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Search Results: 1 - 10 of 221155 matches for " Paul N. Reynolds "
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Improved gene delivery to human saphenous vein cells and tissue using a peptide-modified adenoviral vector
Work Lorraine M,Reynolds Paul N,Baker Andrew H
Genetic Vaccines and Therapy , 2004, DOI: 10.1186/1479-0556-2-14
Abstract: The establishment of efficient gene delivery to target human tissue is a major obstacle for transition of gene therapy from the pre-clinical phases to the clinic. The poor long-term patency rates for coronary artery bypass grafting (CABG) is a major clinical problem that lacks an effective and proven pharmacological intervention. Late vein graft failure occurs due to neointima formation and accelerated atherosclerosis. Since CABG allows a clinical window of opportunity to genetically modify vein ex vivo prior to grafting it represents an ideal opportunity to develop gene-based therapies. Adenoviral vectors have been frequently used for gene delivery to vein ex vivo and pre-clinical studies have shown effective blockade in neointima development by overexpression of candidate therapeutic genes. However, high titers of adenovirus are required to achieve sufficient gene delivery to provide therapeutic benefit. Improvement in the uptake of adenovirus into the vessel wall would therefore be of benefit. Here we determined the ability of an adenovirus serotype 5 vector genetically-engineered with the RGD-4C integrin targeting peptide inserted into the HI loop (Ad-RGD) to improve the transduction of human saphenous vein smooth muscle cells (HSVSMC), endothelial cells (HSVEC) and intact saphenous vein compared to a non-modified virus (Ad-CTL). We exposed each cell type to virus for 10, 30 or 60 mins and measured transgene at 24 h post infection. For both HSVSMC and HSVEC Ad-RGD mediated increased transduction, with the largest increases observed in HSVSMC. When the experiments were repeated with intact human saphenous vein (the ultimate clinical target for gene therapy), again Ad-RGD mediated higher levels of transduction, at all clinically relevant exposures times (10, 30 and 60 mins tissue:virus exposure). Our study demonstrates the ability of peptide-modified Ad vectors to improve transduction to human vein graft cells and tissue and has important implications for gene therapy for CABG.
Disentangling Privacy and Intimacy: Intimate Citizenship, Private Boundaries and Public Transgressions
Paul Reynolds
Human Affairs , 2010, DOI: 10.2478/v10023-010-0004-1
Abstract: Recent theorisations of transformations of intimacy—like Ken Plummer's (2003) Intimate Citizenship project—concentrate on social and cultural transformations that erode the containment of intimacy within the private sphere. They have less to say about the character of and oppositions to that erosion, and specifically how far the idea of the private stands in opposition to intimacy transgressing into the public. In this essay, the private is explored through its constitutive features—liberal codifications of rights, liberty and property, medico-moral discourses and conservative values and legal and political regulation—to give a more political and critical reading. This reading suggests that an explicit disentangling of the private and the intimate is necessary if tendencies toward public and emancipated intimacies are to become meaningful transformations, and this involves a dissembling of and critical engagement with the powerful historically entrenched idea of privacy in western societies.
Property, Patents, or People: What part of NO don t you understand?
Paul Reynolds
Revista Theomai , 2002,
Abstract: Los Maori y otros pueblos indígenas han respetado siempre la santidad y la reciprocidad de la vida. Las patentes no tienen ningún respeto por la vida o por la dignidad de todas las formas de vida. No hay negociación. De hecho, hay un clamor mundial que sostiene que patentar la vida es algo innegociable. En palabras de un activista maori: ? Qué parte es la que no entienden??; así lo dicen los maoríes, pero como la gente sigue preguntando sobre el tema, la otra parte de la pregunta debiera ser: ? Qué parte del NO es la que no entienden??. Mi intención en este texto es esclarecer cómo y por qué las patentes se han hecho de la vida. La construcción histórica y genealógica de la propiedad ha llegado hasta el punto de la creación de patentes que le dan derechos a su titular para poseer de manera privada una determinada forma de vida. Se pueden esgrimir también cantidades de argumentos sobre por qué patentar la vida es ?malo?. Se finaliza con una selección de métodos e ideas que pienso son de utilidad para recapturar la vida.
