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Article ; Online: Gut microbial metabolites as multi-kingdom intermediates.

Krautkramer, Kimberly A / Fan, Jing / Bäckhed, Fredrik

2020 Volume 19, Issue 2, Page(s) 77–94

Abstract: The gut microbiota contributes to host physiology through the production of a myriad of metabolites. These metabolites exert their effects within the host as signalling molecules and substrates for metabolic reactions. Although the study of host- ... ...

Abstract	The gut microbiota contributes to host physiology through the production of a myriad of metabolites. These metabolites exert their effects within the host as signalling molecules and substrates for metabolic reactions. Although the study of host-microbiota interactions remains challenging due to the high degree of crosstalk both within and between kingdoms, metabolite-focused research has identified multiple actionable microbial targets that are relevant for host health. Metabolites, as the functional output of combined host and microorganism interactions, provide a snapshot in time of an extraordinarily complex multi-organism system. Although substantial work remains towards understanding host-microbiota interactions and the underlying mechanisms, we review the current state of knowledge for each of the major classes of microbial metabolites with emphasis on clinical and translational research implications. We provide an overview of methodologies available for measurement of microbial metabolites, and in addition to discussion of key challenges, we provide a potential framework for integration of discovery-based metabolite studies with mechanistic work. Finally, we highlight examples in the literature where this approach has led to substantial progress in understanding host-microbiota interactions.
MeSH term(s)	Animals ; Chromatography, Liquid ; Energy Metabolism/physiology ; Fermentation/physiology ; Gastrointestinal Microbiome/physiology ; Host Microbial Interactions/physiology ; Humans ; Mass Spectrometry ; Metabolome/physiology ; Metabolomics/methods ; Nuclear Magnetic Resonance, Biomolecular ; Spectrum Analysis, Raman
Language	English
Publishing date	2020-09-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	2139054-X
ISSN	1740-1534 ; 1740-1526
ISSN (online)	1740-1534
ISSN	1740-1526
DOI	10.1038/s41579-020-0438-4
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Article ; Online: Chemical signaling between gut microbiota and host chromatin: What is your gut really saying?

Krautkramer, Kimberly A / Rey, Federico E / Denu, John M

The Journal of biological chemistry

2017 Volume 292, Issue 21, Page(s) 8582–8593

Abstract: Mammals and their gut microbial communities share extensive and tightly coordinated co-metabolism of dietary substrates. A large number of microbial metabolites have been detected in host circulation and tissues and, in many cases, are linked to host ... ...

Abstract	Mammals and their gut microbial communities share extensive and tightly coordinated co-metabolism of dietary substrates. A large number of microbial metabolites have been detected in host circulation and tissues and, in many cases, are linked to host metabolic, developmental, and immunological states. The presence of these metabolites in host tissues intersects with regulation of the host's epigenetic machinery. Although it is established that the host's epigenetic machinery is sensitive to levels of endogenous metabolites, the roles for microbial metabolites in epigenetic regulation are just beginning to be elucidated. This review focuses on eukaryotic chromatin regulation by endogenous and gut microbial metabolites and how these regulatory events may impact host developmental and metabolic phenotypes.
MeSH term(s)	Animals ; Chromatin Assembly and Disassembly ; Epigenesis, Genetic ; Gastrointestinal Microbiome ; Humans ; Intestinal Mucosa/metabolism ; Intestines/microbiology ; Signal Transduction
Language	English
Publishing date	2017-04-07
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.R116.761577
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Article ; Online: Metabolic programming of the epigenome: host and gut microbial metabolite interactions with host chromatin.

Krautkramer, Kimberly A / Dhillon, Rashpal S / Denu, John M / Carey, Hannah V

Translational research : the journal of laboratory and clinical medicine

2017 Volume 189, Page(s) 30–50

Abstract: The mammalian gut microbiota has been linked to host developmental, immunologic, and metabolic outcomes. This collection of trillions of microbes inhabits the gut and produces a myriad of metabolites, which are measurable in host circulation and ... ...

