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Book ; Thesis: MTTB als Leitsubstanz einer neuen Klasse von kompetitiven Peroxisom-Proliferator-aktivierten Rezeptor gamma-Antagonisten

Knape, Tilo

Grundlage in der Entwicklung eines neuen Therapiekonzepts zur Behandlung der Sepsis

2015

Author's details	vorgelegt von Tilo Knape
Language	German
Size	29 Seiten, 12 verschieden gezählte Seiten, Diagramme
Publishing place	Frankfurt am Main
Publishing country	Germany
Document type	Book ; Thesis
Thesis / German Habilitation thesis	Dissertation, Johann Wolfgang Goethe-Universität Frankfurt am Main, 2015
HBZ-ID	HT018882097
Database	Catalogue ZB MED Medicine, Health

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Article: RELSA-A multidimensional procedure for the comparative assessment of well-being and the quantitative determination of severity in experimental procedures.

Talbot, Steven R / Struve, Birgitta / Wassermann, Laura / Heider, Miriam / Weegh, Nora / Knape, Tilo / Hofmann, Martine C J / von Knethen, Andreas / Jirkof, Paulin / Häger, Christine / Bleich, André

Frontiers in veterinary science

2022 Volume 9, Page(s) 937711

Abstract: Good science in translational research requires good animal welfare according to the principles of 3Rs. In many countries, determining animal welfare is a mandatory legal requirement, implying a categorization of animal suffering, traditionally dominated ...

Abstract	Good science in translational research requires good animal welfare according to the principles of 3Rs. In many countries, determining animal welfare is a mandatory legal requirement, implying a categorization of animal suffering, traditionally dominated by subjective scorings. However, how such methods can be objectified and refined to compare impairments between animals, subgroups, and animal models remained unclear. Therefore, we developed the RELative Severity Assessment (RELSA) procedure to establish an evidence-based method based on quantitative outcome measures such as body weight, burrowing behavior, heart rate, heart rate variability, temperature, and activity to obtain a relative metric for severity comparisons. The RELSA procedure provided the necessary framework to get severity gradings in TM-implanted mice, yielding four distinct RELSA thresholds L1<0.27, L2<0.59, L3<0.79, and L4<3.45. We show further that severity patterns in the contributing variables are time and model-specific and use this information to obtain contextualized
Language	English
Publishing date	2022-11-11
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2834243-4
ISSN	2297-1769
ISSN	2297-1769
DOI	10.3389/fvets.2022.937711
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Article ; Online: Short-term predictor for COVID-19 severity from a longitudinal multi-omics study for practical application in intensive care units.

Kugler, Sabine / Hahnefeld, Lisa / Kloka, Jan Andreas / Ginzel, Sebastian / Nürenberg-Goloub, Elina / Zinn, Sebastian / Vehreschild, Maria Jgt / Zacharowski, Kai / Lindau, Simone / Ullrich, Evelyn / Burmeister, Jan / Kohlhammer, Jörn / Schwäble, Joachim / Gurke, Robert / Dorochow, Erika / Bennett, Alexandre / Dauth, Stephanie / Campe, Julia / Knape, Tilo /

Laux, Volker / Kannt, Aimo / Köhm, Michaela / Geisslinger, Gerd / Resch, Eduard / Behrens, Frank

Talanta

2023 Volume 268, Issue Pt 1, Page(s) 125295

Abstract: Background: The COVID-19 pandemic challenged the management of technical and human resources in intensive care units (ICU) across the world. Several long-term predictors for COVID-19 disease progression have been discovered. However, predictors to ... ...

