VictorJuiz/thesis huggingface dataset:
Morphology, Phylogeny, and Evolution of Diadectidae (Cotylosauria: Diadectomorpha)
Keywords: Diadectidae
diadectid
Carboniferous
Pennsylvanian
herbivory
Permian

Based on dental, cranial, and postcranial anatomy, members of the Permo-Carboniferous clade Diadectidae are generally regarded as the earliest tetrapods capable of processing high-fiber plant material; presented here is a review of diadectid morphology, phylogeny, taxonomy, and paleozoogeography. Phylogenetic analyses support the monophyly of Diadectidae within Diadectomorpha, the sister-group to Amniota, with Limnoscelis as the sister-taxon to Tseajaia + Diadectidae. Analysis of diadectid interrelationships of all known taxa for which adequate specimens and information are known—the first of its kind conducted—positions Ambedus pusillus as the sister-taxon to all other forms, with Diadectes sanmiguelensis, Orobates pabsti, Desmatodon hesperis, Diadectes absitus, and (Diadectes sideropelicus + Diadectes tenuitectes + Diasparactus zenos) representing progressively more derived taxa in a series of nested clades. In light of these results, it is recommended herein that the species Diadectes sanmiguelensis be referred to the new genus Oradectes, Diadectes absitus be referred to the new genus Silvadectes, and Diasparactus be synonymized with Diadectes to produce Diadectes zenos. The phylogenetic hypothesis also reveals an evolutionary history leading to more efficient oral processing within the lineage, with successive nodes characterized by features indicative of a high-fiber diet. Within Diadectomorpha, diadectids constitute the majority of the species, suggesting that the advent of herbivory resulted in a relatively rapid radiation of species within the group, producing a clade that is markedly more species-rich than other, non-herbivorous diadectomorph taxa. An extensive review of Permo-Carboniferous tetrapod-bearing localities does, however, indicate that diadectids were not a key component of the fauna, discovered at fewer than 50 percent of the sites reviewed. These results counter suggestions that the evolution of Diadectidae led to the formation of the modern terrestrial ecosystem—where a large crop of herbivores supports a much smaller number of carnivores—during the Late Carboniferous and Early Permian.
Intercellular Feedback in Hematopoiesis
Keywords: stem cell
network

Despite the importance of inter-cellular (between cell) communication networks in regulating homeostasis in multicellular organisms, very little is known about their topology, dynamics, or functional significance. Inter-cellular communication networks are particularly relevant in stem cell biology, as stem cell fate decisions (self-renewal, proliferation, lineage specification) are tightly regulated based on physiological demand. Using human blood stem cell cultures as an experimental paradigm, we present an integrated experimental and computational approach to interrogate a hierarchically organized tissue network. We have developed a novel mathematical model of blood stem cell development incorporating cell-level kinetic parameters as functions of secreted molecule-mediated inter-cellular networks. By relation to quantitative cellular assays, our model is capable of predictively simulating many disparate features of both normal and malignant hematopoiesis, relating internal parameters and microenvironmental variables to measurable cell fate outcomes. Through integrated in silico and experimental analyses we show blood stem and progenitor cell fate is regulated by cell-cell feedback, and can be controlled non-cell autonomously by dynamically perturbing inter-cellular signalling. Furthermore, we have compiled genome-scale molecular profiles (transcriptome and secretome), publicly available databases, and literature mining to reconstruct soluble factor-mediated inter-cellular signalling networks regulating cell fate decisions. We find that dynamic interactions between positive and negative regulators, in the context of tuneable cell culture parameters, tip the balance between stem cell supportive vs. non-supportive conditions. The cell-cytokine interactions can be summarized as an antagonistic positive-negative feedback circuit wherein stem cell self-renewal is regulated by a balance of megakaryocyte-derived stimulatory factors vs. monocyte-derived inhibitory factors. To understand how the experimentally identified positive and negative regulatory signals are integrated at the intra-cellular level, we define a literature-derived blood stem cell self-renewal network wherein these extracellular signals converge for coherent processing into cell fate decisions. In summary, this work demonstrates the utility of integrating experimental and computational methods to explore complex cellular systems, and represents the first attempt to comprehensively elucidate non-autonomous signals balancing stem cell homeostasis and regeneration.
Investigation of Atypical Binding Behaviours of the SH3 Domain of the Yeast Protein, Fus1p
Keywords: SH3 domain
protein interactions

