Beyond DNA binding - a review of the potential mechanisms mediating quinacrine's therapeutic activities in parasitic infections, inflammation, and cancers

This is an in-depth review of the history of quinacrine as well as its pharmacokinetic properties and established record of safety as an FDA-approved drug. The potential uses of quinacrine as an anti-cancer agent are discussed with particular attention to its actions on nuclear proteins, the arachidonic acid pathway, and multi-drug resistance, as well as its actions on signaling proteins in the cytoplasm. In particular, quinacrine's role on the NF-κB, p53, and AKT pathways are summarized

Anopheles/Plasmodium interactions at the ookinete-to-oocyst developmental transition

The ookinete to oocyst developmental transition of the Plasmodium parasite represents a major population bottleneck in the malaria life cycle. This suggests that it could be a target for intervention strategies, such as transmission blocking vaccines, provided essential parasite target molecules can be identified. A recent microarray analysis has identified a large number of transcripts differentially expressed during the parasite’s developmental transitions. Genes differentially regulated during the ookinete-to-oocyst transition may determine the development of the parasite within the mosquito host, as well as, participating directly in parasite/mosquito interactions. Yet, the function of the majority of such molecules is largely unknown. This PhD thesis aims to identify and functionally characterise genes putatively involved in ookinete development and/or the interactions between the parasite and the mosquito host in the model system Plasmodium berghei. Thirty three proteins likely to be implicated in the parasite’s interaction with the mosquito immune system and local epithelial response were identified based on their expression pattern and predicted structural features. Generation of knock-out mutants through targeted gene disruption by homologous recombination was the first step towards functional characterization of these candidates.Successful mutants were assessed for their ability to complete their sexual sporogonic development, as well as, their impact on mosquito immunity following infection of Anopheline mosquitoes of various immune backgrounds. Interestingly, two of the successful mutants were hampered in their ability to undergo normal differentiation during ookinete development while the third one’s ability to invade the mosquito midgut epithelium was impaired. The inability to invade implies a potential interaction of this gene product with mosquito midgut ligands. Eventually malaria transmission through Anopheline mosquitoes was affected in all three mutants. Moreover, challenging of a mosquito protein LRIM1, a major parasite antagonist, also revealed potential involvement of the three mutants in mosquito/parasite immune response pathways. Genetic crosses with parasite lines deficient in the production of either male or female fertile gametes demonstrated in the case of two mutants that, this defect in ookinete development is sex dependent, thus underlining the critical importance of maternal and/or paternal control during the first few hours of parasite development in the mosquito

Genetic frontiers for conservation:An assessment of synthetic biology and biodiversity conservation

In recent years synthetic biology has emerged as a suite of techniques and technologies that enable humans to read, interpret, modify, design and manufacture DNA in order to rapidly influence the forms and functions of cells and organisms, with the potential to reach whole species and ecosystems. As synthetic biology continues to evolve, new tools emerge, novel applications are proposed, and basic research is applied. This assessment is one part of IUCN’s effort to provide recommendations and guidance regarding the potential positive and negative impacts of synthetic biology on biodiversity conservation; it comprises a full assessment and a short synthesis report

The utility of molecular genetic analysis of museum specimens in studying deep-sea fish

The damaging effect of formalin on DNA and the inhibition of PCR are serious problems in molecular studies. The aims of the project were to investigate the possibility of using formalin-fixed, Steedman's preserved museum specimens in molecular investigations, especially organisms with unstudied genomes. A number of DNA extraction protocols and different pre-washing/drying regimes were tested. These gave different levels of success, but a guanidinium-based protocol developed in this study gave the best results. RAPD-PCR methodology was employed to test its applicability on preserved specimens, and it was used as a test of the efficiency of DNA extraction/amplifications and for developing species-specific PCR primers. Attempts to amplify mitochondrial DNA sequences with the six mitochondrial genes were mostly unsuccessful. Sporadic amplifications were obtained with primers of 16S and COIII genes. This study provided the first molecular data on deep-sea fish (Nezumia aequalis and N. micronychodon) exclusively using formalin-fixed, Steedman's preserved museum specimens. Two genomic sequences of these fishes were determined and submitted to the GenBank database under accession numbers AY826774 - AY826792. Three specific primer sets (RAPD-derived) for Nezumia aequalis and N. micronychodon were designed to amplify PCR product sizes 300 bp - 350 bp. This study has demonstrated that an appropriate strategy and molecular approach could lead to the successful use of museum and other formalin-fixed archival collections even on organisms with unstudied genomes. Supplementary evidence, related to the method of preservation, the usage of particular DNA extraction protocol and PCR marker system, was obtained from ten differently preserved mackerel (Scomber scombrus) specimens. This study confirmed that the DNA extracted from preserved specimens possesses unique characteristics that make molecular investigations very difficult. Because of this, it is proposed that DNA extracted from preserved specimens should be referred to as "archival DNA (arDNA)"

Aerospace Medicine and Biology: A continuing bibliography with indexes, supplement 267, January 1985

This publication is a cumulative index to the abstracts contained in the Supplements 255 through 266 of Aerospace Medicine and Biology: A Continuing Bibliography. It includes seven indexes--subject, personal author, corporate source, foreign technology, contract number, report number, and accession number