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Article ; Online: Knockdown of Hyaluronan synthase 2 suppresses liver fibrosis in mice via induction of transcriptomic changes similar to 4MU treatment.

Halimani, Noreen / Nesterchuk, Mikhail / Tsitrina, Alexandra A / Sabirov, Marat / Andreichenko, Irina N / Dashenkova, Nataliya O / Petrova, Elizaveta / Kulikov, Alexey M / Zatsepin, Timofei S / Romanov, Roman A / Mikaelyan, Arsen S / Kotelevtsev, Yuri V

Scientific reports

2024 Volume 14, Issue 1, Page(s) 2797

Abstract: Hepatic fibrosis remains a significant clinical challenge due to ineffective treatments. 4-methylumbelliferone (4MU), a hyaluronic acid (HA) synthesis inhibitor, has proven safe in phase one clinical trials. In this study, we aimed to ameliorate liver ... ...

Abstract	Hepatic fibrosis remains a significant clinical challenge due to ineffective treatments. 4-methylumbelliferone (4MU), a hyaluronic acid (HA) synthesis inhibitor, has proven safe in phase one clinical trials. In this study, we aimed to ameliorate liver fibrosis by inhibiting HA synthesis. We compared two groups of mice with CCl
MeSH term(s)	Animals ; Mice ; Gene Expression Profiling ; Hyaluronan Synthases/genetics ; Hyaluronan Synthases/metabolism ; Hyaluronic Acid/metabolism ; Hymecromone/pharmacology ; Liver Cirrhosis/chemically induced ; Liver Cirrhosis/drug therapy ; Liver Cirrhosis/genetics ; RNA, Small Interfering
Chemical Substances	Hyaluronan Synthases (EC 2.4.1.212) ; Hyaluronic Acid (9004-61-9) ; Hymecromone (3T5NG4Q468) ; RNA, Small Interfering ; Has2 protein, mouse (EC 2.4.1.212)
Language	English
Publishing date	2024-02-02
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-024-53089-x
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Article ; Online: 4-Methylumbelliferone Targets Revealed by Public Data Analysis and Liver Transcriptome Sequencing.

Tsitrina, Alexandra A / Halimani, Noreen / Andreichenko, Irina N / Sabirov, Marat / Nesterchuk, Mikhail / Dashenkova, Nataliya O / Romanov, Roman / Bulgakova, Elena V / Mikaelyan, Arsen / Kotelevtsev, Yuri

International journal of molecular sciences

2023 Volume 24, Issue 3

Abstract: 4-methylumbelliferone (4MU) is a well-known hyaluronic acid synthesis inhibitor and an approved drug for the treatment of cholestasis. In animal models, 4MU decreases inflammation, reduces fibrosis, and lowers body weight, serum cholesterol, and insulin ... ...

Abstract	4-methylumbelliferone (4MU) is a well-known hyaluronic acid synthesis inhibitor and an approved drug for the treatment of cholestasis. In animal models, 4MU decreases inflammation, reduces fibrosis, and lowers body weight, serum cholesterol, and insulin resistance. It also inhibits tumor progression and metastasis. The broad spectrum of effects suggests multiple and yet unknown targets of 4MU. Aiming at 4MU target deconvolution, we have analyzed publicly available data bases, including: 1. Small molecule library Bio Assay screening (PubChemBioAssay); 2. GO pathway databases screening; 3. Protein Atlas Database. We also performed comparative liver transcriptome analysis of mice on normal diet and mice fed with 4MU for two weeks. Potential targets of 4MU public data base analysis fall into two big groups, enzymes and transcription factors (TFs), including 13 members of the nuclear receptor superfamily regulating lipid and carbohydrate metabolism. Transcriptome analysis revealed changes in the expression of genes involved in bile acid metabolism, gluconeogenesis, and immune response. It was found that 4MU feeding decreased the accumulation of the glycogen granules in the liver. Thus, 4MU has multiple targets and can regulate cell metabolism by modulating signaling via nuclear receptors.
MeSH term(s)	Mice ; Animals ; Hymecromone/pharmacology ; Transcriptome ; Liver/metabolism ; Inflammation/metabolism ; Signal Transduction ; Lipid Metabolism
Chemical Substances	Hymecromone (3T5NG4Q468)
Language	English
Publishing date	2023-01-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24032129
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Article ; Online: CRISPR/Cas9-generated mouse model with humanizing single-base substitution in the