Abstract	Background: The COVID-19 pandemic challenged the management of technical and human resources in intensive care units (ICU) across the world. Several long-term predictors for COVID-19 disease progression have been discovered. However, predictors to support short-term planning of resources and medication that can be translated to future pandemics are still missing. A workflow was established to identify a predictor for short-term COVID-19 disease progression in the acute phase of intensive care patients to support clinical decision-making. Methods: Thirty-two patients with SARS-CoV-2 infection were recruited on admission to the ICU and clinical data collected. During their hospitalization, plasma samples were acquired from each patient on multiple occasions, excepting one patient for which only one time point was possible, and the proteome (Inflammation, Immune Response and Organ Damage panels from Olink® Target 96), metabolome and lipidome (flow injection analysis and liquid chromatography-mass spectrometry) analyzed for each sample. Patient visits were grouped according to changes in disease severity based on their respiratory and organ function, and evaluated using a combination of statistical analysis and machine learning. The resulting short-term predictor from this multi-omics approach was compared to the human assessment of disease progression. Furthermore, the potential markers were compared to the baseline levels of 50 healthy subjects with no known SARS-CoV-2 or other viral infections. Results: A total of 124 clinical parameters, 271 proteins and 782 unique metabolites and lipids were assessed. The dimensionality of the dataset was reduced, selecting 47 from the 1177 parameters available following down-selection, to build the machine learning model. Subsequently, two proteins (C-C motif chemokine 7 (CCL7) and carbonic anhydrase 14 (CA14)) and one lipid (hexosylceramide 18:2; O2/20:0) were linked to disease progression in the studied SARS-CoV-2 infections. Thus, a predictor delivering the prognosis of an upcoming worsening of the patient's condition up to five days in advance with a reasonable accuracy (79 % three days prior to event, 84 % four to five days prior to event) was found. Interestingly, the predictor's performance was complementary to the clinicians' capabilities to foresee a worsening of a patient. Conclusion: This study presents a workflow to identify omics-based biomarkers to support clinical decision-making and resource management in the ICU. This was successfully applied to develop a short-term predictor for aggravation of COVID-19 symptoms. The applied methods can be adapted for future small cohort studies.
MeSH term(s)	Humans ; COVID-19/diagnosis ; SARS-CoV-2 ; Pandemics ; Multiomics ; Intensive Care Units ; Disease Progression
Language	English
Publishing date	2023-10-09
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1500969-5
ISSN	1873-3573 ; 0039-9140
ISSN (online)	1873-3573
ISSN	0039-9140
DOI	10.1016/j.talanta.2023.125295
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Article ; Online: RELSA - A multidimensional procedure for the comparative assessment of well-being and the quantitative determination of severity in experimental procedures

Talbot, Steven Roger / Struve, Birgitta / Wassermann, Laura / Heider, Miriam / Weegh, Nora / Knape, Tilo / Hofmann, Martine Catharina Josephine / Knethen, Andreas von / Jirkof, Paulin D. / Häger, Christine / Bleich, André

2022

Abstract	Good science in translational research requires good animal welfare according to the principles of 3Rs. In many countries, determining animal welfare is a mandatory legal requirement, implying a categorization of animal suffering, traditionally dominated by subjective scorings. However, how such methods can be objectified and refined to compare impairments between animals, subgroups, and animal models remained unclear. Therefore, we developed the RELative Severity Assessment (RELSA) procedure to establish an evidence-based method based on quantitative outcome measures such as body weight, burrowing behavior, heart rate, heart rate variability, temperature, and activity to obtain a relative metric for severity comparisons. The RELSA procedure provided the necessary framework to get severity gradings in TM-implanted mice, yielding four distinct RELSA thresholds L1<0.27, L2<0.59, L3<0.79, and L4<3.45. We show further that severity patterns in the contributing variables are time and model-specific and use this information to obtain contextualized between animal-model and subgroup comparisons with the severity of sepsis > surgery > restraint stress > colitis. The bootstrapped 95% confidence intervals reliably show that RELSA estimates are conditionally invariant against missing information but precise in ranking the quantitative severity information to the moderate context of the transmitter-implantation model. In conclusion, we propose the RELSA as a validated tool for an objective, computational approach to comparative and quantitative severity assessment and grading. The RELSA procedure will fundamentally improve animal welfare, data quality, and reproducibility. It is also the first step toward translational risk assessment in biomedical research. 9
Keywords	animal experiments ; animal welfare ; colitis model ; data science ; laboratory animal ; sepsis model ; severity assessment ; surgical models
Language	English
Publishing country	de
Document type	Article ; Online
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Article ; Online: Structure optimization of a new class of PPARγ antagonists.

