ORCID Profile
0000-0002-0306-278X
Current Organisation
Department of Jobs, Precincts and Regions
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Springer Science and Business Media LLC
Date: 15-09-2021
Publisher: Wiley
Date: 11-2022
DOI: 10.1111/PAI.13890
Abstract: IgE‐mediated food allergies have been linked to suboptimal naïve CD4 T (nCD4T) cell activation in infancy, underlined by epigenetic and transcriptomic variation. Similar attenuated nCD4T cell activation in adolescents with food allergy have also been reported, but these are yet to be linked to specific epigenetic or transcriptional changes. We generated genome‐wide DNA methylation data in purified nCD4 T cells at quiescence and following activation in a cohort of adolescents (aged 10–15 years old) with peanut allergy (peanut only or peanut + ≥1 additional food allergy) (FA, n = 29), and age‐matched non‐food allergic controls (NA, n = 18). Additionally, we assessed transcriptome‐wide gene expression and cytokine production in these cells following activation. We found widespread changes in DNA methylation in both NA and FA nCD4T cells in response to activation, associated with the T cell receptor signaling pathway. Adolescents with FA exhibit unique DNA methylation signatures at quiescence and post‐activation at key genes involved in Th1/Th2 differentiation ( RUNX3 , RXRA , NFKB1A , IL4R) , including a differentially methylated region (DMR) at the TNFRSF6B promoter, linked to Th1 proliferation. Combined analysis of DNA methylation, transcriptomic data and cytokine output in the same s les identified an attenuated interferon response in nCD4T cells from FA in iduals following activation, with decreased expression of several interferon genes, including IFN‐γ and a DMR at a key downstream gene, BST2 . We find that attenuated nCD4T cell responses from adolescents with food allergy are associated with specific epigenetic variation, including disruption of interferon responses, indicating dysregulation of key immune pathways that may contribute to a persistent FA phenotype. However, we recognize the small s le size, and the consequent restraint on reporting adjusted p ‐value statistics as limitations of the study. Further study is required to validate these findings.
Publisher: Portland Press Ltd.
Date: 15-02-1997
DOI: 10.1042/BJ3220079
Abstract: The cAMP analogue 8-bromo-cAMP (8BrcAMP) inhibits granulocyte-colony-stimulating factor (G-CSF)-stimulated DNA synthesis in myeloid NFS-60 cells. We examined the effect of 8BrcAMP addition on the G-CSF-stimulated extracellular signal-related protein kinase 1 (Erk-1), p21ras and Raf-1 activation. The Erk-1 activity was not down-regulated by the increase in intracellular cAMP levels, whereas p21ras and Raf-1 activities were, suggesting that Erk-1 activity might not be dependent on upstream p21ras and/or Raf-1 activity in this system. To explore this possibility further, we sought to determine whether there were downstream substrates of Raf-1 that were distinguishable from those of Erk-1 by using two-dimensional SDS/PAGE analysis of the protein phosphorylation patterns of NFS-60 cell cytosolic extracts treated with exogenous Raf-1 or Erk-1 in the presence of [γ-32P]ATP. The two phosphorylation patterns were found to have many differences. To gain further insights into the possible relevance of these phosphorylation patterns and as an approach to exploring in more detail the inhibitory effect of 8BrcAMP, two-dimensional SDS/PAGE analysis was performed on the cytosolic extracts of 32P-labelled NFS-60 cells treated with G-CSF, in the absence or presence of 8BrcAMP. It was found that the phosphorylated proteins whose appearance was specific to the action of exogenous Raf-1 were sensitive to the action of 8BrcAMP in vivo, whereas those whose appearance was specific to the action of exogenous Erk-1 alone, or common to the actions of Raf-1 and Erk-1, were 8BrcAMP-insensitive. The results are consistent with a Raf-1-independent pathway for Erk-1 activation in G-CSF-treated myeloid cells, and a number of potential downstream substrates of these kinases have been identified for further characterization.
