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Article ; Online: Citrullination of matrisomal proteins in health and diseases.

Saifi, Mohammad Aslam / Ho, I-Cheng

Philosophical transactions of the Royal Society of London. Series B, Biological sciences

2023 Volume 378, Issue 1890, Page(s) 20220244

Abstract: Proteins once translated are subjected to post-translational modifications (PTMs) that can critically modify their characteristics. Citrullination is a unique type of PTM that is catalysed by peptidylarginine deiminase (PAD) enzymes, which regulate a ... ...

Abstract	Proteins once translated are subjected to post-translational modifications (PTMs) that can critically modify their characteristics. Citrullination is a unique type of PTM that is catalysed by peptidylarginine deiminase (PAD) enzymes, which regulate a multitude of physiological functions such as apoptosis, gene expression and immune response by altering the structure and function of cellular proteins. However, emerging data have unravelled compelling evidence to support that PAD-mediated citrullination is not exclusive to cellular proteins; rather citrullination of extracellular matrix (ECM) proteins also plays a major contributing role in various physiological/pathological conditions. Here, we discuss putative mechanisms for citrullination-induced alterations in the function of ECM proteins. Further, we put emphasis on influential roles of ECM citrullination in various pathological scenarios to underscore the clinical potential of its manipulation in human diseases. This article is part of the Theo Murphy meeting issue 'The virtues and vices of protein citrullination'.
MeSH term(s)	Humans ; Citrullination ; Protein-Arginine Deiminases/genetics ; Protein-Arginine Deiminases/metabolism ; Proteins/genetics ; Protein Processing, Post-Translational
Chemical Substances	Protein-Arginine Deiminases (EC 3.5.3.15) ; Proteins
Language	English
Publishing date	2023-10-02
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	208382-6
ISSN	1471-2970 ; 0080-4622 ; 0264-3839 ; 0962-8436
ISSN (online)	1471-2970
ISSN	0080-4622 ; 0264-3839 ; 0962-8436
DOI	10.1098/rstb.2022.0244
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Article ; Online: Peptidylarginine deiminase 2 citrullinates MZB1 and promotes the secretion of IgM and IgA.

Geary, Benjamin / Sun, Bo / Tilvawala, Ronak R / Barasa, Leonard / Tsoyi, Konstantin / Rosas, Ivan O / Thompson, Paul R / Ho, I-Cheng

Frontiers in immunology

2023 Volume 14, Page(s) 1290585

Abstract: Introduction: MZB1 is an endoplasmic reticulum residential protein preferentially expressed in plasma cells, marginal zone and B1 B cells. Recent studies on murine B cells show that it interacts with the tail piece of IgM and IgA heavy chain and ... ...

Abstract	Introduction: MZB1 is an endoplasmic reticulum residential protein preferentially expressed in plasma cells, marginal zone and B1 B cells. Recent studies on murine B cells show that it interacts with the tail piece of IgM and IgA heavy chain and promotes the secretion of these two classes of immunoglobulin. However, its role in primary human B cells has yet to be determined and how its function is regulated is still unknown. The conversion of peptidylarginine to peptidylcitrulline, also known as citrullination, by peptidylarginine deiminases (PADs) can critically influence the function of proteins in immune cells, such as neutrophils and T cells; however, the role of PADs in B cells remains to be elucidated. Method: An unbiased analysis of human lung citrullinome was conducted to identify citrullinated proteins that are enriched in several chronic lung diseases, including rheumatoid arthritis-associated interstitial lung disease (RA-ILD), chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis, compared to healthy controls. Mass spectrometry, site-specific mutagenesis, and western blotting were used to confirm the citrullination of candidate proteins. Their citrullination was suppressed by pharmacological inhibition or genetic ablation of PAD2 and the impact of their citrullination on the function and differentiation of human B cells was examined with enzyme-linked immunosorbent assay, flow cytometry, and co-immunoprecipitation. Results: Citrullinated MZB1 was preferentially enriched in RA-ILD but not in other chronic lung diseases. MZB1 was a substrate of PAD2 and was citrullinated during the differentiation of human plasmablasts. Ablation or pharmacological inhibition of PAD2 in primary human B cells attenuated the secretion of IgM and IgA but not IgG or the differentiation of IgM or IgA-expressing plasmablasts, recapitulating the effect of ablating MZB1. Furthermore, the physical interaction between endogenous MZB1 and IgM/IgA was attenuated by pharmacological inhibition of PAD2. Discussion: Our data confirm the function of MZB1 in primary human plasmablasts and suggest that PAD2 promotes IgM/IgA secretion by citrullinating MZB1, thereby contributing to the pathogenesis of rheumatoid arthritis and RA-ILD.
MeSH term(s)	Humans ; Mice ; Animals ; Protein-Arginine Deiminases/genetics ; Arthritis, Rheumatoid ; Proteins/metabolism ; Idiopathic Pulmonary Fibrosis ; Lung Diseases, Interstitial ; Immunoglobulin A ; Immunoglobulin M
Chemical Substances	Protein-Arginine Deiminases (EC 3.5.3.15) ; Proteins ; Immunoglobulin A ; Immunoglobulin M
Language	English
Publishing date	2023-11-29
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1290585
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Article ; Online: Differential impacts of TNFα inhibitors on the transcriptome of Th cells.

