ORCID Profile
0000-0002-2853-806X
Current Organisations
The Francis Crick Institute
,
University of Oxford
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Publisher: Elsevier BV
Date: 08-2007
Publisher: Elsevier BV
Date: 06-2003
Publisher: Public Library of Science (PLoS)
Date: 06-07-2015
Publisher: Elsevier BV
Date: 05-2011
Publisher: American Chemical Society (ACS)
Date: 11-07-2012
DOI: 10.1021/JM300677J
Publisher: Wiley
Date: 25-05-2012
Publisher: Elsevier BV
Date: 06-1996
Publisher: Elsevier BV
Date: 09-2004
Publisher: Elsevier BV
Date: 10-2004
Publisher: American Association for the Advancement of Science (AAAS)
Date: 05-07-2019
Abstract: The ability to sense and respond to changes in oxygen levels is critical for most forms of life. To date, mechanistic studies of this process in mammals have focused on the oxygen-sensitive stability of a transcription factor called hypoxia-inducible factor. Masson et al. discovered an enzymatic oxygen sensor in humans that is functionally identical to plant cysteine oxidases, enzymes that control responses to hypoxia in plants. The human and plant enzymes convert the N-terminal cysteine in substrate proteins to cysteine sulfinic acid, a modification that ultimately targets the proteins for degradation. Oxygen sensing is impaired in many human diseases, and further study of the human enzyme could help in the development of strategies for therapeutic intervention. Science , this issue p. 65
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7SC02103H
Abstract: Four compounds in clinical trials for anaemia treatment are potent inhibitors of the hypoxia inducible factor (HIF) prolyl hydroxylases (PHDs), but differ in potency and how they interact with HIF at the PHD active site.
Publisher: Elsevier BV
Date: 03-1998
DOI: 10.1016/S1357-4310(97)01198-2
Abstract: The optimal delivery of oxygen to tissues is essential both to ensure adequate energy provision and to avoid the toxic effects of higher oxygen concentrations. For this to occur, organisms must be able to sense oxygen and respond to changes in oxygen tension by altering gene expression. The analysis of the regulation of erythropoiesis has provided important insights into the mechanisms of oxygen-regulated gene expression. These mechanisms have a role in the regulation of many genes, in many cell types and appear to be of relevance to many common pathologies in which disturbances of oxygen supply are central.
Publisher: Portland Press Ltd.
Date: 14-06-2006
DOI: 10.1042/BJ20051996
Abstract: The heterodimeric transcription factor HIF (hypoxia-inducible factor) is central to the regulation of gene expression by oxygen. Three oxygen-dependent prolyl hydroxylase enzymes [PHD1 (prolyl hydroxylase domain 1), PHD2 and PHD3] control the abundance of HIF. In the presence of oxygen, they hydroxylate specific proline residues in HIF-α, allowing recognition by pVHL (von Hippel-Lindau protein) and subsequent ubiquitylation and proteasomal destruction. The precise roles and regulation of these enzymes are therefore of particular importance in understanding the physiological and pathological responses to hypoxia. In the present study, we define the existence of two species of PHD1 and provide evidence that they are generated by alternative translational initiation. We demonstrate that these alternative forms are both biologically active with similar HIF prolyl hydroxylase activity but that they differ in their responses to oestrogen, cell confluence and proteasomal inhibition. We show that the two PHD1 species are subject to proteolytic regulation but differ markedly in their protein stability. Though each isoform has the potential to interact with members of the Siah (seven in absentia homologue) ubiquitin ligase family, genetic studies indicated that other proteolytic mechanisms are responsible for control of stability under the conditions examined. The data define the existence of a further level of control in the pathway that regulates cellular responses to hypoxia.
Publisher: Elsevier BV
Date: 06-2006
Publisher: Elsevier BV
Date: 10-2011
Publisher: Elsevier BV
Date: 02-2014
Publisher: Elsevier BV
Date: 02-1997
DOI: 10.1038/KI.1997.72
Abstract: As the relationship between the built environment and the sense of human experience becomes increasingly important, emotional geography has begun to focus on sentiments in space and time and improving the quality of urban construction from the perspective of public emotion and mental health. While youth is a powerful force in urban construction, there are no studies on the relationship between urban youth sentiments and the built environment. With the development of the Internet, social media has provided a large source of data for the metrics of youth sentiment. Based on data from more than 10,000 geolocated Sina Weibo comments posted over one week (from 19 to 25 July 2021) in Shanghai and using a machine learning algorithm for attention mechanism, this study calculates the sentiment label and sentiment intensity of each comment. Ten elements in five aspects were selected to assess the built environment at different scales and also to explore the correlations between built environment elements and sentiment intensity at different scales. The study finds that the overall sentiment of Shanghai youth tends to be negative. Sentiment intensity is significantly associated with most built environment elements at smaller scales. Urban youth have a higher proportion of both happy and sad sentiments, within which sad sentiments are more closely related to the built environment and are significantly related to all built environment elements. This study uses a deep learning algorithm to improve the accuracy of sentiment classification and confirms that the built environment has a great impact on sentiment. This research can help cities develop built environment optimization measures and policies to create positive emotional environments and enhance the well-being of urban youth.
