VictorJuiz/thesis huggingface dataset:
Initial Production Capacity Investments for Commercializing Pharmaceutical Products

This thesis is motivated by the investment problems pharmaceutical manufacturing firms face when introducing new drug products./nWe consider two different types of resources that play a role in determining the initial production capacity in pharmaceutical manufacturing:/ngeneric production resources, and specialized facilities and equipment./nDue to the differences in availability of {each resources} type and the dynamics of information the firm receives with respect to the underlying uncertainties,/nthe investment problems posed by these two resource types are very different./nWe build two separate dynamic optimization models to analyze the respective investment strategies./nFor procurement of generic resources, we consider the firm facing random demand while the drug approval arrives at a random time./nThe firm can either increase or decrease inventory of the resources by buying or selling on a spot market where price fluctuates randomly over time./nThe firm's goal on this operation is to maximize expected discounted profit over the procurement process./nWe first show that this optimization problem is equivalent to a two-dimensional singular control problem./nWe then show that the optimal policy is completely characterized by a simple price-dependent two-threshold policy./nFor specialized equipment, we consider a model where the firm must balance two conflicting objectives: on one hand, the delay in scaling-up production once the product is approved must be minimized, and on the other hand, the risk of investing in ultimately unused capacity must be minimized. We develop a stylized model of this type of capacity investment problem, where the firm re-evaluates its capacity investment strategy as information about the potential success of the product is continually updated (for example, via clinical trial results)./nWe identify settings in which by continually reviewing the building strategy, the firm can substantially reduce both the delay of the commercial launch of the new product, and the risk of lost investment./nAlthough, our focus here is on the investment decisions in introducing a new drug product in the pharmaceutical industry,/nthe models described in the following subsections can be applied to the introduction of products which require specialized equipment/nto manufacture and have a long research and development phase.

Advisor: Kaminsky, Philip M
Guo, Xin
The Hecke Stability Method and Ethereal Forms

The purpose of this thesis is to outline the Hecke stability method (HSM), a novel method for the computation of modular forms./nThe HSM relies on the following idea: A finite-dimensional space of ratios of modular forms that is stable under the action of a Hecke operator should consist of modular forms (i.e., without poles). This principle is correct over the complex numbers, but more care is required over finite fields due to complications arising near the supersingular points on modular curves. Formalizing this main idea as a theorem comprises most of our theoretical work./nThough it can be utilized in a variety of settings, the main application of the Hecke stability method is the computation of weight 1 modular forms. These spaces cannot be computed using the algorithms (e.g., modular symbols algorithms) that are typically employed to compute modular forms of higher weight./nFurthermore, to provide a complete picture of the weight 1 modular forms of level N, we must account for certain sporadic discrepancies between the space of classical forms and the space of mod p modular forms. Ultimately, our approach is motivated by the effect this "ethereality" phenomenon may have on the statistics of number fields via the theory of modular Galois representations.

Advisor: Venkatesh, Akshay
The Tangent Functor Monad and Foliations

In category theory, monads, which are monoid objects on endofunctors, play a central role closely related to adjunctions. Monads have been studied mostly in algebraic situations. In this dissertation, we study this concept in some categories of smooth manifolds./nNamely, the tangent functor in the category of smooth manifolds is the functor part of a unique monad, which is the main character of this dissertation./nAfter its construction and the study of uniqueness properties in related categories, we study its algebras, which are to this monad what representations are to a group. We give some examples of algebras, and general conditions that they should satisfy. We characterize them in the category of affine manifolds. We also study an analog of the tangent functor monad and its algebras in algebraic geometry./nWe then prove our main theorem: algebras over the tangent functor monad induce foliations on the manifold on which they are defined./nThis result links the study of these algebras to the study of foliations./nA natural question is then to characterize foliations which arise this way./nWe give some restrictions in terms of the holonomy of such foliations. Finally, we study in greater detail algebras on surfaces, where they take a very simple form, and we nearly characterize them.