Ho, Ching-Huang / Silva, Andrea A / Tomita, Beverly / Weng, Hui-Ying / Ho, I-Cheng

Arthritis research & therapy

2021 Volume 23, Issue 1, Page(s) 199

Abstract: Background: Targeting TNFα is beneficial in many autoimmune and inflammatory diseases, including rheumatoid arthritis. However, the response to each of the existing TNFα inhibitors (TNFis) can be patient- and/or disease-dependent. In addition, TNFis can ...

Abstract	Background: Targeting TNFα is beneficial in many autoimmune and inflammatory diseases, including rheumatoid arthritis. However, the response to each of the existing TNFα inhibitors (TNFis) can be patient- and/or disease-dependent. In addition, TNFis can induce the production of type 1 interferons (IFNs), which contribute to their non-infection side effects, such as pustular psoriasis. Thus far, the molecular mechanisms mediating the drug-specific effects of TNFis and their induction of type 1 IFNs are not fully understood. Methods: Peripheral blood mononuclear cells (PBMCs) were collected from healthy donors and stimulated in vitro with anti-CD3 and anti-CD28 in the absence or presence of adalimumab, etanercept, or certolizumab. Th cells were isolated from the stimulated PBMCs, and their RNA was subjected to RNA-seq and quantitative polymerase chain reaction. Results: Adalimumab and etanercept, which contain Fc, but not certolizumab, which does not contain Fc, inhibited the expression of several effector cytokines by Th cells within anti-CD3/anti-CD28-stimulated PBMCs. Transcriptomic analyses further showed that adalimumab, but not certolizumab, reciprocally induced type 1 IFN signals and the expression of CD96 and SIRPG in Th cells. The unique effects of adalimumab were not due to preferential neutralization of soluble TNFα but instead were mediated by several distinct mechanisms independent or dependent of Fc-facilitated physical interaction between Th cells and CD14+ monocytes. Conclusions: TNFis can have drug-specific effects on the transcriptional profile of Th cells.
MeSH term(s)	Adalimumab/pharmacology ; Antibodies, Monoclonal, Humanized ; Certolizumab Pegol ; Etanercept ; Humans ; Leukocytes, Mononuclear ; T-Lymphocytes, Helper-Inducer/drug effects ; Transcriptome ; Tumor Necrosis Factor Inhibitors/pharmacology
Chemical Substances	Antibodies, Monoclonal, Humanized ; Tumor Necrosis Factor Inhibitors ; Adalimumab (FYS6T7F842) ; Etanercept (OP401G7OJC) ; Certolizumab Pegol (UMD07X179E)
Language	English
Publishing date	2021-07-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2107602-9
ISSN	1478-6362 ; 1478-6354
ISSN (online)	1478-6362
ISSN	1478-6354
DOI	10.1186/s13075-021-02558-z
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Article: Regulation of IL-4 Expression in Immunity and Diseases.

Ho, I-Cheng / Miaw, Shi-Chuen

Advances in experimental medicine and biology

2016 Volume 941, Page(s) 31–77

Abstract: IL-4 was first identified as a T cell-derived growth factor for B cells. Studies over the past several decades have markedly expanded our understanding of its cellular sources and function. In addition to T cells, IL-4 is produced by innate lymphocytes, ... ...