Publisher: Oxford University Press (OUP)
Date: 15-12-2022
DOI: 10.1093/PTJ/PZAC166
Abstract: The objectives of this study were to quantify training adherence and exercise compliance during a workplace-based strength training intervention delivered to office workers over a 12-week period and to analyze the association with clinically relevant pain reductions. A subs le of 269 participants completed a training diary from which measures of training adherence and exercise compliance (training volume, load, and progression) were calculated. The intervention consisted of 5 specific exercises targeting the neck/shoulder area (neck, shoulders, and upper back). The associations of training adherence, quitting time, and measures of exercise compliance with 3-month pain intensity (on a scale from 0 to 9) were analyzed for the whole s le, pain cases (reporting pain of ≥3 at baseline), participants attaining/not attaining clinically relevant pain reductions (≥30%), and participants meeting/not meeting per-protocol training adherence of ≥70%. Participants reported reduced pain in the neck/shoulder area after 12 weeks of specific strength training, especially women and pain cases, with the caveat that attaining clinically relevant pain reductions depended on the levels of training adherence and exercise compliance attained. Over the 12-week intervention, 30% of the participants were absent for a minimum of 2 consecutive weeks (quitting time), with the median quitting time at approximately weeks 6 to 8. With a threshold of 70% training adherence, a total training volume of approximately 11,000 kg (only in women) and progressions of 1 to 2 times baseline values were shown to be significant for clinically relevant pain reductions. Strength training produced clinically relevant reductions in neck/shoulder pain when appropriate levels of training adherence and exercise compliance were attained. This finding was particularly evident for women and pain cases. We advocate for the inclusion of both training adherence and exercise compliance measures in future studies. To optimize intervention benefits, motivational activities after 6 weeks are needed to avoid participants quitting. These data can be used to design and prescribe clinically relevant rehabilitation pain programs and interventions.
Publisher: Frontiers Media SA
Date: 19-11-2021
DOI: 10.3389/FIMMU.2021.757393
Abstract: Inflammatory memory involves the molecular and cellular ‘reprogramming’ of innate immune cells following exogenous stimuli, leading to non-specific protection against subsequent pathogen exposure. This phenomenon has now also been described in non-hematopoietic cells, such as human fetal and adult endothelial cells. In this study we mapped the cell-specific DNA methylation profile and the transcriptomic remodelling during the establishment of inflammatory memory in two distinct fetal endothelial cell types – a progenitor cell (ECFC) and a differentiated cell (HUVEC) population. We show that both cell types have a core transcriptional response to an initial exposure to a viral-like ligand, Poly(I:C), characterised by interferon responsive genes. There was also an ECFC specific response, marked by the transcription factor ELF1, suggesting a non-canonical viral response pathway in progenitor endothelial cells. Next, we show that both ECFCs and HUVECs establish memory in response to an initial viral exposure, resulting in an altered subsequent response to lipopolysaccharide. While the capacity to train or tolerize the induction of specific sets of genes was similar between the two cell types, the progenitor ECFCs show a higher capacity to establish memory. Among tolerized cellular pathways are those involved in endothelial barrier establishment and leukocyte migration, both important for regulating systemic immune-endothelial cell interactions. These findings suggest that the capacity for inflammatory memory may be a common trait across different endothelial cell types but also indicate that the specific downstream targets may vary by developmental stage.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Wiley
Date: 12-10-2009
Publisher: Springer Science and Business Media LLC
Date: 17-02-2022
DOI: 10.1186/S13148-022-01236-4
Abstract: DNA methylation is an epigenetic mark that is influenced by underlying genetic profile, environment, and ageing. In addition to X-linked DNA methylation, sex-specific methylation patterns are widespread across autosomal chromosomes and can be present from birth or arise over time. In in iduals where gender identity and sex assigned at birth are markedly incongruent, as in the case of transgender people, feminization or masculinization may be sought through gender-affirming hormone therapy (GAHT). GAHT is a cornerstone of transgender care, yet no studies to date have investigated its effect on genome-wide methylation. We profiled genome-wide DNA methylation in blood of transgender women ( n = 13) and transgender men ( n = 13) before and during GAHT (6 months and 12 months into feminizing or masculinizing hormone therapy). We identified several thousand differentially methylated CpG sites (DMPs) (Δ β ≥ 0.02, unadjusted p value 0.05) and several differentially methylated regions (DMRs) in both people undergoing feminizing and masculinizing GAHT, the vast majority of which were progressive changes over time. X chromosome and sex-specific autosomal DNA methylation patterns established in early development are largely refractory to change in association with GAHT, with only 3% affected (Δ β ≥ 0.02, unadjusted p value 0.05). The small number of sex-specific DMPs that were affected by GAHT were those that become sex-specific during the lifetime, known as sex-and-age DMPs, including DMRs in PRR4 and VMP1 genes. The GAHT-induced changes at these sex-associated probes consistently demonstrated a shift towards the methylation signature of the GAHT-naïve opposite sex, and we observed enrichment of previously reported adolescence-associated methylation changes. We provide evidence for GAHT inducing a unique blood methylation signature in transgender people. This study advances our understanding of the complex interplay between sex hormones, sex chromosomes, and DNA methylation in the context of immunity. We highlight the need to broaden the field of ‘sex-specific’ immunity beyond cisgender males and cisgender females, as transgender people on GAHT exhibit a unique molecular profile.