Lectins Offer New Perspectives in the Development of Macrophage-Targeted Therapies for COPD/Emphysema
Violet R. Mukaro, Johan Bylund, Greg Hodge, Mark Holmes, Hubertus Jersmann, Paul N. Reynolds, Sandra Hodge
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0056147
Abstract: We have previously shown that the defective ability of alveolar macrophages (AM) to phagocytose apoptotic cells (‘efferocytosis’) in chronic obstructive pulmonary disease/emphysema (COPD) could be therapeutically improved using the C-type lectin, mannose binding lectin (MBL), although the exact mechanisms underlying this effect are unknown. An S-type lectin, galectin-3, is also known to regulate macrophage phenotype and function, via interaction with its receptor CD98. We hypothesized that defective expression of galectin/CD98 would be associated with defective efferocytosis in COPD and that mechanisms would include effects on cytoskeletal remodeling and macrophage phenotype and glutathione (GSH) availability. Galectin-3 was measured by ELISA in BAL from controls, smokers and current/ex-smokers with COPD. CD98 was measured on AM using flow cytometry. We assessed the effects of galectin-3 on efferocytosis, CD98, GSH, actin polymerisation, rac activation, and the involvement of PI3K (using β-actin probing and wortmannin inhibition) in vitro using human AM and/or MH-S macrophage cell line. Significant decreases in BAL galectin-3 and AM CD98 were observed in BAL from both current- and ex-smoker COPD subjects vs controls. Galectin 3 increased efferocytosis via an increase in active GTP bound Rac1. This was confirmed with β-actin probing and the role of PI3K was confirmed using wortmannin inhibition. The increased efferocytosis was associated with increases in available glutathione and expression of CD98. We provide evidence for a role of airway lectins in the failed efferocytosis in COPD, supporting their further investigation as potential macrophage-targeted therapies.
Oxidative Stress Decreases Functional Airway Mannose Binding Lectin in COPD
Hai B. Tran, Jessica Ahern, Greg Hodge, Phillip Holt, Melinda M. Dean, Paul N. Reynolds, Sandra Hodge
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0098571
Abstract: We have previously established that a defect in the ability of alveolar macrophages (AM) to phagocytose apoptotic cells (efferocytosis) and pathogens is a potential therapeutic target in COPD. We further showed that levels of mannose binding lectin (MBL; required for effective macrophage phagocytic function) were reduced in the airways but not circulation of COPD patients. We hypothesized that increased oxidative stress in the airway could be a cause for such disturbances. We therefore studied the effects of oxidation on the structure of the MBL molecule and its functional interactions with macrophages. Oligomeric structure of plasma derived MBL (pdMBL) before and after oxidation (oxMBL) with 2,2′-azobis(2-methylpropionamidine)dihyd？rochroride(AAPH) was investigated by blue native PAGE. Macrophage function in the presence of pd/oxMBL was assessed by measuring efferocytosis, phagocytosis of non-typeable Haemophilus influenzae (NTHi) and expression of macrophage scavenger receptors. Oxidation disrupted higher order MBL oligomers. This was associated with changed macrophage function evident by a significantly reduced capacity to phagocytose apoptotic cells and NTHi in the presence of oxMBL vs pdMBL (eg, NTHi by 55.9 and 27.0% respectively). Interestingly, oxidation of MBL significantly reduced macrophage phagocytic ability to below control levels. Flow cytometry and immunofluorescence revealed a significant increase in expression of macrophage scavenger receptor (SRA1) in the presence of pdMBL that was abrogated in the presence of oxMBL. We show the pulmonary macrophage dysfunction in COPD may at least partially result from an oxidative stress-induced effect on MBL, and identify a further potential therapeutic strategy for this debilitating disease.
Defective Lung Macrophage Function in Lung Cancer±Chronic Obstructive Pulmonary Disease (COPD/Emphysema)-Mediated by Cancer Cell Production of PGE2?
Francis C. Dehle, Violet R. Mukaro, Craig Jurisevic, David Moffat, Jessica Ahern, Greg Hodge, Hubertus Jersmann, Paul N. Reynolds, Sandra Hodge
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0061573
Abstract: In chronic obstructive pulmonary disease (COPD/emphysema) we have shown a reduced ability of lung and alveolar (AM) macrophages to phagocytose apoptotic cells (defective ‘efferocytosis’), associated with evidence of secondary cellular necrosis and a resultant inflammatory response in the airway. It is unknown whether this defect is present in cancer (no COPD) and if so, whether this results from soluble mediators produced by cancer cells. We investigated efferocytosis in AM (26 controls, 15 healthy smokers, 37 COPD, 20 COPD+ non small cell lung cancer (NSCLC) and 8 patients with NSCLC without COPD) and tumor and tumor-free lung tissue macrophages (21 NSCLC with/13 without COPD). To investigate the effects of soluble mediators produced by lung cancer cells we then treated AM or U937 macrophages with cancer cell line supernatant and assessed their efferocytosis ability. We qualitatively identified Arachidonic Acid (AA) metabolites in cancer cells by LC-ESI-MSMS, and assessed the effects of COX inhibition (using indomethacin) on efferocytosis. Decreased efferocytosis was noted in all cancer/COPD groups in all compartments. Conditioned media from cancer cell cultures decreased the efferocytosis ability of both AM and U937 macrophages with the most pronounced effects occurring with supernatant from SCLC (an aggressive lung cancer type). AA metabolites identified in cancer cells included PGE2. The inhibitory effect of PGE2 on efferocytosis, and the involvement of the COX-2 pathway were shown. Efferocytosis is decreased in COPD/emphysema and lung cancer; the latter at least partially a result of inhibition by soluble mediators produced by cancer cells that include PGE2.