Abstract	IL-4 was first identified as a T cell-derived growth factor for B cells. Studies over the past several decades have markedly expanded our understanding of its cellular sources and function. In addition to T cells, IL-4 is produced by innate lymphocytes, such as NTK cells, and myeloid cells, such as basophils and mast cells. It is a signature cytokine of type 2 immune response but also has a nonimmune function. Its expression is tightly regulated at several levels, including signaling pathways, transcription factors, epigenetic modifications, microRNA, and long noncoding RNA. This chapter will review in detail the molecular mechanism regulating the cell type-specific expression of IL-4 in physiological and pathological type 2 immune responses.
MeSH term(s)	Animals ; Basophils/immunology ; Basophils/metabolism ; Disease/genetics ; Gene Expression Regulation ; Humans ; Immunity, Innate/genetics ; Interleukin-4/genetics ; Interleukin-4/metabolism ; Lymphocytes/immunology ; Lymphocytes/metabolism
Chemical Substances	Interleukin-4 (207137-56-2)
Language	English
Publishing date	2016-10-27
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-94-024-0921-5_3
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Article ; Online: m(en)TOR(ing) differentiating T helper cells.

Ho, I-Cheng

Immunity

2009 Volume 30, Issue 6, Page(s) 759–761

Abstract: The decision of naive Th cells to assume the fate of effector or regulator Th cells heavily influences the outcome of adaptive immune responses. In this issue of Immunity, Delgoffe et al. (2009) use genetic approaches and demonstrate that mTOR kinase ... ...

Abstract	The decision of naive Th cells to assume the fate of effector or regulator Th cells heavily influences the outcome of adaptive immune responses. In this issue of Immunity, Delgoffe et al. (2009) use genetic approaches and demonstrate that mTOR kinase plays a critical role in this decision-making process.
MeSH term(s)	Animals ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cell Differentiation/immunology ; Cytokines/immunology ; Cytokines/metabolism ; Mice ; Phosphotransferases (Alcohol Group Acceptor)/genetics ; Phosphotransferases (Alcohol Group Acceptor)/metabolism ; Sirolimus/immunology ; Sirolimus/metabolism ; T-Lymphocyte Subsets/enzymology ; T-Lymphocyte Subsets/immunology ; T-Lymphocytes, Helper-Inducer/enzymology ; T-Lymphocytes, Helper-Inducer/immunology ; TOR Serine-Threonine Kinases ; Transcription Factors/immunology ; Transcription Factors/metabolism
Chemical Substances	Carrier Proteins ; Cytokines ; Transcription Factors ; Phosphotransferases (Alcohol Group Acceptor) (EC 2.7.1.-) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; mTOR protein, mouse (EC 2.7.1.1) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2009-06-19
Publishing country	United States
Document type	Comment ; Journal Article
ZDB-ID	1217235-2
ISSN	1097-4180 ; 1074-7613
ISSN (online)	1097-4180
ISSN	1074-7613
DOI	10.1016/j.immuni.2009.06.002
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Article ; Online: Validation of a Bioassay for Predicting Response to Tumor Necrosis Factor Inhibitors in Rheumatoid Arthritis.

Ho, Ching-Huang / Silva, Andrea A / Giles, Jon T / Bathon, Joan M / Solomon, Daniel H / Liao, Katherine P / Ho, I-Cheng

Arthritis & rheumatology (Hoboken, N.J.)

