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Article ; Online: Functional Characterization of Endogenously Expressed Human RYR1 Variants.

Treves, Susan / Girard, Thierry / Zorzato, Francesco

Journal of visualized experiments : JoVE

2021 , Issue 172

Abstract: More than 700 variants in the RYR1 gene have been identified in patients with different neuromuscular disorders including malignant hyperthermia susceptibility, core myopathies and centronuclear myopathy. Because of the diverse phenotypes linked to RYR1 ... ...

Abstract	More than 700 variants in the RYR1 gene have been identified in patients with different neuromuscular disorders including malignant hyperthermia susceptibility, core myopathies and centronuclear myopathy. Because of the diverse phenotypes linked to RYR1 mutations it is fundamental to characterize their functional effects to classify variants carried by patients for future therapeutic interventions and identify non-pathogenic variants. Many laboratories have been interested in developing methods to functionally characterize RYR1 mutations expressed in patients' cells. This approach has numerous advantages, including: mutations are endogenously expressed, RyR1 is not over-expressed, use of heterologous RyR1 expressing cells is avoided. However, since patients may present mutations in different genes aside RYR1, it is important to compare results from biological material from individuals harboring the same mutation, with different genetic backgrounds. The present manuscript describes methods developed to study the functional effects of endogenously expressed RYR1 variants in: (a) Epstein Barr virus immortalized human B-lymphocytes and (b) satellite cells derived from muscle biopsies and differentiated into myotubes. Changes in the intracellular calcium concentration triggered by the addition of a pharmacological RyR1 activators are then monitored. The selected cell type is loaded with a ratiometric fluorescent calcium indicator and intracellular [Ca
MeSH term(s)	Calcium/metabolism ; Epstein-Barr Virus Infections ; Herpesvirus 4, Human/metabolism ; Humans ; Malignant Hyperthermia ; Muscular Diseases ; Mutation ; Ryanodine Receptor Calcium Release Channel/genetics
Chemical Substances	RYR1 protein, human ; Ryanodine Receptor Calcium Release Channel ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2021-06-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Video-Audio Media
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/62196
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Functional characterization of endogenously expressed human ryr1 variants

Treves, Susan / Girard, Thierry / Zorzato, Francesco

Journal of visualized experiments. 2021 June 09, , no. 172

2021

Abstract	More than 700 variants in the RYR1 gene have been identified in patients with different neuromuscular disorders including malignant hyperthermia susceptibility, core myopathies and centronuclear myopathy. Because of the diverse phenotypes linked to RYR1 mutations it is fundamental to characterize their functional effects to classify variants carried by patients for future therapeutic interventions and identify non-pathogenic variants. Many laboratories have been interested in developing methods to functionally characterize RYR1 mutations expressed in patients' cells. This approach has numerous advantages, including: mutations are endogenously expressed, RyR1 is not over-expressed, use of heterologous RyR1 expressing cells is avoided. However, since patients may present mutations in different genes aside RYR1, it is important to compare results from biological material from individuals harboring the same mutation, with different genetic backgrounds. The present manuscript describes methods developed to study the functional effects of endogenously expressed RYR1 variants in: (a) Epstein Barr virus immortalized human B-lymphocytes and (b) satellite cells derived from muscle biopsies and differentiated into myotubes. Changes in the intracellular calcium concentration triggered by the addition of a pharmacological RyR1 activators are then monitored. The selected cell type is loaded with a ratiometric fluorescent calcium indicator and intracellular [Ca2+] changes are monitored either at the single cell level by fluorescence microscopy or in cell populations using a spectrofluorometer. The resting [Ca2+], agonist dose response curves are then compared between cells from healthy controls and patients harboring RYR1 variants leading to insight into the functional effect of a given variant.
Keywords	B-lymphocytes ; Human gammaherpesvirus 4 ; agonists ; calcium ; dose response ; fluorescence ; fluorescence microscopy ; genes ; humans ; malignant hyperthermia ; muscles ; muscular diseases ; mutation ; myotubes
Language	English
Dates of publication	2021-0609
Size	p. e62196.
Publishing place	Journal of Visualized Experiments
Document type	Article
ZDB-ID	2259946-0
ISSN	1940-087X
ISSN	1940-087X
DOI	10.3791/62196
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Article ; Online: Quantitative proteomic analysis of skeletal muscles from wild-type and transgenic mice carrying recessive

