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Article ; Online: Mechanism of Decision Making between Autophagy and Apoptosis Induction upon Endoplasmic Reticulum Stress.

Kapuy, Orsolya

International journal of molecular sciences

2024 Volume 25, Issue 8

Abstract: Dynamic regulation of the cellular proteome is mainly controlled in the endoplasmic reticulum (ER). Accumulation of misfolded proteins due to ER stress leads to the activation of unfolded protein response (UPR). The primary role of UPR is to reduce the ... ...

Abstract	Dynamic regulation of the cellular proteome is mainly controlled in the endoplasmic reticulum (ER). Accumulation of misfolded proteins due to ER stress leads to the activation of unfolded protein response (UPR). The primary role of UPR is to reduce the bulk of damages and try to drive back the system to the former or a new homeostatic state by autophagy, while an excessive level of stress results in apoptosis. It has already been proven that the proper order and characteristic features of both surviving and self-killing mechanisms are controlled by negative and positive feedback loops, respectively. The new results suggest that these feedback loops are found not only within but also between branches of the UPR, fine-tuning the response to ER stress. In this review, we summarize the recent knowledge of the dynamical characteristic of endoplasmic reticulum stress response mechanism by using both theoretical and molecular biological techniques. In addition, this review pays special attention to describing the mechanism of action of the dynamical features of the feedback loops controlling cellular life-and-death decision upon ER stress. Since ER stress appears in diseases that are common worldwide, a more detailed understanding of the behaviour of the stress response is of medical importance.
MeSH term(s)	Endoplasmic Reticulum Stress ; Autophagy ; Humans ; Apoptosis ; Animals ; Unfolded Protein Response ; Endoplasmic Reticulum/metabolism
Language	English
Publishing date	2024-04-15
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25084368
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: The Dual Role of Sulforaphane-Induced Cellular Stress-A Systems Biological Study.

Holczer, Marianna / Besze, Boglárka / Lehel, Annamária / Kapuy, Orsolya

International journal of molecular sciences

2024 Volume 25, Issue 2

Abstract: The endoplasmic reticulum (ER) plays a crucial role in cellular homeostasis. When ER stress is generated, an autophagic self-digestive process is activated to promote cell survival; however, cell death is induced in the case of excessive levels of ER ... ...

Abstract	The endoplasmic reticulum (ER) plays a crucial role in cellular homeostasis. When ER stress is generated, an autophagic self-digestive process is activated to promote cell survival; however, cell death is induced in the case of excessive levels of ER stress. The aim of the present study was to investigate the effect of a natural compound called sulforaphane (SFN) upon ER stress. Our goal was to investigate how SFN-dependent autophagy activation affects different stages of ER stress induction. We approached our scientific analysis from a systems biological perspective using both theoretical and molecular biological techniques. We found that SFN induced the various cell-death mechanisms in a concentration- and time-dependent manner. The short SFN treatment at low concentrations promoted autophagy, whereas the longer treatment at higher concentrations activated cell death. We proved that SFN activated autophagy in a mTORC1-dependent manner and that the presence of ULK1 was required for its function. A low concentration of SFN pre- or co-treatment combined with short and long ER stress was able to promote cell survival via autophagy induction in each treatment, suggesting the potential medical importance of SFN in ER stress-related diseases.
MeSH term(s)	Isothiocyanates/pharmacology ; Cell Death ; Endoplasmic Reticulum Stress ; Sulfoxides/pharmacology ; Autophagy ; Apoptosis
Chemical Substances	sulforaphane (GA49J4310U) ; Isothiocyanates ; Sulfoxides
Language	English
Publishing date	2024-01-19
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/ijms25021220
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Article ; Online: Chloroquine and COVID-19-A systems biology model uncovers the drug's detrimental effect on autophagy and explains its failure.

Kapuy, Orsolya / Korcsmáros, Tamás

PloS one

2022 Volume 17, Issue 4, Page(s) e0266337

Abstract: The COVID-19 pandemic caused by SARS-CoV-2 has resulted in an urgent need for identifying potential therapeutic drugs. In the first half of 2020 tropic antimalarial drugs, such as chloroquine (CQ) or hydroxochloroquine (HCQ) were the focus of tremendous ... ...

