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Kharlyngdoh, J. B., Pradhan, A. & Olsson, P.-E. (2018). Androgen receptor modulation following combination exposure to brominated flame-retardants. Scientific Reports, 8(1), Article ID 4843.
Open this publication in new window or tab >>Androgen receptor modulation following combination exposure to brominated flame-retardants
2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, no 1, article id 4843Article in journal (Refereed) Published
Abstract [en]

Endocrine disrupting compounds can interfere with androgen receptor (AR) signaling and disrupt steroidogenesis leading to reproductive failure. The brominated flame-retardant (BFR) 1, 2-dibromo-4-(1, 2-dibromoethyl) cyclohexane (TBECH), is an agonist to human, chicken and zebrafish AR. Recently another group of alternative BFRs, allyl 2, 4, 6-tribromophenyl ether (ATE), and 2, 3-dibromopropyl 2, 4, 6-tribromophenyl ether (DPTE) along with its metabolite 2-bromoallyl 2, 4, 6-tribromophenyl ether (BATE) were identified as potent human AR antagonists. These alternative BFRs are present in the environment. The aim of the present study was to determine the effect of mixed exposures to the AR agonist and the AR antagonists at environmentally relevant concentrations. In vitro reporter luciferase assay showed that the AR antagonists, when present at concentration higher than TBECH, were able to inhibit TBECH-mediated AR activity. These AR antagonists also promoted AR nuclear translocation. In vitro gene expression analysis in the non-tumorigenic human prostate epithelial cell RWPE1 showed that TBECH induced AR target genes whereas DPTE repressed these genes. Further analysis of steroidogenic genes showed that TBECH up-regulated most of the genes while DPTE down-regulated the same genes. The results indicate that when TBECH and DPTE are present together they will antagonize each other, thereby reducing their individual effects.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:oru:diva-66052 (URN)10.1038/s41598-018-23181-0 (DOI)000427688100036 ()29556062 (PubMedID)2-s2.0-85044191096 (Scopus ID)
Funder
Knowledge Foundation
Note

Funding Agency:

Örebro University

Available from: 2018-03-27 Created: 2018-03-27 Last updated: 2018-08-20Bibliographically approved
Pradhan, A., Olsson, P.-E. & Jass, J. (2018). Di(2-ethylhexyl) phthalate and diethyl phthalate disrupt lipid metabolism, reduce fecundity and shortens lifespan of Caenorhabditis elegans. Chemosphere, 190, 375-382
Open this publication in new window or tab >>Di(2-ethylhexyl) phthalate and diethyl phthalate disrupt lipid metabolism, reduce fecundity and shortens lifespan of Caenorhabditis elegans
2018 (English)In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 190, p. 375-382Article in journal (Refereed) Published
Abstract [en]

The widespread use of phthalates is of major concern as they have adverse effects on many different physiological functions, including reproduction, metabolism and cell differentiation. The aim of this study was to compare the toxicity of the widely-used di (2-ethydlhexyl) phthalate (DEHP) with its substitute, diethyl phthalate (DEP). We analyzed the toxicity of these two phthalates using Caenorhabditis elegans as a model system. Gene expression analysis following exposure during the L1 to young adult stage showed that DEHP and DEP alter the expression of genes involved in lipid metabolism and stress response. Genes associated with lipid metabolism, including fasn-1, pod-2, fat-5, acs-6 and sbp-1, and vitellogenin were upregulated. Among the stress response genes, ced-1 wah-1, daf-21 and gst-4 were upregulated, while cd-1, cdf-2 and the heat shock proteins (hsp-16.1, hsp-16.48 and sip-1) were down regulated. Lipid staining revealed that DEHP significantly increased lipid content following 1 mu M exposure, however, DEP required 10 mu M exposure to elicit an effect. Both DEHP and DEP reduced the fecundity at 1 mu M concentration. Lifespan analysis indicated that DEHP and DEP reduced the average lifespan from 14 days in unexposed worms to 13 and 12 days, respectively. Expression of lifespan associated genes showed a correlation to shortened lifespan in the exposed groups. As reported previously, our data also indicates that the banned DEHP is toxic to C. elegans, however its substitute DEP has not been previously tested in this model organism and our data revealed that DEP is equally potent as DEHP in regulating C. elegans physiological functions.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Plasticizer, Metabolism, Reproduction, Toxicity, Longevity
National Category
Environmental Sciences
Identifiers
urn:nbn:se:oru:diva-62890 (URN)10.1016/j.chemosphere.2017.09.123 (DOI)000414881600041 ()29020644 (PubMedID)2-s2.0-85030660035 (Scopus ID)
Funder
Swedish Research Council, 201504600Knowledge Foundation, 20140180 20150084
Available from: 2017-12-01 Created: 2017-12-01 Last updated: 2018-01-12Bibliographically approved
Pradhan, A. & Olsson, P.-E. (2018). Germ cell depletion in zebrafish leads to incomplete masculinization of the brain. General and Comparative Endocrinology, 265(SI), 15-21
Open this publication in new window or tab >>Germ cell depletion in zebrafish leads to incomplete masculinization of the brain
2018 (English)In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 265, no SI, p. 15-21Article in journal (Refereed) Published
Abstract [en]