Aplicación de la realidad virtual no inmersiva para Ingenieros Agrícolas
León Guerra,Reynolds;
Revista Ciencias T？？cnicas Agropecuarias , 2012,
Abstract: this paper addresses the use of non-immersive virtual reality in the engineering field today widely used by universities and research centers to develop their research and application in teaching. the work focuses on how virtual reality is used by computer specialists who do not have any knowledge of programming, where they develop a methodology to create virtual world without using programming techniques and how easy to use development tools well known in the field of engineering such as cad / cae systems while not mentioning important aspects on web and vrml that are necessary for a better understanding of the methodology and special considerations to be taken into account to create virtual world or virtual scenes.
A bio-informatics study of the c25 cysteine protease family  [PDF]
K J. Cross, N L. Huq, E C. Reynolds
Open Journal of Genetics (OJGen) , 2012, DOI: 10.4236/ojgen.2012.24B004
Abstract: The oral pathogen Porphyromonas gingivalis is recognized as one of the major aetiological agents of chronic periodontitis. The gingipains, which are the principal virulence factors of P. gingivalis, are multi-domain proteins containing an N-terminal C25 cysteine protease domain. We have conducted a bio-informatics study of the C25 cysteine protease domains and have identified related domains in over two thousand proteins from 739 organisms in 35 distinct phyla. Proteins having significant similarity to the gingipain C25 cysteine protease domain are also found in Gram +ve bacteria, Archaea, algae, higher fungi, and a wide variety of Eukaryotic species.
Bismuth Toxicity: A Rare Cause of Neurologic Dysfunction  [PDF]
Paul T. Reynolds, Kathleen C. Abalos, Jennifer Hopp, Mark E. Williams
International Journal of Clinical Medicine (IJCM) , 2012, DOI: 10.4236/ijcm.2012.31010
Abstract: Bismuth subsalicylate (Pepto-Bismol?) and other bismuth-containing compounds have been used for many years to treat gastroenterological complaints. Although safe in the majority of patients, bismuth can cause a well-described toxic state marked by progressive neurological decline. Features of bismuth toxicity include confusion, postural instability, myoclonus, and problems with language. This presentation can masquerade as other causes of progressive neurologic dysfunction including Creutzfeld-Jakob Disease (CJD), Hashimoto’s Encephalopathy, and others. In this case study, we present a patient who was using bismuth salicylate in toxic quantities to help control diarrhea. On initial presentation, several diagnoses were entertained before bismuth levels were obtained. This case study highlights the fact that bismuth toxicity, while rare, should be considered in a patient with progressive neurological decline. Also, we hope this case reminds physicians of a severe consequence of a common, readily available medication.
TTF-1 regulates α5 nicotinic acetylcholine receptor (nAChR) subunits in proximal and distal lung epithelium
Paul R Reynolds, Camille H Allison, Charles P Willnauer
Respiratory Research , 2010, DOI: 10.1186/1465-9921-11-175
Abstract: α5 was assessed by immunohistochemistry and RT-PCR in mouse lungs from embryonic day (E)13.5 to post-natal day (PN)20. From E13.5 to E18.5, α5 expression was primarily observed in primitive airway epithelial cells while mesenchymal expression was faint and sporadic. α5 expression was detected throughout the proximal lung at PN1 and extensively expressed in the peripheral lung at PN4, an early stage of murine alveologenesis. An interesting shift occurred wherein α5 expression was almost undetectable in the proximal lung from PN4-PN10, but significant localization was again observed at PN20. Transcriptional control of α5 was determined by assessing the activity of reporters containing 2.0-kb and 850-bp of the mouse α5 promoter. Because perinatal expression of α5 was abundant in bronchiolar and alveolar epithelium, we assessed transcriptional control of α5 in Beas2B cells, a human bronchiolar epithelial cell line, and A-549 cells, an alveolar type II cell-like human epithelial cell line. Thyroid Transcription Factor-1 (TTF-1), a key transcription regulator of pulmonary morphogenesis, significantly increased α5 transcription by acting on both the 2.0-kb and 850-bp α5 promoters. Site-directed mutagenesis revealed that TTF-1 activated α5 transcription by binding specific TTF-1 response elements. Exogenous TTF-1 also significantly induced α5 transcription.These data demonstrate that α5 is specifically controlled in a temporal and spatial manner during pulmonary morphogenesis. Ongoing research may demonstrate that precise regulation of α5 is important during normal organogenesis and misexpression correlates with tobacco related lung disease.Mechanisms that control pulmonary development involve highly coordinated processes that require precise reciprocal interactions between endodermally derived respiratory epithelium and the surrounding splanchnic mesenchyme. These interactions are predominantly mediated by cell surface receptors and specific ligands elaborated by communica
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