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Search Results: 1 - 10 of 156787 matches for " Douglas B. Young "
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Does Aristotle Refute the Harmonia Theory of the Soul?  [PDF]
Douglas J. Young
Open Journal of Philosophy (OJPP) , 2013, DOI: 10.4236/ojpp.2013.31008

In Aristotle’s On the Soul he considers and refutes two versions of the harmonia theory of the soul’s relation to the body. According to the harmonia theory, the soul is to the body what the tuning of a musical instrument is to its material parts. Though he believes himself to have entirely dismissed the view, he has not. I argue that Aristotle’s hylomorphic account is, in fact, an instance of the harmonia theory.

Comparison of Mycobacterium tuberculosis Genomes Reveals Frequent Deletions in a 20 kb Variable Region in Clinical Isolates
Timothy B. L. Ho,Brian D. Robertson,G. Michael Taylor,Rory J. Shaw,Douglas B. Young
Comparative and Functional Genomics , 2000, DOI: 10.1002/1097-0061(200012)17:4<272::aid-yea48>3.0.co;2-2
Abstract: The Mycobacterium tuberculosis complex is associated with a remarkably low level of structural gene polymorphism. As part of a search for alternative forms of genetic variation that may act as a source of biological diversity in M. tuberculosis, we have identified a region of the genome that is highly variable amongst a panel of unrelated clinical isolates. Fifteen of 24 isolates examined contained one or more copies of the M. tuberculosis-specific IS6110 insertion element within this 20 kb variable region. In nine of the isolates, including the laboratory-passaged strain H37Rv, genomic deletions were identified, resulting in loss of between two and 13 genes. In each case, deletions were associated with the presence of a copy of the IS6110 element. Absence of flanking tri- or tetra-nucleotide repeats identified homologous recombination between adjacent IS6110 elements as the most likely mechanism of the deletion events. IS6110 insertion into hot-spots within the genome of M. tuberculosis provides a mechanism for generation of genetic diversity involving a high frequency of insertions and deletions.
Mycobacterial Mutants with Defective Control of Phagosomal Acidification
Graham R Stewart ,Janisha Patel,Brian D Robertson,Aaron Rae,Douglas B Young
PLOS Pathogens , 2005, DOI: 10.1371/journal.ppat.0010033
Abstract: The pathogenesis of mycobacterial infection is associated with an ability to interfere with maturation of the phagosomal compartment after ingestion by macrophages. Identification of the mycobacterial components that contribute to this phenomenon will allow rational design of novel approaches to the treatment and prevention of tuberculosis. Microarray-based screening of a transposon library was used to identify mutations that influence the fate of Mycobacterium bovis bacille Calmette-Guérin (BCG) following uptake by macrophages. A screen based on bacterial survival during a 3-d infection highlighted genes previously implicated in growth of Mycobacterium tuberculosis in macrophages and in mice, together with a number of other virulence genes including a locus encoding virulence-associated membrane proteins and a series of transporter molecules. A second screen based on separation of acidified and non-acidified phagosomes by flow cytometry identified genes involved in mycobacterial control of early acidification. This included the KefB potassium/proton antiport. Mutants unable to control early acidification were significantly attenuated for growth during 6-d infections of macrophages. Early acidification of the phagosome is associated with reduced survival of BCG in macrophages. A strong correlation exists between genes required for intracellular survival of BCG and those required for growth of M. tuberculosis in mice. In contrast, very little correlation exists between genes required for intracellular survival of BCG and those that are up-regulated during intracellular adaptation of M. tuberculosis. This study has identified targets for interventions to promote immune clearance of tuberculosis infection. The screening technologies demonstrated in this study will be useful to the study of pathogenesis in many other intracellular microorganisms.
Use of Short Tandem Repeat Sequences to Study Mycobacterium leprae in Leprosy Patients in Malawi and India
Saroj K. Young,Jorg M. Ponnighaus,Suman Jain,Sebastian Lucas,Sujai Suneetha,Diana N. J. Lockwood,Douglas B. Young,Paul E. M. Fine
PLOS Neglected Tropical Diseases , 2008, DOI: 10.1371/journal.pntd.0000214
Abstract: Background Inadequate understanding of the transmission of Mycobacterium leprae makes it difficult to predict the impact of leprosy control interventions. Genotypic tests that allow tracking of individual bacterial strains would strengthen epidemiological studies and contribute to our understanding of the disease. Methodology/Principal Findings Genotyping assays based on variation in the copy number of short tandem repeat sequences were applied to biopsies collected in population-based epidemiological studies of leprosy in northern Malawi, and from members of multi-case households in Hyderabad, India. In the Malawi series, considerable genotypic variability was observed between patients, and also within patients, when isolates were collected at different times or from different tissues. Less within-patient variability was observed when isolates were collected from similar tissues at the same time. Less genotypic variability was noted amongst the closely related Indian patients than in the Malawi series. Conclusions/Significance Lineages of M. leprae undergo changes in their pattern of short tandem repeat sequences over time. Genetic divergence is particularly likely between bacilli inhabiting different (e.g., skin and nerve) tissues. Such variability makes short tandem repeat sequences unsuitable as a general tool for population-based strain typing of M. leprae, or for distinguishing relapse from reinfection. Careful use of these markers may provide insights into the development of disease within individuals and for tracking of short transmission chains.
