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Article ; Online: Evaluation of noninvasive biospecimens for transcriptome studies.

Martorella, Molly / Kasela, Silva / Garcia-Flores, Renee / Gokden, Alper / Castel, Stephane E / Lappalainen, Tuuli

2023 Volume 24, Issue 1, Page(s) 790

Abstract: Transcriptome studies disentangle functional mechanisms of gene expression regulation and may elucidate the underlying biology of disease processes. However, the types of tissues currently collected typically assay a single post-mortem timepoint or are ... ...

Abstract	Transcriptome studies disentangle functional mechanisms of gene expression regulation and may elucidate the underlying biology of disease processes. However, the types of tissues currently collected typically assay a single post-mortem timepoint or are limited to investigating cell types found in blood. Noninvasive tissues may improve disease-relevant discovery by enabling more complex longitudinal study designs, by capturing different and potentially more applicable cell types, and by increasing sample sizes due to reduced collection costs and possible higher enrollment from vulnerable populations. Here, we develop methods for sampling noninvasive biospecimens, investigate their performance across commercial and in-house library preparations, characterize their biology, and assess the feasibility of using noninvasive tissues in a multitude of transcriptomic applications. We collected buccal swabs, hair follicles, saliva, and urine cell pellets from 19 individuals over three to four timepoints, for a total of 300 unique biological samples, which we then prepared with replicates across three library preparations, for a final tally of 472 transcriptomes. Of the four tissues we studied, we found hair follicles and urine cell pellets to be most promising due to the consistency of sample quality, the cell types and expression profiles we observed, and their performance in disease-relevant applications. This is the first study to thoroughly delineate biological and technical features of noninvasive samples and demonstrate their use in a wide array of transcriptomic and clinical analyses. We anticipate future use of these biospecimens will facilitate discovery and development of clinical applications.
MeSH term(s)	Humans ; Transcriptome ; Longitudinal Studies ; Gene Expression Profiling ; Gene Expression Regulation ; Saliva
Language	English
Publishing date	2023-12-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2041499-7
ISSN	1471-2164 ; 1471-2164
ISSN (online)	1471-2164
ISSN	1471-2164
DOI	10.1186/s12864-023-09875-4
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Article: Integrative approach identifies SLC6A20 and CXCR6 as putative causal genes for the COVID-19 GWAS signal in the 3p21.31 locus

Kasela, Silva / Daniloski, Zharko / Bollepalli, Sailalitha / Jordan, Tristan X. / tenOever, Benjamin R. / Sanjana, Neville E. / Lappalainen, Tuuli

Genome biology. 2021 Dec., v. 22, no. 1

2021

Abstract: To date, the locus with the most robust human genetic association to COVID-19 severity is 3p21.31. Here, we integrate genome-scale CRISPR loss-of-function screens and eQTLs in diverse cell types and tissues to pinpoint genes underlying COVID-19 risk. Our ...

Abstract	To date, the locus with the most robust human genetic association to COVID-19 severity is 3p21.31. Here, we integrate genome-scale CRISPR loss-of-function screens and eQTLs in diverse cell types and tissues to pinpoint genes underlying COVID-19 risk. Our findings identify SLC6A20 and CXCR6 as putative causal genes that modulate COVID-19 risk and highlight the usefulness of this integrative approach to bridge the divide between correlational and causal studies of human biology.
Keywords	COVID-19 infection ; humans ; loci ; loss-of-function mutation ; risk
Language	English
Dates of publication	2021-12
Size	p. 242.
Publishing place	BioMed Central
Document type	Article
ZDB-ID	2040529-7
ISSN	1474-760X
ISSN	1474-760X
DOI	10.1186/s13059-021-02454-4
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Article ; Online: The role of depression and antidepressant treatment in antihypertensive medication adherence and persistence: Utilising electronic health record data.

Kariis, Hanna Maria / Kasela, Silva / Jürgenson, Tuuli / Saar, Aet / Lass, Jana / Krebs, Kristi / Võsa, Urmo / Haan, Elis / Milani, Lili / Lehto, Kelli

Journal of psychiatric research

2023 Volume 168, Page(s) 269–278

Abstract: Higher blood pressure levels in patients with depression may be associated with lower adherence to antihypertensive medications (AHMs). Here, we use electronic health record (EHR) data from the Estonian Biobank (EstBB) to investigate the role of lifetime ...

