VictorJuiz/thesis huggingface dataset:
Feeding the Brethren: Grain Provisioning of Norwich Cathedral Priory, c. 1280-1370
Keywords: Late-Medieval England
Economic History
Agrarian History
History of Food
Environmental History
Fourteenth-Century Europe
Monasticism
Norwich Cathedral Priory

The present dissertation attempts to follow and analyze each and every individual stage of food provisioning of a late medieval monastic community. Chapter One is an introductory survey, describing the topic, its status quaestionis, problems and methodology. Chapter Two establishes the geography of crops in the rural hinterland of Norwich, with each manor specializing in different crop. A close analysis of the crop geography partially supports the Von Thünen thesis. Chapter Three looks at the agricultural trends of the demesnes. Roughly speaking, the period between c. 1290 and 1370 was a history of wheat’s expansion at the expense of rye, on the one hand, and legume shrinkage at the expense of grazing land. Chapter Four discusses annual grain acquisition, its components and disposal. It shows that about eighty per cent of the total supply derived from harvest, while the remainder came in form of tithes, grants and purchases. Chapter Five deals with the human and equine interaction. The bovine population was certainly dominant, but the draught horses easily outnumbered the oxen. Each year,the Priory authorities saved a great deal of money, because of (virtually) free customary carting service. Chapter Six explores the space for storing and processing of the annual grain supply. The five adjacent buildings, namely the Great Granary, brewery, bakery, mill and staples, allowed most effective cooperation between dozens of Priory labourers working in victual departments, on the one hand, and decreased transportation costs. Chapter Seven attempts to establish the relation between the Priory population, its annual grain supply and demand. Conversion of the grain into approximate calorific and financial equivalent reveals that the supply must have exceeded the demand. Chapter Eight is deals with the actual consumption of the grain supply. As far as Norwich monks are concerned, their annual bread and ale supply has certainly exceeded their normal requirements and there is no hint about selling the surplus. Joining the bread and ale accounts with those of the cellar, we arrive at astonishing calorific figures. Chapter Nine discusses the charity activities of Norwich Priory, particularly connected to the distribution of bread and ale among the needy. There were three distinctive groups: hermits, prisoners and paupers. According to almoner’s accounts, the Priory allocated generous sums of loaves and ale to the paupers.
Bone Marrow Stem Cell-mediated Airway Epithelial Regeneration
Keywords: Lung biology
Stem cell biology
Bone marrow
Tissue regeneration

It has been suggested that some adult bone marrow cells (BMC) can localize to the injured tissues and develop tissue-specific characteristics including those of the pulmonary epithelium. In Chapter 2 we show that the combination of mild airway injury as a conditioning regimen to direct the site of BMC localization and transtracheal delivery of short-term cultured BMC enhances airway localization and adoption of an epithelial-like phenotype expressing Clara cell secretory protein (CCSP) and pro-surfactant protein-C. Bone marrow cells from transgenic mice expressing green fluorescent protein driven by the epithelial-specific cytokeratin-18 promoter were injected transtracheally into airway-injured wild-type recipients. BMC retention in the lung was observed to be at least 120 days following cell delivery with increasing transgene expression over time. The results indicate that targeted delivery of BMC can promote airway regeneration. Although bone marrow stem/progenitor cells can develop into lung epithelial cells, the specific subpopulation remains unknown. In Chapter 3 we identify a newly discovered population of murine and human BMC that express CCSP. These CCSP+ cells increase in the bone marrow and blood after airway injury and can be expanded in culture. CCSP+ cells are unique in that they express both hematopoietic and mesenchymal stromal cell markers and can give rise to various lung epithelial lineages in vitro. Importantly, bone marrow transplant of CCSP+ cells to CCSP knockout recipients confirms that bone marrow CCSP+ cells contribute to airway epithelium after airway injury. In Chapter 4 we enrich for a stem/progenitor cell population within the CCSP+ using the stem cell antigen (Sca)-1 as a marker. Here we identified a putative epithelial stem/progenitor cell that can be induced to differentiate into various lung epithelial cell lineages expressing markers exclusive to airway or alveolar epithelial cells when cultured under an air liquid interface. These cells also have self-renewal potential in vitro that can proliferate in vivo and repopulate the injured airway epithelium. This newly discovered epithelial-like cells may play a central role in the bone marrow contribution to lung repair and are exciting candidates for cell-based targeted therapy for treatment of lung diseases.
Supporting Communication Between Nurses and Physicians
Keywords: Process Engineering
Interprofessional Care
Multidisciplinary Health Care

