818 research outputs found
How low can you go – Insight into the level of mutated protein required to cause pathogenic effects in hypertrophic cardiomyopathy
Get PDFUsing ‘next-generation’ sequencing in the identification of novel causes of inherited heart diseases
Get PDFNext-generation sequencing methods now allow rapid and cost-effective sequencing of DNA on a scale not previously possible. This offers great opportunities for the research of Mendelian disorders, but also significant challenges. The sequencing of exomes, or whole genomes, has emerged as a powerful clinical research tool, with targeted gene analyses generally being preferred in the clinical diagnostic setting. These methods have been employed here with the aim of identifying novel genetic causes of inherited heart disorders and to gain insights into the utility and limitations of these techniques for clinical diagnosis in these disorders. Data produced from the introduction of a targeted multi-gene next-generation sequencing test into clinical practice has been studied. Variation within the mitochondrial genome has been analysed to assess the importance of mitochondrial DNA variants in patients with hypertrophic cardiomyopathy. The m.4300A>G mutation is identified as an important cause of this disorder, with other previously cardiomyopathy-associated and novel variants also identified. Such multi-gene tests can facilitate interpretable and phenotype-relevant results, but at the expense of limiting more extensive data acquisition. Whole-genome sequencing has been performed in five families with different autosomal dominant inherited heart disease phenotypes of unknown genetic aetiology. In two of these likely pathogenic variants were identified, one in the gene encoding titin (TTN) and the other in the calcium channel subunit gene CACNA1C. In vitro studies were undertaken to support the pathogenicity of the TTN variant and understand the functional effects of this. In the other three families either multiple candidate gene variants were identified or no clear candidate variant was identified. This highlights the difficulties in interpreting these results, even in carefully selected families. Overall, although the research benefits of exome or genome studies are evident, the interpretation and validation of genetic variant data produced remains highly challenging for clinical diagnosis
Characterization of cardiomyopathy causing mutation in muscle lim protein (C58G)
Get PDFMuscle LIM Protein (MLP) is encoded by the gene Cysteine and glycine rich protein 3 (CSRP3), a well-established disease gene for Hypertrophic Cardiomyopathy (HCM). Unlike most HCM disease genes, which code for sarcomere related proteins, MLP is a non-sarcomeric protein that is critical for signalling within the cardiomyocyte. To better understand the mechanism underlying MLP associated HCM a knock-in (KI) mouse model carrying CSRP3 mutation C58G was generated. In vivo phenotyping of homozygous KI/KI mice recapitulated aspects of human cardiomyopathy with diastolic and systolic left ventricular dysfunction. No differences were observed between heterozygous KI/+ and WT littermate controls. RNASeq based transcriptomic analysis revealed activation of pro-fibrotic signalling, induction of the fetal gene programme and activation of markers of hypertrophic signalling in hearts of homozygous animals at 3 months. C58G mutation led to increased degradation of MLP protein in vitro and in vivo. MLP protein expression was reduced by 80% in KI/KI and by 50% in KI/+ mice. The reduced expression was due to increased proteasome activity which was verified by a proteasome reporter mouse. To uncover phenotype in KI/+ mice they were crossed with knock-in mutant mouse for MyBPC, which has been associated with increase proteasome activity. The double mutant failed to show any differences compared to heterozygous knock-in mice. In conclusion, the CSRP3 C58G mouse serves as a unique mouse model to study cardiomyopathy caused by mutations in the non-sarcomeric protein MLP. The results suggest that the lack of protein and proteasomal overload both contribute to the development of disease phenotype
Measuring Vulnerability to Poverty Using Long-Term Panel Data
