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Article ; Online: The epigenetic impacts of social stress: how does social adversity become biologically embedded?

Cunliffe, Vincent T

2016 Volume 8, Issue 12, Page(s) 1653–1669

Abstract: Epigenetic mechanisms are implicated in the processes through which social stressors erode health in humans and other animals. Here I review progress in elucidating the biological pathways underlying the social gradient in health, with particular ... ...

Abstract	Epigenetic mechanisms are implicated in the processes through which social stressors erode health in humans and other animals. Here I review progress in elucidating the biological pathways underlying the social gradient in health, with particular emphasis on how behavioral stresses influence epigenomic variation linked to health. The evidence that epigenetic changes are involved in embedding of social status-linked chronic stress is reviewed in the context of current knowledge about behavior within animal dominance hierarchies and the impacts of social position on behaviors that affect health. The roles of epigenetic mechanisms in responses to trauma and the evidence for their involvement in intergenerational transmission of the biological impacts of traumatic stress are also considered. Taken together, the emerging insights have important implications for development of strategies to improve societal health and well-being.
MeSH term(s)	Animals ; Behavior ; Epigenesis, Genetic ; Humans ; Social Environment ; Stress Disorders, Post-Traumatic/genetics ; Stress, Psychological/genetics ; Wounds and Injuries/genetics
Language	English
Publishing date	2016-11-21
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2537199-X
ISSN	1750-192X ; 1750-1911
ISSN (online)	1750-192X
ISSN	1750-1911
DOI	10.2217/epi-2016-0075
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Article ; Online: Interrenal development and function in zebrafish.

Bacila, Irina / Cunliffe, Vincent T / Krone, Nils P

Molecular and cellular endocrinology

2021 Volume 535, Page(s) 111372

Abstract: In this article we aim to provide an overview of the zebrafish interrenal development and function, as well as a review of its contribution to basic and translational research. A search of the PubMed database identified 41 relevant papers published over ... ...

Abstract	In this article we aim to provide an overview of the zebrafish interrenal development and function, as well as a review of its contribution to basic and translational research. A search of the PubMed database identified 41 relevant papers published over the last 20 years. Based on the common themes identified, we discuss the organogenesis of the interrenal gland and its functional development and we review what is known about the genes involved in zebrafish steroidogenesis. We also outline the consequences of specific defects in steroid biosynthesis, as revealed by evidence from genetically engineered zebrafish models, including cyp11a2, cyp21a2, hsd3b1, cyp11c1 and fdx1b deficiency. Finally, we summarise the impact of different chemicals and environmental factors on steroidogenesis. Our review highlights the utility of zebrafish as a research model for exploring important areas of basic science and human disease, especially in the current context of rapid technological progress in the field of Molecular Biology.
MeSH term(s)	Animals ; Animals, Genetically Modified ; Genetic Engineering ; Interrenal Gland/embryology ; Interrenal Gland/metabolism ; Organogenesis ; Steroids/biosynthesis ; Zebrafish/genetics ; Zebrafish/growth & development ; Zebrafish/metabolism
Chemical Substances	Steroids
Language	English
Publishing date	2021-06-24
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	187438-x
ISSN	1872-8057 ; 0303-7207
ISSN (online)	1872-8057
ISSN	0303-7207
DOI	10.1016/j.mce.2021.111372
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Article ; Online: Experience-sensitive epigenetic mechanisms, developmental plasticity, and the biological embedding of chronic disease risk.

Cunliffe, Vincent T

Wiley interdisciplinary reviews. Systems biology and medicine

2015 Volume 7, Issue 2, Page(s) 53–71

Abstract: Unlabelled: A wide range of developmental, nutritional, environmental, and social factors affect the biological activities of epigenetic mechanisms. These factors change spatiotemporal patterns of gene expression in a variety of different ways and bring ...