Nurses and physicians in General Internal Medicine (GIM) work in a complex environment where patients present with complex (co)morbidities; management of such patients requires input from a full range of medical disciplines. In addition, there is regular resident physician changeover every 8-9 weeks in this teaching environment, and patient “flow” problems caused by overcrowding and placement issues. This complexity causes difficulties in the information exchange between nurses and physicians necessary to manage patient care. Multidisciplinary team meetings have been suggested as helpful to interprofessional communication, and in General Internal Medicine these take place in the form of daily “Bullet Rounds”. More recently the use of process engineering approaches has been suggested as a way to increase efficiency in healthcare; this dissertation evaluates its impact on communication between nurses and physicians. The initial observational field study showed that information exchange was the main focus of dialogue in Bullet Rounds, and identified information gaps between nurses and physicians. Script Theory (Schank and Abelson 1977) was used to propose that information gaps in Bullet Rounds are caused by different knowledge and goals, which result in inconsistent scripts. A process engineering intervention took place in General Internal Medicine. Process engineering methods have been proposed as being helpful in process design and improvement in healthcare but have not been systematically evaluated. The researcher conducted a pre and post intervention study of Bullet Rounds in order to identify and analyse the impacts of a process engineering intervention on information exchange between nurses and physicians. The results showed that information loss decreased after the intervention but that resident physicians were not satisfied with the nurses-physician information exchange. The staff and resident physicians appeared to have distinct and different information needs and perspectives, while the nurses felt that the Bullet Rounds process had improved, but that it needed revisiting, and were not aligned with staff physicians on respective roles and responsibilities. The overall results suggest that even after the process engineering intervention, there was still misalignment of goals and scripts between the two groups of physicians and between the physicians and nurses, and strategies for addressing these gaps are proposed.
The Roles of Presenilin and FKBP14 in Drosophila Development and Notch Signalling
Keywords: Genetic Screen

The Roles of Presenilin and FKBP14 in Drosophila Development and Notch Signalling; Diana L. van de Hoef, Department of Molecular Genetics, University of Toronto, 2008. The multimolecular gamma-secretase complex cleaves type 1 transmembrane proteins such as Notch and one of the genes targeted in Alzheimer’s disease known as APP. This complex comprises four components, known as anterior pharynx defective 1, presenilin enhancer 2, nicastrin and presenilin. Presenilin is an aspartyl protease that comprises the catalytic core of gamma-secretase, and mutated forms of presenilin cause early-onset familial Alzheimer’s disease. To further define the role of Drosophila Presenilin (Psn), I performed a genetic modifier screen to identify Psn-interacting genes. One of the genes that was identified, known as FKBP14, encodes a peptidyl-prolyl isomerase that may be involved in protein folding in the ER. I demonstrate that an immunosuppressant drug known as FK506, which binds FKBPs and abrogates their function, reduced Psn, anterior pharynx defective 1 and presenilin enhancer 2 protein levels in vivo. I also show that FKBP14 colocalized with anterior pharynx defective 1 and Psn in the ER, suggesting a role in gamma-secretase stability. Consistent with this, I demonstrate that FKBP14 binds with Psn and mediates Psn stability and Notch signalling in vivo. To further characterize the role of FKBP14 in development, I analyzed its expression pattern and phenotypes of an FKBP14 null mutant. I show that FKBP14 localized to embryonic hemocytes and larval tissues, in addition to being expressed in developing egg chambers. FKBP14 function is required during development, since FKBP14 null mutants are recessive lethal. These mutants exhibited defects in larval disc development that resulted in eye, wing and notum phenotypes reminiscent of Psn dominant-negative and Notch-dependent phenotypes. Furthermore, FKBP14 mutants displayed enhanced apoptosis in larval tissues, suggesting a possible involvement in apoptosis regulation. I then examined the effects of FKBP14 overexpression, and observed enhanced Psn protein levels in vivo. Interestingly, co-expression of FKBP14 and Psn resulted in synergistic bristle phenotypes, suggesting a role for FKBP14 function in the Notch signalling pathway. Consistent with this, FKBP14 mutants enhanced Notch loss-of-function phenotypes in the wing. Altogether, my data demonstrate an essential role for FKBP14 during development, particularly in Psn protein maintenance and Notch signalling.
Sequence and Structural Analysis of the BTB Domain
Keywords: structural biology
biochemistry
biophysics
x-ray crystallography
bioinformatics
protein-protein interactions