Abstract	The mammalian gut microbiota has been linked to host developmental, immunologic, and metabolic outcomes. This collection of trillions of microbes inhabits the gut and produces a myriad of metabolites, which are measurable in host circulation and contribute to the pathogenesis of human diseases. The link between endogenous metabolite availability and chromatin regulation is a well-established and active area of investigation; however, whether microbial metabolites can elicit similar effects is less understood. In this review, we focus on seminal and recent research that establishes chromatin regulatory roles for both endogenous and microbial metabolites. We also highlight key physiologic and disease settings where microbial metabolite-host chromatin interactions have been established and/or may be pertinent.
MeSH term(s)	Animals ; Cellular Reprogramming/genetics ; Chromatin/metabolism ; Epigenomics ; Gastrointestinal Microbiome/genetics ; Host-Pathogen Interactions/genetics ; Humans ; Metabolome/genetics
Chemical Substances	Chromatin
Language	English
Publishing date	2017-09-01
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2246684-8
ISSN	1878-1810 ; 1532-6543 ; 1931-5244
ISSN (online)	1878-1810 ; 1532-6543
ISSN	1931-5244
DOI	10.1016/j.trsl.2017.08.005
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Article ; Online: Self-organized metabotyping of obese individuals identifies clusters responding differently to bariatric surgery.

Lappa, Dimitra / Meijnikman, Abraham S / Krautkramer, Kimberly A / Olsson, Lisa M / Aydin, Ömrüm / Van Rijswijk, Anne-Sophie / Acherman, Yair I Z / De Brauw, Maurits L / Tremaroli, Valentina / Olofsson, Louise E / Lundqvist, Annika / Hjorth, Siv A / Ji, Boyang / Gerdes, Victor E A / Groen, Albert K / Schwartz, Thue W / Nieuwdorp, Max / Bäckhed, Fredrik / Nielsen, Jens

PloS one

2023 Volume 18, Issue 3, Page(s) e0279335

Abstract: Weight loss through bariatric surgery is efficient for treatment or prevention of obesity related diseases such as type 2 diabetes and cardiovascular disease. Long term weight loss response does, however, vary among patients undergoing surgery. Thus, it ... ...

Abstract	Weight loss through bariatric surgery is efficient for treatment or prevention of obesity related diseases such as type 2 diabetes and cardiovascular disease. Long term weight loss response does, however, vary among patients undergoing surgery. Thus, it is difficult to identify predictive markers while most obese individuals have one or more comorbidities. To overcome such challenges, an in-depth multiple omics analyses including fasting peripheral plasma metabolome, fecal metagenome as well as liver, jejunum, and adipose tissue transcriptome were performed for 106 individuals undergoing bariatric surgery. Machine leaning was applied to explore the metabolic differences in individuals and evaluate if metabolism-based patients' stratification is related to their weight loss responses to bariatric surgery. Using Self-Organizing Maps (SOMs) to analyze the plasma metabolome, we identified five distinct metabotypes, which were differentially enriched for KEGG pathways related to immune functions, fatty acid metabolism, protein-signaling, and obesity pathogenesis. The gut metagenome of the most heavily medicated metabotypes, treated simultaneously for multiple cardiometabolic comorbidities, was significantly enriched in Prevotella and Lactobacillus species. This unbiased stratification into SOM-defined metabotypes identified signatures for each metabolic phenotype and we found that the different metabotypes respond differently to bariatric surgery in terms of weight loss after 12 months. An integrative framework that utilizes SOMs and omics integration was developed for stratifying a heterogeneous bariatric surgery cohort. The multiple omics datasets described in this study reveal that the metabotypes are characterized by a concrete metabolic status and different responses in weight loss and adipose tissue reduction over time. Our study thus opens a path to enable patient stratification and hereby allow for improved clinical treatments.
MeSH term(s)	Humans ; Diabetes Mellitus, Type 2/surgery ; Obesity/surgery ; Bariatric Surgery ; Adipose Tissue ; Algorithms
Language	English
Publishing date	2023-03-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0279335
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Article ; Online: A systems biology approach to study non-alcoholic fatty liver (NAFL) in women with obesity.