Abstract	The COVID-19 pandemic caused by SARS-CoV-2 has resulted in an urgent need for identifying potential therapeutic drugs. In the first half of 2020 tropic antimalarial drugs, such as chloroquine (CQ) or hydroxochloroquine (HCQ) were the focus of tremendous public attention. In the initial periods of the pandemic, many scientific results pointed out that CQ/HCQ could be very effective for patients with severe COVID. While CQ and HCQ have successfully been used against several diseases (such as malaria, autoimmune disease and rheumatic illnesses); long term use of these agents are associated with serious adverse effects (i.e. inducing acute kidney injury, among many others) due to their role in blocking autophagy-dependent self-degradation. Recent experimental and clinical trial data also confirmed that there is no sufficient evidence about the efficient usage of CQ/HCQ against COVID-19. By using systems biology techniques, here we show that the cellular effect of CQ/HCQ on autophagy during endoplasmic reticulum (ER) stress or following SARS-CoV-2 infection results in upregulation of ER stress. By presenting a simple mathematical model, we claim that although CQ/HCQ might be able to ameliorate virus infection, the permanent inhibition of autophagy by CQ/HCQ has serious negative effects on the cell. Since CQ/HCQ promotes apoptotic cell death, here we confirm that addition of CQ/HCQ cannot be really effective even in severe cases. Only a transient treatment seemed to be able to avoid apoptotic cell death, but this type of therapy could not limit virus replication in the infected host. The presented theoretical analysis clearly points out the utility and applicability of systems biology modelling to test the cellular effect of a drug targeting key major processes, such as autophagy and apoptosis. Applying these approaches could decrease the cost of pre-clinical studies and facilitate the selection of promising clinical trials in a timely fashion.
MeSH term(s)	Autophagy ; COVID-19/drug therapy ; Chloroquine/pharmacology ; Chloroquine/therapeutic use ; Humans ; Hydroxychloroquine/adverse effects ; Pandemics ; SARS-CoV-2 ; Systems Biology
Chemical Substances	Hydroxychloroquine (4QWG6N8QKH) ; Chloroquine (886U3H6UFF)
Language	English
Publishing date	2022-04-07
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.0266337
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Article ; Online: Chloroquine and COVID-19-A systems biology model uncovers the drug's detrimental effect on autophagy and explains its failure.

Orsolya Kapuy / Tamás Korcsmáros

PLoS ONE, Vol 17, Iss 4, p e

2022 Volume 0266337

Abstract	The COVID-19 pandemic caused by SARS-CoV-2 has resulted in an urgent need for identifying potential therapeutic drugs. In the first half of 2020 tropic antimalarial drugs, such as chloroquine (CQ) or hydroxochloroquine (HCQ) were the focus of tremendous public attention. In the initial periods of the pandemic, many scientific results pointed out that CQ/HCQ could be very effective for patients with severe COVID. While CQ and HCQ have successfully been used against several diseases (such as malaria, autoimmune disease and rheumatic illnesses); long term use of these agents are associated with serious adverse effects (i.e. inducing acute kidney injury, among many others) due to their role in blocking autophagy-dependent self-degradation. Recent experimental and clinical trial data also confirmed that there is no sufficient evidence about the efficient usage of CQ/HCQ against COVID-19. By using systems biology techniques, here we show that the cellular effect of CQ/HCQ on autophagy during endoplasmic reticulum (ER) stress or following SARS-CoV-2 infection results in upregulation of ER stress. By presenting a simple mathematical model, we claim that although CQ/HCQ might be able to ameliorate virus infection, the permanent inhibition of autophagy by CQ/HCQ has serious negative effects on the cell. Since CQ/HCQ promotes apoptotic cell death, here we confirm that addition of CQ/HCQ cannot be really effective even in severe cases. Only a transient treatment seemed to be able to avoid apoptotic cell death, but this type of therapy could not limit virus replication in the infected host. The presented theoretical analysis clearly points out the utility and applicability of systems biology modelling to test the cellular effect of a drug targeting key major processes, such as autophagy and apoptosis. Applying these approaches could decrease the cost of pre-clinical studies and facilitate the selection of promising clinical trials in a timely fashion.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2022-01-01T00:00:00Z
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: Oscillation of Autophagy Induction under Cellular Stress and What Lies behind It, a Systems Biology Study.

