ORCID Profile
0000-0002-4439-4756
Current Organisation
University of New South Wales
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Publisher: Springer Science and Business Media LLC
Date: 07-01-2020
DOI: 10.1186/S12889-019-8049-6
Abstract: Participation in organised sport and physical activity contributes to health-enhancing levels of leisure time physical activity. In Australia, 58% of children aged 0–14 years participated at least once a week in October 2015 – December 2017. To overcome the frequently cited cost barrier, sports voucher incentives have been widely implemented across Australia. The financial value of jurisdictional vouchers and the National median financial value were used to calculate the proportion of total annual expenditure on children’s participation in sport supported by sports vouchers. Participation rates using AusPlay data were estimated by age, sex and socio-economic index (SEIFA) at state and national level for children aged 0–14 years. Five States and Territories implemented sports vouchers from 2011 to 2018, with a median value of AU$150. Nationally, median annual expenditure for children’s sport participation was AU$447 (IQR $194.2–936), with 27% reported expenditure supported by a sports voucher. The proportion of financial support from sports vouchers increased considerably with social disadvantage, rising to over 60% of total expenditure in the most disadvantaged populations. Socio-economic status was associated with sports-related expenditure and sports participation amongst children. Sport vouchers should target children in the most disadvantaged areas to promote participation in organised sport and physical activity.
Publisher: Springer Science and Business Media LLC
Date: 04-05-2015
DOI: 10.1038/NM.3829
Abstract: Accumulation of visceral adipose tissue correlates with elevated inflammation and increased risk of metabolic diseases. However, little is known about the molecular mechanisms that control its pathological expansion. Transcription factor interferon regulatory factor 5 (IRF5) has been implicated in polarizing macrophages towards an inflammatory phenotype. Here we demonstrate that mice lacking Irf5, when placed on a high-fat diet, show no difference in the growth of their epididymal white adipose tissue (epiWAT) but they show expansion of their subcutaneous white adipose tissue, as compared to wild-type (WT) mice on the same diet. EpiWAT from Irf5-deficient mice is marked by accumulation of alternatively activated macrophages, higher collagen deposition that restricts adipocyte size, and enhanced insulin sensitivity compared to epiWAT from WT mice. In obese in iduals, IRF5 expression is negatively associated with insulin sensitivity and collagen deposition in visceral adipose tissue. Genome-wide analysis of gene expression in adipose tissue macrophages highlights the transforming growth factor β1 (TGFB1) gene itself as a direct target of IRF5-mediated inhibition. This study uncovers a new function for IRF5 in controlling the relative mass of different adipose tissue depots and thus insulin sensitivity in obesity, and it suggests that inhibition of IRF5 may promote a healthy metabolic state during this condition.
Publisher: Oxford University Press (OUP)
Date: 27-09-2011
DOI: 10.1002/STEM.706
Abstract: Recent characterization of mammary stem and progenitor cells has improved our understanding of the transcriptional network that coordinates mammary development however, little is known about the mechanisms that enforce lineage commitment and prevent transdifferentiation in the mammary gland. The E-twenty six transcription factor Elf5 forces the differentiation of mammary luminal progenitor cells to establish the milk producing alveolar lineage. Methylation of the Elf5 promoter has been proposed to act as a lineage gatekeeper during embryonic development. We used bisulphite sequencing to investigate in detail whether Elf5 promoter methylation plays a role in lineage commitment during mammary development. An increase in Elf5 expression was associated with decreasing Elf5 promoter methylation in differentiating HC11 mammary cells. Similarly, purified mammary epithelial cells from mice had increased Elf5 expression and decreased promoter methylation during pregnancy. Finally, analysis of epithelial subpopulations revealed that the Elf5 promoter is methylated and silenced in the basal, stem cell-containing population relative to luminal cells. These results demonstrate that Elf5 promoter methylation is lineage-specific and developmentally regulated in the mammary gland in vivo, and suggest that loss of Elf5 methylation specifies the mammary luminal lineage, while continued Elf5 methylation maintains the stem cell and myoepithelial lineages.
