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Liyanage, Tharika. "Adopting an orphan biomarker." Thesis, https://vimeo.com/showcase/8930173/video/632499667, 2021. http://hdl.handle.net/1885/251900.
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Marchese, Adriano. "Orphan G protein-coupled receptors." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq41468.pdf.
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Ewers, Susann. "Charakterisierung des Orphan-Chemokinrezeptors HCR." [S.l. : s.n.], 2006. http://nbn-resolving.de/urn:nbn:de:bsz:25-opus-50565.
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Freiburg i. Br., Univ., Diss., 2008.Aus: TN Hartmann, M Leick, S Ewers, A Diefenbacher, I Schraufstetter, M Honczarenko and Meike Burger (2008) Human B cells express the orphan chemokine receptor CRAM-A/B in a maturation-stage-dependent and CCL5-modulated manner. Immunology April 2008.
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Ho, M. T. B. "Pharmacology of the orphan opioid receptor." Thesis, University of Cambridge, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.604104.
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The neuropeptide nociceptin/orphanin FQ (OFQ) was recently identified as the endogenous agonist of the orphan opioid receptor ORL1. In this thesis pharmacological studies on the ORL1 receptor were advanced by the comparison of the potencies and efficacies of several ligands at the rat ORL1 receptor stably transfected into chinese hamster ovary (CHO) cells, with those at the native receptor in the central (frontal cortex) and peripheral (anococcygeus muscle) nervous systems. Most notably, the work involved a close examination of the pharmacology of the first selective non-peptide antagonist for the ORL1 receptor, J-113397, and in this case the work extended to the use of in-vivo techniques measuring effects on locomotor activity and food consumption. The work on the pharmacology of the ORL1 receptor in the anococcygeus followed our discovery of the presence of the receptor in this tissue. Under conditions where electrical-field stimulation produced a selective activation of the sympathetic nerves, nociceptin/OFQ fully inhibited the pure adrenergic motor response. The hexapeptides Ac-RYYRWK-NH2 (RWK) and Ac-RYYRIK-NH2 (RIK) were potent partial-agonists whereas [Phe1ψ(CH2-NH)Gly2]nociceptin(1-13)NH2 (FGNC13) and J-113397 had little or no efficacy and were competitive antagonists. This thesis reflects on the various pharmacological actions of nociceptin/OFQ, concentrating on establishing discriminatory effects for selected compounds and possible functional role of the ORL1 receptor in the brain.
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Sniehotta, Maike. "Signaltransduktionsmechanismen in Orphan-Rezeptor-transfizierten CHO-Zellen." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=968891977.
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Johansson, Lotta. "Studies on the atypical orphan receptor SHP /." Stockholm : [Karolinska institutets bibl.], 2001. http://diss.kib.ki.se/2001/91-7349-071-7/.
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Arkenbout, Elisabeth Karin. "TR3 nuclear orphan receptor in cardiovascular disease." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2004. http://dare.uva.nl/document/77443.
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Krämer, Alwin, Gerdt Hübner, Andreas Schneeweiss, Gunnar Folprecht, and Kai Neben. "Carcinoma of Unknown Primary – an Orphan Disease?" Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-136631.
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Carcinoma of unknown primary (CUP) is an intriguing clinical finding that is defined as biopsy-proven metastasis from a malignancy in the absence of an identifiable primary site after a complete clinical work-up. CUP is a relatively common clinical entity, accounting for approximately 3–5% of all cancer diagnoses, and consists of a heterogeneous group of tumors that have acquired the capacity to metastasize before the development of a clinically evident primary lesion. Notable advances have been made over the past years in the treatment of well-defined clinical subgroups of CUP, such as women with peritoneal carcinomatosis and young adults with poorly differentiated carcinomas of midline distribution, but for the majority of patients, the prognosis still remains poor. In this review, we highlight recent advances in the diagnosis and treatment of patients with CUP syndrome, and emphasize the importance of identifying several favorable subsets of CUP, amenable to specific treatment options. In addition, we will point out novel diagnostic and therapeutic approaches which will hopefully improve both our understanding and the prognosis of this more or less neglected diseaseUnter dem Cancer of Unknown Primary (CUP)-Syndrom werden diejenigen Tumorerkrankungen zusammengefasst, bei denen auch nach Abschluss der Diagnostik nur Metastasen, jedoch kein Primärtumor gefunden wird. Das CUP-Syndrom macht ca. 3–5% aller neu diagnostizierten Malignomfälle aus und umfasst eine heterogene Gruppe von Tumoren, die die Fähigkeit zur Metastasierung erlangt haben bevor sich ein klinisch manifester Primärtumor entwickelt hat. Obwohl bemerkenswerte Fortschritte in der Behandlung von Patienten mit bestimmten, gut definierten Erkrankungssubgruppen, wie beispielsweise Frauen mit isolierter Peritonealkarzinose oder jungen Erwachsenen mit gering differenzierten Karzinomen mit Mittellinienverteilung, erzielt werden konnten, ist die Prognose bei der Mehrzahl der Patienten nach wie vor schlecht. Wir berichten im weiteren Verlauf dieser Übersichtsarbeit über Fortschritte in der Diagnostik und Therapie von Patienten mit CUPSyndrom und weisen darauf hin, dass es trotz der immer noch sehr schlechten Prognose von großer Bedeutung ist, Patienten mit bestimmten Subtypen des CUP-Syndroms zu identifizieren, die spezifischen Therapien mit der Option auf Heilung zugeführt werden sollten. Darüber hinaus möchten wir auf neuere diagnostische und therapeutische Bestrebungen aufmerksam machen, die das Verständnis und die Prognose dieses auch in der Onkologie bisher stiefmütterlich behandelten Krankheitsbildes hoffentlich verbessern werden
Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich
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Krämer, Alwin, Gerdt Hübner, Andreas Schneeweiss, Gunnar Folprecht, and Kai Neben. "Carcinoma of Unknown Primary – an Orphan Disease?" Karger, 2008. https://tud.qucosa.de/id/qucosa%3A27719.
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Carcinoma of unknown primary (CUP) is an intriguing clinical finding that is defined as biopsy-proven metastasis from a malignancy in the absence of an identifiable primary site after a complete clinical work-up. CUP is a relatively common clinical entity, accounting for approximately 3–5% of all cancer diagnoses, and consists of a heterogeneous group of tumors that have acquired the capacity to metastasize before the development of a clinically evident primary lesion. Notable advances have been made over the past years in the treatment of well-defined clinical subgroups of CUP, such as women with peritoneal carcinomatosis and young adults with poorly differentiated carcinomas of midline distribution, but for the majority of patients, the prognosis still remains poor. In this review, we highlight recent advances in the diagnosis and treatment of patients with CUP syndrome, and emphasize the importance of identifying several favorable subsets of CUP, amenable to specific treatment options. In addition, we will point out novel diagnostic and therapeutic approaches which will hopefully improve both our understanding and the prognosis of this more or less neglected disease.Unter dem Cancer of Unknown Primary (CUP)-Syndrom werden diejenigen Tumorerkrankungen zusammengefasst, bei denen auch nach Abschluss der Diagnostik nur Metastasen, jedoch kein Primärtumor gefunden wird. Das CUP-Syndrom macht ca. 3–5% aller neu diagnostizierten Malignomfälle aus und umfasst eine heterogene Gruppe von Tumoren, die die Fähigkeit zur Metastasierung erlangt haben bevor sich ein klinisch manifester Primärtumor entwickelt hat. Obwohl bemerkenswerte Fortschritte in der Behandlung von Patienten mit bestimmten, gut definierten Erkrankungssubgruppen, wie beispielsweise Frauen mit isolierter Peritonealkarzinose oder jungen Erwachsenen mit gering differenzierten Karzinomen mit Mittellinienverteilung, erzielt werden konnten, ist die Prognose bei der Mehrzahl der Patienten nach wie vor schlecht. Wir berichten im weiteren Verlauf dieser Übersichtsarbeit über Fortschritte in der Diagnostik und Therapie von Patienten mit CUPSyndrom und weisen darauf hin, dass es trotz der immer noch sehr schlechten Prognose von großer Bedeutung ist, Patienten mit bestimmten Subtypen des CUP-Syndroms zu identifizieren, die spezifischen Therapien mit der Option auf Heilung zugeführt werden sollten. Darüber hinaus möchten wir auf neuere diagnostische und therapeutische Bestrebungen aufmerksam machen, die das Verständnis und die Prognose dieses auch in der Onkologie bisher stiefmütterlich behandelten Krankheitsbildes hoffentlich verbessern werden.
Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
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Warnecke, Marei. "Untersuchungen zur Funktion des nukleären Orphan-Rezeptors Ear2." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972556923.
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Ekman, Diana, and Arne Elofsson. "Identifying and Quantifying Orphan Protein Sequences in Fungi." Stockholms universitet, Institutionen för biokemi och biofysik, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-49277.
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For large regions of many proteins, and even entire proteins, no homology to known domains or proteins can be detected. These sequences are often referred to as orphans. Surprisingly, it has been reported that the large number of orphans is sustained in spite of a rapid increase of available genomic sequences. However, it is believed that de novo creation of coding sequences is rare in comparison to mechanisms such as domain shuffling and gene duplication; hence, most sequences should have homologs in other genomes. To investigate this, the sequences of 19 complete fungi genomes were compared. By using the phylogenetic relationship between these genomes, we could identify potentially de novo created orphans in Saccharomyces cerevisiae. We found that only a small fraction, <2%, of the S. cerevisiae proteome is orphan, which confirms that de novo creation of coding sequences is indeed rare. Furthermore, we found it necessary to compare the most closely related species to distinguish between de novo created sequences and rapidly evolving sequences where homologs are present but cannot be detected. Next, the orphan proteins (OPs) and orphan domains (ODs) were characterized. First, it was observed that both OPs and ODs are short. In addition, at least some of the OPs have been shown to be functional in experimental assays, showing that they are not pseudogenes. Furthermore, in contrast to what has been reported before and what is seen for older orphans, S. cerevisiae specific ODs and proteins are not more disordered than other proteins. This might indicate that many of the older, and earlier classified, orphans indeed are fast-evolving sequences. Finally, >90% of the detected ODs are located at the protein termini, which suggests that these orphans could have been created by mutations that have affected the start or stop codons.authorCount :2
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Esteves, Kristyn M. "Identification of the genetic causes of orphan diseases." Thesis, Boston University, 2013. https://hdl.handle.net/2144/12097.
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Thesis (M.A.)--Boston UniversityBackground: Orphan diseases are defined as any disease, syndrome, or disorder that affects less than 200,000 persons in the United States. Most of these disorders are genetic in origin. However, with so few patients to study, researchers have struggled to collect enough data on any one orphan disease to make progress towards treatment and/or a cure. But, with the recent monumental advances in the field of genetic sequencing techniques, there has been an explosion in the potential avenues of study for these scientists. We hope to use data generated from whole exome studies of our orphan disease patients to identify potential disease-causing genetic lesions, and therefore solve the mystery of the genetic basis of their condition. Methods: For each family enrolled in our study, genomic DNA samples from the proband and his/her mother and father were evaluated for whole exome sequencing (performed by Axeq Technologies). We sorted and filtered these results using a variety of parameters until discovering a genetic variant we believed to potentially explain the phenotype of each patient. Once a gene of interest was identified, we used Sanger sequencing to confirm the mutation. At the present moment, we are at a variety of stages of progress amongst our study of our different patients. For our patients thought to be affected by dysfunctional SPEG, we have been working on a SPEG-CKO mouse model in attempt to recreate the phenotype we see in our patients and further study the function of SPEG. For our patient thought to be affected by dysfunctional PHKG1 and our patient thought to be affected by dysfunctional LAMA1, we are in the process of studying whether their mutations affect the expression and/or function of the associated proteins. Results: While we are still developing our mouse colonies, we have successfully developed a SPEG-CKO mouse model. With respect to PHKG1, we are still searching for another mutation, for both the proband and father are heterozygous for the same frameshift mutation, but only the proband is clinically affected. Our studies of LAMA1 appear promising, for the patient carries two mutations which segregate to each parent. However, more data must be collected on the expression of this protein, particularly with respect to whether it could cause the pontocerebellar hypoplasia phenotype. Conclusion: While major challenges still remain for orphan disease research, we will continue our investigations in hopes of determining the genetic basis of disease in these marginalized patients.
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Knight, Felice F. "Slavery and the Charleston Orphan House, 1790-1860." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1374152542.
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Reed, Julie Perdue Theda. "Family and nation Cherokee orphan care, 1835-1903 /." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2008. http://dc.lib.unc.edu/u?/etd,1805.
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Thesis (M.A.)--University of North Carolina at Chapel Hill, 2008.Title from electronic title page (viewed Dec. 11, 2008). "... in partial fulfillment of the requirements for the degree of Master of Arts in the Department of History." Discipline: History; Department/School: History.
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Heo, Jiyoung Beauchamp Jesse L. "Computational studies of orphan G protein-coupled receptors /." Diss., Pasadena, Calif. : California Institute of Technology, 2007. http://resolver.caltech.edu/CaltechETD:etd-11102006-144154.
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Migeotte, Isabelle. "Study of orphan receptors potentially implicated in leukocyte trafficking." Doctoral thesis, Universite Libre de Bruxelles, 2005. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210922.
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Nisbar, Nur Dayana Binti. "Characterisation of orphan cytochrome P450s from Mycobacterium tuberculosis H37Rv." Thesis, University of Manchester, 2018. https://www.research.manchester.ac.uk/portal/en/theses/characterisation-of-orphan-cytochrome-p450s-from-mycobacterium-tuberculosis-h37rv(5f953958-9722-4531-b8b2-b034adaaabb0).html.