The yeast Fus1p SH3 domain recognizes non-PXXP motif targets. This is contrary to most SH3 domains, which recognize PXXP-containing sequences. In this thesis, I characterized atypical binding of the Fus1p SH3 domain and provide insight into atypical SH3 domain interactions. I demonstrated that the Fus1p SH3 domain binds R(S/T)(S/T)SL-containing peptides derived from yeast proteins, Bnr1p and Ste5p. Through mutagenesis studies and comparisons to other SH3 domains, I showed that the Fus1p SH3 domain utilizes a portion of the same binding surface as typical SH3 domains. However, the PXXP-binding surface is debilitated in the WT domain by the substitution of unusual residues at three key conserved positions. By replacing these residues, I created a version of the Fus1p SH3 domain that binds a PXXP-containing peptide with extremely high affinity. Based on my data and analysis, I clearly delineated two distinct surfaces comprising the typical SH3 domain binding interface, and show that one of these surfaces is the primary mediator of almost every “non-canonical” SH3 domain-mediated interaction. I demonstrated that the Fus1p SH3 domain also binds Bni1p and Pea2p through yeast two-hybrid experiments, which do not contain either PXXP or R(S/T)(S/T)SL motifs. Through mutagenesis studies and two-hybrid experiments, I showed that the Fus1p SH3 domain utilizes a binding surface comprised of two sub-surfaces to interact with Bni1p and Pea2p. The sub-surfaces include the same portion of the binding surface in typical SH3 domains utilized in R(S/T)(S/T)SL binding of the Fus1p SH3 domain, and a novel binding site. I also showed that the protein binding surface of the Fus1p SH3 domain has a role(s) for efficient mating. Based on my findings in this thesis, I propose that dramatic alterations in SH3 domain specificity can be simply explained as a modulation of the binding strengths of sub-binding sites within the binding surface.
On the Permeabilisation and Disruption of Cell Membranes by Ultrasound and Microbubbles
Keywords: Ultrasound Therapy
Sonoporation
Drug Delivery
Microbubble contrast agent

Therapeutic efficacy of drugs depends on their ability to reach the treatment target. Drugs that exert their effect within cells are constrained by an inability to cross the cell membrane. Methods are being developed to overcome this barrier including biochemical and biophysical strategies. The application of ultrasound with microbubbles increases the permeability of cell membranes allowing molecules, which otherwise would be excluded, to enter the intracellular space of cells; a phenomenon known as sonoporation. This thesis describes studies aimed at improving our understanding of the mechanism underpinning sonoporation and of the exposure parameters affecting sonoporation efficiency. Cancer cells (KHT-C) in suspension were exposed to ultrasound and microbubbles – total of 97 exposure conditions. The effects on cells were assessed through uptake of cell-impermeable molecules (10 kDa to 2 MDa FITC-dextran), cell viability and microscopic observations of the plasma membrane using flow cytometry, colony assay and electron microscopy techniques. Sonoporation was a result of the interaction of ultrasound and microbubbles with the cell membrane. Disruptions (30-100 nm) were generated on the cell membrane allowing cell impermeable molecules to cross the membrane. Molecules up to 2 MDa in size were delivered at high efficiency (~70% permeabilisation). Sonoporation was short lived; cells re-established their barrier function within one minute, which allowed compounds to remain inside the cell. Following uptake, cells remained viable; ~50% of sonoporated cells proliferated. Sonoporation efficiency depended on ultrasound and microbubble exposure conditions. Microbubble disruption was a necessary but insufficient indicator of ultrasound-induced permeabilisation. The exposure conditions can be tailored to achieve a desired effect; cell permeability of ~70% with ~25% cell death versus permeability of ~35% with ~2% cell death. In addition, sonoporation depended on position in the cell cycle. Cells in later stages were more prone to being permeabilised and killed by ultrasound and microbubbles. This study indicated that sonoporation can be controlled through exposure parameters and that molecular size may not be a limiting factor. However, the transient nature may necessitate that the drug be in close vicinity to target cells in sonoporation-mediated therapies. Future work will extend the investigation into in vivo models.
Experimental Investigations of Physical and Chemical Processes at Air-ice Interfaces
Keywords: Ice
QLL
Chemistry
Heterogeneous
Photolysis
Halogen activation
PAHs
Environmental Chemistry
Atmospheric Chemistry

