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  1. Article ; Online: SERCA2a microdomain cAMP changes in heart failure with preserved ejection fraction.

    Gotthardt, Michael / Lehnart, Stephan E

    Cardiovascular research

    2024  Volume 120, Issue 3, Page(s) 220–222

    MeSH term(s) Humans ; Stroke Volume ; Diabetes Mellitus, Type 2 ; Ventricular Function, Left ; Obesity ; Heart Failure
    Language English
    Publishing date 2024-01-24
    Publishing country England
    Document type Editorial ; Research Support, Non-U.S. Gov't ; Comment
    ZDB-ID 80340-6
    ISSN 1755-3245 ; 0008-6363
    ISSN (online) 1755-3245
    ISSN 0008-6363
    DOI 10.1093/cvr/cvae030
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 565: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article: Cardiac sarcomere mechanics in health and disease.

    Crocini, Claudia / Gotthardt, Michael

    Biophysical reviews

    2021  Volume 13, Issue 5, Page(s) 637–652

    Abstract: The sarcomere is the fundamental structural and functional unit of striated muscle and is directly responsible for most of its mechanical properties. The sarcomere generates active or contractile forces and determines the passive or elastic properties of ...

    Abstract The sarcomere is the fundamental structural and functional unit of striated muscle and is directly responsible for most of its mechanical properties. The sarcomere generates active or contractile forces and determines the passive or elastic properties of striated muscle. In the heart, mutations in sarcomeric proteins are responsible for the majority of genetically inherited cardiomyopathies. Here, we review the major determinants of cardiac sarcomere mechanics including the key structural components that contribute to active and passive tension. We dissect the molecular and structural basis of active force generation, including sarcomere composition, structure, activation, and relaxation. We then explore the giant sarcomere-resident protein titin, the major contributor to cardiac passive tension. We discuss sarcomere dynamics exemplified by the regulation of titin-based stiffness and the titin life cycle. Finally, we provide an overview of therapeutic strategies that target the sarcomere to improve cardiac contraction and filling.
    Language English
    Publishing date 2021-10-12
    Publishing country Germany
    Document type Journal Article ; Review
    ZDB-ID 2486483-3
    ISSN 1867-2469 ; 1867-2450
    ISSN (online) 1867-2469
    ISSN 1867-2450
    DOI 10.1007/s12551-021-00840-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Titin's cardiac-specific N2B element is critical to mechanotransduction during volume overload of the heart.

    Strom, Joshua / Bull, Mathew / Gohlke, Jochen / Saripalli, Chandra / Methawasin, Mei / Gotthardt, Michael / Granzier, Henk

    Journal of molecular and cellular cardiology

    2024  Volume 191, Page(s) 40–49

    Abstract: The heart has the ability to detect and respond to changes in mechanical load through a process called mechanotransduction. In this study, we focused on investigating the role of the cardiac-specific N2B element within the spring region of titin, which ... ...

    Abstract The heart has the ability to detect and respond to changes in mechanical load through a process called mechanotransduction. In this study, we focused on investigating the role of the cardiac-specific N2B element within the spring region of titin, which has been proposed to function as a mechanosensor. To assess its significance, we conducted experiments using N2B knockout (KO) mice and wildtype (WT) mice, subjecting them to three different conditions: 1) cardiac pressure overload induced by transverse aortic constriction (TAC), 2) volume overload caused by aortocaval fistula (ACF), and 3) exercise-induced hypertrophy through swimming. Under conditions of pressure overload (TAC), both genotypes exhibited similar hypertrophic responses. In contrast, WT mice displayed robust left ventricular hypertrophy after one week of volume overload (ACF), while the KO mice failed to undergo hypertrophy and experienced a high mortality rate. Similarly, swim exercise-induced hypertrophy was significantly reduced in the KO mice. RNA-Seq analysis revealed an abnormal β-adrenergic response to volume overload in the KO mice, as well as a diminished response to isoproterenol-induced hypertrophy. Because it is known that the N2B element interacts with the four-and-a-half LIM domains 1 and 2 (FHL1 and FHL2) proteins, both of which have been associated with mechanotransduction, we evaluated these proteins. Interestingly, while volume-overload resulted in FHL1 protein expression levels that were comparable between KO and WT mice, FHL2 protein levels were reduced by over 90% in the KO mice compared to WT. This suggests that in response to volume overload, FHL2 might act as a signaling mediator between the N2B element and downstream signaling pathways. Overall, our study highlights the importance of the N2B element in mechanosensing during volume overload, both in physiological and pathological settings.
    Language English
    Publishing date 2024-04-10
    Publishing country England
    Document type Journal Article
    ZDB-ID 80157-4
    ISSN 1095-8584 ; 0022-2828
    ISSN (online) 1095-8584
    ISSN 0022-2828
    DOI 10.1016/j.yjmcc.2024.04.006
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 426: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. Book ; Thesis: Adenoviren zum stabilen Gentransfer