Publisher: Elsevier BV
Date: 06-2002
DOI: 10.1016/S0960-894X(02)00219-6
Abstract: The hypoxic response in animals is mediated by hydroxylation of proline residues in the alpha-subunit of hypoxia inducible factor (HIF). Hydroxylation is catalysed by prolyl-4-hydroxylases (PHD isozymes in humans) which are iron(II) and 2-oxoglutarate dependent oxygenases. Mutation of the arginine proposed to bind 2-oxoglutarate and of the 2His-1-carboxylate iron(II) binding motif in PHD1 dramatically reduces its activity. The source of the oxygen of the product alcohol is (>95%) dioxygen.
Publisher: MDPI AG
Date: 22-09-2020
Abstract: Although drowning is a common phenomenon, the behaviour of drowning persons is poorly understood. The purpose of this study is to provide a quantitative and qualitative analysis of this behaviour. This was an observational study of drowning videos observed by 20 international experts in the field of water safety. For quantitative analysis, each video was analysed with Lince observation software by four participants. A Nominal Group Technique generated input for the qualitative analysis and the two principal investigators conducted a post-hoc analysis. A total of 87.5% of the 23 videos showed drowning in swimming pools, 50% of the drowned persons were male, and 58.3% were children or teenagers. Nineteen persons were rescued before unconsciousness and showed just the beginning of downing behaviour. Another five were rescued after unconsciousness, which allowed the observation of their drowning behaviour from the beginning to the end. Significant differences were found comparing both groups regarding the length of disappearances underwater, number, and length of resurfacing (resp. p = 0.003, 0.016, 0.005) and the interval from the beginning of the incident to the rescue (p = 0.004). All persons drowned within 2 min. The qualitative analysis showed previously suggested behaviour patterns (immediate disappearance n = 5, distress n = 6, instinctive drowning response n = 6, climbing ladder motion n = 3) but also a striking new pattern (backward water milling n = 19). This study confirms previous assumptions of drowning behaviour and provides novel evidence-based information about the large variety of visible behaviours of drowning persons. New behaviours, which mainly include high-frequency resurfacing during a struggle for less than 2 min and backward water milling, have been recognised in this study.
Publisher: Elsevier BV
Date: 05-1989
DOI: 10.1038/KI.1989.117
Abstract: To assess the prevalence and patterns of cardiac abnormalities as detected by cardiac magnetic resonance imaging (MRI) in systemic sclerosis (SSc). Fifty-two consecutive patients with SSc underwent cardiac MRI to determine morphological, functional, perfusion at rest and delayed enhancement abnormalities. At least one abnormality on cardiac MRI was observed in 39/52 patients (75%). Increased myocardial signal intensity in T2 was observed in 6 patients (12%), thinning of left ventricle (LV) myocardium in 15 patients (29%) and pericardial effusion in 10 patients (19%). LV and right ventricle (RV) ejection fractions were altered in 12 patients (23%) and 11 patients (21%), respectively. LV diastolic dysfunction was found in 15/43 patients (35%). LV kinetic abnormalities were found in 16/52 patients (31%) and myocardial delayed contrast enhancement was detected in 11/52 patients (21%). No perfusion defects at rest were found. Patients with limited SSc had similar MRI abnormalities to patients with diffuse SSc. Seven of 40 patients (17%) without pulmonary arterial hypertension had RV dilatation. This study shows that MRI is a reliable and sensitive technique for diagnosing heart involvement in SSc and for analysing its mechanisms, including its inflammatory, microvascular and fibrotic components. Compared with echocardiography, MRI appears to provide additional information by visualising myocardial fibrosis and inflammation. RV dilatation appeared to be non-specific for pulmonary arterial hypertension but could also reflect myocardial involvement related to SSc. Further studies are needed to determine whether cardiac MRI abnormalities have an impact on the prognosis and treatment strategy.