Studies were performed to characterize the physical nature of the air-ice interface, and to clarify its role in processes that occur there. A glancing-angle Raman probe was developed to monitor hydrogen bonding at atmospheric interfaces; we saw enhanced hydrogen-bonding on ice compared to on water. Using glancing-angle laser-induced fluorescence (LIF), we determined that small acids and bases dissociated to similar extents at air-water and air-ice interfaces, but aromatic compounds were less well solvated at air-ice interfaces, resulting in self-association even at low surface coverages. We measured uptake kinetics of organic compounds using LIF and Raman spectroscopy. The uptake kinetics can be adequately fit by a single-exponential growth equation, but in order to properly describe the self-association of aromatics observed at the air-ice interface, equations accounting for self-association should be incorporated into the uptake model. A simple model was developed for naphthalene which included terms for self-association; good fits to the observed growth of intensity from monomeric and self-associated naphthalene were obtained. Direct photolysis of aromatics was faster at air-ice interfaces than in bulk ice or aqueous solution. While red shifts in the absorption spectra of benzene and naphthalene at air-ice interfaces could explain their enhanced reactivity there, the enhanced anthracene photolysis kinetics on ice are likely due to enhanced absorption cross sections or photolysis quantum yields, or to a different photolysis mechanism there. Oxidation rates of aromatics by photo-formed hydroxyl radicals are suppressed at air-ice interfaces, but not in bulk ice. Similarly, gas-phase OH reacts rapidly with aromatics at air-water interfaces, but no reaction is observed at air-ice interfaces. Conversely, the reactivity of ozone toward phenanthrene is enhanced there. This is not due to temperature effects or to enhanced partitioning of ozone to ice. Ozonation of bromide is also more rapid at air-ice interfaces than at air-water interfaces at environmentally relevant bromide concentrations. This enhancement could be due to exclusion of bromide to the air-ice interface during freezing. The rapid reactions of ozone with bromide and phenanthrene at air-ice interfaces suggest that both reactions could be atmospherically important.
Holy Body, Wholly Other: Sanctity and Society in the Lives of Irish Saints
Keywords: Ireland
Irish hagiography
hagiography
medieval
hagiology
saints
Irish saints
saints' lives
sanctity
vitae
bethada
saintly vengeance
miracles
saintly healing
holiness
holy body
saints' cults
early Ireland

“Holy Body, Wholly Other: Sanctity and Society in the Lives of Irish Saints” focuses on the ways in which Ireland’s hagiographers portrayed holy otherness in the Lives of their subjects, using the Latin vitae, the vernacular bethada and the Lives containing both languages that survive from the 600s through the end of the fourteenth century. This study considers three broad themes, namely the transition of a sanctified essence into a holy body and the resulting alteration of an otherwise mortal form into a wholly other, the saintly prosecution of vengeance against those who wrong the body Christian and the enactment of hagiographical healing to bring the community of the faithful back to full integrity. These themes are analyzed within the social and cultural context of medieval Ireland, and are particularly compared with the biblical, apocryphal, heroic and legal writings of the Irish Middle Ages. Depictions of male and female saints are also compared and contrasted, as are the shifts in such depictions that occur between Latin and Irish narratives. Throughout the Lives the language of the laws of church and society inform the saint’s portrait, firmly situating these holy men and women within the sphere of medieval Ireland. Elements of Irish sanctity are drawn from vernacular heroic saga, but the predominant influence upon the Lives of Ireland’s sanctified is a powerful combination of apocryphal and canonical scriptures, demonstrating that Irish holiness can only have emanated from heaven. This combination, moreover, differs between male and female saints and between Latin and Irish Lives; holy men are modeled very strongly upon both Old and New Testament figures, while lady saints are painted more in the hues of imitatio Christi. Further, Latin vitae follow patterns capable of speaking to both Irish and non-Irish audiences alike, while vernacular Lives observe models that needed to appeal only to the Irish themselves.
Sources and Fate of Organochlorine Pesticides in North America and the Arctic
Keywords: organochlorine pesticides
air-water gas exchange
toxaphene
hexachlorocyclohexanes