The BTB domain is a eukaryotic protein-protein interaction motif found in variety of proteins. This thesis describes an investigation into the general and specific properties of the sequence, structure and self-association properties of this domain. The work is divided by two complementary approaches. Chapter 2 describes compu-tational work in assembling a collection of BTB domain sequences from completely se-quenced eukaryotic genomes. This chapter describes analyses on this collection including the genomic distribution, domain architectures, identification of putative novel domains and predictions of interactions. Chapters 3, 4 and 5 are founded on experimental analyses on BTB domains from human BTB-ZF proteins. Chapter 3 describes the structure of the BTB domain from Leu-kemia/Lymphoma Related Factor (LRF). The structure closely resembles the previously determined structures of BTB domains. The structure showed a large number of sequence substitutions on the surface of the LRF BTB domain that is equivalent to the surface in-volved in an interaction between the BTB domain from B-Cell Lymphoma 6 (BCL6) and a peptide derived from the SMRT co-repressor (the SMRT-BBD). We show the LRF BTB domain does not interact with this peptide. Chapter 4 describes the structures of the BTB domains from FAZF and Miz-1. These proteins conserve most of the BTB fold but show some unexpected changes. The BTB domain from FAZF lacks domain swapping which is a novel feature. The BTB do-main from Miz-1 contains a naturally truncated N-terminus and a novel movement of 10 residues away from a conserved three-stranded β-sheet. We show these BTB domains are dimeric within a specific concentration range and that they do not interact with the SMRT-BBD. Chapter 5 describes the structure of the BTB domain from Kaiso. This structure showed interactions between Kaiso BTB domain dimers that extend through the crystal. We identified similar interactions between dimers in a number of other structures of other BTB domains which suggested a common mode of oligomerization.
Elucidation of the Catalytic Mechanism of Golgi alpha-mannosidase II
Keywords: Glycosylation
Cancer
X-Ray Crystallography
Glycoside hydrolase
Catalytic mechanism
Drug Design

