VictorJuiz/thesis huggingface dataset:
Resolving Multiplicities in the Tensor Product of Irreducible Representations of Semisimple Lie Algebras
Keywords: Lie algebra
Representation theory
tensor product
multiplicity

When the tensor product of two irreducible representations contains multiple copies of some of its irreducible constituents, there is a problem of choosing specific copies: resolving the multiplicity. This is typically accomplished by some ad hoc method chosen primarily for convenience in labelling and calculations. This thesis addresses the possibility of making choices according to other criteria. One possible criterion is to choose copies for which the Clebsch-Gordan coefficients have a simple form. A method fulfulling this is introduced for the tensor product of three irreps of su(2). This method is then extended to the tensor product of two irreps of su(3). In both cases the method is shown to construct a full nested sequence of basis independent highest weight subspaces. Another possible criterion is to make choices which are intrinsic, independent of all choices of bases. This is investigated in the final part of the thesis with a basis independent method that applies to the tensor product of finite dimensional irreps of any semisimple Lie algebra over [special characters omitted].
RNA and DNA Inactivation Strategies to Prevent or Inhibit HIV-1 Replication via Gene Therapy
Keywords: HIV-1 gene therapy
Interfering RNA
CCR5 co-receptor
Integrase
Hammerhead ribozyme
Group II intron

AIDS is caused by a lentivirus, HIV-1. In addition to antiretroviral drugs that are currently in use for HIV/AIDS therapy, a number of gene therapy strategies have been designed as alternative therapies. Most of these therapies target HIV RNA/proteins, which are subject to high rate of mutation, resulting in escape mutants. Viral entry is mediated by CCR5 co-receptor in most routes of transmission. To downregulate CCR5 as a gene therapy approach, we targeted seven unique sites within the CCR5 mRNA by a multimeric hammerhead ribozyme, Rz1-7. Hammerhead ribozyme is a small RNA that cleaves a target RNA upon binding to it. Expressing the Rz1-7 from HIV-1- and MSCV-based vectors in otherwise susceptible cells inhibited replication of a CCR5-tropic strain of HIV-1 by 99-100%. The Rz1-7 will be tested for inhibition of HIV-1 replication in the CD4+ T-lymphoid and myeloid progeny of transduced human CD34+ hematopoietic progenitor stem cells. It may be preferable to interfere HIV-1 life cycle at the DNA level since a one-time inactivation might suffice to confer a complete and permanent inhibition of virus replication in the gene modified cells and their progeny. This is what other strategies that target the HIV-1 RNA/protein can hardly offer. For this purpose, group II introns, which are able to splice out and get incorporated into a specific DNA sequence, can be designed/modified to gain novel DNA targeting specificities. As a novel approach, we have examined whether insertion of a modified intron into an infectious HIV-1 clone at two sites within the integrase domain of HIV-1 pol gene could inhibit virus replication. Intron insertion into the HIV-1 clone was induced and mammalian cells were transfected with intron-inserted HIV-1 clones. Although similar amounts of HIV-1 RNA, protein, and progeny virus were produced from the clones as from wild-type HIV-1 provirus DNA, in the absence of a functional integrase, the HIV-1 reverse-transcribed DNA failed to integrate and virus replication was aborted. These results demonstrate that modified group II introns can confer complete inhibition of virus replication at the level of second round of infection. We are now developing vectors to assess whether intron insertion can take place in mammalian cells.
Characterization of Polysaccharide Biosynthesis, Structure and Regulation in Vibrio vulnificus
Keywords: Polysaccharide biosynthesis
Vibrio vulnificus
virulence factors
capsule
lipopolysaccharide
cyclic diguanylate
horizontal gene transfer

