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Search Results: 1 - 10 of 144413 matches for " B. Hackett "
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Predicting preferential DNA vector insertion sites: implications for functional genomics and gene therapy
Christopher S Hackett, Aron M Geurts, Perry B Hackett
Genome Biology , 2007, DOI: 10.1186/gb-2007-8-s1-s12
Abstract: Elements such as viruses and transposons, through evolution with their host organisms, have acquired the ability to integrate into host genomes and ultimately shuffle genetic material between organisms. These elements have an established history in molecular biology and genetics research because of their ability to deliver specific genetic cargo, randomly disrupt host genomes for genetic screens, and serve as vectors for delivery of therapeutic expression cassettes to treat human disease. Viral vectors have been the predominant tools for these applications for three reasons: the ease and efficiency with which specific viral genetic cassettes can be introduced into cells; the vast accumulated knowledge of viruses and their mechanisms of gene transfer into chromosomes; and the large number of sites in genomes into which they can integrate. Retroviruses in particular have been used for random insertion into chromatin to interrupt host genes (insertional mutagenesis) and thereby identify their function [1-3] as well as for delivery of therapeutic genes [4-6]. Moreover, viral activation of oncogenes and, more recently, inactivation of tumor suppressors have been used to discover several novel genes that are involved in cancer progression [7-12]. The consequence of insertional activation of host cell oncogenes by viral vectors, however, has emerged as a major risk/obstacle in gene therapy, with a few cases of leukemia arising from oncogene activation by therapeutic vectors [13,14]. The potential genetic consequences of insertions of integrating vectors are summarized in Figure 1.Activation of oncogenes in mice by insertionally mutagenic retroviruses suggested that inadvertent oncogene activation resulting from the use of relatively benign therapeutic vectors is a potential risk associated with gene therapy. Gene therapy vectors are extensively minimized to eliminate their replicative potential and reduce their collateral effects on the target genome [15]. However, extensi
Potassium Dichromate Induced Cytotoxicity, Genotoxicity and Oxidative Stress in Human Liver Carcinoma (HepG2) Cells
Anita K. Patlolla,Constance Barnes,Diahanna Hackett,Paul B. Tchounwou
International Journal of Environmental Research and Public Health , 2009, DOI: 10.3390/ijerph6020643
Abstract: Chromium is a widespread industrial waste. The soluble hexavalent chromium Cr (VI) is an environmental contaminant widely recognized to act as a carcinogen, mutagen and teratogen towards humans and animals. The fate of chromium in the environment is dependent on its oxidation state. Hexavalent chromium primarily enters the cells and undergoes metabolic reduction to trivalent chromium, resulting in the formation of reactive oxygen species together with oxidative tissue damage and a cascade of cellular events. However, the results from in vitro studies are often conflicting. The aim of this study was to develop a model to establish relationships between cytotoxicity, genotoxicity and oxidative stress, in human liver carcinoma [HepG2] cells exposed to potassium dichromate. HepG2 cells were cultured following standard protocols and exposed to various concentrations [0-50 μM] of potassium dichromate [K2Cr2O7]. Following exposure to the toxic metal, the MTT assay was performed to assess the cytotoxicity, the thiobarbituric acid test to evaluate the degree of lipid peroxidation as an indicator of oxidative stress and the alkaline comet assay was used to assess DNA damage to study genotoxicity. The results of the study indicated that potassium dichromate was cytotoxic to HepG2 cells. The LD50 values of 8.83 ± 0.89 μg/ml, 6.76 ± 0.99 μg/ml, respectively, for cell mortality at 24 and 48 hrs were observed, indicating a dose- and time-dependent response with regard to the cytotoxic effects of potassium dichromate. A statistically significant increase in the concentration of malondialdehyde [MDA], an indicator of lipid peroxidation, was recorded in exposed cells [15.9 – 69.9 μM] compared to control [13 μM]. Similarly, a strong dose-response relationship (p<0.05) was also obtained with respect to potassium dichromate induced DNA damage (comet assay) in HepG2 cells exposed [3.16 ± 0.70 – 24.84 ± 1.86 microns – mean comet tail length]; [12.4 ± 1.45% – 76 ± 1.49% – % tail DNA] to potassium dichromate than control [3.07 ± 0.26 microns – mean comet tail length]; [2.69 + 0.19% – % Tail DNA], respectively. The results demonstrated that potassium dichromatewas highly cytotoxic to HepG2 cells, and its cytotoxicity seems to be mediated by oxidative stress and DNA damage.