Zebrafish sex differentiation is under the control of multiple genes, but also relies on germ cell number for gonadal development. Morpholino and chemical mediated germ cell depletion leads to sterile male development in zebrafish. In this study we produced sterile males, using a dead end gene morpholino, to determine gonadal-brain interactions. Germ cell depletion following dnd inhibition downregulated the germ cell markers, vasa and ziwi, and later the larvae developed as sterile males. Despite lacking proper testis, the gonadal 11-ketotestosterone (11-KT) and estradiol (E2) levels of sterile males were similar to wild type males. Qualitative analysis of sexual behavior of sterile males demonstrated that they behaved like wild type males. Furthermore, we observed that brain 11-KT and E2 levels in sterile males remained the same as in the wild type males. In female brain, 11-KT was lower in comparison to wild type males and sterile males, while E2 was higher when compared to wild type males. qRT-PCR analysis revealed that the liver transcript profile of sterile adult males was similar to wild type males while the brain transcript profile was similar to wild type females. The results demonstrate that proper testis development may not be a prerequisite for male brain development in zebrafish but that it may be needed to fully masculinize the brain.

Place, publisher, year, edition, pages
Academic Press, 2018
Keywords
Dimorphism, Gonads, Reproduction, Sex differentiation, Steroid hormone
National Category
Developmental Biology
Identifiers
urn:nbn:se:oru:diva-68509 (URN)10.1016/j.ygcen.2018.02.001 (DOI)000442712600003 ()29408375 (PubMedID)2-s2.0-85044373533 (Scopus ID)
Funder
Swedish Research Council
Note

Funding Agency:

Örebro University 

Available from: 2018-08-17 Created: 2018-08-17 Last updated: 2018-09-06Bibliographically approved
Pradhan, A., Ivarsson, P., Ragnvaldsson, D., Berg, H., Jass, J. & Olsson, P.-E. (2017). Transcriptional responses of zebrafish to complex metal mixtures in laboratory studies overestimates the responses observed with environmental water. Science of the Total Environment, 584-585, 1138-1146
Open this publication in new window or tab >>Transcriptional responses of zebrafish to complex metal mixtures in laboratory studies overestimates the responses observed with environmental water
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2017 (English)In: Science of the Total Environment, ISSN 0048-9697, E-ISSN 1879-1026, Vol. 584-585, p. 1138-1146Article in journal (Refereed) Published
Abstract [en]