Vibrio vulnificus are marine bacteria causing fatal septicemia through wound infections or consumption of contaminated seafood. V. vulnificus is an excellent model for the study of surface polysaccharides, as it is capable of synthesizing capsular polysaccharide (CPS), lipopolysaccharide (LPS) and exopolysaccharide (EPS). V. vulnificus strains exhibit a multitude of carbotypes that evolve through unknown mechanisms. CPS is a confirmed virulence factor, but the genetics of its biosynthesis are unknown. The main objective of these experiments was to gain insight into the biosynthesis, regulation and evolution of ATCC 27562 outer surface polysaccharides. A miniTn10 transposon (Tn) system was used for mutagenesis and single insertions were confirmed through Southern analysis. A novel 25 kb CPS biosynthesis locus was identified through sequencing of regions surrounding Tn insertions; a region encoding putative LPS core biosynthetic functions was identified adjacent to the CPS cluster. The CPS locus contained features of O-antigen biosynthetic loci and was unusual in carrying characteristics of both group I and IV capsular biosynthetic loci. Mutations in this region resulted in elimination of CPS and LPS, and both were shown to be dependent on the activity of the polymerase Wzy. Evidence is presented here supporting horizontal transfer (HT) as a contributor to V. vulnificus CPS evolution. CPS regions of V. vulnificus 27562, YJ016 and CMCP6 contain strain specific genes surrounded by conserved regions, suggestive of HT. Moreover, a CPS locus virtually identical to that of 27562 was discovered in Shewanella putrefaciens strain 200. 27562 CPS is distinctive as it contains N-acetylmuramic acid. Genes encoding murA and murB activities were identified within the cluster and shown to be functionally redundant, supporting HT acquisition of this region. A screen of V. vulnificus gDNA library using CPS biosynthesis and transport mutants identified a cyclic diguanylate cyclase, dcpA. dcpA-mediated increase in cyclic diguanylate lead to EPS production, rugosity phenotypes and enhanced biofilm formation. Interestingly, virulence and motility were not affected suggesting complexity of cyclic diguanylate regulation in V. vulnificus, supported by the large number of cyclic diguanylate related proteins in Vulnificus strains.
Aldosterone and its Antagonists Modulate Elastin Deposition in the Heart
Keywords: Aldosterone
mineralocorticoid receptor antagonists
elastic fibers
myocardial infarction
fibrosis

Myocardial infarction activates the renin-angiotensin system, consequently upregulating aldosterone production that may stimulate pathological cardiac fibrosis via mineralocorticoid receptor (MR) activation. Results presented in this thesis were derived from an in vitro experimental model using cultures of human cardiac fibroblasts to study the effect of aldosterone on elastin production. They first confirmed that treatment with 1-50 nM of aldosterone leads to a significant increase in collagen type I production via MR activation. Most importantly, we discovered that treatment with 1-50 nM of aldosterone also increases elastin mRNA levels, tropoelastin synthesis, and elastic fiber deposition. Strikingly, pretreatment with MR antagonist spironolactone did not eliminate aldosterone-induced increases in elastin production. Interestingly, while cultures treated with elevated aldosterone concentrations (100 nM and 1 µM) showed a further increase (~3.5-fold) in collagen and (~3-fold) in elastin mRNA levels, they demonstrated subsequent increases only in the net deposition of collagen but not elastin. In fact, cultures treated with elevated aldosterone concentrations displayed a striking decrease in the net deposition of insoluble elastin, which could be reversed with spironolactone or with MMP inhibitors doxycycline or GM6001. Most importantly, we discovered that the pro-elastogenic effect of aldosterone involves a rapid increase in tyrosine phosphorylation of the insulin-like growth factor-I receptor (IGF-IR) and that the IGF-IR kinase inhibitor AG1024 or an anti-IGF-IR neutralizing antibody inhibits both IGF-I- and aldosterone-induced elastogenesis (Bunda et al., Am J Pathol. 171:809-819, 2007). Furthermore, we showed that the PI3 kinase signaling pathway propagates the elastogenic signal following IGF-IR activation and that activation of c-Src is an important prerequisite for aldosterone-dependent facilitation of the IGF-IR/PI3 kinase signaling. Results of explorative microarray analysis of 1 hour aldosterone-treated cultures revealed that aldosterone treatment upregulated expression of a heterotrimeric G protein, Gα13, that activates the PI3 kinase signaling pathway. We additionally demonstrated that aldosterone treatment transiently increases the interaction between Gα13 and c-Src and that siRNA-dependent elimination of Gα13 inhibited the pro-elastogenic effect of aldosterone. In summary, aldosterone, which stimulates collagen production in cardiac fibroblasts through the MR-dependent pathway, also increases elastogenesis via a parallel MR-independent pathway involving the activation of Gα13, c-Src, and IGF-IR/PI3 kinase signaling.
A Novel Model System is Applied to Examine the Interplay of Notch and GATA Factors during T Lineage Committment
Keywords: lymphopoiesis
T cell development
OP9-DL1
embryonic stem cell
GATA
Notch

T lymphocytes comprise one arm of the adaptive immune system and are critical for immunity to neoplasia and infection. A full understanding of their development has important implications for the treatment of autoimmunity, immunodeficiency, and leukemias arising from T cell developmental intermediates. The Notch signaling pathway is already known to be absolutely required for T cell commitment and development, but its collaboration with other factors is poorly understood. Unfortunately, deficiency in many of the genes critical to hematopoiesis, including Notch, causes early embryonic lethality by disrupting multiple developmental processes. This complicates the study of such genes by in vivo models or ex vivo hematopoietic progenitors. To circumvent these difficulties, this thesis describes the use of in vitro-differentiated embryonic stem cell-derived T progenitors to examine the roles of two GATA family members during early T cell development. GATA-2, while not required for T cell development, is shown to act downstream of Notch signals to inhibit myelopoiesis. These findings both characterize a novel role for GATA-2, and demonstrate that T progenitor maturation and exclusion of non-T cell fates are distinct and separable events. GATA-3, in contrast to GATA-2, is absolutely required for T lymphopoiesis. However, the current literature does not distinguish between a requirement for GATA-3 in homing to the thymic environment, committing to the T cell fate, or surviving such a commitment event. This thesis demonstrates that GATA-3 is dispensable for commitment itself, but required to permit survival and proliferation after commitment. Taken together, the results presented in this thesis employ a novel model system to characterize the interactions of two important collaborators with Notch signals during T cell development, and further dissect the stages through which early T cell development is enacted.
Immune Evasion and Viral Replication: Examining the Pressures that Influence the Evolution of CD8+ T-cell Epitope Sequences During HIV Infection
Keywords: Immunology
virology
HIV