Eckhardt, Jan / Ruiz, Alexis / Koenig, Stéphane / Frieden, Maud / Meier, Hervé / Schmidt, Alexander / Treves, Susan / Zorzato, Francesco

eLife

2023 Volume 12

Abstract: Skeletal muscles are a highly structured tissue responsible for movement and metabolic regulation, which can be broadly subdivided into fast and slow twitch muscles with each type expressing common as well as specific sets of proteins. Congenital ... ...

Abstract	Skeletal muscles are a highly structured tissue responsible for movement and metabolic regulation, which can be broadly subdivided into fast and slow twitch muscles with each type expressing common as well as specific sets of proteins. Congenital myopathies are a group of muscle diseases leading to a weak muscle phenotype caused by mutations in a number of genes including
MeSH term(s)	Mice ; Animals ; Mice, Transgenic ; Ryanodine Receptor Calcium Release Channel/genetics ; Ryanodine Receptor Calcium Release Channel/metabolism ; Proteomics ; Muscle, Skeletal/metabolism ; Muscular Diseases/genetics ; Mutation
Chemical Substances	Ryanodine Receptor Calcium Release Channel
Language	English
Publishing date	2023-03-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.83618
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Article ; Online: Functional characterization of RYR1 variants identified in malignant hyperthermia susceptible individuals.

Noda, Yuko / Miyoshi, Hirotsugu / Benucci, Sofia / Gonzalez, Asensio / Bandschapp, Oliver / Girard, Thierry / Treves, Susan / Zorzato, Francesco

Neuromuscular disorders : NMD

2023 Volume 33, Issue 12, Page(s) 951–963

Abstract: Malignant hyperthermia is a pharmacogenetic disorder triggered by halogenated anesthetic agents in genetically predisposed individuals. Approximately 70 % of these individuals carry mutations in RYR1, the gene encoding the ryanodine receptor calcium ... ...

Abstract	Malignant hyperthermia is a pharmacogenetic disorder triggered by halogenated anesthetic agents in genetically predisposed individuals. Approximately 70 % of these individuals carry mutations in RYR1, the gene encoding the ryanodine receptor calcium channel of skeletal muscle. In this study, we performed functional analysis of 5 RYR1 variants identified in members from 8 families who had been diagnosed by the IVCT. Of the 68 individuals enrolled in the study, 43 were diagnosed as MHS, 23 as MHN, and 2 individuals were not tested. Here we demonstrate that the 5 RyR1 variants cause hypersensitivity to RyR1 agonist-mediated calcium release. According to the EMHG scoring matrix these five genetic variants can be classified as follows: c.8638G>A (p.E2880K) and c.11314C>T (p.R3772W) likely pathogenic, c.11416G>A (p.G3806R), c.14627A>G (p.K4876R) and c.14813T>C (p.I4938T), pathogenic (RefSeq NM_000540.3). We propose that the newly functionally characterized RYR1 variants, be included in the panel of variants to be used for the molecular diagnosis of MHS.
MeSH term(s)	Humans ; Calcium/metabolism ; Genetic Predisposition to Disease/genetics ; Malignant Hyperthermia/genetics ; Muscle, Skeletal ; Mutation ; Ryanodine Receptor Calcium Release Channel/genetics
Chemical Substances	Calcium (SY7Q814VUP) ; Ryanodine Receptor Calcium Release Channel ; RYR1 protein, human
Language	English
Publishing date	2023-11-03
Publishing country	England
Document type	Journal Article
ZDB-ID	1077681-3
ISSN	1873-2364 ; 0960-8966
ISSN (online)	1873-2364
ISSN	0960-8966
DOI	10.1016/j.nmd.2023.10.019
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Article ; Online: A novel, patient-derived RyR1 mutation impairs muscle function and calcium homeostasis in mice.

