ORCID Profile
0000-0001-6106-3425
Current Organisations
Griffith University
,
Bond University
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: Wiley
Date: 2007
DOI: 10.1113/EXPPHYSIOL.2006.035568
Abstract: While inhibition of ischaemic contracture was one of the first documented cardioprotective actions of exogenously applied adenosine, it is not known whether this is a normal function of endogenous adenosine generated during ischaemic stress. Additionally, the relevance of delayed contracture to postischaemic outcome is unclear. We tested the ability of endogenous versus exogenous adenosine to modify contracture (and postischaemic outcomes) in C57/Bl6 mouse hearts. During ischaemia, untreated hearts developed peak contracture (PC) of 85 +/- 5 mmHg at 8.9 +/- 0.8 min, with time to reach 20 mmHg (time to onset of contracture TOC) of 4.4 +/- 0.3 min. Adenosine (50 microm) delayed TOC to 6.7 +/- 0.6 min, as did pretreatment with 10 microm 2-chloroadenosine (7.2 +/- 0.5 min) or 50 nm of A(1) adenosine receptor (AR) agonist N(6)-cyclohexyladenosine (CHA) (6.7 +/- 0.3 min), but not A(2A)AR or A(3)AR agonists (20 nm 2-[4-(2-carboxyethyl) phenethylamino]-5' N-methylcarboxamidoadenosine (CGS21680) or 150 nm 2-chloro-N(6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA), respectively). Adenosinergic contracture inhibition was eliminated by A(1)AR gene knockout (KO), mimicked by A(1)AR overexpression, and was associated with preservation of myocardial [ATP]. This adenosine-mediated inhibition of contracture was, however, only evident after prolonged (10 or 15 min) and not brief (3 min) pretreatment. Ischaemic contracture was also insensitive to endogenously generated adenosine, since A(1)AR KO, and non-selective and A(1)AR-selective antagonists (50 microm 8-sulphophenyltheophylline and 150 nm 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX), respectively), all failed to alter intrinsic contracture development. Finally, delayed contracture with A(1)AR agonism/overexpression or ischaemic 2,3-butanedione monoxime (BDM 5 microm to target Ca(2+) cross-bridge formation) was linked to enhanced postischaemic outcomes. In summary, adenosinergic inhibition of contracture is solely A(1)AR mediated the response is 'supraphysiological', evident only with significant periods of pre-ischaemic AR agonism (or increased A(1)AR density) and ischaemic contracture appears insensitive to locally generated adenosine, potentially owing to the rapidity of contracture development versus the finite time necessary for expression of AR-mediated cardioprotection.
Publisher: Elsevier BV
Date: 2020
Publisher: Springer Science and Business Media LLC
Date: 15-09-2027
DOI: 10.1186/S12929-021-00733-7
Abstract: Low cardiorespiratory fitness (V̇O 2peak ) is highly associated with chronic disease and mortality from all causes. Whilst exercise training is recommended in health guidelines to improve V̇O 2peak , there is considerable inter-in idual variability in the V̇O 2peak response to the same dose of exercise. Understanding how genetic factors contribute to V̇O 2peak training response may improve personalisation of exercise programs. The aim of this study was to identify genetic variants that are associated with the magnitude of V̇O 2 peak response following exercise training. Participant change in objectively measured V̇O 2 peak from 18 different interventions was obtained from a multi-centre study (Predict-HIIT). A genome-wide association study was completed (n = 507), and a polygenic predictor score (PPS) was developed using alleles from single nucleotide polymorphisms (SNPs) significantly associated ( P 1 × 10 –5 ) with the magnitude of V̇O 2 peak response. Findings were tested in an independent validation study (n = 39) and compared to previous research. No variants at the genome-wide significance level were found after adjusting for key covariates (baseline V̇O 2 peak , in idual study, principal components which were significantly associated with the trait). A Quantile–Quantile plot indicates there was minor inflation in the study. Twelve novel loci showed a trend of association with V̇O 2 peak response that reached suggestive significance ( P 1 × 10 –5 ). The strongest association was found near the membrane associated guanylate kinase, WW and PDZ domain containing 2 ( MAGI2 ) gene (rs6959961, P = 2.61 × 10 –7 ). A PPS created from the 12 lead SNPs was unable to predict V̇O 2 peak response in a tenfold cross validation, or in an independent (n = 39) validation study ( P 0.1). Significant correlations were found for beta coefficients of variants in the Predict-HIIT ( P 1 × 10 –4 ) and the validation study ( P × 10 –6 ), indicating that general effects of the loci exist, and that with a higher statistical power, more significant genetic associations may become apparent. Ongoing research and validation of current and previous findings is needed to determine if genetics does play a large role in V̇O 2 peak response variance, and whether genomic predictors for V̇O 2 peak response trainability can inform evidence-based clinical practice. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR), Trial Id: ACTRN12618000501246, Date Registered: 06/04/2018, www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374601& isReview=true .
Publisher: S. Karger AG
Date: 2009
DOI: 10.1159/000230992
Publisher: Wiley
Date: 30-06-2021
DOI: 10.1002/JCSM.12741
Abstract: Knowledge of age‐related DNA methylation changes in skeletal muscle is limited, yet this tissue is severely affected by ageing in humans. We conducted a large‐scale epigenome‐wide association study meta‐analysis of age in human skeletal muscle from 10 studies (total n = 908 muscle methylomes from men and women aged 18–89 years old). We explored the genomic context of age‐related DNA methylation changes in chromatin states, CpG islands, and transcription factor binding sites and performed gene set enrichment analysis. We then integrated the DNA methylation data with known transcriptomic and proteomic age‐related changes in skeletal muscle. Finally, we updated our recently developed muscle epigenetic clock ( ackages/release/bioc/html/MEAT.html ). We identified 6710 differentially methylated regions at a stringent false discovery rate .005, spanning 6367 unique genes, many of which related to skeletal muscle structure and development. We found a strong increase in DNA methylation at Polycomb target genes and bivalent chromatin domains and a concomitant decrease in DNA methylation at enhancers. Most differentially methylated genes were not altered at the mRNA or protein level, but they were nonetheless strongly enriched for genes showing age‐related differential mRNA and protein expression. After adding a substantial number of s les from five datasets (+371), the updated version of the muscle clock (MEAT 2.0, total n = 1053 s les) performed similarly to the original version of the muscle clock (median of 4.4 vs. 4.6 years in age prediction error), suggesting that the original version of the muscle clock was very accurate. We provide here the most comprehensive picture of DNA methylation ageing in human skeletal muscle and reveal widespread alterations of genes involved in skeletal muscle structure, development, and differentiation. We have made our results available as an open‐access, user‐friendly, web‐based tool called MetaMeth ( sarah‐voisin.shinyapps.io/MetaMeth/ ).
Publisher: Inter-Research Science Center
Date: 25-07-2006
DOI: 10.3354/DAO071149
Abstract: Chytridiomycosis is an emerging infectious disease of hibians associated with mass mortalities and population declines worldwide. Recent technological advances have resulted in a highly sensitive, non-invasive technique for diagnosing the disease based on a quantitative (real-time) polymerase chain reaction (qPCR) assay. The qPCR assay yields the most accurate and informative data of any available detection technique. However, due to the relatively high costs involved, it has yet to attain widespread use by chytridiomycosis researchers. Using the results of a disease survey of 467 wild frogs from eastern Queensland, Australia, we examine the necessity of triplicate assays in qPCR detection of chytridiomycosis. We describe a singlicate qPCR assay that can be used to substantially decrease costs, with no significant decrease in sensitivity. We also demonstrate that detection of chytridiomycosis by use of the conventional PCR assay may lead to appreciable underestimations in disease prevalence. We recommend that hibian disease researchers adopt the singlicate qPCR assay as the primary means of chytridiomycosis detection.
Publisher: Springer Science and Business Media LLC
Date: 24-04-2011
DOI: 10.1007/S00414-010-0455-3
Abstract: DNA becomes progressively more fragmented as biological tissue degrades resulting in decreasing ability to gain a complete DNA profile. Successful identification of s les exhibiting very high levels of DNA degradation may be complicated by presenting in minute quantities. The industry standard method for human DNA identification utilising short tandem repeats (STR) may produce partial or no DNA profile with such s les. We report a comparative study of genotyping using STRs, mini-STRs and single nucleotide polymorphisms (SNPs) with template at different levels of degradation in varying amounts. Two methods of assessing quantity and quality of a DNA s le prior to genotyping were investigated. The QIAxcel capillary gel electrophoresis system provided a rapid, cost effective screening method for assessing s le quality. A real-time quantitative PCR (qPCR) assay was able to simultaneously quantify total human DNA, male DNA, DNA degradation and PCR inhibition. The extent of DNA degradation could be assessed with reasonable accuracy to 62.5 pg and genomic targets could be quantified to a lower limit of 15.6 pg. The qPCR assay was able to detect male DNA to a lower limit of 20 pg in a 1:1,000 background of female DNA. By considering the amount of DNA and the degradation ratio of a s le, a general prediction of genotyping success using AmpFlSTR® Profiler Plus®, MiniFiler™ kits and SNP analysis can be made. The results indicate mini-STRs and SNP markers are usually more successful in typing degraded s les and in cases of extreme DNA degradation (≤200 bp) and template amounts below 250 pg, mini-STR and SNP analysis yielded significantly more complete profiles and lower match probabilities than corresponding STR profiles.
