Reports have linked atypical antipsychotics (AAPs) with weight gain. The polymorphic CYP2D6 involved in metabolism has been associated with medication morbidity. Eleven subjects receiving olanzapine were genotyped for CYP2D6 to examine the relationship between 2D6 and AAP weight gain. Using a linear regression, the dependent variable was percent change in body mass index (BMI). Genotype, dose and duration of treatment were independent. Genotype was significant (P < 0.0097) for those with a *1/*3 or *4 genotype experiencing a larger percent BMI change than those with a *1/*1 genotype. This may be due to increased olanzapine concentrations leading to increased exposure, which may trigger AAP weight gain.

Cette thèse a pour but de démontrer la faisabilité de la technique de Nucléation non-Photochimique Induite par Laser (NPLIN) appliquée aux composés pharmaceutiques organiques. Avec nos résultats expérimentaux, ceux obtenus dans la littérature et calculs théoriques ab initio, nous avons discuté du mécanisme de la méthode NPLIN.Cette thèse a décrit en premier lieu, le nouveau montage expérimental semi-automatisé adapté aux exigences des études NPLIN développé à CentraleSupelec. Des expériences NPLIN sur le sulfathiazole (STZ), l-acid glutamique (LGA) et la glycine (GLY) sont menées pour étudier l’impact des paramètres du laser et de la sursaturation des solutions sur leur cristallisation. Les résultats expérimentaux montrent que la technique NPLIN permet d’obtenir des cristaux de STZ, LGA and GLY. L’efficacité de la nucléation croit avec l’augmentation de la densité d’énergie du laser et de la sursaturation. Un indice nouveau Ind50 a été défini correspondant au couple densité d’énergie/sursaturation où 50% nucléation est atteinte. Son comportement est discuté. Il est trouvé que le nombre cristaux STZ induits par laser dépend linéairement avec le temps d’irradiation. Une dépendance du polymorphe des cristaux induit par le laser avec la polarisation du faisceau laser est également découvert pour STZ et GLY. Un autre indice Det(A) est utilisé pour caractériser l’impact de la polarisation sur le polymorphisme. Des calculs théoriques ab initio par le logiciel Gaussian09 permettent de donner une estimation des énergies d’interaction des différents dimères pour des polymorphes de STZ, LGA, GLY, l-histidine (LH) et urée. L’empilement des molécules dans les clusters pré-existant est prédit en accord avec la détermination des énergies d’interaction. L’analyse de corrélation entre la symétrie d’empilement et des résultats expérimentaux souligne l’hypothèse de l’effet Kerr pour expliquer cet impact de la polarisation du faisceau laser sur le polymorphisme. / This thesis concerns the demonstration of the feasibility of Non-Photochemical Laser Induced Nucleation (NPLIN) of some organic pharmaceutical compounds. Using our experimental results and those obtained in literature together with ab initio theoretical calculations we have been able to discuss the mechanism of the NPLIN method.This thesis presents a new experimental set-up developed at CentraleSupelec and dedicated to perform NPLIN experiments. NPLIN experiments on sulfathiazole (STZ), l-glutamic acid (LGA) and glycine (GLY) have been carried out to examine the impact of laser parameters and solution supersaturation on their crystallization. Experimental results show that crystals of STZ, LGA and GLY have been obtained by means of NPLIN. For these compounds, nucleation efficiency increases with laser power density and solution supersaturation. A new index Ind50 corresponding to the couple (energy density/supersaturation) where 50% of nucleation is teached, has been defined. Its behavior has been discussed. It was found that laser induced STZ crystal number depends almost linearly on exposure duration. Moreover, for STZ and GLY, a dependance of laser induced crystal polymorph on laser polarization has been found. Another new index Det(A), has been used for characterization of the impact of the polymorphism. Ab initio quantum computations using Gaussian09, provided an interaction energy estimate for different dimers in different polymorphs of STZ, LGA, GLY, l-histidine (LH) and urea. Packing mode in pre-existing clusters is predicted in agreement with interaction energy determinations. Correlation analysis between packing symmetry and experimental results, shed new light on the Kerr effect hypothesis relative to the impact of laser polarization on polymorphism.