Publisher: Frontiers Media SA
Date: 18-12-2019
Publisher: American Society for Microbiology
Date: 06-2005
DOI: 10.1128/AAC.49.6.2322-2328.2005
Abstract: Kappacin, nonglycosylated κ-casein(106-169), is a novel antimicrobial peptide produced from κ-casein found in bovine milk. There are two major genetic forms of kappacin, A and B, and using synthetic peptides corresponding to the active region, κ-casein(138-158), of these forms, we have shown that the Asp 148 to Ala 148 substitution is responsible for the lesser antibacterial activity of κ-casein-B(106-169). Kappacin was shown to have membranolytic action at concentrations above 30 μM at acidic pH when tested against artificial liposomes. There was little membranolytic activity at neutral pH, which is consistent with the lack of antibacterial activity of kappacin against Streptococcus mutans at this pH. Kappacin specifically bound two zinc or calcium ions per mol, and this binding enhanced antibacterial activity at neutral pH. Nuclear magnetic resonance analysis indicated that a κ-casein-A(138-158) synthetic peptide undergoes a conformational change in the presence of the membrane solvent trifluoroethanol and excess alent metal ions. This change in conformation is presumably responsible for the increase in antibacterial activity of kappacin detected in the presence of excess zinc or calcium ions at neutral pH. When tested against the oral bacterial pathogen S. mutans cultured as a biofilm in a constant-depth film fermentor, a preparation of 10 g/liter kappacin and 20 mM ZnCl 2 reduced bacterial viability by 3 log 10 and suppressed recovery of viability. In contrast 20 mM ZnCl 2 alone reduced bacterial viability by ≈1 log 10 followed by rapid recovery. In conclusion, kappacin has a membranolytic, antibacterial effect that is enhanced by the presence of alent cations.
Publisher: American Society for Microbiology
Date: 03-2010
DOI: 10.1128/JB.01211-09
Abstract: Porphyromonas gingivalis is a late-colonizing bacterium of the subgingival dental plaque biofilm associated with periodontitis. Two P. gingivalis genes, fimR and fimS , are predicted to encode a two-component signal transduction system comprising a response regulator (FimR) and a sensor histidine kinase (FimS). In this study, we show that fimS and fimR , although contiguous on the genome, are not part of an operon. We inactivated fimR and fimS in both the afimbriated strain W50 and the fimbriated strain ATCC 33277 and demonstrated that both mutants formed significantly less biofilm than their respective wild-type strains. Quantitative reverse transcription-real-time PCR showed that expression of fimbriation genes was reduced in both the fimS and fimR mutants of strain ATCC 33277. The mutations had no effect, in either strain, on the P. gingivalis growth rate or on the response to hydrogen peroxide or growth at pH 9, at 41°C, or at low hemin availability. Transcriptome analysis using DNA microarrays revealed that inactivation of fimS resulted in the differential expression of 10% of the P. gingivalis genome ( .5-fold P 0.05). Notably genes encoding seven different transcriptional regulators, including the fimR gene and three extracytoplasmic sigma factor genes, were differentially expressed in the fimS mutant.