Advisor: Weinstein, Alan D
Proto-Ersuic

This is a reconstruction of Proto-Ersuic, the ancestor language of Lizu, Tosu, and Ersu, three closely related languages spoken in southwestern Sichuan which are generally considered to be part of the Qiangic branch of Tibeto-Burman. To date, no in-depth historical work has been carried out on these languages. Approximately 800 lexical items are reconstructed based primarily on data from six sources: Mianning Lizu (data collected by the author in Mianning County, Sichuan, in 2008 and 2010), two sources for Kala Lizu (Muli County, one modern and one older source), Naiqu Lizu (Jiulong County), and two varieties of Ersu (Zeluo and Qingshui, both in Ganluo County)./nChapter 1 provides a general introduction to Lizu, Tosu, and Ersu, along with basic information for each source to help the reader properly interpret the phonetic transcriptions and parse the individual forms for each language./nChapter 2 presents the Proto-Ersuic syllable canon, providing the skeleton upon which the individual reconstructions are built./nChapters 3 and 4 lay out the complete inventory of Proto-Ersuic initials and rhymes. All reconstructed consonants and vowels are supported by comprehensive cognate sets demonstrating regular sound correspondences across the languages, with exceptions carefully noted./nChapter 5 offers a reconstruction of the lexical tones of Proto-Ersuic, with a general unmarked tone assigned to most words and a second, marked, tone of unclear origin specified on a minority of the lexicon./nChapter 6 presents an outline of shared morphosyntax that can be reconstructed to the Proto-Ersuic level, specifically morphosyntax related to nouns, verbs, and numerals/classifiers./nChapter 7 brings together all the sound changes that yielded the regular correspondences presented in Chapters 3 and 4, organizing them by language, and ordering them chronologically. From these sound changes emerges a picture of the internal structure (i.e. subgrouping) of Ersuic./nChapter 8 takes a top-down approach, examining the sound changes from Proto-Tibeto-Burman to Proto-Ersuic and attempting to find regular patterns in the development of Proto-Tibeto-Burman rhymes, initials, and prefixes. Comparisons with other languages and branches of Tibeto-Burman are made as well in an attempt to uncover new roots./nThe final chapter (Chapter 9) addresses the place of Proto-Ersuic in Tibeto-Burman, summarizing current views on the matter and offering some speculations on how the results of the present study might help us decide how Proto-Ersuic fits in the larger Tibeto-Burman family tree.

Advisor: Matisoff, James A.
Gender Identity: Pending? Identity Development and Health Care Experiences of Transmasculine/Genderqueer Identified Individuals

The purpose of this study was to explore the identity development process and health care experiences of individuals who identify their gender somewhere along the transmasculine spectrum. Using a qualitative grounded theory approach, data were collected through semi-structured interviews with 28 transmasculine identified individuals. Additionally, results from a pilot study with 15 genderqueer identified individuals supplemented these interview data. The interviews focused on the process of transmasculine identity development and experiences in seeking and receiving health care services across a variety of practice settings. Participants also shared how their interactions with individual health and mental health care providers, organizations, and the larger managed care system impacted (both positively and negatively) their experiences of gender identity development./nThe results of this research also indicate that various components of health care provision may impact transmasculine identity development. Access to trans-friendly health care organizations and providers, an informed consent model of health care provision, trans-friendly organizational policies, insurance coverage for transgender health needs, and relationship-centered communication with health providers all lend themselves to a positive, affirming experience of identity.

Advisor: Gambrill, Eileen
Mercury Sensing with Optically Responsive Gold Nanoparticles