The central dogma of molecular biology outlines the process of information transfer from a DNA sequence, to a protein chain. Beyond the step of protein synthesis, there are a variety of post-translational modiﬁcations that can take place, one of which is addition of carbohydrate chains to nascent proteins, known as glycosylation. The N-linked glycosylation pathway is responsible for the covalent attachment of multifunctional carbohydrate chains on asparagine residues of nascent proteins at Asn-X-Ser/Thr consensus sequences. These carbohydrate chains are thought to aid in cell signaling, immune recognition, and other processes. Golgi alpha-mannosidase II (GMII) is the enzyme in the N-glycosylation pathway that is responsible for cleaving two mannose linkages in the oligosaccharide GnMan5Gn2 (where Gn is N-acetylglucosamine and Man is mannose), thereby producing GnMan3Gn2 , which is the committed step in complex N-glycan synthesis. It has been speculated that GMII is an excellent therapeutic target for cancer treatment, as the unusual distribution of carbohydrates on the surface of tumour cells has been characterized in many cancers. In addition, swainsonine-—a strong, yet nonspecific inhibitor of GMII—-has been shown to block metastasis and improve the clinical outcome of patients with certain cancers, including those of the colon, breast and skin. This thesis examines Golgi alpha-mannosidase II from Drosophila melanogaster (dGMII) as a model for all GMII enzymes. First, a 1.80 Angstrom resolution crystal structure of a weak inhibitor, kifunensine, binding to dGMII provides mechanistic insights into the substrate distortion in the GMII reaction. It is hypothesized that the GMII reaction proceeds via a 1 Sinterintermedi-ate. Second, a 1.40 Angstrom resolution structure of a mutant dGMII bound to its natural substrate, GnMan5Gn, identiﬁes key substrate binding and catalytic residues, as well as expanding the deﬁnition of the GMII active site to include two distant sugar−binding subsites. Finally, the results are taken together, with knowledge of other related enzymes to synthesize a plausible itinerary for the GMII reaction.
Optimization of Imaging Performance and Conspicuity in Dual-Energy X-ray Radiography
Keywords: Medical Imaging
Dual-energy X-ray Imaging

Dual-energy (DE) x-ray imaging of the chest decomposes two radiographs acquired at low- and high x-ray energies into 'soft-tissue' and 'bone' images, reducing the influence of background anatomical noise and providing increased conspicuity of subtle underlying structures compared to conventional radiography. This thesis derives a quantitative theoretical model of imaging performance in DE x-ray imaging and employs the resulting framework to system optimization in thoracic imaging. Fourier domain metrics of signal and noise performance - including the noise-power spectrum (NPS), modulation transfer function (MTF), detective quantum efficiency (DQE), and noise-equivalent quanta (NEQ) - were computed using cascaded systems analysis extended to DE imaging and combined with a quantitative model of imaging task to yield estimates of detectability across a broad range of DE image acquisition and decomposition techniques. Specifically, the detectability index provided an objective function for optimizing the selection of kVp pair, added filtration, allocation of dose between low- and high- energy views, and choice of decomposition algorithm and parameters therein. Theoretical calculations were validated in comparison to measurements of NPS, MTF, DQE, and NEQ performed on an experimental DE imaging system and through human observer studies for a variety of imaging tasks. Overall, the detectability index was found to provide a reliable predictor of human observer performance. Results identified optimal DE image acquisition and decomposition techniques that boost detectability beyond that achieved by conventional radiography or other DE imaging approaches, in many cases boosting conspicuity of subtle lesions from barely visible to highly conspicuous at fixed dose to the patient. The results are particularly encouraging, as such performance was achieved with the DE imaging dose equivalent to that of a single chest radiograph. The theoretical framework provided a valuable guide to optimization of a clinical prototype for high-performance DE chest imaging and may be extended to other DE imaging approaches, such as DE mammography and DE computed tomography.
Distribution of Human Tissue Kallikrein-Related Peptidases in Tissues and Biological Fluids: Localization, Hormonal Regulation and Physiological Functions in the Female Reproductive System
Keywords: kallikrein
reproduction
serine protease
vaginal physiology

