Publications by authors named "Christopher McKenzie"

15 Publications

  • Page 1 of 1

Cell-to-cell spread of vaccinia virus is promoted by TGF-β-independent Smad4 signalling.

Cell Microbiol 2020 08 28;22(8):e13206. Epub 2020 Apr 28.

School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales, Australia.

The induction of Smad signalling by the extracellular ligand TGF-β promotes tissue plasticity and cell migration in developmental and pathological contexts. Here, we show that vaccinia virus (VACV) stimulates the activity of Smad transcription factors and expression of TGF-β/Smad-responsive genes at the transcript and protein levels. Accordingly, infected cells share characteristics to those undergoing TGF-β/Smad-mediated epithelial-to-mesenchymal transition (EMT). Depletion of the Smad4 protein, a common mediator of TGF-β signalling, results in an attenuation of viral cell-to-cell spread and reduced motility of infected cells. VACV induction of TGF-β/Smad-responsive gene expression does not require the TGF-β ligand or type I and type II TGF-β receptors, suggesting a novel, non-canonical Smad signalling pathway. Additionally, the spread of ectromelia virus, a related orthopoxvirus that does not activate a TGF-β/Smad response, is enhanced by the addition of exogenous TGF-β. Together, our results indicate that VACV orchestrates a TGF-β-like response via a unique activation mechanism to enhance cell migration and promote virus spread.
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http://dx.doi.org/10.1111/cmi.13206DOI Listing
August 2020

A Comparison of the Arterial Blood Concentration of Isoflurane During Cardiopulmonary Bypass Between 2 Polypropylene Oxygenators.

J Cardiothorac Vasc Anesth 2020 May 21;34(5):1184-1190. Epub 2019 Aug 21.

Clinical Research Facility Mass Spectrometry Core Centre for Cardiovascular Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK.

Objective: The primary objective was to compare arterial blood concentration of isoflurane during cardiopulmonary bypass (CPB) between 2 polypropylene oxygenators of different designs. Secondary objectives were to compare levels of Bispectral Index Score (BIS) during CPB between the 2 oxygenators and to examine the relationships between oxygenator exhaust and arterial blood concentrations of isoflurane and BIS.

Design: Single, blinded, randomized control trial.

Setting: Teaching hospital.

Participants: Twenty-five patients undergoing cardiac surgery with CPB.

Interventions: Subjects were randomly assigned (1:1) to Inspire 8F (Sorin) or Affinity Fusion (Medtronic) oxygenators.

Measurements And Main Results: The mean arterial blood concentration in the Inspire 8F (Sorin) group was 59 (standard deviation [SD] 23) µg/mL, compared with 53 (SD 17) µg/mL in the Affinity Fusion (Medtronic) group with a nonsignificant mean difference of 6 (95% confidence interval = -11, 22) µg/mL (t[23] = 0.676, p = 0.50). No significant difference in BIS was found between the groups (p = 0.896). Moderate and strong, negative correlations respectively, were found between arterial and oxygenator exhaust correlations and BIS (r = -0.472, p < 0.05; r = -0.812, p < 0.001). A strong, positive correlation was found between arterial and exhaust isoflurane concentration (r = 0.810, p < 0.0005).

Conclusions: No significant difference in arterial blood concentration of isoflurane or BIS was found between the Inspire 8F (Sorin) and Affinity Fusion (Medtronic) oxygenators. A significant positive correlation was found between arterial blood and oxygenator exhaust concentrations of isoflurane, as well as significant negative correlations between both arterial and oxygenator exhaust concentrations of isoflurane and BIS.
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http://dx.doi.org/10.1053/j.jvca.2019.08.023DOI Listing
May 2020

Divergent roles of β- and γ-actin isoforms during spread of vaccinia virus.

Cytoskeleton (Hoboken) 2017 Apr 17;74(4):170-183. Epub 2017 Mar 17.

School of Life and Environmental Sciences, The University of Sydney, Australia.

Actin is a major component of the cytoskeleton and is present as two isoforms in non-muscle cells: β- and γ-cytoplasmic actin. These isoforms are strikingly conserved, differing by only four N-terminal amino acids. During spread from infected cells, vaccinia virus (VACV) particles induce localized actin nucleation that propel virus to surrounding cells and facilitate cell-to-cell spread of infection. Here we show that virus-tipped actin comets are composed of β- and γ-actin. We employed isoform-specific siRNA knockdown to examine the role of the two isoforms in VACV-induced actin comets. Despite the high level of similarity between the actin isoforms, and their colocalization, VACV-induced actin nucleation was dependent exclusively on β-actin. Knockdown of β-actin led to a reduction in the release of virus from infected cells, a phenotype dependent on virus-induced Arp2/3 complex activity. We suggest that local concentrations of actin isoforms may regulate the activity of cellular actin nucleator complexes.
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http://dx.doi.org/10.1002/cm.21356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162416PMC
April 2017

Congenital Tuberculosis Complicated by Hemophagocytic Lymphohistiocytosis.