The evolution of immune escape during HIV infection is well documented, yet some CD8+ T-cell epitopes remain conserved even in the presence of strong cognate responses. This report investigates the frequency of sequence variability within the HLA-A2 restricted immunodominant epitope SLYNTVATL (SL9). Sequencing results, from 15 HIV+ HLA-A2+ individuals, support a very high degree of conservation of this epitope sequence with only focused, conservative changes evident in proviral quasispecies. These observations suggest that changes to the SL9 sequence may have deleterious effects on viral replication and are therefore limited in vivo. To investigate the sequence constraints imposed on the SL9 epitope by HIV replicative fitness, HIV plasmid clones incorporating synonymous and non-synonymous mutations throughout the SL9 epitope region were constructed. Growth of the resultant congenic viruses in mono-infection assays indicated a wide diversity of SL9 variant viruses that grew efficiently. Furthermore, dual-infection viral competition assays demonstrated that SL9 variants known to arise in vivo were equally fit to consensus SL9 virus and several novel epitope variants were also able to compete effectively. Collectively, the data reported in this thesis reveal that the viral pressures acting to conserve the SL9 epitope sequence are less than previously assumed and highlight the lack of understanding of protective CD8+ T-cell action during HIV infection.
The Quality of Surgical Care for Radical Cystectomy in Ontario from 1992 to 2004
Keywords: Epidemiology
Medicine and Surgery
Clinical epidemiology
Bladder cancer
Outcomes
Health Services Research
Volume
Wait times

This thesis is composed of three studies pertaining to the quality of care for radical cystectomy in Ontario between 1992 and 2004. In the first paper, the associations between provider volume and both operative and overall mortality were assessed. In the second paper, potential factors that could explain the association between volume and outcome were explored. In the final paper, the impact of waiting for cystectomy on survival outcomes was evaluated. Methods: A total of 3296 patients undergoing cystectomy for bladder cancer in Ontario between 1992 and 2004 were identified using the Canadian Institute for Health Information Discharge Abstract Database and the Ontario Cancer Registry. The effects of hospital and surgeon volume on operative mortality and overall survival were assessed using random effects logistic regression and marginal Cox Proportional Hazards modeling, respectively. To elucidate the factors underlying the volume-outcome association, the ability of a number of structure and process of care variables to attenuate the impact of volume was assessed. The effect of waiting for care, from transurethral resection to cystectomy, on overall survival was also assessed using marginal Cox models. Results: Neither hospital nor surgeon volume was significantly associated with operative mortality; however, both were associated with overall mortality. Of the measured structure/process measures, hospital factors caused the greatest attenuation of the volume hazard ratios, albeit to a limited degree. The wait time between the decision for surgery and cystectomy was also significantly associated with overall survival. The impact of delayed care was greatest for patients with lower stage disease. The data suggested a maximum wait time of 40 days for cystectomy. Conclusions: In this thesis, gaps in the quality of care for radical cystectomy in Ontario were identified. Patients treated by low volume hospitals and surgeons or those with long wait times all experienced worse outcomes. Since the underlying measures responsible for provider volume remain elusive, additional work is required to understand what these factors are. Initiatives to decrease wait times, however, are under way in Ontario. Whether these interventions decrease wait times and benefit patients remains to be seen.
Assessment of Operative Strategies to Improve Coronary Bypass Graft Patency
Keywords: Coronary Bypass Surgery
Clinical Trials
Imaging
Quality Assurance