Mercury, a potent neurotoxin, is a global environmental problem. New mercury sensing technologies are needed to meet the expanding demands on the mercury observation network. We demonstrate the utility of gold nanoparticles as a stand-alone, inexpensive, and sensitive mercury monitor. Gold nanoparticles display a peak in the visible range of their UV-vis absorbance spectra due to localized surface plasmon resonance (LSPR). The energy of this resonance is affected by adsorption of mercury. Isolated individual gold nanorods with an average length and diameter of 60 and 20 nm saturate after adsorption of 4 attograms of elemental mercury, and produce a 3 nm blue shift in their LSPR, with the shift dependent on the surface-area-to-volume ratio and aspect ratio. A modified Gans theory model predicts the shift at saturation given the particle dimensions if saturation occurs with 45% monolayer coverage./nNanoparticle films on a transparent substrate show potential as a practical and robust method for sensing low levels of mercury vapor. The adsorption of 15 atoms of Hg causes a 1 nm shift in the LSPR wavelength of 5 nm gold spheres. The rate of shift in the peak absorbance is linear with mercury concentrations from 1 to 825 µgHg/mair3. The speed of the sensor response is limited by diffusive mass transfer and can be enhanced by optimizing the sample flow characteristics. We modeled the diffusive mass transfer and optimized the sample delivery accordingly. Regeneration of the sensing films, done by heating to 160°C, allows for repeatable measurements on the same film.

Advisor: Koshland, Catherine P
Fernandez-Pello, Carlos
NAIPs: Building an Innate Immune Barrier against Pathogenic Bacteria

The innate immune system of mammals encodes several families of immune detector proteins that monitor the cytosol for signs of pathogen invasion. One important but poorly understood family of cytosolic immunosurveillance proteins is the NLR (nucleotide binding domain, leucine-rich repeat containing) proteins. Work presented here demonstrates that one subfamily of NLRs, the NAIPs (NLR family, Apoptosis Inhibitory Proteins), are activated by specific interaction with bacterial ligands, such as flagellin. NAIP activation leads to assembly of a large multiprotein complex called the inflammasome, which initiates innate immune responses by activation of the Caspase-1 protease. NAIPs therefore appear to detect pathogen molecules via a simple and direct receptor-ligand mechanism. Interestingly, other NLR family members appear to detect pathogens indirectly, perhaps by responding to host cell `stress' caused by the pathogen. Thus, the NLR family may have evolved surprisingly diverse mechanisms for detecting pathogens./nSusceptibility to the intracellular bacterial pathogen Legionella pneumophila was mapped to a discrete genetic locus in the mouse containing multiple tandem gene paralogues constituting the NAIP gene array over ten years ago, but functional understanding of the NAIP array, and in particular whether different genes in the array perform diverse or redundant functions in host defense remains enigmatic. Here we show that NAIP proteins monitor the cytoplasm of host innate immune cells for the presence of bacterial flagellin, and the inner-rod proteins of bacterial type III secretion systems. Specific interaction of NAIP5 and NAIP6 with bacterial flagellin, and NAIP2 with inner-rod proteins (from a variety of pathogenic bacteria) promotes inflammasome assembly and activation. The `orphan' receptor NAIP1 appears to detect a narrow subset of inner-rod proteins, but the structural basis for this selectivity and its functional importance are unknown./nFinally, we have mapped the ligand-specificity determining region of the NAIPs to a ~200 amino acid region of the LRR domain that spans seven structural repeats that exhibit a high degree of polymorphism among the NAIP paralogues. Whether the region is sufficient for binding specific ligands is an open question. We have used structural modeling and polymorphism mapping of the NAIP LRR domains to identify putative ligand-binding residues that may be under selective pressure from bacterial pathogens. Thus, the NAIP gene array has evolved to recognize functionally constrained molecules of pathogenic bacteria, and represents an exquisite mechanism of host defense.

Advisor: Vance, Russell E
Ion Energy Distribution in Collisionless and Collisional, Capacitive RF Sheath

Capacitively driven radio frequency (rf) discharges are commonly used for plasma-assisted material processing. Because of the significant difference in the mobility of electrons and ions, a thin layer of sheath is always established at the boundary, which separates the discharge into two regions: quasi-neutral bulk plasma and positively charged sheath. Within the sheath, ions are accelerated by electric fields and therefore, bombard the electrode with significant energies. The ion energy distribution (IED) on the substrate is essentially important in the optimization of discharge operations. For plasmas sources typically operated at higher densities and lower pressures, the ion motion in the rf sheath is mainly collisionless since the ion mean free path is much larger than the sheath width. At high operating pressures and large sheath voltage drops, the sheaths are typically collisional./nA fast and simple model consisting of a series of computational steps is of great value to predict the plasma parameters and IEDs, given the control parameters of the discharge. Respective models for IEDs in collisionless and collisional capacitive rf sheaths are developed in this dissertation, based on the sheath models developed in late 1980s. Both models do not rely on any intermediate parameters from simulation or experimental results and only take a few seconds (collisionless) or minutes (collisional) to get the final IEDs. Ion-neutral charge exchange reactions are considered for collisional rf sheaths. Energy dependent ion mean free path is taken into account. Particle-in-cell (PIC) simulations are used to verify the previous sheath models and the IED models./nThe PIC code OOPD1, being developed with a powerful capability as the development of the collisional IED model goes on, is introduced in this dissertation. Comparisons with XPDP1 are presented, which confirms OOPD1 as a trustable, friendly, and extensible simulation tool to observe the rf discharges.