No full textMeasuring Vulnerability to Poverty Using Long-Term Panel Data Author & abstract Download & other version 16 References 4 Citations Related works & more Corrections Author Listed: Katja Landau (Georg-August-University Göttingen) Stephan Klasen (Georg-August-University Göttingen) Walter Zucchini (Georg-August-University Göttingen) Registered: Stephan Klasen Abstract We investigate the accuracy of ex ante assessments of vulnerability to income poverty using cross-sectional data and panel data. We use long-term panel data from Germany and apply di fferent regression models, based on household covariates and previous-year equivalence income, to classify a household as vulnerable or not. Predictive performance is assessed using the Receiver Operating Characteristics (ROC), which takes account of false positive as well as true positive rates. Estimates based on cross-sectional data are much less accurate than those based on panel data, but for Germany, the accuracy of vulnerability predictions is limited even when panel data are used. In part this low accuracy is due to low poverty incidence and high mobility in and out of poverty
Resilience as a positive lever: An analysis of sensemaking and meaningful work in the context of organizational change
No full textAuthor Katja SchwarzMasterarbeit Johannes Kepler Universität Linz 2024Arbeit nach Ablauf der Sperre auf den öffentlichen PCs in den Bibliotheken der JKU+Medizin abrufba
Measuring Vulnerability to Poverty Using Long-Term Panel Data
No full textMeasuring Vulnerability to Poverty Using Long-Term Panel Data Author & abstract Download & other version 16 References 4 Citations Related works & more Corrections Author Listed: Katja Landau (Georg-August-University Göttingen) Stephan Klasen (Georg-August-University Göttingen) Walter Zucchini (Georg-August-University Göttingen) Registered: Stephan Klasen Abstract We investigate the accuracy of ex ante assessments of vulnerability to income poverty using cross-sectional data and panel data. We use long-term panel data from Germany and apply di fferent regression models, based on household covariates and previous-year equivalence income, to classify a household as vulnerable or not. Predictive performance is assessed using the Receiver Operating Characteristics (ROC), which takes account of false positive as well as true positive rates. Estimates based on cross-sectional data are much less accurate than those based on panel data, but for Germany, the accuracy of vulnerability predictions is limited even when panel data are used. In part this low accuracy is due to low poverty incidence and high mobility in and out of poverty
Resilience as a positive lever: An analysis of sensemaking and meaningful work in the context of organizational change
No full textAuthor Katja SchwarzMasterarbeit Johannes Kepler Universität Linz 2024Arbeit nach Ablauf der Sperre auf den öffentlichen PCs in den Bibliotheken der JKU+Medizin abrufba
Structural and signaling proteins in the Z-disk and their role in cardiomyopathies
Get PDFThe sarcomere is the smallest functional unit of muscle contraction. It is delineated by a protein-rich structure known as the Z-disk, alternating with M-bands. The Z-disk anchors the actin-rich thin filaments and plays a crucial role in maintaining the mechanical stability of the cardiac muscle. A multitude of proteins interact with each other at the Z-disk and they regulate the mechanical properties of the thin filaments. Over the past 2 decades, the role of the Z-disk in cardiac muscle contraction has been assessed widely, however, the impact of genetic variants in Z-disk proteins has still not been fully elucidated. This review discusses the various Z-disk proteins (alpha-actinin, filamin C, titin, muscle LIM protein, telethonin, myopalladin, nebulette, and nexilin) and Z-disk-associated proteins (desmin, and obscurin) and their role in cardiac structural stability and intracellular signaling. This review further explores how genetic variants of Z-disk proteins are linked to inherited cardiac conditions termed cardiomyopathies.</p
Structures of force transduction in cross-striated muscle tissues : protein-protein interactions and mechanisms of their regulation
No full textIm Mittelpunkt dieser Arbeit standen Signaltransduktionsprozesse in den Strukturen der Kraftübertragung quergestreifter Muskelzellen, d. h. in den Costameren (Zell-Matrix-Kontakten) und den Glanzstreifen (Zell-Zell-Kontakten der Kardiomyozyten).Es ließ sich zeigen, dass sich die Morphologie der Zell-Matrix-Kontakte während der Differenzierung von Skelettmuskelzellen dramatisch ändert, was mit einer veränderten Proteinzusammensetzung einhergeht. Immunfluoreszenz-Analysen von Skelettmuskelzellen verschiedener Differenzierungsstadien implizieren, dass die Signalwege, welche die Dynamik der Fokalkontakte in Nichtmuskelzellen bestimmen, nur für frühe Stadien der Muskeldifferenzierung Relevanz haben können. Ausgehend von diesem Befund wurde begonnen, noch unbekannte Signalwege zu identifizieren, welche die Ausbildung