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Article ; Online: Activation of Hippo Pathway Damages Slit Diaphragm by Deprivation of Ajuba Proteins.

Gilhaus, Kevin / Cepok, Claudia / Kamm, David / Surmann, Beate / Nedvetsky, Pavel I / Emich, Jana / Sundukova, Alina / Saatkamp, Katharina / Nüsse, Harald / Klingauf, Jürgen / Wennmann, Dirk O / George, Britta / Krahn, Michael P / Pavenstädt, Hermann-Joseph / Vollenbröker, Beate A

Journal of the American Society of Nephrology : JASN

2023 Volume 34, Issue 6, Page(s) 1039–1055

Abstract: Significance statement: Nuclear exclusion of the cotranscription factor YAP, which is a consequence of activation of the Hippo signaling pathway, leads to FSGS and podocyte apoptosis. Ajuba proteins play an important role in the glomerular filtration ... ...

Abstract	Significance statement: Nuclear exclusion of the cotranscription factor YAP, which is a consequence of activation of the Hippo signaling pathway, leads to FSGS and podocyte apoptosis. Ajuba proteins play an important role in the glomerular filtration barrier by keeping the Hippo pathway inactive. In nephrocytes from Drosophila melanogaster , a well-established model system for podocyte research, Ajuba proteins ensure slit diaphragm (SD) formation and function. Hippo pathway activation leads to mislocalization of Ajuba proteins, decreased SD formation, rearrangement of the actin cytoskeleton, and increased SD permeability. Targeting the kinases of the Hippo pathway with specific inhibitors in the glomerulus could, therefore, be a promising strategy for therapy of FSGS. Background: The highly conserved Hippo pathway, which regulates organ growth and cell proliferation by inhibiting transcriptional cofactors YAP/TAZ, plays a special role in podocytes, where activation of the pathway leads to apoptosis. The Ajuba family proteins (Ajuba, LIM domain-containing protein 1 (LIMD1) and Wilms tumor protein 1-interacting protein [WTIP]) can bind and inactivate large tumor suppressor kinases 1 and 2, (LATS1/2) two of the Hippo pathway key kinases. WTIP, furthermore, connects the slit diaphragm (SD), the specialized cell-cell junction between podocytes, with the actin cytoskeleton. Methods: We used garland cell nephrocytes of Drosophila melanogaster to monitor the role of Ajuba proteins in Hippo pathway regulation and structural integrity of the SD. Microscopy and functional assays analyzed the interplay between Ajuba proteins and LATS2 regarding expression, localization, interaction, and effects on the functionality of the SD. Results: In nephrocytes, the Ajuba homolog Djub recruited Warts (LATS2 homolog) to the SD. Knockdown of Djub activated the Hippo pathway. Reciprocally, Hippo activation reduced the Djub level. Both Djub knockdown and Hippo activation led to morphological changes in the SD, rearrangement of the cortical actin cytoskeleton, and increased SD permeability. Knockdown of Warts or overexpression of constitutively active Yki prevented these effects. In podocytes, Hippo pathway activation or knockdown of YAP also decreased the level of Ajuba proteins. Conclusions: Ajuba proteins regulate the structure and function of the SD in nephrocytes, connecting the SD protein complex to the actin cytoskeleton and maintaining the Hippo pathway in an inactive state. Hippo pathway activation directly influencing Djub expression suggests a self-amplifying feedback mechanism.
MeSH term(s)	Animals ; Hippo Signaling Pathway ; Signal Transduction ; Adaptor Proteins, Signal Transducing/metabolism ; Drosophila melanogaster/metabolism ; Glomerulosclerosis, Focal Segmental ; YAP-Signaling Proteins ; Intercellular Junctions ; Warts ; Drosophila Proteins/metabolism
Chemical Substances	Adaptor Proteins, Signal Transducing ; YAP-Signaling Proteins ; Drosophila Proteins
Language	English
Publishing date	2023-03-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.0000000000000107
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Article ; Online: Umgang mit COVID-19 in der Notaufnahme : Erfahrungsbericht der interdisziplinären Notaufnahme des Universitätsklinikums Münster.