Pediatr Infect Dis J 2016 Jan;35(1):108-10

From the *Infectious Diseases Unit, The Royal Children's Hospital Melbourne, Parkville, Victoria, Australia; †Division of Pediatric Infectious Diseases, Department of Pediatrics, University of British Columbia, BC Children's Hospital, Vancouver, British Columbia, Canada; ‡Murdoch Children's Research Institute; §Department of General Medicine, The Royal Children's Hospital Melbourne, Parkville, Victoria, Australia; ¶Paediatric Department, Likas Women's and Children's Hospital, Sabah, Malaysia; and ‖Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia.

We present the case of a male infant with congenital tuberculosis in a nonendemic setting complicated by hemophagocytic lymphohistiocytosis, who was treated successfully with antituberculous therapy and corticosteroids. We review the pediatric literature concerning the unusual association of these 2 rare conditions.
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http://dx.doi.org/10.1097/INF.0000000000000932DOI Listing
January 2016

Anterior Cruciate Ligament Reconstruction Rehabilitation: MOON Guidelines.

Sports Health 2015 May;7(3):239-43

University of Iowa, Iowa City, Iowa.

Context: Anterior cruciate ligament (ACL) reconstruction rehabilitation has evolved over the past 20 years. This evolution has been driven by a variety of level 1 and level 2 studies.

Evidence Acquisition: The MOON Group is a collection of orthopaedic surgeons who have developed a prospective longitudinal cohort of the ACL reconstruction patients. To standardize the management of these patients, we developed, in conjunction with our physical therapy committee, an evidence-based rehabilitation guideline.

Study Design: Clinical review.

Level Of Evidence: Level 2.

Results: This review was based on 2 systematic reviews of level 1 and level 2 studies. Recently, the guideline was updated by a new review. Continuous passive motion did not improve ultimate motion. Early weightbearing decreases patellofemoral pain. Postoperative rehabilitative bracing did not improve swelling, pain range of motion, or safety. Open chain quadriceps activity can begin at 6 weeks.

Conclusion: High-level evidence exists to determine appropriate ACL rehabilitation guidelines. Utilizing this protocol follows the best available evidence.
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http://dx.doi.org/10.1177/1941738113517855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4482298PMC
May 2015

Lumbopelvic control and days missed because of injury in professional baseball pitchers.

Am J Sports Med 2014 Nov 26;42(11):2734-40. Epub 2014 Aug 26.

School of Health & Rehabilitation Sciences, The Ohio State University, Columbus, Ohio, USA.

Background: Recently, lumbopelvic control has been linked to pitching performance, kinematics, and loading; however, poor lumbopelvic control has not been prospectively investigated as a risk factor for injuries in baseball pitchers.

Hypothesis: Pitchers with poor lumbopelvic control during spring training are more likely to miss ≥30 days because of an injury through an entire baseball season than pitchers with good lumbopelvic control.

Study Design: Cohort study; Level of evidence, 2.

Methods: A total of 347 professional baseball pitchers were enrolled into the study during the last 2 weeks of spring training and stayed with the same team for the entire season. Lumbopelvic control was quantified by peak anterior-posterior deviation of the pelvis relative to the starting position during a single-leg raise test (APScore). Days missed because of an injury through the entire season were recorded by each team's medical staff.

Results: A higher APScore was significantly associated with a higher likelihood of missing ≥30 days (P = .023, χ(2) test). When divided into tertiles based on their APScore, participants in the highest tertile were 3.0 times and 2.2 times more likely to miss at least 30 days throughout the course of a baseball season relative to those in the lowest or middle tertiles, respectively. A higher APScore was also significantly associated with missing more days because of an injury within participants who missed at least 1 day (P = .018, ANOVA), with participants in the highest tertile missing significantly more days (mean, 98.6 days) than those in the middle tertile (mean, 45.8 days; P = .017) or lowest tertile (mean, 43.8 days; P = .017).

Conclusion: This study found that poor lumbopelvic control in professional pitchers was associated with an increased risk of missing significant time because of an injury.
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http://dx.doi.org/10.1177/0363546514545861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4216605PMC
November 2014

Peripheral blood monocyte-derived chemokine blockade prevents murine transfusion-related acute lung injury (TRALI).