Hernandez-Olmos, Victor / Knape, Tilo / Heering, Jan / von Knethen, Andreas / Kilu, Whitney / Kaiser, Astrid / Wurglics, Mario / Helmstädter, Moritz / Merk, Daniel / Schubert-Zsilavecz, Manfred / Parnham, Michael J / Steinhilber, Dieter / Proschak, Ewgenij

Bioorganic & medicinal chemistry

2019 Volume 27, Issue 21, Page(s) 115082

Abstract: Peroxisome proliferator-activated receptor gamma (PPARγ) modulators have found wide application for the treatment of cancers, metabolic disorders and inflammatory diseases. Contrary to PPARγ agonists, PPARγ antagonists have been much less studied and ... ...

Abstract	Peroxisome proliferator-activated receptor gamma (PPARγ) modulators have found wide application for the treatment of cancers, metabolic disorders and inflammatory diseases. Contrary to PPARγ agonists, PPARγ antagonists have been much less studied and although they have shown immunomodulatory effects, there is still no therapeutically useful PPARγ antagonist on the market. In contrast to non-competitive, irreversible inhibition caused by 2-chloro-5-nitrobenzanilide (GW9662), the recently described (E)-2-(5-((4-methoxy-2-(trifluoromethyl)quinolin-6-yl)methoxy)-2-((4-(trifluoromethyl)benzyl)oxy)-benzylidene)-hexanoic acid (MTTB, T-10017) is a promising prototype for a new class of PPARγ antagonists. It exhibits competitive antagonism against rosiglitazone mediated activation of PPARγ ligand binding domain (PPARγLBD) in a transactivation assay in HEK293T cells with an IC
MeSH term(s)	Animals ; Cinnamates/chemical synthesis ; Cinnamates/pharmacokinetics ; Cinnamates/pharmacology ; HEK293 Cells ; Humans ; Male ; Mice ; Microsomes, Liver/metabolism ; Molecular Structure ; PPAR gamma/antagonists & inhibitors ; Quinolines/chemical synthesis ; Quinolines/pharmacokinetics ; Quinolines/pharmacology ; Rats ; Rosiglitazone/pharmacology ; Structure-Activity Relationship
Chemical Substances	2-(5-((4-methoxy-2-(trifluoromethyl)quinolin-6-yl)methoxy)-2-((4-(trifluoromethyl)benzyl)oxy)benzylidene)hexanoic acid ; Cinnamates ; PPAR gamma ; Quinolines ; Rosiglitazone (05V02F2KDG)
Language	English
Publishing date	2019-08-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1161284-8
ISSN	1464-3391 ; 0968-0896
ISSN (online)	1464-3391
ISSN	0968-0896
DOI	10.1016/j.bmc.2019.115082
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Article ; Online: One score to rule them all: severity assessment in laboratory mice

Talbot, Steven R. / Struve, Birgitta / Wassermann, Laura / Heider, Miriam / Weegh, Nora / Knape, Tilo / Hofmann, Martine C. J. / von Knethen, Andreas / Jirkof, Paulin / Keubler, Lydia / Bleich, André / Häger, Christine

bioRxiv

Abstract: Animal welfare and the refinement of experimental procedures are fundamental aspects of biomedical research. They provide the basis for robust experimental designs and reproducibility of results. In many countries, the determination of welfare is a ... ...

Abstract	Animal welfare and the refinement of experimental procedures are fundamental aspects of biomedical research. They provide the basis for robust experimental designs and reproducibility of results. In many countries, the determination of welfare is a mandatory legal requirement and implies the assessment of the degree of the severity that an animal experiences during an experiment. However, for an effective severity assessment, an objective and exact approach/system/strategy is needed. In light of these demands, we have developed the Relative Severity Assessment (RELSA) score. This comprehensive composite score was established on the basis of physiological and behavioral data from a surgical mouse study. Body weight, the Mouse Grimace Scale score, burrowing behavior, and the telemetry-derived parameters heart rate, heart rate variability, temperature, and general activity were used to investigate the quality of indicating severity during postoperative recovery. The RELSA scores not only revealed individual severity levels but also allowed a comparison of severity in distinct mouse models addressing colitis, sepsis, and restraint stress using a k-means clustering approach with the maximum achieved RELSA scores. We discriminated and classified data from sepsis nonsurvivors into the highest relative severity level. Data from mice after intraperitoneal transmitter implantation and sepsis survivor al were located in the next lower cluster, while data from mice subjected to colitis and restraint stress were placed in the lowest severity cluster. Analysis of individual variables and their combinations revealed model- and time-dependent contributions to severity levels. In conclusion, we propose the RELSA score as a validated tool for objective real-time applicability in severity assessment and as a first step towards a unified and accessible risk assessment tool in biomedical research. As an effective severity assessment system, it will fundamentally improve animal welfare, as well as data quality and reproducibility.
Keywords	covid19
Publisher	BioRxiv
Document type	Article ; Online
DOI	10.1101/2020.06.23.166801
Database	COVID19