Publisher: MDPI AG
Date: 16-08-2020
Abstract: Many studies document the relationship between housing quality and health status. Poor housing in Aboriginal communities continues to be linked to the compromised health status of Aboriginal Australians. The New South Wales (NSW) Housing for Health (HfH) program has been assessing and repairing Aboriginal community housing across the state for 20 years using a standardised intervention methodology that aims to improve the health of Aboriginal people in NSW by improving their living environments. Items are tested and repairs are prioritised to maximise safety and health benefits and measured against 11 Critical Healthy Living Priorities (e.g., safety, facilities for washing people and clothes, removing waste and preparing food). Descriptive analysis of data collected pre- and post-intervention from 3670 houses was conducted to determine the effectiveness of the program. Analysis demonstrated statistically significant improvements in the ability of the houses to support safe and healthy living for all critical healthy living priorities post-interventions. Trend analysis demonstrated the magnitude of these improvements increased over 20 years. In 24 communities (n = 802 houses) where projects were repeated (5–17 years later), results indicate sustainability of improvements for 9 of 11 priorities. However, the overall condition of health-related hardware in Aboriginal community housing across NSW pre-intervention has not significantly changed during the program’s 20 years. Results suggest a systematic lack of routine maintenance and quality control continues to be the overwhelming cause for this lack of improvement pre-intervention. Our evaluation of the HfH program demonstrated that fidelity to a standardised housing testing and repair methodology to improve residents’ safety and health can have sustainable effects on housing infrastructure and associated health benefits, such as a 40% reduction in infectious disease hospital separations. Housing and health agencies should collaborate more closely on social housing programs and ensure programs are adequately resourced to address safety and health issues.
Publisher: American Association for Cancer Research (AACR)
Date: 07-2004
DOI: 10.1158/1078-0432.CCR-03-0232
Abstract: Purpose: The purpose is to compare the presence of proteins with known associations with breast cancer—progesterone receptor (PgR), estrogen receptor, and p53, with the prevalence of mouse mammary tumor virus (MMTV)-like DNA sequences in human female breast cancers. Experimental Design: A cohort of 128 Australian female breast cancers were screened for MMTV-like DNA sequences using PCR. The presence of PgR, estrogen receptor, and nuclear accumulation of p53 protein was assessed in the same s les using immunohistochemical staining. Results: Nuclear accumulation of p53 was significantly more prevalent (P = 0.05) in archival human breast cancers containing MMTV-like DNA sequences. The presence of progesterone receptor was significantly higher in MMTV-positive than MMTV-negative breast cancers (P = 0.01). No correlation between estrogen receptor and MMTV-like DNA sequences was found. Conclusions: MMTV causes breast cancer in mice, and hormones up-regulate expression of virus in mice mammary tissue. It is unknown if this is the case in human breast cancers shown to contain DNA of MMTV-like viruses. The positive association between MMTV-like DNA sequences and PgR indicates hormones and MMTV may play a role in human breast cancer. Mutations of the tumor suppressor gene p53 are common in human breast cancer and are associated with higher grades of cancer. The association of MMTV-like DNA sequences with higher grades of cancer, and the positive association between p53 and MMTV-like DNA sequences clearly warrant additional investigation.
Publisher: Proceedings of the National Academy of Sciences
Date: 17-08-2015
Abstract: Many of the world’s major chronic diseases are driven by inflammation. The most abundant inflammatory cells in these diseases are myeloid cells, such as macrophages and neutrophils. Both cell types show remarkable phenotypic ersity among tissues. Defining molecular factors that control this ersity provides abundant scope for the generation of more specific and effective therapeutics, as the lack of specificity of the current most widely used antiinflammatory approaches, such as glucocorticoids and nonsteroidal antiinflammatory molecules, leads to widespread problems if used long term, even at relatively low doses. In this study we demonstrate that a transcription factor called IFN regulatory factor 5 controls macrophage and neutrophil aspects of inflammation, and thus its blockade might be an effective therapeutic strategy for multiple indications.
Publisher: Elsevier BV
Date: 2021
Publisher: The Endocrine Society
Date: 07-2005
DOI: 10.1210/ME.2004-0254
Abstract: The secretory activation stage of mammary gland development occurs after parturition and converts inactive lobuloalveoli to active milk secretion. This process is triggered by progestin withdrawal and depends upon augmented prolactin (Prl) signaling. Little is known about the Prl-induced transcriptional changes that occur in the mammary gland to drive this process. To examine changes in the mammary transcriptome responsible for secretory activation, we have used transcript profiling of three mouse models that exhibit failure of secretory activation: knockout of galanin (a regulator of pituitary Prl production and a mammary cell autonomous modulator of Prl action) treatment with S179D Prl (a phosphoprolactin mimic) and knockout of a single Prl receptor allele. A significant reduction in expression was observed in genes belonging to 46 gene ontologies including those representing milk proteins, metabolism, lipid, cholesterol and fatty acid biosynthetic enzymes, immune response, and key transcription factors. A set of 35 genes, commonly regulated in all three models, was identified and their role in lactogenesis was validated by examining their expression in response to Prl stimulation or signal transducer and activator of transcription 5 knockdown in the HC11 mouse mammary cell culture model. The transcript profiles provided by these experiments identify 35 key genes (many for the first time) involved in the secretory activation phase of mammary gland development, show that S179D acts as an antagonist of Prl action, and provide insight into the partial penetrance of failed lactation in Prl receptor heterozygous females.
