction can be viewed as a stack version of Spanier-Whitehead type construction. From this point of view, we will extend their results and prove a K(n)-version of Poincare duality for Deligne-Mumford stacks. A few examples of stacks defined by finite groups and moduli stack of Riemann surfaces will be discussed at the end.

Keywords: Mathematics
Advisor: Galatius Søren
Carlsson G. (Gunnar)
Cohen Ralph L.
Dynamic control of light in on-chip microresonators [electronic resource]

Optical microresonators have generated much progress in many aspects of optical science, such as in optical buffering, wavelength division-multiplexed filters for optical networks, optical switching, and in the enhancement of nonlinear effects. All these applications are made possible by the confinement of light within a small modal volume in the microresonator. The ability to actively tune the resonance within a microresonator has resulted in systems that can dynamically manipulate the flow of light. This thesis discusses some of the novel capabilities of these dynamic systems. Chapters 3 - 4 discusses the use of a dynamic delay line to suppress dispersion, and to overcome the gain-bandwidth product constraint of slow-light structures. This is followed by Chapter 5 which introduces a light-stopping scheme based on loss modulation. Finally, Chapter 6 shows how coherent control can be used in a microresonator system to enhance optical switching.

Keywords: Electrical Engineering
Advisor: Fan Shanhui
Fejer Martin M. (Martin Michael) primary advisor. Thesis advisor
Solgaard Olav advisor. Thesis advisor
Dynamic empirical Bayes models and their applications to longitudinal data [electronic resource]

In the field of insurance rate-making, the framework of standard credibility theory was laid down by Buhlmann in an empirical Bayes setting. However, evolutionary credibility models, in which the individual risk profile that is embedded in a collective evolves over time, are not yet well developed. We develop a new class of dynamic linear empirical Bayes (EB) models as an alternative to linear state-space models for evolutionary credibility. This new dynamic EB modeling approach can be readily extended to a generalized framework, which provides flexible and computationally efficient methods for modeling longitudinal data. Our dynamic EB approach pools the cross-sectional information over individual time series to replace an inherently complicated hidden Markov model by a considerably simpler generalized linear mixed model. We also review the Pepe-Couper (1997) approach to modeling longitudinal data and propose a more general formulation of the approach in terms of "information sets" for prediction. This formulation unifies the marginal and transitional modeling approaches and strikes a balance between the flexibility of the marginal approach and the predictive power of transitional modeling. We further extend our predictive dynamic EB models to resolve the problem of "excess zeros" in longitudinal data. The advantages of using these models are illustrated using examples in insurance, default modeling of corporate loans in finance and predicting baseball batting averages.

Keywords: Statistics
Advisor: Lai T. L. primary advisor. Thesis advisor
Walther Guenther advisor. Thesis advisor
Zhang Nancy R. (Nancy Ruonan) advisor. Thesis advisor