2021 Volume 73, Issue 6, Page(s) 1086–1087

MeSH term(s)	Adalimumab/pharmacology ; Adalimumab/therapeutic use ; Aged ; Arthritis, Rheumatoid/drug therapy ; Arthritis, Rheumatoid/genetics ; Biological Assay ; Etanercept/pharmacology ; Etanercept/therapeutic use ; Humans ; Middle Aged ; Prognosis ; Protein Tyrosine Phosphatase, Non-Receptor Type 22/drug effects ; Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics ; Reproducibility of Results ; Transcriptome/drug effects ; Treatment Outcome ; Tumor Necrosis Factor Inhibitors/pharmacology ; Tumor Necrosis Factor Inhibitors/therapeutic use
Chemical Substances	Tumor Necrosis Factor Inhibitors ; PTPN22 protein, human (EC 3.1.3.48) ; Protein Tyrosine Phosphatase, Non-Receptor Type 22 (EC 3.1.3.48) ; Adalimumab (FYS6T7F842) ; Etanercept (OP401G7OJC)
Language	English
Publishing date	2021-04-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Validation Study
ZDB-ID	2756371-6
ISSN	2326-5205 ; 2326-5191
ISSN (online)	2326-5205
ISSN	2326-5191
DOI	10.1002/art.41645
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Article ; Online: Ets1 Promotes the Differentiation of Post-Selected iNKT Cells through Regulation of the Expression of Vα14Jα18 T Cell Receptor and PLZF.

Chuang, Ya-Ting / Chuang, Wan-Chu / Liu, Chih-Chun / Liu, Chia-Wei / Huang, Yu-Wen / Yang, Huang-Yu / Ho, I-Cheng / Tai, Tzong-Shyuan

International journal of molecular sciences

2021 Volume 22, Issue 22

Abstract: The transcription factor Ets1 is essential for the development/differentiation of invariant Natural Killer T (iNKT) cells at multiple stages. However, its mechanisms of action and target genes in iNKT cells are still elusive. Here, we show that Ets1 is ... ...

Abstract	The transcription factor Ets1 is essential for the development/differentiation of invariant Natural Killer T (iNKT) cells at multiple stages. However, its mechanisms of action and target genes in iNKT cells are still elusive. Here, we show that Ets1 is required for the optimal expression of the Vα14Jα18 T cell receptor (TCR) in post-selected thymic iNKT cells and their immediate differentiation. Ets1 is also critical for maintaining the peripheral homeostasis of iNKT cells, which is a role independent of the expression of the Vα14Jα18 TCR. Genome-wide transcriptomic analyses of post-selected iNKT cells further reveal that Ets1 controls leukocytes activation, proliferation differentiation, and leukocyte-mediated immunity. In addition, Ets1 regulates the expression of ICOS and PLZF in iNKT cells. More importantly, restoring the expression of PLZF and the Vα14Jα18 TCR partially rescues the differentiation of iNKT cells in the absence of Ets1. Taken together, our results establish a detailed molecular picture of how Ets1 regulates the stepwise differentiation of iNKT cells.
MeSH term(s)	Animals ; Cell Differentiation/genetics ; Cell Differentiation/immunology ; Gene Expression Regulation/immunology ; Mice ; Mice, Knockout ; Natural Killer T-Cells/immunology ; Promyelocytic Leukemia Zinc Finger Protein/genetics ; Promyelocytic Leukemia Zinc Finger Protein/immunology ; Proto-Oncogene Protein c-ets-1/genetics ; Proto-Oncogene Protein c-ets-1/immunology ; Receptors, Antigen, T-Cell, alpha-beta/genetics ; Receptors, Antigen, T-Cell, alpha-beta/immunology
Chemical Substances	Ets1 protein, mouse ; Promyelocytic Leukemia Zinc Finger Protein ; Proto-Oncogene Protein c-ets-1 ; Receptors, Antigen, T-Cell, alpha-beta ; Zbtb16 protein, mouse
Language	English
Publishing date	2021-11-11
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/ijms222212199
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Article ; Online: Ets1 regulates the differentiation and function of iNKT cells through both Pointed domain-dependent and domain-independent mechanisms.

Tai, Tzong-Shyuan / Tsao, Hsiao-Wei / Chuang, Wan-Chu / Liu, Chih-Chun / Huang, Yu-Wen / Oettgen, Peter / Chuang, Ya-Ting / Ho, I-Cheng

Cellular & molecular immunology

2020 Volume 17, Issue 11, Page(s) 1198–1200

MeSH term(s)	Animals ; Cell Differentiation ; Integrases/metabolism ; Mice, Transgenic ; Natural Killer T-Cells/cytology ; Natural Killer T-Cells/metabolism ; Protein Domains ; Proto-Oncogene Protein c-ets-1/chemistry ; Proto-Oncogene Protein c-ets-1/metabolism ; Structure-Activity Relationship
Chemical Substances	Proto-Oncogene Protein c-ets-1 ; Cre recombinase (EC 2.7.7.-) ; Integrases (EC 2.7.7.-)
Language	English
Publishing date	2020-03-05
Publishing country	China
Document type	Letter ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2435097-7
ISSN	2042-0226 ; 1672-7681
ISSN (online)	2042-0226
ISSN	1672-7681
DOI	10.1038/s41423-020-0382-2
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Article ; Online: A sequential mediation model of perceived social support, mindfulness, perceived hope, and mental health literacy: An empirical study on Taiwanese university students.

