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The purpose of this study was to examine differences in the genotype frequency distribution of thirty-three single nucleotide variants (SNVs) between youth development phase (YDP) and professional development phase (PDP) academy football... more
The purpose of this study was to examine differences in the genotype frequency distribution of thirty-three single nucleotide variants (SNVs) between youth development phase (YDP) and professional development phase (PDP) academy football players. One hundred and sixty-six male football players from two Category 1 and Category 3 English academies were examined within their specific age phase: YDP (n = 92; aged 13.84 ± 1.63 years) and PDP (n = 74; aged 18.09 ± 1.51 years). Fisher’s exact tests were used to compare individual genotype frequencies, whereas unweighted and weighted total genotype scores (TGS; TWGS) were computed to assess differences in polygenic profiles. In isolation, the IL6 (rs1800795) G allele was overrepresented in PDP players (90.5%) compared to YDP players (77.2%; p = 0.023), whereby PDP players had nearly three times the odds of possessing a G allele (OR = 2.83, 95% CI: 1.13–7.09). The TGS (p = 0.001) and TWGS (p < 0.001) were significant, but poor, in disting...
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MYC is a target of the Wnt signalling pathway and governs numerous cellular and developmental programmes hijacked in cancers. The amplification of MYC is a frequently occurring genetic alteration in cancer genomes, and this transcription... more
MYC is a target of the Wnt signalling pathway and governs numerous cellular and developmental programmes hijacked in cancers. The amplification of MYC is a frequently occurring genetic alteration in cancer genomes, and this transcription factor is implicated in metabolic reprogramming, cell death, and angiogenesis in cancers. In this review, we analyse MYC gene networks in solid cancers. We investigate the interaction of MYC with long non-coding RNAs (lncRNAs). Furthermore, we investigate the role of MYC regulatory networks in inducing changes to cellular processes, including autophagy and mitophagy. Finally, we review the interaction and mutual regulation between MYC and lncRNAs, and autophagic processes and analyse these networks as unexplored areas of targeting and manipulation for therapeutic gain in MYC-driven malignancies.
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The COPD corpus is a semantically annotated corpus, focussed on phenotypic information, consisting of 30 full-text articles. The corpus has been manually annotated with named entities, using a fine-grained annotation scheme, which aims to... more
The COPD corpus is a semantically annotated corpus, focussed on phenotypic information, consisting of 30 full-text articles. The corpus has been manually annotated with named entities, using a fine-grained annotation scheme, which aims to capture detailed information about COPD phenotypes. In particular, the annotations may be "nested" within each other. This is to take into account the potentially complex and nested nature of phenotype descriptions, which may include mentions of various other types of concepts within them
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Cancer stem cells (CSCs) possess properties such as self-renewal, resistance to apoptotic cues, quiescence, and DNA-damage repair capacity. Moreover, CSCs strongly influence the tumour microenvironment (TME) and may account for cancer... more
Cancer stem cells (CSCs) possess properties such as self-renewal, resistance to apoptotic cues, quiescence, and DNA-damage repair capacity. Moreover, CSCs strongly influence the tumour microenvironment (TME) and may account for cancer progression, recurrence, and relapse. CSCs represent a distinct subpopulation in tumours and the detection, characterisation, and understanding of the regulatory landscape and cellular processes that govern their maintenance may pave the way to improving prognosis, selective targeted therapy, and therapy outcomes. In this review, we have discussed the characteristics of CSCs identified in various cancer types and the role of autophagy and long noncoding RNAs (lncRNAs) in maintaining the homeostasis of CSCs. Further, we have discussed methods to detect CSCs and strategies for treatment and relapse, taking into account the requirement to inhibit CSC growth and survival within the complex backdrop of cellular processes, microenvironmental interactions, an...
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Gene expression programmes driving cell identity are established by tightly regulated transcription factors that auto- and cross-regulate in a feed-forward manner, forming core regulatory circuitries (CRCs). CRC transcription factors... more
Gene expression programmes driving cell identity are established by tightly regulated transcription factors that auto- and cross-regulate in a feed-forward manner, forming core regulatory circuitries (CRCs). CRC transcription factors create and engage super-enhancers by recruiting acetylation writers depositing permissive H3K27ac chromatin marks. These super-enhancers are largely associated with BET proteins, including BRD4, that influence higher-order chromatin structure. The orchestration of these events triggers accessibility of RNA polymerase machinery and the imposition of lineage-specific gene expression. In cancers, CRCs drive cell identity by superimposing developmental programmes on a background of genetic alterations. Further, the establishment and maintenance of oncogenic states are reliant on CRCs that drive factors involved in tumour development. Hence, the molecular dissection of CRC components driving cell identity and cancer state can contribute to elucidating mechan...