Publisher: Wiley
Date: 11-1995
DOI: 10.1111/J.1432-1033.1995.092_C.X
Abstract: Recent studies on the induction of erythropoietin gene expression by hypoxia have indicated that erythropoietin forms part of a widely operative system of gene regulation by oxygen. Similar responses to hypoxia, cobaltous ions and desferrioxamine have indicated that the action of these agents is closely connected with the mechanism of oxygen sensing. To consider further the mechanisms underlying these responses, the effect of iodonium compounds was tested on five genes which show oxygen-regulated expression erythropoietin, vascular endothelial growth factor (VEGF), lactate dehydrogenase-A (LDH-A), glucose transporter-1 (GLUT-1) and placental growth factor (PLGF). In each case, the response to hypoxia was specifically inhibited by low doses of diphenylene iodonium (Ph1I+). This occurred irrespective of whether the hypoxic response was induction of gene expression (erythropoietin, vascular endothelial growth factor, lactate dehydrogenase-A, glucose transporter-1) or inhibition of gene expression (PLGF). In contrast, the induction of gene expression by cobaltous ions or desferrioxamine was not inhibited by Ph2I+. The differential action of Ph2I+ on the response to hypoxia versus the response to cobaltous ions or desferrioxamine must reflect a difference in the mechanism of action of these stimuli, which will require accommodation in any model of the oxygen-sensing mechanism. Based on the known properties of Ph2I+, the implication of these findings is that the mechanism of oxygen sensing most probably involves the operation of a flavoprotein oxidoreductase.
Publisher: Elsevier BV
Date: 04-1997
Publisher: Proceedings of the National Academy of Sciences
Date: 22-07-1997
Abstract: Recent studies of tissue culture cells have defined a widespread system of oxygen-regulated gene expression based on the activation of a heterodimeric transcription factor termed hypoxia-inducible factor-1 (HIF-1). To determine whether the HIF-1 transcriptional response is activated within solid tumors and to define the consequences, we have studied tumor xenografts of a set of hepatoma (Hepa-1) cells that are wild type (wt), deficient (c4), and revertant (Rc4) for an obligatory component of the HIF-1 heterodimer, HIF-1β. Because HIF-1β is also essential for the xenobiotic response (in which it is termed the aryl hydrocarbon receptor nuclear translocator), we also studied c31 cells, which have a different defect in the xenobiotic response and form the HIF-1 complex normally. Two genes that show different degrees of HIF-1-dependent hypoxia-inducible expression in cell culture were selected for analysis—the glucose transporter, GLUT3, and vascular endothelial growth factor (VEGF). In situ hybridization showed intense focal induction of gene expression in tumors derived from wt, Rc4, and c31 cells, which was reduced (VEGF) or not seen (GLUT3) in those derived from c4 cells. In association with these changes, tumors of c4 cells had reduced vascularity and grew more slowly. These findings show that HIF-1 activation occurs in hypoxic regions of tumors and demonstrate a major influence on gene expression, tumor angiogenesis, and growth.
Publisher: Public Library of Science (PLoS)
Date: 07-09-2004
Publisher: Informa UK Limited
Date: 10-2002
Publisher: INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols
Date: 16-03-2022
DOI: 10.37766/INPLASY2022.3.0074
Abstract: Review question / Objective: This systematic review aims to provide evidence of attributes for the concept and structure of the term physical literacy for its understanding in Spanish-speaking countries mainly from Latin America and Spain. Condition being studied: Many definitions of physical literacy refer to a lifelong participation in physical activity, presenting multiple benefits for people's health. Therefore, many organizations (universities, government entities, research groups) in different countries promote interventions for its development. However, the approach to these interventions is based on different concepts and attributes, depending on the country where they are organized. Taking into account that physical literacy is a global approach that is being disseminated worldwide, it is necessary to analyze its different conceptualizations, carrying out a systematic review that presents evidence of how physical literacy is being understood around the world. By describing the attributes characterizing the concept and structure of physical literacy, we aim to contextualize and enhance the understanding of physical literacy in Spanish-speaking countries and regions from Spain, Latin America, Africa and Asia which involve more than 500 millions of people.
