Towards an understanding of the side effects of anti-HIV drugs using Caenorhabditis elegans

Since the discovery of HIV-1 as a cause for AIDS, many antiretroviral drugs - such as the nucleoside reverse transcriptase inhibitors (NRTIs) and the protease inhibitors (PIs) - have been developed to target viral replication. The therapeutic use of a combination of drugs, more commonly known as Highly Active Anti-Retroviral Therapy (HAART), has significantly improved the quality and length of patient lives. Overshadowing this success, however, is the problem that HIV-1 infected patients are afflicted with drug induced adverse events, some of which can be life threatening. Most adverse events seem to be related to tissues with high-energy demand and have predominantly been found to be caused by mitochondrial toxicity. In this thesis the nematode Caenorhabditis elegans is used as a model system to study the adverse side effects of HIV-1 antiretroviral medicines administered alone or in combination. Using an array of established and novel molecular techniques, drugs that have similar chemical structure and modes of action are shown to each have distinct toxicity profiles. Evidence is shown in support of an earlier proposal that there are modes to NRTI toxicity beyond the polymerase-γ theory and a novel hypothesis that NRTIs cause premature and accelerated aging is assessed. Interestingly, the observed mitochondrial dysfunction and toxicity phenotypes of both NRTIs and PIs could be attenuated by antioxidants. Taken together, this project has endeavoured to shed some light on the mechanisms behind HIV drug toxicity and ultimately benefit the development of new, effective, and less toxic compounds

Bosonization Approach For Bilayer Quantum Hall Systems At νt=1

We develop a nonperturbative bosonization approach for bilayer quantum Hall systems at νT=1, which allows us to systematically study the existence of an exciton condensate in these systems. An effective boson model is derived and the excitation spectrum is calculated in both the Bogoliubov and the Popov approximations. In the latter case, we show that the ground state of the system is an exciton condensate only when the distance between the layers is very small compared to the magnetic length, indicating that the system possibly undergoes another phase transition before the incompressible-compressible one. The effect of a finite electron interlayer tunneling is included and a quantitative phase diagram is proposed. © 2006 The American Physical Society.9718(1997) Perspectives in Quantum Hall Effects, , edited by S. Das Sarma and A. Pinczuk (Wiley, New York)Eisenstein, J.P., MacDonald, A.H., (2004) Nature (London), 432, p. 691. , NATUAS 0028-0836 10.1038/nature03081Eisenstein, J.P., (2004) Science, 305, p. 950. , SCIEAS 0036-8075 10.1126/science.1099386Murphy, S.Q., (1994) Phys. Rev. Lett., 72, p. 728. , PRLTAO 0031-9007 10.1103/PhysRevLett.72.728Girvin, S.M., cond-mat/0108181Spielman, I.B., (2000) Phys. Rev. Lett., 84, p. 5808. , PRLTAO 0031-9007 10.1103/PhysRevLett.84.5808Spielman, I.B., (2001) Phys. Rev. Lett., 87, p. 036803. , PRLTAO 0031-9007 10.1103/PhysRevLett.87.036803Fertig, H.A., Straley, J.P., (2003) Phys. Rev. Lett., 91, p. 046806. , PRLTAO 0031-9007 10.1103/PhysRevLett.91.046806Kellogg, M., (2004) Phys. Rev. Lett., 93, p. 036801. , PRLTAO 0031-9007 10.1103/PhysRevLett.93.036801Wiersma, R.D., (2004) Phys. Rev. Lett., 93, p. 266805. , PRLTAO 0031-9007 10.1103/PhysRevLett.93.266805Wen, X.G., Zee, A., (1992) Phys. Rev. Lett., 69, p. 1811. , PRLTAO 0031-9007 10.1103/PhysRevLett.69.1811Fertig, H.A., (1989) Phys. Rev. B, 40, p. 1087. , PRBMDO 0163-1829 10.1103/PhysRevB.40.1087MacDonald, A.H., (1990) Phys. Rev. Lett., 65, p. 775. , PRLTAO 0031-9007 10.1103/PhysRevLett.65.775Joglekar, Y.N., MacDonald, A.H., (2001) Phys. Rev. B, 64, p. 155315. , PRBMDO 0163-1829 10.1103/PhysRevB.64.155315Fertig, H.A., Murthy, G., (2005) Phys. Rev. Lett., 95, p. 156802. , PRLTAO 0031-9007 10.1103/PhysRevLett.95.156802Doretto, R.L., Caldeira, A.O., Girvin, S.M., (2005) Phys. Rev. B, 71, p. 045339. , PRBMDO 0163-1829 10.1103/PhysRevB.71.045339Kallin, C., Halperin, B.I., (1984) Phys. Rev. B, 30, p. 5655. , PRBMDO 0163-1829 10.1103/PhysRevB.30.5655Fetter, A.L., Walecka, J.D., (2003) Quantum Theory of Many-Particle Systems, , Dover, MineolaStoof, H.T.C., Bijlsma, M., (1993) Phys. Rev. E, 47, p. 939. , PLEEE8 1063-651X 10.1103/PhysRevE.47.939Shi, H., Griffin, A., (1998) Phys. Rep., 304, p. 1. , PRPLCM 0370-1573 10.1016/S0370-1573(98)00015-5Chen, X.M., Quinn, J.J., (1992) Phys. Rev. B, 45, p. 11054. , PRBMDO 0163-1829 10.1103/PhysRevB.45.1105