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Tuberculosis is a disease that kills more people every year than any other infectious disease and is caused by the human pathogen, Mycobacterium tuberculosis (Mtb). This disease can be treated by a standard six month course of four antimicrobial drugs that have been in use since the 1960s. However, the rise of multi-drug resistant and extensively drug-resistant strains of TB has complicated the efforts to eradicate the disease. Therefore, there is a critical need for the development of new anti-TB drugs with a novel mechanism of action that can speed up treatment duration and help avoid resistance. The discovery of twenty genes encoding cytochrome P450 enzymes in the Mtb H37Rv genome sequence has pointed to the significance of these enzymes in the physiology and pathogenicity of this bacterium. Consequently, the characterisation of these Mtb P450 enzymes may define their physiological roles of which can be a novel anti-tubercular drug target. To date, the characterisations of selected Mtb P450 enzymes have highlighted their diverse and unexpected roles in the metabolism of cholesterol and lipids and the production of secondary metabolites. Biochemical and biophysical studies of these enzymes provided knowledge of their active site properties that may be exploited for drug discovery. Therefore, with the prospect of defining novel functions and identifying novel drug targets, characterisations of the remaining orphan Mtb P450s is of interest. M. tuberculosis CYP141A1 and CYP143A1 are orphan enzymes with unknown physiological function in Mtb which is characterised in this study through use of various spectroscopic and biophysical techniques. Interestingly, CYP141A1 can be expressed in form of which 54 amino acids (Del54CYP141A1) are deleted from the N-terminus. Although Del54CYP141A1 still retain spectroscopic characteristics, this form of P450 cannot be crystallized. Optimisation of full-length CYP141A1 buffer composition resulted to the formation of reproducible crystals and determination of CYP141A1 structure. Spectroscopic and structural characterisations presented in this thesis revealed many characteristics of CYP141A1 and CYP143A1 are comparable to previous Mtb P450s reported to date. CYP141A1 and CYP143A1 active site consist of b-type heme iron ligated by cysteine residue and a water molecule at its proximal and distal face, respectively. Both enzymes bind tightly to azole antifungal drugs highlighting their potential as a drug target. In addition, fragment-based screening applied to CYP141A1 and CYP143A1 provided the starting point for the development of potent, isoform-specific inhibitors for both orphan Mtb P450 enzymes. The first crystal structure of CYP141A1 and identification of new fragment binders of CYP141A1 and CYP143A1 are presented in this thesis. Overall, this research remains significant in providing new knowledge on the spectroscopic and structural properties of the M. tuberculosis P450s CYP141A1 and CYP143A1.
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Pereira, Franco Joao Pedro. "Similarity in the context of the orphan drug legislation." Thesis, University of Sheffield, 2015. http://etheses.whiterose.ac.uk/10148/.
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An orphan drug is a medicinal product intended for the treatment of a rare disease that affects only a small number of patients, e.g., five in ten thousand. According to the current European orphan drug legislation, the European Union shall not, for a period of ten years, accept another orphan medicinal product for the same therapeutic indication, in respect of a similar medicinal product. Thus far, the European Medicines Agency has used human judgments of similarity when assessing new medicines for rare diseases. The project reported here seeks to develop quantitative methods for this purpose. The project began with an analysis of the correlation between human and computed judgments of similarity for 100 pairs of molecules chosen from the Drug Bank 3.0 database. The human similarity assessments for these pairs of molecules were obtained from a total of 143 experts from Europe, Asia and the US, with the experts being asked to state whether each pair was, or was not, similar. The percentage of the experts judging a pair to be similar was then compared to the Tanimoto coefficient computed using a range of different types of descriptors (1D, 2D and 3D), with the aim of identifying those descriptors that correlated most closely with the human judgments. The following types of fingerprint were studied: ECFP4, ECFC4, Daylight, Unity, BCI, MDL as implemented in the Pipeline Pilot system; and CDK Extended, CDK Standard, Estate, PubChem, MACCS, Morgan, Feat Morgan, Atom Pair, Torsion, RDKit, Avalon, Layers, FP:TGD and FP:TGT as implemented in the KNIME system. The 3D fingerprints studied were the following: FP:TAD and FP:TAT as implemented in the KNIME protocol. 1D molecular property descriptors were also studied but these proved to be of only limited effectiveness for this application. Logistic regression models were developed for each type of descriptor, relating the Tanimoto similarity for a pair of molecules computed with the probability of the human experts regarding that pair as being similar. The resulting regression models were then validated using a separate test-set containing 100 pairs of molecules that had previously been evaluated by the European Medicines Agency in the context of the authorisation of medicines for rare diseases. The best models were able to reproduce over 95% of the human judgments. This success rate was increased to 98-99% using a simple data fusion approach in which a pair of molecules is classified as similar (or non-similar) when three or more of the individual fingerprints are in agreement. The results obtained here suggest that computed Tanimoto values based on 2D descriptors could provide a useful source of information when assessing new active substances that are being proposed for the treatment of rare diseases.
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Aubourg, Diana 1975. "Expanding the first line of defense : AIDS, orphans and community-centered orphan-care institutions in Sub-Saharan Africa : cases from Zambia." Thesis, Massachusetts Institute of Technology, 2002. http://hdl.handle.net/1721.1/63222.
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Thesis (M.C.P.)--Massachusetts Institute of Technology, Dept. of Urban Studies and Planning, 2002.Includes bibliographical references (leaves 67-69).
This thesis is about expanding the "first line of defense" for children and families affected by AIDS in sub-Saharan Africa. The overwhelming consensus among actors leading the fight against AIDS, ranging from USAID and UNICEF to local NGOs, is that extended families and communities are the "first line of defense" and will absorb the millions of children orphaned by AIDS. With this basic premise, the thinking follows that 1) families are almost always the best place for the child; 2) primary interventions should be centered on building the capacities of families to care for orphans and; 3) residential orphan care is the least desirable option for children because "orphan care institutions" are inherently "anti-community". I challenge this prevailing wisdom. I argue that this donor-driven approach, loosely termed "community based orphan care", is limited by, among other things, AIDS induced pressures on families and growing numbers of children disconnected from families (e.g. street children). Additionally, the approach imposes a false dichotomy between "the community" and "orphan care institutions". Drawing from case studies of three residential institutions caring for orphans and street children in Zambia, I deconstruct the common perceptions of orphan-care institutions. In particular, I challenge the characterization that they are isolated and disconnected from communities. My findings reveal a more complicated picture in which a subset of orphan care institutions share objectives and practices with the prevailing donor model of community-based orphan care - such as mobilizing local volunteers to care for orphans. I describe this neglected subset as "community-centered orphan care institutions" and explore the various ways in which they are embedded in and support communities. I assert that as the AIDS epidemic expands and the orphan crisis worsens, community-centered orphan care institutions must serve as key actors in expanding the first line of defense.
by Diana Aubourg.
M.C.P.
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Båvner, Ann. "Molecular mechanisms of transcriptional repression by the orphan receptor SHP /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-212-8/.
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Ruan, Xuan 1974. "Differential circadian regulation of Bmal1 transcription by orphan nuclear receptors." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=112358.
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In mammals, circadian rhythms are generated by transcriptional-translational feedback loops consisting of a set of clock genes and their protein products. Among them, Bmal1 is a critical clock gene in generating and maintaining circadian rhythms. Moreover, orphan nuclear receptors REV-ERBs and RORs were known to respectively repress and activate Bmal1 transcription. In our study, we further demonstrated that: (1) REV-ERBalpha might be the main regulator in maintaining Bmal1 oscillation in thymus. (2) Rorgamma mRNA is constant in muscle and testis, and rhythmic in liver, while Rorgammat mRNA is only expressed in thymus, at constant levels. Moreover, the expressions of these two Rorgamma isoforms are affected in Clock mutant mice in a distinct way. (3) RORgamma and RORgammat can activate Bmal1 transcription at a similar level. (4) Rorgamma is a clock-controlled gene. Altogether, our results suggest that the crucial role of REV-ERBs and RORs in peripheral clocks. Furthermore, our work highlights functional differences among mammalian peripheral clocks, which provides important insights into the complexity of the circadian system.
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Nicholson, Janet Rachel. "Investigation of the orphan opioid receptor in the nervous system." Thesis, University of Cambridge, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.624221.
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Crompton, Helen Patricia. "The social construction of orphan drugs : innovation through knowledge networks." Thesis, Manchester Metropolitan University, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.412483.