Polikarpova, Anna V / Egorova, Tatiana V / Lunev, Evgenii A / Tsitrina, Alexandra A / Vassilieva, Svetlana G / Savchenko, Irina M / Silaeva, Yuliya Y / Deykin, Alexey V / Bardina, Maryana V

Frontiers in genome editing

2023 Volume 5, Page(s) 1034720

Abstract: The development of personalized medicine for genetic diseases requires preclinical testing in the appropriate animal models. GNAO1 encephalopathy is a severe neurodevelopmental disorder caused by ... ...

Abstract	The development of personalized medicine for genetic diseases requires preclinical testing in the appropriate animal models. GNAO1 encephalopathy is a severe neurodevelopmental disorder caused by heterozygous
Language	English
Publishing date	2023-04-03
Publishing country	Switzerland
Document type	Journal Article
ISSN	2673-3439
ISSN (online)	2673-3439
DOI	10.3389/fgeed.2023.1034720
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Article ; Online: Visceral adipocyte size links obesity with dysmetabolism more than fibrosis, and both can be estimated by circulating miRNAs.

Pincu, Yair / Makarenkov, Nataly / Tsitrina, Alexandra A / Rosengarten-Levine, Marina / Haim, Yulia / Yoel, Uri / Liberty, Idit F / Dukhno, Oleg / Kukeev, Ivan / Blüher, Matthias / Veksler-Lublinsky, Isana / Rudich, Assaf

Obesity (Silver Spring, Md.)

2023 Volume 31, Issue 12, Page(s) 2986–2997

Abstract: Objective: In obesity, adipocyte hypertrophy is detrimental to health, but its' interrelation with fibrosis in the visceral adipose tissue (VAT) depot remains unclear. Because VAT is less accessible via biopsy, biomarkers for VAT quality are needed. The ...

Abstract	Objective: In obesity, adipocyte hypertrophy is detrimental to health, but its' interrelation with fibrosis in the visceral adipose tissue (VAT) depot remains unclear. Because VAT is less accessible via biopsy, biomarkers for VAT quality are needed. The authors hypothesized that VAT adipocyte size and fibrosis are interrelated and can be estimated by circulating microRNAs (circ-miRNAs), contributing to subphenotyping obesity. Methods: Adipocyte size and AT fibrosis were estimated in n = 43 participants (BMI ≥ 30 kg/m Results: Participants with above- versus below-median VAT adipocyte area exhibited metabolic dysfunction but lower total and pericellular fibrosis. VAT adipocyte size remained associated with metabolic dysfunction even when controlling for BMI or VAT fibrosis in the entire cohort, as in matched-pairs subanalyses. Next Generation Sequencing uncovered 22 and 6 circ-miRNAs associated with VAT adipocyte size and fibrosis, respectively, with miRNA-130b-3p common to both analyses. The combination of miRNA-130b-3p + miR-150-5p + high-density lipoprotein cholesterol discriminated among those with large versus small VAT adipocytes (receiver operating characteristic-area under the curve: 0.872 [95% CI: 0.747-0.996]), whereas miRNA-130b-3p + miRNA-15a-5p + high-density lipoprotein cholesterol discriminated among those with low and high fibrosis (receiver operating characteristic-area under the curve: 0.823 [95% CI: 0.676-0.97]). Conclusions: These findings suggest that VAT adipocyte size and fibrosis are inversely correlated in obesity and can be estimated by distinct circ-miRNAs, providing a potential tool to subphenotype obesity via a liquid biopsy-like approach to assess VAT health in nonsurgical patients.
MeSH term(s)	Humans ; Obesity/metabolism ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Adipocytes/metabolism ; Fibrosis ; Lipoproteins, HDL/metabolism ; Cholesterol
Chemical Substances	MicroRNAs ; Lipoproteins, HDL ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2023-09-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	2230457-5
ISSN	1930-739X ; 1071-7323 ; 1930-7381
ISSN (online)	1930-739X
ISSN	1071-7323 ; 1930-7381
DOI	10.1002/oby.23899
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Zs.A 4061: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: A role of BPTF in viral oncogenicity delineated through studies of heritable Kaposi sarcoma.

