ORCID Profile
0000-0003-3673-7015
Current Organisations
CRES - Centre for Renewable Energy Sources and Saving
,
University of Queensland
,
University of Exeter Business School
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Innate immunity | Biochemistry and cell biology | Signal transduction | Receptors and membrane biology
ANZSRC Socio-Economic Objective (SEO)
Related Links
Publications
The E3 ubiquitin ligase RNF144B is LPS-inducible in human, but not mouse, macrophages and promotes inducible IL-1β expression
Publisher: Oxford University Press (OUP)
Date: 27-01-2016
Abstract: Differences in human and mouse immune responses may partly reflect species-specific adaptations and can provide important insights into human immunity. In this study, we show that RNF144B, which encodes an E3 ubiquitin ligase, was lipopolysaccharide-inducible in primary human macrophages and in human macrophage–like THP-1 cells. In contrast, Rnf144b was not lipopolysaccharide-inducible in several mouse cell populations, including primary macrophages from C57BL/6 and BALB/c mice and RAW264.7 macrophages. Similarly, Rnf144b was not up-regulated by infection of C57BL/6 mice with Escherichia coli. Although the human and mouse RNF144B genes have conserved transcription start sites, cap analysis of gene expression data confirmed that the RNF144B promoter directs transcription in human but not mouse macrophages. The human and mouse RNF144B genes are controlled by highly conserved TATA-containing promoters, but subtle differences in transcription factor binding sites may account for differential regulation. Using gene silencing, we showed that RNF144B is necessary for priming of inflammasome responses in primary human macrophages. Specifically, RNF144B promotes lipopolysaccharide-inducible IL-1b mRNA expression but does not regulate expression of several other lipopolysaccharide-inducible cytokines (e.g., interleukin-10, interferon-γ) or affect expression of inflammasome components or substrates (e.g., procaspase-1, pro-interleukin-18). Our findings thus revealed a species-specific regulatory mechanism for selective inflammasome priming in human macrophages.
Generation of a Genome Scale Lentiviral Vector Library for EF1α Promoter-Driven Expression of Human ORFs and Identification of Human Genes Affecting Viral Titer
Publisher: Public Library of Science (PLoS)
Date: 12-12-2012
Increasing situation awareness in healthcare through real-time simulation
Publisher: Informa UK Limited
Date: 16-11-2023
Nitric Oxide on Extracorporeal Membrane Oxygenation in Neonates and Children (NECTAR Trial): Protocol for a Randomized Controlled Trial
Publisher: JMIR Publications Inc.
Date: 15-03-2023
DOI: 10.2196/43760
Abstract: Extracorporeal membrane oxygenation (ECMO) provides support for the pulmonary or cardiovascular function of children in whom the predicted mortality risk remains very high. The inevitable host inflammatory response and activation of the coagulation cascade due to the extracorporeal circuit contribute to additional morbidity and mortality in these patients. Mixing nitric oxide (NO) into the sweep gas of ECMO circuits may reduce the inflammatory and coagulation cascade activation during ECMO support. The purpose of this study is to test the feasibility and safety of mixing NO into the sweep gas of ECMO systems and assess its effect on inflammation and coagulation system activation through a pilot randomized controlled trial. The Nitric Oxide on Extracorporeal Membrane Oxygenation in Neonates and Children (NECTAR) trial is an open-label, parallel-group, pilot randomized controlled trial to be conducted at a single center. Fifty patients who require ECMO support will be randomly assigned to receive either NO mixed into the sweep gas of the ECMO system at 20 ppm for the duration of ECMO or standard care (no NO) in a 1:1 ratio, with stratification by support type (veno-venous vs veno-arterial ECMO). Outcome measures will focus on feasibility (recruitment rate and consent rate, and successful inflammatory marker measurements), the safety of the intervention (oxygenation and carbon dioxide control within defined parameters and methemoglobin levels), and proxy markers of efficacy (assessment of cytokines, chemokines, and coagulation factors to assess the impact of NO on host inflammation and coagulation cascade activation, clotting of ECMO components, including computer tomography scanning of oxygenators for clot assessments), bleeding complications, as well as total blood product use. Survival without ECMO and the length of stay in the pediatric intensive care unit (PICU) are clinically relevant efficacy outcomes. Long-term outcomes include neurodevelopmental assessments (Ages and Stages Questionnaire, Strength and Difficulties Questionnaire, and others) and quality of life (Pediatric Quality of Life Inventory and others) measured at 6 and 12 months post ECMO cannulation. Analyses will be conducted on an intention-to-treat basis. The NECTAR study investigates the safety and feasibility of NO as a drug intervention during extracorporeal life support and explores its efficacy. The study will investigate whether morbidity and mortality in patients treated with ECMO can be improved with NO. The intervention targets adverse outcomes in patients who are supported by ECMO and who have high expected mortality and morbidity. The study will be one of the largest randomized controlled trials performed among pediatric patients supported by ECMO. Australian New Zealand Clinical Trials Registry ACTRN12619001518156 www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376869 DERR1-10.2196/43760
RP105 Facilitates Macrophage Activation by Mycobacterium tuberculosis Lipoproteins
Publisher: Elsevier BV
Date: 2009
Bacterial pathogenesis and interleukin-17: interconnecting mechanisms of immune regulation, host genetics, and microbial virulence that influence severity of infection
Publisher: Informa UK Limited
Date: 18-01-2018
From Conceptualization of Hybrid Modelling & Simulation to Empirical Studies in Hybrid Modelling
Publisher: IEEE
Date: 11-12-2022
Recombinant Wnt3a and Wnt5a elicit macrophage cytokine production and tolerization to microbial stimulation via Toll-like receptor 4
Publisher: Wiley
Date: 07-03-2014
Abstract: An increasing number of studies address the roles of Wnt proteins in shaping leukocyte functions. Recombinant Wnt3a and Wnt5a, prototypical activators of β-Catenin-dependent and -independent Wnt signaling, respectively, are widely used to investigate the effects of Wnt proteins on myeloid cell functions. Recent reports describe both proinflammatory and immunemodulatory effects of Wnt3a and Wnt5a on macrophages, DCs, and microglia. The underlying molecular mechanisms for this ergence are unclear. We show here that recombinant Wnt3a- and Wnt5a-induced cytokine production from murine C57BL/6 macrophages was dependent on TLR4 and inhibited by Polymyxin B. Similarly, impairment of TLR-induced cytokine production upon preexposure to Wnt proteins was TLR4 dependent. The extent of Wnt3a- and Wnt5a-induced inflammatory gene expression greatly varied between Wnt protein lots. We conclude that cytokine responses and TLR tolerization induced by recombinant Wnt proteins are likely explained by contaminating TLR4 agonists, although we cannot fully exclude that Wnt proteins have an intrinsic capacity to signal via TLR4. This study emphasizes the need for careful, independent verification of Wnt-mediated cellular responses.