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Innovation has been studied from the perspectives of social psychology, economics, business studies, sociology and science and technology studies. Collyer (1996) claims that factors in the social or technical environment are subsumed in psychology, by an emphasis on the personality structure or cognitive activity within the individual. In the area of business studies and economics the emphasis has been on the development and transfer of products to the market rather than on the creation of new products - largely ignoring inventions that have no, or limited, commercial application (like orphan drugs) Few studies have concentrated on the social, cultural or political process of innovation, the focus being on the adoption and diffusion processes. According to Collyer (1996) most studies, which theorise the social formation of ideas and knowledge, focus on the locus of scientific knowledge production, in the research laboratory (see Knorr- Cetina 1995 in Jasanoff et al 1995, Latour 1987). These studies ignore the political and ideological influences from external sources and other sites of knowledge production (ergo Mode 2 sites in industry and for example, medical practitioners seeking solutions to practical problems, or especially in this case the patients and their advocates). Mode 1 (knowledge production) is mainly to be found in basic research, mostly academic, producing scientific documentation. Mode 2 is mainly to be found in applied research, mostly industrial, producing patents through the development of applications or processes. There may be crossovers into strategic applied research by both modes but in general they are different types of knowledge production, or the mechanism by which research benefits economic growth. Nowotny et al (2001) suggest that society is changing and the line that previously separated science and society is continually being transgressed. New networks are forming and the public speaks back to science creating new public arenas ('agoras') where the constitution of science policy involves 'negotiation', 'mediation', 'consultation' and 'contestation' challenging science and technology to produce 'socially robust' knowledge. In the orphan drug 'market' we can see industry, researchers (public and private), charitable organisations (as advocates), regulators (politics) and venture capitalists brought together in a public forum. This theses makes a significant contribution to knowledge by using a social constructionist approach as the innovation process unfolds and by providing a further methodological conceptual framework for Mode 2 knowledge production. Whilst providing evidence for Nowotny et aI's agora it also provides a model of the relationship between scientific expertise and policy making extending the decisionist and technocratic model following Edwards's (1999) claim that there is no adequate model available to demonstrate the relationships between scientific expertise, public policy making and the public.
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Misra, Raju V. "Characterising orphan enzyme activities using bioinformatic, biochemical and proteomic approaches." Thesis, University of York, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.441018.
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Disney, Tom. "Between care and control? : orphan geographies in the Russian Federation." Thesis, University of Birmingham, 2015. http://etheses.bham.ac.uk//id/eprint/6298/.
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While many countries in the West have been broadly pursing policies of deinstitutionalisation since the latter half of the 20th Century, orphanages remain the norm for many countries. Orphanage research has often tended to be conducted through a bio-psychological lens, and there remains little qualitative research to reveal the nuances of micro-scale practices taking place within these institutions. This thesis employs a multi-sited ethnography and explores the orphanage as a complex institution influenced by Soviet and Post-Soviet practices of childcare. In particular, this research draws upon an ethnography conducted in an orphanage for children with severe intellectual disabilities. The thesis considers the multiscalar nature of this institution and explores childhood mobilities, agency and elements of discipline and control within the institution, destabilising the notion of the orphanage as an environment of care. This research addresses significant empirical lacunae in human geography and studies of post-socialism through an ethnographic study of Russia's disability orphanages. This research also challenges understandings of mobility in children's geographies by drawing upon theories of coerced and disciplined mobility. Finally, in highlighting the vulnerability of these children, this thesis develops the concept of 'contingent agency' to provide a more nuanced understanding of agency in children's geographies.
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Proyrungroj, Raweewan. "Orphan volunteer tourism in Thailand : understanding motivations, experiences and interactions." Thesis, University of Bedfordshire, 2013. http://hdl.handle.net/10547/294282.
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This research investigates volunteer tourists’ motivations and on-site experiences, alongside hosts’ attitudes towards volunteer tourists at the Home and Life orphanage in Phang Nga province, Thailand. An interpretive paradigm utilising qualitative data collection methods (semi-structured interviews, a focus group, participant observation and diaries) was adopted. The informants included twenty-four volunteer tourists, on a working vacation at the Home and Life orphanage between 1stJuly and 30th September 2011, and twenty hosts from Thai Muang subdistrict. The findings of the research suggest that the volunteer tourists’ motivations and on-site experiences are multidimensional. Five main themes of motivations have been identified: (i) to help the children who were affected by the 2004 Boxing Day tsunami; (ii) to gain personal development and growth; (iii) to gain new experiences; (iv) to learn about/be immersed in local culture; and (v) to meet and make friends. Amongst these, a desire to help the children was the most dominant motivational factor, which was strongly influenced the 2004 Boxing Day tsunami. In terms of the volunteer tourists’ on-site experiences, four experiential dimensions were found: (i) personal development and growth; (ii) social; (iii) cultural; and (iv) feeling. The study suggests that the children had played a significant role in making the volunteer tourists’ experience a beneficial one because they were an important source for cultural learning and their lives had taught a number of things to the volunteer tourists. This research also investigates hosts’ attitudes towards the volunteer tourists. It was found that they had very positive attitudes towards the volunteer tourists, based upon two main factors: the volunteer tourists’ conduct and performance; and the perceived benefits they gained from the work of these tourists. The opportunity for the children to study English with English native speakers was cited as the most significant benefit. However, the hosts also had concerns about some aspects of the volunteer tourists’ behaviour and perceived underperformance, which were found to be mainly the result of cultural differences. Additionally, interactions and relationships between volunteer tourists and hosts were also examined by using social exchange theory. The study suggests that the interactions were reciprocal, and that both the volunteer tourists and the hosts enjoyed satisfactory benefits from one another: the volunteer tourist had a desired experience, and the hosts gained benefits from the work of the volunteer tourists.
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Nüßeler, Elke. "Charakterisierung des Chemokinrezeptor-ähnlichen orphan-Rezeptors CXCR1-like der Maus." [S.l. : s.n.], 2006. http://nbn-resolving.de/urn:nbn:de:bsz:289-vts-55569.
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Madon, Katelyn, and Chris Dr Pritchett. "Investigating Orphan Response Regulators in the Opportunistic Pathogen Pseudomonas aeruginosa." Digital Commons @ East Tennessee State University, 2018. https://dc.etsu.edu/asrf/2018/schedule/127.
Full textAbstract:
The opportunistic pathogen Pseudomonas aeruginosa utilizes a variety of virulence factors to infect a wide range of hosts. Virulence genes in this organism are many times controlled by two-component regulatory systems consisting of a sensor histidine kinase and a response regulator giving them high importance in research. Orphan response regulators consist of genes that have been proposed to be a response regulator but have not been studied to determine if they do work in a two-component regulatory system or not. Investigating these orphan response regulators could potentially lead to the finding of another regulator of virulence genes. Non-polar deletions were designed using splicing of genomic segments by overlapping extension. A variety of phenotypic assays, liquid-killing assays with the nematode C. elegans, and virulence assays with macrophages were utilized to determine if these orphans were different from the wild-type strain PAO1. If attenuated, these genes can be further studied to find new and novel regulators of virulence in Pseudomonas aeruginosa.
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Singh, Sumitra. "Health status and health needs of orphan children of Kathmandu Nepal." Thesis, Available from the University of Aberdeen Library and Historic Collections Digital Resources. Restricted: contains 3rd party material and therefore cannot be made available electronically, 2009. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?application=DIGITOOL-3&owner=resourcediscovery&custom_att_2=simple_viewer&pid=53383.
Full textAbstract:
Thesis (Ph.D.)--Aberdeen University, 2009.With: Health status and health needs of the orphan children of Kathmandu Nepal : the findings of the pilot study / S. Sing, Edwin R. Van Teijlingen, P. Simkhada. Stupa Journal of health services. 2007: 3, 1-2. With: Health status and health needs of orphan children of Kathmandu Nepal / S. Sing, P. Simkhada, Edwin R. Van Teijlingen. Journal of Nepal Heath Research Council. 2007: 5, 2. Includes bibliographical references.
