Thesis (Ph. D.)--University of Texas at Austin, 2006. / Vita. Includes bibliographical references.

Thesis (Ph.D.)--University of Nebraska-Lincoln, 2008. / Title from title screen (site viewed Feb. 17, 2009). PDF text: 105 p. : ill. (some col.) ; 3 Mb. UMI publication number: AAT 3328258. Includes bibliographical references. Also available in microfilm and microfiche formats.

A multidisciplinary hypothesis testing approach is adopted to investigate the intraspecific relationships, and venom evolution within the polytypic species, Crotalus viridis, in western North America. A molecular phylogeny is reconstructed from mitochondrial cytochrome b (678 bp) and NADH dehydrogenase subunit 4 (ND4; 669 bp) DNA sequence information. The phylogeny is not concordant with the conventional subspecies categories, but shows strong geographical structuring corresponding to the major geographic regions of the western U. S. The basal split gives rise to two lineages (5.1-6.4% sequence divergence) corresponding to haplotypes east and west of the Rocky Mountains. Within the western lineage, Crotalus viridis cerberus forms a sister group to the other western haplotypes, and appears to have a long, independent evolutionary history. Multivariate morphometric analysis also reveals regional structuring. Clear eastern and western forms are apparent, although these populations are not totally reproductively isolated. North-south clinal variation in morphology is found among populations east of the Rocky Mountains between Montana and Arizona. Among the western forms, there is clearly a zone of intergradation between the Great Basin and Pacific Coast forms, represented by a morphological cline in Idaho. Clinal variation was also found between the northern and southern Pacific Coast forms. Venom evolution is of interest in C. viridis, since C. v. concolor is the only subspecies of C. viridis to secrete a high toxicity PLA2 phospholipase (Concolor toxin) in its venom in adulthood. Isoelectric focusing of venom proteins revealed 14 variable bands, of which only one was unique (pI 8.52) to C. v. concolor. Principal coordinates analysis revealed three main venom types, corresponding to the Pacific Coast, C. v. concolor, and the remaining populations respectively. However, C. v. concolor tends to cluster with the latter group when the unique venom band is excluded from the analysis. 1 Phylogeny, rather than ecology, appears to be an important cause of geographic variation in both morphology and venom, as revealed by partial Mantel tests. Many characters are influenced by both phylogeny and ecology, however, probably because many causes of variation are intercorrelated. It is suggested that selection on venom composition probably varies according to the function of individual components. The systematics of Crotalus viridis complex is reviewed according the criteria of the general lineage concept of species. Combined evidence from the molecular phylogeny and morphology (and to a lesser extent venom) suggests the existence of three species, to be named Crotalus viridis, Crotalus cerberus, and Crotalus oreganus (including the subspecies C. o. oreganus, C. o. lutosus and C. o. concolor).

Background: A third of HIV-infected patients are co-infected with HCV in the developed world, and more of co-infected patients than ever before are dying because of liver related diseases today. Drug-related hepatotoxicity is a growing concern among human immunodeficiency virus (HIV) / hepatitis C virus (HCV) co-infected population. Nucleotide analogues containing HIV antiretroviral therapy, namely highly active anti-retroviral therapy (HAART), can induce mitochondrial toxicity. However, little is known about the effect of nucleotide analogues on the liver at the cellular and molecular level, and how it may affect treatment. Objective: To investigate whether liver tissue from HIV/HCV co-infected individuals will show greater liver mitochondrial toxicity if currently receiving antiviral HIV medication, compared to those who are not taking it. Methods: Liver biopsies were collected from 23 HIV/HCV co-infected males. Fourteen patients were on stable HAART (ON-HAART) and 9 were OFF-HAART, including 4 who stopped HAART >6 months prior and 5 who were HAART-nave. Liver mitochondrial toxicity was assessed by transmission electron microscopy-based quantitative stereological analyses of hepatocyte and mitochondrial morphometry, as well as by mitochondrial DNA (mtDNA) and mtRNA (COX1/(ß-actin) real-time-PCR quantification. Results: Hepatocytes tended to be larger in the ON-HAART group than in the OFF-HAART group (p=0.05), but they both showed similar mitochondrial volume fraction of the cell and mitochondrial crista density. Liver mtDNA and mtRNA levels were not significantly differentbetween ON-HAART and OFF-HAART. Hepatocyte lipid accumulation was significantly higher in HCV genotype 3 compared to genotype 1 infection ()=0.002), but was not associated with HAART status. Conclusions: We found no evidence or trend of increased mitochondrial toxicity in HIV/HCV co-infected individuals currently on HAART compared to those who are not. This finding could be relevant to the decision-making process with respect to initiating HCV therapy in this population. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

Rhomboid peptidases are conserved intramembrane serine proteases with mitochondrial family members being involved in mitochondrial dynamics and apoptosis. The Saccharomyces cerevisiae mitochondrial rhomboid, Pcp1p, catalyzes the cleavage of two substrates: Ccp1p, which breaks down reactive oxygen species, and Mgm1p, a GTPase mediating mitochondrial fusion events. As an initial approach to determine the structural basis of Pcp1p activity, a screen to identify temperature sensitive alleles of PCP1 was performed using hydroxylamine mutagenesis. Eight mutants were identified from a pool of 30,000 colonies that exhibited either temperature sensitive growth or respiratory defects. These mutants also exhibited defects in Mgm1p and Ccp1p processing and some degree of abnormal mitochondrial morphology. The majority of amino acid changes occurred within the fourth and sixth transmembrane domains of Pcp1p, the location of the active site serine and histidine residues, supporting a role for these transmembrane helices in Pcp1p activity.

No description available.

Long-term maintenance of adult neural stem cells (NSCs) is an intricate process of activation, expansion, and differentiation while preserving the stem cell pool. Several regulatory mechanisms underlie the delicate balance in the choice between quiescence versus activation for lifelong NSC maintenance and continuous neurogenesis. Perturbations in this dynamic process result in disease manifestation. The quiescence/activation of NSC was shown to be regulated by the Rb/E2F axis through a molecular program mediated by REST (RE1 Silencing Transcription Factor). Loss of Rb family increased NSC activation at the expense of quiescence through activator E2F transcription factors. The activation and neurogenesis of NSCs were impaired by the loss of effector E2Fs, as well as loss of Opa1, the latter indicating that mitochondrial dynamics is important to maintain stem cell state. Single-cell transcriptome analysis from NSC lineages isolated from adult mouse hippocampus revealed that stem cell progenies are uniquely affected in Opa1-KO leading to impairments in NSC activation and differentiation. Unbiased transcriptional profiling suggested a mitochondrial dysfunction in Opa1-KO that results in activation of classic cellular stress response pathway genes (Atf4, Slc7a11 and Chac1). Thus, the regulatory gene network comprising quiescence (Rb) and activation (E2Fs) programs, and mitochondrial metabolism (Opa1) and their interplay ensures the maintenance of the molecular program of NSC, particularly revealing how it enables stem cells survive stress.

No description available.

Abstract not available

Diss. (sammanfattning) Stockholm : Karololinska institutet, 2006. / Härtill 5 uppsatser.