Wennmann, D O / Dlugos, C P / Hofschröer, A / Hennies, M / Kühn, J / Hafezi, W / Kampmeier, S / Mellmann, A / Triphaus, S / Sackarnd, J / Tepasse, P / Keller, M / Van Aken, H / Pavenstädt, H / Kümpers, P

Medizinische Klinik, Intensivmedizin und Notfallmedizin

2020 Volume 115, Issue 5, Page(s) 380–387

Abstract: With the COVID-19 pandemic, emergency rooms are faced with major challenges because they act as the interface between outpatient and inpatient care. The dynamics of the pandemic forced emergency care at the University Hospital Münster to extensively ... ...

Title translation	Handling of COVID-19 in the emergency department : Field report of the emergency ward of the University Hospital Münster.
Abstract	With the COVID-19 pandemic, emergency rooms are faced with major challenges because they act as the interface between outpatient and inpatient care. The dynamics of the pandemic forced emergency care at the University Hospital Münster to extensively adjust their processes, which had to be carried out in the shortest time possible. This included the establishment of an outpatient coronavirus test center and a medical student-operated telephone hotline. Inside the hospital, new isolation capacities in the emergency room and a dedicated COVID-19 ward were set up. The patient flow was reorganized using flow diagrams for both the outpatient and inpatient areas. The general and special emergency management was optimized for the efficient treatment of COVID-19-positive patients and the staff were trained in the use of protective equipment. This report of our experience is intended to support other emergency departments in their preparation for the COVID-19 pandemic.
MeSH term(s)	Betacoronavirus ; COVID-19 ; Coronavirus Infections/epidemiology ; Emergency Medical Services ; Emergency Service, Hospital ; Humans ; Pandemics ; Patient Isolation ; Pneumonia, Viral/epidemiology ; SARS-CoV-2 ; Triage
Keywords	covid19
Language	German
Publishing date	2020-04-22
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2636018-4
ISSN	2193-6226 ; 1435-1420 ; 0723-5003 ; 2193-6218 ; 0175-3851
ISSN (online)	2193-6226 ; 1435-1420
ISSN	0723-5003 ; 2193-6218 ; 0175-3851
DOI	10.1007/s00063-020-00693-0
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Article ; Online: Umgang mit COVID-19 in der Notaufnahme ; Erfahrungsbericht der interdisziplinären Notaufnahme des Universitätsklinikums Münster

Wennmann, D. O. / Dlugos, C. P. / Hofschröer, A. / Hennies, M. / Kühn, J. / Hafezi, W. / Kampmeier, S. / Mellmann, A. / Triphaus, S. / Sackarnd, J. / Tepasse, P. / Keller, M. / Van Aken, H. / Pavenstädt, H. / Kümpers, P.

Medizinische Klinik - Intensivmedizin und Notfallmedizin

2020 Volume 115, Issue 5, Page(s) 380–387

Keywords	Internal Medicine ; Critical Care and Intensive Care Medicine ; Emergency ; Emergency Medicine ; covid19
Language	German
Publisher	Springer Science and Business Media LLC
Publishing country	us
Document type	Article ; Online
ISSN	2193-6218
DOI	10.1007/s00063-020-00693-0
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Umgang mit COVID-19 in der Notaufnahme : Erfahrungsbericht der interdisziplinären Notaufnahme des Universitätsklinikums Münster./ [Handling of COVID-19 in the emergency department : Field report of the emergency ward of the University Hospital Münster]

Med Klin Intensivmed Notfmed

Abstract	With the COVID-19 pandemic, emergency rooms are faced with major challenges because they act as the interface between outpatient and inpatient care. The dynamics of the pandemic forced emergency care at the University Hospital Münster to extensively adjust their processes, which had to be carried out in the shortest time possible. This included the establishment of an outpatient coronavirus test center and a medical student-operated telephone hotline. Inside the hospital, new isolation capacities in the emergency room and a dedicated COVID-19 ward were set up. The patient flow was reorganized using flow diagrams for both the outpatient and inpatient areas. The general and special emergency management was optimized for the efficient treatment of COVID-19-positive patients and the staff were trained in the use of protective equipment. This report of our experience is intended to support other emergency departments in their preparation for the COVID-19 pandemic.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #102305
Database	COVID19

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Article ; Online: Prediction of Bone Marrow Biopsy Results From MRI in Multiple Myeloma Patients Using Deep Learning and Radiomics.