Yogev, Yuval / Schaffer, Moshe / Shlapobersky, Mark / Jean, Matan M / Wormser, Ohad / Drabkin, Max / Halperin, Daniel / Kassem, Riad / Livoff, Alejandro / Tsitrina, Alexandra A / Asna, Noam / Birk, Ohad S

Journal of medical virology

2023 Volume 96, Issue 2, Page(s) e29436

Abstract: Kaposi sarcoma (KS), caused by Herpesvirus-8 (HHV-8; KSHV), shows sporadic, endemic, and epidemic forms. While familial clustering of KS was previously recorded, the molecular basis of hereditary predilection to KS remains largely unknown. We demonstrate ...

Abstract	Kaposi sarcoma (KS), caused by Herpesvirus-8 (HHV-8; KSHV), shows sporadic, endemic, and epidemic forms. While familial clustering of KS was previously recorded, the molecular basis of hereditary predilection to KS remains largely unknown. We demonstrate through genetic studies that a dominantly inherited missense mutation in BPTF segregates with a phenotype of classical KS in multiple immunocompetent individuals in two families. Using an rKSHV.219-infected CRISPR/cas9-model, we show that BPTF
MeSH term(s)	Humans ; Carcinogenesis ; Herpesvirus 8, Human/physiology ; NF-kappa B/metabolism ; Sarcoma, Kaposi/genetics ; Virus Latency/genetics ; Virus Replication
Chemical Substances	NF-kappa B ; fetal Alzheimer antigen
Language	English
Publishing date	2023-12-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	752392-0
ISSN	1096-9071 ; 0146-6615
ISSN (online)	1096-9071
ISSN	0146-6615
DOI	10.1002/jmv.29436
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Article ; Online: Macrophage

Sapach, Anastasiia Yu / Sindeeva, Olga A / Nesterchuk, Mikhail V / Tsitrina, Alexandra A / Mayorova, Oksana A / Prikhozhdenko, Ekaterina S / Verkhovskii, Roman A / Mikaelyan, Arsen S / Kotelevtsev, Yuri V / Sukhorukov, Gleb B

ACS applied materials & interfaces

2022 Volume 14, Issue 46, Page(s) 51579–51592

Abstract: A new promising trend in personalized medicine is the use of autologous cells (macrophages or stem cells) for cell-based therapy and also as a "Trojan horse" for targeted delivery of a drug carrier. The natural ability of macrophages for chemotaxis ... ...

Abstract	A new promising trend in personalized medicine is the use of autologous cells (macrophages or stem cells) for cell-based therapy and also as a "Trojan horse" for targeted delivery of a drug carrier. The natural ability of macrophages for chemotaxis allows them to deliver cargo to the damaged area, significantly reducing side effects on healthy organ tissues. Therefore, it is important to develop tools to track their behavior in the organism. While labeled containers can serve as anchored tags for imaging macrophages
MeSH term(s)	Capsules ; Drug Carriers ; Drug Delivery Systems ; Macrophages ; Cell Tracking
Chemical Substances	Capsules ; Drug Carriers
Language	English
Publishing date	2022-11-11
Publishing country	United States
Document type	Journal Article
ISSN	1944-8252
ISSN (online)	1944-8252
DOI	10.1021/acsami.2c12004
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Article ; Online: Phenotypic Alteration of BMDM In Vitro Using Small Interfering RNA.

Halimani, Noreen / Nesterchuk, Mikhail / Andreichenko, Irina N / Tsitrina, Alexandra A / Elchaninov, Andrey / Lokhonina, Anastasia / Fatkhudinov, Timur / Dashenkova, Nataliya O / Brezgina, Vera / Zatsepin, Timofei S / Mikaelyan, Arsen S / Kotelevtsev, Yuri V

Cells

2022 Volume 11, Issue 16

Abstract: Autologous macrophage transfer is an emerging platform for cell therapy. It is anticipated that conventional macrophage reprogramming based on ex vivo polarization using cytokines and ligands of TLRs may enhance the therapeutic effect. We describe an ... ...