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.JDENT.2019.103225
Abstract: To determine if chewing gum containing casein phosphopeptide stabilised amorphous calcium phosphate (CPP-ACP) promoted an increase in the abundance of Streptococcus sanguinis and other species associated with dental health in supragingival plaque in a clinical study. Nineteen participants were recruited for a three-leg cross-over, randomised, controlled clinical trial. Participants chewed a sugar-free gum with or without CPP-ACP six times daily for 20 min over two weeks. The study also involved no gum chewing (no gum) for the same two week period. Participants were randomly assigned to one of the test gums or no gum for each intervention period. Participants abstained from oral hygiene and had washout periods of two weeks between intervention periods. After each intervention period, supragingival plaque was collected and analysed for bacterial composition by sequencing the V4 variable region of the 16S rRNA gene. Data were analysed using a linear mixed model. The CPP-ACP gum intervention produced a significant (p < 0.01) increase in the proportions of S. sanguinis (112%), as well as the commensal species Rothia dentocariosa (127%), Corynebacterium durum (80%) and Streptococcus mitis (55%) when compared with the no gum intervention. All the species that were promoted by the CPP-ACP gum are known to possess one or both of the alkali-producing enzymes arginine deiminase and nitrate reductase. This clinical study demonstrated that chewing a sugar-free gum containing CPP-ACP promoted prebiosis by significantly increasing the proportion of S. sanguinis and other health-associated bacterial species in supragingival plaque. Regular chewing of CPP-ACP sugar-free gum increases the proportions of health-associated commensal species in supragingival plaque to promote prebiosis and oral homeostasis.
Publisher: American Society for Microbiology
Date: 12-2001
DOI: 10.1128/IAI.69.12.7527-7534.2001
Abstract: Extracellular Arg-x- and Lys-x-specific cysteine proteinases are considered important virulence factors and pathogenic markers for Porphyromonas gingivalis , a bacterium implicated as a major etiological agent of chronic periodontitis. Three genes. rgpA , rgpB, and kgp, encode an Arg-x-specific proteinase and adhesins (RgpA), an Arg-x-specific proteinase (RgpB), and a Lys-x-specific proteinase and adhesins (Kgp), respectively. The contribution to pathogenicity of each of the proteinase genes of P. gingivalis W50 was investigated in a murine lesion model using isogenic mutants lacking RgpA, RgpB, and Kgp. Whole-cell Arg-x-specific proteolytic activity of both the RgpA − and RgpB − isogenic mutants was significantly reduced (3- to 4-fold) relative to that of the wild-type W50. However, for the Kgp − isogenic mutant, whole-cell Arg-x activity was similar to that of the wild-type strain. Whole-cell Lys-x proteolytic activity of the RgpA − and RgpB − mutants was not significantly different from that of wild-type W50, whereas the Kgp − mutant was devoid of Lys-x whole-cell proteolytic activity. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot analysis using proteinase-specific antibodies of cell sonicates of the wild-type and mutant strains showed that the proteinase catalytic domain of each of the mutants was not expressed. This analysis further showed that RgpB appeared as 72- and 80-kDa bands, and the catalytic domains of RgpA and Kgp appeared as processed 45-kDa and 48-kDa bands, respectively. In the murine lesion model, mice were challenged with three doses of each mutant and wild-type strain. At the lower dose (3.0 × 10 9 viable-cells), no lesions were recorded for each of the mutants, whereas wild-type W50 induced large ulcerative lesions. At a dose of 6.0 × 10 9 viable-cells, all the mice challenged with the wild-type strain died, whereas mice challenged with the RgpA − and RgpB − isogenic mutants did not die but developed lesions. Mice challenged with the Kgp − isogenic mutant at this dose did not develop lesions. At a 1.2 × 10 10 viable-cell dose, only 40% of mice challenged with the Kgp − mutant developed lesions, and these lesions were significantly smaller than lesions induced by the wild-type strain at the 3.0 × 10 9 viable-cell dose. All the mice challenged with the RgpA − mutant died at the 1.2 × 10 10 viable-cell dose, whereas only 20% died when challenged with the RgpB − mutant at this dose. Wild-type phenotype was restored to the RgpB − mutant by complementation with plasmid pNJR12:: rgpB containing the rgpB gene. There was no difference between the pNJR12:: rgpB -complemented RgpB − mutant and the wild-type W50 strain in whole-cell Arg-x activity, protein profile, or virulence in the murine lesion model. These results show that the three proteinases, RgpA, RgpB, and Kgp, all contributed to virulence of P. gingivalis W50 in the murine lesion model and that the order in which they contributed was Kgp ≫ RgpB ≥ RgpA.