Publisher: Wiley
Date: 26-09-2014
DOI: 10.1002/ART.38755
Abstract: Tumor necrosis factor (TNF) signals via 2 receptors, TNFR type I (TNFRI) and TNFRII, with distinct cellular distribution and signaling functions. In rheumatoid arthritis (RA), the net effect of TNFR signaling favors inflammatory responses while inhibiting the activity of regulatory T cells. TNFRII signaling has been shown to promote Treg cell function. To assess the relative contributions of TNFRI and TNFRII signaling to inflammatory and regulatory responses in vivo, we compared the effect of TNF blockade, hence TNFRI/II, versus TNFRI alone in collagen-induced arthritis (CIA) as a model of RA. Mice with established arthritis were treated for 10 days with anti-mouse TNFRI domain antibody (dAb DMS5540), an isotype control dAb (DMS5538), or murine TNFRII genetically fused with mouse IgG1 Fc domain (mTNFRII-Fc) beginning on the day of arthritis onset, and disease progression was monitored. Systemic cytokine concentrations and numbers of T cell subsets in lymph nodes and spleens were measured, and intrinsic Treg cell function was determined by ex vivo suppression assays. Progression of CIA was suppressed similarly by TNFRI (DMS5540) and TNFRI/II (mTNFRII-Fc) blockade. However, blockade of TNFRI/II led to increased effector T cell activity, which was not observed after selective TNFRI blockade, suggesting an immunoregulatory role of TNFRII. In support of this, TNFRI blockade, but not TNFRI/II blockade, expanded and activated Treg cells. Furthermore, a dramatic increase in expression of the Treg cell signature genes FoxP3 and TNFRII was observed in joints undergoing remission, which supports the notion that these molecules have a physiologic role in the resolution of inflammation. We propose that a therapeutic strategy that targets TNFRI while sparing TNFRII has the potential to both inhibit inflammation and promote Treg cell activity, which might be superior to TNF blockade.
Publisher: Bioscientifica
Date: 11-2006
DOI: 10.1677/JOE.1.06685
Abstract: Mammalian hair growth is cyclic, with hair-producing follicles alternating between active (anagen) and quiescent (telogen) phases. The timing of hair cycles is advanced in prolactin receptor (PRLR) knockout mice, suggesting that prolactin has a role in regulating follicle cycling. In this study, the relationship between profiles of circulating prolactin and the first post-natal hair growth cycle was examined in female Balb/c mice. Prolactin was found to increase at 3 weeks of age, prior to the onset of anagen 1 week later. Expression of PRLR mRNA in skin increased fourfold during early anagen. This was followed by upregulation of prolactin mRNA, also expressed in the skin. Pharmacological suppression of pituitary prolactin advanced dorsal hair growth by 3.5 days. Normal hair cycling was restored by replacement with exogenous prolactin for 3 days. Increasing the duration of prolactin treatment further retarded entry into anagen. However, prolactin treatments, which began after follicles had entered anagen at 26 days of age, did not alter the subsequent progression of the hair cycle. Skin from PRLR-deficient mice grafted onto endocrine-normal hosts underwent more rapid hair cycling than comparable wild-type grafts, with reduced duration of the telogen phase. These experiments demonstrate that prolactin regulates the timing of hair growth cycles in mice via a direct effect on the skin, rather than solely via the modulation of other endocrine factors.
Publisher: The Royal Society
Date: 09-06-2021
Abstract: Social animals are expected to face a trade-off between producing a signal that is detectible by mates and rivals, but not obvious to predators. This trade-off is fundamental for understanding the design of many animal signals, and is often the lens through which the evolution of alternative communication strategies is viewed. We have a reasonable working knowledge of how conspecifics detect signals under different conditions, but how predators exploit conspicuous communication of prey is complex and hard to predict. We quantified predation on 1566 robotic lizard prey that performed a conspicuous visual display, possessed a conspicuous ornament or remained cryptic. Attacks by free-ranging predators were consistent across two contrasting ecosystems and showed robotic prey that performed a conspicuous display were equally likely to be attacked as those that remained cryptic. Furthermore, predators avoided attacking robotic prey with a fixed, highly visible ornament that was novel at both locations. These data show that it is prey familiarity—not conspicuousness—that determine predation risk. These findings replicated across different predator–prey communities not only reveal how conspicuous signals might evolve in high predation environments, but could help resolve the paradox of aposematism and why some exotic species avoid predation when invading new areas.