Meijnikman, Abraham S / Lappa, Dimitra / Herrema, Hilde / Aydin, Omrum / Krautkramer, Kimberly A / Tremaroli, Valentina / Olofsson, Louise E / Lundqvist, Annika / Bruin, Sjoerd / Acherman, Yair / Verheij, Joanne / Hjorth, Siv / Gerdes, Victor E A / Schwartz, Thue W / Groen, Albert K / Bäckhed, Fredrik / Nielsen, Jens / Nieuwdorp, Max

iScience

2022 Volume 25, Issue 8, Page(s) 104828

Abstract: Non-alcoholic fatty liver disease (NAFLD) is now the most frequent global chronic liver disease. Individuals with NAFLD exhibited an increased risk of all-cause mortality driven by extrahepatic cancers and liver and cardiovascular disease. Once the ... ...

Abstract	Non-alcoholic fatty liver disease (NAFLD) is now the most frequent global chronic liver disease. Individuals with NAFLD exhibited an increased risk of all-cause mortality driven by extrahepatic cancers and liver and cardiovascular disease. Once the disease is established, women have a higher risk of disease progression and worse outcome. It is therefore critical to deepen the current knowledge on the pathophysiology of NAFLD in women. Here, we used a systems biology approach to investigate the contribution of different organs to this disease. We analyzed transcriptomics profiles of liver and adipose tissues, fecal metagenomes, and plasma metabolomes of 55 women with and without NAFLD. We observed differences in metabolites, expression of human genes, and gut microbial features between the groups and revealed that there is substantial crosstalk between these different omics sets. Multi-omics analysis of individuals with NAFLD may provide novel strategies to study the pathophysiology of NAFLD in humans.
Language	English
Publishing date	2022-08-05
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2022.104828
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Article ; Online: Metabolic regulation of histone post-translational modifications.

Fan, Jing / Krautkramer, Kimberly A / Feldman, Jessica L / Denu, John M

ACS chemical biology

2015 Volume 10, Issue 1, Page(s) 95–108

Abstract: Histone post-translational modifications regulate transcription and other DNA-templated functions. This process is dynamically regulated by specific modifying enzymes whose activities require metabolites that either serve as cosubstrates or act as ... ...

Abstract	Histone post-translational modifications regulate transcription and other DNA-templated functions. This process is dynamically regulated by specific modifying enzymes whose activities require metabolites that either serve as cosubstrates or act as activators/inhibitors. Therefore, metabolism can influence histone modification by changing local concentrations of key metabolites. Physiologically, the epigenetic response to metabolism is important for nutrient sensing and environment adaption. In pathologic states, the connection between metabolism and histone modification mediates epigenetic abnormality in complex disease. In this review, we summarize recent studies of the molecular mechanisms involved in metabolic regulation of histone modifications and discuss their biological significance.
MeSH term(s)	Acetyl Coenzyme A/metabolism ; Acetylation ; Adaptation, Physiological/genetics ; Animals ; DNA Methylation ; Epigenesis, Genetic ; Histone Deacetylases/metabolism ; Histones/genetics ; Histones/metabolism ; Humans ; Neoplasms/metabolism ; Protein Processing, Post-Translational ; Transcription, Genetic
Chemical Substances	Histones ; Acetyl Coenzyme A (72-89-9) ; Histone Deacetylases (EC 3.5.1.98)
Language	English
Publishing date	2015-01-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/cb500846u
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Article ; Online: Quantification of SAHA-Dependent Changes in Histone Modifications Using Data-Independent Acquisition Mass Spectrometry.

Krautkramer, Kimberly A / Reiter, Lukas / Denu, John M / Dowell, James A

Journal of proteome research

2015 Volume 14, Issue 8, Page(s) 3252–3262

Abstract: Histone post-translational modifications (PTMs) are important regulators of chromatin structure and gene expression. Quantitative analysis of histone PTMs by mass spectrometry remains extremely challenging due to the complex and combinatorial nature of ... ...