Hajdú, Bence / Csabai, Luca / Márton, Margita / Holczer, Marianna / Korcsmáros, Tamás / Kapuy, Orsolya

International journal of molecular sciences

2023 Volume 24, Issue 8

Abstract: One of the main inducers of autophagy-dependent self-cannibalism, called ULK1, is tightly regulated by the two sensor molecules of nutrient conditions and energy status, known as mTOR and AMPK kinases, respectively. Recently, we developed a freely ... ...

Abstract	One of the main inducers of autophagy-dependent self-cannibalism, called ULK1, is tightly regulated by the two sensor molecules of nutrient conditions and energy status, known as mTOR and AMPK kinases, respectively. Recently, we developed a freely available mathematical model to explore the oscillatory characteristic of the AMPK-mTOR-ULK1 regulatory triangle. Here, we introduce a systems biology analysis to explain in detail the dynamical features of the essential negative and double-negative feedback loops and also the periodic repeat of autophagy induction upon cellular stress. We propose an additional regulatory molecule in the autophagy control network that delays some of AMPK's effect on the system, making the model output more consistent with experimental results. Furthermore, a network analysis on AutophagyNet was carried out to identify which proteins could be the proposed regulatory components in the system. These regulatory proteins should satisfy the following rules: (1) they are induced by AMPK; (2) they promote ULK1; (3) they down-regulate mTOR upon cellular stress. We have found 16 such regulatory components that have been experimentally proven to satisfy at least two of the given rules. Identifying such critical regulators of autophagy induction could support anti-cancer- and ageing-related therapeutic efforts.
MeSH term(s)	AMP-Activated Protein Kinases/metabolism ; Intracellular Signaling Peptides and Proteins/pharmacology ; Autophagy-Related Protein-1 Homolog/genetics ; Autophagy-Related Protein-1 Homolog/metabolism ; Systems Biology ; TOR Serine-Threonine Kinases/metabolism ; Autophagy
Chemical Substances	AMP-Activated Protein Kinases (EC 2.7.11.31) ; Intracellular Signaling Peptides and Proteins ; Autophagy-Related Protein-1 Homolog (EC 2.7.11.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2023-04-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24087671
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Article ; Online: Fine-Tuning of mTORC1-ULK1-PP2A Regulatory Triangle Is Crucial for Robust Autophagic Response upon Cellular Stress.

Hajdú, Bence / Holczer, Marianna / Horváth, Gergely / Szederkényi, Gábor / Kapuy, Orsolya

Biomolecules

2022 Volume 12, Issue 11

Abstract: Autophagy-dependent cellular survival is tightly regulated by both kinases and phosphatases. While mTORC1 inhibits autophagy by phosphorylating ULK1, PP2A is able to remove this phosphate group from ULK1 and promotes the key inducer of autophagosome ... ...

Abstract	Autophagy-dependent cellular survival is tightly regulated by both kinases and phosphatases. While mTORC1 inhibits autophagy by phosphorylating ULK1, PP2A is able to remove this phosphate group from ULK1 and promotes the key inducer of autophagosome formation. However, ULK1 inhibits mTORC1, mTORC1 is able to down-regulate PP2A. In addition, the active ULK1 promotes PP2A via phosphorylation. We claim that these double-negative (mTORC1 -\| PP2A -\| mTORC1, mTORC1 -\| ULK1 -\| mTORC1) and positive (ULK1 -> PP2A -> ULK1) feedback loops are all necessary for the robust, irreversible decision making process between the autophagy and non-autophagy states. We approach our scientific analysis from a systems biological perspective by applying both theoretical and molecular biological techniques. For molecular biological experiments, HEK293T cell line is used, meanwhile the dynamical features of the regulatory network are described by mathematical modelling. In our study, we explore the dynamical characteristic of mTORC1-ULK1-PP2A regulatory triangle in detail supposing that the positive feedback loops are essential to manage a robust cellular answer upon various cellular stress events (such as mTORC1 inhibition, starvation, PP2A inhibition or ULK1 silencing). We confirm that active ULK1 can up-regulate PP2A when mTORC1 is inactivated. By using theoretical analysis, we explain the importance of cellular PP2A level in stress response mechanism. We proved both experimentally and theoretically that PP2A down-regulation (via addition of okadaic acid) might generate a periodic repeat of autophagy induction. Understanding how the regulation of the cell survival occurs with the precise molecular balance of ULK1-mTORC1-PP2A in autophagy, is highly relevant in several cellular stress-related diseases (such as neurodegenerative diseases or diabetes) and might help to promote advanced therapies in the near future, too.
MeSH term(s)	Humans ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Autophagy-Related Protein-1 Homolog/genetics ; Autophagy-Related Protein-1 Homolog/metabolism ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Multiprotein Complexes/genetics ; Multiprotein Complexes/metabolism ; HEK293 Cells ; Phosphorylation
Chemical Substances	Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Autophagy-Related Protein-1 Homolog (EC 2.7.11.1) ; Intracellular Signaling Peptides and Proteins ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; Multiprotein Complexes ; ULK1 protein, human (EC 2.7.11.1)
Language	English
Publishing date	2022-10-28
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom12111587
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Article ; Online: Autophagy-dependent survival is controlled with a unique regulatory network upon various cellular stress events.