Benucci, Sofia / Ruiz, Alexis / Franchini, Martina / Ruggiero, Lucia / Zoppi, Dario / Sitsapesan, Rebecca / Lindsay, Chris / Pelczar, Pawel / Pietrangelo, Laura / Protasi, Feliciano / Treves, Susan / Zorzato, Francesco

The Journal of general physiology

2024 Volume 156, Issue 4

Abstract: RYR1 is the most commonly mutated gene associated with congenital myopathies, a group of early-onset neuromuscular conditions of variable severity. The functional effects of a number of dominant RYR1 mutations have been established; however, for ... ...

Abstract	RYR1 is the most commonly mutated gene associated with congenital myopathies, a group of early-onset neuromuscular conditions of variable severity. The functional effects of a number of dominant RYR1 mutations have been established; however, for recessive mutations, these effects may depend on multiple factors, such as the formation of a hypomorphic allele, or on whether they are homozygous or compound heterozygous. Here, we functionally characterize a new transgenic mouse model knocked-in for mutations identified in a severely affected child born preterm and presenting limited limb movement. The child carried the homozygous c.14928C>G RYR1 mutation, resulting in the p.F4976L substitution. In vivo and ex vivo assays revealed that homozygous mice fatigued sooner and their muscles generated significantly less force compared with their WT or heterozygous littermates. Electron microscopy, biochemical, and physiological analyses showed that muscles from RyR1 p.F4976L homozygous mice have the following properties: (1) contain fewer calcium release units and show areas of myofibrillar degeneration, (2) contain less RyR1 protein, (3) fibers show smaller electrically evoked calcium transients, and (4) their SR has smaller calcium stores. In addition, single-channel recordings indicate that RyR1 p.F4976L exhibits higher Po in the presence of 100 μM [Ca2+]. Our mouse model partly recapitulates the clinical picture of the homozygous human patient and provides significant insight into the functional impact of this mutation. These results will help understand the pathology of patients with similar RYR1 mutations.
MeSH term(s)	Animals ; Child ; Humans ; Mice ; Calcium ; Disease Models, Animal ; Homeostasis ; Mice, Transgenic ; Muscles ; Muscular Diseases ; Ryanodine Receptor Calcium Release Channel/genetics
Chemical Substances	Calcium (SY7Q814VUP) ; Ryanodine Receptor Calcium Release Channel ; RYR1 protein, human ; ryanodine receptor 1, mouse
Language	English
Publishing date	2024-03-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	3118-5
ISSN	1540-7748 ; 0022-1295
ISSN (online)	1540-7748
ISSN	0022-1295
DOI	10.1085/jgp.202313486
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Uc I Zs.150: Show issues

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Article ; Online: ORAI1 inhibition as an efficient preclinical therapy for tubular aggregate myopathy and Stormorken syndrome.

Silva-Rojas, Roberto / Pérez-Guàrdia, Laura / Simon, Alix / Djeddi, Sarah / Treves, Susan / Ribes, Agnès / Silva-Hernández, Lorenzo / Tard, Céline / Laporte, Jocelyn / Böhm, Johann

JCI insight

2024 Volume 9, Issue 6

Abstract: Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) are clinically overlapping disorders characterized by childhood-onset muscle weakness and a variable occurrence of multisystemic signs, including short stature, thrombocytopenia, and ... ...