Publisher: SAGE Publications
Date: 22-09-2020
Abstract: Coronavirus (COVID-19) has led to high levels of psychological distress in the community. This study aimed to examine whether emergency departments (EDs) also recorded a rise in mental health presentations. Changes in the number, and type, of mental health presentations to Western Australia EDs were examined between January and May 2020, and compared to 2019. Data showed an unexpected decrease in the number of mental health presentations, compared to 2019, which was temporally coincident with the rise in local COVID-19 cases. Presentations for anxiety and panic symptoms, and social and behavioural issues, increased by 11.1% and 6.5%, respectively, but suicidal and self-harm behaviours decreased by 26%. A rise in local COVID-19 cases was associated with a decrease in mental health presentations to EDs. This has important implications for the planning and provision of healthcare services in the current pandemic.
Publisher: S. Karger AG
Date: 2012
DOI: 10.1159/000337240
Abstract: Remineralisation has been shown to be an effective mechanism of preventing the progression of enamel caries. The aim of this double-blind, randomised, cross-over in situ study was to compare enamel remineralisation by chewing sugar-free gum with or without casein phosphopeptide amorphous calcium phosphate (CPP-ACP) where the enamel lesions were exposed to dietary intake and some were covered with gauze to promote plaque formation. Participants wore removable palatal appliances containing 3 recessed enamel half-slabs with subsurface lesions covered with gauze and 3 without gauze. Mineral content was measured by transverse microradiography, and plaque composition was analysed by real-time polymerase chain reaction. For both the gauze-free and gauze-covered lesions, the greatest amount of remineralisation was produced by the CPP-ACP sugar-free gum, followed by the gum without CPP-ACP and then the no-gum control. Recessing the enamel in the appliance allowed plaque accumulation without the need for gauze. There was a trend of less remineralisation and greater variation in mineral content for the gauze-covered lesions. The cell numbers of total bacteria and streptococci were slightly higher in the plaque from the gauze-covered enamel for 2 of the 3 treatment legs however, there was no significant difference in i Streptococcus mutans /i cell numbers. In conclusion, chewing sugar-free gum containing CPP-ACP promoted greater levels of remineralisation than a sugar-free gum without CPP-ACP or a no-gum control using an in situ remineralisation model including dietary intake irrespective of whether gauze was used to promote plaque formation or not.
Publisher: SAGE Publications
Date: 09-01-2022
DOI: 10.1177/10398562211037334
Abstract: Aripiprazole is often prescribed to young people, although there remain unanswered questions about its effects on weight gain. This study undertook a meta-analysis of weight gain occurring in young people with early psychosis who were prescribed aripiprazole. A systematic search was conducted for studies reporting on aripiprazole and weight change in young people with a psychotic disorder. A meta-analysis integrated the data into an estimate of effect size. Eleven studies met the inclusion criteria amounting to 886 participants (mean age 18 years). The results showed significant weight gain averaging 2.7 kg. These increases were associated with a longer duration of exposure to aripiprazole but not a higher dosage. The results highlight the importance of regular patient monitoring and the early implementation of interventions to manage antipsychotic-related weight gain.