Pseudocholinesterase Deficiency: A Case Report and Literature Review  [PDF]
Patrick J. Hackett, Tetsuro Sakai
Open Journal of Anesthesiology (OJAnes) , 2012, DOI: 10.4236/ojanes.2012.24043
Abstract: A 72-year-old male underwent neck dissection and parotidectomy with facial nerve preservation. Endotracheal intubation was facilitated with succinylcholine. Prolonged muscle paralysis which was first detected after failure to stimulate the facial nerve with electrocautery, lasted five hours. Laboratory tests indicated pseudocholinesterase (PChE) deficiency. A thyroidectomy one month later was performed uneventfully using rocuronium as a muscle relaxant. Literature review revealed a total of 40 PChE deficiency cases being reported since 1956.
Invariants of Spin Networks from Braided Ribbon Networks
Jonathan Hackett
Physics , 2011,
Abstract: We connect Braided Ribbon Networks to the states of loop quantum gravity. Using this connection we present the reduced link as an invariant which captures information from the embedding of the spin-networks. We also present a means of understanding higher valent nodes in the context of braided ribbon networks and an interpretation of the dual of these nodes as polygons or polyhedra.
Invariants of Braided Ribbon Networks
Jonathan Hackett
Physics , 2011,
Abstract: We present a consistent definition for braided ribbon networks in 3-dimensional manifolds, unifying both three and four valent networks in a single framework. We present evolution moves for these networks which are dual to the Pachner moves on simplices and present an invariant of this evolution. Finally we relate these results back to previous work in the subject.
Asymptotic Flatness in Rainbow Gravity
Jonathan Hackett
Physics , 2005, DOI: 10.1088/0264-9381/23/11/010
Abstract: A construction of conformal infinity in null and spatial directions is constructed for the Rainbow-flat space-time corresponding to doubly special relativity. From this construction a definition of asymptotic DSRness is put forward which is compatible with the correspondence principle of Rainbow gravity. Furthermore a result equating asymptotically flat space-times with asymptotically DSR spacetimes is presented.
Quantitative Analysis of α-L-Iduronidase Expression in Immunocompetent Mice Treated with the Sleeping Beauty Transposon System
Elena L. Aronovich, Bryan C. Hall, Jason B. Bell, R. Scott McIvor, Perry B. Hackett
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0078161
Abstract: The Sleeping Beauty transposon system, a non-viral, integrating vector that can deliver the alpha-L-iduronidase-encoding gene, is efficient in correcting mucopolysaccharidosis type I in NOD/SCID mice. However, in previous studies we failed to attain reliable long-term alpha-L-iduronidase expression in immunocompetent mice. Here, we focused on achieving sustained high-level expression in immunocompetent C57BL/6 mice. In our standard liver-directed treatment we hydrodynamically infuse mice with plasmids containing a SB transposon-encoding human alpha-L-iduronidase, along with a source of SB transposase. We sought to 1) minimize expression of the therapeutic enzyme in antigen-presenting cells, while avoiding promoter shutdown and gender bias, 2) increase transposition efficiency and 3) improve immunosuppression. By using a liver-specific promoter to drive IDUA expression, the SB100X hyperactive transposase and transient cyclophosphamide immunosuppression we achieved therapeutic-level (>100 wild-type) stabilized expression for 1 year in 50% of C57BL/6 mice. To gain insights into the causes of variability in transgene expression, we quantified the rates of alpha-L-iduronidase activity decay vis-a-vis transposition and transgene maintenance using the data obtained in this and previous studies. Our analyses showed that immune responses are the most important variable to control in order to prevent loss of transgene expression. Cumulatively, our results allow transition to pre-clinical studies of SB-mediated alpha-L-iduronidase expression and correction of mucopolysaccharidosis type I in animal models.