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Objectives Chronic obstructive pulmonary disease (COPD) phenotypes cover a range of lung abnormalities. To allow text mining methods to identify pertinent and potentially complex information about these phenotypes from textual data, we... more
Objectives Chronic obstructive pulmonary disease (COPD) phenotypes cover a range of lung abnormalities. To allow text mining methods to identify pertinent and potentially complex information about these phenotypes from textual data, we have developed a novel annotated corpus, which we use to train a neural network-based named entity recognizer to detect fine-grained COPD phenotypic information. Materials and methods Since COPD phenotype descriptions often mention other concepts within them (proteins, treatments, etc.), our corpus annotations include both outermost phenotype descriptions and concepts nested within them. Our neural layered bidirectional long short-term memory conditional random field (BiLSTM-CRF) network firstly recognizes nested mentions, which are fed into subsequent BiLSTM-CRF layers, to help to recognize enclosing phenotype mentions. Results Our corpus of 30 full papers (available at: http://www.nactem.ac.uk/COPD) is annotated by experts with 27 030 phenotype-rela...
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We previously identified dipeptidylpeptidase 10 () on chromosome 2 as a human asthma susceptibility gene, through positional cloning. Initial association results were confirmed in many subsequent association studies but the functional... more
We previously identified dipeptidylpeptidase 10 () on chromosome 2 as a human asthma susceptibility gene, through positional cloning. Initial association results were confirmed in many subsequent association studies but the functional role of DPP10 in asthma remains unclear. Using the MRC Harwell N-ethyl-N-nitrosourea (ENU) DNA archive, we identified a point mutation inthat caused an amino acid change from valine to aspartic acid in the β-propeller region of the protein. Mice carrying this point mutation were recovered and a congenic line was established (). Macroscopic examination and lung histology revealed no significant differences between wild-type andmice. However, after house dust mite (HDM) treatment,mutant mice showed significantly increased airway resistance in response to 100 mg/ml methacholine. Total serum IgE levels and bronchoalveolar lavage (BAL) eosinophil counts were significantly higher in homozygotes than in control mice after HDM treatment. DPP10 protein is prese...
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Fully automated text mining (TM) systems promote efficient literature searching, retrieval, and review but are not sufficient to produce ready-to-consume curated documents. These systems are not meant to replace biocurators, but instead... more
Fully automated text mining (TM) systems promote efficient literature searching, retrieval, and review but are not sufficient to produce ready-to-consume curated documents. These systems are not meant to replace biocurators, but instead to assist them in one or more literature curation steps. To do so, the user interface is an important aspect that needs to be considered for tool adoption. The BioCreative Interactive task (IAT) is a track designed for exploring user-system interactions, promoting development of useful TM tools, and providing a communication channel between the biocuration and the TM communities. In BioCreative V, the IAT track followed a format similar to previous interactive tracks, where the utility and usability of TM tools, as well as the generation of use cases, have been the focal points. The proposed curation tasks are user-centric and formally evaluated by biocurators. In BioCreative V IAT, seven TM systems and 43 biocurators participated. Two levels of user...
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The development of ontologies for describing animal behaviour has proved to be one of the most difficult of all scientific knowledge domains. Ranging from neurological processes to human emotions, the range and scope needed for such... more
The development of ontologies for describing animal behaviour has proved to be one of the most difficult of all scientific knowledge domains. Ranging from neurological processes to human emotions, the range and scope needed for such ontologies is highly challenging, but if data integration and computational tools such as automated reasoning are to be fully applied in this important area the underlying principles of these ontologies need to be better established and development needs detailed coordination. Whilst the state of scientific knowledge is always paramount in ontology and formal description framework design, this is a particular problem with neurobehavioural ontologies where our understanding of the relationship between behaviour and its underlying biophysical basis is currently in its infancy. In this commentary, we discuss some of the fundamental problems in designing and using behaviour ontologies, and present some of the best developed tools in this domain.