Publisher: American Society for Microbiology
Date: 2014
DOI: 10.1128/AAC.01375-13
Abstract: Bacterial pathogens commonly associated with chronic periodontitis are the spirochete Treponema denticola and the Gram-negative, proteolytic species Porphyromonas gingivalis and Tannerella forsythia . These species rely on complex anaerobic respiration of amino acids, and the anthelmintic drug oxantel has been shown to inhibit fumarate reductase (Frd) activity in some pathogenic bacteria and inhibit P. gingivalis homotypic biofilm formation. Here, we demonstrate that oxantel inhibited P. gingivalis Frd activity with a 50% inhibitory concentration (IC 50 ) of 2.2 μM and planktonic growth of T. forsythia with a MIC of 295 μM, but it had no effect on the growth of T. denticola . Oxantel treatment caused the downregulation of six P. gingivalis gene products and the upregulation of 22 gene products. All of these genes are part of a regulon controlled by heme availability. There was no large-scale change in the expression of genes encoding metabolic enzymes, indicating that P. gingivalis may be unable to overcome Frd inhibition. Oxantel disrupted the development of polymicrobial biofilms composed of P. gingivalis , T. forsythia , and T. denticola in a concentration-dependent manner. In these biofilms, all three species were inhibited to a similar degree, demonstrating the synergistic nature of biofilm formation by these species and the dependence of T. denticola on the other two species. In a murine alveolar bone loss model of periodontitis oxantel addition to the drinking water of P. gingivalis -infected mice reduced bone loss to the same level as the uninfected control.
Publisher: SAGE Publications
Date: 12-11-2020
Abstract: Ketamine is a potential rapid-acting treatment for depression. Studies have suggested that the side effects are minimal and temporary, but the psychotic symptom side effects have yet to be fully examined. This study investigated whether ketamine infusion in the treatment of mood disorders is associated with increases in positive symptoms and whether these symptom effects endure over time. A systematic review and meta-analysis of studies of ketamine in the treatment of depression. Embase and Medline databases were searched for studies including (a) participants with major affective disorders, (b) 0.4 or 0.5 mg intravenously administered ketamine, (c) measurement of positive symptoms using BPRS+, and (d) a within-subject repeated-measures design with participants serving as their own baseline. Seventeen studies met the inclusion criteria, comprising 458 participants. The meta-analyses examined symptom change occurring within the first 4 h, after 1 day, and after 3 days. Results showed significant BPRS+ increases within the first 30–60 min in 72% of studies, followed by a return to baseline levels. Peak symptom change occurred within the first hour post infusion. There are limited data to determine if ketamine is safe in the longer term, but there were no indications that psychotic symptoms re-occurred after the first hour and in the days following administration.
Publisher: American Society for Microbiology
Date: 05-2002
DOI: 10.1128/IAI.70.5.2480-2486.2002
Abstract: A major virulence factor of Porphyromonas gingivalis is the extracellular noncovalently associated complexes of Arg-X- and Lys-X-specific cysteine proteinases and adhesins designated the RgpA-Kgp complexes. In this study we investigated the ability of RgpA-Kgp as an immunogen to protect against P. gingivalis -induced periodontal bone loss in the rat. Specific-pathogen-free Sprague-Dawley rats were immunized with either formalin-killed whole P. gingivalis ATCC 33277 cells with incomplete Freund's adjuvant, RgpA-Kgp with incomplete Freund's adjuvant, or incomplete Freund's adjuvant alone. The animals were then challenged by oral inoculation with live P. gingivalis ATCC 33277 cells. Marked periodontal bone loss was observed in animals immunized with incomplete Freund's adjuvant alone this bone loss was significantly ( P 0.05) greater than that detected in animals immunized with formalin-killed whole cells or RgpA-Kgp or in unchallenged animals. There was no significant difference in periodontal bone loss between animals immunized with formalin-killed whole cells and those immunized with RgpA-Kgp. The bone loss in these animals was also not significantly different from that in unchallenged animals. DNA probe analysis of subgingival plaque s les showed that 100% of the animals immunized with incomplete Freund's adjuvant alone and challenged with P. gingivalis ATCC 33277 were positive for the bacterium. However, P. gingivalis ATCC 33277 could not be detected in subgingival plaque s les from animals immunized with formalin-killed whole cells or with RgpA-Kgp. Immunization with formalin-killed whole cells or RgpA-Kgp induced a high-titer serum immunoglobulin G2a response. Western blot analysis of RgpA-Kgp using pooled protective antisera taken from rats immunized with RgpA-Kgp revealed immunodominant bands at 44, 39, and 27 kDa. In conclusion, immunization with RgpA-Kgp restricted colonization by P. gingivalis and periodontal bone loss in the rat.