    Gotthardt, Michael

    1997  

    Author's details von Michael Gotthardt
    Language German
    Size IV, 87 Bl. : Ill., graph. Darst.
    Edition [Mikrofiche-Ausg.]
    Document type Book ; Thesis
    Thesis / German Habilitation thesis Berlin, Humboldt-Univ., Diss., 1997
    Note Mikrofiche-Ausg.: 1 Mikrofiche : 24x
    HBZ-ID HT008712845
    Database Catalogue ZB MED Medicine, Health

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    In stock of ZB MED Cologne/Königswinter

    Shelf markLoan statusLocation
    1998 MB 1234 order for loan Magazin

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  5. Article: The IgCAM CAR Regulates Gap Junction-Mediated Coupling on Embryonic Cardiomyocytes and Affects Their Beating Frequency.

    Matthaeus, Claudia / Jüttner, René / Gotthardt, Michael / Rathjen, Fritz G

    Life (Basel, Switzerland)

    2022  Volume 13, Issue 1

    Abstract: The IgCAM coxsackie-adenovirus receptor (CAR) is essential for embryonic heart development and electrical conduction in the mature heart. However, it is not well-understood how CAR exerts these effects at the cellular level. To address this question, we ... ...

    Abstract The IgCAM coxsackie-adenovirus receptor (CAR) is essential for embryonic heart development and electrical conduction in the mature heart. However, it is not well-understood how CAR exerts these effects at the cellular level. To address this question, we analyzed the spontaneous beating of cultured embryonic hearts and cardiomyocytes from wild type and CAR knockout (KO) embryos. Surprisingly, in the absence of the CAR, cultured cardiomyocytes showed increased frequencies of beating and calcium cycling. Increased beatings of heart organ cultures were also induced by the application of reagents that bind to the extracellular region of the CAR, such as the adenovirus fiber knob. However, the calcium cycling machinery, including calcium extrusion via SERCA2 and NCX, was not disrupted in CAR KO cells. In contrast, CAR KO cardiomyocytes displayed size increases but decreased in the total numbers of membrane-localized Cx43 clusters. This was accompanied by improved cell-cell coupling between CAR KO cells, as demonstrated by increased intercellular dye diffusion. Our data indicate that the CAR may modulate the localization and oligomerization of Cx43 at the plasma membrane, which could in turn influence electrical propagation between cardiomyocytes via gap junctions.
    Language English
    Publishing date 2022-12-21
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2662250-6
    ISSN 2075-1729
    ISSN 2075-1729
    DOI 10.3390/life13010014
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Author Correction: Assessment of nanoindentation in stiffness measurement of soft biomaterials: kidney, liver, spleen and uterus.

    Wu, Guanlin / Gotthardt, Michael / Gollasch, Maik

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 7035

    Language English
    Publishing date 2021-03-23
    Publishing country England
    Document type Published Erratum
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-021-86044-1
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  7. Article ; Online: Molecular basis of titin exon exclusion by RBM20 and the novel titin splice regulator PTB4.

    Dauksaite, Vita / Gotthardt, Michael

    Nucleic acids research

    2018  Volume 46, Issue 10, Page(s) 5227–5238

    Abstract: RNA-binding motif protein 20 (RBM20) is a cardiac splice regulator that adapts cardiac filling via its diverse substrates-including the sarcomeric protein titin. The molecular basis and regulation of RBM20-dependent exon exclusion are largely unknown. In ...