M. tuberculosis induces potent activation of IDO-1, but this is not essential for the immunological control of infection
Publisher: Public Library of Science (PLoS)
Date: 23-05-2012
Dengue virus NS1 protein activates immune cells via TLR4 but not TLR2 or TLR6
Publisher: Wiley
Date: 21-02-2017
DOI: 10.1038/ICB.2017.5
Abstract: The secreted hexameric form of the dengue virus (DENV) non-structural protein 1 (NS1) has recently been shown to elicit inflammatory cytokine release and disrupt endothelial cell monolayer integrity. This suggests that circulating NS1 contributes to the vascular leak that plays a major role in the pathology of dengue haemorrhagic fever and shock. Pathways activated by NS1 are thus of great interest as potential therapeutic targets. Recent works have separately implicated both toll-like receptor 4 (TLR4) and the TLR2/6 heterodimer in immune cell activation by NS1. Here we have used mouse gene knockout macrophages and antibodies blocking TLR function in human peripheral blood mononuclear cells to show that recombinant NS1, expressed and purified from eukaryotic cells, induces cytokine production via TLR4 but not TLR2/6. Furthermore, the commercial Escherichia coli-derived recombinant NS1 preparation used in other work to implicate TLR2/6 in the response is not correctly folded and appears to be contaminated by several microbial TLR ligands. Thus TLR4 remains a therapeutic target for DENV infections, with TLR4 antagonists holding promise for the treatment of dengue disease.
Functions of the WNT Signaling Network in Shaping Host Responses to Infection
Publisher: Frontiers Media SA
Date: 08-11-2019
PI3K-p110δ contributes to antibody responses by macrophages in chronic lymphocytic leukemia
Publisher: Springer Science and Business Media LLC
Date: 28-08-2019
DOI: 10.1038/S41375-019-0556-Z
Abstract: Fcγ receptor (FcγR) signalling in monocyte derived macrophages from chronic lymphocytic leukaemia (CLL) patients is poorly understood. This signalling pathway is the key determinant of the ability of the macrophages to respond to therapeutic antibodies in current clinical use for CLL. Muted FcγR signalling activity accompanies disease progression and results in resistance to therapeutic antibodies. The molecular mechanisms controlling FcγR signalling and resistance are unknown. Here, we demonstrate that the class I phosphoinositide 3-kinase (PI3K) catalytic subunit p110δ is essential for CLL-derived macrophages to respond to therapeutic antibodies. Inhibition of p110δ in the macrophages reduces FcγR-mediated antibody immune responses. Surprisingly, our studies indicated that FcγR downstream signalling is independent of SYK and BTK activity. Thus, we show that FcγR antibody responses occur via a previously unidentified p110δ-dependent pathway, which is independent of the previously described SYK/BTK activation pathway. These data provide novel insights into the effectors of antibody responses. Our data also provide mechanistic insights into therapy resistance in CLL.
Induction of ER Stress in Macrophages of Tuberculosis Granulomas
Publisher: Public Library of Science (PLoS)
Date: 15-09-2010
WNT ligands contribute to the immune response during septic shock and amplify endotoxemia-driven inflammation in mice
Publisher: American Society of Hematology
Date: 10-07-2017
DOI: 10.1182/BLOODADVANCES.2017006163
Abstract: Differential expression of WNT ligands in patients with septic shock and a mouse model of endotoxemia correlates with inflammatory cytokines. WNT ligands and WNT/β-catenin signaling positively regulate lipopolysaccharide-induced pro-inflammatory cytokines without impairing IL-10.
Neutrophil extracellular traps and their histones promote Th17 cell differentiation directly via TLR2
Publisher: Springer Science and Business Media LLC
Date: 26-01-2022
DOI: 10.1038/S41467-022-28172-4
Abstract: Neutrophils perform critical functions in the innate response to infection, including through the production of neutrophil extracellular traps (NETs) - web-like DNA structures which are extruded from neutrophils upon activation. Elevated levels of NETs have been linked to autoimmunity but this association is poorly understood. By contrast, IL-17 producing Th17 cells are a key player in various autoimmune diseases but are also crucial for immunity against fungal and bacterial infections. Here we show that NETs, through their protein component histones, directly activate T cells and specifically enhance Th17 cell differentiation. This modulatory role of neutrophils, NETs and their histones is mediated downstream of TLR2 in T cells, resulting in phosphorylation of STAT3. The innate stimulation of a specific adaptive immune cell subset provides an additional mechanism demonstrating a direct link between neutrophils, NETs and T cell autoimmunity.
Cavin‐1/PTRF alters prostate cancer cell‐derived extracellular vesicle content and internalization to attenuate extracellular vesicle‐mediated osteoclastogenesis and osteoblast proliferation
Publisher: Wiley
Date: 2014
DOI: 10.3402/JEV.V3.23784
Glucocorticoid Sensitivity Is Highly Variable in Critically Ill Patients With Septic Shock and Is Associated With Disease Severity*
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2016
DOI: 10.1097/CCM.0000000000001633
Abstract: To measure tissue glucocorticoid sensitivity in patients with septic shock and determine its relationship to standard measurements of adrenal function and of outcome. Prospective observational trial. Teaching hospital ICU. Forty-one patients and 20 controls were studied. Glucocorticoid sensitivity was measured by in vitro suppression of cytokine production from lipopolysaccharide-stimulated leukocytes. There was no significant difference between the groups in the relative suppression of cytokine production, although there was a greater range and variance in the patient data. Patients in the lowest quartile of glucocorticoid sensitivity had higher Acute Physiology and Chronic Health Evaluation II scores (25 [24–28] vs 20 [14–23] p = 0.02) and a trend toward higher mortality (30% vs 0% p = 0.2) compared to those in the highest. The mRNA expression of the β variant of the glucocorticoid receptor and the 11-β hydroxysteroid dehydrogenase 2 isozyme were significantly higher in patients compared to controls (8.6-fold, p = 0.002 and 10.1-fold, p = 0.0002, respectively). Changes in mRNA expression of these genes did not correlate with measurements of glucocorticoid sensitivity. Patients with septic shock and controls do not differ in their median glucocorticoid sensitivity. However, patients exhibited a greater variability in glucocorticoid responsiveness and had evidence of association between increased sickness sensitivity and reduced glucocorticoid sensitivity. Sensitivity to glucocorticoids did not appear to be mediated by changes in the expression of the β variant of the glucocorticoid receptor or the 11-β hydroxysteroid dehydrogenase 2 isozyme.
Tuberculosis and host metabolism: ancient associations, fresh insights
Publisher: Elsevier BV
Date: 07-2009
DOI: 10.1016/J.TRSL.2009.04.004
Abstract: Epidemiologic studies have repeatedly identified malnutrition as a risk factor for tuberculosis (TB), which is the leading bacterial cause of deaths worldwide. The biologic basis for this association, however, remains unclear. Recent work has uncovered a large array of signaling molecules lying at the intersection of metabolic and immune signaling, among which nuclear hormone receptors (NHRs) and the insulin receptor have emerged as 2 prototypic ex les. Existing knowledge indicates that the physiologic functions of many NHRs overlap with known epidemiologic risk factors for TB and that diabetes, itself, predisposes to TB. Here, we assimilate these data and identify a potential mechanism that may help to explain the long-standing clinical association between TB and host metabolism. Together, these data emphasize the underused potential of interdisciplinary dialog in current TB research efforts.
Nitric Oxide on Extracorporeal Membrane Oxygenation in Neonates and Children (NECTAR Trial): Protocol for a Randomized Controlled Trial (Preprint)
Publisher: JMIR Publications Inc.