Abstract	Unlabelled: A wide range of developmental, nutritional, environmental, and social factors affect the biological activities of epigenetic mechanisms. These factors change spatiotemporal patterns of gene expression in a variety of different ways and bring significant impacts to bear on development, physiology, and disease risk throughout the life course. Abundant evidence demonstrates that behavioral stressors and adverse nutritional conditions are particularly potent inducers of epigenetic changes and enhancers of chronic disease risks. Recent insights from both human clinical studies and research with model organisms further indicate that such experience-dependent changes to the epigenome can be transmitted through the germline across multiple generations, with important consequences for the heritability of both adaptive and maladaptive phenotypes. Epigenetics research thus offers many possibilities for developing informative biomarkers of acquired chronic disease risk and determining the effectiveness of preventive and therapeutic interventions. Moreover, the experience-sensitive nature of these disease risks raises important questions about societal and individual responsibilities for the prevention of ill-health and the promotion of well-being during development, across the life course and between generations. Better understanding of how epigenetic mechanisms regulate developmental plasticity and mediate the biological embedding of chronic disease risks is therefore likely to shed important new light on the nature of the pathophysiological mechanisms linking social and health inequalities, and will help to inform public policy initiatives in this area. Conflict of interest: The author has declared no conflicts of interest for this article.
MeSH term(s)	Chromatin/metabolism ; Chronic Disease ; DNA Methylation ; Epigenesis, Genetic ; Gene Expression Regulation, Developmental ; Humans ; Neurons/metabolism ; Oxidative Stress ; Receptors, Glucocorticoid/metabolism ; Signal Transduction
Chemical Substances	Chromatin ; Receptors, Glucocorticoid
Language	English
Publishing date	2015-03
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2503323-2
ISSN	1939-005X ; 1939-5094
ISSN (online)	1939-005X
ISSN	1939-5094
DOI	10.1002/wsbm.1291
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Article ; Online: Building a zebrafish toolkit for investigating the pathobiology of epilepsy and identifying new treatments for epileptic seizures.

Cunliffe, Vincent T

Journal of neuroscience methods

2015 Volume 260, Page(s) 91–95

Abstract: Recent advances in genomics and genome sequencing technologies provide a wealth of DNA sequence data that sheds new light on the causes of epilepsy. Animal models help to elucidate the biological significance of such disease-associated DNA sequence ... ...

Abstract	Recent advances in genomics and genome sequencing technologies provide a wealth of DNA sequence data that sheds new light on the causes of epilepsy. Animal models help to elucidate the biological significance of such disease-associated DNA sequence variation by enabling functional relationships between disease genotypes and phenotypes to be defined. Here I review the unique combination of attributes that is allowing the zebrafish to play increasingly prominent roles in investigating the mechanisms underlying epilepsy and in discovering new drugs to treat this condition. New techniques for genome editing now allow the zebrafish genome to be engineered to recapitulate key elements of the patterns of genomic variation that are observed in epilepsy patients. Moreover, a sophisticated range of imaging technologies enables spatio-temporal patterns of neural activity to be visualised in the intact zebrafish nervous system with single-cell levels of resolution. These technologies, together with refined techniques for electrophysiological analysis and non-invasive modulation of specific neuronal circuit functions, allow the impacts of defined genetic variation on in vivo patterns of neural activity to be analysed in unprecedented depth. The pharmacological tractability of the zebrafish, and the amenability of its embryonic and larval stages to high throughput phenotype analysis, are also enabling advances in anti-epileptic drug discovery. Combining such pharmacological screening approaches with new tools for genome editing, live imaging, electrophysiology, conditional manipulation of circuit activity and behavioural analysis of zebrafish, could facilitate step changes in both understanding of epileptogenesis and in vivo discovery of new and improved anti-epileptic drugs.
MeSH term(s)	Animals ; Animals, Genetically Modified/genetics ; Disease Models, Animal ; Epilepsy/genetics ; Epilepsy/therapy ; Genetic Engineering/methods ; Genetic Predisposition to Disease/genetics ; Nerve Net/physiopathology ; Zebrafish/genetics
Language	English
Publishing date	2015-07-26
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	282721-9
ISSN	1872-678X ; 0165-0270
ISSN (online)	1872-678X
ISSN	0165-0270
DOI	10.1016/j.jneumeth.2015.07.015
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Article: Interrenal development and function in zebrafish

Bacila, Irina / Cunliffe, Vincent T. / Krone, Nils P.