Research Interests: Genetics, Computer Science, Ontology, Animal Behavior, Biology, and 6 moreFormal Ontology, Medicine, Humans, Animals, Phenotype, and IDEF
Most genome-wide methylation studies (EWAS) of multifactorial disease traits use targeted arrays or enrichment methodologies preferentially covering CpG-dense regions, to characterize sufficiently large samples. To overcome this... more
Most genome-wide methylation studies (EWAS) of multifactorial disease traits use targeted arrays or enrichment methodologies preferentially covering CpG-dense regions, to characterize sufficiently large samples. To overcome this limitation, we present here a new customizable, cost-effective approach, methylC-capture sequencing (MCC-Seq), for sequencing functional methylomes, while simultaneously providing genetic variation information. To illustrate MCC-Seq, we use whole-genome bisulfite sequencing on adipose tissue (AT) samples and public databases to design AT-specific panels. We establish its efficiency for high-density interrogation of methylome variability by systematic comparisons with other approaches and demonstrate its applicability by identifying novel methylation variation within enhancers strongly correlated to plasma triglyceride and HDL-cholesterol, including at CD36. Our more comprehensive AT panel assesses tissue methylation and genotypes in parallel at ∼4 and ∼3 M s...
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Dietary calcium (Ca) positively modulates the susceptibility to colon cancer, but its effects on related or earlier colonic pathologies, such as inflammation and mucosal dysregulation, are poorly understood. We tested the effects of... more
Dietary calcium (Ca) positively modulates the susceptibility to colon cancer, but its effects on related or earlier colonic pathologies, such as inflammation and mucosal dysregulation, are poorly understood. We tested the effects of differing dietary Ca levels on acute dextran sulfate sodium (DSS)-induced colitis in mice. BALB/c mice received a normal Ca (NCa) diet (0.5% Ca), a high Ca (HCa) diet (1.5% Ca), a low Ca (LCa) diet (0.05% Ca), or a very low Ca (VLCa) diet (0.009% Ca) for 3 wk. Mucosal caspases 1, 3, and 9 were assessed by Western blotting, and the histological crypt score was assessed by microscopy. Half of the mice in each group received DSS (1.5%) for 20 d in their drinking water, and disease activity was assessed. Increasing or lowering dietary Ca increased mucosal caspases (P < 0.0001 vs. NCa). Crypt scores increased with decreasing dietary Ca levels (P < 0.0001, r = -0.675), indicating that elevated caspases in LCa groups reflected early subclinical inflammati...
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/ Thematic Poster Session / Tuesday, May 18/8:15 AM-4:00 PM / Area C34 NON-INVASIVE ASSESSMENT OF AIRWAYS DISEASE ... A, Hall G (First Level), Morial Convention Center ... Inflammatory Mediators Levels In Sputum Supernatant Of Normal... more
/ Thematic Poster Session / Tuesday, May 18/8:15 AM-4:00 PM / Area C34 NON-INVASIVE ASSESSMENT OF AIRWAYS DISEASE ... A, Hall G (First Level), Morial Convention Center ... Inflammatory Mediators Levels In Sputum Supernatant Of Normal Smokers And COPD Patients Are ...
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Research Interests: Genetics, Biology, Epigenetics, Medicine, Linear models, and 15 moreHumans, Methylation, Female, Male, DNA methylation, CpG islands, Gene Network, Aged, Middle Aged, Adult, Single Nucleotide Polymorphism, Quantitative Trait Loci, Biochemistry and cell biology, Epigenome, and Medical biochemistry and metabolomics
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Research Interests: Genetics, Biology, Medicine, Gene expression, Biological Sciences, and 15 moreHumans, Regulation of Gene Expression, Female, Heritability, Skin, Gene, Genetic linkage analysis, Aged, Middle Aged, Adult, Quantitative Trait Loci, Lymphocytes, Gene Expression Regulation, Medical and Health Sciences, and Subcutaneous fat
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Post-translational modifications of histones, particularly acetylation, are associated with the regulation of inflammatory gene expression. We used two animal models of inflammation of the bowel and biopsy samples from patients with... more
Post-translational modifications of histones, particularly acetylation, are associated with the regulation of inflammatory gene expression. We used two animal models of inflammation of the bowel and biopsy samples from patients with Crohn's disease (CD) to study the expression of acetylated histones (H) 3 and 4 in inflamed mucosa. Acetylation of histone H4 was significantly elevated in the inflamed mucosa in the trinitrobenzene sulfonic acid model of colitis particularly on lysine residues (K) 8 and 12 in contrast to non-inflamed tissue. In addition, acetylated H4 was localised to inflamed tissue and to Peyer's patches (PP) in dextran sulfate sodium (DSS)-treated rat models. Within the PP, H3 acetylation was detected in the mantle zone whereas H4 acetylation was seen in both the periphery and the germinal centre. Finally, acetylation of H4 was significantly upregulated in inflamed biopsies and PP from patients with CD. Enhanced acetylation of H4K5 and K16 was seen in the PP....