Abstract	Higher blood pressure levels in patients with depression may be associated with lower adherence to antihypertensive medications (AHMs). Here, we use electronic health record (EHR) data from the Estonian Biobank (EstBB) to investigate the role of lifetime depression in AHM adherence and persistence. We also explore the relationship between antidepressant initiation and intraindividual change in AHM adherence among hypertension (HTN) patients with newly diagnosed depression. Diagnosis and pharmacy refill data were obtained from the National Health Insurance database. Adherence and persistence to AHMs were determined for hypertension (HTN) patients initiating treatment between 2009 and 2017 with a three-year follow-up period. Multivariable regression was used to explore the associations between depression and AHM adherence or persistence, adjusting for sociodemographic, genetic, and health-related factors. A linear mixed-effects model was used to estimate the effect of antidepressant treatment initiation on antihypertensive medication adherence, adjusting for age and sex. We identified 20,724 individuals with newly diagnosed HTN (6294 depression cases and 14,430 controls). Depression was associated with 6% lower probability of AHM adherence (OR = 0.943, 95%CI = 0.909-0.979) and 12% lower odds of AHM persistence (OR = 0.876, 95%CI = 0.821-0.936). Adjusting for sociodemographic, genetic, and health-related factors did not significantly influence these associations. AHM adherence increased 8% six months after initiating antidepressant therapy (N = 132; β = 0.078; 95%CI = 0.025-0.131). Based on the EHR data on EstBB participants, depression is associated with lower AHM adherence and persistence. Additionally, antidepressant therapy may help improve AHM adherence in patients with depression.
MeSH term(s)	Humans ; Antihypertensive Agents/therapeutic use ; Electronic Health Records ; Depression/drug therapy ; Depression/epidemiology ; Depression/complications ; Medication Adherence ; Hypertension/drug therapy ; Hypertension/epidemiology ; Hypertension/complications ; Antidepressive Agents/therapeutic use ; Retrospective Studies
Chemical Substances	Antihypertensive Agents ; Antidepressive Agents
Language	English
Publishing date	2023-10-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3148-3
ISSN	1879-1379 ; 0022-3956
ISSN (online)	1879-1379
ISSN	0022-3956
DOI	10.1016/j.jpsychires.2023.10.018
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Article: Integrative approach identifies

Kasela, Silva / Daniloski, Zharko / Jordan, Tristan X / tenOever, Benjamin R / Sanjana, Neville E / Lappalainen, Tuuli

medRxiv : the preprint server for health sciences

2021

Abstract: To date the locus with the most robust human genetic association to COVID-19 susceptibility is 3p21.31. Here, we integrate genome-scale CRISPR loss-of-function screens and eQTLs in diverse cell types and tissues to pinpoint genes underlying COVID-19 risk. ...

Abstract	To date the locus with the most robust human genetic association to COVID-19 susceptibility is 3p21.31. Here, we integrate genome-scale CRISPR loss-of-function screens and eQTLs in diverse cell types and tissues to pinpoint genes underlying COVID-19 risk. Our findings identify
Language	English
Publishing date	2021-04-13
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.04.09.21255184
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Article ; Online: Integrative approach identifies SLC6A20 and CXCR6 as putative causal genes for the COVID-19 GWAS signal in the 3p21.31 locus.

Kasela, Silva / Daniloski, Zharko / Bollepalli, Sailalitha / Jordan, Tristan X / tenOever, Benjamin R / Sanjana, Neville E / Lappalainen, Tuuli

Genome biology

2021 Volume 22, Issue 1, Page(s) 242

Abstract	To date, the locus with the most robust human genetic association to COVID-19 severity is 3p21.31. Here, we integrate genome-scale CRISPR loss-of-function screens and eQTLs in diverse cell types and tissues to pinpoint genes underlying COVID-19 risk. Our findings identify SLC6A20 and CXCR6 as putative causal genes that modulate COVID-19 risk and highlight the usefulness of this integrative approach to bridge the divide between correlational and causal studies of human biology.
MeSH term(s)	COVID-19/genetics ; Chromosomes, Human, Pair 3/genetics ; Humans ; Membrane Transport Proteins/genetics ; Phenotype ; Quantitative Trait Loci ; Receptors, CXCR6/genetics
Chemical Substances	CXCR6 protein, human ; Membrane Transport Proteins ; Receptors, CXCR6 ; SLC6A20 protein, human
Language	English
Publishing date	2021-08-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2040529-7
ISSN	1474-760X ; 1474-760X
ISSN (online)	1474-760X
ISSN	1474-760X
DOI	10.1186/s13059-021-02454-4
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Article ; Online: Genomic Insights into Myasthenia Gravis Identify Distinct Immunological Mechanisms in Early and Late Onset Disease.