Molecular and cellular endocrinology. 2021 Sept. 15, v. 535

2021

Abstract	In this article we aim to provide an overview of the zebrafish interrenal development and function, as well as a review of its contribution to basic and translational research. A search of the PubMed database identified 41 relevant papers published over the last 20 years. Based on the common themes identified, we discuss the organogenesis of the interrenal gland and its functional development and we review what is known about the genes involved in zebrafish steroidogenesis. We also outline the consequences of specific defects in steroid biosynthesis, as revealed by evidence from genetically engineered zebrafish models, including cyp11a2, cyp21a2, hsd3b1, cyp11c1 and fdx1b deficiency. Finally, we summarise the impact of different chemicals and environmental factors on steroidogenesis. Our review highlights the utility of zebrafish as a research model for exploring important areas of basic science and human disease, especially in the current context of rapid technological progress in the field of Molecular Biology.
Keywords	Danio rerio ; biosynthesis ; databases ; endocrinology ; human diseases ; models ; molecular biology ; organogenesis ; steroidogenesis
Language	English
Dates of publication	2021-0915
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	187438-x
ISSN	1872-8057 ; 0303-7207
ISSN (online)	1872-8057
ISSN	0303-7207
DOI	10.1016/j.mce.2021.111372
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Analysis of the distal urinary tract in larval and adult zebrafish reveals homology to the human system.

Jubber, Ibrahim / Morhardt, Duncan R / Griffin, Jonathan / Cumberbatch, Marcus G / Glover, Maggie / Zheng, Yang / Rehman, Ishtiaq / Loynes, Catherine A / Hussain, Syed A / Renshaw, Stephen A / Leach, Steven D / Cunliffe, Vincent T / Catto, James W F

Disease models & mechanisms

2023 Volume 16, Issue 7

Abstract: Little is known about the distal excretory component of the urinary tract in Danio rerio (zebrafish). This component is affected by many human diseases and disorders of development. Here, we have undertaken multi-level analyses to determine the structure ...

Abstract	Little is known about the distal excretory component of the urinary tract in Danio rerio (zebrafish). This component is affected by many human diseases and disorders of development. Here, we have undertaken multi-level analyses to determine the structure and composition of the distal urinary tract in the zebrafish. In silico searches identified uroplakin 1a (ukp1a), uroplakin 2 (upk2) and uroplakin 3b (upk3b) genes in the zebrafish genome (orthologues to genes that encode urothelium-specific proteins in humans). In situ hybridization demonstrated ukp1a expression in the zebrafish pronephros and cloaca from 96 h post-fertilization. Haematoxylin and Eosin staining of adult zebrafish demonstrated two mesonephric ducts uniting into a urinary bladder that leads to a distinct urethral opening. Immunohistochemistry identified Uroplakin 1a, Uroplakin 2 and GATA3 expression in zebrafish urinary bladder cell layers that match human urothelial expression. Fluorescent dye injections demonstrated zebrafish urinary bladder function, including urine storage and intermittent micturition, and a urethral orifice separate from the larger anal canal and rectum. Our findings reveal homology between the urinary tracts of zebrafish and humans, and offer the former as a model system to study disease.
MeSH term(s)	Animals ; Humans ; Adult ; Zebrafish/metabolism ; Membrane Glycoproteins/metabolism ; Uroplakin Ia/metabolism ; Uroplakin II/metabolism ; Urinary Bladder/metabolism
Chemical Substances	Membrane Glycoproteins ; Uroplakin Ia ; Uroplakin II
Language	English
Publishing date	2023-07-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2451104-3
ISSN	1754-8411 ; 1754-8403
ISSN (online)	1754-8411
ISSN	1754-8403
DOI	10.1242/dmm.050110
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Article ; Online: Glucocorticoid receptor regulates protein chaperone, circadian clock and affective disorder genes in the zebrafish brain.