    Abstract RNA-binding motif protein 20 (RBM20) is a cardiac splice regulator that adapts cardiac filling via its diverse substrates-including the sarcomeric protein titin. The molecular basis and regulation of RBM20-dependent exon exclusion are largely unknown. In tissue culture experiments, we show that the combination of RNA recognition motif (RRM) and C-terminus is necessary and sufficient for RBM20 activity, indicating an important function of the ZnF2 domain in splicing repression. Using splice reporter and in vitro binding assays targeting titin exons 241-243, we identified a minimal genomic segment that is necessary for RBM20-mediated splicing repression of the alternative exon. Here, RBM20 binds the cluster containing most RBM20 binding motifs through its RRM domain and represses the upstream and downstream introns. For subsequent exon exclusion, specific regions upstream, downstream and within the alternative exon 242 are required. Regulation of exon exclusion involves PTB4 as a novel titin splice regulator, which counteracts RBM20 repressor activity in HEK293 cells. Together, these mechanistic insights into the regulation and action of RBM20 and PTB4 provide a basis for the future development of RBM20 modulators that adapt titin elasticity in cardiac disease.
    MeSH term(s) Alternative Splicing ; Binding Sites ; Connectin/genetics ; Connectin/metabolism ; Exons ; HEK293 Cells ; Heterogeneous-Nuclear Ribonucleoproteins/genetics ; Heterogeneous-Nuclear Ribonucleoproteins/metabolism ; Humans ; Introns ; Polypyrimidine Tract-Binding Protein/genetics ; Polypyrimidine Tract-Binding Protein/metabolism ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; beta-Globins/genetics
    Chemical Substances Connectin ; Heterogeneous-Nuclear Ribonucleoproteins ; PTBP1 protein, human ; RNA-Binding Proteins ; TTN protein, human ; beta-Globins ; ribonucleic acid binding motif protein 20, human ; Polypyrimidine Tract-Binding Protein (139076-35-0)
    Language English
    Publishing date 2018-03-07
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gky165
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1067: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  8. Article: Proteome-wide quantitative RNA-interactome capture identifies phosphorylation sites with regulatory potential in RBM20

    Vieira-Vieira, Carlos Henrique / Dauksaite, Vita / Sporbert, Anje / Gotthardt, Michael / Selbach, Matthias

    Molecular cell. 2022 June 02, v. 82, no. 11

    2022  

    Abstract: Cellular mRNA-binding proteins (mRBPs) are major posttranscriptional regulators of gene expression. Although many posttranslational modification sites in mRBPs have been identified, little is known about how these modifications regulate mRBP function. ... ...

    Abstract Cellular mRNA-binding proteins (mRBPs) are major posttranscriptional regulators of gene expression. Although many posttranslational modification sites in mRBPs have been identified, little is known about how these modifications regulate mRBP function. Here, we developed quantitative RNA-interactome capture (qRIC) to quantify the fraction of mRBPs pulled down with polyadenylated mRNAs. Combining qRIC with phosphoproteomics allowed us to systematically compare pull-down efficiencies of phosphorylated and nonphosphorylated forms of mRBPs. Almost 200 phosphorylation events affected pull-down efficiency compared with the unmodified mRBPs and thus have regulatory potential. Our data capture known regulatory phosphorylation sites in ELAVL1, SF3B1, and UPF1 and identify potential regulatory sites. Follow-up experiments on the splicing regulator RBM20 revealed multiple phosphorylation sites in the C-terminal disordered region affecting nucleocytoplasmic localization, association with cytoplasmic ribonucleoprotein granules, and alternative splicing. Together, we show that qRIC in conjunction with phosphoproteomics is a scalable method to identify functional posttranslational modification sites in mRBPs.
    Keywords gene expression ; phosphorylation ; post-translational modification ; proteomics ; ribonucleoproteins
    Language English
    Dates of publication 2022-0602
    Size p. 2069-2083.e8.
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2022.03.024
    Database NAL-Catalogue (AGRICOLA)

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    In stock of ZB MED Bonn / Germany

    Z 2005/501: Show issues

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  9. Article ; Online: Assessment of nanoindentation in stiffness measurement of soft biomaterials: kidney, liver, spleen and uterus.