Publisher: Public Library of Science (PLoS)
Date: 21-08-2013
Publisher: Elsevier BV
Date: 06-2021
Publisher: Springer Science and Business Media LLC
Date: 2010
Publisher: American Medical Association (AMA)
Date: 07-2003
Publisher: Springer Science and Business Media LLC
Date: 16-04-2013
Publisher: Wiley
Date: 02-05-2023
DOI: 10.1111/ACEL.13859
Abstract: Exercise training prevents age‐related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late‐life exercise mitigates epigenetic aging in rodent muscle. Whether exercise training can decelerate, or reverse epigenetic aging in humans is unknown. Here, we performed a powerful meta‐analysis of the methylome and transcriptome of an unprecedented number of human skeletal muscle s les ( n = 3176). We show that: (1) in iduals with higher baseline aerobic fitness have younger epigenetic and transcriptomic profiles, (2) exercise training leads to significant shifts of epigenetic and transcriptomic patterns toward a younger profile, and (3) muscle disuse “ages” the transcriptome. Higher fitness levels were associated with attenuated differential methylation and transcription during aging. Furthermore, both epigenetic and transcriptomic profiles shifted toward a younger state after exercise training interventions, while the transcriptome shifted toward an older state after forced muscle disuse. We demonstrate that exercise training targets many of the age‐related transcripts and DNA methylation loci to maintain younger methylome and transcriptome profiles, specifically in genes related to muscle structure, metabolism, and mitochondrial function. Our comprehensive analysis will inform future studies aiming to identify the best combination of therapeutics and exercise regimes to optimize longevity.
Publisher: Cold Spring Harbor Laboratory
Date: 29-12-2022
DOI: 10.1101/2022.12.27.522062
Abstract: Exercise training prevents age-related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late-life exercise mitigates epigenetic aging in rodent muscle. Whether exercise training can decelerate, or reverse epigenetic aging in humans is unknown. Here, we performed a powerful meta-analysis of the methylome and transcriptome of an unprecedented number of human skeletal muscle s les (n = 3,176). We show that: 1) in iduals with higher baseline aerobic fitness have younger epigenetic and transcriptomic profiles, 2) exercise training leads to significant shifts of epigenetic and transcriptomic patterns towards a younger profile, and 3) muscle disuse “ages” the transcriptome. Higher fitness levels were associated with attenuated differential methylation and transcription during aging. Furthermore, both epigenetic and transcriptomic profiles shifted towards a younger state after exercise training interventions, while the transcriptome shifted towards an older state after forced muscle disuse. We demonstrate that exercise training targets many of the age-related transcripts and DNA methylation loci to maintain younger methylome and transcriptome profiles, specifically in genes related to muscle structure, metabolism and mitochondrial function. Our comprehensive analysis will inform future studies aiming to identify the best combination of therapeutics and exercise regimes to optimize longevity.
Publisher: Springer Science and Business Media LLC
Date: 03-11-2021
DOI: 10.1186/S13148-021-01188-1
Abstract: Nearly all human complex traits and diseases exhibit some degree of sex differences, with epigenetics being one of the main contributing factors. Various tissues display sex differences in DNA methylation however, this has not yet been explored in skeletal muscle, despite skeletal muscle being among the tissues with the most transcriptomic sex differences. For the first time, we investigated the effect of sex on autosomal DNA methylation in human skeletal muscle across three independent cohorts (Gene SMART, FUSION, and GSE38291) using a meta-analysis approach, totalling 369 human muscle s les (222 males and 147 females), and integrated this with known sex-biased transcriptomics. We found 10,240 differentially methylated regions (DMRs) at FDR 0.005, 94% of which were hypomethylated in males, and gene set enrichment analysis revealed that differentially methylated genes were involved in muscle contraction and substrate metabolism. We then investigated biological factors underlying DNA methylation sex differences and found that circulating hormones were not associated with differential methylation at sex-biased DNA methylation loci however, these sex-specific loci were enriched for binding sites of hormone-related transcription factors (with top TFs including androgen ( AR ), estrogen ( ESR1 ), and glucocorticoid ( NR3C1 ) receptors). Fibre type proportions were associated with differential methylation across the genome, as well as across 16% of sex-biased DNA methylation loci (FDR 0.005). Integration of DNA methylomic results with transcriptomic data from the GTEx database and the FUSION cohort revealed 326 autosomal genes that display sex differences at both the epigenome and transcriptome levels. Importantly, transcriptional sex-biased genes were overrepresented among epigenetic sex-biased genes ( p value = 4.6e−13), suggesting differential DNA methylation and gene expression between male and female muscle are functionally linked. Finally, we validated expression of three genes with large effect sizes ( FOXO3A , ALDH1A1 , and GGT7 ) in the Gene SMART cohort with qPCR. GGT7 , involved in antioxidant metabolism, displays male-biased expression as well as lower methylation in males across the three cohorts. In conclusion, we uncovered 8420 genes that exhibit DNA methylation differences between males and females in human skeletal muscle that may modulate mechanisms controlling muscle metabolism and health.
Publisher: InTech
Date: 13-03-2013
DOI: 10.5772/53440
Publisher: Elsevier BV
Date: 11-2003
DOI: 10.1016/J.MOLBRAINRES.2003.09.008
Abstract: Multiple sclerosis (MS) is a complex autoimmune disorder of the CNS with both genetic and environmental contributing factors. Clinical symptoms are broadly characterized by initial onset, and progressive debilitating neurological impairment. In this study, RNA from MS chronic active and MS acute lesions was extracted, and compared with patient matched normal white matter by fluorescent cDNA microarray hybridization analysis. This resulted in the identification of 139 genes that were differentially regulated in MS plaque tissue compared to normal tissue. Of these, 69 genes showed a common pattern of expression in the chronic active and acute plaque tissues investigated (Pvalue or = 1.5-fold) in either acute or chronic active tissues. These results included known markers of MS such as the myelin basic protein (MBP) and glutathione S-transferase (GST) M1, nerve growth factors, such as nerve injury-induced protein 1 (NINJ1), X-ray and excision DNA repair factors (XRCC9 and ERCC5) and X-linked genes such as the ribosomal protein, RPS4X. Primers were then designed for seven array-selected genes, including transferrin (TF), superoxide dismutase 1 (SOD1), glutathione peroxidase 1 (GPX1), GSTP1, crystallin, alpha-B (CRYAB), phosphomannomutase 1 (PMM1) and tubulin beta-5 (TBB5), and real time quantitative (Q)-PCR analysis was performed. The results of comparative Q-PCR analysis correlated significantly with those obtained by array analysis (r=0.75, Pvalue<0.01, by Pearson's bivariate correlation). Both chronic active and acute plaques shared the majority of factors identified suggesting that quantitative, rather than gross qualitative differences in gene expression pattern may define the progression from acute to chronic active plaques in MS.
Publisher: Cold Spring Harbor Laboratory
Date: 11-11-2019
DOI: 10.1101/821009
Abstract: Ageing is associated with DNA methylation changes in all human tissues, and epigenetic markers can estimate chronological age based on DNA methylation patterns across tissues. However, the construction of the original pan-tissue epigenetic clock did not include skeletal muscle s les, and hence exhibited a strong deviation between DNA methylation and chronological age in this tissue. To address this, we developed a more accurate, muscle-specific epigenetic clock based on the genome-wide DNA methylation data of 682 skeletal muscle s les from 12 independent datasets (18-89 years old, 22% women, 99% Caucasian), all generated with Illumina HumanMethylation arrays (HM27, HM450 or HMEPIC). We also took advantage of the large number of s les to conduct an epigenome-wide association study (EWAS) of age-associated DNA methylation patterns in skeletal muscle. The newly developed clock uses 200 CpGs to estimate chronological age in skeletal muscle, 16 of which are in common with the 353 CpGs of the pan-tissue clock. The muscle clock outperformed the pan-tissue clock, with a median error of only 4.6 years across datasets ( vs 13.1 years for the pan-tissue clock, p 0.0001) and an average correlation of ρ = 0.62 between actual and predicted age across datasets ( vs ρ = 0.51 for the pan-tissue clock). Lastly, we identified 180 differentially methylated regions (DMRs) with age in skeletal muscle at a False Discovery Rate 0.005. However, Gene Set Enrichment Analysis did not reveal any enrichment for Gene Ontologies. We have developed a muscle-specific epigenetic clock that predicts age with better accuracy than the pan-tissue clock. We implemented the muscle clock in an R package called MEAT available on Bioconductor to estimate epigenetic age in skeletal muscle s les. This clock may prove valuable in assessing the impact of environmental factors, such as exercise and diet, on muscle-specific biological ageing processes.
Publisher: Springer Science and Business Media LLC
Date: 11-2017
Publisher: Wiley
Date: 05-02-2021
DOI: 10.1113/EP089301
Abstract: What is the central question of this study? The extent to which genetics determines adaptation to endurance versus resistance exercise is unclear. Previously, a ergent selective breeding rat model showed that genetic factors play a major role in the response to aerobic training. Here, we asked: do genetic factors that underpin poor adaptation to endurance training affect adaptation to functional overload? What is the main finding and its importance? Our data show that heritable factors in low responders to endurance training generated differential gene expression that was associated with impaired skeletal muscle hypertrophy. A maladaptive genotype to endurance exercise appears to dysregulate biological processes responsible for mediating exercise adaptation, irrespective of the mode of contraction stimulus. Divergent skeletal muscle phenotypes result from chronic resistance‐type versus endurance‐type contraction, reflecting the principle of training specificity. Our aim was to determine whether there is a common set of genetic factors that influence skeletal muscle adaptation to ergent contractile stimuli. Female rats were obtained from a genetically heterogeneous rat population and were selectively bred from high responders to endurance training (HRT) or low responders to endurance training (LRT n = 6/group generation 19). Both groups underwent 14 days of synergist ablation to induce functional overload of the plantaris muscle before comparison to non‐overloaded controls of the same phenotype. RNA sequencing was performed to identify Gene Ontology biological processes with differential (LRT vs. HRT) gene set enrichment. We found that running distance, determined in advance of synergist ablation, increased in response to aerobic training in HRT but not LRT (65 ± 26 vs. −6 ± 18%, mean ± SD, P 0.0001). The hypertrophy response to functional overload was attenuated in LRT versus HRT (20.1 ± 5.6 vs. 41.6 ± 16.1%, P = 0.015). Between‐group differences were observed in the magnitude of response of 96 upregulated and 101 downregulated pathways. A further 27 pathways showed contrasting upregulation or downregulation in LRT versus HRT in response to functional overload. I n conclusion, low responders to aerobic endurance training were also low responders for compensatory hypertrophy, and attenuated hypertrophy was associated with differential gene set regulation. Our findings suggest that genetic factors that underpin aerobic training maladaptation might also dysregulate the transcriptional regulation of biological processes that contribute to adaptation to mechanical overload.