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 11-07-2014
Publisher: Springer Science and Business Media LLC
Date: 26-08-2016
DOI: 10.1038/NCOMMS12673
Abstract: The response to hypoxia in animals involves the expression of multiple genes regulated by the αβ-hypoxia-inducible transcription factors (HIFs). The hypoxia-sensing mechanism involves oxygen limited hydroxylation of prolyl residues in the N- and C-terminal oxygen-dependent degradation domains (NODD and CODD) of HIFα isoforms, as catalysed by prolyl hydroxylases (PHD 1–3). Prolyl hydroxylation promotes binding of HIFα to the von Hippel–Lindau protein (VHL)–elongin B/C complex, thus signalling for proteosomal degradation of HIFα. We reveal that certain PHD2 variants linked to familial erythrocytosis and cancer are highly selective for CODD or NODD. Crystalline and solution state studies coupled to kinetic and cellular analyses reveal how wild-type and variant PHDs achieve ODD selectivity via different dynamic interactions involving loop and C-terminal regions. The results inform on how HIF target gene selectivity is achieved and will be of use in developing selective PHD inhibitors.
Publisher: Portland Press Ltd.
Date: 26-11-2008
DOI: 10.1042/BJ20081238
Abstract: The transcription factor HIF (hypoxia-inducible factor) mediates a highly pleiotrophic response to hypoxia. Many recent studies have focused on defining the extent of this transcriptional response. In the present study we have analysed regulation by hypoxia among transcripts encoding human Fe(II)- and 2-oxoglutarate-dependent oxygenases. Our results show that many of these genes are regulated by hypoxia and define two groups of histone demethylases as new classes of hypoxia-regulated genes. Patterns of induction were consistent across a range of cell lines with JMJD1A (where JMJD is Jumonji-domain containing) and JMJD2B demonstrating robust, and JMJD2C more modest, up-regulation by hypoxia. Functional genetic and chromatin immunoprecipitation studies demonstrated the importance of HIF-1α in mediating these responses. Given the importance of histone methylation status in defining patterns of gene expression under different physiological and pathophysiological conditions, these findings predict a role for the HIF system in epigenetic regulation.
Publisher: Oxford University Press (OUP)
Date: 11-1997
Publisher: Elsevier BV
Date: 07-2002
Publisher: Portland Press Ltd.
Date: 02-1996
DOI: 10.1042/BJ3130809
Abstract: Recent studies have indicated that regulatory mechanisms underlying the oxygen-dependent expression of the haematopoietic growth factor erythropoietin are widely operative in non-erythropoietin-producing cells and are involved in the regulation of other genes. An important characteristic of this system is that the inducible response to hypoxia is mimicked by exposure to particular transition metals such as cobaltous ions, and by iron chelation. We have investigated the extent of operation of this system in the regulation of a range of genes concerned with energy metabolism. The effects of hypoxia (1% oxygen), cobaltous ions and desferrioxamine on gene expression in tissue-culture cells was studied using RNase protection assays. Hypoxia induced the expression of glucose transporters in an isoform-specific manner GLUT-1 and GLUT-3 were induced by hypoxia, whereas expression of GLUT-2 was decreased. Isoenzyme-specific regulation by hypoxia was also observed for genes encoding phosphofructokinase, aldolase and lactate dehydrogenase. For all of these genes, responses to cobaltous ions and desferrioxamine correlated in both direction and magnitude with the response to hypoxia. In contrast, a reduction in mitochondrial transcripts was observed in hypoxia, but these changes were not mimicked by either cobaltous ions or desferrioxamine. These findings indicate that similarities with erythropoietin regulation extend to the oxygen-dependent regulation of genes encoding glucose transporters and glycolytic enzymes but not to the regulation of mitochondrial transcripts, and they show that in glucose metabolism regulation by this system is isoenzyme- or isoform-specific.
Publisher: Springer Science and Business Media LLC
Date: 18-05-2201
DOI: 10.1038/NG.3304
Publisher: Elsevier BV
Date: 10-2001
DOI: 10.1016/S0092-8674(01)00507-4
Abstract: HIF is a transcriptional complex that plays a central role in mammalian oxygen homeostasis. Recent studies have defined posttranslational modification by prolyl hydroxylation as a key regulatory event that targets HIF-alpha subunits for proteasomal destruction via the von Hippel-Lindau ubiquitylation complex. Here, we define a conserved HIF-VHL-prolyl hydroxylase pathway in C. elegans, and use a genetic approach to identify EGL-9 as a dioxygenase that regulates HIF by prolyl hydroxylation. In mammalian cells, we show that the HIF-prolyl hydroxylases are represented by a series of isoforms bearing a conserved 2-histidine-1-carboxylate iron coordination motif at the catalytic site. Direct modulation of recombinant enzyme activity by graded hypoxia, iron chelation, and cobaltous ions mirrors the characteristics of HIF induction in vivo, fulfilling requirements for these enzymes being oxygen sensors that regulate HIF.
Publisher: Elsevier BV
Date: 06-2009
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Peter Ratcliffe.