Metals released into the environment continue to be of concern for human health. However, risk assessment of metal exposure is often based on total metal levels and usually does not take bioavailability data, metal speciation or matrix effects into consideration. The continued development of biological endpoint analyses are therefore of high importance for improved eco-toxicological risk analyses. While there is an on-going debate concerning synergistic or additive effects of low-level mixed exposures there is little environmental data confirming the observations obtained from laboratory experiments. In the present study we utilized qRT-PCR analysis to identify key metal response genes to develop a method for biomonitoring and risk-assessment of metal pollution. The gene expression patterns were determined for juvenile zebrafish exposed to waters from sites down-stream of a closed mining operation. Genes representing different physiological processes including stress response, inflammation, apoptosis, drug metabolism, ion channels and receptors, and genotoxicity were analyzed. The gene expression patterns of zebrafish exposed to laboratory prepared metal mixes were compared to the patterns obtained with fish exposed to the environmental samples with the same metal composition and concentrations. Exposure to environmental samples resulted in fewer alterations in gene expression compared to laboratory mixes. A biotic ligand model (BLM) was used to approximate the bioavailability of the metals in the environmental setting. However, the BLM results were not in agreement with the experimental data, suggesting that the BLM may be overestimating the risk in the environment. The present study therefore supports the inclusion of site-specific biological analyses to complement the present chemical based assays used for environmental risk-assessment.

Place, publisher, year, edition, pages
Amsterdam, Netherlands: Elsevier, 2017
Keywords
Cocktail effect; Synergistic effects; Risk-assessment; Toxicogenetics; Bioavailability; Metal speciation
National Category
Environmental Sciences
Research subject
Enviromental Science
Identifiers
urn:nbn:se:oru:diva-55403 (URN)10.1016/j.scitotenv.2017.01.174 (DOI)000399358500112 ()28159303 (PubMedID)2-s2.0-85011082322 (Scopus ID)
Funder
Swedish Research Council, 20110183
Note

Funding agencies:

Örebro University J61900

Available from: 2017-03-10 Created: 2017-03-10 Last updated: 2017-10-18Bibliographically approved
Pradhan, A. & Olsson, P.-E. (2016). Regulation of zebrafish gonadal sex differentiation. AIMS Molecular Science, 3(4), 567-584
Open this publication in new window or tab >>Regulation of zebrafish gonadal sex differentiation
2016 (English)In: AIMS Molecular Science, ISSN 2372-028X, Vol. 3, no 4, p. 567-584Article, review/survey (Refereed) Published
Abstract [en]

While the master regulator gene Sry on the mammalian Y chromosome controls the switch for initiating male sex differentiation, many other species rely on environmental factors for gonadal sex differentiation. Yet other species, like zebrafish, appears to rely on a multitude of genetic cues for gonadal sex differentiation. Zebrafish gonadal differentiation initiates with the onset of a juvenile ovary stage and depending on the influence of unknown genetic factors either maintains oocyte development or initiate apoptotic processes to override the female differentiation pathway. In this review, we explore the role of different factors and genes that have been reported to influence zebrafish gonadal sex differentiation. We also give a brief insight of primordial germ cell (PGC) involvement in shaping male and female signaling pathway in gonadal development.

Place, publisher, year, edition, pages
American Institute of Mathematical Sciences, 2016
Keywords
NF kappa B, prostaglandin, retinoic acid, gonads, primordial germ cell, gene regulation, sex chromosome
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:oru:diva-55087 (URN)10.3934/molsci.2016.4.567 (DOI)000390892700005 ()
Funder
Swedish Research CouncilKnowledge Foundation
Note

Funding Agency:

Örebro University

Available from: 2017-01-31 Created: 2017-01-31 Last updated: 2017-10-18Bibliographically approved
Kharlyngdoh, J. B., Asnake, S., Pradhan, A. & Olsson, P.-E. (2016). TBECH, 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane, alters androgen receptor regulation in response to mutations associated with prostate cancer. Toxicology and Applied Pharmacology, 307, 91-101
Open this publication in new window or tab >>TBECH, 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane, alters androgen receptor regulation in response to mutations associated with prostate cancer
2016 (English)In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 307, p. 91-101Article in journal (Refereed) Published
Abstract [en]