Natural Killer Cell Cytokine Response to M. bovis BCG Is Associated with Inhibited Proliferation, Increased Apoptosis and Ultimate Depletion of NKp44+CD56bright Cells
Damien Portevin, Douglas Young
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0068864
Abstract: Mycobacterium bovis BCG, a live attenuated strain of M. bovis initially developed as a vaccine against tuberculosis, is also used as an adjuvant for immunotherapy of cancers and for treatment of parasitic infections. The underlying mechanisms are thought to rely on its immunomodulatory properties including the recruitment of natural killer (NK) cells. In that context, we aimed to study the impact of M. bovis BCG on NK cell functions. We looked at cytotoxicity, cytokine production, proliferation and cell survival of purified human NK cells following exposure to single live particles of mycobacteria. We found that M. bovis BCG mediates apoptosis of NK cells only in the context of IL-2 stimulation during which CD56bright NK cells are releasing IFN-γ in response to mycobacteria. We found that the presence of mycobacteria prevented the IL-2 induced proliferation and surface expression of NKp44 receptor by the CD56bright population. In summary, we observed that M. bovis BCG is modulating the functions of CD56bright NK cells to drive this subset to produce IFN-γ before subsequent programmed cell death. Therefore, IFN-γ production by CD56bright cells constitutes the main effector mechanism of NK cells that would contribute to the benefits observed for M. bovis BCG as an immunotherapeutic agent.
A Small RNA Encoded in the Rv2660c Locus of Mycobacterium tuberculosis Is Induced during Starvation and Infection
Joanna Houghton, Teresa Cortes, Olga Schubert, Graham Rose, Angela Rodgers, Megan De Ste Croix, Rudolf Aebersold, Douglas B. Young, Kristine B. Arnvig
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0080047
Abstract: Enhanced transcription of the Rv2660c locus in response to starvation of Mycobacterium tuberculosis H37Rv encouraged addition of the predicted Rv2660c protein to an improved vaccine formulation. Using strand-specific RNA sequencing, we show that the up-regulated transcript is in fact a small RNA encoded on the opposite strand to the annotated Rv2660c. The transcript originates within a prophage and is expressed only in strains that carry PhiRv2. The small RNA contains both host and phage sequences and provides a useful biomarker to monitor bacterial starvation during infection and/or non-replicating persistence. Using different approaches we do not find any evidence of Rv2660c at the level of mRNA or protein. Further efforts to understand the mechanism by which Rv2660c improves efficacy of the H56 vaccine are likely to provide insights into the pathology and immunology of tuberculosis.
Prolonged Opioid-Sparing Pain Control after Hemorrhoidectomy with Liposome Bupivacaine: Results from a Cohort of 95 Patients  [PDF]
Allen B. Jetmore, Douglas Hagen
Pain Studies and Treatment (PST) , 2016, DOI: 10.4236/pst.2016.41002
Abstract: The objective of this retrospective study was to examine the effects of an intraoperative injection of liposome bupivacaine on the quality and duration of postsurgical pain control, patient satisfaction, and opioid use in a cohort of patients undergoing hemorrhoidectomy in an outpatient setting. Patients underwent ambulatory hemorrhoidectomy conducted by a single surgeon. Liposome bupivacaine 266 mg/20 mL was administered via infiltration at the end of surgery. After discharge, pain-related outcomes were assessed via telephone interviews. Outcomes of interest included first onset of pain after surgery, patient-reported pain intensity (0 = no pain; 10 = worst pain imaginable), time to first use of orally administered opioids after surgery, number of opioid tablets consumed postsurgery, and patient’s satisfaction with postsurgical pain control. A total of 95 patients were included; the average number of hemorrhoids excised was 3.0 (median, 2.7) per patient. Mean time to first onset of pain after surgery was 36 hours; mean time to first consumption of postsurgical opioids was 38 hours. Mean pain intensity scores remained <5 through 72 hours after surgery. The average number of opioid analgesic tablets consumed after surgery was 12.4; 13% (12/95) of patients required no postsurgical opioids. Seventy-five percent of patients reported being “very satisfied” or “perfectly satisfied” with their overall pain control. No liposome bupivacaine-related adverse events were observed. A single intraoperative injection of liposome bupivacaine safely facilitated ambulatory hemorrhoidectomy, eliminated the need for intravenous opioids, minimized opioid use, and was associated with high levels of patient satisfaction.