Date: 24-10-2022
Abstract: xtracorporeal membrane oxygenation (ECMO) provides support for the pulmonary or cardiovascular function of children in whom the predicted mortality risk remains very high. The inevitable host inflammatory response and activation of the coagulation cascade due to the extracorporeal circuit contribute to additional morbidity and mortality in these patients. Mixing nitric oxide (NO) into the sweep gas of ECMO circuits may reduce the inflammatory and coagulation cascade activation during ECMO support. he purpose of this study is to test the feasibility and safety of mixing NO into the sweep gas of ECMO systems and assess its effect on inflammation and coagulation system activation through a pilot randomized controlled trial. he Nitric Oxide on Extracorporeal Membrane Oxygenation in Neonates and Children (NECTAR) trial is an open-label, parallel-group, pilot randomized controlled trial to be conducted at a single center. Fifty patients who require ECMO support will be randomly assigned to receive either NO mixed into the sweep gas of the ECMO system at 20 ppm for the duration of ECMO or standard care (no NO) in a 1:1 ratio, with stratification by support type (veno-venous vs veno-arterial ECMO). utcome measures will focus on feasibility (recruitment rate and consent rate, and successful inflammatory marker measurements), the safety of the intervention (oxygenation and carbon dioxide control within defined parameters and methemoglobin levels), and proxy markers of efficacy (assessment of cytokines, chemokines, and coagulation factors to assess the impact of NO on host inflammation and coagulation cascade activation, clotting of ECMO components, including computer tomography scanning of oxygenators for clot assessments), bleeding complications, as well as total blood product use. Survival without ECMO and the length of stay in the pediatric intensive care unit (PICU) are clinically relevant efficacy outcomes. Long-term outcomes include neurodevelopmental assessments (Ages and Stages Questionnaire, Strength and Difficulties Questionnaire, and others) and quality of life (Pediatric Quality of Life Inventory and others) measured at 6 and 12 months post ECMO cannulation. Analyses will be conducted on an intention-to-treat basis. he NECTAR study investigates the safety and feasibility of NO as a drug intervention during extracorporeal life support and explores its efficacy. The study will investigate whether morbidity and mortality in patients treated with ECMO can be improved with NO. The intervention targets adverse outcomes in patients who are supported by ECMO and who have high expected mortality and morbidity. The study will be one of the largest randomized controlled trials performed among pediatric patients supported by ECMO. ustralian New Zealand Clinical Trials Registry ACTRN12619001518156 www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376869 ERR1-10.2196/43760
Detection of the 4977 bp deletion of mitochondrial DNA in different human blood cells
Publisher: Elsevier BV
Date: 02-2004
Triosephosphate isomerase is dispensable in vitro yet essential for Mycobacterium tuberculosis to establish infection
Publisher: American Society for Microbiology
Date: 05-2014
Abstract: Triosephosphate isomerase (TPI) catalyzes the interconversion of dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (G3P). This reaction is required for glycolysis and gluconeogenesis, and tpi has been predicted to be essential for growth of Mycobacterium tuberculosis . However, when studying a conditionally regulated tpi knockdown mutant, we noticed that depletion of TPI reduced growth of M. tuberculosis in media containing a single carbon source but not in media that contained both a glycolytic and a gluconeogenic carbon source. We used such two-carbon-source media to isolate a tpi deletion (Δ tpi ) mutant. The Δ tpi mutant did not survive with single carbon substrates but grew like wild-type (WT) M. tuberculosis in the presence of both a glycolytic and a gluconeogenic carbon source. 13 C metabolite tracing revealed the accumulation of TPI substrates in Δ tpi and the absence of alternative triosephosphate isomerases and metabolic bypass reactions, which confirmed the requirement of TPI for glycolysis and gluconeogenesis in M. tuberculosis . The Δ tpi strain was furthermore severely attenuated in the mouse model of tuberculosis, suggesting that M. tuberculosis cannot simultaneously access sufficient quantities of glycolytic and gluconeogenic carbon substrates to establish infection in mice. IMPORTANCE The importance of central carbon metabolism for the pathogenesis of M. tuberculosis has recently been recognized, but the consequences of depleting specific metabolic enzymes remain to be identified for many enzymes. We investigated triosephosphate isomerase (TPI) because it is central to both glycolysis and gluconeogenesis and had been predicted to be essential for growth of M. tuberculosis . This work identified metabolic conditions that make TPI dispensable for M. tuberculosis growth in culture and proved that M. tuberculosis relies on a single TPI enzyme and has no metabolic bypass for the TPI-dependent interconversion of dihydroxyacetone phosphate and glyceraldehyde-3-phosphate in glycolysis and gluconeogenesis. Finally, we demonstrate that TPI is essential for growth of the pathogen in mouse lungs.
Wollamide Cyclic Hexapeptides Synergize with Established and New Tuberculosis Antibiotics in Targeting Mycobacterium tuberculosis
Publisher: American Society for Microbiology
Date: 17-08-2023
DOI: 10.1128/SPECTRUM.00465-23
Abstract: Tuberculosis (TB) is an infectious disease that affects millions of people globally, with 1.6 million deaths annually. TB treatment requires combinations of multiple different antibiotics for many months, and toxic side effects can occur.
CD4+CD8β+ double-positive T cells in skin-draining lymph nodes respond to inflammatory signals from the skin
Publisher: Oxford University Press (OUP)
Date: 21-06-2017
Abstract: CD4+CD8+ double-positive (DP), mature, peripheral T cells are readily detectable in a variety of species and tissues. Despite a common association with autoimmune and malignant skin disorders, however, little is understood about their role or function. Herein, we show that DP T cells are readily detectable in the blood, spleen, and peripheral lymph nodes of naïve C57BL/6 mice. DP T cells were also present in Jα18−/− and CD1d−/− mice, indicating that these cells are not NK-T cells. After skin administration of CASAC adjuvant, but not Quil A adjuvant, both total DP T cells and skin-infiltrating DP T cells increased in number. We explored the possibility that DP T cells could represent aggregates between CD4+ and CD8+ single-positive T cells and found strong evidence that a large proportion of apparent DP T cells were indeed aggregates. However, the existence of true CD4+CD8+ DP T cells was confirmed by Amnis ImageStream (Millipore Sigma, Billerica, MA, USA) imaging. Multiple rounds of FACS sorting separated true DP cells from aggregates and indicated that conventional analyses may lead to ∼10-fold overestimation of DP T cell numbers. The high degree of aggregate contamination and overestimation of DP abundance using conventional analysis techniques may explain discrepancies reported in the literature for DP T cell origin, phenotype, and function.
Construction of a deep-rough mutant of Burkholderia cepacia ATCC 25416 and characterization of its chemical and biological properties
Publisher: Elsevier BV
Date: 2003
Distinct contributions of the innate immune receptors TLR2 and RP105 to formation and architecture of structured lung granulomas in mice infected with Mycobacterium tuberculosis
Publisher: Wiley
Date: 22-11-2023
DOI: 10.1111/IMM.13606
Abstract: Granulomas are key histopathological features of Mycobacterium tuberculosis (Mtb) infection, with complex roles in pathogen control and dissemination. Thus, understanding drivers and regulators of granuloma formation is important for improving tuberculosis diagnosis, treatment, and prevention. Yet, molecular mechanisms underpinning granuloma formation and dynamics remain poorly understood. Here we used low-dose Mtb infection of C57BL/6 mice, which elicits structured lung granulomas composed of central macrophage clusters encased by a lymphocyte mantle, alongside the disorganized lymphocyte and macrophage clusters commonly observed in Mtb-infected mice. Using gene-deficient mice, we observed that Toll-like receptor (TLR) 2 and the TLR-related Radioprotective 105 kDa protein (RP105) contributed to the extent and spatial positioning of pathology in infected lung tissues, consistent with functional cooperation between TLR2 and RP105 in the innate immune recognition of Mtb. In mice infected with the highly virulent Mtb clinical isolate HN878, TLR2, but not RP105, positively regulated the extent of central macrophage regions within structured granulomas. Moreover, RP105, but not TLR2, promoted the formation of structured lung granulomas, suggesting that the functions of RP105 as an innate immune sensor for Mtb reach beyond its roles as TLR2 co-receptor. TLR2 and RP105 contributions to lung pathology are governed by Mtb biology, as neither receptor affected the frequency or architecture of structured granulomas in mice infected with the reference strain Mtb H37Rv. Thus, by revealing distinctive as well as cooperative functions of TLR2 and RP105 in lung pathology, our data identify TLRs as molecular determinants of TB granuloma formation and architecture, and expand understanding of how interactions between innate immune receptors and Mtb shape TB disease manifestation.