Blood 2014 May 17;123(22):3496-503. Epub 2014 Mar 17.

Toronto Platelet Immunobiology Group, Toronto, ON, Canada; Keenan Center for Biomedical Research, St. Michael's Hospital, Toronto, ON, Canada; Canadian Blood Services, Toronto, ON, Canada; and Departments of Medicine, Pharmacology, and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related mortality and can occur with any type of transfusion. TRALI is thought to be primarily mediated by donor antibodies activating recipient neutrophils resulting in pulmonary endothelial damage. Nonetheless, details regarding the interactions between donor antibodies and recipient factors are unknown. A murine antibody-mediated TRALI model was used to elucidate the roles of the F(ab')2 and Fc regions of a TRALI-inducing immunoglobulin G anti-major histocompatibility complex (MHC) class I antibody (34.1.2s). Compared with intact antibody, F(ab')2 fragments significantly increased serum levels of the neutrophil chemoattractant macrophage inflammatory protein 2 (MIP-2); however, pulmonary neutrophil levels were only moderately increased, and no pulmonary edema or mortality occurred. Fc fragments did not modulate any of these parameters. TRALI induction by intact antibody was completely abrogated by in vivo peripheral blood monocyte depletion by gadolinium chloride (GdCl3) or chemokine blockade with a MIP-2 receptor antagonist but was restored upon repletion with purified monocytes. The results suggest a two-step process for antibody-mediated TRALI induction: the first step involves antibody binding its cognate antigen on blood monocytes, which generates MIP-2 chemokine production that is correlated with pulmonary neutrophil recruitment; the second step occurs when antibody-coated monocytes increase Fc-dependent lung damage.
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http://dx.doi.org/10.1182/blood-2013-11-536755DOI Listing
May 2014

Allogeneic platelet transfusions prevent murine T-cell-mediated immune thrombocytopenia.

Blood 2014 Jan 20;123(3):422-7. Epub 2013 Nov 20.

The Toronto Platelet Immunobiology Group.

Platelet transfusions are life-saving treatments for many patients with thrombocytopenia; however, their use is generally discouraged in the autoimmune disorder known as immune thrombocytopenia (ITP). We examined whether allogeneic platelet major histocompatibility complex (MHC) class I transfusions affected antiplatelet CD61-induced ITP. BALB/c CD61 knockout mice (CD61(-)/H-2(d)) were immunized against platelets from wild-type syngeneic BALB/c (CD61(+)/H-2(d)), allogeneic C57BL/6 (CD61(+)/H-2(b)), or C57BL/6 CD61 KO (CD61(-)/H-2(b)) mice, and their splenocytes were transferred into severe combined immunodeficient (SCID) mice to induce ITP. When nondepleted splenocytes were transferred to induce antibody-mediated ITP, both CD61(+) platelet immunizations generated immunity that caused thrombocytopenia independently of allogeneic MHC molecules. In contrast, when B-cell-depleted splenocytes were transferred to induce T-cell-mediated ITP, transfer of allogeneic MHC-immunized splenocytes completely prevented CD61-induced ITP development. In addition, allogeneic platelet transfusions into SCID mice with established CD61-induced ITP rescued the thrombocytopenia. Compared with thrombocytopenic mice, bone marrow histology in the rescued mice showed normalized megakaryocyte morphology, and in vitro CD61-specific T-cell cytotoxicity was significantly suppressed. These results indicate that antibody-mediated ITP is resistant to allogeneic platelet transfusions, while the T-cell-mediated form of the disease is susceptible, suggesting that transfusion therapy may be beneficial in antibody-negative ITP.
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http://dx.doi.org/10.1182/blood-2013-08-523308DOI Listing
January 2014

Cellular immune dysfunction in immune thrombocytopenia (ITP).

Br J Haematol 2013 Oct 12;163(1):10-23. Epub 2013 Aug 12.

Toronto Platelet Immunobiology Group, University of Toronto, Toronto, ON, Canada; Keenan Research Centre in the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada; Canadian Blood Services, University of Toronto, Toronto, ON, Canada.

Over the past decades, a wealth of information has been reported about the pathogenic features of immune thrombocytopenia (ITP). To this day, however, it is unclear whether the immune abnormalities associated with ITP play causative roles in the disease or are secondary epiphenomena brought on by the inflammatory processes that are associated with the disorder. Like the majority of all autoimmune diseases, ITP is an organ-specific disease and abnormalities in immune cell types, such as antigen-presenting cells (APC), T cells and B cells have been shown to play some sort of role in the initiation and/or perpetuation of the disease. This review will discuss recent advances in understanding three immune cells important in ITP pathophysiology: APC, T cells and B cells, and will review how they interact with each other to initiate and perpetuate ITP, particularly the chronic form of the disorder. It will also focus on new data related to the genetics of the disorder and discuss relevant animal models of ITP.
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http://dx.doi.org/10.1111/bjh.12480DOI Listing
October 2013

Ybp1 and Gpx3 signaling in Candida albicans govern hydrogen peroxide-induced oxidation of the Cap1 transcription factor and macrophage escape.