Handunnetthi, Lahiru / Knezevic, Bogdan / Kasela, Silva / Burnham, Katie L / Milani, Lili / Irani, Sarosh R / Fang, Hai / Knight, Julian C

Annals of neurology

2021 Volume 90, Issue 3, Page(s) 455–463

Abstract: Objective: The purpose of this study was to identify disease relevant genes and explore underlying immunological mechanisms that contribute to early and late onset forms of myasthenia gravis.: Methods: We used a novel genomic methodology to integrate ...

Abstract	Objective: The purpose of this study was to identify disease relevant genes and explore underlying immunological mechanisms that contribute to early and late onset forms of myasthenia gravis. Methods: We used a novel genomic methodology to integrate genomewide association study (GWAS) findings in myasthenia gravis with cell-type specific information, such as gene expression patterns and promotor-enhancer interactions, in order to identify disease-relevant genes. Subsequently, we conducted additional genomic investigations, including an expression quantitative analysis of 313 healthy people to provide mechanistic insights. Results: We identified several genes that were specifically linked to early onset myasthenia gravis including TNIP1, ORMDL3, GSDMB, and TRAF3. We showed that regulators of toll-like receptor 4 signaling were enriched among these early onset disease genes (fold enrichment = 3.85, p = 6.4 × 10 Interpretation: The disease-relevant genes identified in this study are a unique resource for many disciplines, including clinicians, scientists, and the pharmaceutical industry. The distinct immunological pathways linked to early and late onset myasthenia gravis carry important implications for drug repurposing opportunities and for future studies of drug development. ANN NEUROL 2021;90:455-463.
MeSH term(s)	Adult ; Age of Onset ; Female ; Genetic Variation/physiology ; Genome-Wide Association Study/methods ; Humans ; Immunity, Innate/physiology ; Male ; Middle Aged ; Myasthenia Gravis/diagnosis ; Myasthenia Gravis/genetics ; Myasthenia Gravis/immunology ; Polymorphism, Single Nucleotide/physiology
Language	English
Publishing date	2021-08-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80362-5
ISSN	1531-8249 ; 0364-5134
ISSN (online)	1531-8249
ISSN	0364-5134
DOI	10.1002/ana.26169
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Article ; Online: Interaction molecular QTL mapping discovers cellular and environmental modifiers of genetic regulatory effects.

American journal of human genetics

2024 Volume 111, Issue 1, Page(s) 133–149

Abstract: Bulk-tissue molecular quantitative trait loci (QTLs) have been the starting point for interpreting disease-associated variants, and context-specific QTLs show particular relevance for disease. Here, we present the results of mapping interaction QTLs ( ... ...

Abstract	Bulk-tissue molecular quantitative trait loci (QTLs) have been the starting point for interpreting disease-associated variants, and context-specific QTLs show particular relevance for disease. Here, we present the results of mapping interaction QTLs (iQTLs) for cell type, age, and other phenotypic variables in multi-omic, longitudinal data from the blood of individuals of diverse ancestries. By modeling the interaction between genotype and estimated cell-type proportions, we demonstrate that cell-type iQTLs could be considered as proxies for cell-type-specific QTL effects, particularly for the most abundant cell type in the tissue. The interpretation of age iQTLs, however, warrants caution because the moderation effect of age on the genotype and molecular phenotype association could be mediated by changes in cell-type composition. Finally, we show that cell-type iQTLs contribute to cell-type-specific enrichment of diseases that, in combination with additional functional data, could guide future functional studies. Overall, this study highlights the use of iQTLs to gain insights into the context specificity of regulatory effects.
MeSH term(s)	Humans ; Quantitative Trait Loci/genetics ; Gene Expression Regulation ; Genotype ; Phenotype
Language	English
Publishing date	2024-01-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	219384-x
ISSN	1537-6605 ; 0002-9297
ISSN (online)	1537-6605
ISSN	0002-9297
DOI	10.1016/j.ajhg.2023.11.013
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Article ; Online: Psychiatric disorders and subsequent risk of cardiovascular disease: a longitudinal matched cohort study across three countries.