Atmospheric transport and air-water exchange of organochlorine pesticides (OCPs) were investigated in temperate North America and the Arctic. OCPs studied were hexachlorocyclohexanes (HCHs, a-, b- and g-isomers), components of technical chlordane (trans- and cis-chlordane, trans-nonachlor), dieldrin, heptachlor exo-epoxide and toxaphene. Air and water samples were taken on cruises in the Great Lakes and Arctic to determine concentrations and gas exchange flux direction and magnitude. The Henry’s law constant, which describes the equilibrium distribution of a chemical between air and water, was determined for several OCPs as a function of temperature and used to assess the net direction of air-water exchange. Air samples were collected in Alabama to investigate southern U.S. sources of OCPs. Chemical markers (isomers, and enantiomers of chiral OCPs) were employed to infer sources and trace gas exchange. Elevated air concentrations of toxaphene and chlordanes were found in Alabama relative to the Great Lakes, indicating a southern U.S. source. Profiles of toxaphene compounds in air were similar to those in soil by being depleted in easily degraded species, suggesting that soil emissions control air concentrations. Gas exchange fluxes in the Great Lakes indicated near-equilibrium between air and water with excursions to net volatilization or deposition. Net volatilization of a-HCH from the Arctic Ocean was traced by evasion of non-racemic a-HCH into the atmosphere.
Ligand-based Reactions of Metal Bis- and Trisdithiolenes: Fresh Insights into Old Reactions and New Frontiers
Keywords: dithiolene
transition metal
nickel
iron
platinum
coordination
ligand
noninnocent

Metal dithiolenes [M(S2C2R2)n] have been studied for decades because of their interesting chemical and spectroscopic properties, which are related to the unusual electronic properties of the dithiolene ligand. The ligand-based reactivity of metal bisdithiolenes [M(S2C2R2)2] toward alkenes has been proposed for use in alkene purification schemes. According to the proposal, compounds Ni(S2C2R2)2 (R=CF3,CN) react with simple alkenes to form stable S,S-interligand adducts and the alkene can be released from the adduct by reduction. We showed that Ni(S2C2(CF3)2)2 reacts with ethylene and 1-hexene to form, preferentially, S,S-intraligand adducts, which rapidly decompose to inactive metal-containing materials and dihydrodithiins. However, the product selectivity can be significantly modified so that stable S,S-interligand adducts are obtained as dominant products by adding [Ni(S2C2(CF3)2)2]- to Ni(S2C2(CF3)2)2/alkene reaction mixtures. Mechanistic implications are discussed. Next, the reactions of Pt(S2C2(CF3)2)2 with 2,3-dimethyl-1,3-butadiene are addressed. Prior to our report, only symmetry-allowed S,S-interligand adducts had been observed as products in the reactions between conjugated dienes and metal bisdithiolenes. We discovered a novel mode of diene binding, where two dienes bind to one dithiolene ligand of Pt(S2C2(CF3)2)2, in an C,S-intraligand fashion, forming a new chiral bisthioether ligand. From bisdithiolenes, the focus shifts to new mixed-ligand molybdenum trisdithiolenes [Mo(S2C2(CF3)2)2(S2C6H4) and Mo(S2C6H4)2(S2C2(CF3)2)]. These complexes rapidly and cleanly bind ethylene, in an S,S-intraligand fashion, as predicted by MO arguments. The resulting intraligand adducts are sufficiently stable to be characterized, in contrast to the nickel bisdithiolene case. The metal-chelated dihydrobenzodithiin, formed upon ethylene addition, can be substituted with a variety of donor ligands, allowing access to new types of molybdenum dithiolenes. We have recently extended these studies to catalytic reactions: Mo(S2C2(CF3)2)2(S2C6H4) was used as a catalyst to form dihydrobenzodithiins from (S2C6H4)2 and a variety of alkenes, in the first example of dithiolene-based reactivity being exploited for carbon-heteroatom bond-forming catalysis. Finally, the synthesis, characterization and redox reactivity of a new Fe2Ni bis-double-decker complex is described, demonstrating for the first time a sandwich complex of a metal bisdithiolene with both NiS2C2 rings in an η5 π-donating mode. For the radical cation, experimental and computation evidence indicates that the lone electron is delocalized over the entire molecule.
Remote, Non-contact Gaze Estimation with Minimal Subject Cooperation
Keywords: Gaze
Point-of-gaze
Point-of-regard
Eye-gaze
Eye-tracking
Remote
Non-contact
Minimal subject cooperation
Single-point calibration
Minimal calibration
Pupil
Corneal reflection