von Costameren kontrollieren: In den Vorläuferstrukturen der Costamere gelang es, eine transiente Interaktion der Proteine Paxillin und Ponsin zu identifizieren. Biochemische Untersuchungen legen nahe, dass Ponsin über eine Skelettmuskel-spezifische Insertion im Carboxyterminus das Adapterprotein Nck2 in diesen Komplex rekrutiert. Es wird vorgeschlagen, dass die drei Proteine einen ternären Signalkomplex bilden, der die Umbauvorgänge der Zell-Matrix-Kontakte kontrolliert und dessen Aktivität von mitogen activated protein kinases (MAPK) reguliert wird.Die Anpassungsvorgänge der Strukturen der Kraftübertragung an pathologische Situtation (Kardiomyopathien) in der adulten quergestreiften Muskulatur wurden ausgehend von einem zweiten Protein, dem muscle LIM protein (MLP), untersucht. Es konnte gezeigt werden, dass ein mutiertes MLP-Protein, das im Menschen eine hypertrophe Kardiomyopathie (HCM) auslöst, strukturelle Defekte aufweist und weniger stabil ist. Weiterhin zeigte dieses mutierte Protein eine verringerte Bindungsfähigkeit an die beiden Liganden N-RAP und alpha-Actinin. Die molekulare Grundlage der HCM-verursachenden Mutationen im MLP-Gen könnte folglich eine Veränderung der Homöostase im ternären Komplex MLP – N-RAP – alpha-Actinin sein. Die Expressionsdaten eines neu generierten monoklonalen MLP-Antikörpers deuten darauf hin, dass die Funktionen des MLP nicht nur für die Integrität des Myokards, sondern auch für die der Skelettmuskulatur notwendig sind.The cell-matrix-contacts (costameres) and cell-cell-contacts (intercalated discs of cardiomyocytes) of cross-striated muscle cells transmit mechanical forces to the exterior. On top of this mechanical function, both structures have been implied to be involved in signal transduction processes.Dramatic morphological changes in the overall structure of cell-matrix-contacts of skeletal muscle cells were revealed during differentiation. Moreover, this reorganisation was accompanied by alterations in protein composition. Immunofluorescence microscopy indicated that signalling pathways which control the dynamics of focal contacts in non-muscle cells seem to be important only for early differentiation stages of skeletal muscle cells. To explore novel signalling pathways involved in regulating the formation of costameres, signalling molecules engaged were identified. Thus, paxillin and ponsin transiently interact at the precursors of costameres during muscle development. In addition, biochemical data indicate that a skeletal muscle specific module in the carboxyterminal part of ponsin can recruit the adapter protein Nck2 to this complex. Hence, the three proteins might form a ternary signalling complex involved in controlling the reorganisation of cell-matrix-contacts. Apparently, the activity of this signalling complex is regulated by mitogen activated protein kinases (MAPK).A second approach has focussed on adaptational processes of the same structures observed in pathological situations. In particular, the role of muscle LIM protein (MLP) in hypertrophic cardiomyopathy (HCM) was investigated. It was shown that a HCM-causing mutant MLP protein fails to fold properly and that the consequent loss of stability is reflected in altered binding properties: the mutant MLP protein shows decreased binding to both N-RAP and alpha-actinin. Hence, the molecular basis for HCM-causing mutations in the MLP gene might be an altered homeostasis of the ternary complex MLP – N-RAP – alpha-actinin. Increasing evidence indicates that the functions of MLP are required not only for the integrity of the myocardium. In addition, MLP seems to have regulatory functions in skeletal muscle tissues
"Meghillàt Estèr". Toward a Transcultural Concept of Religion in Katja Petrowskaja\u27s Novel Vielleicht Esther
No full textIl presente contributo intende rileggere il romanzo Vielleicht Esther (2014) di Katja Petrowskaja proponendo come chiave di lettura la Meghillàt Estèr della Bibbia ebraica. Si vuole dimostrare come, attraverso questo implicito ma preciso riferimento intertestuale, l’autrice affronti nel romanzo anche una riflessione su una possibile transreligione capace di rispecchiare il contesto transculturale contemporaneo.This contribution analyzes Katja Petrowskaja’s novel Vielleicht Esther (2014) by proposing the Megillàt Estèr from the Hebrew Bible as a key interpretative lens. The aim is to demonstrate how, through this subtle yet deliberate intertextual reference, the author weaves into the novel a reflection on the notion of a transreligion, one that resonates with and articulates the complexities of our contemporary transcultural landscape
- …