Wollamides: Antimycobacterial cyclic hexapeptides from an australian soil Streptomyces
Publisher: American Chemical Society (ACS)
Date: 17-09-2014
DOI: 10.1021/OL502472C
Abstract: A soil Streptomyces nov. sp. (MST-115088) isolated from semiarid terrain near Wollogorang Station, Queensland, returned two known and two new ex les of a rare class of cyclic hexapeptide, desotamides A and B (1 and 2) and E and F (3 and 4), respectively, together with two new d-Orn homologues, wollamides A and B (5 and 6). Structures were assigned by detailed spectroscopic and C3 Marfey's analysis. The desotamides/wollamides exhibit growth inhibitory activity against Gram-positive bacteria (IC50 0.6-7 μM) and are noncytotoxic to mammalian cells (IC50 >30 μM). The wollamides exhibit antimycobacterial activity (IC50 2.8 and 3.1 μM), including reduction in the intracellular mycobacterial survival in murine bone marrow-derived macrophages.
Aranciamycins I and J, Antimycobacterial Anthracyclines from an Australian Marine-Derived Streptomyces sp.
Publisher: American Chemical Society (ACS)
Date: 19-03-2015
DOI: 10.1021/ACS.JNATPROD.5B00095
Abstract: Chemical analysis of an Australian marine-derived Streptomyces sp. (CMB-M0150) yielded two new anthracycline antibiotics, aranciamycins I (1) and J (2), as well as the previously reported aranciamycin A (3) and aranciamycin (4). The aranciamycins 1-4, identified by detailed spectroscopic analysis, were noncytotoxic when tested against selected Gram-negative bacteria and fungi (IC50 >30 μM) and exhibited moderate and selective cytotoxicity against Gram-positive bacteria (IC50 >1.1 μM) and a panel of human cancer cell lines (IC50 > 7.5 μM). Significantly, 1-4 were cytotoxic (IC50 0.7-1.7 μM) against the Mycobacterium tuberculosis surrogate M. bovis bacille Calmette-Guérin.
Control of Mycobacterial Replication in Human Macrophages: Roles of Extracellular Signal-Regulated Kinases 1 and 2 and p38 Mitogen-Activated Protein Kinase Pathways
Publisher: American Society for Microbiology
Date: 09-2002
DOI: 10.1128/IAI.70.9.4961-4967.2002
Abstract: Intracellular persistence of mycobacteria may result from an intricate balance between bacterial replication and signaling events leading to antimicrobial macrophage activities. Using human monocyte-derived macrophages, we investigated the relevance of mitogen-activated protein kinase activation for the growth control of Mycobacterium avium isolates differing in their abilities to multiply intracellularly. The highly replicative smooth transparent morphotype of M. avium strain 2151 induced significantly less p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation than the smooth opaque morphotype of the same strain, which was gradually eliminated from macrophage cultures. Inhibition of the p38 pathway by highly specific inhibitors did not significantly affect mycobacterial replication within macrophages, regardless of the in vitro virulence of the M. avium strain. However, repression of the ERK1/2 pathway further enhanced intracellular growth of highly replicative M. avium strains, although it did not increase survival of the poorly replicating M. avium isolate. Inhibition of the ERK1/2 pathway resulted in decreased tumor necrosis alpha (TNF-α) secretion irrespective of the virulence of the M. avium isolate used for infection, revealing that TNF-α could have been only partially responsible for the control of intracellular M. avium growth. In conclusion, ERK1/2- and TNF-α-independent pathways are sufficient to limit intramacrophage growth of less-virulent M. avium strains, but early ERK1/2 activation in infected macrophages is critically involved in controlling the growth of highly replicative M. avium strains.
A promoter-level mammalian expression atlas
Publisher: Springer Science and Business Media LLC
Date: 03-2014
DOI: 10.1038/NATURE13182
Class IIa Histone Deacetylases Drive Toll-like Receptor-Inducible Glycolysis and Macrophage Inflammatory Responses via Pyruvate Kinase M2.
Publisher: Elsevier BV
Date: 02-2020
Hybrid Modelling and Simulation (MS): Driving Innovation in the Theory and Practice of MS
Publisher: IEEE
Date: 14-12-2020
Efficient biodistribution and gene silencing in the lung epithelium via intravenous liposomal delivery of siRNA
Publisher: Elsevier BV
Date: 2013
DOI: 10.1038/MTNA.2013.22
The RP105/MD-1 complex: Molecular signaling mechanisms and pathophysiological implications
Publisher: Oxford University Press (OUP)
Date: 11-04-2017
DOI: 10.1189/JLB.2VMR1215-582R
Abstract: Radioprotective 105 kDa (CD180) is an unusual TLR that lacks an intracellular Toll-IL-1R signaling domain and exhibits unconventional homodimerization behavior. Differential expression and functions of radioprotective 105 kDa have been associated with immune-mediated pathologies, including infection, chronic inflammation, and autoimmune disorders. Radioprotective 105 kDa activates macrophages and B cells independently of canonical TLR signaling. Current understanding of the functional consequences of radioprotective 105 kDa signaling in B cells, macrophages, and dendritic cells indicates overlapping, but also some apparent opposing, cell-specific roles for radioprotective 105 kDa in shaping cellular functions. This review compares interactions of radioprotective 105 kDa with its coreceptors, CD19, TLR4, and TLR2 integrates recent, novel findings on radioprotective 105 kDa-mediated molecular signaling mechanisms and summarizes current understanding of its contributions to infectious, inflammatory, and autoimmune disease.
IL-18, but not IL-12, induces production of IFN-γ in the immunosuppressive environment of HPV16 E7 transgenic hyperplastic skin
Publisher: Elsevier BV
Date: 10-2014
DOI: 10.1038/JID.2014.201
Roles of WNT, NOTCH, and Hedgehog signaling in the differentiation and function of innate and innate-like lymphocytes
Publisher: Oxford University Press (OUP)
Date: 12-10-2017
Abstract: Innate lymphoid cells (ILCs) and innate-like lymphocytes have important roles in immune responses in the context of infection, cancer, and autoimmunity. The factors involved in driving the differentiation and function of these cell types remain to be clearly defined. There are several cellular signaling pathways involved in embryogenesis, which continue to function in adult tissue. In particular, the WNT, NOTCH, and Hedgehog signaling pathways are emerging as regulators of hematopoietic cell development and differentiation. This review discusses the currently known roles of WNT, NOTCH, and Hedgehog signaling in the differentiation and function of ILCs and innate-like lymphocytes.