Research Interests: Immunology, IBD, Inflammation, Research, Medicine, and 15 moreGene expression, Inflammatory Bowel Disease, In Vitro, Regulatory T cells, Animal Model, Clinical Sciences, Colitis, Histones, Acetylation, Rat Model, Histone, Crohns Disease, Histone Acetylation, Intestinal Inflammation, and Pharmacology and pharmaceutical sciences
Chronic obstructive pulmonary disease (COPD) is a common chronic inflammatory disease of the lungs with little or no response to glucocorticoids and a high level of oxidative stress. Histone deacetylase (HDAC) activity is reduced in cells... more
Chronic obstructive pulmonary disease (COPD) is a common chronic inflammatory disease of the lungs with little or no response to glucocorticoids and a high level of oxidative stress. Histone deacetylase (HDAC) activity is reduced in cells of cigarette smokers, and low concentrations of theophylline can increase HDAC activity. We measured the effect of theophylline on HDAC activity and inflammatory gene expression in alveolar macrophages (AM) from patients with COPD. AM from normal smokers showed a decrease in HDAC activity compared with normal control subjects, and this was further reduced in COPD patients (51% decrease, P < 0.01). COPD AMs also showed increased basal release of IL-8 and TNF-α, which was poorly suppressed by dexamethasone. Theophylline induced a sixfold increase in HDAC activity in COPD AM lysates and significantly enhanced dexamethasone suppression of induced IL-8 release, an effect that was blocked by the HDAC inhibitor trichostatin A. Therefore, theophylline m...
Research Interests: Endocrinology, Asthma, Gene expression, Dexamethasone, Humans, and 15 moreCOPD, Female, HIstone Deacetylase, Glutathione, Association, Aged, Experimental Medicine, Chronic obstructive pulmonary disease, Alpha, Hydroxamic Acids, Enzyme Linked Immunosorbent Assay, Glucocorticoids, Histone deacetylases, Alveolar Macrophage, and Bronchodilator agents
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The 13th Annual European Respiratory Society congress was held recently (27 September – 1 October, 2003) at the International Conference Centre in Vienna. With over 14,800 delegates this was the largest respiratory meeting in the world... more
The 13th Annual European Respiratory Society congress was held recently (27 September – 1 October, 2003) at the International Conference Centre in Vienna. With over 14,800 delegates this was the largest respiratory meeting in the world this year. The meeting covered all areas of respiratory disease and treatments with a particular focus on asthma and chronic obstructive pulmonary disease (COPD). Asthma and COPD are among the most common diseases in the world, with an alarming increase in global prevalence [1,2]. Both diseases involve airway obstruction and chronic inflammation of the respiratory tract; however, the inflammation in asthma and COPD is markedly different in terms of the inflammatory cells involved, the mediators released and the inflammatory effects [3]. A particularly striking difference is the response to corticosteroids; asthma is controlled in most patients by low doses of inhaled corticosteroids, whereas high doses of inhaled corticosteroids are virtually ineffective in patients with COPD [3]. In COPD there is a marked increase in oxidative stress [3]. Understanding how oxidative stress attenuates the anti-inflammatory actions of corticosteroids may lead to the development of new therapeutic strategies for COPD [3]. One of the several sessions devoted to oxidative stress mechanisms shall be discussed, as well as one Assembly Symposium that was devoted to steroid resistance in lung diseases, which highlighted how, in certain instances, oxidant stress induced by cigarette smoke can attenuate corticosteroid actions in asthma.