Publisher: Elsevier BV
Date: 02-2006
DOI: 10.1016/J.EXGER.2005.10.013
Abstract: Aged hearts exhibit reduced tolerance to ischemia-reperfusion, together with altered structure and post-ischemic remodelling. The molecular bases of such changes are unclear. Using cDNA microarrays and quantitative RT-PCR we characterized shifts in gene expression patterns with aging in normoxic and post-ischemic (20 min global ischemia, 60 min reperfusion) murine hearts (young: 2-4 months aged: 16-18 months). We identified an age-associated up-regulation of transcripts involved in cell death, oxygen transport and metabolism in normoxic hearts. Down-regulated transcripts were involved in transporter activity, protein binding and hydrolase activity, changes in MAPK, WNT and TGF-beta signalling with aging were also observed. Ischemic stress generated a much greater degree of contractile impairment and cellular damage in aged vs. young hearts. This was associated with a substantially modified transcriptional response, with selective changes in Ca2+, WNT, NOTCH and G-protein coupled receptor signalling paths in aged vs. young hearts. Despite some common responses to ischemia in young and aged hearts (induction of heat shock protein transcripts), aging selectively modified ischemic responses of immediate early genes, and genes involved in modulating apoptosis and remodelling/angiogenesis. In summary, aging is associated with shifts in cardiovascular gene expression consistent with the phenotypic features of older hearts. Reduced tolerance with age may be related to modification of signalling (particularly WNT and TGF-beta), and shifts in expression of immediate early genes, and genes important in control of cell death/survival, angiogenesis, and cardiac remodelling.
Publisher: Public Library of Science (PLoS)
Date: 09-2022
DOI: 10.1371/JOURNAL.PONE.0273925
Abstract: Skeletal muscle unloading due to joint immobilization induces muscle atrophy, which has primarily been attributed to reductions in protein synthesis in humans. However, no study has evaluated the skeletal muscle proteome response to limb immobilization using SWATH proteomic methods. This study characterized the shifts in in idual muscle protein abundance and corresponding gene sets after 3 and 14 d of unilateral lower limb immobilization in otherwise healthy young men. Eighteen male participants (25.4 ±5.5 y, 81.2 ±11.6 kg) underwent 14 d of unilateral knee-brace immobilization with dietary provision and following four-weeks of training to standardise acute training history. Participant phenotype was characterized before and after 14 days of immobilization, and muscle biopsies were obtained from the vastus lateralis at baseline (pre-immobilization) and at 3 and 14 d of immobilization for analysis by SWATH-MS and subsequent gene-set enrichment analysis (GSEA). Immobilization reduced vastus group cross sectional area (-9.6 ±4.6%, P .0001), immobilized leg lean mass (-3.3 ±3.9%, P = 0.002), unilateral 3-repetition maximum leg press (-15.6 ±9.2%, P .0001), and maximal oxygen uptake (-2.9 ±5.2%, P = 0.044). SWATH analyses consistently identified 2281 proteins. Compared to baseline, two and 99 proteins were differentially expressed (FDR .05) after 3 and 14 d of immobilization, respectively. After 14 d of immobilization, 322 biological processes were different to baseline (FDR .05, P 0.001). Most (77%) biological processes were positively enriched and characterized by cellular stress, targeted proteolysis, and protein-DNA complex modifications. In contrast, mitochondrial organization and energy metabolism were negatively enriched processes. This study is the first to use data independent proteomics and GSEA to show that unilateral lower limb immobilization evokes mitochondrial dysfunction, cellular stress, and proteolysis. Through GSEA and network mapping, we identify 27 hub proteins as potential protein/gene candidates for further exploration.
Publisher: InTech
Date: 13-03-2013
DOI: 10.5772/53316
Publisher: Springer US
Date: 2003
Publisher: Public Library of Science (PLoS)
Date: 13-01-2022
DOI: 10.1371/JOURNAL.PONE.0261723
Abstract: Skeletal muscle atrophy is a physiological response to disuse, aging, and disease. We compared changes in muscle mass and the transcriptome profile after short-term immobilization in a ergent model of high and low responders to endurance training to identify biological processes associated with the early atrophy response. Female rats selectively bred for high response to endurance training (HRT) and low response to endurance training (LRT n = 6/group generation 19) underwent 3 day hindlimb cast immobilization to compare atrophy of plantaris and soleus muscles with line-matched controls (n = 6/group). RNA sequencing was utilized to identify Gene Ontology Biological Processes with differential gene set enrichment. Aerobic training performed prior to the intervention showed HRT improved running distance (+60.6 ± 29.6%), while LRT were unchanged (-0.3 ± 13.3%). Soleus atrophy was greater in LRT vs. HRT (-9.0 ±8.8 vs. 6.2 ±8.2% P .05) and there was a similar trend in plantaris (-16.4 ±5.6% vs. -8.5 ±7.4% P = 0.064). A total of 140 and 118 biological processes were differentially enriched in plantaris and soleus muscles, respectively. Soleus muscle exhibited ergent LRT and HRT responses in processes including autophagy and immune response. In plantaris, processes associated with protein ubiquitination, as well as the atrogenes ( Trim63 and Fbxo32 ), were more positively enriched in LRT. Overall, LRT demonstrate exacerbated atrophy compared to HRT, associated with differential gene enrichments of biological processes. This indicates that genetic factors that result in ergent adaptations to endurance exercise, may also regulate biological processes associated with short-term muscle unloading.
Publisher: Oxford University Press (OUP)
Date: 07-2006
DOI: 10.1016/J.CARDIORES.2006.03.006
Abstract: Adenosine deaminase (ADA) may be multifunctional, regulating adenosine levels and adenosine receptor (AR) agonism, and potentially modifying AR functionality. Herein we assess effects of ADA (and A1AR) deficiency on AR-mediated responses and ischaemic tolerance. Normoxic function and responses to 20 or 25 min ischaemia and 45 min reperfusion were studied in isolated hearts from wild-type mice and from mice deficient in ADA and/or A1ARs. Neither ADA or A1AR deficiency significantly modified basal contractility, although ADA deficiency reduced resting heart rate (an effect abrogated by A1AR deficiency). Bradycardia and vasodilation in response to AR agonism (2-chloroadenosine) were unaltered by ADA deficiency, while A1AR deficiency eliminated the heart rate response. Adenosine efflux increased 10- to 20-fold with ADA deficiency (at the expense of inosine). Deletion of ADA improved outcome from 25 min ischaemia, reducing ventricular diastolic pressure (by 45% 21+/-4 vs. 38+/-3mm Hg) and lactate dehydrogenase (LDH) efflux (by 40% 0.12+/-0.01 vs. 0.21+/-0.02 U/g/min ischaemia), and enhancing pressure development (by 35% 89+/-6 vs. 66+/-5mm Hg). Similar protection was evident after 20 min ischaemia, and was mimicked by the ADA inhibitor EHNA (5 microM). Deletion of ADA also enhanced tolerance in A1AR deficient hearts, though effects on diastolic pressure were eliminated. Deficiency of ADA does not alter sensitivities of cardiovascular A1 or A2ARs (despite markedly elevated [adenosine]), but significantly improves ischaemic tolerance. Conversely, A1AR deficiency impairs ischaemic tolerance. Effects of ADA deficiency on diastolic pressure appear solely A1AR-dependent while other ARs or processes additionally contribute to improved contractile recovery and reduced cell death.
Publisher: Wiley
Date: 06-2003
Publisher: American Physiological Society
Date: 02-2014
DOI: 10.1152/JAPPLPHYSIOL.00909.2013
Abstract: Reprogramming of gene expression is fundamental for skeletal muscle adaptations in response to endurance exercise. This study investigated the time course-dependent changes in the muscular transcriptome after an endurance exercise trial consisting of 1 h of intense cycling immediately followed by 1 h of intense running. Skeletal muscle s les were taken at baseline, 3 h, 48 h, and 96 h postexercise from eight healthy, endurance-trained men. RNA was extracted from muscle. Differential gene expression was evaluated using Illumina microarrays and validated with qPCR. Gene set enrichment analysis identified enriched molecular signatures chosen from the Molecular Signatures Database. Three hours postexercise, 102 gene sets were upregulated [family wise error rate (FWER), P 0.05], including groups of genes related with leukocyte migration, immune and chaperone activation, and cyclic AMP responsive element binding protein (CREB) 1 signaling. Forty-eight hours postexercise, among 19 enriched gene sets (FWER, P 0.05), two gene sets related to actin cytoskeleton remodeling were upregulated. Ninety-six hours postexercise, 83 gene sets were enriched (FWER, P 0.05), 80 of which were upregulated, including gene groups related to chemokine signaling, cell stress management, and extracellular matrix remodeling. These data provide comprehensive insights into the molecular pathways involved in acute stress, recovery, and adaptive muscular responses to endurance exercise. The novel 96 h postexercise transcriptome indicates substantial transcriptional activity potentially associated with the prolonged presence of leukocytes in the muscles. This suggests that muscular recovery, from a transcriptional perspective, is incomplete 96 h after endurance exercise involving muscle damage.