Hybrid Models with Real-time Data: Characterising Real-time Simulation and Digital Twins
Publisher: Operational Research Society
Date: 27-03-2023
DOI: 10.36819/SW23.031
FANTOM5 CAGE profiles of human and mouse samples
Publisher: Springer Science and Business Media LLC
Date: 29-08-2017
Abstract: In the FANTOM5 project, transcription initiation events across the human and mouse genomes were mapped at a single base-pair resolution and their frequencies were monitored by CAGE (Cap Analysis of Gene Expression) coupled with single-molecule sequencing. Approximately three thousands of s les, consisting of a variety of primary cells, tissues, cell lines, and time series s les during cell activation and development, were subjected to a uniform pipeline of CAGE data production. The analysis pipeline started by measuring RNA extracts to assess their quality, and continued to CAGE library production by using a robotic or a manual workflow, single molecule sequencing, and computational processing to generate frequencies of transcription initiation. Resulting data represents the consequence of transcriptional regulation in each analyzed state of mammalian cells. Non-overlapping peaks over the CAGE profiles, approximately 200,000 and 150,000 peaks for the human and mouse genomes, were identified and annotated to provide precise location of known promoters as well as novel ones, and to quantify their activities.
Participatory design research for the development of real-time simulation models in healthcare
Publisher: Informa UK Limited
Date: 09-02-2023
Lipopolysaccharide promotes Drp1‐dependent mitochondrial fission and associated inflammatory responses in macrophages
Publisher: Wiley
Date: 20-07-2020
DOI: 10.1111/IMCB.12363
Facets of trust in simulation studies
Publisher: Elsevier BV
Date: 02-2021
Type I interferons in the pathogenesis of tuberculosis: Molecular drivers and immunological consequences
Publisher: Frontiers Media SA
Date: 27-11-2017
Lincolnenins A-D: Isomeric Bactericidal Bianthracenes from Streptomyces lincolnensis
Publisher: American Chemical Society (ACS)
Date: 15-12-2021
LprG-Mediated Surface Expression of Lipoarabinomannan Is Essential for Virulence of Mycobacterium tuberculosis
Publisher: Public Library of Science (PLoS)
Date: 18-09-2014
RH-RT: A data analytics framework for reducing wait time at emergency departments and centres for urgent care
Publisher: IEEE
Date: 12-2019
Deletion of Wntless in myeloid cells exacerbates liver fibrosis and the ductular reaction in chronic liver injury
Publisher: Springer Science and Business Media LLC
Date: 15-10-2015
A Hybrid Modelling Approach Using Forecasting and Real-Time Simulation to Prevent Emergency Department Overcrowding
Publisher: IEEE
Date: 12-2019
Strategic resource planning of endoscopy services using hybrid modelling for future demographic and policy change
Publisher: Informa UK Limited
Date: 26-05-2023
A hybrid approach using forecasting and discrete-event simulation for endoscopy services
Publisher: IEEE
Date: 12-2017
Simultaneous analysis of multiple mycobacterium tuberculosis knockdown mutants in vitro and in vivo
Publisher: Public Library of Science (PLoS)
Date: 22-12-2010
EU-SOLARIS: The European Infrastructure for Concentrated Solar Thermal and Solar Chemistry Technologies
Publisher: Elsevier BV
Date: 2017
The N-terminal peptide moiety of the Mycobacterium tuberculosis 19 kDa lipoprotein harbors RP105-agonistic properties
Publisher: Oxford University Press (OUP)
Date: 09-01-2018
DOI: 10.1002/JLB.2MA0517-190RR
Abstract: Radioprotective 105 kDa (RP105, CD180) is a member of the Toll-like receptor (TLR) family that interacts with TLR2 and facilitates recognition of mature lipoproteins expressed by Mycobacterium tuberculosis and Mycobacterium bovis BCG. In this study, we used synthetic lipopeptide analogs of the M. tuberculosis 19 kDa lipoprotein to define structural characteristics that promote RP105-mediated host cell responses. A tripalmitoylated lipopeptide composed of the first 16 N-terminal amino acids of the M. tuberculosis 19 kDa lipoprotein induced RP105-dependent TNF and IL-6 production by macrophages. Di- and tripalmitoylated variants of this lipopeptide elicited an equivalent RP105-dependent response, indicating that while the lipid moiety is required for macrophage activation, it is not a determinant of RP105 dependency. Instead, substitution of two polar threonine residues at positions 7 and 8 with nonpolar alanine residues resulted in reduced RP105 dependency. These results strongly suggest that the amino acid composition of the M. tuberculosis 19 kDa lipoprotein, and likely other mycobacterial lipoproteins, is a key determinant of RP105 agonism.
RP105 Engages Phosphatidylinositol 3-Kinase p110δ To Facilitate the Trafficking and Secretion of Cytokines in Macrophages during Mycobacterial Infection
Publisher: The American Association of Immunologists
Date: 15-10-2015
Abstract: Cytokines are key regulators of adequate immune responses to infection with Mycobacterium tuberculosis. We demonstrate that the p110δ catalytic subunit of PI3K acts as a downstream effector of the TLR family member RP105 (CD180) in promoting mycobacteria-induced cytokine production by macrophages. Our data show that the significantly reduced release of TNF and IL-6 by RP105−/− macrophages during mycobacterial infection was not accompanied by diminished mRNA or protein expression. Mycobacteria induced comparable activation of NF-κB and p38 MAPK signaling in wild-type (WT) and RP105−/− macrophages. In contrast, mycobacteria-induced phosphorylation of Akt was abrogated in RP105−/− macrophages. The p110δ-specific inhibitor, Cal-101, and small interfering RNA–mediated knockdown of p110δ diminished mycobacteria-induced TNF secretion by WT but not RP105−/− macrophages. Such interference with p110δ activity led to reduced surface-expressed TNF in WT but not RP105−/− macrophages, while leaving TNF mRNA and protein expression unaffected. Activity of Bruton’s tyrosine kinase was required for RP105-mediated activation of Akt phosphorylation and TNF release by mycobacteria-infected macrophages. These data unveil a novel innate immune signaling axis that orchestrates key cytokine responses of macrophages and provide molecular insight into the functions of RP105 as an innate immune receptor for mycobacteria.