30
Basile, Walter. "Orphan Genes Bioinformatics : Identification and properties of de novo created genes." Doctoral thesis, Stockholms universitet, Institutionen för biokemi och biofysik, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-149168.
Full textAbstract:
Even today, many genes are without any known homolog. These "orphans" are found in all species, from Viruses to Prokaryotes and Eukaryotes. For a portion of these genes, we might simply not have enough data to find homologs yet. Some of them are imported from taxonomically distant organisms via lateral transfer; others have homologs, but mutated beyond the point of recognition. However, a sizeable fraction of orphan genes is unambiguously created via "de novo" mechanisms. The study of such novel genes can contribute to our understanding of the emergence of functional novelty and the adaptation of species to new ecological niches. In this work, we first survey the field of orphan studies, and illustrate some of the common issues. Next, we analyze some of the intrinsic properties of orphans proteins, including secondary structure elements and Intrinsic Structural Disorder; specifically, we observe that in young proteins the relationship between these properties and the G+C content of their coding sequence is stronger than in older proteins. We then tackle some of the methodological problems often found in orphan studies. We find that using evolutionarily close species, and sensitive, state-of-the art homology recognition methods is instrumental to the identification of a set of orphans enriched in de novo created ones. Finally, we compare how intrinsic disorder is distributed in bacteria versus eukaryota. Eukaryotic proteins are longer and more disordered; the difference is to be attributed primarily to eukaryotic-specific domains and linker regions. In these sections of the proteins, a higher frequency of the disorder-promoting amino acid Serine can be observed in Eukaryotes.At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Submitted. Paper 4: Manuscript.
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Castro, Diogo Sampaio e. "Functional studies on the orphan receptor Nurr1 and related retinoid receptors /." Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4608-6/.
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Remmele, Corinna. "Arzneimittel für seltene Leiden ("Orphan Drugs") im EG- und US-Recht /." Aachen : Shaker, 2007. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=016256867&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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Henstridge, Christopher Michael. "The cellular signalling and physiological significance of the orphan receptor GPR55." Thesis, University of Dundee, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.510685.
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Sharma, Seema. "Targeting the orphan homeobox protein STF-1 to pancreatic islet cells /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 1997. http://wwwlib.umi.com/cr/ucsd/fullcit?p9735270.
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Zydenbos, Robert J. "The calf became an orphan : a study in contemporary Kannada fiction /." Pondichéry : [Paris] : Institut français de Pondichéry ; Ecole française d'Extrême-Orient, 1996. http://catalogue.bnf.fr/ark:/12148/cb361665233.
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Mylne, Joshua Scott. "Finding functions for novel and orphan arabidopsis genes : the EST advantage /." St. Lucia, Qld, 2001. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16435.pdf.
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Ding, Jin. "Evolution and dynamics of the sectoral system of innovation : a case study of orphan drug innovation in the US." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/33059.
Full textAbstract:
Drugs for treating rare diseases had been neglected by the pharmaceutical industry for a long time, due to the complex and costly drug R&D process as well as a small unprofitable market. Since its introduction in 1983, the Orphan Drug Act (ODA) has sought to prompt the innovation of drugs for minority diseases by reducing the regulatory and economic barriers. The incentives of the ODA have been effected through market protection, tax credit, fee waiver and grants to increase the accessibility of orphan products for the public. The number of orphan drugs available in the market has risen sharply from just ten in the decade before 1983 to over 400 since 1983. This increase implies a substantial improvement of the healthcare of patients suffering rare diseases and a success of the orphan drug legislation with the aim to motivate the development and manufacture of products that have low commercial potentials. Although it is evident that the ODA has successfully stimulated drug companies to develop numerous orphan products, treatments are very expensive. The sales of blockbuster orphan drugs have provided drug companies with unusually highprofit margins and limited patient access to treatments. The dilemma presented by the ODA reflects many of the issues currently faced by policymakers. In this thesis, we have analyzed the long-term evolution of the biopharmaceutical industry. In particular, we have examined drug discovery in the period of random screening, rational design and network collaboration, and explored the influence of the ODA. We have taken the theory of the sectoral system of innovation, and combined it with the complex adaptive model of innovation, and found that the complex version of that theory is capable of explaining the comprehensive drug innovation system. A Multi-agent Based Model has been introduced to identify and analyze the dynamics of bio-pharmaceutical innovation. The model has explored the roles of the main players in the sector and the influence of their relationships embedded in the process of orphan drug innovation. Through this model, we have investigated the mechanisms of how the incentives stimulate orphan drug innovation during the period from 1983- 2012. Moreover, the model has been applied to solve the dilemma of the ODA through analyzing how to achieve the best trade-off between orphan drug developments. Drawing upon the results of the simulation, we provide a sound basis for adjusting the ODA incentives to strikes an appropriate balance between stimulating orphan drug innovation and providing benefits to society, propose some resolutions to the ODA, while also to motivate orphan drug development in a financial way. The Advice for other countries planning to enact the orphan drug legislation and directions for further research suggested by this model have been put forward.
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Chintharlapalli, Sudhakar Reddy. "New mechanism-based anticancer drugs that act as orphan nuclear receptor agonists." Diss., Texas A&M University, 2003. http://hdl.handle.net/1969.1/5978.
Full textAbstract:
1,1-Bis(3'-indolyl)-1-(p-substitutedphenyl)methanes containing ptrifluoromethyl
(DIM-C-pPhCF3), p-t-butyl (DIM-C-pPhtBu), and phenyl (DIM-CpPhC6H5)
substituents have been identified as a new class of peroxisome proliferatoractivated
receptor ó (PPARó) agonists that exhibit antitumorigenic activity. In this study,
the PPARó-active compounds decreased HT-29, HCT-15, RKO, HCT116 and SW480
colon cancer cell survival and KU7 and 253JB-V33 bladder cancer cell survival. In HT-
29, HCT-15, SW480 and KU7 cells, the PPARó agonists induced caveolin-1 expression
and this induction was significantly downregulated after cotreatment with the PPARó
antagonist GW9662. Since overexpression of caveolin-1 is known to suppress cancer
cell and tumor growth, the growth inhibitory effects of the DIM compounds in these cell
lines are associated with PPARó-dependent induction of caveolins. These PPARó-active
compounds did not induce caveolin-1 in HCT-116 cells. However, these compounds
induced NSAID-activated gene-1 (NAG-1) and apoptosis in this cell line. This
represents a novel receptor-independent pathway for C-DIM-induced growth inhibition and apoptosis in colon cancer cells. In SW480 colon cancer cells 2.5-7.5 üM C-DIMs
induced caveolin-1 whereas high concentrations (10 üM) induced pro-apoptotic NAG-1
expression. In athymic nude mice bearing SW480 cell xenografts DIM-C-pPhC6H5
inhibited tumor growth and immunohistochemical staining of the tumors show induction
of apoptosis and NAG-1 expression. Thus, the PPARó-active compounds induce both
receptor-dependent and-independent responses in SW480 cells which are separable over
a narrow range of concentrations and this dual mechanism of action enhances their
antiproliferative and anticancer activities. Similar results were obtained for another
structural class of PPARó agonists namely 2-cyano-3,12-dioxoolean-1,9-dien-28-oic
acid (CDDO) and the corresponding methyl (CDDO-Me) and imidazole (CDDO-Im)
esters. Structure-activity studies show that 1,1-bis(3'-indolyl)-1-(psubstitutedphenyl)
methanes containing p-trifluoromethyl (DIM-C-pPhCF3), hydrogen
(DIM-C-pPh) and p-methoxy (DIM-C-pPhOCH3) substituents activate Nur77 and induce
apoptosis in pancreatic, prostate, and breast cancer cell lines. Nur77 agonists activate the
nuclear receptor, and downstream responses include decreased cell survival, induction of
cell death pathways including tumor necrosis factor related apoptosis-inducing ligand
(TRAIL) and PARP cleavage. Nur77 agonists also inhibit tumor growth in vivo in
athymic nude mice bearing Panc-28 cell xenografts.