Point mutations in the AR ligand-binding domain (LBD) can result in altered AR structures leading to changes of ligand specificity and functions. AR mutations associated to prostate cancer (PCa) have been shown to result in receptor activation by non-androgenic substances and anti-androgenic drugs. Two AR mutations known to alter the function of anti-androgens are the ART877A mutation, which is frequently detected mutation in PCa tumors and the ARW741C that is rare and has been derived in vitro following exposure of cells to the anti-androgen bicalutamide. AR activation by non-androgenic environmental substances has been suggested to affect PCa progression. In the present study we investigated the effect of AR mutations (ARW741C and ART877A) on the transcriptional activation following exposure of cells to an androgenic brominated flame retardant, 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane (TBECH, also named DBE-DBCH). The AR mutations resulted in higher interaction energies and increased transcriptional activation in response to TBECH diastereomer exposures. The ART877A mutation rendered AR highly responsive to low levels of DHT and TBECH and led to increased AR nuclear translocation. Gene expression analysis showed a stronger induction of AR target genes in LNCaP cells (ART877A) compared to T-47D cells (ARWT) following TBECH exposure. Furthermore, AR knockdown experiments confirmed the AR dependency of these responses. The higher sensitivity of ART877A and ARW741C to low levels of TBECH suggests that cells with these AR mutations are more susceptible to androgenic endocrine disrupters.

Place, publisher, year, edition, pages
Elsevier, 2016
Keywords
Steroid hormone, endocrine disrupting compounds, nuclear localization, receptor, nuclear localization
National Category
Cell Biology Pharmacology and Toxicology
Identifiers
urn:nbn:se:oru:diva-51471 (URN)10.1016/j.taap.2016.07.018 (DOI)000382417400009 ()27473015 (PubMedID)2-s2.0-84980328031 (Scopus ID)
Funder
Knowledge Foundation
Note

Funding Agency:

Örebro University, Sweden 

Available from: 2016-08-05 Created: 2016-08-02 Last updated: 2018-01-10Bibliographically approved
Kumar, R., Pradhan, A., Khan, F. A., Lindström, P., Ragnvaldsson, D., Ivarsson, P., . . . Jass, J. (2015). Comparative analysis of stress induced gene expression in caenorhabditis elegans following exposure to environmental and lab reconstituted complex metal mixture. PLoS ONE, 10(7), Article ID e0132896.
Open this publication in new window or tab >>Comparative analysis of stress induced gene expression in caenorhabditis elegans following exposure to environmental and lab reconstituted complex metal mixture
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, article id e0132896Article in journal (Refereed) Published
Abstract [en]

Metals are essential for many physiological processes and are ubiquitously present in the environment. However, high metal concentrations can be harmful to organisms and lead to physiological stress and diseases. The accumulation of transition metals in the environment due to either natural processes or anthropogenic activities such as mining results in the contamination of water and soil environments. The present study used Caenorhabditis elegans to evaluate gene expression as an indicator of physiological response, following exposure to water collected from three different locations downstream of a Swedish mining site and a lab reconstituted metal mixture. Our results indicated that the reconstituted metal mixture exerted a direct stress response in C. elegans whereas the environmental waters elicited either a diminished or abrogated response. This suggests that it is not sufficient to use the biological effects observed from laboratory mixtures to extrapolate the effects observed in complex aquatic environments and apply this to risk assessment and intervention.

National Category
Environmental Sciences
Research subject
Enviromental Science
Identifiers
urn:nbn:se:oru:diva-45584 (URN)10.1371/journal.pone.0132896 (DOI)000358193100095 ()26168046 (PubMedID)
Funder
Knowledge Foundation, 20110183
Note

Funding Agencies:

Örebro Universitet J62200

Boliden Mineral AB

Envix Nord AB

ALS Scandinavia AB

Available from: 2015-08-18 Created: 2015-08-18 Last updated: 2017-12-04Bibliographically approved
Banjop-Kharlygdoh, J., Pradhan, A., Asnake, S., Walstad, A., Ivarsson, P. & Olsson, P.-E. (2015). Identification of a group of brominated flame retardants as novel androgen receptor antagonists and potential neuronal and endocrine disrupters. Environment International, 74, 60-70
Open this publication in new window or tab >>Identification of a group of brominated flame retardants as novel androgen receptor antagonists and potential neuronal and endocrine disrupters
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2015 (English)In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 74, p. 60-70Article in journal (Refereed) Published
Abstract [en]