Statistical analysis plan for the NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC) trial
Publisher: Elsevier BV
Date: 03-2021
DOI: 10.51893/2021.1.OA4
Abstract: Abstract Background: The NITric oxide during cardiopulmonary bypass (CPB) to improve Recovery in Infants with Congenital heart defects (NITRIC) trial, a 1320-patient, multicentre, randomised controlled trial, is aiming to improve survival free of ventilation after CPB by using nitric oxide delivered into the oxygenator of the CPB. Objective: To provide a statistical analysis plan before completion of patient recruitment and data monitoring. Final analyses for this study will adhere to this statistical analysis plan, which details all key pre-planned analyses. Stata scripts for analyses have been prepared alongside this statistical analysis plan. Methods: The statistical analysis plan was designed collaboratively by the chief investigators and trial statistician and builds on the previously published study protocol. All authors remain blinded to treatment allocation. Detail is provided on statistical analyses including cohort description, analysis of primary and secondary outcomes and adverse events. Statistical methods to compare outcomes are planned in detail to ensure methods are verifiable and reproducible. Results: The statistical analysis plan developed provides the trial outline, list of mock tables, and analysis scripts. The plan describes statistical analyses on cohort and baseline description, primary and secondary outcome analyses, process of care measures, physiological descriptors, and safety and adverse event reporting. We define the pre-specified subgroup analyses and the respective statistical tests used to compare subgroups. Conclusion: The statistical analysis plan for the NITRIC trial establishes detailed pre-planned analyses alongside Stata scripts to analyse the largest trial in the field of neonatal and paediatric heart surgery. The plan ensures standards for trial analysis validity aiming to minimise bias of analyses. Trial registration: ACTRN12617000821392
Microbiome-immune interactions in tuberculosis
Publisher: Public Library of Science (PLoS)
Date: 15-04-2021
DOI: 10.1371/JOURNAL.PPAT.1009377
Abstract: Tuberculosis (TB) remains an infectious disease of global significance and a leading cause of death in low- and middle-income countries. Significant effort has been directed towards understanding Mycobacterium tuberculosis genomics, virulence, and pathophysiology within the framework of Koch postulates. More recently, the advent of “-omics” approaches has broadened our appreciation of how “commensal” microbes have coevolved with their host and have a central role in shaping health and susceptibility to disease. It is now clear that there is a erse repertoire of interactions between the microbiota and host immune responses that can either sustain or disrupt homeostasis. In the context of the global efforts to combatting TB, such findings and knowledge have raised important questions: Does microbiome composition indicate or determine susceptibility or resistance to M . tuberculosis infection? Is the development of active disease or latent infection upon M . tuberculosis exposure influenced by the microbiome? Does microbiome composition influence TB therapy outcome and risk of reinfection with M . tuberculosis ? Can the microbiome be actively managed to reduce risk of M . tuberculosis infection or recurrence of TB? Here, we explore these questions with a particular focus on microbiome-immune interactions that may affect TB susceptibility, manifestation and progression, the long-term implications of anti-TB therapy, as well as the potential of the host microbiome as target for clinical manipulation.
Amycolatopsins A–C: antimycobacterial glycosylated polyketide macrolides from the Australian soil Amycolatopsis sp. MST-108494
Publisher: Springer Science and Business Media LLC
Date: 25-10-2017
DOI: 10.1038/JA.2017.119
Abstract: A southern Australian soil isolate, Amycolatopsis sp. MST-108494, was subjected to a panel of fermentation and media optimization trials, supported by analytical chemical profiling, to detect and enhance production of a rare class of secondary metabolites. Chemical fractionation of two complementary fermentations yielded three new polyketides, identified by detailed spectroscopic analysis as the glycosylated macrolactones, amycolatopsins A (1), B (2) and C (3), closely related to the ammocidins and apoptolidins. Amycolatopsins 1 and 3 selectively inhibited growth of Mycobacterium bovis (BCG) and Mycobacterium tuberculosis (H37Rv) when compared with other Gram-positive or Gram-negative bacteria, with 3 exhibiting low levels of cytotoxicity toward mammalian cells. Thus, our data reveal promising structure activity relationship correlations where the antimycobacterial properties of amycolatopsins are enhanced by hydroxylation of the 6-Me (that is, 1 and 3), whereas mammalian cytotoxicity is decreased by hydrolysis of the disaccharide moiety (that is, 3).
Indoleamine 2,3-Dioxygenase Activity Contributes to Local Immune Suppression in the Skin Expressing Human Papillomavirus Oncoprotein E7
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1038/JID.2013.222
Inhibition of the master regulator of Listeria monocytogenes virulence enables bacterial clearance from spacious replication vacuoles in infected macrophages.
Publisher: Public Library of Science (PLoS)
Date: 10-01-2022
DOI: 10.1371/JOURNAL.PPAT.1010166
Abstract: A hallmark of Listeria (L . ) monocytogenes pathogenesis is bacterial escape from maturing entry vacuoles, which is required for rapid bacterial replication in the host cell cytoplasm and cell-to-cell spread. The bacterial transcriptional activator PrfA controls expression of key virulence factors that enable exploitation of this intracellular niche. The transcriptional activity of PrfA within infected host cells is controlled by allosteric coactivation. Inhibitory occupation of the coactivator site has been shown to impair PrfA functions, but consequences of PrfA inhibition for L . monocytogenes infection and pathogenesis are unknown. Here we report the crystal structure of PrfA with a small molecule inhibitor occupying the coactivator site at 2.0 Å resolution. Using molecular imaging and infection studies in macrophages, we demonstrate that PrfA inhibition prevents the vacuolar escape of L . monocytogenes and enables extensive bacterial replication inside spacious vacuoles. In contrast to previously described spacious Listeria -containing vacuoles, which have been implicated in supporting chronic infection, PrfA inhibition facilitated progressive clearance of intracellular L . monocytogenes from spacious vacuoles through lysosomal degradation. Thus, inhibitory occupation of the PrfA coactivator site facilitates formation of a transient intravacuolar L . monocytogenes replication niche that licenses macrophages to effectively eliminate intracellular bacteria. Our findings encourage further exploration of PrfA as a potential target for antimicrobials and highlight that intra-vacuolar residence of L . monocytogenes in macrophages is not inevitably tied to bacterial persistence.
Evaluating the Sensitivity of Mycobacterium tuberculosis to Biotin Deprivation Using Regulated Gene Expression
Publisher: Public Library of Science (PLoS)
Date: 29-09-2011
Policies and strategies to retain and support the return of experienced GPs in direct patient care: the ReGROUP mixed-methods study
Publisher: National Institute for Health and Care Research
Date: 04-2019
DOI: 10.3310/HSDR07140
Abstract: UK general practice faces a workforce crisis, with general practitioner (GP) shortages, organisational change, substantial pressures across the whole health-care system and an ageing population with increasingly complex health needs. GPs require lengthy training, so retaining the existing workforce is urgent and important. (1) To identify the key policies and strategies that might (i) facilitate the retention of experienced GPs in direct patient care or (ii) support the return of GPs following a career break. (2) To consider the feasibility of potentially implementing those policies and strategies. This was a comprehensive, mixed-methods study. This study took place in primary care in England. General practitioners registered in south-west England were surveyed. Interviews were with purposively selected GPs and primary care stakeholders. A RAND/UCLA Appropriateness Method (RAM) panel comprised GP partners and GPs working in national stakeholder organisations. Stakeholder consultations included representatives from regional and national groups. Systematic review – factors affecting GPs’ decisions to quit and to take career breaks. Survey – proportion of GPs likely to quit, to take career breaks or to reduce hours spent in patient care within 5 years of being surveyed. Interviews – themes relating to GPs’ decision-making. RAM – a set of policies and strategies to support retention, assessed as ‘appropriate’ and ‘feasible’. Predictive risk modelling – predictive model to identify practices in south-west England at risk of workforce undersupply within 5 years. Stakeholder consultation – comments and key actions regarding implementing emergent policies and strategies from the research. Past research identified four job-related ‘push’ factors associated with leaving general practice: (1) workload, (2) job dissatisfaction, (3) work-related stress and (4) work–life balance. The survey, returned by 2248 out of 3370 GPs (67%) in the south-west of England, identified a high likelihood of quitting (37%), taking a career break (36%) or reducing hours (57%) within 5 years. Interviews highlighted three drivers of leaving general practice: (1) professional identity and value of the GP role, (2) fear and risk associated with service delivery and (3) career choices. The RAM panel deemed 24 out of 54 retention policies and strategies to be ‘appropriate’, with most also considered ‘feasible’, including identification of and targeted support for practices ‘at risk’ of workforce undersupply and the provision of formal career options for GPs wishing to undertake portfolio roles. Practices at highest risk of workforce undersupply within 5 years are those that have larger patient list sizes, employ more nurses, serve more deprived and younger populations, or have poor patient experience ratings. Actions for national organisations with an interest in workforce planning were identified. These included collection of data on the current scope of GPs’ portfolio roles, and the need for formal career pathways for key primary care professionals, such as practice managers. The survey, qualitative research and modelling were conducted in one UK region. The research took place within a rapidly changing policy environment, providing a challenge in informing emergent policy and practice. This research identifies the basis for current concerns regarding UK GP workforce capacity, drawing on experiences in south-west England. Policies and strategies identified by expert stakeholders after considering these findings are likely to be of relevance in addressing GP retention in the UK. Collaborative, multidisciplinary research partnerships should investigate the effects of rolling out some of the policies and strategies described in this report. This study is registered as PROSPERO CRD42016033876 and UKCRN ID number 20700. The National Institute for Health Research Health Services and Delivery Research programme.