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Goerzen, Christy Sharon. "Narratives of transformation : orphan girls, dolls and secret spaces in children's literature." Thesis, University of British Columbia, 2006. http://hdl.handle.net/2429/32613.
Full textAbstract:
Many critics working in the field of literature for children have acknowledged the
prevalence of orphan characters, dolls and doll characters and "children-only" spaces in the
literature. While many have discussed their significance separately, to the best of my
knowledge no one has thus far examined how they can function and operate together in
literature for children. This examination of these formerly separate topics together is
grounded in the question: How do dolls, secret spaces and the play associated with them
function in literature for children such that the marginalized and displaced orphan girl
characters therein undergo positive psychological transformation?
My study is based in literary and psychological analysis. The theoretical framework
employs the play theories of D.W. Winnicott and Erik Erikson, in conjunction with Gaston
Bachelard's and Yi-Fu Tuan's theories of space. The methodology of this study builds upon
psychological analyses of the orphan girl protagonists, within the context of their secret space
environments and their relationships with dolls in the novels.
This thesis analyzes four distinct novels featuring orphan girl protagonists, secret
spaces and dolls, and examines the forms of psychological transformation experienced by
each protagonist: Rumer Godden's Miss Happiness and Miss Flower, Sylvia Cassedy's Lucie
Babbidge's House, Enys Tregarthen's The Doll Who Came Alive and Sylvia Cassedy's
Behind the Attic Wall. In each case, this positive outcome is encouraged and facilitated by
the girl's relationship to her dolls and her place of solace, or secret space. The patterns found
here can point to ways of discovering the psychological changes in other protagonists in
literature for children, and how playthings and secret spaces can work to facilitate these
changes.Arts, Faculty of
Library, Archival and Information Studies (SLAIS), School of
Graduate
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Miller, Leanne R. "Understanding Attachment and Perceptions of Orphan Caregivers in Institutional Care in Kenya." Thesis, The Chicago School of Professional Psychology, 2015. http://pqdtopen.proquest.com/#viewpdf?dispub=3720289.
Full textAbstract:
This concurrent nested mixed methods study assessed institutional caregivers’ perception on their role as caregivers and caregivers’ attachment orientation in Kenya. Additionally, the study looked for a connection between attachment and perception. Participants were 15 female caregivers, 8 from a government institution and 7 from a nongovernment institution. Data from a semi-structured interview indicated that caregivers, regardless of attachment, were emotionally invested in the children’s wellbeing, felt a sense of duty, and stated their job was challenging but rewarding. ECR-R assessed attachment and found that attachment varied slightly between institutions. The most significant difference was between institutions with 4 secure caregivers in the nongovernment institution and only 1 secure caregiver in the government institution. A slight relationship between attachment and perception was found as all secure caregivers indicated they believed both physical and emotional needs of children were essential. Results indicate additional cultural studies on attachment and perception are warranted.
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Peters, Laura Lynn. "'Shades of the prison-house' : the disciplining of the Victorian literary orphan." Thesis, University of Kent, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.240674.
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Sene, Ayshka. "The orphan story of British women in occupied France : history, memory, legacy." Thesis, Cardiff University, 2018. http://orca.cf.ac.uk/118498/.
Full textAbstract:
This thesis examines the 'orphan story' of British women in occupied France. It focuses in particular on the experiences of British women interned in Besançon and Vittel, two internment camps in Eastern France, during the Second World War. It contextualises such stories of incarceration within the broader experiences and narratives of British women in wartime France, and it questions why these experiences of internment have been overlooked until now. Existing work on British women in France has tended to focus on the exploits of young women who served as Special Operations Executive agents (Pattinson 2007), contributing to a highlighting of the heroic and glamorous aspects of resistance. This reflects a small proportion of the British women in Occupied France when compared with the 3900 internees in Besançon in December 1940, and does not account for the everyday experiences of British women from different generations and social backgrounds. Drawing on biographies published between 2007 and 2014 about British women interned in Besançon and Vittel, and a significant corpus of archival material (unpublished diaries, correspondence, oral history recordings, foreign office reports, photographs, and drawings related to their experiences), this thesis interrogates such current understandings and stereotypes about British women during the Second World War in France. Since wartime is a 'particularly fertile time at which to see the nation at work' (Purcell 2007, p.7), it does so by highlighting how notions of 'Britishness' and national identity influenced these women. Indeed, this study reveals the importance of national identity in shaping British women's experiences between 1939 and 1944. Until December 1940, despite the increasing Nazi threat, women with the strongest sense of belonging to France were the most likely to remain, undeterred by strong recommendations from the British government to leave. Categories such as 'enemy alien' meant that British women who had 'belonged' in France for decades were ostracised by some French people, as Britain was labelled an enemy and a traitor in Vichy and Nazi propaganda. This thesis reveals the slippage between national identities experienced by these women and demonstrates that many internees discovered or reawakened their sense of Britishness during this period. Some actively chose to 'flag' (Billig 1995), their British nationality over other identities to survive. Finally, using biographies written by relatives of these women, it evaluates the inter-generational transmission of these wartime experiences. It argues that their life stories have remained peripheral in popular memories of the war. These are 'orphan stories' as such life experiences sat in-between national narratives in Britain and France, and, even today, do not align with depictions of the British national self as 'triumphant' or 'tragically defeated' (Daase 2010, p.19).
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La, Prairie Gillian Phillippe. "Social and behavioural development in a group of wild-born orphan chimpanzees." Thesis, University of Cambridge, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.620925.
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Duvall, Mark. "The New Orleans Female Orphan Society: Labor, Education, and Americanization, 1817-1833." ScholarWorks@UNO, 2009. http://scholarworks.uno.edu/td/997.
Full textAbstract:
In the first few decades of the nineteenth century, Americans and immigrants moved to New Orleans hoping to take advantage of the opportunities the city offered. Many American citizens moved from cities like Boston, New York, and Philadelphia. Recognizing the lack of social welfare programs and assistance given to the poor, a group of women established the Female Orphan Society. From its creation, the Female Orphan Society worked in providing aid to indigent mothers and their children through providing religious, vocational, and educational training. In a short time, the FOS emerged as the only private, Protestant female refuge for immigrant families and their children in New Orleans. This involvement elevated the role of the asylum in the city and heightened the influence of an institution run by southern, upper-class white women.
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Eisen, Natalie. ""She's Not a Real Monster": Orphan Black's Helena and the Monstrous-Feminine." Scholarship @ Claremont, 2017. http://scholarship.claremont.edu/scripps_theses/929.
Full textAbstract:
This thesis explores the idea of the “monstrous-feminine,” or the idea that female monsters of television and film are linked to their femininity in a way that male monsters are not linked to their masculinity. Using the work of scholars such as Barbara Creed, Shelley Stamp Lindsey, and Jane M. Ussher, the thesis covers various facets of women’s lives as seen through the distorted lens of the monstrous. The character of Helena from the television show Orphan Black is used as a concrete example of the stages of the monstrous-feminine: the girl-child, menstruation and puberty, sexuality, and motherhood.