Brominated flame-retardants (BFRs) are used in industrial products to reduce the risk of fire. However, their continuous release into the environment is a concern as they are often persistent, bioaccumulating and toxic. Information on the impact these compounds have on human health and wildlife is limited and only a few of them have been identified to disrupt hormone receptor functions. In the present study we used in silico modeling to determine the interactions of selected BFRs with the human androgen receptor (AR). Three compounds were found to dock into the ligand-binding domain of the human AR and these were further tested using in vitro analysis. Allyl 2,4,6-tribromophenyl ether (ATE), 2-bromoallyl 2,4,6-tribromophenyl ether (BATE) and 2,3-dibromopropyl-2,4,6-tribromophenyl ether (DPTE) were observed to act as AR antagonists. These BFRs have recently been detected in the environment, in house dust and in aquatic animals. The compounds have been detected at high concentrations in both blubber and brain of seals and we therefore also assessed their impact on the expression of L-type amino acid transporter system (LAT) genes, that are needed for amino acid uptake across the blood-brain barrier, as disruption of LAT gene function has been implicated in several brain disorders. The three BFRs down-regulated the expression of AR target genes that encode for prostate specific antigen (PSA), 5. α-reductases and β-microseminoprotein. The potency of PSA inhibition was of the same magnitude as the common prostate cancer drugs, demonstrating that these compounds are strong AR antagonists. Western blot analysis of AR protein showed that ATE, BATE and DPTE decreased the 5. α-dihydrotestosterone-induced AR protein levels, further confirming that these BFRs act as AR antagonists. The transcription of the LAT genes was altered by the three BFRs, indicating an effect on amino-acid uptake across cellular membranes and blood-brain barrier. This study demonstrated that ATE, BATE and DPTE are potent AR antagonists and the alterations in LAT gene transcription suggest that these compounds can affect neuronal functions and should be considered as potential neurotoxic and endocrine disrupting compounds.

Keywords
Gene regulation; Human; PSA; LAT
National Category
Environmental Sciences
Research subject
Biology
Identifiers
urn:nbn:se:oru:diva-41508 (URN)10.1016/j.envint.2014.09.002 (DOI)000346681700008 ()25454221 (PubMedID)2-s2.0-84908626070 (Scopus ID)
Funder
Knowledge Foundation, 20110183
Note

Funding Agency:

Örebro University J61900

Available from: 2015-01-14 Created: 2015-01-14 Last updated: 2017-12-05Bibliographically approved
Pradhan, A., Asnake, S., Kharlyngdoh, J. B., Modig, C. & Olsson, P.-E. (2015). In silico and biological analysis of anti-androgen activity of the brominated flame retardants ATE, BATE and DPTE in zebrafish. Chemico-Biological Interactions, 233, 35-45
Open this publication in new window or tab >>In silico and biological analysis of anti-androgen activity of the brominated flame retardants ATE, BATE and DPTE in zebrafish
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2015 (English)In: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 233, p. 35-45Article in journal (Refereed) Published
Abstract [en]