This thesis presents a novel system that estimates the point-of-gaze (where a person is looking at) remotely while allowing for free head movements and minimizing personal calibration requirements. The point-of-gaze is estimated from the pupil and corneal reflections (virtual images of infrared light sources that are formed by reflection on the front corneal surface, which acts as a convex mirror) extracted from eye images captured by video cameras. Based on the laws of geometrical optics, a detailed general mathematical model for point-of-gaze estimation using the pupil and corneal reflections is developed. Using this model, the full range of possible system configurations (from one camera and one light source to multiple cameras and light sources) is analyzed. This analysis shows that two cameras and two light sources is the simplest system configuration that can be used to reconstruct the optic axis of the eye in 3-D space, and therefore measure eye movements, without the need for personal calibration. To estimate the point-of-gaze, a simple single-point personal calibration procedure is needed. The performance of the point-of-gaze estimation depends on the geometrical arrangement of the cameras and light sources and the method used to reconstruct the optic axis of the eye. Using a comprehensive simulation framework developed from the mathematical model, the performance of several gaze estimation methods of varied complexity is investigated for different geometrical system setups in the presence of noise in the extracted eye features, deviation of the corneal shape from the ideal spherical shape and errors in system parameters. The results of this investigation indicate the method(s) and geometrical setup(s) that are optimal for different sets of conditions, thereby providing guidelines for system implementation. Experimental results with adults, obtained with a system that follows those guidelines, exhibit RMS point-of-gaze estimation errors of 0.4-0.6º of visual angle (comparable to the best commercially available systems, which require multiple-point personal calibration procedures). Preliminary results with infants demonstrate the ability of the proposed system to record infants' visual scanning patterns, enabling applications that are very difficult or impossible to carry out with previously existing technologies (e.g., study of infants' visual and oculomotor systems).
Investigating Sources of Variability in Pharmacological Response to Nausea and Vomiting of Pregnancy
Keywords: nausea and vomiting of pregnancy
pregnancy

Nausea and vomiting of pregnancy (NVP) is the most common medical condition in pregnancy, and, unfortunately, variability exists among pregnant women in the therapeutic effect of anti-emetics as well as in factors that can exacerbate NVP. Identifying and managing these sources of variability will result in significant improvements in the quality of life of pregnant woman. This dissertation addressed clinical pharmacology strategies in managing NVP by focusing on three predominant areas of variability. The first challenge addressed in this dissertation was women with pre-existing gastrointestinal (GI) conditions and adherence and tolerability to prenatal multivitamin supplementation. To identify the role of iron in reducing adherence and increasing NVP and GI symptoms, two separate studies were conducted. In the first study, women randomized to a prenatal multivitamin supplementation with higher iron content experienced more adverse GI effects and increased severity of NVP symptoms. In the second study, after discontinuing iron-containing prenatal multivitamins, two-thirds of women in a prospective cohort reported improvement in their NVP symptoms which was corroborated with validated scales to quantify NVP severity. The second challenge addressed in this dissertation was the effect of heartburn and acid reflux on the severity of NVP. In a controlled, prospective study, women experiencing heartburn and acid reflux experienced greater severity of NVP compared to women with no GI symptoms. Furthermore, treatment of heartburn and acid reflux with acid-reducing pharmacotherapy with associated with a reduction in GI symptoms and NVP severity. Therefore, histamine 2 blockers or proton pump inhibitors, which do not appear to be associated with increased fetal risks, should be administered when required. The third clinical pharmacology challenge addressed in this dissertation was to determine the pharmacokinetic variability of the active ingredients of Diclectin®, first-line pharmacotherapy for the treatment of NVP. Large variability was observed in the area under the curve for both active metabolites: a 6.5-fold difference for pyridoxal-5’-phosphate and a 2.1-fold difference for doxylamine. Whether these pharmacokinetic differences contribute to suboptimal efficacy remains to be determined. In conclusion, based on the results presented in this dissertation, several improvements in clinical pharmacology strategies can be made to enhance management of NVP.