46
Wiss, Johanna. "Healthcare Priority Setting and Rare Diseases : What Matters When Reimbursing Orphan Drugs." Doctoral thesis, Linköpings universitet, Avdelningen för hälso- och sjukvårdsanalys, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-136820.
Full textAbstract:
The rarity of a disease can give rise to challenges that differ from conventional diseases. For example, rarity hampers research and development of new drugs, and patients with severe, rare diseases have limited access to qualified treatments. When drugs are available, clinical evidence has higher uncertainty and the drugs can be very expensive. When setting priorities in the healthcare sector, treatments aimed at patients with rare diseases, so called orphan drugs, have become a source of concern. Orphan drugs seldom show solid evidence of effectiveness or cost-effectiveness. Still, treatments for rare disease patients, available on the European market, has increased rapidly since the adoption of a regulation offering incentives for research and development of orphan drugs. The question arises as to whether the publicly funded health care system should provide such expensive treatments, and if so, to what extent. This doctoral thesis aims to investigate healthcare priority setting and rare diseases in the context of orphan drug reimbursement. Priority setting for orphan drugs is located at the intersection of economic, ethical and psychological perspectives. This intersection is explored by studying the public’s view on the relevance of rarity when setting priorities for orphan drugs, and by examining how orphan drugs are managed when making reimbursement decisions in practice. Papers I and II in this thesis employ quantitative, experimental methods in order to investigate preferences for prioritising rare diseases, and the extent to which psychological factors influence such preferences. Papers III and IV employ qualitative methods to further explore what factors (apart from rarity) influence priority-setting decisions for orphan drugs, as well as how decisions regarding orphan drugs are made in practice in England, France, the Netherlands, Norway and Sweden. Combining quantitative and qualitative methods has provided a more comprehensive understanding of the topic explored in the thesis, and the methods have complemented each other. Paper I shows that there is no general preference for giving higher priority to rare disease patients when allocating resources between rare and common disease patients. However, results show that preferences for treating the rare patients are malleable to a set of psychological factors, in particular “proportion dominance”. Paper II shows that the identifiability of an individual has no, or a negative, influence on the share of respondents choosing to allocate resources to him/her (compared to a nonidentified individual). Paper III confirms that rarity per se is not seen as a factor that should influence priority-setting decisions (i.e. accept a greater willingness to pay for orphan drugs), however, other factors such as disease severity, treatment effect and whether there are treatment alternatives were seen as relevant for consideration. Paper IV explores the challenges with and solutions for orphan drug reimbursement, as perceived by different actors in five European countries. Perceived challenges are related to the components involved when making reimbursement decisions, to the reimbursement system, and to the acceptance of the final decision. Solutions are either specific for orphan drugs, or general measures that can be used for orphan drugs as well as for other drugs. In conclusion, priority setting for orphan drugs is complex and requires particular attention from decision makers. There are many factors to consider when making reimbursement decisions for orphan drugs. The consequences of a decision are potentially severe (both for rare disease patients and for common disease patients, depending on the decision) and psychological factors can potentially influence decisions.
47
Bubacz, Beryl M. "The Female and Male Orphan Schools in New South Wales, 1801-1850." Thesis, The University of Sydney, 2007. http://hdl.handle.net/2123/2474.
Full textAbstract:
This thesis is concerned with an examination and re-assessment of the establishment, operation and management of the Female and Male Orphan Schools, in the first half of the nineteenth century in New South Wales. The chaplains and governors in the early penal settlement were faced with a dilemma, as they beheld the number of children who were ‘orphaned’, neglected, abandoned and destitute. In order to understand the reasons why these children were in necessitous circumstances, the thesis seeks to examine the situations of the convict women, who were the mothers of these children. Governors Philip Gidley King and Lachlan Macquarie respectively in 1801 and 1819 established the Schools, which provided elementary education, training and residential care within a religious setting. Researching the motives underlying the actions of these men has been an important part of the thesis. An examination of the social backgrounds of some of the children admitted to these Schools has been undertaken, in order to provide a greater understanding of the conditions under which the children were living prior to their admissions. Information about family situations, and the social problems encountered by parents that led them to place their children in the Schools, have been explored. The avenues open to the girls and boys when they left the Schools, has formed part of the study. Some children were able to be reunited with family members, but the majority of them were apprenticed. A study of the nature of these apprenticeships, has led to a greater understanding of employment opportunities for girls and boys at that time. In 1850 the Schools were amalgamated into the Protestant Orphan School at Parramatta. By examining the governance and operation of the Schools during their last two decades as separate entities, we have more knowledge about and understanding of these two colonial institutions. It is the conclusion of this thesis that some of the harsher judgements of revisionist social historians need to be modified. It was the perception that more social disorder would occur if action was not taken to ‘rescue’ the ‘orphaned’ children, usually of convict parentage. However genuine charity, philanthropy and concern was displayed for the children in grave physical and moral danger. The goals of the founders were not always reached in the Orphan Schools, nevertheless they performed an invaluable service in the lives of many children.
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Bubacz, Beryl M. "The Female and Male Orphan Schools in New South Wales, 1801-1850." University of Sydney, 2007. http://hdl.handle.net/2123/2474.
Full textAbstract:
Doctor of PhilosophyThis thesis is concerned with an examination and re-assessment of the establishment, operation and management of the Female and Male Orphan Schools, in the first half of the nineteenth century in New South Wales. The chaplains and governors in the early penal settlement were faced with a dilemma, as they beheld the number of children who were ‘orphaned’, neglected, abandoned and destitute. In order to understand the reasons why these children were in necessitous circumstances, the thesis seeks to examine the situations of the convict women, who were the mothers of these children. Governors Philip Gidley King and Lachlan Macquarie respectively in 1801 and 1819 established the Schools, which provided elementary education, training and residential care within a religious setting. Researching the motives underlying the actions of these men has been an important part of the thesis. An examination of the social backgrounds of some of the children admitted to these Schools has been undertaken, in order to provide a greater understanding of the conditions under which the children were living prior to their admissions. Information about family situations, and the social problems encountered by parents that led them to place their children in the Schools, have been explored. The avenues open to the girls and boys when they left the Schools, has formed part of the study. Some children were able to be reunited with family members, but the majority of them were apprenticed. A study of the nature of these apprenticeships, has led to a greater understanding of employment opportunities for girls and boys at that time. In 1850 the Schools were amalgamated into the Protestant Orphan School at Parramatta. By examining the governance and operation of the Schools during their last two decades as separate entities, we have more knowledge about and understanding of these two colonial institutions. It is the conclusion of this thesis that some of the harsher judgements of revisionist social historians need to be modified. It was the perception that more social disorder would occur if action was not taken to ‘rescue’ the ‘orphaned’ children, usually of convict parentage. However genuine charity, philanthropy and concern was displayed for the children in grave physical and moral danger. The goals of the founders were not always reached in the Orphan Schools, nevertheless they performed an invaluable service in the lives of many children.
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Rupertus, Christian John. "Anxieties Of Belonging: The Trope Of the Orphan In African American Novels." Diss., Temple University Libraries, 2018. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/485357.
Full textAbstract:
EnglishPh.D.