Wennmann, Markus / Ming, Wenlong / Bauer, Fabian / Chmelik, Jiri / Klein, André / Uhlenbrock, Charlotte / Grözinger, Martin / Kahl, Kim-Celine / Nonnenmacher, Tobias / Debic, Manuel / Hielscher, Thomas / Thierjung, Heidi / Rotkopf, Lukas T / Stanczyk, Nikolas / Sauer, Sandra / Jauch, Anna / Götz, Michael / Kurz, Felix T / Schlamp, Kai /

Investigative radiology

2023 Volume 58, Issue 10, Page(s) 754–765

Abstract: Objectives: In multiple myeloma and its precursor stages, plasma cell infiltration (PCI) and cytogenetic aberrations are important for staging, risk stratification, and response assessment. However, invasive bone marrow (BM) biopsies cannot be performed ...

Abstract	Objectives: In multiple myeloma and its precursor stages, plasma cell infiltration (PCI) and cytogenetic aberrations are important for staging, risk stratification, and response assessment. However, invasive bone marrow (BM) biopsies cannot be performed frequently and multifocally to assess the spatially heterogenous tumor tissue. Therefore, the goal of this study was to establish an automated framework to predict local BM biopsy results from magnetic resonance imaging (MRI). Materials and methods: This retrospective multicentric study used data from center 1 for algorithm training and internal testing, and data from center 2 to 8 for external testing. An nnU-Net was trained for automated segmentation of pelvic BM from T1-weighted whole-body MRI. Radiomics features were extracted from these segmentations, and random forest models were trained to predict PCI and the presence or absence of cytogenetic aberrations. Pearson correlation coefficient and the area under the receiver operating characteristic were used to evaluate the prediction performance for PCI and cytogenetic aberrations, respectively. Results: A total of 672 MRIs from 512 patients (median age, 61 years; interquartile range, 53-67 years; 307 men) from 8 centers and 370 corresponding BM biopsies were included. The predicted PCI from the best model was significantly correlated ( P ≤ 0.01) to the actual PCI from biopsy in all internal and external test sets (internal test set: r = 0.71 [0.51, 0.83]; center 2, high-quality test set: r = 0.45 [0.12, 0.69]; center 2, other test set: r = 0.30 [0.07, 0.49]; multicenter test set: r = 0.57 [0.30, 0.76]). The areas under the receiver operating characteristic of the prediction models for the different cytogenetic aberrations ranged from 0.57 to 0.76 for the internal test set, but no model generalized well to all 3 external test sets. Conclusions: The automated image analysis framework established in this study allows for noninvasive prediction of a surrogate parameter for PCI, which is significantly correlated to the actual PCI from BM biopsy.
MeSH term(s)	Male ; Humans ; Middle Aged ; Multiple Myeloma/diagnostic imaging ; Multiple Myeloma/genetics ; Bone Marrow/diagnostic imaging ; Deep Learning ; Retrospective Studies ; Magnetic Resonance Imaging/methods ; Biopsy ; Chromosome Aberrations
Language	English
Publishing date	2023-05-22
Publishing country	United States
Document type	Multicenter Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80345-5
ISSN	1536-0210 ; 0020-9996
ISSN (online)	1536-0210
ISSN	0020-9996
DOI	10.1097/RLI.0000000000000986
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Zs.A 734: Show issues

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Article ; Online: The Hippo pathway is controlled by Angiotensin II signaling and its reactivation induces apoptosis in podocytes.

Wennmann, D O / Vollenbröker, B / Eckart, A K / Bonse, J / Erdmann, F / Wolters, D A / Schenk, L K / Schulze, U / Kremerskothen, J / Weide, T / Pavenstädt, H

Cell death & disease

2014 Volume 5, Page(s) e1519

Abstract: The Hippo pathway fulfills a crucial function in controlling the balance between proliferation, differentiation and apoptosis in cells. Recent studies showed that G protein-coupled receptors (GPCRs) serve as upstream regulators of Hippo signaling, that ... ...