Antioxid Redox Signal 2013 Dec 9;19(18):2244-60. Epub 2013 Jul 9.

1 Faculty of Medical Sciences, Institute for Cell and Molecular Biosciences, Newcastle University , Newcastle upon Tyne, United Kingdom .

Aims: As Candida albicans is the major fungal pathogen of humans, there is an urgent need to understand how this pathogen evades toxic reactive oxygen species (ROS) generated by the host immune system. A key regulator of antioxidant gene expression, and thus ROS resistance, in C. albicans is the AP-1-like transcription factor Cap1. Despite this, little is known regarding the intracellular signaling mechanisms that underlie the oxidation and activation of Cap1. Therefore, the aims of this study were; (i) to identify the regulatory proteins that govern Cap1 oxidation, and (ii) to investigate the importance of Cap1 oxidation in C. albicans pathogenesis.

Results: In response to hydrogen peroxide (H2O2), but not glutathione-depleting/modifying oxidants, Cap1 oxidation, nuclear accumulation, phosphorylation, and Cap1-dependent gene expression, is mediated by a glutathione peroxidase-like enzyme, which we name Gpx3, and an orthologue of the Saccharomyces cerevisiae Yap1 binding protein, Ybp1. In addition, Ybp1 also functions to stabilise Cap1 and this novel function is conserved in S. cerevisiae. C. albicans cells lacking Cap1, Ybp1, or Gpx3, are unable to filament and thus, escape from murine macrophages after phagocytosis, and also display defective virulence in the Galleria mellonella infection model.

Innovation: Ybp1 is required to promote the stability of fungal AP-1-like transcription factors, and Ybp1 and Gpx3 mediated Cap1-dependent oxidative stress responses are essential for the effective killing of macrophages by C. albicans.

Conclusion: Activation of Cap1, specifically by H2O2, is a prerequisite for the subsequent filamentation and escape of this fungal pathogen from the macrophage.
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http://dx.doi.org/10.1089/ars.2013.5199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869436PMC
December 2013

Interactions between macrophages and cell wall oligosaccharides of Candida albicans.

Methods Mol Biol 2012 ;845:247-60

Departamento de Biología, Universidad de Guanajuato, Guanajuato, México.

The fungal cell wall is the armour that protects the cell from changes in the external environment. The wall of Candida albicans, an opportunistic human pathogen, is also the immediate point of contact with the host immune system and contains most of the pathogen-associated molecular patterns recognised by innate immune cells. Along with the use of mutants altered in cell wall composition, the isolation and purification of cell wall components has proven useful in the identification of receptors involved in the sensing of these molecules, and assessment of the relative relevance of ligand-receptor interactions during the sensing of C. albicans by the immune system. Here, we describe protocols for the isolation of cell wall chitin, N-linked and O-linked mannans from C. albicans, and how they can subsequently be used to assess immunological activities such as phagocytosis and cytokine production by myeloid cells.
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http://dx.doi.org/10.1007/978-1-61779-539-8_16DOI Listing
June 2012

Lumbopelvic control and pitching performance of professional baseball pitchers.

J Strength Cond Res 2011 Aug;25(8):2127-32

Ohio State University Sports Medicine, Ohio State University, Columbus, Ohio, USA.

This study assessed the correlation between lumbopelvic control during a single-leg balancing task and in-game pitching performance in Minor-League baseball pitchers. Seventy-five healthy professional baseball pitchers performed a standing lumbopelvic control test during the last week of spring training for the 2008 and 2009 seasons while wearing a custom-designed testing apparatus, the "Level Belt." With the Level Belt secured to the waist, subjects attempted to transition from a 2-leg to a single-leg pitching stance and balance while maintaining a stable pelvic position. Subjects were graded on the maximum sagittal pelvic tilt from a neutral position during the motion. Pitching performance, number of innings pitched (IP), and injuries were compared for all subjects who pitched at least 50 innings during a season. The median Level Belt score for the study group was 7°. Two-sample t-tests with equal variances were used to determine if pitchers with a Level Belt score <7° or ≥7° were more likely to perform differently during the baseball season, and chi-square analysis was used to compare injuries between groups. Subjects scoring <7° on the Level Belt test had significantly fewer walks plus hits per inning than subjects scoring ≥7° (walks plus hits per inning pitched, 1.352 ± 0.251 vs. 1.584 ± 0.360, p = 0.013) and significantly more IP during the season (IP, 78.89 ± 38.67 vs. 53.38 ± 42.47, p = 0.043). There was no significant difference in the number of pitchers injured between groups. These data suggest that lumbopelvic control influences overall performance for baseball pitchers and that a simple test of lumbopelvic control can potentially identify individuals who have a better chance of pitching success.
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http://dx.doi.org/10.1519/JSC.0b013e31820f5075DOI Listing
August 2011