This dissertation investigates the trope of the orphan in African-American novels and analyzes the prevalence of the figurative expression in the genre over time. Alienated from and deemed illegitimate by the larger society throughout their history, African Americans have grappled with competing desires to at once belong to the nation-as-family and to simultaneously be liberated from its White supremacist underpinnings. Systematically deprived of their rightful familial and cultural inheritances from their initial arrival to the Americas, Blacks have operated out of a perpetual state of orphanhood in the United States ever since, demanding acknowledgement as equal citizens while cobbling together their own intra-racial kinship bonds. By replacing nation-as-family with race-as-family to stem the tide of oppression, African Americans endeavored to carve out protective spaces for themselves within a hostile environment. The frequent deployment of Black orphan characters in African-American novels alternately reflects and interrogates this interplay between longing and liberation, transmuting over time to foreground how the exigencies of the moment come to bear on African Americans’ collective quest to find what scholar Amy Lang calls “a home for those without a home in the nation.” In order to conduct this work, I first construct a lens through which to evaluate Black orphan characters as tropological revisions, one of the four modes of double-voiced textual relations or significations delineated by Henry Louis Gates Jr. in the Signifying Monkey. This opens a field of vision from which I analyze conceptualizations of kinship, home, and their relationship with what Toni Morrison calls the “anxieties of belonging” in African-American novels. Her phrase furnishes a framework for viewing orphanhood as a metaphor for historical conditions that have caused African Americans to confront the absence of ancestral history, a circumstance precipitated first by their forced deportation from the continent of Africa and then concatenated by the subsequent dissolution of Black family ties through the mechanics of chattel slavery. While White American novels like Huck Finn, for instance, rehearse a desire for independence and the disavowal of familial ties in favor of formulating one’s own identity, African-American narratives function as meditations on how forced dependence sought to sever Blacks from their heritage and preclude the formulation of identity, and how Blacks could resist those dehumanizing effects. My dissertation consists of six chapters that match seminal works of African-American literature with the tenor of the times around their publication date; thereby, it plots points of intersection between historical exigencies and cultural enterprises personified in the literary tradition. Opening with the narratives of Frederick Douglass and Harriet Jacobs, this investigation authenticates the parameters and topographies of the trope of the orphan that recur in subsequent African-American novels, including those that are the focus of my work: Frank J. Webb’s The Garies and Their Friends (1857); Frances Ellen Watkins Harper’s Iola Leroy (1892); Nella Larsen’s Passing (1929); Octavia Butler’s Kindred (1979); and Paul Beatty’s White Boy Shuffle (1996). By identifying characters in the given novels as instances or inflections of the trope of the orphan and its evolution over time, I demonstrate that historical conditions have rendered orphanhood a powerful symbol for the Black experience in American society, one that has come to stand for the cultural, political, and nationalistic anxieties. In plotting the coordinates of these tensions through the use of Black orphan characters, African-American novels destabilize fixed notions of identity. Moreover, they chart a course for attaining an authentic sense of belonging by cobbling together both intra- and inter-racial communities predicated on the acknowledgement of the full humanity of the orphaned character, and by extension, of African Americans as a whole.
Temple University--Theses
50
Galeazzi, Luca. "Identificazione dell'enzima nicotinammide mononucleotide deamidasi, "orphan enzyme" della biosinstesi della vitamina B3." Doctoral thesis, Università Politecnica delle Marche, 2011. http://hdl.handle.net/11566/242221.
Full textAbstract:
Nell’ultimo decennio le nostre conoscenze relative alla biosintesi e al riciclo della vitamina
B3 negli eubatteri sono notevolmente aumentate sia grazie al sequenziamento del genoma
di numerose specie batteriche che ha consentito lo sviluppo di analisi di genomica
comparativa, sia grazie all’avanzamento degli studi sulla struttura e funzione di molti degli
enzimi coinvolti. Tuttavia, alcuni enzimi chiave rimangono ancora appartenenti alla
categoria dei cosiddetti “orphan enzymes”, enzimi la cui attività è stata sperimentalmente
dimostrata, ma di cui non si conoscono ancora i geni corrispondenti. Fa parte di questa
categoria l’enzima nicotinammide mononucleotide (NMN) deamidasi il quale catalizza la
conversione dell’ NMN a nicotinato mononucleotide (NaMN) e quindi gioca un ruolo
essenziale nella conversione della vitamina B3 nella sua forma coenzimatica NAD.
L’esistenza di questo enzima è documentata in numerosi studi che hanno dimostrato
direttamente la presenza di una significativa attività NMN deamidasica in estratti di cellule
batteriche. Inoltre, nei batteri il cui genoma è stato sequenziato, l’esistenza dell’enzima può
essere indirettamente predetta attraverso la ricostruzione in silico dell’insieme delle vie
metaboliche responsabili della biosintesi e della conversione a NAD della vitamina. Infatti,
la ricostruzione del pattern metabolico nelle specie batteriche in grado di convertire la
vitamina B3 a NMN, ma che mancano dell’enzima che catalizza la conversione diretta dell’
NMN a NAD, evidenzia l’esistenza di un gap metabolico (missing gene) che può essere
colmato solo ipotizzando l’esistenza di un’ attività NMN deamidasica in grado di
indirizzare l’NMN alla via deamidata per la sintesi del NAD, che appare priva di gaps. Oltre
a svolgere un ruolo chiave nella conversione della vitamina B3 a NAD, l’NMN deamidasi
potrebbe essere importante per il controllo dei livelli intracellulari di NMN: è riportata
infatti un’azione tossica dell’NMN nei confronti dei batteri a causa della suo effetto
inibitorio sulla DNA ligasi NAD-dipendente. In aggiunta l’enzima potrebbe essere
coinvolto anche nella biosintesi della vitamina B12 in quanto il prodotto della reazione
catalizzata, l’NaMN, è il donatore del gruppo riboso-fosfato indispensabile per la sintesi
della vitamina B12. Nonostante numerosi tentativi il gene codificante l’NMN deamidasi
rimane sconosciuto. In questo lavoro viene descritta l’identificazione del gene per mezzo
della purificazione e del sequenziamento dell’enzima NMN deamidasi dal batterio
Shewanella oneidensis.In the last decade our understanding of the enzymology of vitamin B3 biosynthesis and recycling in eubacteria has greatly advanced thanks to the development of genomic sequencing and comparative analysis, as well structural studies. However, some key enzymes still remain in the category of “orphan enzymes”, i.e. enzymes described in literature, for which no corresponding genes have been so far reported. Among them is the enzyme nicotinamide mononucleotide (NMN) deamidase that converts NMN into nicotinate mononucleotide (NaMN) and plays a key role in the conversion of vitamin B3 to its coenzymatic form NAD. The existence of such an enzyme is demonstrated by the detection of a significant catalytic activity in bacterial cell extracts, as well as by the in silico metabolic reconstruction of the potential biosynthetic machinery of vitamin B3 and NAD in the sequenced bacterial genomes. This analysis in fact underscores the existence of a metabolic gap (missing gene) in the pathway of those species where the conversion of vitamin B3 into NMN occurs in the absence of an enzyme able to directly convert NMN to NAD. Such a gap would be filled by an enzymatic activity channeling NMN toward the deamidated NAD biosynthetic pathway. Besides playing a key role in the conversion of vitamin B3 to NAD, the enzyme NMN deamidase might be involved in the control of intracellular NMN levels: NMN is in fact believed to be toxic for bacteria, due to its inhibitory effect on NAD-dependent DNA ligase. In addition, the enzyme might be also involved in vitamin B12 biosynthesis; in fact the product of the catalyzed reaction, NaMN, is the donor of the phospho-ribose group, essential for vitamin B12 biosynthesis. Despite many attempts, a gene encoding NMN deamidase remains missing. Here, we describe the identification of the gene, following purification and partially sequencing of NMN deamidase from the bacterium Shewanella oneidensis.