    Wu, Guanlin / Gotthardt, Michael / Gollasch, Maik

    Scientific reports

    2020  Volume 10, Issue 1, Page(s) 18784

    Abstract: Nanoindentation technology with high spatial resolution and force sensitivity is widely used to measure the mechanical properties of hard biomaterials and tissues. However, its reliability to analyze soft biomaterials and organs has not been tested. Here, ...

    Abstract Nanoindentation technology with high spatial resolution and force sensitivity is widely used to measure the mechanical properties of hard biomaterials and tissues. However, its reliability to analyze soft biomaterials and organs has not been tested. Here, we evaluated the utility of nanoindentation to measure the passive mechanical properties of soft biological specimen. Kidney, liver, spleen and uterus samples were harvested from C57BL/6 N mice. We assessed test-retest repeatability in biological specimen and hydrogel controls using Bland-Altman diagrams, intraclass correlation coefficients (ICCs) and the within-subject coefficients of variation (COVs). The results were calculated using Hertzian, JKR and Oliver & Pharr models. Similar to hydrogels, Bland-Altman plots of all biological specimen showed good reliability in stiffness test and retest examinations. In gels, ICCs were larger than 0.8 and COVs were smaller than 15% in all three models. In kidney, liver, spleen and uterus, ICCs were consistently larger than 0.8 only in the Hertzian model but not in the JKR and Oliver & Pharr models. Similarly, COVs were consistently smaller than 15% in kidney, liver, spleen and uterus only in the Hertzian model but not in the other models. We conclude that nanoindentation technology is feasible in detecting the stiffness of kidney, liver, spleen and uterus. The Hertzian model is the preferred method to provide reliable results on ex vivo organ stiffness of the biological specimen under study.
    MeSH term(s) Animals ; Biocompatible Materials ; Biomechanical Phenomena ; Feasibility Studies ; Female ; Hydrogels ; Kidney ; Liver ; Male ; Mice, Inbred C57BL ; Nanotechnology/methods ; Spleen ; Uterus ; Vascular Stiffness
    Chemical Substances Biocompatible Materials ; Hydrogels
    Language English
    Publishing date 2020-11-02
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-020-75738-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: RBM20-Related Cardiomyopathy: Current Understanding and Future Options.

    Koelemen, Jan / Gotthardt, Michael / Steinmetz, Lars M / Meder, Benjamin

    Journal of clinical medicine

    2021  Volume 10, Issue 18

    Abstract: Splice regulators play an essential role in the transcriptomic diversity of all eukaryotic cell types and organ systems. Recent evidence suggests a contribution of splice-regulatory networks in many diseases, such as cardiomyopathies. Adaptive splice ... ...

    Abstract Splice regulators play an essential role in the transcriptomic diversity of all eukaryotic cell types and organ systems. Recent evidence suggests a contribution of splice-regulatory networks in many diseases, such as cardiomyopathies. Adaptive splice regulators, such as RNA-binding motif protein 20 (RBM20) determine the physiological mRNA landscape formation, and rare variants in the RBM20 gene explain up to 6% of genetic dilated cardiomyopathy (DCM) cases. With ample knowledge from RBM20-deficient mice, rats, swine and induced pluripotent stem cells (iPSCs), the downstream targets and quantitative effects on splicing are now well-defined and the prerequisites for corrective therapeutic approaches are set. This review article highlights some of the recent advances in the field, ranging from aspects of granule formation to 3D genome architectures underlying RBM20-related cardiomyopathy. Promising therapeutic strategies are presented and put into context with the pathophysiological characteristics of RBM20-related diseases.
    Language English
    Publishing date 2021-09-11
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2662592-1
    ISSN 2077-0383
    ISSN 2077-0383
    DOI 10.3390/jcm10184101
    Database MEDical Literature Analysis and Retrieval System OnLINE

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