Indiana University-Purdue University Indianapolis (IUPUI) / 2022-08-31

A thesis submitted to the Faculty of Medicine, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctor of Philosophy. / The subject of this thesis is mitochondrial DNA (mtDNA) variation in southern African populations. The purpose of this study was twofold. Firstly, mtDNA variations were used to investigate the genetic affinities of Negroid, Khoisan, Caucasoid and "Coloured" populations in an attempt to refine theories on southern African population affinities and prehistory. MtDNA variations were detected using two different methods. The first method makes use of restriction fragment length polymorphisms (RFLPs) detected with the restriction enzymes Hpal, BamUI, Haell, Mspl, Avail and Hindi in 795 unrelated individuals from twenty ethnic groups within the Khoisan, Negroid, Caucasoid and "Coloured" populations from South Africa and Namibia. The combinations of the various restriction enzyme patterns (morphs) for the enzymes Hpal, Bam HI, Hae II, Mspl, Avail and Hindi (in this order), were used to derive the mtDNA type for each individual studied. This resulted in the discovery of 52 distinct mtDNA types: 30 of which had been previously reported, 28 out of 32 resulted from new combinations of enzyme morphs and 4/32 were due to the discovery of new enzyme morphs (MspI-17 in the Ashkenazi Jewish population and AvaII-31, AvaII-32 and AvaII-33 in the South African "Coloured" population). The second method involves sequencing approximately 750 base pairs of mtDNA contained within the two hypervariable segments within the non-coding control region of the mtDNA molecule in 144 individuals, most of whom where investigated for mtDNA RFLP variations. Pairwise comparisons of mtDNA sequences revealed 119 variant sites which gave rise to 129 unique mtDNA types. / WHSLYP2017

No description available.

Transposable elements (TEs) are mobile genetic elements. They are a significant component of many eukaryotic genomes. They are involved in chromosomal rearrangement by serving as substrates for homologous recombination, in creating new genes through a process of TE "domestication", and in modifying and shuffling existing genes by transducing neighboring sequences (Lander et al., 2001). Therefore, both active and inactive TEs are potentially potent agents for genomic change (Kidwell and Lisch, 2001, 2002; Rizzon et al., 2002; Petrov et al., 2003). In the meantime, active TEs are being explored as useful tools for genetic transformation and possible gene drive mechanisms to deliver genes in natural populations (Ashburner et al.,1998; Alphey et al.,2002; Handler and O'Brochta, 2004). My thesis project focuses on AGH1, a novel DNA-mediated TE in Anopheles gambiae and related mosquitoes. I have studied its genomic structure, insertion polymorphism, evolution, and transposition activity. As part of the sequence and structural characterization of AGH1 in the A. gambiae genome, the boundaries of AGH1were determined. The TA target site duplications flanking AGH1 were verified by comparing a genomic sequence that had an AGH1 insertion with the sequence of a corresponding empty site. AGH1 has relatively long, 350bp, TIRs (Terminal inverted repeats). In addition to the transposase ORF (ORF1) that contains a DD34E catalytic motif, it contains an unusual ORF2 with unknown function. Phylogenic analyses clearly suggest that unlike most DD34E transposons that are similar to the Tc1 family, AGH1 belongs to a different clade that is related to the previously characterized fungal TE Ant and protozoan TEC1 and TEC2. Truncated AGH1 and AGH1-related MITE (Miniature inverted-repeat TE) families were also identified. AGH1 insertion polymorphism was studied using 4 natural populations that belong to two molecular forms of A. gambiae, M and S. AGH1 insertions showed considerable differences between M and S forms and the insertions of AGH1 are highly variable in two populations of M. These results are potentially significant in light of the hypothesis that M forms are newly derived incipient species that are only found in West Africa. PCR and sequencing results showed more than 99% sequence identity between AGH1 sequences in A. gambiae, A. arabiensis, and A. melas, which may indicate either purifying selection or recent horizontal transfer. To assess whether AGH1 is currently active, inverse PCR was performed which provided evidence for extrachromosomal circular AGH1 that may be a product of imprecise excision. RT-PCR detected transcripts for both intact and truncated transposase. Preliminary TE display experiments using genomic DNA isolated from different passages of an A. gambiae Sua1B cell line showed possible new insertions and deletions of AGH1 related elements, which may have been mobilized by AGH1. In summary, the structural and genomic characteristics of AGH1 and the phylogenetic relationship between AGH1 and other known transposons in the IS630-Tc1-mariner superfamily have been determined. Significant divergence was shown between M and S forms of A. gambiae according to AGH1 insertion patterns. Observations of high level of insertion polymorphism and low insertion frequency per site in M populations are preliminary indications that AGH1 may be active in some populations. AGH1 has at least been recently transposing and there are also indications for its current activity in A. gambiae cell lines. If AGH1 is indeed active, it has the potential to be used as genetic tools to study mosquito biology and to spread refractory genes into the field populations to help control mosquito-borne diseases. Although a few active DNA transposons have been discovered in different insects and are being used as tools to transform mosquitoes, no DNA active transposons have been reported in mosquitoes. It is our hope that active endogenous DNA transposons may present new features that will help us overcome some of the deficiencies of current transformation tools developed based on exogenous transposons. In addition, the discovery of an active DNA transposon will help us understand how TEs spread in natural populations of mosquitoes, which is critical if we are to use TEs to drive refractory genes into mosquito populations to control vector-borne infectious diseases. The differential insertion patterns of AGH1 in M and S populations are consistent with the hypothesis that the M and S forms of A. gambiae are in the process of incipient speciation. AgH1 showed much higher levels of insertion polymorphisms in two west African populations of the M molecular form compared to two east African S populations. Similarly, the maximum level of chromosomal differentiation is observed in west African dry savannah areas, while a much lower degree of chromosomal polymorphism is observed in east Africa. Therefore our insertion data support the hypothesis that the speciation process is likely to be originated in west Africa, probably as the result of the need of ecological flexibility created by the greater ecological variability of this region. From a biomedical perspective, this type of analysis is critical because the genetic differences between M and S forms may directly impact the effectiveness of mosquito control measure and perhaps disease transmission. / Master of Science