Publisher: Elsevier BV
Date: 05-1999
Publisher: Elsevier BV
Date: 07-1996
Abstract: The addition of cAMP inhibits G-CSF-mediated proliferation and suppresses pRB phosphorylation in NFS-60 cells. We show that the latter could be attributed to different effects of cAMP in these cells: (i) down-regulation of the levels of cyclins D2 and D3, and cdk4, and (ii) induction of the p27Kip1 inhibitor of cdk4.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 05-08-2022
Abstract: Trained immunity describes the capacity of innate immune cells to develop heterologous memory in response to certain exogenous exposures. This phenomenon mediates, at least in part, the beneficial off-target effects of the BCG vaccine. Using an in vitro model of trained immunity, we show that BCG exposure induces a persistent change in active histone modifications, DNA methylation, transcription, and adenosine-to-inosine RNA modification in human monocytes. By profiling DNA methylation of circulating monocytes from infants in the MIS BAIR clinical trial, we identify a BCG-associated DNA methylation signature that persisted more than 12 months after neonatal BCG vaccination. Genes associated with this epigenetic signature are involved in viral response pathways, consistent with the reported off-target protection against viral infections in neonates, adults, and the elderly. Our findings indicate that the off-target effects of BCG in infants are accompanied by epigenetic remodeling of circulating monocytes that lasts more than 1 year.
Publisher: Informa UK Limited
Date: 2020
Publisher: Springer Science and Business Media LLC
Date: 24-12-2019
DOI: 10.1038/S41598-019-56233-0
Abstract: Human microbiomes are predicted to assemble in a reproducible and ordered manner yet there is limited knowledge on the development of the complex bacterial communities that constitute the oral microbiome. The oral microbiome plays major roles in many oral diseases including early childhood caries (ECC), which afflicts up to 70% of children in some countries. Saliva contains oral bacteria that are indicative of the whole oral microbiome and may have the ability to reflect the dysbiosis in supragingival plaque communities that initiates the clinical manifestations of ECC. The aim of this study was to determine the assembly of the oral microbiome during the first four years of life and compare it with the clinical development of ECC. The oral microbiomes of 134 children enrolled in a birth cohort study were determined at six ages between two months and four years-of-age and their mother’s oral microbiome was determined at a single time point. We identified and quantified 356 operational taxonomic units (OTUs) of bacteria in saliva by sequencing the V4 region of the bacterial 16S RNA genes. Bacterial alpha ersity increased from a mean of 31 OTUs in the saliva of infants at 1.9 months-of-age to 84 OTUs at 39 months-of-age. The oral microbiome showed a distinct shift in composition as the children matured. The microbiome data were compared with the clinical development of ECC in the cohort at 39, 48, and 60 months-of-age as determined by ICDAS-II assessment. Streptococcus mutans was the most discriminatory oral bacterial species between health and current disease, with an increased abundance in disease. Overall our study demonstrates an ordered temporal development of the oral microbiome, describes a limited core oral microbiome and indicates that saliva testing of infants may help predict ECC risk.