Abstract	Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) are clinically overlapping disorders characterized by childhood-onset muscle weakness and a variable occurrence of multisystemic signs, including short stature, thrombocytopenia, and hyposplenism. TAM/STRMK is caused by gain-of-function mutations in the Ca2+ sensor STIM1 or the Ca2+ channel ORAI1, both of which regulate Ca2+ homeostasis through the ubiquitous store-operated Ca2+ entry (SOCE) mechanism. Functional experiments in cells have demonstrated that the TAM/STRMK mutations induce SOCE overactivation, resulting in excessive influx of extracellular Ca2+. There is currently no treatment for TAM/STRMK, but SOCE is amenable to manipulation. Here, we crossed Stim1R304W/+ mice harboring the most common TAM/STRMK mutation with Orai1R93W/+ mice carrying an ORAI1 mutation partially obstructing Ca2+ influx. Compared with Stim1R304W/+ littermates, Stim1R304W/+Orai1R93W/+ offspring showed a normalization of bone architecture, spleen histology, and muscle morphology; an increase of thrombocytes; and improved muscle contraction and relaxation kinetics. Accordingly, comparative RNA-Seq detected more than 1,200 dysregulated genes in Stim1R304W/+ muscle and revealed a major restoration of gene expression in Stim1R304W/+Orai1R93W/+ mice. Altogether, we provide physiological, morphological, functional, and molecular data highlighting the therapeutic potential of ORAI1 inhibition to rescue the multisystemic TAM/STRMK signs, and we identified myostatin as a promising biomarker for TAM/STRMK in humans and mice.
MeSH term(s)	Animals ; Mice ; Blood Platelet Disorders ; Calcium/metabolism ; Dyslexia ; Erythrocytes, Abnormal ; Ichthyosis ; Migraine Disorders/drug therapy ; Miosis/drug therapy ; Miosis/genetics ; Miosis/metabolism ; Muscle Fatigue ; Myopathies, Structural, Congenital/drug therapy ; Myopathies, Structural, Congenital/genetics ; Myopathies, Structural, Congenital/metabolism ; ORAI1 Protein/genetics ; ORAI1 Protein/metabolism ; Spleen/metabolism ; Spleen/abnormalities
Chemical Substances	Calcium (SY7Q814VUP) ; ORAI1 Protein
Language	English
Publishing date	2024-03-05
Publishing country	United States
Document type	Journal Article
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.174866
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Article ; Online: Improvement of muscle strength in a mouse model for congenital myopathy treated with HDAC and DNA methyltransferase inhibitors.

Ruiz, Alexis / Benucci, Sofia / Duthaler, Urs / Bachmann, Christoph / Franchini, Martina / Noreen, Faiza / Pietrangelo, Laura / Protasi, Feliciano / Treves, Susan / Zorzato, Francesco

eLife

2022 Volume 11

Abstract: To date there are no therapies for patients with congenital myopathies, muscle disorders causing poor quality of life of affected individuals. In approximately 30% of the cases, patients with congenital myopathies carry either dominant or recessive ... ...

Abstract	To date there are no therapies for patients with congenital myopathies, muscle disorders causing poor quality of life of affected individuals. In approximately 30% of the cases, patients with congenital myopathies carry either dominant or recessive mutations in the ryanodine receptor 1 (
MeSH term(s)	Animals ; DNA/metabolism ; Disease Models, Animal ; Histone Deacetylases/genetics ; Histone Deacetylases/metabolism ; Humans ; Methyltransferases/metabolism ; Mice ; Muscle Strength/genetics ; Muscle, Skeletal/metabolism ; Muscular Diseases ; Mutation ; Myotonia Congenita/drug therapy ; Myotonia Congenita/genetics ; Quality of Life ; Ryanodine Receptor Calcium Release Channel/genetics ; Ryanodine Receptor Calcium Release Channel/metabolism
Chemical Substances	Ryanodine Receptor Calcium Release Channel ; DNA (9007-49-2) ; Methyltransferases (EC 2.1.1.-) ; Histone Deacetylases (EC 3.5.1.98)
Language	English
Publishing date	2022-03-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.73718
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Article ; Online: Ca

Treves, Susan / Jungbluth, Heinz / Voermans, Nicol / Muntoni, Francesco / Zorzato, Francesco

Seminars in cell & developmental biology

2017 Volume 64, Page(s) 201–212

Abstract: The physiological process by which ... ...

Abstract	The physiological process by which Ca
Language	English
Publishing date	2017-04
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1312473-0
ISSN	1096-3634 ; 1084-9521
ISSN (online)	1096-3634
ISSN	1084-9521
DOI	10.1016/j.semcdb.2016.07.017
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Zs.A 2918: Show issues

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Article ; Online: Molecular basis of impaired extraocular muscle function in a mouse model of congenital myopathy due to compound heterozygous Ryr1 mutations.

Eckhardt, Jan / Bachmann, Christoph / Benucci, Sofia / Elbaz, Moran / Ruiz, Alexis / Zorzato, Francesco / Treves, Susan

Human molecular genetics

2020 Volume 29, Issue 8, Page(s) 1330–1339

Abstract: Mutations in the RYR1 gene are the most common cause of human congenital myopathies, and patients with recessive mutations are severely affected and often display ptosis and/or ophthalmoplegia. In order to gain insight into the mechanism leading to ... ...