Publisher: Elsevier BV
Date: 12-2012
DOI: 10.1016/J.JAD.2012.03.037
Abstract: Immune dysfunction associated with a disease often has a molecular basis. A novel group of molecules known as microRNAs (miRNAs) have been associated with suppression of translational processes involved in cellular development and proliferation, protein secretion, apoptosis, immune function and inflammatory processes. MicroRNAs may be implicated in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME), where immune function is impaired. The objective of this study was to determine the association between miRNAs in cytotoxic cells and CFS/ME. Natural Killer (NK) and CD8(+)T cells were preferentially isolated from peripheral blood mononuclear cells from all participants (CFS/ME, n=28 mean age=41.8±9.6 years and controls, n=28 mean age=45.3±11.7 years), via negative cell enrichment. Following total RNA extraction and subsequent synthesis of cDNA, reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) was used to determine the expression levels of nineteen miRNAs. There was a significant reduction in the expression levels of miR-21, in both the NK and CD8(+)T cells in the CFS/ME sufferers. Additionally, the expression of miR-17-5p, miR-10a, miR-103, miR-152, miR-146a, miR-106, miR-223 and miR-191 was significantly decreased in NK cells of CFS/ME patients in comparison to the non-fatigued controls. The results from these investigations are not yet transferable into the clinical setting, further validatory studies are now required. Collectively these miRNAs have been associated with apoptosis, cell cycle, development and immune function. Changes in miRNAs in cytotoxic cells may reduce the functional capacity of these cells and disrupt effective cytotoxic activity along with other immune functions in CFS/ME patients.
Publisher: Public Library of Science (PLoS)
Date: 19-09-2014
Publisher: Wiley
Date: 03-2022
DOI: 10.1113/JP282395
Abstract: Circulating bilirubin is associated with reduced serum cholesterol concentrations in humans and in hyperbilirubinaemic Gunn rats. However, mechanisms contributing to hypocholesterolaemia remain unknown. Therefore, this study aimed to investigate cholesterol synthesis, transport and excretion in mutant Gunn rats. Adult Gunn and control rats were assessed for daily faecal sterol excretion using metabolic cages, and water was supplemented with [1‐ 13 C]‐acetate to determine cholesterol synthesis. Bile was collected to measure biliary lipid secretion. Serum and liver were collected for biochemical analysis and for gene rotein expression using RT‐qPCR and western blot, respectively. Additionally, serum was collected and analysed from juvenile rats. A significant interaction of sex, age and phenotype on circulating lipids was found with adult female Gunn rats reporting significantly lower cholesterol and phospholipids. Female Gunn rats also demonstrated elevated cholesterol synthesis, greater biliary lipid secretion and increased total faecal cholesterol and bile acid excretion. Furthermore, they possessed increased hepatic low‐density lipoprotein (LDL) receptor and SREBP2 expression. In contrast, there were no changes to sterol metabolism in adult male Gunn rats. This is the first study to demonstrate elevated faecal sterol excretion in female hyperbilirubinaemic Gunn rats. Increased sterol excretion creates a negative intestinal sterol balance that is compensated for by increased cholesterol synthesis and LDL receptor expression. Therefore, reduced circulating cholesterol is potentially caused by increased hepatic uptake via the LDL receptor. Future studies are required to further evaluate the sexual dimorphism of this response and whether similar findings occur in females with benign unconjugated hyperbilirubinaemia (Gilbert's syndrome). Female adult hyperbilirubinaemic (Gunn) rats demonstrated lower circulating cholesterol, corroborating human studies that report a negative association between bilirubin and cholesterol concentrations. Furthermore, female Gunn rats had elevated sterol excretion creating a negative intestinal sterol balance that was compensated for by elevated cholesterol synthesis and increased hepatic low‐density lipoprotein (LDL) receptor expression. Therefore, elevated LDL receptor expression potentially leads to reduced circulating cholesterol levels in female Gunn rats providing an explanation for the hypocholesterolaemia observed in humans with elevated bilirubin levels. This study also reports a novel interaction of sex with the hyperbilirubinaemic phenotype on sterol metabolism because changes were only reported in females and not in male Gunn rats. Future studies are required to further evaluate the sexual dimorphism of this response and whether similar findings occur in females with benign unconjugated hyperbilirubinaemia (Gilbert's syndrome).
Publisher: Elsevier BV
Date: 02-2005
DOI: 10.1016/J.YJMCC.2004.09.014
Abstract: Aging is associated with reduced tolerance to ischemic insult, and genesis of this intolerant phenotype is poorly understood. We characterized effects of aging and gender on cardiovascular function and cell damage during 20 min ischemia and 60 min reperfusion in isolated hearts from young adult (2-4 months), mature adult (8 months), middle-aged (12 months), aged (18 months), and senescent (24-28 months) C57/Bl6 mice. Aging substantially impaired recovery of ventricular contractility, with this change primarily evident within 12 months of age. In males ventricular developed pressure recovered to 72 +/- 8 mmHg in young hearts vs. only 44 +/- 7, 30 +/- 3, 24 +/- 5, and 27 +/- 4 mmHg in mature, middle-aged, aged and senescent hearts, respectively. This pattern was largely due to worsened diastolic dysfunction. Coronary flow recovered to below pre-ischemic levels in all ages, correlating with contractile recovery. However, coronary dysfunction (impaired responses to 2-chloroadenosine and ADP) was unaltered by senescence. Lactate dehydrogenase (LDH) loss, a marker for oncosis, increased to middle-age (approximately twofold), then fell with further aging to a value no longer different from that in young adult hearts. Similar patterns of change were observed in female hearts, although LDH efflux was significantly lower in mature adult and middle-aged female vs. male hearts, with functional tolerance also tending to be greater at these ages (though not achieving significance). Overall, our data reveal age-related ischemic intolerance develops well before senescence, being primarily evident by "middle-age". Phenotypic changes appear selective for myocardial vs. vascular injury, and functional vs. oncotic injury. Similar changes occur in males and females, though there is evidence of a protected phenotype in mature to middle-aged female vs. male hearts.
Publisher: Springer Science and Business Media LLC
Date: 28-05-2011
Abstract: Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is characterised by severe prolonged fatigue, and decreases in cognition and other physiological functions, resulting in severe loss of quality of life, difficult clinical management and high costs to the health care system. To date there is no proven pathomechanism to satisfactorily explain this disorder. Studies have identified abnormalities in immune function but these data are inconsistent. We investigated the profile of markers of immune function (including novel markers) in CFS/ME patients. We included 95 CFS/ME patients and 50 healthy controls. All participants were assessed on natural killer (NK) and CD8 + T cell cytotoxic activities, Th1 and Th2 cytokine profile of CD4 + T cells, expression of vasoactive intestinal peptide receptor 2 (VPACR2), levels of NK phenotypes (CD56 bright and CD56 dim ) and regulatory T cells expressing FoxP3 transcription factor. Compared to healthy in iduals, CFS/ME patients displayed significant increases in IL-10, IFN-γ, TNF-α, CD4 + CD25 + T cells, FoxP3 and VPACR2 expression. Cytotoxic activity of NK and CD8 + T cells and NK phenotypes, in particular the CD56 bright NK cells were significantly decreased in CFS/ME patients. Additionally granzyme A and granzyme K expression were reduced while expression levels of perforin were significantly increased in the CFS/ME population relative to the control population. These data suggest significant dysregulation of the immune system in CFS/ME patients. Our study found immunological abnormalities which may serve as biomarkers in CFS/ME patients with potential for an application as a diagnostic tool.
Publisher: Springer Science and Business Media LLC
Date: 02-01-2020
DOI: 10.1007/S00438-019-01639-8
Abstract: Adaptation to exercise training is a complex trait that may be influenced by genetic variants. We identified 36 single nucleotide polymorphisms (SNPs) that had been previously associated with endurance or strength performance, exercise-related phenotypes or exercise intolerant disorders. A MassARRAY multiplex genotyping assay was designed to identify associations with these SNPs against collected endurance fitness phenotype parameters obtained from two exercise cohorts (Gene SMART study n = 58 and Hawaiian Ironman Triathlon 2008 n = 115). These parameters included peak power output (PP), a time trial (TT), lactate threshold (LT), maximal oxygen uptake (VO
Publisher: American Physiological Society
Date: 15-10-2014
DOI: 10.1152/AJPHEART.00001.2014
Abstract: Mildly elevated circulating unconjugated bilirubin (UCB) is associated with protection against hypertension and ischemic heart disease. We assessed whether endogenously elevated bilirubin in Gunn rats modifies cardiovascular function and resistance to ischemic insult. Hearts were assessed ex vivo (Langendorff perfusion) and in vivo (Millar catheterization and echocardiography), and left ventricular myocardial gene expression was measured via quantitative real-time PCR. Ex vivo analysis revealed reduced intrinsic contractility in the Gunn myocardium (+dP/d t: 1,976 ± 622 vs. 2,907 ± 334 mmHg/s, P 0.01 −dP/d t: −1,435 ± 372 vs. −2,234 ± 478 mmHg/s, P 0.01), which correlated positively with myocardial UCB concentration ( P 0.05). In vivo analyses showed no changes in left ventricular contractile parameters and ejection (fractional shortening and ejection fraction). However, Gunn rats exhibited reductions in the rate of aortic pressure development (3,008 ± 461 vs. 4,452 ± 644 mmHg/s, P 0.02), mean aortic velocity (439 ± 64 vs. 644 ± 62 mm/s, P 0.01), and aortic volume time integral pressure gradient (2.32 ± 0.65 vs. 5.72 ± 0.74 mmHg, P 0.01), in association with significant aortic dilatation (12–24% increase in aortic diameter, P 0.05). Ex vivo Gunn hearts exhibited improved ventricular function after 35 min of ischemia and 90 min of reperfusion (63 ± 14 vs. 35 ± 12%, P 0.01). These effects were accompanied by increased glutathione peroxidase and reduced superoxide dismutase and phospholamban gene expression in Gunn rat myocardium ( P 0.05). These data collectively indicate that hyperbilirubinemia in Gunn rats 1) reduces intrinsic cardiac contractility, which is compensated for in vivo 2) induces aortic dilatation, which may beneficially influence aortic ejection velocities and pressures and 3) may improve myocardial stress resistance in association with beneficial transcriptional changes. These effects may contribute to protection from cardiovascular disease with elevated bilirubin.