Abstract	Histone post-translational modifications (PTMs) are important regulators of chromatin structure and gene expression. Quantitative analysis of histone PTMs by mass spectrometry remains extremely challenging due to the complex and combinatorial nature of histone PTMs. The most commonly used mass spectrometry-based method for high-throughput histone PTM analysis is data-dependent acquisition (DDA). However, stochastic precursor selection and dependence on MS1 ions for quantification impede comprehensive interrogation of histone PTM states using DDA methods. To overcome these limitations, we utilized a data-independent acquisition (DIA) workflow that provides superior run-to-run consistency and postacquisition flexibility in comparison to DDA methods. In addition, we developed a novel DIA-based methodology to quantify isobaric, co-eluting histone peptides that lack unique MS2 transitions. Our method enabled deconvolution and quantification of histone PTMs that are otherwise refractory to quantitation, including the heavily acetylated tail of histone H4. Using this workflow, we investigated the effects of the histone deacetylase inhibitor SAHA (suberoylanilide hydroxamic acid) on the global histone PTM state of human breast cancer MCF7 cells. A total of 62 unique histone PTMs were quantified, revealing novel SAHA-induced changes in acetylation and methylation of histones H3 and H4.
MeSH term(s)	Acetylation/drug effects ; Amino Acid Sequence ; Blotting, Western ; Chromatography, Liquid ; Histone Code/drug effects ; Histone Deacetylase Inhibitors/pharmacology ; Histones/metabolism ; Humans ; Hydroxamic Acids/pharmacology ; MCF-7 Cells ; Mass Spectrometry/methods ; Methylation/drug effects ; Molecular Sequence Data ; Peptides/metabolism ; Protein Processing, Post-Translational/drug effects ; Proteomics/methods ; Reproducibility of Results ; Spectrometry, Mass, Electrospray Ionization ; Tandem Mass Spectrometry
Chemical Substances	Histone Deacetylase Inhibitors ; Histones ; Hydroxamic Acids ; Peptides ; vorinostat (58IFB293JI)
Language	English
Publishing date	2015-08-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021/acs.jproteome.5b00245
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Article ; Online: Self-organized metabotyping of obese individuals identifies clusters responding differently to bariatric surgery

Dimitra Lappa / Abraham S. Meijnikman / Kimberly A. Krautkramer / Lisa M. Olsson / Ömrüm Aydin / Anne-Sophie Van Rijswijk / Yair I. Z. Acherman / Maurits L. De Brauw / Valentina Tremaroli / Louise E. Olofsson / Annika Lundqvist / Siv A. Hjorth / Boyang Ji / Victor E. A. Gerdes / Albert K. Groen / Thue W. Schwartz / Max Nieuwdorp / Fredrik Bäckhed / Jens Nielsen

PLoS ONE, Vol 18, Iss

2023 Volume 3

Abstract	Weight loss through bariatric surgery is efficient for treatment or prevention of obesity related diseases such as type 2 diabetes and cardiovascular disease. Long term weight loss response does, however, vary among patients undergoing surgery. Thus, it is difficult to identify predictive markers while most obese individuals have one or more comorbidities. To overcome such challenges, an in-depth multiple omics analyses including fasting peripheral plasma metabolome, fecal metagenome as well as liver, jejunum, and adipose tissue transcriptome were performed for 106 individuals undergoing bariatric surgery. Machine leaning was applied to explore the metabolic differences in individuals and evaluate if metabolism-based patients’ stratification is related to their weight loss responses to bariatric surgery. Using Self-Organizing Maps (SOMs) to analyze the plasma metabolome, we identified five distinct metabotypes, which were differentially enriched for KEGG pathways related to immune functions, fatty acid metabolism, protein-signaling, and obesity pathogenesis. The gut metagenome of the most heavily medicated metabotypes, treated simultaneously for multiple cardiometabolic comorbidities, was significantly enriched in Prevotella and Lactobacillus species. This unbiased stratification into SOM-defined metabotypes identified signatures for each metabolic phenotype and we found that the different metabotypes respond differently to bariatric surgery in terms of weight loss after 12 months. An integrative framework that utilizes SOMs and omics integration was developed for stratifying a heterogeneous bariatric surgery cohort. The multiple omics datasets described in this study reveal that the metabotypes are characterized by a concrete metabolic status and different responses in weight loss and adipose tissue reduction over time. Our study thus opens a path to enable patient stratification and hereby allow for improved clinical treatments.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Self-organized metabotyping of obese individuals identifies clusters responding differently to bariatric surgery.