Publisher: Elsevier BV
Date: 04-2013
Publisher: Rockefeller University Press
Date: 04-05-2015
DOI: 10.1084/JEM.20140995
Abstract: The most studied biological role of type III interferons (IFNs) has so far been their antiviral activity, but their role in autoimmune and inflammatory diseases remains largely unexplored. Here, we show that treatment with IFN-λ2/IL-28A completely halts and reverses the development of collagen-induced arthritis (CIA) and discover cellular and molecular mechanisms of IL-28A antiinflammatory function. We demonstrate that treatment with IL-28A dramatically reduces numbers of proinflammatory IL-17–producing Th17 and γδ T cells in the joints and inguinal lymph nodes, without affecting T cell proliferative responses or levels of anticollagen antibodies. IL-28A exerts its antiinflammatory effect by restricting recruitment of IL-1b–expressing neutrophils, which are important for lification of inflammation. We identify neutrophils as cells expressing high levels of IFN-λ receptor 1 (IFNLR1)–IL-28 receptor α (IL28RA) and targeted by IL-28A. Our data highlight neutrophils as contributors to the pathogenesis of autoimmune arthritis and present IFN-λs or agonists of IFNLR1–IL28RA as putative new therapeutics for neutrophil-driven inflammation.
Publisher: The American Association of Immunologists
Date: 15-11-2011
Abstract: Excessive inflammation during bacterial and viral infections is destructive to the host and involves elevated production of proinflammatory cytokines. It is especially deleterious in organs with space constraints such as lung and the CNS. Indeed, a number of viruses that infect lungs, such as avian influenza virus, SARS-associated coronavirus, and respiratory syncytial virus, elicit a very high level of proinflammatory cytokines however, it is unclear what triggers their production. In this study, we show that IL-17 commonly produced during viral infection specifically augments a proinflammatory response by directly synergizing with antiviral signaling. Costimulation of primary human fibroblasts with IL-17 greatly enhanced respiratory syncytial virus-induced or synthetic dsRNA-based viral mimic polyinosinic:polycytidylic acid-induced expression of proinflammatory genes without affecting expression of IFN-β–stimulated or IFN-stimulated genes. Knockdown of expression of known mediators of the antiviral signaling pathway revealed that the IL-17–poly(I:C) synergy depends on the presence of the transcriptional factors RelA and IFN regulatory factor 3 and IκB kinases. Moreover, this synergy was blocked by an IκB kinase inhibitor, BAY 11-7082. These findings shed light on the molecular mechanisms behind IL-17–dependent immunopathology observed in viral infections.
Publisher: The Endocrine Society
Date: 07-2010
DOI: 10.1210/ME.2009-0516
Abstract: Prolactin and progesterone act together to regulate mammary alveolar development, and both hormones have been implicated in breast cancer initiation and progression. Here we show that Elf5, a prolactin-induced ETS transcription factor that specifies the mammary secretory cell lineage, is also induced by progestins in breast cancer cells via a direct mechanism. To define the transcriptional response to progestin elicited via Elf5, we made an inducible Elf5 short hairpin-RNA knock-down model in T47D breast cancer cells and used it to prevent the progestin-induction of Elf5. Functional analysis of Affymetrix gene expression data using Gene Ontologies and Gene Set Enrichment Analysis showed enhancement of the progestin effects on cell cycle gene expression. Cell proliferation assays showed a more efficacious progestin-induced growth arrest when Elf5 was kept at baseline levels. These results showed that progestin induction of Elf5 expression tempered the antiproliferative effects of progestins in T47D cells, providing a further mechanistic link between prolactin and progestin in the regulation of mammary cell phenotype.
Publisher: Hindawi Limited
Date: 2013
DOI: 10.1155/2013/245804
Abstract: Macrophages are an integral part of the innate immune system and key players in pathogen clearance and tissue remodelling. Both functions are accomplished by a pivotal network of different macrophage subtypes, including proinflammatory M1 and anti-inflammatory M2 macrophages. Previously, our laboratory identified the transcription factor interferon regulatory factor 5 (IRF5) as the master regulator of the M1 macrophage polarisation. IRF5 was found to be highly expressed in human M1 compared to M2 macrophages. Furthermore, IRF5 dictates the expression of proinflammatory genes such as IL12b and IL23a whilst repressing anti-inflammatory genes like IL10 . Here we show that murine bone marrow derived macrophages differentiated in vitro with GM-CSF are also characterised by high levels of IRF5 mRNA and protein and express proinflammatory cytokines upon LPS stimulation. These macrophages display characteristic expression of M1-marker MHC II but lack the M2-marker CD206. Significantly, we develop intracellular staining of IRF5- expressing macrophages and utilise it to recapitulate the in vitro results in an in vivo model of antigen-induced arthritis, emphasising their physiological relevance. Thus, we establish the species-invariant role of IRF5 in controlling the inflammatory macrophage phenotype both in vitro and in in vivo .