Publisher: Springer Science and Business Media LLC
Date: 02-2005
DOI: 10.1007/S11010-005-5279-Y
Abstract: Cardiac ischemia reperfusion leads to oxidative stress and poor physiological recovery. Selenium deficiency down-regulates thioredoxin reductase (Txnrd) and glutathione peroxidase (Gpx) activity, impairing recovery from ischemia-reperfusion. Furthermore, selenium supplementation has been shown to be cardioprotective and lessens oxidative stress in reperfused rat hearts. In this study we have investigated the role of selenium in the mRNA expression of these, and related antioxidant proteins, post ischemia-reperfusion. Male rats were fed varying doses of selenium for five weeks. Hearts were isolated and perfused using the Langendorff method with 22.5 min of global ischemia and 45 min reperfusion. RNA was extracted for quantitative real-time PCR analysis of glutathione peroxidase (Gpx)-1 and 4, glutathione reductase (Gsr), thioredoxin peroxidase-2 (Prdx2), thioredoxin (Txn) and thioredoxin reductase (Txnrd)-1 and 2 gene expression. Selenium deficiency produced significant reductions in Gpx-1, Gpx-4, Prdx2, Txnrd-1 and Txnrd-2 expression. Conversely, selenium supplementation of 1000 microg/kg significantly up-regulated Gpx-1, Gpx-4, Txn, Txnrd-1 and Txnrd-2 transcription. Our results show selenium modulates the cardiac mRNA expression of thioredoxin and glutathione related enzymes post ischemia-reperfusion, and impacts on tolerance to ischemia-reperfusion.
Publisher: Springer Science and Business Media LLC
Date: 11-2017
Publisher: American Physiological Society
Date: 29-10-2002
DOI: 10.1152/PHYSIOLGENOMICS.00008.2002
Abstract: Transgenic mice with cardiac-specific overexpression of adenosine A 1 receptors (A 1 AR) have demonstrated metabolic and functional tolerance to myocardial ischemia. We utilized cDNA microarrays to test the hypothesis that the cardioprotective mechanism(s) of A 1 overexpression involves altered gene expression. Total RNA extracted from the left ventricles from A 1 transgenic ( n = 4) and wild-type ( n = 6) mice was hybridized to Affymetrix mgU74A chips. Comparison of RNA expression levels in transgenic to wild-type myocardium revealed ∼636 known genes with expression significantly altered by greater than 25%. We observed increased expressions of genes including NADH dehydrogenase, the GLUT4 glucose transporter, Na-K-ATPase, sarcolemmal K ATP channels, and Bcl-xl in A 1 AR-overexpressing hearts. We also observed decreased expression of pro-apoptotic genes including a 50% reduction in message level of caspase-8. Protein expression of GLUT4 and caspase-8 was also altered comparable to the differences in gene expression. These data illustrate genes with chronically altered patterns of expression in A 1 transgenic mouse myocardium that may be related to adenosine receptor overexpression-mediated cardioprotection.
Publisher: American Physiological Society
Date: 05-2012
DOI: 10.1152/AJPREGU.00406.2011
Abstract: Exercise triggers hormesis, conditioning hearts against damaging consequences of subsequent ischemia-reperfusion (I/R). We test whether “low-stress” voluntary activity modifies I/R tolerance and molecular determinants of cardiac survival. Male C57BL/6 mice were provided 7-day access to locked (7SED) or rotating (7EX) running-wheels before analysis of cardiac prosurvival (Akt, ERK 1/2) and prodeath (GSK3β) kinases, transcriptomic adaptations, and functional tolerance of isolated hearts to 25-min ischemia/45-min reperfusion. Over 7 days, 7EX mice increased running from 2.1 ± 0.2 to 5.3 ± 0.3 km/day (mean speed 38 ± 2 m/min), with activity improving myocardial I/R tolerance: 7SED hearts recovered 43 ± 3% of ventricular force with diastolic contracture of 33 ± 3 mmHg, whereas 7EX hearts recovered 63 ± 5% of force with diastolic dysfunction reduced to 23 ± 2 mmHg ( P 0.05). Cytosolic expression (total protein) of Akt and GSK3β was unaltered, while ERK 1/2 increased 30% in 7EX vs. 7SED hearts. Phosphorylation of Akt and ERK 1/2 was unaltered, whereas GSK3β phosphorylation increased ∼90%. Microarray interrogation identified significant changes (≥1.3-fold expression change, ≤5% FDR) in 142 known genes, the majority (92%) repressed. Significantly modified paths/networks related to inflammatory/immune function (particularly interferon-dependent), together with cell movement, growth, and death. Of only 14 induced transcripts, 3 encoded interrelated sarcomeric proteins titin, α-actinin, and myomesin-2, while transcripts for protective actin-stabilizing ND1-L and activator of mitochondrial biogenesis ALAS1 were also induced. There was no transcriptional evidence of oxidative heat-shock or other canonical “stress” responses. These data demonstrate that relatively brief voluntary activity substantially improves cardiac ischemic tolerance, an effect independent of shifts in Akt, but associated with increased total ERK 1/2 and phospho-inhibition of GSK3β. Transcriptomic data implicate inflammatory/immune and sarcomeric modulation in activity-dependent protection.
Publisher: Cold Spring Harbor Laboratory
Date: 28-09-2020
DOI: 10.1101/2020.09.28.315838
Abstract: Knowledge of age-related DNA methylation changes in skeletal muscle is limited, yet this tissue is severely affected by aging in humans. Using a large-scale epigenome-wide association study (EWAS) meta-analysis of age in human skeletal muscle from 10 studies (total n = 908 human muscle methylomes), we identified 9,986 differentially methylated regions at a stringent false discovery rate 0.005, spanning 8,748 unique genes, many of which related to skeletal muscle structure and development. We then integrated the DNA methylation results with known transcriptomic and proteomic age-related changes in skeletal muscle, and found that even though most differentially methylated genes are not altered at the mRNA or protein level, they are nonetheless strongly enriched for genes showing age-related differential expression. We provide here the most comprehensive picture of DNA methylation aging in human skeletal muscle, and have made our results available as an open-access, user-friendly, web-based tool called MetaMeth ( sarah-voisin.shinyapps.io/MetaMeth/ ).
Publisher: Springer US
Date: 2006
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-02-2005
DOI: 10.1161/01.RES.0000156075.00127.C3
Abstract: Adenosine receptors may be important determinants of intrinsic ischemic tolerance. Genetically modified mice were used to examine effects of global A 1 adenosine receptor (A 1 AR) knockout (KO) on function and ischemic tolerance in perfused mouse hearts. Baseline contractile function and heart rate were unaltered by A 1 AR KO, which was shown to abolish the negative chronotropic effects of 2-chloroadenosine (A 1 AR-mediated) without altering A 2 adenosine receptor–mediated coronary dilation. Tolerance to 25 minutes global normothermic ischemia (followed by 45 minutes reperfusion) was significantly limited by A 1 AR KO, with impaired contractile recovery (reduced by ≈25%) and enhanced lactate dehydrogenase (LDH) efflux (increased by ≈100%). Functional effects of A 1 AR KO involved worsened systolic pressure development with little to no change in diastolic dysfunction. In contrast, cardiac specific A 1 AR overexpression enhanced ischemic tolerance with a primary action on diastolic dysfunction. Nonselective receptor agonism (10 μmol/L 2-chloroadenosine) protected wild-type and also A 1 AR KO hearts (albeit to a lesser extent), implicating protection via subtypes additional to A 1 ARs. However, A 1 AR KO abrogated effects of 2-chloroadenosine on ischemic contracture and diastolic dysfunction. These data are the first demonstrating global deletion of the A 1 AR limits intrinsic myocardial resistance to ischemia. Data indicate the function of intrinsically activated A 1 ARs appears primarily to be enhancement of postischemic contractility and limitation of cell death.
Publisher: Springer Science and Business Media LLC
Date: 18-05-2017
Publisher: Oxford University Press (OUP)
Date: 2002
DOI: 10.1016/S0008-6363(01)00424-2
Abstract: To characterize effects of A(3) adenosine receptor (A(3)AR) activation and gene knock-out on responses to ischemia-reperfusion in mouse heart. Perfused hearts from wild-type and A(3)AR gene knock-out (A(3)AR KO) mice were subjected to 20 min ischemia and 30 min reperfusion. Functional responses were assessed and changes in energy metabolism and cytosolic pH monitored via 31P-NMR spectroscopy. Selective A(3)AR agonism with 100 nM 2-chloro-N(6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (chloro-IB-MECA) enhanced post-ischemic contractile recovery without altering contracture development in wild-type hearts, an effect unrelated to non-selective activation of A(1) or A(2) adenosine receptors. Chloro-IB-MECA also improved recovery in hearts overexpressing A(1)ARs. Paradoxically, post-ischemic recovery was enhanced by A(3)AR KO. Developed pressure, +dP/dt, and -dP/dt all recovered to higher levels in A(3)AR KO (70-80% of pre-ischemia) vs. wild-type hearts (45-50% of pre-ischemia) (P<0.05). Enhanced recovery was unrelated to recoveries of ATP, phosphocreatine (PCr), inorganic phosphate (P(i)), energy state ([ATP]/[ADP] x [P(i)], DeltaG(ATP)) or cytosolic pH. Selective A(3)AR activation is cardioprotective in wild-type hearts and hearts overexpressing A(1)ARs, yet A(3)AR gene deletion generates an ischemia-tolerant phenotype without altering energy metabolism or pH. This may be due to compensatory changes or undefined genotypic differences in A(3)AR KO vs. wild-type hearts.