Eachus, Helen / Oberski, Lara / Paveley, Jack / Bacila, Irina / Ashton, John-Paul / Esposito, Umberto / Seifuddin, Fayaz / Pirooznia, Mehdi / Elhaik, Eran / Placzek, Marysia / Krone, Nils P / Cunliffe, Vincent T

Disease models & mechanisms

2023 Volume 16, Issue 9

Abstract: Glucocorticoid resistance is commonly observed in depression, and has been linked to reduced expression and/or function of the glucocorticoid receptor (NR3C1 in human, hereafter referred to as GR). Previous studies have shown that GR-mutant zebrafish ... ...

Abstract	Glucocorticoid resistance is commonly observed in depression, and has been linked to reduced expression and/or function of the glucocorticoid receptor (NR3C1 in human, hereafter referred to as GR). Previous studies have shown that GR-mutant zebrafish exhibit behavioural abnormalities that are indicative of an affective disorder, suggesting that GR plays a role in brain function. We compared the brain methylomes and brain transcriptomes of adult wild-type and GR-mutant zebrafish, and identified 249 differentially methylated regions (DMRs) that are regulated by GR. These include a cluster of CpG sites within the first intron of fkbp5, the gene encoding the glucocorticoid-inducible heat shock protein co-chaperone Fkbp5. RNA-sequencing analysis revealed that genes associated with chaperone-mediated protein folding, the regulation of circadian rhythm and the regulation of metabolism are particularly sensitive to loss of GR function. In addition, we identified subsets of genes exhibiting GR-regulated transcription that are known to regulate behaviour, and are linked to unipolar depression and anxiety. Taken together, our results identify key biological processes and novel molecular mechanisms through which the GR is likely to mediate responses to stress in the adult zebrafish brain, and they provide further support for the zebrafish GR mutant as a model for the study of affective disorders.
MeSH term(s)	Animals ; Adult ; Humans ; Receptors, Glucocorticoid/genetics ; Receptors, Glucocorticoid/metabolism ; Circadian Clocks/genetics ; Zebrafish/genetics ; Zebrafish/metabolism ; Brain/metabolism ; Mood Disorders/metabolism
Chemical Substances	Receptors, Glucocorticoid
Language	English
Publishing date	2023-10-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2451104-3
ISSN	1754-8411 ; 1754-8403
ISSN (online)	1754-8411
ISSN	1754-8403
DOI	10.1242/dmm.050141
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Article ; Online: Epigenetics and primary care.

Lehane, David B / Cunliffe, Vincent T / Mitchell, Caroline / Burton, Chris

The British journal of general practice : the journal of the Royal College of General Practitioners

2018 Volume 68, Issue 666, Page(s) 8–9

MeSH term(s)	Epigenomics ; Gene-Environment Interaction ; Humans ; Primary Health Care ; Socioeconomic Factors
Language	English
Publishing date	2018-01-16
Publishing country	England
Document type	Editorial
ZDB-ID	1043148-2
ISSN	1478-5242 ; 0035-8797 ; 0960-1643
ISSN (online)	1478-5242
ISSN	0035-8797 ; 0960-1643
DOI	10.3399/bjgp17X693977
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Zs.B 576: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: 11β-Hydroxylase loss disrupts steroidogenesis and reproductive function in zebrafish.

Oakes, James A / Barnard, Lise / Storbeck, Karl-Heinz / Cunliffe, Vincent T / Krone, Nils P

The Journal of endocrinology

2020 Volume 247, Issue 2, Page(s) 197–212

Abstract: The roles of androgens in male reproductive development and function in zebrafish are poorly understood. To investigate this topic, we employed CRISPR/Cas9 to generate cyp11c1 (11β-hydroxylase) mutant zebrafish lines. Our study confirms recently ... ...