The brominated flame retardants (BFRs) 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane (TBECH or DBE-DCBH) and allyl 2,4,6-tribromophenyl ether (ATE or TBP-AE) are alternative BFRs that have been introduced to replace banned BFRs. TBECH is a potential endocrine disrupter in human, chicken and zebrafish and in a recent study we showed that ATE, along with the structurally similar BFR 2,3-dibromopropyl 2,4,6-tribromophenyl ether (DPTE or TBP-DBPE) and its metabolite 2-bromoallyl 2,4,6-tribromophenyl ether (BATE or TBP-BAE) are potential endocrine and neuronal disrupters in human. In this study we analyzed ATE, BATE and DPTE for zebrafish androgen receptor (zAR) modulating properties. In silico analysis with two softwares, Molecular Operating Environment (MOE) and Internal Coordinate Mechanics (ICM), showed that ATE, BATE and DPTE bind to zAR. In vitro AR activation assay revealed that these three BFRs down-regulate 11-ketotestosterone (KT) mediated zAR activation. Exposure to 10 mu M DPTE resulted in reduced hatching success and like TBECH, BATE and DPTE at 10 mu M also had teratogenic properties with 20% and 50% back-bone curvature respectively. Gene transcription analysis in zebrafish embryos as well as in juveniles showed down-regulation of the androgen receptor and androgen response genes, which further support that these BFRs are androgen antagonists and potential endocrine disrupting compounds. Genes involved in steroidogenesis were also down-regulated by these BFRs. In view of this, the impact of these BFRs on humans and wildlife needs further analysis.

Keywords
Gene regulation; Steroidogenesis; TBP-AE; TBP-BAE; TBP-DBPE; Teratogenesis
National Category
Biological Sciences
Research subject
Biology
Identifiers
urn:nbn:se:oru:diva-44811 (URN)10.1016/j.cbi.2015.03.023 (DOI)000354139600004 ()25818047 (PubMedID)2-s2.0-84926156248 (Scopus ID)
Funder
Knowledge Foundation
Note

Funding Agency:

Örebro University

Available from: 2015-06-03 Created: 2015-06-03 Last updated: 2017-10-18Bibliographically approved
Pradhan, A. & Olsson, P.-E. (2015). Inhibition of retinoic acid synthesis disrupts spermatogenesis and fecundity in zebrafish. General and Comparative Endocrinology, 217, 81-91
Open this publication in new window or tab >>Inhibition of retinoic acid synthesis disrupts spermatogenesis and fecundity in zebrafish
2015 (English)In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 217, p. 81-91Article in journal (Refereed) Published
Abstract [en]

Timing of germ cell entry into meiosis is sexually dimorphic in mammals. However it was recently shown that germ cells initiate meiosis at the same time in male and female zebrafish. Retinoic acid (RA) has been shown to be critical for mammalian spermatogenesis. Inhibition of RA synthesis by WIN 18,446 has been reported to inhibit spermatogenesis in a wide variety of animals including humans and was once used as a contraceptive in humans. In this study we explored the role of RA in zebrafish spermatogenesis. In silico analysis with Internal coordinate mechanics docking software showed that WIN 18,446 can bind to the rat, human and zebrafish Aldh1a2 catalytic domain with equivalent potency. RA exposure resulted in upregulation of the RA metabolizing enzyme genes cyp26a1, cyp26b1 and cyp26c1 in vitro and in vivo. Exposure to WIN 18,446 resulted in down-regulation of Aldh1a2, cyp26a1 and cyp26b1 in vivo. WIN 18,446 was effective in disrupting spermatogenesis and fecundity in zebrafish but the reduction in sperm count and fecundity was only observed when zebrafish were maintained on a strict Artemia nauplii diet which is known to contain low levels of vitamin A. This study shows that RA is involved in spermatogenesis as well as oocyte development in zebrafish. As the zebrafish Aldh1a2 structure and function is similar to the mammalian counterpart, Aldh1a2 inhibitor screening using zebrafish as a model system may be beneficial in the discovery and development of new and safe contraceptives for humans.

Keywords
WIN 18, 446, Sex differentiation, Docking, Germ cell, Internal coordinate mechanics, Vitamin A
National Category
Developmental Biology
Research subject
Biology
Identifiers
urn:nbn:se:oru:diva-45302 (URN)10.1016/j.ygcen.2015.02.002 (DOI)000356398600010 ()25687389 (PubMedID)2-s2.0-84930868600 (Scopus ID)
Funder
Knowledge Foundation
Note

Funding Agency:

Örebro University

Available from: 2015-07-22 Created: 2015-07-20 Last updated: 2017-12-04Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-3302-7106

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