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1016/J.PHARMTHERA.2013.06.002
Abstract: Intra- and extracellular adenosine levels rise in response to physiological stimuli and with metabolic/energetic perturbations, inflammatory challenge and tissue injury. Extracellular adenosine engages members of the G-protein coupled adenosine receptor (AR) family to mediate generally beneficial acute and adaptive responses within all constituent cells of the heart. In this way the four AR sub-types-A1, A2A, A2B, and A3Rs-regulate myocardial contraction, heart rate and conduction, adrenergic control, coronary vascular tone, cardiac and vascular growth, inflammatory-vascular cell interactions, and cellular stress-resistance, injury and death. The AR sub-types exert both distinct and overlapping effects, and may interact in mediating these cardiovascular responses. The roles of the ARs in beneficial modulation of cardiac and vascular function, growth and stress-resistance render them attractive therapeutic targets. However, interactions between ARs and with other receptors, and their ubiquitous distribution throughout the body, can pose a challenge to the implementation of site- and target-specific AR based pharmacotherapy. This review outlines cardiovascular control by adenosine and the AR family in health and disease, including interactions between AR sub-types within the heart and vessels.
Publisher: Cold Spring Harbor Laboratory
Date: 20-02-2020
DOI: 10.1101/2020.02.20.957340
Abstract: Mitochondria supply intracellular energy requirements during exercise. Specific mitochondrial haplogroups and mitochondrial genetic variants have been associated with athletic performance, and exercise responses. However, these associations were discovered using underpowered, candidate gene approaches, and consequently have not been replicated. Here, we used whole-mitochondrial genome sequencing, in conjunction with high-throughput genotyping arrays, to discover novel genetic variants associated with exercise responses in the Gene SMART (Skeletal Muscle Adaptive Response to Training) cohort (n=62 completed). We performed a Principal Component Analysis of cohort aerobic fitness measures to build composite traits and test for variants associated with exercise outcomes. None of the mitochondrial genetic variants but nine nuclear encoded variants in eight separate genes were found to be associated with exercise responses (FDR .05) (rs11061368: DIABLO, rs113400963: FAM185A, rs6062129 and rs6121949: MTG2, rs7231304: AFG3L2, rs2041840: NDUFAF7, rs7085433: TIMM23, rs1063271: SPTLC2, rs2275273: ALDH18A1). Additionally, we outline potential mechanisms by which these variants may be contributing to exercise phenotypes. Our data suggest novel nuclear-encoded SNPs and mitochondrial pathways associated with exercise response phenotypes. Future studies should focus on validating these variants across different cohorts and ethnicities. Previous exercise genetic studies contain many flaws that impede the growth in knowledge surrounding change in exercise outcomes. In particular, exercise studies looking at mtDNA variants have looked at very small portions of the mitochondrial genome. Mitochondria are the ‘power house’ of the cell and therefore understanding the mitochondrial genetics behind adaptations to training can help us fill knowledge gaps in current research. Here, we utilised a new mitochondrial genetic sequencing technique to examine all mitochondrial and mitochondrial related genetic variations. We have shown that there were no mitochondrial specific variants that influenced exercise training however there were 9 related variants that were significantly associated with exercise phenotypes. Additionally, we have shown that building composite traits increased the significance of our association testing and lead to novel findings. We will be able to understand why response to training is so varied and increase the effectiveness of exercise training on a host of metabolic disorders.
Publisher: Springer Science and Business Media LLC
Date: 06-07-2020
DOI: 10.1038/S41598-020-67870-1
Abstract: Mitochondria supply intracellular energy requirements during exercise. Specific mitochondrial haplogroups and mitochondrial genetic variants have been associated with athletic performance, and exercise responses. However, these associations were discovered using underpowered, candidate gene approaches, and consequently have not been replicated. Here, we used whole-mitochondrial genome sequencing, in conjunction with high-throughput genotyping arrays, to discover novel genetic variants associated with exercise responses in the Gene SMART (Skeletal Muscle Adaptive Response to Training) cohort (n = 62 completed). We performed a Principal Component Analysis of cohort aerobic fitness measures to build composite traits and test for variants associated with exercise outcomes. None of the mitochondrial genetic variants but eight nuclear encoded variants in seven separate genes were found to be associated with exercise responses (FDR 0.05) ( rs11061368 : DIABLO , rs113400963 : FAM185A , rs6062129 and rs6121949 : MTG2 , rs7231304 : AFG3L2 , rs2041840 : NDUFAF7 , rs7085433 : TIMM23 , rs1063271 : SPTLC2 ) . Additionally, we outline potential mechanisms by which these variants may be contributing to exercise phenotypes. Our data suggest novel nuclear-encoded SNPs and mitochondrial pathways associated with exercise response phenotypes. Future studies should focus on validating these variants across different cohorts and ethnicities.
Publisher: Elsevier BV
Date: 04-2007
DOI: 10.1016/J.YJMCC.2006.12.012
Abstract: The adenosine receptor system has been attributed with a broad range of both physiological and so-called 'retaliatory' functions in the heart and vessels. Despite many years of research, the precise roles of adenosine within the cardiovascular system continue to be debated, and new functions are continually emerging. Adenosine acts via 4 known G-protein-coupled receptor (GPCR) sub-types: A(1), A(2A), A(2B), and A(3) adenosine receptors (ARs). In addition to roles in cardiovascular control, these receptors may represent therapeutic targets, having been attributed with roles in modifying cell death and injury, inflammatory processes, and cardiac and vascular remodeling during/after ischemic or hypoxic insult. A number of models have been developed in which AR sub-types and adenosine handling enzymes have been genetically deleted or transgenically overexpressed in an attempt to more equivocally identify the regulatory functions of these proteins, to identify their potential value as therapeutic targets, and to uncover new regulatory functions of this receptor family. Findings generally support current dogma regarding cardioprotection via A(1) and A(3)ARs, and coronary vasoregulation via A(2)AR sub-types. However, some outcomes are both novel and controversial. This review outlines AR-modified murine models currently under study from the perspective of cardiovascular phenotype.
Publisher: Elsevier BV
Date: 04-1998
DOI: 10.1016/S0190-9622(98)70132-X
Abstract: Adenoviral infections in neonates are associated with high rates of mortality due to the lack of humoral immunity. A comprehensive search of published literature in PubMed, Google Scholar, and Science Direct electronic databases was conducted for case reports published between the years 1990 and 2021. The aim of our study is to investigate the risk factors, clinical manifestations, treatment, and outcomes of adenoviral infections in neonates. In our study, 36 cases were included. The most common type of infection was disseminated one (14/36, 38.8%), followed by adenoviral pneumonia (13/36, 36.1%). Cidofovir was administered in seven cases (19.4%), and death was reported in six of them. One preterm low birthweight neonate with disseminated adenoviral infection was treated with a combination of cidofovir, intravenous immune globulin, and haploidentical virus-specific T lymphocytes (VSTs) and survived. In this review, we found a statistically significant difference in the outcome based on the type of adenoviral infection (p=0.001). Disseminated infection and pneumonia are associated with the worst prognosis. In addition, mortality was observed to be higher in neonates with disseminated disease in contrast to neonates with localized infection (p=0.002). However, the antiviral treatment had no statistically significant effect on the mortality rate (p=0.137). There is a necessity for further investigation and randomized studies to validate the results of the present study.
Publisher: Springer Science and Business Media LLC
Date: 30-09-2017
Publisher: American Physiological Society
Date: 15-11-2012
DOI: 10.1152/PHYSIOLGENOMICS.00081.2012
Abstract: All animals require molecular oxygen for aerobic energy production, and oxygen availability has played a particularly important role in the evolution of aquatic animals. This study investigates how previous exposure to hypoxia (preconditioning) primes protective transcriptional responses in a hypoxia-tolerant vertebrate species, the epaulette shark ( Hemiscyllium ocellatum). The epaulette shark is a basal cartilaginous fish that in its natural environment experiences cyclic hypoxic periods. We evaluated whether the transcription of a set of crucial prosurvival genes is affected differently by a single short-term (2 h) exposure to sublethal hypoxia compared with eight such successive hypoxia exposures (hypoxia preconditioning). We discovered that hypoxia preconditioning lifies transcriptional responses compared with animals that experienced a single hypoxic bout. In the heart we observed that hypoxic preconditioning, but not a single hypoxic exposure, resulted in higher transcript levels of genes that regulate oxygen and energy homeostasis, including those of hypoxia-inducible factor-1 alpha, adenosine signaling pathway components, and genes affecting circulation [prostaglandin synthetase 2 ( cox-2) and natriuretic peptide C]. This suggests that in a single short-term hypoxic bout, the responses to low oxygen are regulated at the level of pre-existing proteins or translational and posttranslational machinery, whereas transcriptional responses are induced in experiments that parallel the natural environmental cycles of oxygen availability. These findings have general implications for understanding how vertebrates regulate protective gene expression upon physiological stress.