Northern Ellesmere Island, 1953 And 1954

Account of the Ellesmere Ice Shelf Expeditions, organized by the Defence Research Board and Geological Survey of Canada. On reconnaissance Apr.-Aug. 1953, G.F. Hattersley-Smith and R.G. Blackadar made glaciological and geological observations west from Alert to Markham Bay (including Ross River and Feilden Peninsula), east to Cape Sheridan, and southwest along Wood River toward the United States Range. In 1954 (Apr.-Sept.), G.F. Hattersley-Smith, E.W. Marshall, A.P. Crary, and R.L. Christie made their main base on the ice shelf at Ward Hunt Island (83 05 N, 75 W), from which trips were made east to Cape Albert Edward and Cape Columbia, and west to Kruger Island on the edge of Nansen Sound, completing glaciological and geological reconnaissance of the north coast of Ellesmere. On the ice shelf near the Ward Hunt Island base, geological, geophysical, glaciological and oceanographic investigations, survey and leveling work, and meteorological observations were carried on. Reports are made on the glaciological work by G.F. Hattersley-Smith; geophysical and oceanographic studies, by A.P. Crary; and geological observations, 1954, by R.L. Christie. New place names (11) submitted to the Canadian Board on Geographical Names, also records and relics recovered from cairns of earlier expeditions, are reported. The account is introduced by a useful summary of parties visiting Northern Ellesmere 1876-1951, and of work on ice island T-3

Reliability of functional outcome measures in adults with neurofibromatosis 1

Objectives: To determine intra-rater and inter-rater reliability of functional outcome measures in adults with neurofibromatosis 1 (NF1) and to ascertain how closely objective and subjective measures align. Methods: Forty-nine ambulant adults with NF1 aged 16 years and over were included in this observational study. Median age 31 years (range 16-66), 29 females, 20 males. Participants were video-recorded or photographed performing four functional outcome measures. Four raters from the Neurofibromatosis centre multi-disciplinary team independently scored the measures to determine inter-rater reliability. One rater scored the measures a second time on a separate occasion to determine intra-rater reliability. The measures evaluated were the functional reach, timed up and go, ten metre walk and a modified nine-hole peg tests. Participants also completed a disease specific quality of life questionnaire (INF1-QOL). Results: Inter-rater reliability and intra-rater reliability scores (intra-class coefficient, ICC) were similar for each outcome measure. Excellent rater agreement (ICC r ≥ 0.9) was found for the functional reach, timed up and go and the 10 metre walk tests. Rater agreement was good for the modified 9-hole peg test; ICC r= 0.75 for intra-rater reliability and 0.76 for inter-rater reliability. The timed up and go and the 10 metre walk tests correlated highly with perceived mobility challenges in the quality of life questionnaire (INF1-QOL). Conclusions: The functional reach, timed up and go and 10 metre walk tests are potentially useful outcome measures for monitoring NF1 treatment and will be assessed for validity and reliability in future multi-centre studies

Intellectual functioning in clinically confirmed fetal valproate syndrome

Background: An increased risk of impaired intelligence (IQ) has been documented in valproate-exposed children, but investigations have not previously focused on those with a clinical diagnosis of Fetal Valproate Syndrome (FVS). Methods: This cross sectional observational study recruited individuals with a diagnosis of FVS and completed standardized assessments of intellectual abilities making comparisons to a normative comparison group. Both mean difference (MD) and prevalence of scores below the lower average range were analyzed. Results: The mean full-scale IQ in 31 individuals with FVS (mean age 14.97; range 6–27 years) was 19 points lower (19.55, 95% CI −24.94 to 14.15), and IQ scores <70 were present in 26%. The mean differences for verbal comprehension (21.07, 95% CI −25.84 to −16.29), working memory (19.77, 95% CI −25.00 to −14.55) and processing speed (16.87, 95% CI −22.24 to −11.50) performances were poorer than expected with the mean differences over one standard deviation from the comparison group. Sixty one percent of cases demonstrated disproportionately lower verbal comprehension ability. There were no significant group differences for IQ in high vs. moderate dose valproate or mono vs. polytherapy. There were no differences in IQ between those with and those without a major congenital malformation. The requirement for educational intervention was high at 74%. Conclusion: Intellectual difficulties are a central feature of FVS and are more severe in their presentation in individuals with a diagnosis of valproate embryopathy. Individuals with FVS who present with the characteristic facial presentation should be considered at high risk of cognitive difficulties regardless of the dose of valproate exposure or the presence of a major congenital malformation

Enhanced mapping of artificially modified ground in urban areas : using borehole, map and remotely sensed data

The report described here is focused on how using boreholes and attributes from boreholes increased and enhanced the mapping of Artificially Modified Ground, and helped measure landscape evolution change in the urban environment. These attributes from boreholes include the presence of AMG in a borehole, the thickness of AMG recorded, the start height of a borehole and the location of boreholes (and other boreholes in close proximity) with modern topological features and geological maps

Trace Complexity of Chaotic Reversible Cellular Automata

Delvenne, K\r{u}rka and Blondel have defined new notions of computational complexity for arbitrary symbolic systems, and shown examples of effective systems that are computationally universal in this sense. The notion is defined in terms of the trace function of the system, and aims to capture its dynamics. We present a Devaney-chaotic reversible cellular automaton that is universal in their sense, answering a question that they explicitly left open. We also discuss some implications and limitations of the construction.Comment: 12 pages + 1 page appendix, 4 figures. Accepted to Reversible Computation 2014 (proceedings published by Springer