Advisor: Lieberman, Michael A
Verboncoeur, John P
Probing Atomic-Scale Properties of Magnetic and Optoelectronic Nanostructures

This dissertation presents scanning tunneling microscopy and spectroscopy studies of individual molecules and graphene nanoribbons (GNRs) bound to a substrate. Understanding the local electronic properties of these systems is importance from a fundamental physics viewpoint and for advancing potential technological applications in nanoelectronics. Two molecular systems, tetracyanoethylene (TCNE), and bithiophene naphthalene diimide (BND), were investigated. The basic questions addressed are (1) how do molecules respond to a condensed matter environment (i.e. a metal or semiconducting surface), (2) how do spins behave in molecule-scale structures, and (3) how do the intrinsic electronic properties of molecules affect their self-assembly behavior. We find that TCNE molecules display variable surface coupling and enable tunable magnetic exchange coupling between covalently bonded spin centers in Vx(TCNE)y complexes. We also were able to determine the TCNE adsorption site within a molecular monolayer on Ag(100) through a combination of inelastic electron tunneling spectroscopy and density functional theory calculations. We find that BND molecules exhibit type-II heterojunction energy level alignment. The interplay between the bipolar electronic nature of the molecule and the substrate results in different self-assembly patterns on a Au(111) surface. In GNRs we have demonstrated the presence of magnetic edge states for chiral nanoribbons with atomically smooth edges. We have further controlled GNR edges via hydrogen plasma etching, and have determined their exact edge termination.

Advisor: Crommie, Michael F.
Circadian Rhythms and Clock Genes in Inter-episode Bipolar Disorder

Objectives: Circadian rhythms are hypothesized to be disturbed in bipolar disorder (BD). However, the empirical evidence for this hypothesis is mixed. Hence, the goals of the current investigation were to extend and contribute to clarifying the literature on circadian rhythms in inter-episode BD by comparing proxies for circadian rhythm functioning in BD I and II individuals, relative to healthy controls./nMethods: Thirty-five adults diagnosed with inter-episode BD I and II were compared to 37 healthy controls of similar age and gender. All participants completed a questionnaire assessing chronotype, reported daily sleep and wake times for four weeks, and wore wrist actigraphy for four weeks in order to assess objective estimates of sleep and wake timing and to calculate the cosinor variables, MESOR, amplitude and acrophase, as proxies for circadian modulation of activity. Participants also provided a saliva sample in order to analyze DNA for polymorphisms of the clock genes PER3 and CLOCK./nResults: There were no significant differences between the BD and control groups on questionnaire reported chronotype, although there was a trend for significance such that BD individuals were more likely to report an evening chronotype. BD individuals exhibited more instability in sleep and wake timing as assessed by both sleep diary and actigraphy. There were no significant differences between the BD and control groups on any of the cosinor analysis variables; namely, MESOR, amplitude and acrophase. There was a trend for differences in MESOR among BD individuals who were carriers of the C-allele of the CLOCK gene. There were no differences in circadian cosinor variables for any of the genotype groups of PER3./nConclusions: The current findings are not consistent with previous hypotheses that abnormal circadian activity rhythms are enduring (trait) characteristics of BD individuals. However, instability in sleep timing may be characteristic of the inter-episode period.