Publisher: Humana Press
Date: 2007
Publisher: Elsevier BV
Date: 12-2003
DOI: 10.1016/J.BBRC.2003.10.127
Abstract: The well-documented age-related change in ischemic tolerance may result from impaired adenosine-mediated cardioprotection. Additionally, ischemia itself may potentially modify adenosine signalling, contributing to the post-ischemic phenotype. This study investigates age- and ischemia-dependent changes in adenosine receptor transcript levels (Adora) for the A(1), A(2A), A(2B), and A(3) receptor subtypes in mouse myocardium. Hearts from young (2-4 months) and moderately aged (16-18 months) mice were subjected to 20-min ischemia and 45-min reperfusion. Ischemic tolerance was impaired in aged hearts, which recovered less than 30% ventricular pressure development (compared with approximately 70% in young hearts), and lost 2-fold higher levels of lactate dehydrogenase during reperfusion (reflecting cellular disruption). Real-time PCR analyses revealed an age-related decline in Adora3 levels and induction of Adora2B. Curiously, this effect was mimicked by ischemia, which acutely reduced Adora3 levels and induced Adora2B in young (but not old) hearts. In contrast, in aged hearts ischemia selectively reduced levels of Adora1 transcript ( approximately 2-fold) without altering transcript levels for the other receptors. These results demonstrate selective modulation of cardioprotective adenosine receptor transcription by both aging and ischemia. Reduced A(3) adenosine receptor transcription may contribute to impaired ischemic tolerance in aged hearts, whereas changes in Adora transcription induced by ischemia may impact on the post-ischemic phenotype at later time points.
Publisher: Oxford University Press (OUP)
Date: 05-2005
DOI: 10.1016/J.CARDIORES.2004.11.008
Abstract: With aging, it appears the heart's ability to withstand injury declines markedly. Unfortunately, the incidence of ischemic disorders increases dramatically with age. Though the genesis of the ischemia-intolerant phenotype is incompletely understood (and likely multi-factorial), it may involve changes in intrinsic cardioprotective responses. In this respect we and others have interrogated the role of the adenosine receptor (AR) system in dictating ischemic tolerance and the impact of age on AR-mediated cardioprotection. It is intriguing to note ARs impact on many processes implicated in myocardial 'aging': adenosine counters Ca2+ influx and oxidant injury, modifies substrate metabolism to improve tolerance, is pro-angiogenic, inhibits myocardial fibrosis, and can limit apoptosis. Thus, dysregulation of the AR system could contribute to many features of aged hearts (including ischemic intolerance). The latter is borne out by observations that AR-mediated protective responses decline with intrinsic tolerance and that transgenic manipulation of the AR system restores intrinsic tolerance and protective responses in aged hearts. Mechanisms underlying failure in adenosinergic protection remain undefined. Here we review data on the effects of aging on cardiovascular AR transcription and expression, generation of signal (adenosine formation), and protective signaling coupled to ARs.
Publisher: World Scientific Pub Co Pte Ltd
Date: 30-11-2022
DOI: 10.1142/S2661318223300027
Abstract: Background: It is currently inconclusive whether different intracytoplasmic sperm injection (ICSI) timings post oocyte retrieval (POR) lead to altered chance of clinical pregnancy and live birth following in vitro fertilization (IVF) treatment. This study, therefore, aimed to synthesize literature-based evidence for better clinical guidance regarding ICSI practice. Methods: A systematic review and meta-analysis were performed according to PRISMA guidelines. Studies were searched for in PubMed, MEDLINE, EMBASE, and the Cochrane Library. Outcome endpoints included clinical pregnancy and live birth rates (LBRs). Results: A total of 605 records were retrieved in the initial search. After exclusion, 30 articles were included for further screening for eligibility. For meta-analysis, 1 prospective and 5 retrospective cohort studies were included for pooled analysis, from which clinical pregnancy rates (CPRs) were evaluated in 6 studies while LBRs were evaluated in 3 studies. CPRs were comparable when ICSI was performed at (a) [Formula: see text] hours POR (risk ratio or RR = 1.00, [Formula: see text] confidence interval [CI] 0.94–1.08) vs [Formula: see text] hours, (b) [Formula: see text] hours (RR = 1.01, [Formula: see text] CI 0.88–1.16) vs [Formula: see text] hours, (c) [Formula: see text] hours (RR = 0.99, [Formula: see text] CI 0.93–1.05) vs [Formula: see text] hours, (d) [Formula: see text] hours (RR = 0.98, [Formula: see text] CI 0.93–1.02) vs [Formula: see text] hours, and (e) [Formula: see text] hours (RR = 1.05, [Formula: see text] CI 0.90–1.23) vs [Formula: see text] hours. However, LBR was reduced when ICSI was performed [Formula: see text] hours POR vs [Formula: see text] hours (RR = 0.94, [Formula: see text] CI 0.89–0.99), but such reduction disappeared when comparing [Formula: see text] hours POR (RR = 1.09, [Formula: see text] CI 0.85–1.38) vs [Formula: see text] hours. Conclusions: CPRs remain comparable when ICSI is performed at a range of timings up to 6-hour POR. However, LBR may benefit slightly by scheduling ICSI between 5- and 6-hour POR.
Publisher: Inter-Research Science Center
Date: 18-01-2007
DOI: 10.3354/DAO073257
Publisher: Elsevier BV
Date: 07-2003
DOI: 10.1016/S0379-0738(03)00128-2
Abstract: This study investigated potential markers within chromosomal, mitochondrial DNA (mtDNA) and ribosomal RNA (rRNA) with the aim of developing a DNA based method to allow differentiation between animal species. Such discrimination tests may have important applications in the forensic science, agriculture, quarantine and customs fields. DNA s les from five different animal in iduals within the same species for 10 species of animal (including human) were analysed. DNA extraction and quantitation followed by PCR lification and GeneScan visualisation formed the basis of the experimental analysis. Five gene markers from three different types of genes were investigated. These included genomic markers for the beta-actin and TP53 tumor suppressor gene. Mitochondrial DNA markers, designed by Bataille et al. [Forensic Sci. Int. 99 (1999) 165], examined the Cytochrome b gene and Hypervariable Displacement Loop (D-Loop) region. Finally, a ribosomal RNA marker for the 28S rRNA gene optimised by Naito et al. [J. Forensic Sci. 37 (1992) 396] was used as a possible marker for speciation. Results showed a difference of only several base pairs between all species for the beta-actin and 28S markers, with the exception of Sus scrofa (pig) beta-actin fragment length, which produced a significantly smaller fragment. Multiplexing of Cytochrome b and D-Loop markers gave limited species information, although positive discrimination of human DNA was evident. The most specific and discriminatory results were shown using the TP53 gene since this marker produced greatest fragment size differences between animal species studied. S le differentiation for all species was possible following TP53 lification, suggesting that this gene could be used as a potential animal species identifier.
Publisher: Wiley
Date: 17-02-2020
DOI: 10.1002/JCSM.12556
Publisher: Springer Science and Business Media LLC
Date: 09-05-2012
Publisher: Elsevier BV
Date: 09-2001
DOI: 10.1046/J.0022-202X.2001.01434.X
Abstract: In an attempt to define genomic copy number changes associated with the development of basal cell carcinoma, we investigated 15 sporadic tumors by comparative genomic hybridization. With the incorporation of tissue microdissection and degenerate oligonucleotide primed-polymerase chain reaction we were able to isolate, and then universally lify, DNA from the tumor type. This combined approach allows the investigation of chromosomal imbalances within a histologically distinct region of tissue. Using comparative genomic hybridization we have observed novel and recurrent chromosomal gains at 6p (47%), 6q (20%), 9p (20%), 7 (13%), and X (13%). In addition comparative genomic hybridization revealed regional loss on 9q in 33% of tested tumors encompassing 9q22.3 to which the putative tumor suppressor gene, Patched, has been mapped. The deletion of Patched has been indicated in the development of hereditary and sporadic basal cell carcinomas. The identification of these recurrent genetic aberrations suggests that basal cell carcinomas may not be as genetically stable as previously thought. Further investigation of these regions may lead to the identification of other genes responsible for basal cell carcinoma formation.
Publisher: Wiley
Date: 15-04-2005
DOI: 10.1002/GCC.20183
Abstract: Since the advent of cytogenetic analysis, knowledge about fundamental aspects of cancer biology has increased, allowing the processes of cancer development and progression to be more fully understood and appreciated. Classical cytogenetic analysis of solid tumors had been considered difficult, but new advances in culturing techniques and the addition of new cytogenetic technologies have enabled a more comprehensive analysis of chromosomal aberrations associated with solid tumors. Our purpose in this review is to discuss the cytogenetic findings on a number of nonmelanoma skin cancers, including squamous- and basal cell carcinomas, keratoacanthoma, squamous cell carcinoma in situ (Bowen's disease), and solar keratosis. Through classical cytogenetic techniques, as well as fluorescence-based techniques such as fluorescence in situ hybridization and comparative genomic hybridization, numerous chromosomal alterations have been identified. These aberrations may aid in further defining the stages and classifications of nonmelanoma skin cancer and also may implicate chromosomal regions involved in progression and metastatic potential. This information, along with the development of newer technologies (including laser capture microdissection and comparative genomic hybridization arrays) that allow for more refined analysis, will continue to increase our knowledge about the role of chromosomal events at all stages of cancer development and progression and, more specifically, about how they are associated with nonmelanoma skin cancer.