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Glucocorticoids are highly effective in controlling chronic inflammatory diseases by inhibiting the expression of cytokines and chemokines. Glucocorticoids act through binding of their receptor resulting to inhibition of transcription... more
Glucocorticoids are highly effective in controlling chronic inflammatory diseases by inhibiting the expression of cytokines and chemokines. Glucocorticoids act through binding of their receptor resulting to inhibition of transcription factors such as nuclear factor kappa B (NF-kappa B). This may occur via the transcription integrator protein, CREB binding protein (CBP), which has intrinsic histone acetylase (HAT) activity. Interleukin (IL)-1 beta caused a significant increase in NF-kappa B-mediated granulocyte/macrophage colony stimulating factor (GM-CSF) release, which was inhibited by the glucocorticoid mometasone furoate (MF) (EC(50)=2 x 10(-11) M). This effect was inhibited by CBP over-expression. The role of histone acetylation and DNA methylation in the transcription of GM-CSF was indicated by trichostatin A (TSA), an inhibitor of histone deacetylases, and 5-azacytidine (5-aza), a DNA methylase inhibitor, to increase GM-CSF expression partially blocking glucocorticoid inhibition of IL-1 beta-stimulated GM-CSF release. These data suggest that the mechanism of glucocorticoid action in suppressing interleukin-1 beta-stimulated GM-CSF release in A549 cells may involve modulation of CBP-mediated histone-acetylase activity and DNA methylation.
Research Interests: Biology, Epigenetics, Medicine, Dexamethasone, Humans, and 15 moreHIstone Deacetylase, DNA methylation, Transcription Factor, Inflammatory disease, European, Histones, Histone acetyltransferases, Topical Drug Administration, Acetylation, Nuclear Factor-kappaB, Histone, Glucocorticoids, Histone Acetylation, Interleukin, and Pharmacology and pharmaceutical sciences
Research Interests: Biology, Asthma, Enzyme Inhibitors, Epigenetics, Epigenomics, and 15 moreHumans, Cancer epigenetics, Animals, HIstone Deacetylase, DNA methylation, Histones, Histone acetyltransferases, Acetylation, Immune Tolerance, Histone, Hydroxamic Acids, Gene Expression Regulation, Histone deacetylase inhibitors, Histone deacetylases, and Airway Inflammation
Summary There is accumulating evidence that the transrepressional effect of glucocorticoids in down-regulating proinflammatory gene expression might be regulated by an action on histone acetylation. To investigate this, we studied the... more
Summary There is accumulating evidence that the transrepressional effect of glucocorticoids in down-regulating proinflammatory gene expression might be regulated by an action on histone acetylation. To investigate this, we studied the effect of two glucocorticoids (dexamethasone and triamcinolone acetonide) on reducing lipopolysaccharide (LPS)- and tumour necrosis factor (TNF)-α-induced interleukin (IL)-8 release in a monocytic cell line and two lymphocytic cell lines (HUT-78 and Jurkat). The effect of the histone deacetylase inhibitor trichostatin A (TSA) on LPS- and TNF-α-induced IL-8 release and its repression by glucocorticoids was also examined. LPS and TNF-α induced IL-8 release in all three cell lines and this induction was inhibited by both dexamethasone and triamcinolone. Pretreatment of cells with TSA enhanced basal and LPS- and TNFα-stimulated IL-8 release in all three cell lines. TSA also attenuated the inhibitory effect of glucocorticoids on stimulated IL-8 release. Chr...
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Gene expression, at least in part, is regulated by changes in histone acetylation status induced by activation of the proinflammatory redox-sensitive transcription factors activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB).... more
Gene expression, at least in part, is regulated by changes in histone acetylation status induced by activation of the proinflammatory redox-sensitive transcription factors activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB). Hyperacetylated histone is associated with open actively transcribed DNA and enhanced inflammatory gene expression. In contrast, hypoacetylated histone is linked to a closed repressed DNA state and a lack of gene expression. The degree of inflammatory gene expression is a result of a balance between histone acetylation and histone deacetylation. One of the major mechanisms of glucocorticoid function is to recruit histone deacetylase enzymes to the site of active gene expression, thus reducing inflammation. Oxidative stress can enhance inflammatory gene expression by further stimulating AP-1- and NF-kappaB-mediated gene expression and elevating histone acetylation. In addition, oxidants can reduce glucocorticoid function by attenuating histone deacetylase activity and expression. Thus, oxidant stress, acting through changes in chromatin structure, can enhance inflammation and induce a state of relative glucocorticoid insensitivity. This may account for the lack of glucocorticoid sensitivity in patients with chronic obstructive pulmonary disease. Antioxidants should reduce the inflammation and restore glucocorticoid sensitivity in these subjects.
Research Interests: Chemistry, Inflammation, Oxidative Stress, Medicine, DNA, and 15 moreAntioxidants, Humans, Animals, HIstone Deacetylase, Chromatin, Histones, HDAC, Acetylation, Histone, Glucocorticoids, Oxidants, Gene Expression Regulation, Histone deacetylases, Inflammatory response, and Medical biochemistry and metabolomics
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