Abstract	The Hippo pathway fulfills a crucial function in controlling the balance between proliferation, differentiation and apoptosis in cells. Recent studies showed that G protein-coupled receptors (GPCRs) serve as upstream regulators of Hippo signaling, that either activate or inactivate the Hippo pathway via the large tumor suppressor kinase (LATS) and its substrate, the co-transcription factor Yes-associated protein (YAP). In this study, we focused on the Angiotensin II type 1 receptor (AT1R), which belongs to the GPCR family and has an essential role in the control of blood pressure and water homeostasis. We found that Angiotensin II (Ang II) inactivates the pathway by decreasing the activity of LATS kinase; therefore, leading to an enhanced nuclear shuttling of unphosphorylated YAP in HEK293T cells. This shuttling of YAP is actin-dependent as disruption of the actin cytoskeleton inhibited dephosphorylation of LATS and YAP. Interestingly, in contrast to HEK293T cells, podocytes, which are a crucial component of the glomerular filtration barrier, display a predominant nuclear YAP localization in vivo and in vitro. Moreover, stimulation with Ang II did not alter Hippo pathway activity in podocytes, which show a deactivated pathway. Reactivation of the LATS kinase activity in podocytes resulted in an increased cytoplasmic YAP localization accompanied by a strong induction of apoptosis. Thus, our work indicates that the control of LATS activation and subsequent YAP localization is important for podocyte homeostasis and survival.
MeSH term(s)	Actin Cytoskeleton/chemistry ; Actin Cytoskeleton/metabolism ; Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Angiotensin II/pharmacology ; Animals ; Apoptosis/genetics ; Cell Line, Transformed ; Cell Survival ; Gene Expression Regulation ; HEK293 Cells ; Homeostasis ; Humans ; Mice ; Mice, Transgenic ; Organ Specificity ; Phosphoproteins/genetics ; Phosphoproteins/metabolism ; Phosphorylation ; Podocytes/cytology ; Podocytes/metabolism ; Primary Cell Culture ; Protein Transport ; Protein-Serine-Threonine Kinases/genetics ; Protein-Serine-Threonine Kinases/metabolism ; Receptor, Angiotensin, Type 1/genetics ; Receptor, Angiotensin, Type 1/metabolism ; Signal Transduction ; Transcription Factors
Chemical Substances	Adaptor Proteins, Signal Transducing ; Phosphoproteins ; Receptor, Angiotensin, Type 1 ; Transcription Factors ; YAP1 protein, human ; Angiotensin II (11128-99-7) ; LATS1 protein, human (EC 2.7.1.-) ; Hippo protein, human (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2014-11-13
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/cddis.2014.476
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Common exonic missense variants in the C2 domain of the human KIBRA protein modify lipid binding and cognitive performance.

Duning, K / Wennmann, D O / Bokemeyer, A / Reissner, C / Wersching, H / Thomas, C / Buschert, J / Guske, K / Franzke, V / Flöel, A / Lohmann, H / Knecht, S / Brand, S-M / Pöter, M / Rescher, U / Missler, M / Seelheim, P / Pröpper, C / Boeckers, T M /

Makuch, L / Huganir, R / Weide, T / Brand, E / Pavenstädt, H / Kremerskothen, J

Translational psychiatry

2013 Volume 3, Page(s) e272

Abstract: The human KIBRA gene has been linked to human cognition through a lead intronic single-nucleotide polymorphism (SNP; rs17070145) that is associated with episodic memory performance and the risk to develop Alzheimer's disease. However, it remains unknown ... ...