The histone deacetylase Hdac7 supports LPS-inducible glycolysis and Il-1β production in murine macrophages via distinct mechanisms
Publisher: Oxford University Press (OUP)
Date: 23-11-2021
Abstract: TLRs reprogram macrophage metabolism, enhancing glycolysis and promoting flux through the tricarboxylic acid cycle to enable histone acetylation and inflammatory gene expression. The histone deacetylase (HDAC) family of lysine deacetylases regulates both TLR-inducible glycolysis and inflammatory responses. Here, we show that the TLR4 agonist LPS, as well as agonists of other TLRs, rapidly increase enzymatic activity of the class IIa HDAC family (HDAC4, 5, 7, 9) in both primary human and murine macrophages. This response was abrogated in murine macrophages deficient in histone deacetylase 7 (Hdac7), highlighting a selective role for this specific lysine deacetylase during immediate macrophage activation. With the exception of the TLR3 agonist polyI:C, TLR-inducible activation of Hdac7 enzymatic activity required the MyD88 adaptor protein. The rapid glycolysis response, as assessed by extracellular acidification rate, was attenuated in Hdac7-deficient mouse macrophages responding to submaximal LPS concentrations. Surprisingly however, reconstitution of these cells with either wild-type or an enzyme-dead mutant of Hdac7 enhanced LPS-inducible glycolysis, whereas only the former promoted production of the inflammatory mediators Il-1β and Ccl2. Thus, Hdac7 enzymatic activity is required for TLR-inducible production of specific inflammatory mediators, whereas it acts in an enzyme-independent fashion to reprogram metabolism in macrophages responding to submaximal LPS concentrations. Hdac7 is thus a bifurcation point for regulated metabolism and inflammatory responses in macrophages. Taken together with existing literature, our findings support a model in which submaximal and maximal activation of macrophages via TLR4 instruct glycolysis through distinct mechanisms, leading to ergent biological responses.
Temporal regulation of natural killer T cell interferon gamma responses by β-catenin-dependent and-independent wnt signaling
Publisher: Frontiers Media SA
Date: 16-03-2018
Study protocol: NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC trial): a randomised controlled trial
Publisher: BMJ
Date: 08-2019
DOI: 10.1136/BMJOPEN-2018-026664
Abstract: Congenital heart disease (CHD) is a major cause of infant mortality. Many infants with CHD require corrective surgery with most operations requiring cardiopulmonary bypass (CPB). CPB triggers a systemic inflammatory response which is associated with low cardiac output syndrome (LCOS), postoperative morbidity and mortality. Delivery of nitric oxide (NO) into CPB circuits can provide myocardial protection and reduce bypass-induced inflammation, leading to less LCOS and improved recovery. We hypothesised that using NO during CPB increases ventilator-free days (VFD) (the number of days patients spend alive and free from invasive mechanical ventilation up until day 28) compared with standard care. Here, we describe the NITRIC trial protocol. The NITRIC trial is a randomised, double-blind, controlled, parallel-group, two-sided superiority trial to be conducted in six paediatric cardiac surgical centres. One thousand three-hundred and twenty infants years of age undergoing cardiac surgery with CPB will be randomly assigned to NO at 20 ppm administered into the CPB oxygenator for the duration of CPB or standard care (no NO) in a 1:1 ratio with stratification by age ( and ≥6 weeks), single ventricle physiology (Y/N) and study centre. The primary outcome will be VFD to day 28. Secondary outcomes include a composite of LCOS, need for extracorporeal membrane oxygenation or death within 28 days of surgery length of stay in intensive care and in hospital and, healthcare costs. Analyses will be conducted on an intention-to-treat basis. Preplanned secondary analyses will investigate the impact of NO on host inflammatory profiles postsurgery. The study has ethical approval (HREC/17/QRCH/43, dated 26 April 2017), is registered in the Australian New Zealand Clinical Trials Registry (ACTRN12617000821392) and commenced recruitment in July 2017. The primary manuscript will be submitted for publication in a peer-reviewed journal. ACTRN12617000821392
Simulation as Experimentation
Publisher: Springer International Publishing
Date: 2023
Resistance and susceptibility to tuberculosis analysed at the transcriptome level: lessons from mouse macrophages
Publisher: Elsevier BV
Date: 2004
The duality of macrophage function in chronic lymphocytic leukaemia.
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.BBCAN.2017.03.006
Abstract: Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia and, in some patients, is accompanied by resistance to both chemotherapeutics and immunotherapeutics. In this review we will discuss the role of tumour associated macrophages (TAMs) in promoting CLL cell survival and resistance to immunotherapeutics. In addition, we will discuss mechanisms by which TAMs suppress T-cell mediated antitumour responses. Thus, targeting macrophages could be used to i) reduce the leukaemic burden via the induction of T-cell-mediated antitumour responses, ii) to reduce pro-survival signalling and enhance response to conventional chemotherapeutics or iii) enhance the response to therapeutic antibodies in current clinical use.
Proactive service recovery in emergency departments: A hybrid modelling approach using forecasting and real-time simulation
Publisher: ACM
Date: 29-05-2019
Structure-Activity Relationships of Wollamide Cyclic Hexapeptides with Activity against Drug-Resistant and Intracellular Mycobacterium tuberculosis.
Publisher: American Society for Microbiology
Date: 03-2019
DOI: 10.1128/AAC.01773-18
Abstract: Wollamides are cyclic hexapeptides, recently isolated from an Australian soil Streptomyces isolate, that exhibit promising in vitro antimycobacterial activity against Mycobacterium bovis Bacille Calmette Guérin without displaying cytotoxicity against a panel of mammalian cells. Here, we report the synthesis and antimycobacterial activity of 36 new synthetic wollamides, collated with all known synthetic and natural wollamides, to reveal structure characteristics responsible for in vitro growth-inhibitory activity against Mycobacterium tuberculosis (H37Rv, H37Ra, CDC1551, HN878, and HN353).
Mollemycin A: an antimalarial and antibacterial glyco-hexadepsipeptide-polyketide from an Australian marine-derived Streptomyces sp. (CMB-M0244).