Shen, Qing / Mikkelsen, Dorte Helenius / Luitva, Laura Birgit / Song, Huan / Kasela, Silva / Aspelund, Thor / Bergstedt, Jacob / Lu, Yi / Sullivan, Patrick F / Ye, Weimin / Fall, Katja / Tornvall, Per / Pawitan, Yudi / Andreassen, Ole A / Buil, Alfonso / Milani, Lili / Fang, Fang / Valdimarsdóttir, Unnur

EClinicalMedicine

2023 Volume 61, Page(s) 102063

Abstract: Background: Several psychiatric disorders have been associated with increased risk of cardiovascular disease (CVD), however, the role of familial factors and the main disease trajectories remain unknown.: Methods: In this longitudinal cohort study, ... ...

Abstract	Background: Several psychiatric disorders have been associated with increased risk of cardiovascular disease (CVD), however, the role of familial factors and the main disease trajectories remain unknown. Methods: In this longitudinal cohort study, we identified a cohort of 900,240 patients newly diagnosed with psychiatric disorders during January 1, 1987 and December 31, 2016, their 1,002,888 unaffected full siblings, and 1:10 age- and sex-matched reference population from nationwide medical records in Sweden, who had no prior diagnosis of CVD at enrolment. We used flexible parametric models to determine the time-varying association between first-onset psychiatric disorders and incident CVD and CVD death, comparing rates of CVD among patients with psychiatric disorders to the rates of unaffected siblings and matched reference population. We also used disease trajectory analysis to identify main disease trajectories linking psychiatric disorders to CVD. Identified associations and disease trajectories of the Swedish cohort were validated in a similar cohort from nationwide medical records in Denmark (N = 875,634 patients, same criteria during January 1, 1969 and December 31, 2016) and in Estonian cohorts from the Estonian Biobank (N = 30,656 patients, same criteria during January 1, 2006 and December 31, 2020), respectively. Findings: During up to 30 years of follow-up of the Swedish cohort, the crude incidence rate of CVD was 9.7, 7.4 and 7.0 per 1000 person-years among patients with psychiatric disorders, their unaffected siblings, and the matched reference population. Compared with their siblings, patients with psychiatric disorders experienced higher rates of CVD during the first year after diagnosis (hazard ratio [HR], 1.88; 95% confidence interval [CI], 1.79-1.98) and thereafter (1.37; 95% CI, 1.34-1.39). Similar rate increases were noted when comparing with the matched reference population. These results were replicated in the Danish cohort. We identified several disease trajectories linking psychiatric disorders to CVD in the Swedish cohort, with or without mediating medical conditions, including a direct link between psychiatric disorders and hypertensive disorder, ischemic heart disease, venous thromboembolism, angina pectoris, and stroke. These trajectories were validated in the Estonian Biobank cohort. Interpretation: Independent of familial factors, patients with psychiatric disorders are at an elevated risk of subsequent CVD, particularly during first year after diagnosis. Increased surveillance and treatment of CVDs and CVD risk factors should be considered as an integral part of clinical management, in order to reduce risk of CVD among patients with psychiatric disorders. Funding: This research was supported by EU Horizon 2020 Research and Innovation Action Grant, European Research Council Consolidator grant, Icelandic Research fund, Swedish Research Council, US NIMH, the Outstanding Clinical Discipline Project of Shanghai Pudong, the Fundamental Research Funds for the Central Universities, and the European Union through the European Regional Development Fund; the Research Council of Norway; the South-East Regional Health Authority, the Stiftelsen Kristian Gerhard Jebsen, and the EEA-RO-NO-2018-0535.
Language	English
Publishing date	2023-06-22
Publishing country	England
Document type	Journal Article
ISSN	2589-5370
ISSN (online)	2589-5370
DOI	10.1016/j.eclinm.2023.102063
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Article ; Online: Transcription factor regulation of eQTL activity across individuals and tissues.