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Article ; Online: Activation of the peroxisome proliferator-activated receptor γ counteracts sepsis-induced T cell cytotoxicity toward alloantigenic target cells.

von Knethen, Andreas / Sha, Lisa Katharina / Knape, Tilo / Kuchler, Laura / Giegerich, Annika Klara / Schulz, Martin / Hauser, Ingeborg A / Brüne, Bernhard

Journal of molecular medicine (Berlin, Germany)

2015 Volume 93, Issue 6, Page(s) 633–644

Abstract: Unlabelled: Sepsis still emerges as a major cause of patient death in intensive care units. Therefore, new therapeutic approaches are mandatory. Because during sepsis progression cytotoxic T lymphocytes (CTLs) can be activated in an autoimmune fashion ... ...

Abstract	Unlabelled: Sepsis still emerges as a major cause of patient death in intensive care units. Therefore, new therapeutic approaches are mandatory. Because during sepsis progression cytotoxic T lymphocytes (CTLs) can be activated in an autoimmune fashion contributing to multiorgan damage, it remains unclear whether CTLs are activated toward alloantigenic cells. This is important for patients receiving an immunosuppressive therapy to permit organ transplantation and, thus, known to be at high risk for developing sepsis. Therefore, we analyzed whether sepsis activates CTL toward alloantigenic target cells and whether this can be inhibited by PPARγ activation, known to block T helper cell responses. To mimic septic conditions, CTLs were isolated from cecal ligation and puncture-operated mice. CTL cytotoxicity was analyzed following a direct alloantigenic activation regime or following classical ex vivo splenocyte-driven activation in a cytotoxicity assay. With this readout, we found that CTL derived from septic mice enhanced cytotoxicity toward alloantigenic target cells, which was lowered by in vivo and ex vivo PPARγ activation. With CTL derived from T cell-specific PPARγ knockout mice, PPARγ activation was ineffective, pointing to a PPARγ-dependent mechanism. In vivo and ex vivo PPARγ activation reduced Fas and granzyme B expression in activated CTL. Key message: In the sepsis CLP mouse model, CTLs are activated toward alloantigenic target cells. Sepsis-mediated alloantigenic CTL activation is blocked in vivo by PPARγ activation. PPARγ deletion or antagonization restored rosiglitazone-dependent inhibition of CTL cytotoxicity. PPARγ inhibits the expression of Fas and granzyme B in CTLs.
MeSH term(s)	Animals ; Cytotoxicity, Immunologic ; Gene Expression Regulation ; Granzymes/genetics ; Humans ; Isoantigens/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; PPAR gamma/genetics ; PPAR gamma/immunology ; Sepsis/genetics ; Sepsis/immunology ; Sepsis/pathology ; T-Lymphocytes, Cytotoxic/immunology ; T-Lymphocytes, Cytotoxic/metabolism ; T-Lymphocytes, Cytotoxic/pathology ; fas Receptor/genetics
Chemical Substances	Isoantigens ; PPAR gamma ; fas Receptor ; Granzymes (EC 3.4.21.-)
Language	English
Publishing date	2015-06
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1223802-8
ISSN	1432-1440 ; 0946-2716
ISSN (online)	1432-1440
ISSN	0946-2716
DOI	10.1007/s00109-014-1249-8
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Article ; Online: Flow cytometry-based FRET identifies binding intensities in PPARγ1 protein-protein interactions in living cells.