Human tissue kallikrein-related peptidases (KLK) are fifteen genes located on chromosome 19q13.4, encoding hormonally regulated, secreted serine proteases with trypsin/chymotrypsin-like activity. I identified expression of many KLKs in tissues throughout the female reproductive system and in cervico-vaginal fluid (CVF). The female reproductive system is hormonally regulated during the menstrual cycle, suggesting KLKs may also be regulated by these hormones. Measurement of KLKs levels in CVF and saliva samples throughout the menstrual cycle revealed a peak in expression following ovulation in both fluids. Progesterone levels rise during this period suggesting KLK regulation by progesterone during the menstrual cycle. Using proteomic techniques, I resolved the CVF proteome to identify potential KLK substrates. Among 685 proteins identified, several cell-cell adhesion molecules, cervical mucins and defense-related proteins were found. KLKs play a role in the desquamation of skin corneocytes through cleavage of cell-cell adhesion proteins. The vaginal epithelium undergoes cyclical changes during the menstrual cycle involving desquamation of cells upon rising progesterone levels. The post-ovulatory peak in KLK expression suggests that KLKs may contribute to cell desquamation during the menstrual cycle. Cervical mucus acts to block the uterus from vaginal microorganisms. Around ovulation, cervical mucus loses viscosity to facilitate sperm passage through the cervix. Proteolytic enzymes are thought to aid in this mucus remodelling. Our immunohistochemical studies localized KLK expression to the mucus secreting cervical epithelium and I investigated KLK processing of cervical mucin proteins in vitro. KLKs 5 and 12 were found to cleave mucins, suggesting their potential involvement in cervical mucus remodelling. CVF plays a role in host defense. KLKs are known to process the antimicrobial cathelicidin protein in skin and I investigated whether KLKs may also process antimicrobial proteins found in CVF. KLK5 was found to cleave defensin-1 alpha, in vitro, suggesting KLKs may aid in defense of the female reproductive system. Here I provide evidence of potential physiological roles for KLKs in the female reproductive system: in desquamation of vaginal epithelial cells, remodelling of cervical mucus and processing of antimicrobial proteins. These findings suggest KLKs may function in female fertility, in pathological conditions such as vaginitis and in host defense.
Proteomic Analysis of Prostate Cancer Cell Line Conditioned Media for the Discovery of Candidate BIomarkers for Prostate Cancer
Keywords: Prostate Cancer
Biomarker
Proteomics
Conditioned Media
Mass Spectrometry
Cell Culture

Early detection of prostate cancer is problematic due to the lack of a marker that has high diagnostic sensitivity and specificity. The prostate specific antigen test, in combination with digital rectal examination, is the gold standard for prostate cancer diagnosis. However, this modality suffers from low specificity. Therefore, specific markers for clinically relevant prostate cancer are needed. Our objective was to proteomically characterize the conditioned media from human prostate cancer cell lines to identify secreted proteins that could serve as novel prostate cancer biomarkers. An initial proof of principle study of the PC3 prostate cancer cell line was conducted. From this study over 200 proteins were identified in the conditioned media. Through gene ontology analysis and literature searches Mac-2 binding protein was selected as a candidate biomarker for validation in the serum of prostate cancer patients. A preliminarily validation showed that Mac-2 binding protein has discriminatory ability in prostate cancer diagnosis. However, an extended validation did not confirm this. Based on our proof of principle study we optimized our workflow and extended our analysis by culturing three different prostate cell lines [PC3 (bone metastasis), LNCaP (lymph node metastasis), and 22Rv1 (localized to prostate)]. We conducted a bottom-up analysis of each cell line by 2-dimensional liquid chromatography and tandem mass spectrometry. Of the 2124 proteins identified, 12% (329) were classified as extracellular and 18% (504) as membrane-bound. Among the identified proteins were known prostate cancer biomarkers such as PSA and KLK2. To select the most promising candidates for further investigation, tissue specificity, biological function, disease association based on literature searches, and comparison of protein overlap with the proteome of seminal plasma and serum were examined. Based on these results, several candidates were selected for validation in serum of patients with and without prostate cancer. Of these four novel candidates: follistatin, chemokine (C-X-C motif) ligand 16, pentraxin 3 and spondin 2 showed discriminatory ability. Of the four candidates, follistatin was further studied in an extended validation in serum of patients with biopsy confirmed prostate cancer and tissues of prostate cancer patients of low and high grade tumours by immunohistochemistry. In addition, follistatin was also investigated in the tissue of colon and lung cancer where intense staining was observed in one specimen of lung squamous carcinoma.