The Heat Shock Response of Mycobacterium tuberculosis: Linking Gene Expression, Immunology and Pathogenesis
Graham R. Stewart,Lorenz Wernisch,Richard Stabler,Joseph A. Mangan,Jason Hinds,Ken G. Laing,Philip D. Butcher,Douglas B. Young
Comparative and Functional Genomics , 2002, DOI: 10.1002/cfg.183
Abstract: The regulation of heat shock protein (HSP) expression is critically important to pathogens such as Mycobacterium tuberculosis and dysregulation of the heat shock response results in increased immune recognition of the bacterium and reduced survival during chronic infection. In this study we use a whole genome spotted microarray to characterize the heat shock response of M. tuberculosis. We also begin a dissection of this important stress response by generating deletion mutants that lack specific transcriptional regulators and examining their transcriptional profiles under different stresses. Understanding the stimuli and mechanisms that govern heat shock in mycobacteria will allow us to relate observed in vivo expression patterns of HSPs to particular stresses and physiological conditions. The mechanisms controlling HSP expression also make attractive drug targets as part of a strategy designed to enhance immune recognition of the bacterium.
Conserved Immune Recognition Hierarchy of Mycobacterial PE/PPE Proteins during Infection in Natural Hosts
H. Martin Vordermeier, R. Glyn Hewinson, Robert J. Wilkinson, Katalin A. Wilkinson, Hannah P. Gideon, Douglas B. Young, Samantha L. Sampson
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040890
Abstract: The Mycobacterium tuberculosis genome contains two large gene families encoding proteins of unknown function, characterized by conserved N-terminal proline and glutamate (PE and PPE) motifs. The presence of a large number of PE/PPE proteins with repetitive domains and evidence of strain variation has given rise to the suggestion that these proteins may play a role in immune evasion via antigenic variation, while emerging data suggests that some family members may play important roles in mycobacterial pathogenesis. In this study, we examined cellular immune responses to a panel of 36 PE/PPE proteins during human and bovine infection. We observed a distinct hierarchy of immune recognition, reflected both in the repertoire of PE/PPE peptide recognition in individual cows and humans and in the magnitude of IFN-γ responses elicited by stimulation of sensitized host cells. The pattern of immunodominance was strikingly similar between cattle that had been experimentally infected with Mycobacterium bovis and humans naturally infected with clinical isolates of M. tuberculosis. The same pattern was maintained as disease progressed throughout a four-month course of infection in cattle, and between humans with latent as well as active tuberculosis. Detailed analysis of PE/PPE responses at the peptide level suggests that antigenic cross-reactivity amongst related family members is a major determinant in the observed differences in immune hierarchy. Taken together, these results demonstrate that a subset of PE/PPE proteins are major targets of the cellular immune response to tuberculosis, and are recognized at multiple stages of infection and in different disease states. Thus this work identifies a number of novel antigens that could find application in vaccine development, and provides new insights into PE/PPE biology.
Sequence-Based Analysis Uncovers an Abundance of Non-Coding RNA in the Total Transcriptome of Mycobacterium tuberculosis
Kristine B. Arnvig ,I?aki Comas,Nicholas R. Thomson,Joanna Houghton,Helena I. Boshoff,Nicholas J. Croucher,Graham Rose,Timothy T. Perkins,Julian Parkhill,Gordon Dougan,Douglas B. Young
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002342
Abstract: RNA sequencing provides a new perspective on the genome of Mycobacterium tuberculosis by revealing an extensive presence of non-coding RNA, including long 5’ and 3’ untranslated regions, antisense transcripts, and intergenic small RNA (sRNA) molecules. More than a quarter of all sequence reads mapping outside of ribosomal RNA genes represent non-coding RNA, and the density of reads mapping to intergenic regions was more than two-fold higher than that mapping to annotated coding sequences. Selected sRNAs were found at increased abundance in stationary phase cultures and accumulated to remarkably high levels in the lungs of chronically infected mice, indicating a potential contribution to pathogenesis. The ability of tubercle bacilli to adapt to changing environments within the host is critical to their ability to cause disease and to persist during drug treatment; it is likely that novel post-transcriptional regulatory networks will play an important role in these adaptive responses.
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