Publisher: Cold Spring Harbor Laboratory
Date: 03-2008
DOI: 10.1101/GAD.1614608
Abstract: Hormonal cues regulate mammary development, but the consequent transcriptional changes and cell fate decisions are largely undefined. We show that knockout of the prolactin-regulated Ets transcription factor Elf5 prevented formation of the secretory epithelium during pregnancy. Conversely, overexpression of Elf5 in an inducible transgenic model caused alveolar differentiation and milk secretion in virgin mice, disrupting ductal morphogenesis. CD61 + luminal progenitor cells accumulated in Elf5-deficient mammary glands and were diminished in glands with Elf5 overexpression. Thus Elf5 specifies the differentiation of CD61 + progenitors to establish the secretory alveolar lineage during pregnancy, providing a link between prolactin, transcriptional events, and alveolar development.
Publisher: Cold Spring Harbor Laboratory
Date: 22-02-2022
DOI: 10.1101/2022.02.21.22271299
Abstract: The impact of COVID-19 international travel restrictions has to date, not been fully explored, and with the ongoing threat that new variants could potentially restrict movement further, it is important to consider the impacts that travel restrictions have on community members. This study aimed to evaluate the psychological and financial impact of COVID-19 travel restrictions on those separated from their partners or immediate families, as well as temporary visa holders who were unable to migrate. Between 4 November 2021 to 1 December 2021, we executed a cross-sectional online survey targeting three specific groups (1) those stranded from their partners (2) those stranded from immediate families and (3) temporary visa holders unable to migrate or cross international borders. We collected data on respondents’ demographic profile the nature of COVID-19-related travel impacts depression, anxiety, and stress levels (using the validated DASS-21) and finally, data on respondents financial, employment and accommodation situation. 1363 respondents located globally completed the survey. 71.2% reported financial stress, 76.8% ( , SD=5.94) reported moderate-to-extremely severe depression, 51.6% ( , SD=5.49) moderate-to-extremely severe anxiety, and 62.6% ( , SD=5.55) moderate-to-extremely severe stress levels. Statistically significant factors associated with moderate-to-extremely severe depression, anxiety, and stress included being female, chronic illness, and experiencing financial stress. Employment during COVID-19 – specifically essential services workers or unemployed – was associated with higher levels of anxiety and stress, with only essential workers being a predictor of higher stress severity. Factors that provided psychological protection included being older and having children. This study is one of the first to explore the impact COVID-19-related international travel restrictions have had on the financial status and psychological health of affected in iduals. It highlights the significant human cost associated with the restrictions and identifies psychologically vulnerable populations. These results will help the design of targeted health and social policy responses.
Publisher: Elsevier BV
Date: 05-2021
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1016/J.IMMUNI.2013.05.010
Abstract: Type I interferon (IFN) is crucial during infection through its antiviral properties and by coordinating the immunocompetent cells involved in antiviral or antibacterial immunity. Type I IFN (IFN-α and IFN-β) is produced after virus or bacteria recognition by cytosolic receptors or membrane-bound TLR receptors following the activation of the transcription factors IRF3 or IRF7. IFN-β production after fungal infection was recently reported, although the underlying mechanism remains controversial. Here we describe that IFN-β production by dendritic cells (DCs) induced by Candida albicans is largely dependent on Dectin-1- and Dectin-2-mediated signaling. Dectin-1-induced IFN-β production required the tyrosine kinase Syk and the transcription factor IRF5. Type I IFN receptor-deficient mice had a lower survival after C. albicans infection, paralleled by defective renal neutrophil infiltration. IFN-β production by renal infiltrating leukocytes was severely reduced in C. albicans-infected mice with Syk-deficient DCs. These data indicate that Dectin-induced IFN-β production by renal DCs is crucial for defense against C. albicans infection.
Publisher: Wiley
Date: 04-2012
Abstract: Cell survival transcription factor FOXO3 has been recently implicated in moderating pro-inflammatory cytokine production by dendritic cells (DCs), but the molecular mechanisms are unclear. It was suggested that FOXO3 could antagonize NF-κB activity, while IKK-β was demonstrated to inactivate FOXO3, suggesting a cross-talk between the two pathways. Therefore, FOXO3 activity must be tightly regulated to allow for an appropriate inflammatory response. Here, we show that in human monocyte-derived DCs (MDDCs), FOXO3 is able to antagonize signaling intermediates downstream of the Toll-like receptor (TLR) 4, such as NF-κB and interferon regulatory factors (IRFs), resulting in inhibition of interferon (IFN)-β expression. We also demonstrate that the activity of FOXO3 itself is regulated by IKK-ε, a kinase involved in IFN-β production, which phosphorylates and inactivates FOXO3 in response to TLR4 agonists. Thus, we identify FOXO3 as a new IKK-ε-controlled check-point of IRF activation and regulation of IFN-β expression, providing new insight into the role of FOXO3 in immune response control.