Publisher: American Chemical Society (ACS)
Date: 11-03-2014
DOI: 10.1021/OL5003913
Abstract: A marine-derived Streptomyces sp. (CMB-M0244) isolated from a sediment collected off South Molle Island, Queensland, produced mollemycin A (1) as a new first in class glyco-hexadepsipeptide-polyketide. The structure of 1 was assigned by detailed spectroscopic analysis, supported by chemical derivatization and degradation, and C3 Marfey's analysis. Mollemycin A (1) exhibits exceptionally potent and selective growth inhibitory activity against Gram-positive and Gram-negative bacteria (IC50 10-50 nM) and drug-sensitive (3D7 IC50 7 nM) and multidrug-resistant (Dd2 IC50 9 nM) clones of the malaria parasite Plasmodium falciparum.
IL-17 suppresses immune effector functions in human papillomavirus-associated epithelial hyperplasia
Publisher: The American Association of Immunologists
Date: 09-2014
Abstract: Persistent infection with high-risk human papillomaviruses (HPV) causes epithelial hyperplasia that can progress to cancer and is thought to depend on immunosuppressive mechanisms that prevent viral clearance by the host. IL-17 is a cytokine with erse functions in host defense and in the pathology of autoimmune disorders, chronic inflammatory diseases, and cancer. We analyzed biopsies from patients with HPV-associated cervical intraepithelial neoplasia grade 2/3 and murine skin displaying HPV16 E7 protein-induced epithelial hyperplasia, which closely models hyperplasia in chronic HPV lesions. Expression of IL-17 and IL-23, a major inducer of IL-17, was elevated in both human HPV-infected and murine E7-expressing lesions. Using a skin-grafting model, we demonstrated that IL-17 in HPV16 E7 transgenic skin grafts inhibited effective host immune responses against the graft. IL-17 was produced by CD3+ T cells, predominantly CD4+ T cells in human, and CD4+ and γδ T cells in mouse hyperplastic lesions. IL-23 and IL-1β, but not IL-18, induced IL-17 production in E7 transgenic skin. Together, these findings demonstrate an immunosuppressive role for IL-17 in HPV-associated epithelial hyperplasia and suggest that blocking IL-17 in persistent viral infection may promote antiviral immunity and prevent progression to cancer.
Common and Unique Gene Expression Signatures of Human Macrophages in Response to Four Strains of Mycobacterium avium That Differ in Their Growth and Persistence Characte
Publisher: American Society for Microbiology
Date: 06-2005
DOI: 10.1128/IAI.73.6.3330-3341.2005
Abstract: Classification of pathogenic species according to the distinct host transcriptional responses that they elicit may become a relevant tool for microarray-based diagnosis of infection. In idual strains of Mycobacterium avium , an opportunistic pathogen in humans, have previously been shown to differ in terms of growth and persistence. In order to cover a wide spectrum of virulence, we selected four M. avium isolates (2151SmO, 2151SmT, SE01, TMC724) that have distinct intramacrophage replication characteristics and cause differential activation in human macrophages. Following infection with each of these strains, the expression of 12,558 genes in human macrophages was systematically analyzed by microarray technology. Fifty genes (including genes encoding proinflammatory cytokines, chemokines, signaling, and adhesion molecules) were differentially expressed more than twofold in response to all of the M. avium isolates investigated and therefore constitute a common macrophage signature in response to M. avium . The magnitude of regulation of most of these genes was directly correlated with the host cell-activating capacity of the particular M. avium strain. The regulation of a number of genes not previously associated with mycobacterial infections was apparent these genes included genes encoding lymphocyte antigen 64 and myosin X. In addition, in idual response patterns typical for some M. avium isolates could be defined by the pronounced upregulation of interleukin-12p40 (IL-12p40) (in the case of 2151SmO) or the specific upregulation of SOCS-1 and IL-10 (in the case of SE01) in macrophages. TMC724, a strain of avian origin, could not be classified by any one of these schemes, possibly indicating the limits of pathogen categorization solely by immune response signatures.
The Issue of Trust and Implementation of Results in Healthcare Modeling and Simulation Studies
Publisher: IEEE
Date: 11-12-2022
Small GTPase Rab8a-recruited phosphatidylinositol 3-kinase γ regulates signaling and cytokine outputs from endosomal toll-like receptors
Publisher: Elsevier BV
Date: 03-2017
Correction: LprG-Mediated Surface Expression of Lipoarabinomannan Is Essential for Virulence of Mycobacterium tuberculosis
Publisher: Public Library of Science (PLoS)
Date: 09-12-2015
The Wingless homolog WNT5A and its receptor Frizzled-5 regulate inflammatory responses of human mononuclear cells induced by microbial stimulation
Publisher: American Society of Hematology
Date: 08-2006
DOI: 10.1182/BLOOD-2005-12-5046
Abstract: Microarray - assisted gene - expression screens of human macrophages revealed WNT5A, a homolog of Wingless, a key regulator of Drosophila melanogaster embryonic segmentation and patterning, to be consistently up-regulated following stimulation with different mycobacterial species and conserved bacterial structures. The expression of WNT5A required Toll-like receptor signaling and NF-κB activation, which identifies a novel induction pathway for a Wingless homolog. We show that human peripheral-blood mononuclear cells express the WNT5A receptor Frizzled-5 (FZD5). Both WNT5A and FZD5 also were detected in granulomatous lesions in the lungs of Mycobacterium tuberculosis–infected patients. Functional studies showed that WNT5A and FZD5 regulate the microbially induced interleukin-12 response of antigen-presenting cells and interferon-γ production by mycobacterial antigenstimulated T cells. Our findings implicate the evolutionarily conserved WNT/Frizzled signaling system in bridging innate and adaptive immunity to infections.
Immunity against Moraxella catarrhalis requires guanylate‐binding proteins and caspase‐11‐ NLRP3 inflammasomes
Publisher: EMBO
Date: 10-02-2023
Abstract: Moraxella catarrhalis is an important human respiratory pathogen and a major causative agent of otitis media and chronic obstructive pulmonary disease. Toll‐like receptors contribute to, but cannot fully account for, the complexity of the immune response seen in M. catarrhalis infection. Using primary mouse bone marrow‐derived macrophages to examine the host response to M. catarrhalis infection, our global transcriptomic and targeted cytokine analyses revealed activation of immune signalling pathways by both membrane‐bound and cytosolic pattern‐recognition receptors. We show that M. catarrhalis and its outer membrane vesicles or lipooligosaccharide (LOS) can activate the cytosolic innate immune sensor caspase‐4/11, gasdermin‐D‐dependent pyroptosis, and the NLRP3 inflammasome in human and mouse macrophages. This pathway is initiated by type I interferon signalling and guanylate‐binding proteins (GBPs). We also show that inflammasomes and GBPs, particularly GBP2, are required for the host defence against M. catarrhalis in mice. Overall, our results reveal an essential role for the interferon‐inflammasome axis in cytosolic recognition and immunity against M. catarrhalis , providing new molecular targets that may be used to mitigate pathological inflammation triggered by this pathogen.
Hybrid models as transdisciplinary research enablers
Publisher: Elsevier BV
Date: 06-2021
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Related Funding Activities
ARC Future Fellowships - Grant ID: FT220100487
Start Date: 2023
End Date: 12-2026
Amount: $1,127,924.00
Funder: Australian Research Council
View Funded Activity