Kapuy, Orsolya / Holczer, Marianna / Márton, Margita / Korcsmáros, Tamás

Cell death & disease

2021 Volume 12, Issue 4, Page(s) 309

Abstract: Although autophagy is a type of programmed cell death, it is also essential for cell survival upon tolerable level of various stress events. For the cell to respond adequately to an external and/or internal stimulus induced by cellular stress, autophagy ... ...

Abstract	Although autophagy is a type of programmed cell death, it is also essential for cell survival upon tolerable level of various stress events. For the cell to respond adequately to an external and/or internal stimulus induced by cellular stress, autophagy must be controlled in a highly regulated manner. By using systems biology techniques, here we explore the dynamical features of autophagy induction. We propose that the switch-like characteristic of autophagy induction is achieved by a control network, containing essential feedback loops of four components, so-called autophagy inducer, autophagy controller, mTORC1 and autophagy executor, respectively. We show how an autophagy inducer is capable to turn on autophagy in a cellular stress-specific way. The autophagy controller acts as a molecular switch and not only promotes autophagy but also blocks the permanent hyperactivation of the process via downregulating the autophagy inducer. In this theoretical analysis, we explore in detail the properties of all four proposed controlling elements and their connections. Here we also prove that the kinetic features of this control network can be considered accurate in various stress processes (such as starvation, endoplasmic reticulum stress and oxidative stress), even if the exact components may be different. The robust response of the resulting control network is essential during cellular stress.
MeSH term(s)	Autophagy/genetics ; Cell Survival/genetics ; Humans ; Stress, Physiological/genetics
Language	English
Publishing date	2021-03-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-021-03599-7
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Article ; Online: Therapeutic Approach of KRAS Mutant Tumours by the Combination of Pharmacologic Ascorbate and Chloroquine.

Kapuy, Orsolya / Makk-Merczel, Kinga / Szarka, András

Biomolecules

2021 Volume 11, Issue 5

Abstract: The Warburg effect has been considered a potential therapeutic target to fight against cancer progression. In KRAS mutant cells, PKM2 (pyruvate kinase isozyme M2) is hyper-activated, and it induces GLUT1 expression; therefore, KRAS has been closely ... ...

Abstract	The Warburg effect has been considered a potential therapeutic target to fight against cancer progression. In KRAS mutant cells, PKM2 (pyruvate kinase isozyme M2) is hyper-activated, and it induces GLUT1 expression; therefore, KRAS has been closely involved in the initiation of Warburg metabolism. Although mTOR (mammalian target of rapamycin), a well-known inhibitor of autophagy-dependent survival in physiological conditions, is also activated in KRAS mutants, many recent studies have revealed that autophagy becomes hyper-active in KRAS mutant cancer cells. In the present study, a mathematical model was built containing the main elements of the regulatory network in KRAS mutant cancer cells to explore the further possible therapeutic strategies. Our dynamical analysis suggests that the downregulation of KRAS, mTOR and autophagy are crucial in anti-cancer therapy. PKM2 has been assumed to be the key switch in the stress response mechanism. We predicted that the addition of both pharmacologic ascorbate and chloroquine is able to block both KRAS and mTOR pathways: in this case, no GLUT1 expression is observed, meanwhile autophagy, essential for KRAS mutant cancer cells, is blocked. Corresponding to our system biological analysis, this combined pharmacologic ascorbate and chloroquine treatment in KRAS mutant cancers might be a therapeutic approach in anti-cancer therapies.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Autophagy/drug effects ; Chloroquine/pharmacology ; Models, Theoretical ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Proto-Oncogene Proteins p21(ras)/genetics ; Proto-Oncogene Proteins p21(ras)/metabolism ; Pyruvate Kinase/drug effects ; Pyruvate Kinase/metabolism ; Signal Transduction/drug effects ; Sirolimus/pharmacology ; TOR Serine-Threonine Kinases/metabolism ; Warburg Effect, Oncologic/drug effects
Chemical Substances	Antineoplastic Agents ; KRAS protein, human ; Chloroquine (886U3H6UFF) ; Pyruvate Kinase (EC 2.7.1.40) ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2021-04-28
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom11050652
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Article ; Online: Fine-Tuning of mTORC1-ULK1-PP2A Regulatory Triangle Is Crucial for Robust Autophagic Response upon Cellular Stress