Publisher: Mary Ann Liebert Inc
Date: 10-1996
Abstract: The myeloid cell line, NFS-60, is dependent on granulocyte colony-stimulating factor (G-CSF) or interleukin-3 (IL-3) for survival and growth. Long-term G-CSF-dependent proliferation was found to be completely inhibited by interferon-gamma (IFN-gamma), cyclic AMP, and dimethylamiloride and partially inhibited by IFN-alpha and lipopolysaccharide. With the exception of IFN-gamma, these agents exhibited a corresponding pattern of inhibition of DNA synthesis in quiescent NFS-60 cells stimulated with G-CSF. IFN-gamma was only a weak inhibitor of DNA synthesis, suggesting that it may act at a later stage to block proliferation. The addition of G-CSF to NFS-60 cells resulted in phosphorylation of the retinoblastoma protein (pRB) and activation of E2F DNA binding activity. The inhibitors were found to suppress the phosphorylation of pRB, lead to the production of higher order E2F complexes, and suppress the expression of c-myc and proliferating cell nuclear antigen (PCNA) to an extent that correlated with their ability to block DNA synthesis. These findings are consistent with the notion that the ratio of free/bound E2F binding activity is critical in controlling cell cycle progression through G1 to S-phase in these cells.
Publisher: Elsevier BV
Date: 07-2005
Publisher: Springer Science and Business Media LLC
Date: 09-03-2016
Publisher: SAGE Publications
Date: 04-11-2018
Abstract: Dental caries is associated with plaque dysbiosis, leading to an increase in the proportions of acidogenic and aciduric bacteria at the expense of alkali-generating commensal species. Stannous fluoride (SnF 2 ) slows the progression of caries by remineralization of early lesions but has also been suggested to inhibit glycolysis of aciduric bacteria. Casein phosphopeptide–amorphous calcium phosphate (CPP-ACP) promotes fluoride remineralization by acting as a salivary biomimetic that releases bioavailable calcium and phosphate ions, and the peptide complex has also been suggested to modify plaque composition. We developed a polymicrobial biofilm model of caries using 6 bacterial species representative of supragingival plaque that were cultured on sound human enamel and pulsed with sucrose 4 times a day to produce a high cariogenic challenge. We used this model to explore the mechanisms of action of SnF 2 and CPP-ACP. Bacterial species in the biofilms were enumerated with 16S rRNA gene sequence analyses, and mineral loss and lesion formation were determined in the enamel directly under the polymicrobial biofilms via transverse microradiography. The model tested the twice-daily addition of SnF 2 , CPP-ACP, or both. SnF 2 treatment reduced demineralization by 50% and had a slight effect on the composition of the polymicrobial biofilm. CPP-ACP treatment caused a similar inhibition of enamel demineralization (50%), a decrease in Actinomyces naeslundii and Lactobacillus casei abundance, and an increase in Streptococcus sanguinis and Fusobacterium nucleatum abundance in the polymicrobial biofilm. A combination of SnF 2 and CPP-ACP resulted in a greater suppression of the acidogenic and aciduric bacteria and a significant 72% inhibition of enamel demineralization.
Publisher: Mary Ann Liebert Inc
Date: 02-1997
Abstract: Like other cytokines, granulocyte colony-stimulating factor (G-CSF) activates a complex array of signal transduction pathways involving multiple kinases and phosphatases. We sought to identify phosphoproteins specific to G-CSF signaling. Using 2D-SDS-PAGE of 32P-labeled cytosolic extracts, we compared phosphoprotein patterns of NFS-60 cells treated with G-CSF or interleukin-3 (IL-3). We also compared the patterns found after stimulation of M-NFS-60 cells with macrophage-CSF (M-CSF). A large number of phosphoproteins were found that were specific for the G-CSF response. Their distribution contrasted with that of Erk-1-related spots, identified by Western blotting, which were common to G-CSF, M-CSF (CSF-1), and IL-3 responses. The activation of Erk-1 by these cytokines was confirmed by in vitro kinase assays. The 2D-SDS-PAGE approach was also used to demonstrate that a series of unrelated G1 phase inhibitors of the mitogenic action of G-CSF elicited both common and erse protein phosphorylation changes in G-CSF-treated NFS-60 cells that were not dependent on the inhibition of Erk-1 activity, as demonstrated by both in vitro kinase assays and 2D-SDS-PAGE. Therefore, 2D-SDS-PAGE has potential to dissect both the signal transduction pathways lying downstream of the G-CSF receptor (and of the receptors for other CSFs) and also the site of action of proliferation inhibitors.
Location: No location found
No related grants have been discovered for Brigitte Hoffmann.