Insertion sequence-driven evolution of Escherichia coli in chemostats.

J Mol Evol 2011 Apr 12;72(4):398-412. Epub 2011 Mar 12.

Laboratoire Adaptation et Pathogénie des Microorganismes, Université Joseph Fourier Grenoble 1, BP 170, 38042, Grenoble Cedex 9, France.

Insertion sequence (IS) elements are present in almost all bacterial genomes and are mobile enough to provide genomic tools to differentiate closely related isolates. They can be used to estimate genetic diversity and identify fitness-enhancing mutations during evolution experiments. Here, we determined the genomic distribution of eight IS elements in 120 genomes sampled from Escherichia coli populations that evolved in glucose- and phosphate-limited chemostats by comparison to the ancestral pattern. No significant differential transposition of the various IS types was detected across the environments. The phylogenies revealed substantial diversity amongst clones sampled from each chemostat, consistent with the phenotypic diversity within populations. Two IS-related changes were common to independent chemostats, suggesting parallel evolution. One of them corresponded to insertions of IS1 elements within rpoS encoding the master regulator of stress conditions. The other parallel event was an IS5-dependent deletion including mutY involved in DNA repair, thereby providing the molecular mechanism of generation of mutator clones in these evolving populations. These deletions occurred in different co-existing genotypes within single populations and were of various sizes. Moreover, differential locations of IS elements combined with their transpositional activity provided evolved clones with different phenotypic landscapes. Therefore, IS elements strongly influenced the evolutionary processes in continuous E. coli cultures by providing a way to modify both the global regulatory network and the mutation rates of evolving cells.
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http://dx.doi.org/10.1007/s00239-011-9439-2DOI Listing
April 2011

Divergence involving global regulatory gene mutations in an Escherichia coli population evolving under phosphate limitation.

Genome Biol Evol 2010 Jul 16;2:478-87. Epub 2010 Jul 16.

Many of the important changes in evolution are regulatory in nature. Sequenced bacterial genomes point to flexibility in regulatory circuits but we do not know how regulation is remodeled in evolving bacteria. Here, we study the regulatory changes that emerge in populations evolving under controlled conditions during experimental evolution of Escherichia coli in a phosphate-limited chemostat culture. Genomes were sequenced from five clones with different combinations of phenotypic properties that coexisted in a population after 37 days. Each of the distinct isolates contained a different mutation in 1 of 3 highly pleiotropic regulatory genes (hfq, spoT, or rpoS). The mutations resulted in dissimilar proteomic changes, consistent with the documented effects of hfq, spoT, and rpoS mutations. The different mutations do share a common benefit, however, in that the mutations each redirect cellular resources away from stress responses that are redundant in a constant selection environment. The hfq mutation lowers several individual stress responses as well the small RNA-dependent activation of rpoS translation and hence general stress resistance. The spoT mutation reduces ppGpp levels, decreasing the stringent response as well as rpoS expression. The mutations in and upstream of rpoS resulted in partial or complete loss of general stress resistance. Our observations suggest that the degeneracy at the core of bacterial stress regulation provides alternative solutions to a common evolutionary challenge. These results can explain phenotypic divergence in a constant environment and also how evolutionary jumps and adaptive radiations involve altered gene regulation.
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http://dx.doi.org/10.1093/gbe/evq035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2997555PMC
July 2010

Genomic identification of a novel mutation in hfq that provides multiple benefits in evolving glucose-limited populations of Escherichia coli.

J Bacteriol 2010 Sep 11;192(17):4517-21. Epub 2010 Jun 11.

School of Molecular Bioscience, University of Sydney, New South Wales, Australia.

Beneficial mutations in diversifying glucose-limited Escherichia coli populations are mostly unidentified. The genome of an evolved isolate with multiple differences from that of the ancestor was fully assembled. Remarkably, a single mutation in hfq was responsible for the multiple benefits under glucose limitation through changes in at least five regulation targets.
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http://dx.doi.org/10.1128/JB.00368-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2937378PMC
September 2010
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