Abstract	The human KIBRA gene has been linked to human cognition through a lead intronic single-nucleotide polymorphism (SNP; rs17070145) that is associated with episodic memory performance and the risk to develop Alzheimer's disease. However, it remains unknown how this relates to the function of the KIBRA protein. Here, we identified two common missense SNPs (rs3822660G/T [M734I], rs3822659T/G [S735A]) in exon 15 of the human KIBRA gene to affect cognitive performance, and to be in almost complete linkage disequilibrium with rs17070145. The identified SNPs encode variants of the KIBRA C2 domain with distinct Ca(2+) dependent binding preferences for monophosphorylated phosphatidylinositols likely due to differences in the dynamics and folding of the lipid-binding pocket. Our results further implicate the KIBRA protein in higher brain function and provide direction to the cellular pathways involved.
MeSH term(s)	Cognition/physiology ; Exons/genetics ; Exons/physiology ; Female ; Genotype ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/physiology ; Linkage Disequilibrium/genetics ; Linkage Disequilibrium/physiology ; Lipid Metabolism/genetics ; Lipid Metabolism/physiology ; Male ; Middle Aged ; Mutation, Missense/genetics ; Mutation, Missense/physiology ; Neuropsychological Tests ; Phosphatidylinositols/metabolism ; Phosphoproteins/genetics ; Phosphoproteins/physiology ; Polymorphism, Single Nucleotide/genetics
Chemical Substances	Intracellular Signaling Peptides and Proteins ; Phosphatidylinositols ; Phosphoproteins ; WWC1 protein, human
Language	English
Publishing date	2013-06-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2609311-X
ISSN	2158-3188 ; 2158-3188
ISSN (online)	2158-3188
ISSN	2158-3188
DOI	10.1038/tp.2013.49
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Book ; Online: Bericht zu möglichen Synergien der Nutzung neuer molekularbiologischer Techniken für eine nachhaltige Landwirtschaft ; Report on possible synergies of the use of new genomic techniques for sustainable agriculture

Wilhelm, Ralf / Bartsch, Detlef / Consmüller, Nicola / de Witte, Thomas / Ehlers, Ulrich / Feike, Til / Gocht, Alexander / Hartung, Frank / Kahrmann, Jens / Kehlenbeck, Hella / Leggewie, Georg / Lehnert, Heike / Ordon, Frank / Sprink, Thorben / Beer, Holger / Bloem, Elke / Hausmann, Johannes / Flachowsky, Henryk / Gathmann, Achim /

Herrmann, Daniel / Herz, Annette / Jacobs, Anna / Jehle, Johannes / Joachim, Christoph / Kämpfer, Christoph / Kohl, Christian / König, Janine / Kottmann, Lorenz / Marthe, Frank / Nothnagel, Thomas / Peil, Andreas / Rautmann, Dirk / Rodemann, Bernd / Söchting, Hans-Peter / Stahl, Andreas / Töpfer, Reinhard / Trapp, Oliver / Ulber, Lena / Vaasen, Anja / Vogler, Ute / Wegener, Jens Karl / Wennmann, Jörg / Will, Torsten / Zetzsche, Holger / Julius Kühn-Institut

2021

Keywords	Text ; ddc:630
Language	German
Publisher	Julius Kühn-Institut
Publishing country	de
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Activation of Hippo Pathway Damages Slit Diaphragm by Deprivation of Ajuba Proteins.

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Article ; Online: Umgang mit COVID-19 in der Notaufnahme : Erfahrungsbericht der interdisziplinären Notaufnahme des Universitätsklinikums Münster.

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Article ; Online: Umgang mit COVID-19 in der Notaufnahme ; Erfahrungsbericht der interdisziplinären Notaufnahme des Universitätsklinikums Münster

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Article: Umgang mit COVID-19 in der Notaufnahme : Erfahrungsbericht der interdisziplinären Notaufnahme des Universitätsklinikums Münster./ [Handling of COVID-19 in the emergency department : Field report of the emergency ward of the University Hospital Münster]

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Article ; Online: Prediction of Bone Marrow Biopsy Results From MRI in Multiple Myeloma Patients Using Deep Learning and Radiomics.

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Article ; Online: The Hippo pathway is controlled by Angiotensin II signaling and its reactivation induces apoptosis in podocytes.

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Article ; Online: Common exonic missense variants in the C2 domain of the human KIBRA protein modify lipid binding and cognitive performance.

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Book ; Online: Bericht zu möglichen Synergien der Nutzung neuer molekularbiologischer Techniken für eine nachhaltige Landwirtschaft ; Report on possible synergies of the use of new genomic techniques for sustainable agriculture

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