The ultimate success of bypass surgery depends on the construction of a technically perfect bypass graft to an appropriate coronary vessel using a conduit which will remain durable for the lifetime of the patient. This thesis explores methods to improve coronary surgery by enhancing intraoperative imaging and conduit selection in the operating room. It is known that technical errors in graft construction cause failure of up to 12% of coronary bypass grafts in the operating room. We performed investigations of a new technique of intraoperative fluorescence angiography using indocyanine green dye to determine graft patency. We developed optimal methods of obtaining images and preliminary investigations revealed the technique was highly reproducible. In a follow-up trial, we demonstrated that over 80% of technical errors which would otherwise have been missed were identifiable with indocyanine green angiography, while only 25% of these errors were identified by transit-time ultrasonic flow measurement, the current clinical standard. We also determine that coronary surgery with indocyanine green angiographic graft patency verification was associated with less perioperative myocardial injury than bypass surgery without graft patency assessment. The long term graft patency of saphenous vein grafts is sub-optimal, with over 40% of such grafts totally occluded and a further 30% significantly diseased at ten years. We attempted to improve these outcomes by increasing the use of arterial grafts, which are less prone to intimal hyperplasia. In a multicentre clinical trial, we demonstrated a 40% relative risk reduction in graft occlusion at one year when radial arteries were used as bypass conduits versus saphenous veins. We identified that women and patients with small coronary vessels maximally benefited from radial artery bypass grafts. Conversely, in settings of less severe target vessel stenosis or concomitant peripheral vascular disease, saphenous veins performed as well as radial arteries. We have demonstrated that high quality imaging to identify technical errors during the operation, increased use of radial artery grafts and careful consideration of individual patient and target vessel characteristics can all improve graft patency. Future studies will be aimed at identifying the role of intraoperative imaging and arterial grafting in improving long-term clinical outcomes.
Supporting Recent Immigrants in their Effort to Access Information on Health and Health-related Services: The Case Of 211 Toronto
Keywords: Access to health services
Health information

The objectives of this thesis are to: 1) obtain a snapshot of callers of 211 Toronto, a free information and referral service, understanding how representative they are of Toronto’s general population; 2) understand how 211 Toronto callers seeking health-related information use the information they obtain when contacting the service and their overall level of satisfaction, and; 3) better understand the experience and information needs of recent immigrants struggling to navigate an unfamiliar health care system. The study had three phases: 1) a cross-sectional phone interview with 211 Toronto callers; 2) a follow-up phone interview of 211 Toronto callers who had asked health-related questions; and, 3) qualitative interviews with callers who were Spanish speakers from Latin American countries. Participants were randomly selected adult callers living within the boundaries of Toronto’s Census Metropolitan Area (CMA). Respondents were compared with the general adult population living in Toronto’s CMA, using 2001 Census data, to identify under- or overrepresented population groups. A sub-set of callers who had asked health-related questions was followed up to understand how they had used the information received and their level of satisfaction with the service. Qualitative interviews were conducted with callers who were recent immigrants and native Spanish speakers from Latin America to explore their post-migration experiences. Recent immigrants experience significant information challenges. Health-related questions reflect the multifaceted nature of the concept of health in the experience of users. Negative experiences with the health care system are common. Recent immigrants have access to disorganized, confusing, often poor quality information. 211 Toronto represents an efficient and effective way to gain access to information but does not achieve its full potential. Newcomers should receive timely, appropriate, and reliable information on existing health and health-related services as soon as possible after they relocate to Canada. Appropriate information should also be made available to potential immigrants in their countries of origin. Information and communication technologies should be used to support newcomers, increasing the efficiency and effectiveness of services such as 211 Toronto.
Healing the Wounds: Commemorations, Myths, and the Restoration of Leningrad's Imperial Heritage, 1941-1950
Keywords: Postwar Russia
Blockade of Leningrad
Historic Preservation
Commemorations

This dissertation is a study of Leningrad during World War II and the period of postwar restoration (1941-1950). Leningrad was besieged by the Germans for nearly nine-hundred days. As hundreds of thousands of people died from bombings, shelling, cold, and starvation, local authorities surprisingly instituted measures to ensure that the city’s historic monuments be safeguarded from destruction. When Leningrad was liberated in January 1944, a concerted effort was put into place to breath life into these damaged and destroyed monuments and to heal the wounds inflicted on the city. Instead of using the damage to modernize the city, Leningrad and Soviet authorities opted to privilege the country’s tsarist heritage. In the postwar period, municipal authorities proclaimed that restored monuments commemorate the determination and heroism shown by the people of Leningrad during the war. The memory of the blockade, it was argued, was a “red thread” that must run through and be inscribed in all restoration works. Although this dissertation is a local study of war and postwar restoration, it speaks to broader trends within the Soviet Union before, during, and after World War II. I argue that the care shown for Leningrad’s imperial monuments was the result of an ideological shift that began in the mid-1930s away from iconoclasm toward rehabilitating and respecting certain events and characters from the past. With international tensions rising in the 1930s, this turn to the past acted as a unifying force that had a tremendous influence on the patriotism shown during the war with the Nazis. In the postwar period, as the Soviet state began to redefine its image based on the myth of war and the country’s tsarist heritage, this patriotism was further promoted, resulting in a flurry of work throughout the Soviet Union to restore the vessels of the country’s past. Like many other modernizing states, the Soviet Union looked to its past to create a united and patriotic citizenry.