Abstract	The roles of androgens in male reproductive development and function in zebrafish are poorly understood. To investigate this topic, we employed CRISPR/Cas9 to generate cyp11c1 (11β-hydroxylase) mutant zebrafish lines. Our study confirms recently published findings from a different cyp11c1-/- mutant zebrafish line, and also reports novel aspects of the phenotype caused by loss of Cyp11c1 function. We report that Cyp11c1-deficient zebrafish display predominantly female secondary sex characteristics, but may possess either ovaries or testes. Moreover, we observed that cyp11c1-/- mutant male zebrafish are profoundly androgen- and cortisol-deficient. These results provide further evidence that androgens are dispensable for testis formation in zebrafish, as has been demonstrated previously in androgen-deficient and androgen-resistant zebrafish. Herein, we show that the testes of cyp11c1-/- mutant zebrafish exhibit a disorganised tubular structure; and for the first time demonstrate that the spermatic ducts, which connect the testes to the urogenital orifice, are severely hypoplastic in androgen-deficient zebrafish. Furthermore, we show that spermatogenesis and characteristic breeding behaviours are impaired in cyp11c1-/- mutant zebrafish. Expression of nanos2, a type A spermatogonia marker, was significantly increased in the testes of Cyp11c1-deficient zebrafish, whereas expression of markers for later stages of spermatogenesis was significantly decreased. These observations indicate that in zebrafish, production of type A spermatogonia is androgen-independent, but differentiation of type A spermatogonia is an androgen-dependent process. Overall, our results demonstrate that whilst androgens are not required for testis formation, they play important roles in determining secondary sexual characteristics, proper organisation of seminiferous tubules, and differentiation of male germ cells.
MeSH term(s)	Animals ; Gene Expression Regulation, Developmental ; Male ; Mixed Function Oxygenases/genetics ; Mixed Function Oxygenases/metabolism ; Spermatogenesis/genetics ; Spermatogenesis/physiology ; Spermatozoa/metabolism ; Testis/metabolism ; Zebrafish
Chemical Substances	Mixed Function Oxygenases (EC 1.-)
Language	English
Publishing date	2020-07-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3028-4
ISSN	1479-6805 ; 0022-0795
ISSN (online)	1479-6805
ISSN	0022-0795
DOI	10.1530/JOE-20-0160
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Article ; Online: Eloquent silence: developmental functions of Class I histone deacetylases.

Cunliffe, Vincent T

Current opinion in genetics & development

2008 Volume 18, Issue 5, Page(s) 404–410

Abstract: Histone deacetylases (HDACs) are essential catalytic components of the transcription silencing machinery and they play important roles in the programming of multicellular development. HDACs are present within multisubunit protein complexes, other ... ...

Abstract	Histone deacetylases (HDACs) are essential catalytic components of the transcription silencing machinery and they play important roles in the programming of multicellular development. HDACs are present within multisubunit protein complexes, other components of which govern HDAC target gene specificity by controlling interactions with sequence-specific DNA-binding proteins. Here, I review the different developmental roles of the Sin3, NuRD, CoREST and NCoR/SMRT Class I HDAC complexes. With their distinct subunit composition, these versatile molecular devices function in many different settings, to promote axis specification and tissue patterning, to maintain stem cell pluripotency, facilitate self-renewal, guide lineage commitment and drive cell differentiation.
MeSH term(s)	Body Patterning ; Cell Differentiation/genetics ; DNA-Binding Proteins/physiology ; Gene Silencing/physiology ; Histone Deacetylases/physiology ; Mi-2 Nucleosome Remodeling and Deacetylase Complex ; Models, Genetic ; Nuclear Receptor Co-Repressor 2 ; Protein Subunits/physiology ; Repressor Proteins/physiology ; Signal Transduction ; Sin3 Histone Deacetylase and Corepressor Complex ; Substrate Specificity
Chemical Substances	DNA-Binding Proteins ; Nuclear Receptor Co-Repressor 2 ; Protein Subunits ; Repressor Proteins ; Histone Deacetylases (EC 3.5.1.98) ; Mi-2 Nucleosome Remodeling and Deacetylase Complex (EC 3.5.1.98) ; Sin3 Histone Deacetylase and Corepressor Complex (EC 3.5.1.98)
Language	English
Publishing date	2008-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1077312-5
ISSN	1879-0380 ; 0959-437X
ISSN (online)	1879-0380
ISSN	0959-437X
DOI	10.1016/j.gde.2008.10.001
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