Lo, Chih-Cheng / Chen, I-Chen / Ho, Wei-Sho / Cheng, Yao-Chung

Acta psychologica

2023 Volume 240, Page(s) 104016

Abstract: This study explored the mediation of mindfulness and perceived hope between perceived social support and mental health literacy in university students. Of 568 students (205 males, 363 females, average age 20.97) from 70 Taiwanese universities, tools like ...

Abstract	This study explored the mediation of mindfulness and perceived hope between perceived social support and mental health literacy in university students. Of 568 students (205 males, 363 females, average age 20.97) from 70 Taiwanese universities, tools like the Perceived Social Support Scale, General Health Questionnaire, Mindful Attention Awareness Scale, and State Hope Scale were used, adapted to Traditional Chinese through back-translation. Confirmatory factor analysis affirmed model validity. Hayes' PROCESS Model 6 analyzed the data. The results showed an indirect effect of social support on mental health literacy via mindfulness and hope (B = 0.091, 95 % CI: 0.0613 to 0.1258). Three mediation paths were: (1) mindfulness (B = 0.035); (2) hope (B = 0.052); and (3) a combined effect (B = 0.003). A direct effect of social support on mental health literacy was significant (B = 0.120). The model explained 33.9 % of the variance in mental health literacy. The research underscores the link between social support, mindfulness, hope, and mental health literacy, identifying mindfulness and hope as mediators. It stresses the mediation impact and suggests strategies to boost mental health literacy in university students. Future research should expand to cross-cultural studies, further examine the evolving dynamics of social support, and incorporate both qualitative and experimental methodologies. The inclusion of factors such as alienation, well-being, and resilience can enrich the theoretical framework.
MeSH term(s)	Male ; Female ; Humans ; Young Adult ; Adult ; Health Literacy ; Mindfulness/methods ; Universities ; Students/psychology ; Social Support
Language	English
Publishing date	2023-09-18
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	1480049-4
ISSN	1873-6297 ; 0001-6918
ISSN (online)	1873-6297
ISSN	0001-6918
DOI	10.1016/j.actpsy.2023.104016
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Article ; Online: Ets1 Promotes the Differentiation of Post-Selected iNKT Cells through Regulation of the Expression of Vα14Jα18 T Cell Receptor and PLZF

Ya-Ting Chuang / Wan-Chu Chuang / Chih-Chun Liu / Chia-Wei Liu / Yu-Wen Huang / Huang-Yu Yang / I-Cheng Ho / Tzong-Shyuan Tai

International Journal of Molecular Sciences, Vol 22, Iss 12199, p

2021 Volume 12199

Abstract	The transcription factor Ets1 is essential for the development/differentiation of invariant Natural Killer T (iNKT) cells at multiple stages. However, its mechanisms of action and target genes in iNKT cells are still elusive. Here, we show that Ets1 is required for the optimal expression of the Vα14Jα18 T cell receptor (TCR) in post-selected thymic iNKT cells and their immediate differentiation. Ets1 is also critical for maintaining the peripheral homeostasis of iNKT cells, which is a role independent of the expression of the Vα14Jα18 TCR. Genome-wide transcriptomic analyses of post-selected iNKT cells further reveal that Ets1 controls leukocytes activation, proliferation differentiation, and leukocyte-mediated immunity. In addition, Ets1 regulates the expression of ICOS and PLZF in iNKT cells. More importantly, restoring the expression of PLZF and the Vα14Jα18 TCR partially rescues the differentiation of iNKT cells in the absence of Ets1. Taken together, our results establish a detailed molecular picture of how Ets1 regulates the stepwise differentiation of iNKT cells.
Keywords	iNKT cells ; Ets1 ; ICOS ; PLZF ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	570
Language	English
Publishing date	2021-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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