Abstract	Mutations in the RYR1 gene are the most common cause of human congenital myopathies, and patients with recessive mutations are severely affected and often display ptosis and/or ophthalmoplegia. In order to gain insight into the mechanism leading to extraocular muscle (EOM) involvement, we investigated the biochemical, structural and physiological properties of eye muscles from mouse models we created knocked-in for Ryr1 mutations. Ex vivo force production in EOMs from compound heterozygous RyR1p.Q1970fsX16+p.A4329D mutant mice was significantly reduced compared with that observed in wild-type, single heterozygous mutant carriers or homozygous RyR1p.A4329D mice. The decrease in muscle force was also accompanied by approximately a 40% reduction in RyR1 protein content, a decrease in electrically evoked calcium transients, disorganization of the muscle ultrastructure and a decrease in the number of calcium release units. Unexpectedly, the superfast and ocular-muscle-specific myosin heavy chain-EO isoform was almost undetectable in RyR1p.Q1970fsX16+p.A4329D mutant mice. The results of this study show for the first time that the EOM phenotype caused by the RyR1p.Q1970fsX16+p.A4329D compound heterozygous Ryr1 mutations is complex and due to a combination of modifications including a direct effect on the macromolecular complex involved in calcium release and indirect effects on the expression of myosin heavy chain isoforms.
MeSH term(s)	Animals ; Disease Models, Animal ; Heterozygote ; Humans ; Mice ; Muscle Weakness/genetics ; Muscle Weakness/pathology ; Muscle, Skeletal/metabolism ; Muscle, Skeletal/pathology ; Mutation/genetics ; Myosin Heavy Chains/genetics ; Myotonia Congenita/genetics ; Myotonia Congenita/pathology ; Oculomotor Muscles/metabolism ; Oculomotor Muscles/pathology ; Phenotype ; Ryanodine Receptor Calcium Release Channel/genetics
Chemical Substances	Ryanodine Receptor Calcium Release Channel ; ryanodine receptor 1, mouse ; Myosin Heavy Chains (EC 3.6.4.1)
Language	English
Publishing date	2020-04-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddaa056
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Zs.A 3469: Show issues

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Article ; Online: Improvement of muscle strength in a mouse model for congenital myopathy treated with HDAC and DNA methyltransferase inhibitors

Alexis Ruiz / Sofia Benucci / Urs Duthaler / Christoph Bachmann / Martina Franchini / Faiza Noreen / Laura Pietrangelo / Feliciano Protasi / Susan Treves / Francesco Zorzato

eLife, Vol

2022 Volume 11

Abstract	To date there are no therapies for patients with congenital myopathies, muscle disorders causing poor quality of life of affected individuals. In approximately 30% of the cases, patients with congenital myopathies carry either dominant or recessive mutations in the ryanodine receptor 1 (RYR1) gene; recessive RYR1 mutations are accompanied by reduction of RyR1 expression and content in skeletal muscles and are associated with fiber hypotrophy and muscle weakness. Importantly, muscles of patients with recessive RYR1 mutations exhibit increased content of class II histone deacetylases and of DNA genomic methylation. We recently created a mouse model knocked-in for the p.Q1970fsX16+ p.A4329D RyR1 mutations, which are isogenic to those carried by a severely affected child suffering from a recessive form of RyR1-related multi-mini core disease. The phenotype of the RyR1 mutant mice recapitulates many aspects of the clinical picture of patients carrying recessive RYR1 mutations. We treated the compound heterozygous mice with a combination of two drugs targeting DNA methylases and class II histone deacetylases. Here, we show that treatment of the mutant mice with drugs targeting epigenetic enzymes improves muscle strength, RyR1 protein content, and muscle ultrastructure. This study provides proof of concept for the pharmacological treatment of patients with congenital myopathies linked to recessive RYR1 mutations.
Keywords	ryanodine receptor mutations ; congenital myopathy ; treatment ; muscle function ; epigenetic enzymes ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	616
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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