Advisor: Harvey, Allison G
The Nuclear Functions of Host Cytoplasmic Poly(A) Binding Protein during Viral Infection

Poly(A) tail length is emerging as an important marker of mRNA fate, where deviations from the canonical length can signal degradation or nuclear retention of transcripts. Pathways regulating polyadenylation thus have the potential to broadly influence gene expression. Here we demonstrate that accumulation of cytoplasmic poly(A) binding protein (PABPC) in the nucleus, which can occur during viral infection or other forms of cellular stress, causes mRNA hyperadenylation and nuclear accumulation of poly(A) RNA. This inhibits gene expression but does not affect mRNA stability. Unexpectedly, PABPC-induced hyperadenylation can occur independently of mRNA 3' end processing yet requires the canonical mRNA poly(A) polymerase II. We find that nuclear PABPC-induced hyperadenylation is triggered by multiple divergent viral factors, suggesting that altering the subcellular localization of PABPC may be a commonly used mechanism to regulate cellular gene expression in a polyadenylation-linked manner. PABPC is predominantly cytoplasmic at steady state. The molecular events that trigger relocalization of PABPC and the mechanisms by which it translocates into the nucleus to block gene expression are not understood. Here, we reveal an RNA-based mechanism of retaining PABPC in the cytoplasm. Expression of either viral proteins that promote mRNA turnover or of a cytoplasmic deadenylase drives nuclear relocalization of PABPC in a manner dependent on the PABPC RNA recognition motifs (RRMs). Using multiple independent binding sites within its RRMs, PABPC interacts with importin alpha, a component of the classical nuclear import pathway. Finally, we demonstrate that the direct association of PABPC with importin alpha, is antagonized by the presence of poly(A) RNA but not poly(C) RNA, supporting a model in which RNA binding masks nuclear import signals within the PABPC RRMs, thereby ensuring efficient cytoplasmic retention of this protein in normal cells. These findings further suggest that cells must carefully calibrate the ratio of PABPC to mRNA, as events that offset this balance can dramatically influence gene expression.

Advisor: Glaunsinger, Britt A
Regulation of Imprinted Gene and Small RNA Expression in the Arabidopsis Endosperm

The Arabidopsis endosperm is an unique tissue to angiosperms, and is the main tissue where imprinting occurs. Using high-throughput sequencing we found 123 new imprinted genes and expect that the total number of imprinted genes present in the endosperm ranges from 200-500. From the 114 maternally expressed imprinted genes we found 29 genes which expression mechanism are controlled by DNA methylation and/or PcG activity. For the rest of imprinted genes and presumably the majority of p4-siRNAs, the maternal expression may be controlled by other mechanisms or use homolog of known imprinting proteins.

Advisor: Fischer, Robert
Gāruḍa Medicine: A History of Snakebite and Religious Healing in South Asia

This thesis introduces, contextualizes, and closely examines the Gāruḍa Tantras, an early medieval branch of Śaiva scripture that has hitherto not been a proper object of study. The Gāruḍa Tantras were religiously-oriented and divinely-revealed medical manuals whose chief concern was treating snakebite envenomation. Although previously deemed lost, this dissertation establishes the survival and influence of this class of scriptures by drawing on unpublished manuscript sources. The first chapter outlines the scant past research on snakebite and mantras in early South Asian medical systems, and proposes a more nuanced approach based on empathetic skepticism. The long second chapter surveys the theme of snakebite medicine in Sanskrit and Prakrit texts from the Veda down to modern compositions, and establishes the widespread influence of the Gāruḍa Tantras. The third and fourth chapters closely examine the masculine mantra and feminine vidyā systems respectively, with the aim of understanding the intricate levels of meaning encoded in ritual practices. The fifth chapter analyzes Garuḍa as a nonsectarian deity, with particular reference to how his identity functions in the possession ritual at the core of the Gāruḍika's practice. The sixth chapter concludes and recommends directions for future research. Part II of the thesis is an introduction, critical edition, and English translation of nine chapters of the Kriyākālaguṇottara, an early scriptural compilation that preserves a great deal of archaic material from the Gāruḍa Tantras.

Advisor: Goldman, Robert P
von Rospatt, Alexander