Publisher: AMPCo
Date: 10-12-2018
DOI: 10.5694/MJA18.00841
Abstract: The Mamil (middle-aged man in Lycra) appears to be an emergent cycling-focused species. To explore the nature and distribution of the Mamilian species to determine whether rates of cycling by middle-aged men in Australia have changed since the pre-Mamilian era. Secondary analysis of representative population-based datasets. National sport participation data from the Exercise, Recreation and Sport (2002-2004, 2008-2010) and Ausplay surveys (2016) were analysed to assess trends in recreational and exercise-related cycling, including by middle-aged men (45-64 years of age). Data from New South Wales Population Health Surveys (2006, 2010, 2014) and Australian censuses (2006, 2011, 2014) were analysed to assess trends in cycling to work. Cycling participation rates (at least once or at least once a week in the past 12 months) rates of cycling to work. The proportion of middle-aged men who cycled for exercise or recreational purposes at least once a week during the previous year increased from 6.2% (95% CI, 5.5-7.0%) during 2002-2004 to 13.2% (95% CI, 11.9-14.6%) in 2016. The prevalence of Mamils in the most affluent residential areas has more than doubled since 2002-2004, and is twice as high as in the least advantaged locations. Media reports of "Mamils" corroborate these temporal trends. Mamils in Australia are socially graded, and also grade themselves according to bicycle-related expenditure and hill gradients overcome. They often form cohesive and supportive groups, but may not reflect a population-wide social movement to increase physical activity among adult Australians.
Publisher: Elsevier BV
Date: 02-2021
Publisher: Cold Spring Harbor Laboratory
Date: 09-12-2021
DOI: 10.1101/2021.12.08.21267218
Abstract: With the easing of COVID-19-related international travel restrictions in late 2021 it is time to consider the direct and indirect social, emotional, and financial impacts that these border closures have had. The study aims to evaluate the psychological and financial distress reported by people stranded abroad due to international travel restrictions introduced in response to the COVID-19 pandemic. Between July and September 2021, we implemented a cross-sectional online survey targeting in iduals stranded abroad due to international travel restrictions. The survey collected data about COVID-19 travel restriction-related travel impacts personal stress, anxiety, and depression (using the validated DASS-21tool) as well as impacts on housing and financial security and demographic data. We had 1054 participants complete the survey most were trying to return to the Oceania region (75.4%), with 45% stranded in Europe. Overall, 64.2% reported financial distress while stranded abroad. 64.4% (x̄ =9.43, SD=5.81) reported either a moderate or severe (based on the DASS-21 classification) level of depression, 41.7% for anxiety (x̄ =5.46, SD=4.74), and 58.1% for stress (x̄ =10.64, SD=5.26). Statistically significant factors associated with moderate to extremely severe depression, anxiety, and stress were financial stress, an employment change, being yrs, having a high perceived risk of contracting COVID-19 abroad and being stranded for months. The study is among the first to explore the psychological and financial distress-related impacts associated with being stranded abroad due to COVID-19 travel restrictions. It highlights a range of unintended consequences that arise from pandemic-related travel restriction, identifies the health and social needs for a particularly vulnerable population, and provides clues as to the types of support that may be adopted to best support them. This research will assist policymakers in identifying support packages for people stranded abroad due to global disaster.
Publisher: Elsevier BV
Date: 09-2014
Publisher: American Society of Hematology
Date: 03-06-2010
DOI: 10.1182/BLOOD-2010-01-263020
Abstract: Spatially and temporally controlled expression of inflammatory mediators is critical for an appropriate immune response. In this study, we define the role for interferon regulatory factor 5 (IRF5) in secretion of tumor necrosis factor (TNF) by human dendritic cells (DCs). We demonstrate that DCs but not macrophages have high levels of IRF5 protein, and that IRF5 is responsible for the late-phase expression of TNF, which is absent in macrophages. Sustained TNF secretion is essential for robust T-cell activation by DCs. Systematic bioinformatic and biochemical analyses of the TNF gene locus map 2 sites of IRF5 recruitment: 5′ upstream and 3′ downstream of the TNF gene. Remarkably, while IRF5 can directly bind to DNA in the upstream region, its recruitment to the downstream region depends on the protein-protein interactions with NF-κB RelA. This study provides new insights into erse molecular mechanisms employed by IRF5 to regulate gene expression and implicates RelA-IRF5 interactions as a putative target for cell-specific modulation of TNF expression.