Dimitra Lappa / Abraham S Meijnikman / Kimberly A Krautkramer / Lisa M Olsson / Ömrüm Aydin / Anne-Sophie Van Rijswijk / Yair I Z Acherman / Maurits L De Brauw / Valentina Tremaroli / Louise E Olofsson / Annika Lundqvist / Siv A Hjorth / Boyang Ji / Victor E A Gerdes / Albert K Groen / Thue W Schwartz / Max Nieuwdorp / Fredrik Bäckhed / Jens Nielsen

PLoS ONE, Vol 18, Iss 3, p e

2023 Volume 0279335

Abstract	Weight loss through bariatric surgery is efficient for treatment or prevention of obesity related diseases such as type 2 diabetes and cardiovascular disease. Long term weight loss response does, however, vary among patients undergoing surgery. Thus, it is difficult to identify predictive markers while most obese individuals have one or more comorbidities. To overcome such challenges, an in-depth multiple omics analyses including fasting peripheral plasma metabolome, fecal metagenome as well as liver, jejunum, and adipose tissue transcriptome were performed for 106 individuals undergoing bariatric surgery. Machine leaning was applied to explore the metabolic differences in individuals and evaluate if metabolism-based patients' stratification is related to their weight loss responses to bariatric surgery. Using Self-Organizing Maps (SOMs) to analyze the plasma metabolome, we identified five distinct metabotypes, which were differentially enriched for KEGG pathways related to immune functions, fatty acid metabolism, protein-signaling, and obesity pathogenesis. The gut metagenome of the most heavily medicated metabotypes, treated simultaneously for multiple cardiometabolic comorbidities, was significantly enriched in Prevotella and Lactobacillus species. This unbiased stratification into SOM-defined metabotypes identified signatures for each metabolic phenotype and we found that the different metabotypes respond differently to bariatric surgery in terms of weight loss after 12 months. An integrative framework that utilizes SOMs and omics integration was developed for stratifying a heterogeneous bariatric surgery cohort. The multiple omics datasets described in this study reveal that the metabotypes are characterized by a concrete metabolic status and different responses in weight loss and adipose tissue reduction over time. Our study thus opens a path to enable patient stratification and hereby allow for improved clinical treatments.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Iron Deprivation Induces Transcriptional Regulation of Mitochondrial Biogenesis.

Rensvold, Jarred W / Krautkramer, Kimberly A / Dowell, James A / Denu, John M / Pagliarini, David J

The Journal of biological chemistry

2016 Volume 291, Issue 40, Page(s) 20827–20837

Abstract: Mitochondria are essential organelles that adapt to stress and environmental changes. Among the nutrient signals that affect mitochondrial form and function is iron, whose depletion initiates a rapid and reversible decrease in mitochondrial biogenesis ... ...

Abstract	Mitochondria are essential organelles that adapt to stress and environmental changes. Among the nutrient signals that affect mitochondrial form and function is iron, whose depletion initiates a rapid and reversible decrease in mitochondrial biogenesis through unclear means. Here we demonstrate that, unlike the canonical iron-induced alterations to transcript stability, loss of iron dampens the transcription of genes encoding mitochondrial proteins with no change to transcript half-life. Using mass spectrometry, we demonstrate that these transcriptional changes are accompanied by dynamic alterations to histone acetylation and methylation levels that are largely reversible upon readministration of iron. Moreover, histone deacetylase inhibition abrogates the decreased histone acetylation observed upon iron deprivation and restores normal transcript levels at genes encoding mitochondrial proteins. Collectively, we demonstrate that deprivation of an essential nutrient induces transcriptional repression of organellar biogenesis involving epigenetic alterations.
MeSH term(s)	Acetylation ; Animals ; Epigenesis, Genetic ; Histones/metabolism ; Iron Deficiencies ; Mice ; Mitochondria, Muscle/metabolism ; Mitochondrial Proteins/biosynthesis ; Transcription, Genetic
Chemical Substances	Histones ; Mitochondrial Proteins
Language	English
Publishing date	2016-08-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M116.727701
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