Flynn, Elise D / Tsu, Athena L / Kasela, Silva / Kim-Hellmuth, Sarah / Aguet, Francois / Ardlie, Kristin G / Bussemaker, Harmen J / Mohammadi, Pejman / Lappalainen, Tuuli

PLoS genetics

2022 Volume 18, Issue 1, Page(s) e1009719

Abstract: Tens of thousands of genetic variants associated with gene expression (cis-eQTLs) have been discovered in the human population. These eQTLs are active in various tissues and contexts, but the molecular mechanisms of eQTL variability are poorly understood, ...

Abstract	Tens of thousands of genetic variants associated with gene expression (cis-eQTLs) have been discovered in the human population. These eQTLs are active in various tissues and contexts, but the molecular mechanisms of eQTL variability are poorly understood, hindering our understanding of genetic regulation across biological contexts. Since many eQTLs are believed to act by altering transcription factor (TF) binding affinity, we hypothesized that analyzing eQTL effect size as a function of TF level may allow discovery of mechanisms of eQTL variability. Using GTEx Consortium eQTL data from 49 tissues, we analyzed the interaction between eQTL effect size and TF level across tissues and across individuals within specific tissues and generated a list of 10,098 TF-eQTL interactions across 2,136 genes that are supported by at least two lines of evidence. These TF-eQTLs were enriched for various TF binding measures, supporting with orthogonal evidence that these eQTLs are regulated by the implicated TFs. We also found that our TF-eQTLs tend to overlap genes with gene-by-environment regulatory effects and to colocalize with GWAS loci, implying that our approach can help to elucidate mechanisms of context-specificity and trait associations. Finally, we highlight an interesting example of IKZF1 TF regulation of an APBB1IP gene eQTL that colocalizes with a GWAS signal for blood cell traits. Together, our findings provide candidate TF mechanisms for a large number of eQTLs and offer a generalizable approach for researchers to discover TF regulators of genetic variant effects in additional QTL datasets.
MeSH term(s)	Alleles ; Binding Sites ; Gene Knockdown Techniques ; Gene-Environment Interaction ; Genome-Wide Association Study ; Humans ; Interferon Regulatory Factor-1/genetics ; Models, Genetic ; Phenotype ; Quantitative Trait Loci ; Transcription Factors/metabolism ; Transcription Factors/physiology
Chemical Substances	IRF1 protein, human ; Interferon Regulatory Factor-1 ; Transcription Factors
Language	English
Publishing date	2022-01-31
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1009719
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Article ; Online: Altered Gene Expression Associated with microRNA Binding Site Polymorphisms.

Võsa, Urmo / Esko, Tõnu / Kasela, Silva / Annilo, Tarmo

PloS one

2015 Volume 10, Issue 10, Page(s) e0141351

Abstract: Allele-specific gene expression associated with genetic variation in regulatory regions can play an important role in the development of complex traits. We hypothesized that polymorphisms in microRNA (miRNA) response elements (MRE-SNPs) that either ... ...

Abstract	Allele-specific gene expression associated with genetic variation in regulatory regions can play an important role in the development of complex traits. We hypothesized that polymorphisms in microRNA (miRNA) response elements (MRE-SNPs) that either disrupt a miRNA binding site or create a new miRNA binding site can affect the allele-specific expression of target genes. By integrating public expression quantitative trait locus (eQTL) data, miRNA binding site predictions, small RNA sequencing, and Argonaute crosslinking immunoprecipitation (AGO-CLIP) datasets, we identified genetic variants that can affect gene expression by modulating miRNA binding efficiency. We also identified MRE-SNPs located in regions associated with complex traits, indicating possible causative mechanisms associated with these loci. The results of this study expand the current understanding of gene expression regulation and help to interpret the mechanisms underlying eQTL effects.
MeSH term(s)	3' Untranslated Regions ; Base Sequence ; Binding Sites ; Cell Cycle Proteins ; Gene Expression ; Gene Frequency ; Genome-Wide Association Study ; Humans ; Iron-Sulfur Proteins/genetics ; Linkage Disequilibrium ; MicroRNAs/metabolism ; Nuclear Proteins/genetics ; Polymorphism, Single Nucleotide ; Proto-Oncogene Proteins/genetics ; Quantitative Trait Loci ; RNA Interference
Chemical Substances	3' Untranslated Regions ; Cell Cycle Proteins ; ISCU protein, human ; Iron-Sulfur Proteins ; MDM4 protein, human ; MicroRNAs ; Nuclear Proteins ; Proto-Oncogene Proteins
Language	English
Publishing date	2015-10-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0141351
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