Publisher: Springer Science and Business Media LLC
Date: 06-2011
DOI: 10.1007/S00239-011-9450-7
Abstract: SEF/IL-17R/CIKS/ACT1 homology (SEFIR) domain containing proteins, which include the IL-17 receptors and an adaptor protein Act1, have essential roles in vertebrate immunity. However, the molecular mechanisms of Act1 function remain largely unexplored. In this article, we employed an evolutionary analysis to discover novel structural and functional properties of Act1. Firstly, we have found that the previously identified helix-loop-helix and Ufd2-box domains in human Act1 have relatively recent evolutionary origins in higher vertebrates. Zebrafish Act1, which lacks these domains, is unable to induce JNK phosphorylation and activate cytokine expression when expressed in human cells. Secondly, we have established that Act1-like proteins contain DEATH-domains in basal animals, such as Hydra and primitive chordates, but lack this domain in vertebrates. Finally, we have shown that Act1-TRAF6 interactions are conserved throughout vertebrate evolution: Act1 derived from zebrafish can bind to TRAF6 and activate NF-κB in human cells. Moreover, we have identified a novel highly conserved motif at the amino-terminus of Act1, which is critical for binding to TRAF6 and activating NF-κB-dependent gene expression. We propose a model of evolutionary changes in Act1-mediated signalling, which contributes to a better understanding of evolution of the vertebrate immunity.
Publisher: The American Association of Immunologists
Date: 24-10-2012
Abstract: Double-stranded RNA-induced antiviral gene expression in mammalian cells requires activation of IFN regulatory factor 3 (IRF3). In this study, we show that the IL-17R adaptor protein Act1/CIKS is involved in this process. Small interfering RNA-mediated knockdown of Act1 in primary human skin fibroblasts specifically attenuates expression of IFN-β and IFN-stimulated antiviral genes induced by a synthetic viral mimic, polyinosinic-polycytidylic acid. Ectopic expression of Act1 potentiates the IRF3-driven expression of a synthetic reporter construct as well as the induction of antiviral genes. We demonstrate that this effect is dependent on the ability of Act1 to functionally and physically interact with IκB kinase ε (IKKε), a known IRF3 kinase, and IRF3: 1) Act1 binds IKKε and IRF3 2) Act1-induced IRF3 activation can be blocked specifically by coexpression of a catalytically inactive mutant of IKKε and 3) mutants of IRF3, either lacking the C terminus or mutated at the key phosphorylation sites, important for its activation by IKKε, do not support Act1-dependent IRF3 activation. We also show that a zebrafish Act1 protein is able to trigger antiviral gene expression in human cells, which suggests an evolutionarily conserved function of vertebrate Act1 in the host defense against viruses. On the whole, our study demonstrates that Act1 is a component of antiviral signaling.
Publisher: The Endocrine Society
Date: 05-2006
DOI: 10.1210/ME.2005-0473
Abstract: The proliferative phase of mammary alveolar morphogenesis is initiated during early pregnancy by rising levels of serum prolactin and progesterone, establishing a program of gene expression that is ultimately responsible for the development of the lobuloalveoli and the onset of lactation. To explore this largely unknown genetic program, we constructed transcript profiles derived from transplanted mammary glands formed by recombination of prolactin receptor (Prlr) knockout or wild-type mammary epithelium with wild-type mammary stroma. Comparison with profiles derived from prolactin-treated Scp2 mammary epithelial cells produced a small set of commonly prolactin-regulated genes that included the negative regulator of cytokine signaling, Socs2 (suppressor of cytokine signaling 2), and the ets transcription factor, E74-like factor 5 (Elf5). Homozygous null mutation of Socs2 rescued the failure of lactation and reduction of mammary signal transducer and activator of transcription 5 phosphorylation that characterizes Prlr heterozygous mice, demonstrating that mammary Socs2 is a key regulator of the prolactin-signaling pathway. Reexpression of Elf5 in Prlr nullizygous mammary epithelium restored lobuloalveolar development and milk production, demonstrating that Elf5 is a transcription factor capable of substituting for prolactin signaling. Thus, Socs2 and Elf5 are key members of the set of prolactin-regulated genes that mediate prolactin-driven mammary development.