Publisher: Wiley
Date: 14-03-2017
DOI: 10.1111/APHA.12858
Abstract: Bilirubin is associated with reduced risk of cardiovascular disease, as evidenced in conditions of mild hyperbilirubinaemia (Gilbert's Syndrome). Little is known regarding myocardial stress resistance in hyperbilirubinaemic conditions or whether life-long exposure modifies cardiac function, which might contribute to protection from cardiovascular disease. Hyperbilirubinaemic rats and littermate controls underwent echocardiography at 3, 6 and 12 months of age, with hearts subsequently assessed for resistance to 30 min of ischaemia. Heart tissue was then collected for assessment of bilirubin content. No difference in baseline cardiac function was evident until 6 months onwards, where Gunn rats demonstrated aortic dilatation and reduced peak ejection velocities. Additionally, duration of ventricular ejection increased progressively, indicating a negative inotropic effect of bilirubin in vivo. Ex vivo analysis of baseline function revealed reduced left ventricular pressure development (LVDP) and contractility in hyperbilirubinaemic rats. Furthermore, stress resistance was improved in Gunn hearts: post-ischaemic recoveries of LVDP (76 ± 22% vs. 29 ± 17% Control, P < 0.01) and coronary flow (96 ± 9% vs. 86 ± 16% Control, P < 0.01) were improved in Gunn hearts, accompanied by reduced infarct area (21 ± 5% vs. 47 ± 15% Control, P < 0.01), and ventricular malondialdehyde and protein carbonyl content. Expression of myocardial nitric oxide-regulating genes including Nos1 and Noa1 were not significantly different. These data reveal life-long hyperbilirubinaemia induces age-dependent hypocontractility in male Gunn rats, and improved stress resistance. In addition, bilirubin exerts sex-independent effects on vascular structure, myocardial function and ischaemic tolerance, the latter likely mediated via bilirubin's antioxidant properties.
Publisher: Elsevier BV
Date: 07-2013
Publisher: Wiley
Date: 04-2003
DOI: 10.1002/DDR.10179
Publisher: Springer Science and Business Media LLC
Date: 11-01-2010
Publisher: Elsevier BV
Date: 2023
DOI: 10.1016/J.EXGER.2022.112011
Abstract: Phenotypic and transcriptomic evidence of early cardiac aging, and associated mechanisms, were investigated in young to middle-aged male mice (C57Bl/6 ages 8, 16, 32, 48 wks). Left ventricular gene expression (profiled via Illumina MouseWG-6 BeadChips), contractile and coronary function, and stress-resistance were assessed in Langendorff perfused hearts under normoxic conditions and following ischemic insult (20 min global ischemia-45 min reperfusion I-R). Baseline or normoxic contractile function was unaltered by age, while cardiac and coronary 'reserves' (during β-adrenoceptor stimulation 1 μM isoproterenol) declined by 48 wks. Resistance to I-R injury fell from 16 to 32 wks. Age-dependent transcriptional changes In un-stressed hearts were limited to 104 genes (>1.3-fold 0.05 FDR), supporting: up-regulated innate defenses (glutathione and xenobiotic metabolism, chemotaxis, interleukins) and catecholamine secretion and down-regulated extracellular matrix (ECM), growth factor and survival (PI3K/Akt) signaling. In stressed (post-ischemic) myocardium, ∼15-times as many genes (1528) were age-dependent, grouped into 6 clusters (>1.3-fold change 0.05 FDR): most changing from 16 wks (45 % up/44 % down), a further 5 % declining from 32 wks. Major age-dependent Biological Processes in I-R hearts reveal: declining ATP metabolism, oxidative phosphorylation, cardiac contraction and morphogenesis, phospholipid metabolism and calcineurin signaling increasing proteolysis and negative control of MAPK and mixed changes in nuclear transport and angiogenic genes. Pathway analysis supports reductions in: autophagy, stress response, ER protein processing, mRNA surveillance and ribosome/translation genes with later falls in mitochondrial biogenesis, oxidative phosphorylation and proteasome genes in I-R hearts. Summarizing, early cardiac aging is evident from 16 to 32 wks in male mice, characterized by: declining cardiovascular reserve and stress-resistance, transcriptomic evidence of constitutive stress and altered catecholamine and survival/growth signaling in healthy hearts and declining stress response, quality control, mitochondrial energy metabolism and cardiac modeling processes in stressed hearts. These very early changes, potentially key substrate for advanced aging, may inform approaches to healthy aging and cardioprotection in the adult heart.
Publisher: American Physiological Society
Date: 15-09-2014
DOI: 10.1152/AJPHEART.00081.2014
Abstract: Cholesterol-rich caveolar microdomains and associated caveolins influence sarcolemmal ion channel and receptor function and protective stress signaling. However, the importance of membrane cholesterol content to cardiovascular function and myocardial responses to ischemia-reperfusion (I/R) and cardioprotective stimuli are unclear. We assessed the effects of graded cholesterol depletion with methyl-β-cyclodextrin (MβCD) and lifelong knockout (KO) or overexpression (OE) of caveolin-3 (Cav-3) on cardiac function, I/R tolerance, and opioid receptor (OR)-mediated protection. Langendorff-perfused hearts from young male C57Bl/6 mice were untreated or treated with 0.02–1.0 mM MβCD for 25 min to deplete membrane cholesterol and disrupt caveolae. Hearts were subjected to 25-min ischemia/45-min reperfusion, and the cardioprotective effects of morphine applied either acutely or chronically [sustained ligand-activated preconditioning (SLP)] were assessed. MβCD concentration dependently reduced normoxic contractile function and postischemic outcomes in association with graded (10–30%) reductions in sarcolemmal cholesterol. Cardioprotection with acute morphine was abolished with ≥20 μM MβCD, whereas SLP was more robust and only inhibited with ≥200 μM MβCD. Deletion of Cav-3 also reduced, whereas Cav-3 OE improved, myocardial I/R tolerance. Protection via SLP remained equally effective in Cav-3 KO mice and was additive with innate protection arising with Cav-3 OE. These data reveal the membrane cholesterol dependence of normoxic myocardial and coronary function, I/R tolerance, and OR-mediated cardioprotection in murine hearts (all declining with cholesterol depletion). In contrast, baseline function appears insensitive to Cav-3, whereas cardiac I/R tolerance parallels Cav-3 expression. Novel SLP appears unique, being less sensitive to cholesterol depletion than acute OR protection and arising independently of Cav-3 expression.
Publisher: Oxford University Press (OUP)
Date: 03-2003
DOI: 10.1016/S0008-6363(02)00738-1
Abstract: To identify potential molecular genetic determinants of cardiovascular ischemic tolerance in wild-type and transgenic hearts overexpressing A(1) adenosine receptors (A(1)ARs). cDNA microarrays were used to explore expression of 1824 genes in wild-type hearts and ischemia-tolerant mouse hearts overexpressing A(1)ARs. Overexpression of A(1)ARs reduced post-ischemic contractile dysfunction, limited arrhythmogenesis, and reduced necrosis by approximately 80% in hearts subjected to 30 min global ischemia 60 min reperfusion. Cardioprotection was abrogated by acute A(1)AR antagonism, and only a small number (19) of genes were modified by A(1)AR overexpression in normoxic hearts. Ischemia-reperfusion significantly altered expression of 75 genes in wild-type hearts (14 induced, 61 down-regulated), including genes for metabolic enzymes, structural/motility proteins, cell signaling proteins, defense/growth proteins, and regulators of transcription and translation. A(1)AR overexpression reversed the majority of gene down-regulation whereas gene induction was generally unaltered. Additionally, genes involved in cell defence, signaling and gene expression were selectively modified by ischemia in transgenic hearts (33 induced, 10 down-regulated), possibly contributing to the protected phenotype. Real-time PCR verified changes in nine selected genes, revealing concordance with array data. Transcription of the A(1)AR gene was also modestly reduced post-ischemia, consistent with impaired functional sensitivity to A(1)AR stimulation Data are presented regarding the early post-ischemic gene profile of intact heart. Reduced A(1)AR transcription is observed which may contribute to poor outcome from ischemia. A(1)AR overexpression selectively modifies post-ischemic gene expression, potentially contributing to ischemic-tolerance.
Publisher: Wiley
Date: 25-06-2014
DOI: 10.1111/JFB.12422
Abstract: The barcoding of mitochondrial cytochrome c oxidase subunit 1 (coI) gene was lified and sequenced from 16 species of freshwater fishes found in Lake Wivenhoe (south-eastern Queensland, Australia) to support monitoring of reservoir fish populations, ecosystem function and water health. In this study, 630-650 bp sequences of the coI barcoding gene from 100 specimens representing 15 genera, 13 families and two subclasses of fishes allowed 14 of the 16 species to be identified and differentiated. The mean ± s.e. Kimura 2 parameter ergence within and between species was 0.52 ± 0.10 and 23.8 ± 2.20% respectively, indicating that barcodes can be used to discriminate most of the fish species accurately. The two terapontids, Amniataba percoides and Leiopotherapon unicolor, however, shared coI DNA sequences and could not be differentiated using this gene. A barcoding database was established and a qPCR assay was developed using coI sequences to identify and quantify proportional abundances of fish species in ichthyoplankton s les from Lake Wivenhoe. These methods provide a viable alternative to the time-consuming process of manually enumerating and identifying ichthyoplankton s les.
Publisher: Hindawi Limited
Date: 2013
DOI: 10.1155/2013/813256
Abstract: Heat shock proteins (HSPs) are important molecules required for ideal protein function. Extensive research on the functional properties of HSPs indicates that HSPs may be implicated in a wide range of physiological functions including immune function. In the immune system, HSPs are involved in cell proliferation, differentiation, cytokine release, and apoptosis. Therefore, the ability of the immune system, in particular immune cells, to function optimally and in unison with other physiological systems is in part dependent on signaling transduction processes, including bidirectional communication with HSPs. Regulatory T cells (Tregs) are important T cells with suppressive functions and impairments in their function have been associated with a number of autoimmune disorders. The purpose of this paper is to examine the relationship between HSPs and Tregs. The interrelationship between cells and proteins may be important in cellular functions necessary for cell survival and expansion during diseased state.
Start Date: 2012
End Date: 2015
Funder: Judith Jane Mason and Harold Stannett Williams Memorial Foundation
View Funded ActivityStart Date: 2010
End Date: 2011
Funder: National Heart Foundation of Australia
View Funded ActivityStart Date: 2005
End Date: 2008
Funder: National Health and Medical Research Council
View Funded Activity