Paraoxonase-1 (PON1) has an anti-oxidative function in preventing the formation of oxidized lipoproteins (LDL and HDL) and hydrolyzing the active metabolites of some organophosphate insecticides (e.g., paraoxon and diazoxon) and other non-physiological substrates. PON1Q192R affects PON1 hydrolytic activity and its protective role against oxidative stress, thereby influencing susceptibility to cardiovascular disease among individuals. The objectives of this study were to determine the effect of race, gender, and age on PON1 activities and PON1192 genotypes in Caucasian and African American Southerners. Serum samples from 200 individuals (equally distributed race and gender classes, ages 25-55) were assayed spectrophotometrically for paraoxon and diazoxon hydrolysis. Data indicate a positive correspondence between PON1192 genotypes and race and PON1 activity and race. Data do not indicate an influence of gender and age on PON1 activities or PON1192 genotypes. These results are useful in explaining the increased risk of cardiovascular disease in African Americans compared to Caucasians

No description available.

The human pathogenic Cryptococcus neoformans species complex are agents of a common AIDS-defining disease, which causes about 181,000 deaths each year. There are several specific features distinguishing this species from other fungi, including the presence of a polysaccharide capsule and melanin pigment production, both of which contribute to its virulence. A large number of studies about this pathogen used two model strains JEC20 and JEC21. In these studies, these two strains are assumed to be “isogenic”, differ only at the mating type region. Consequently, their phenotypic differences, including virulence, have been attributed to this region. Here, we applied second-generation sequencing and bioinformatics tools to identify sequence polymorphisms between the two genomes. Beside the Mating Type locus, two other regions were found to contain high frequencies of SNPs. To further understand the effects of these loci on the phenotypic differences, four phenotyping assays (mating ability, melanin pigment production, capsule formation, and high temperature growth ability) were conducted on the recombinant progeny obtained from the cross between JEC20 and JEC21. In addition, genomic sequences of these progeny were obtained to identify the complete distributions of other SNPs among the strains. Finally, we identified several novel SNPs contributing to virulence-related traits in this species, which suggest that caution should be placed in attributing phenotypic differences to specific genomic regions in “isogenic” strains derived from classical breeding experiments. / Thesis / Master of Science (MSc) / Cryptococcosis is a globally distributed infection that is prevalent among immune-compromised individuals, such as HIV/AIDS patients. This disease can be attributed to a group of opportunistic fungal pathogens – Cryptococcus neoformans species complex. During the past century, significant resources have been put in an effort to understand its ecology, evolution, life cycle, pathogenesis and virulence factors, and molecular and cellular processes. Most of the laboratory-based studies have relied on two model strains assumed to differ only at the mating type locus. My thesis investigated this assumption and found there are several additional significant genetic differences between these two strains and that such differences contribute to the observed phenotypic differences between them. My results highlight the complexity of genotype-phenotype relationships and the continued evolution of strains even in lab environments in C. neoformans.

A survey of restriction enzyme polymorphisms was performed with fifteen iso-female lines of D. melanogaster amd eighteen single representaives of other Drosophila species. Three enzymes: Bam H1, Eco R1, and Pst 1 were used to probe the genetic structure of the region containing the genes Hsp 22, Hsp 23, Hsp 26, and Hsp 27. The results for within D. melanogaster show that all variation in the DNA sequence is limited to the non-coding region. The restriction patterns confirm the hypothesis that the hsp 22-27 genes are a result of tandem duplications. The values for Nei's estimate of sequence diversity (delta) are 0.034 between populations of D. melanogaster, 0.113 between sibling species, and 0.123 between nonsibling species. These estimates were compared to values obtained for protein and enzyme variation. DNA sequence divergence between nonsibling species versus nonsibling species show less differentiation than protein and enzyme divergence. The restriction enzyme phenotype was used to generate phylogenies which is in approximate agreement with previously reported phylogenies. Molecular drive and selectionist hypotheses of differential rates of evolution during cladogenesis and anagenesis are discussed. / Thesis / Master of Science (MS)