Publisher: Frontiers Media SA
Date: 23-06-2021
DOI: 10.3389/FIMMU.2021.705292
Abstract: Autoimmune Autonomic Ganglionopathy (AAG) is an uncommon immune-mediated neurological disease that results in failure of autonomic function and is associated with autoantibodies directed against the ganglionic acetylcholine receptor (gnACHR). The antibodies are routinely detected by immunoprecipitation assays, such as radioimmunoassays (RIA), although these assays do not detect all patients with AAG and may yield false positive results. Autoantibodies against the gnACHR exert pathology by receptor modulation. Flow cytometric analysis is able to determine if this has occurred, in contrast to the assays in current use that rely on immunoprecipitation. Here, we describe the first high-throughput, non-radioactive flow cytometric assay to determine autoantibody mediated gnACHR immunomodulation. Previously identified gnACHR antibody seronegative and seropositive sera s les (RIA confirmed) were blinded and obtained from the Oxford Neuroimmunology group along with s les collected locally from patients with or without AAG. All s les were assessed for the ability to cause gnACHR immunomodulation utilizing the prototypical gnACHR expressing cell line, IMR-32. Decision limits were calculated from healthy controls, and Receiver Operating Characteristic (ROC) curves were constructed after unblinding all s les. One hundred and ninety serum s les were analyzed all 182 expected negative s les (from healthy controls, autonomic disorders not thought to be AAG, other neurological disorders without autonomic dysfunction and patients with Systemic Lupus Erythematosus) were negative for immunomodulation (& %), as were the RIA negative AAG and unconfirmed AAG s les. All RIA positive s les displayed significant immunomodulation. There were no false positive or negative s les. There was perfect qualitative concordance as compared to RIA, with an Area Under ROC of 1. Detection of Immunomodulation by flow cytometry for the identification of gnACHR autoantibodies offers excellent concordance with the gnACHR antibody RIA, and overcomes many of the shortcomings of immunoprecipitation assays by directly measuring the pathological effects of these autoantibodies at the cellular level. Further work is needed to determine the correlation between the degree of immunomodulation and disease severity.
Publisher: Springer Science and Business Media LLC
Date: 16-01-2011
DOI: 10.1038/NI.1990
Abstract: Polymorphisms in the gene encoding the transcription factor IRF5 that lead to higher mRNA expression are associated with many autoimmune diseases. Here we show that IRF5 expression in macrophages was reversibly induced by inflammatory stimuli and contributed to the plasticity of macrophage polarization. High expression of IRF5 was characteristic of M1 macrophages, in which it directly activated transcription of the genes encoding interleukin 12 subunit p40 (IL-12p40), IL-12p35 and IL-23p19 and repressed the gene encoding IL-10. Consequently, those macrophages set up the environment for a potent T helper type 1 (T(H)1)-T(H)17 response. Global gene expression analysis demonstrated that exogenous IRF5 upregulated or downregulated expression of established phenotypic markers of M1 or M2 macrophages, respectively. Our data suggest a critical role for IRF5 in M1 macrophage polarization and define a previously unknown function for IRF5 as a transcriptional repressor.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 19-02-2020
DOI: 10.2215/CJN.07070619
Abstract: Survival in pediatric kidney transplant recipients has improved over the past five decades, but changes in cause-specific mortality remain uncertain. The aim of this retrospective cohort study was to estimate the associations between transplant era and overall and cause-specific mortality for child and adolescent recipients of kidney transplants. Data were obtained on all children and adolescents (aged years) who received their first kidney transplant from 1970 to 2015 from the Australian and New Zealand Dialysis and Transplant Registry. Mortality rates were compared across eras using Cox regression, adjusted for confounders. A total of 1810 recipients (median age at transplantation 14 years, 58% male, 52% living donor) were followed for a median of 13.4 years. Of these, 431 (24%) died, 174 (40%) from cardiovascular causes, 74 (17%) from infection, 50 (12%) from cancer, and 133 (31%) from other causes. Survival rates improved over time, with 5-year survival rising from 85% for those first transplanted in 1970–1985 (95% confidence interval [95% CI], 81% to 88%) to 99% in 2005–2015 (95% CI, 98% to 100%). This was primarily because of reductions in deaths from cardiovascular causes (adjusted hazard ratio [aHR], 0.25 95% CI, 0.08 to 0.68) and infections (aHR, 0.16 95% CI, 0.04 to 0.70 both for 2005–2015 compared with 1970–1985). Compared with patients transplanted 1970–1985, mortality risk was 72% lower among those transplanted 2005–2015 (aHR, 0.28 95% CI, 0.18 to 0.69), after adjusting for potential confounders. Survival after pediatric kidney transplantation has improved considerably over the past four decades, predominantly because of marked reductions in cardiovascular- and infection-related deaths.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Katrina Blazek.