Polyunsaturated Fatty Acid Dietary Supplementation Induces Lipid Peroxidation in Normal Dogs
John M. Walters,Timothy B. Hackett,Gregory K. Ogilvie,Martin J. Fettman
Veterinary Medicine International , 2010, DOI: 10.4061/2010/619083
Abstract: Polyunsaturated fatty acids (PUFAs) have anti-inflammatory effects at low concentrations; however increased dietary consumption may conversely increase susceptibility to oxidation by free radicals. The objective of this study was to determine the effects of PUFAs on selective oxidative injury and inflammatory biomarkers in canine urine and serum. Dogs (=54) consumed a diet supplemented with 0.5% conjugated linoleic acid/dry matter, 1.0% conjugated linoleic acid/dry matter, or 200 mg/kg docosahexaenoic acid/eicosapentaenoic acid for 21 days. All dogs exhibited significantly increased plasma PUFA concentrations. All dogs had significant elevations in urinary F2 isoprostane concentration, though dogs consuming a diet containing 1.0% conjugated linoleic acid/dry matter had the highest increase (=.0052). Reduced glutathione concentrations within erythrocytes decreased significantly in all three dietary treatment groups (=.0108). Treatment with diets containing 1.0% conjugated linoleic acid/dry matter resulted in the greatest increase in oxidant injury. Caution should be exercised when supplementing PUFAs as some types may increase oxidation.
Effective Gene Trapping Mediated by Sleeping Beauty Transposon
Guili Song, Qing Li, Yong Long, Qilin Gu, Perry B. Hackett, Zongbin Cui
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044123
Abstract: Gene trapping is a high-throughput approach to elucidate gene functions by disrupting and recapitulating expression of genes in a target genome. A number of transposon-based gene-trapping systems are developed for mutagenesis in cells and model organisms, but there is still much room for the improvement of their efficiency in gene disruption and mutation. Herein, a gene-trapping system mediated by Sleeping Beauty (SB) transposon was developed by inclusion of three functional cassettes. The mutation cassette can abrogate the splice of trapped genes and terminate their translation. Once an endogenous gene is captured, the finding cassette independently drives the translation of reporter gene in HeLa cells and zebrafish embryos. The efficiency cassette controls the remobilization of integrated traps through inducible expression of SB gene. Analysis of transposon-genome junctions indicate that most of trap cassettes are integrated into an intron without an obvious 3′ bias. The transcription of trapped genes was abrogated by alternative splicing of the mutation cassette. In addition, integrated transposons can be induced to excise from their original insertion sites. Furthermore, the Cre/LoxP system was introduced to delete the efficiency cassette for stabilization of gene interruption and bio-safety. Thus, this gene-trap vector is an alternative and effective tool for the capture and disruption of endogenous genes in vitro and in vivo.
Incorporating Chiral Symmetry in Extrapolations of Octet Baryon Magnetic Moments
E. J. Hackett-Jones,D. B. Leinweber,A. W. Thomas
Physics , 2000, DOI: 10.1016/S0370-2693(00)00899-6
Abstract: We explore methods of extrapolating lattice calculations of hadronic observables to the physical regime, while respecting the constraints of chiral symmetry and heavy quark effective theory. In particular, we extrapolate lattice results for magnetic moments of the spin-1/2 baryon octet to the physical pion mass and compare with experimental measurements. The success previously reported for extrapolations of the nucleon magnetic moments carries over to the Sigma baryons. A study of the residual discrepancies in the Xi baryon moments suggests that it is important to have new simulation data with a more realistic strange quark mass.
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