Bence Hajdú / Marianna Holczer / Gergely Horváth / Gábor Szederkényi / Orsolya Kapuy

Biomolecules, Vol 12, Iss 1587, p

2022 Volume 1587

Abstract	Autophagy-dependent cellular survival is tightly regulated by both kinases and phosphatases. While mTORC1 inhibits autophagy by phosphorylating ULK1, PP2A is able to remove this phosphate group from ULK1 and promotes the key inducer of autophagosome formation. However, ULK1 inhibits mTORC1, mTORC1 is able to down-regulate PP2A. In addition, the active ULK1 promotes PP2A via phosphorylation. We claim that these double-negative (mTORC1 –\| PP2A –\| mTORC1, mTORC1 –\| ULK1 –\| mTORC1) and positive (ULK1 -> PP2A -> ULK1) feedback loops are all necessary for the robust, irreversible decision making process between the autophagy and non-autophagy states. We approach our scientific analysis from a systems biological perspective by applying both theoretical and molecular biological techniques. For molecular biological experiments, HEK293T cell line is used, meanwhile the dynamical features of the regulatory network are described by mathematical modelling. In our study, we explore the dynamical characteristic of mTORC1-ULK1-PP2A regulatory triangle in detail supposing that the positive feedback loops are essential to manage a robust cellular answer upon various cellular stress events (such as mTORC1 inhibition, starvation, PP2A inhibition or ULK1 silencing). We confirm that active ULK1 can up-regulate PP2A when mTORC1 is inactivated. By using theoretical analysis, we explain the importance of cellular PP2A level in stress response mechanism. We proved both experimentally and theoretically that PP2A down-regulation (via addition of okadaic acid) might generate a periodic repeat of autophagy induction. Understanding how the regulation of the cell survival occurs with the precise molecular balance of ULK1-mTORC1-PP2A in autophagy, is highly relevant in several cellular stress-related diseases (such as neurodegenerative diseases or diabetes) and might help to promote advanced therapies in the near future, too.
Keywords	mTORC1 ; PP2A ; ULK1 ; autophagy ; systems biology ; feedback loop ; Microbiology ; QR1-502
Subject code	612
Language	English
Publishing date	2022-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Vitamin C and Cell Death.

Szarka, András / Kapuy, Orsolya / Lőrincz, Tamás / Bánhegyi, Gábor

Antioxidants & redox signaling

2020 Volume 34, Issue 11, Page(s) 831–844

Abstract: Significance: ...

Abstract	Significance:
MeSH term(s)	Apoptosis/drug effects ; Ascorbic Acid/therapeutic use ; Autophagy/drug effects ; Cell Death/drug effects ; Cell Death/genetics ; DNA Breaks, Double-Stranded/drug effects ; Ferroptosis/drug effects ; Humans ; Necroptosis/drug effects ; Neoplasms/diet therapy ; Neoplasms/metabolism ; Neoplasms/pathology ; Oxidative Stress/drug effects ; Poly (ADP-Ribose) Polymerase-1/genetics ; Reactive Oxygen Species/metabolism
Chemical Substances	Reactive Oxygen Species ; Poly (ADP-Ribose) Polymerase-1 (EC 2.4.2.30) ; Ascorbic Acid (PQ6CK8PD0R)
Language	English
Publishing date	2020-08-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1483836-9
ISSN	1557-7716 ; 1523-0864
ISSN (online)	1557-7716
ISSN	1523-0864
DOI	10.1089/ars.2019.7897
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