Trümper, Verena / von Knethen, Andreas / Preuß, Annegret / Ermilov, Eugeny / Hackbarth, Steffen / Kuchler, Laura / Gunne, Sandra / Schäfer, Anne / Bornhütter, Tobias / Vereb, György / Ujlaky-Nagy, Lázló / Brüne, Bernhard / Röder, Beate / Schindler, Michael / Parnham, Michael J / Knape, Tilo

Theranostics

2019 Volume 9, Issue 19, Page(s) 5444–5463

Abstract: PPARγ is a pharmacological target in inflammatory and metabolic diseases. Upon agonistic treatment or following antagonism, binding of co-factors is altered, which consequently affects PPARγ-dependent transactivation as well as its DNA-independent ... ...

Abstract	PPARγ is a pharmacological target in inflammatory and metabolic diseases. Upon agonistic treatment or following antagonism, binding of co-factors is altered, which consequently affects PPARγ-dependent transactivation as well as its DNA-independent properties. Therefore, establishing techniques to characterize these interactions is an important issue in living cells.
MeSH term(s)	Animals ; Dimerization ; Flow Cytometry/methods ; Fluorescence Resonance Energy Transfer/methods ; HEK293 Cells ; Humans ; Mice ; Nuclear Receptor Co-Repressor 1/chemistry ; Nuclear Receptor Co-Repressor 1/genetics ; Nuclear Receptor Co-Repressor 1/metabolism ; PPAR gamma/chemistry ; PPAR gamma/genetics ; PPAR gamma/metabolism ; Protein Binding ; Protein Domains ; Retinoid X Receptor alpha/chemistry ; Retinoid X Receptor alpha/genetics ; Retinoid X Receptor alpha/metabolism
Chemical Substances	NCOR1 protein, human ; Nuclear Receptor Co-Repressor 1 ; PPAR gamma ; Retinoid X Receptor alpha
Language	English
Publishing date	2019-07-28
Publishing country	Australia
Document type	Evaluation Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2592097-2
ISSN	1838-7640 ; 1838-7640
ISSN (online)	1838-7640
ISSN	1838-7640
DOI	10.7150/thno.29367
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Article ; Online: Shooting three inflammatory targets with a single bullet: Novel multi-targeting anti-inflammatory glitazones.

Elzahhar, Perihan A / Alaaeddine, Rana / Ibrahim, Tamer M / Nassra, Rasha / Ismail, Azza / Chua, Benjamin S K / Frkic, Rebecca L / Bruning, John B / Wallner, Nadja / Knape, Tilo / von Knethen, Andreas / Labib, Hala / El-Yazbi, Ahmed F / Belal, Ahmed S F

European journal of medicinal chemistry

2019 Volume 167, Page(s) 562–582

Abstract: In search for effective multi-targeting drug ligands (MTDLs) to address low-grade inflammatory changes of metabolic disorders, we rationally designed some novel glitazones-like compounds. This was achieved by incorporating prominent pharmacophoric motifs ...

Abstract	In search for effective multi-targeting drug ligands (MTDLs) to address low-grade inflammatory changes of metabolic disorders, we rationally designed some novel glitazones-like compounds. This was achieved by incorporating prominent pharmacophoric motifs from previously reported COX-2, 15-LOX and PPARγ ligands. Challenging our design with pre-synthetic docking experiments on PPARγ showed encouraging results. In vitro tests have identified 4 compounds as simultaneous partial PPARγ agonist, potent COX-2 antagonist (nanomolar IC
MeSH term(s)	Animals ; Anti-Inflammatory Agents/chemistry ; Anti-Inflammatory Agents/pharmacology ; Arachidonate 15-Lipoxygenase/drug effects ; Cyclooxygenase 2 Inhibitors/pharmacology ; Drug Design ; Humans ; Ligands ; Molecular Docking Simulation ; PPAR gamma/agonists ; Protein Binding ; Thiazolidinediones/chemistry ; Thiazolidinediones/pharmacology ; Thiazolidinediones/therapeutic use
Chemical Substances	Anti-Inflammatory Agents ; Cyclooxygenase 2 Inhibitors ; Ligands ; PPAR gamma ; Thiazolidinediones ; Arachidonate 15-Lipoxygenase (EC 1.13.11.33)
Language	English
Publishing date	2019-02-13
Publishing country	France
Document type	Journal Article
ZDB-ID	188597-2
ISSN	1768-3254 ; 0009-4374 ; 0223-5234
ISSN (online)	1768-3254
ISSN	0009-4374 ; 0223-5234
DOI	10.1016/j.ejmech.2019.02.034
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Article ; Online: Autophagy-dependent PELI3 degradation inhibits proinflammatory IL1B expression.