Abstract	Autologous macrophage transfer is an emerging platform for cell therapy. It is anticipated that conventional macrophage reprogramming based on ex vivo polarization using cytokines and ligands of TLRs may enhance the therapeutic effect. We describe an alternative approach based on small interfering RNA (siRNA) knockdown of selected molecular cues of macrophage polarization, namely EGR2, IRF3, IRF5, and TLR4 in Raw264.7 monocyte/macrophage cell line and mouse-bone-marrow-derived macrophages (BMDMs). The impact of IRF5 knockdown was most pronounced, curtailing the expression of other inflammatory mediators such as IL-6 and NOS2, especially in M1-polarized macrophages. Contrary to IRF5, EGR2 knockdown potentiated M1-associated markers while altogether abolishing M2 marker expression, which is indicative of the principal role of EGR2 in the maintenance of alternative phenotypes. IRF3 knockdown suppressed M1 polarization but upregulated Arg 1, a canonical marker of alternative polarization in M1 macrophages. As anticipated, the knockdown of TLR4 also attenuated the M1 phenotype but, akin to IRF3, significantly induced Arginase 1 in M0 and M1, driving the phenotype towards M2. This study validates RNAi as a viable option for the alteration and maintenance of macrophage phenotypes.
MeSH term(s)	Animals ; Biomarkers/metabolism ; Interferon Regulatory Factors/genetics ; Interferon Regulatory Factors/metabolism ; Macrophage Activation ; Mice ; Phenotype ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; Toll-Like Receptor 4/genetics ; Toll-Like Receptor 4/metabolism
Chemical Substances	Biomarkers ; Interferon Regulatory Factors ; Irf5 protein, mouse ; RNA, Small Interfering ; Toll-Like Receptor 4
Language	English
Publishing date	2022-08-11
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11162498
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Article ; Online: Inhibition of hyaluronan secretion by novel coumarin compounds and chitin synthesis inhibitors.

Tsitrina, Alexandra A / Krasylov, Igor V / Maltsev, Dmitry I / Andreichenko, Irina N / Moskvina, Viktoria S / Ivankov, Dmitry N / Bulgakova, Elena V / Nesterchuk, Mikhail / Shashkovskaya, Vera / Dashenkova, Nataliya O / Khilya, Vladimir P / Mikaelyan, Arsen / Kotelevtsev, Yuri

Glycobiology

2021 Volume 31, Issue 8, Page(s) 959–974

Abstract: Elevated plasma levels of hyaluronic acid (HA) is a disease marker in liver pathology and other inflammatory disorders. Inhibition of HA synthesis with coumarin 4-methylumbelliferone (4MU) has a beneficial effect in animal models of fibrosis, ... ...

Abstract	Elevated plasma levels of hyaluronic acid (HA) is a disease marker in liver pathology and other inflammatory disorders. Inhibition of HA synthesis with coumarin 4-methylumbelliferone (4MU) has a beneficial effect in animal models of fibrosis, inflammation, cancer and metabolic syndrome. 4MU is an active compound of approved choleretic drug hymecromone with low bioavailability and a broad spectrum of action. New, more specific and efficient inhibitors of hyaluronan synthases (HAS) are required. We have tested several newly synthesized coumarin compounds and commercial chitin synthesis inhibitors to inhibit HA production in cell culture assay. Coumarin derivative compound VII (10'-methyl-6'-phenyl-3'H-spiro[piperidine-4,2'-pyrano[3,2-g]chromene]-4',8'-dione) demonstrated inhibition of HA secretion by NIH3T3 cells with the half-maximal inhibitory concentration (IC50) = 1.69 ± 0.75 μΜ superior to 4MU (IC50 = 8.68 ± 1.6 μΜ). Inhibitors of chitin synthesis, etoxazole, buprofezin, triflumuron, reduced HA deposition with IC50 of 4.21 ± 3.82 μΜ, 1.24 ± 0.87 μΜ and 1.48 ± 1.44 μΜ, respectively. Etoxazole reduced HA production and prevented collagen fibre formation in the CCl4 liver fibrosis model in mice similar to 4MU. Bioinformatics analysis revealed homology between chitin synthases and HAS enzymes, particularly in the pore-forming domain, containing the proposed site for etoxazole binding.
MeSH term(s)	Animals ; Chitin ; Hyaluronan Synthases/metabolism ; Hyaluronic Acid/metabolism ; Hymecromone/pharmacology ; Mice ; NIH 3T3 Cells
Chemical Substances	Chitin (1398-61-4) ; Hymecromone (3T5NG4Q468) ; Hyaluronic Acid (9004-61-9) ; Hyaluronan Synthases (EC 2.4.1.212)
Language	English
Publishing date	2021-05-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1067689-2
ISSN	1460-2423 ; 0959-6658
ISSN (online)	1460-2423
ISSN	0959-6658
DOI	10.1093/glycob/cwab038
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Article ; Online: The Role of Two-Pore Channels in Norepinephrine-Induced [Ca

