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Recombinational mechanisms in human genetic diversityWilliams, Louise Jane January 2000 (has links)
No description available.
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A biochemical and genetic investigation of the beta subunit of E. coli RNA polymeraseBuyukuslu, Nihal January 1996 (has links)
No description available.
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Studies of the misprocessing mutations R1202D and E1204K in the drug and organic anion transporter, MRP1 (ABCC1) in cultured HEK cellsChan, MARINA 19 November 2013 (has links)
Multidrug resistance protein 1 (MRP1) is a drug and organic anion transporter of the ATP-binding cassette superfamily. Previous studies showed that opposite charge substitutions of Arg1202 or Glu1204 in transmembrane helix (TM) 16 cause a >80% reduction in MRP1 levels when expressed in human embryonic kidney (HEK) cells. These substitutions disrupt the folding and/or assembly of MRP1 which targets it for degradation. Attempts were made to enhance levels of the R1202D and E1204K misprocessing mutants by incubating transfected HEK cells at 30 ºC or 27 ºC. At both temperatures, cells expressed both fully glycosylated and underglycosylated mutants at levels 60–70% lower than wild-type MRP1in cells grown at 37 ºC. The subcellular localization patterns of the two mutants were similar to wild-type MRP1 at all three temperatures, with most of the transporter at the plasma membrane at 37 ºC, and in the endoplasmic reticulum at 30 ºC or 27 ºC. Thus, although poorly expressed, the R1202D and E1204K mutants retained the ability to traffic to the plasma membrane. Attempts were also made to enhance R1202D and E1204K levels by exposing transfected HEK cells to chemical chaperones. Dimethyl sulfoxide and glycerol increased E1204K levels by 20-30% but decreased or had no effect on R1202D and wild-type MRP1. 4-Phenylbutyric acid had little or no effect on either wild-type or mutant MRP1. Thus both mutants were relatively resistant to rescue by chemical chaperones. Finally, a “second-site rescue mutation” approach was taken, guided by an atomic homology model of MRP1. Mutations of Tyr1133 alone decreased MRP1 levels, like R1202D; however, although substituting TM15-Tyr1133 with Phe, His and Ala in R1202D was predicted to re-establish TM15-TM16 bonding interactions, levels of this mutant did not increase. E1204K levels were also not improved by substituting TM17-Val1248 with Asp or Glu although these substitutions were predicted to re-establish TM16-TM17 bonds disrupted in E1204K. These results suggest that the bonding interactions of Arg1202 and Glu1204 with other amino acids predicted by the MRP1 homology model used in this study are insufficient to predict the critical helix-helix interactions necessary for stable MRP1 expression in mammalian cells. / Thesis (Ph.D, Pharmacology & Toxicology) -- Queen's University, 2013-11-19 08:17:31.441
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Studies of mutations affecting a high-affinity methionine transport system of Salmonella typhimuriumCottam, A. N. January 1986 (has links)
No description available.
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Cellular and biochemical analyses of TDP1 mediated chromosomal break repairWells, Owen Spencer January 2014 (has links)
Tyrosyl DNA phosphodiesterase 1 (TDP1) is an end- rocessing enzyme involved in the repair of abortive topoisomerase I (Top1) complexes. Although not essential for survival, a hypomorphic mutation in TDP1 is linked to the autosomal recessive ataxia, spinocerebellar ataxia with axonal neuropathy 1 (SCAN1). SCAN1 is a rare human condition linked with neurodegeneration and ataxic gait and patients are usually wheel chair bound by their early teens. TDP1 primarily cleaves lesions at the 3'-end of DNA breaks and its most prominent substrate is stalled Top1 linked to the 3'-terminus of DNA. The enzymatic mechanism by which TDP1 functions are well understood and inhibitors are now being investigated for treatment of cancer. In contrast, the processes involved in TDP1 recruitment, localisation and regulation during the DNA damage response remain unclear. This thesis investigates how the evolutionarily driven N-terminus of TDP1, not conserved in lower Eukaryotes, is required for optimal cellular protection against genotoxic stress. I also characterise how post-translational modifications of TDP1 allow for efficient repair of transcriptionally associated, chromosomal single-strand breaks and uncover new protein interacting partners of TDP1 and their role in TDP1 mediated repair.
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Influence of serum and albumin on echinocandin pharmacodynamicsNasar, Aasya Saira 08 November 2012 (has links)
Background: The use of human serum (HS) or bovine serum albumin (BSA) during
susceptibility testing may help discriminate between echinocandin susceptible and
resistant C. albicans and C. glabrata strains. However, the influence of these protein
components and that of specific FKS mutations on the in vitro potency of the
echinocandins remains unclear. Our objective was to evaluate the in vitro
pharmacodynamics of the echinocandins in the presence and absence of these biological
matrices against resistant C. albicans and C. glabrata isolates.
Methods: Thirteen C. albicans clinical isolates (2 wild-type and 11 FKS mutants (F641S
and S645P) and twenty C. glabrata clinical isolates (16 FKS mutants and 4 with
unknown resistance mechanisms) were used. MICs were measured in duplicate according
to the CLSI M27-A3 guideline for caspofungin, micafungin, and anidulafungin in RPMI,
or RPMI supplemented with either 5% HS or 5% BSA. Pharmacodynamic analysis was
also performed with the XTT viability assay, and non-linear regression analysis was usedto determine the IC50 values. Differences in geometric mean (GM) MICs and mean IC50
values were assessed by ANOVA and the Student’s t-test.
Results: The addition of BSA significantly increased the GM MIC (6-24 fold) and IC50
(9-25 fold) of each echinocandin compared to RPMI (p < 0.0001) for isolates with FKS
mutations. Increases in MIC (4-12 fold) and IC50 values (3-5 fold) were also observed
with the addition of HS. Although increases in MICs and IC50s were also observed
against the wild-type isolates, these values remained < 1 μg/mL for each echinocandin.
When comparing the results of specific FKS mutations in C. albicans, the MIC and IC50
values were higher in each growth condition for isolates with S645P mutations (HS &
BSA GM 8.0 & 12 μg/mL; mean IC50 5.5 & 21 μg/mL, respectively) compared to those
with F641S mutations (HS & BSA GM 3.7 & 9.8 μg/mL; IC50 4.0 & 16 μg/mL,
respectively).
Conclusions: The addition of HS and BSA significantly influenced the
pharmacodynamics of the echinocandins, but to different degrees. The specific FKS
mutation may influence these in vitro potency changes, but further work is needed to
evaluate these matrices and standardize echinocandin testing in their presence. / text
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Identification and functional analysis of inherited variation in the CYP3A4 gene regulatory regionHamzeiy, Hossein January 2002 (has links)
No description available.
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Chromosome 21, the amyloid precursor gene and Alzheimer's diseaseCrawford, Fiona Caroline January 1993 (has links)
No description available.
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Analyse mutationnelle de familles québécoises avec polykystose rénale autosomique dominante (ADPKD)Hupé, Patrick January 1997 (has links)
Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.
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Functional characterization of cancer-related mutations of ERK3Alsaran, Hadel Mohammed January 2016 (has links)
No description available.
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