Giegerich, Annika Klara / Kuchler, Laura / Sha, Lisa Katharina / Knape, Tilo / Heide, Heinrich / Wittig, Ilka / Behrends, Christian / Brüne, Bernhard / von Knethen, Andreas

Autophagy

2014 Volume 10, Issue 11, Page(s) 1937–1952

Abstract: Lipopolysaccharide (LPS)-induced activation of TLR4 (toll-like receptor 4) is followed by a subsequent overwhelming inflammatory response, a hallmark of the first phase of sepsis. Therefore, counteracting excessive innate immunity by autophagy is ... ...

Abstract	Lipopolysaccharide (LPS)-induced activation of TLR4 (toll-like receptor 4) is followed by a subsequent overwhelming inflammatory response, a hallmark of the first phase of sepsis. Therefore, counteracting excessive innate immunity by autophagy is important to contribute to the termination of inflammation. However, the exact molecular details of this interplay are only poorly understood. Here, we show that PELI3/Pellino3 (pellino E3 ubiquitin protein ligase family member 3), which is an E3 ubiquitin ligase and scaffold protein in TLR4-signaling, is impacted by autophagy in macrophages (MΦ) after LPS stimulation. We noticed an attenuated mRNA expression of proinflammatory Il1b (interleukin 1, β) in Peli3 knockdown murine MΦ in response to LPS treatment. The autophagy adaptor protein SQSTM1/p62 (sequestosome 1) emerged as a potential PELI3 binding partner in TLR4-signaling. siRNA targeting Sqstm1 and Atg7 (autophagy related 7), pharmacological inhibition of autophagy by wortmannin as well as blocking the lysosomal vacuolar-type H(+)-ATPase by bafilomycin A1 augmented PELI3 protein levels, while inhibition of the proteasome had no effect. Consistently, treatment to induce autophagy by MTOR (mechanistic target of rapamycin (serine/threonine kinase)) inhibition or starvation enhanced PELI3 degradation and reduced proinflammatory Il1b expression. PELI3 was found to be ubiquitinated upon LPS stimulation and point mutation of PELI3-lysine residue 316 (Lys316Arg) attenuated Torin2-dependent degradation of PELI3. Immunofluorescence analysis revealed that PELI3 colocalized with the typical autophagy markers MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 β) and LAMP2 (lysosomal-associated membrane protein 2). Our observations suggest that autophagy causes PELI3 degradation during TLR4-signaling, thereby impairing the hyperinflammatory phase during sepsis.
MeSH term(s)	Adenosine Triphosphatases/metabolism ; Animals ; Autophagy ; Cell Line ; Cytokines/metabolism ; Immunity, Innate ; Inflammation ; Interleukin-1beta/metabolism ; Lipopolysaccharides/metabolism ; Macrophages/metabolism ; Mice ; Naphthyridines/metabolism ; Point Mutation ; RNA, Messenger/metabolism ; RNA, Small Interfering/metabolism ; Sepsis/metabolism ; Signal Transduction ; Toll-Like Receptor 4/metabolism ; Ubiquitin/metabolism ; Ubiquitin-Protein Ligases/metabolism
Chemical Substances	9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo(h)(1,6)naphthyridin-2(1H)-one ; Cytokines ; IL1B protein, mouse ; Interleukin-1beta ; Lipopolysaccharides ; Naphthyridines ; RNA, Messenger ; RNA, Small Interfering ; Tlr4 protein, mouse ; Toll-Like Receptor 4 ; Ubiquitin ; PELI3 protein, mouse (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Adenosine Triphosphatases (EC 3.6.1.-)
Language	English
Publishing date	2014
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.4161/auto.32178
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