Trufanov, Sergei K / Rybakova, Elena Yu / Avdonin, Piotr P / Tsitrina, Alexandra A / Zharkikh, Irina L / Goncharov, Nikolay V / Jenkins, Richard O / Avdonin, Pavel V

Cells

2019 Volume 8, Issue 10

Abstract: Second messenger nicotinic acid adenine dinucleotide phosphate (NAADP) triggers ... ...

Abstract	Second messenger nicotinic acid adenine dinucleotide phosphate (NAADP) triggers Ca
MeSH term(s)	Animals ; Aorta/cytology ; Aorta/drug effects ; Aorta/metabolism ; Calcium/metabolism ; Calcium Channels/physiology ; Carbolines/pharmacology ; Cells, Cultured ; Human Umbilical Vein Endothelial Cells ; Humans ; Intracellular Space/drug effects ; Intracellular Space/metabolism ; Male ; Myocardial Contraction/drug effects ; Myocytes, Smooth Muscle/drug effects ; Myocytes, Smooth Muscle/metabolism ; Norepinephrine/pharmacology ; Piperazines/pharmacology ; Rats ; Rats, Wistar
Chemical Substances	1-(3-((4-(2-fluorophenyl)piperazin-1-yl)methyl)-4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole-3-carboxylic acid ; Calcium Channels ; Carbolines ; Piperazines ; TPCN1 protein, human ; Tpcn1 protein, rat ; Tpcn2 protein, rat ; Calcium (SY7Q814VUP) ; Norepinephrine (X4W3ENH1CV)
Language	English
Publishing date	2019-09-25
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells8101144
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Article: VAS2870 Inhibits Histamine-Induced Calcium Signaling and vWF Secretion in Human Umbilical Vein Endothelial Cells.

Avdonin, Pavel V / Rybakova, Elena Yu / Avdonin, Piotr P / Trufanov, Sergei K / Mironova, Galina Yu / Tsitrina, Alexandra A / Goncharov, Nikolay V

Cells

2019 Volume 8, Issue 2

Abstract: In this study, we investigated the effects of NAD(P)H oxidase (NOX) inhibitor VAS2870 (3-benzyl-7-(2-benzoxazolyl)thio-1,2,3-triazolo[4,5-d]pyrimidine) on the histamine-induced elevation of free cytoplasmic calcium concentration ([ ... ...

Abstract	In this study, we investigated the effects of NAD(P)H oxidase (NOX) inhibitor VAS2870 (3-benzyl-7-(2-benzoxazolyl)thio-1,2,3-triazolo[4,5-d]pyrimidine) on the histamine-induced elevation of free cytoplasmic calcium concentration ([Ca
MeSH term(s)	Animals ; Aorta/drug effects ; Aorta/metabolism ; Benzoxazoles/pharmacology ; Calcium Signaling/drug effects ; Histamine/pharmacology ; Human Umbilical Vein Endothelial Cells/drug effects ; Human Umbilical Vein Endothelial Cells/metabolism ; Humans ; Male ; Norepinephrine/pharmacology ; Oxidation-Reduction ; Peptide Fragments/pharmacology ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Triazoles/pharmacology ; von Willebrand Factor/metabolism
Chemical Substances	3-benzyl-7-(2-benzoxazolyl)thio-1,2,3-triazolo(4,5-d)pyrimidine ; Benzoxazoles ; Peptide Fragments ; Reactive Oxygen Species ; Triazoles ; thrombin receptor peptide (42-47) ; von Willebrand Factor ; Histamine (820484N8I3) ; Norepinephrine (X4W3ENH1CV)
Language	English
Publishing date	2019-02-23
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409
ISSN	2073-4409
DOI	10.3390/cells8020196
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