15 research outputs found
“This Unique Empire” : Sylvia Plath and Anne Sexton’s Embodied Poetry as L’Ecriture Feminine
This thesis seeks to place the poetry of Sylvia Plath and Anne Sexton within a larger discussion of contemporary feminist thought regarding corporeality and Hélène Cixous’ idea of l’ecriture feminine from her 1976 essay “The Laugh of the Medusa.” Beginning with the basic premise of the mind/body dichotomy that was the basis for western philosophy, this thesis argues that contemporary feminist discourse shies away from viewing women’s bodies as a source of empowerment, hoping to avoid exposure to bioessentialist critiques, and instead focusing on women’s access to areas of intellectual power. This thesis posits that rather than uphold the power dynamics imbued within the mind/body dichotomy, feminist theory has much to gain from refiguring this restrictive binary in a way where women’s bodies are viewed as a locus of power and strength, rather than a site of weakness.
To achieve these aims, this thesis discusses poetry of Sylvia Plath (“Edge” and “The Applicant”) and Anne Sexton (“Menstruation at Forty” and “In Celebration of My Uterus”) as examples of l’ecriture feminine. Plath’s poetics utilize images of women’s bodies as sites of violence and brutality to demonstrate the dangers for women inherent within patriarchal systems. In Sexton’s poetics, she utilizes both form and content to move towards a feminine writing that mirrors the biological processes of the body, as argued in “Laugh of the Medusa.” While Plath’s poetics figure women’s brutalized bodies as what is left in the wake of patriarchal power structures, Sexton’s poetics go a step further, and move towards l’ecriture feminine as a Cixous understood it: a reconfiguring of language that mirrors women’s bodies, as a way out of the insidious hegemonic power structures that ensnare, brutalize, and eventually destroy women as collateral damage
Development of a fluorescent probe applicable for screening new inhibitors targeting mitogen-activated protein kinase kinase 4 (MKK4)
Development of a Fluorescent Probe Applicable for Screening New Inhibitors Targeting Mitogen-Activated Protein Kinase Kinase 4 (MKK4)
Dissertation ist gesperrt bis 01. Februar 2023 !In den letzten Jahren ist die Anzahl an Patienten, welche unter chronischen Lebererkrankungen leiden, konstant gestiegen. Obwohl die Leber das einzige Organ darstellt, welches sich nach Gewebeschädigung in Kürze komplett regenerieren kann, ist dies nur bis zu einem bestimmten Anteil an verbleibendem gesundem Lebergewebe möglich. MKK4 wurde dabei als Schlüsselregulator der Leberregeneration identifiziert. Unter Laborbedingungen konnte eine direkte Korrelation zwischen reduzierter Protein-Expression von MKK4 mit shRNA und einer erhöhten Regenerationsfähigkeit der Hepatozyten gezeigt werden. Zeitgleich wurde mit dem BRAF-Inhibitor Vemurafenib ein Startpunkt gefunden, welcher MKK4 als off-target bindet. Bis heute gibt es jedoch nur wenige veröffentlichte Inhibitoren mit guter Selektivität für MKK4, was den dringenden Bedarf an neuen Strukturklassen zu Adressierung von MKK4 unterstreicht. Diese Lücke kann mit der Identifizierung neuer Inhibitoren für MKK4 in einem Fluoreszenzpolarisations-basierten Hochdurchsatz-Screening geschlossen werden. Dafür bedarf es der Entwicklung einer fluoreszenten Sonde zur Adressierung von MKK4 in einem entsprechenden Assay. Diesbezüglich wurden zwei parallele Synthesestrategien verfolgt, welche auf strukturell verwandten Grundgerüsten des Vemurafenibs, Azaindol und Carbolin, basieren. Mit Hilfe von Linker-Systemen, welche sich in Länge, Basis und Positionierung des Fluoreszenzfarbstoffes am Grundgerüst unterscheiden, konnte die Carbolin-basierte Verbindung 55 entwickelt werden, welche eine hohe Affinität (POC = 1.3, Konz. 100 nM) und Inhibition (IC50 = 1.03 μM) zu MKK4 zeigte. Mit Hilfe dieser fluoreszenten Sonde konnten bekannte MKK4 Inhibitoren in ihrer Potenz bestätigt werden. Außerdem war diese Verbindung fähig neue Strukturklassen in einem HT-screening zu finden, welche zur Weiterentwicklung neuer Inhibitoren geeignet sind. Die gefundenen Hits wurden in einem zweiten Assay bestätigt und anhand ihrer synthetischen Zugänglichkeit, Struktur und Stabilität bewertet. Diese zwei Hits, welche ein Aminopyrimidin- und ein Imidazol-Grundgerüst enthalten, wurden für weitere Untersuchungen ausgewählt. Für beide Verbindungen konnte eine zugängliche Synthese etabliert werden, die in kurzer Zeit eine ZUSAMMENFASSUNG VIII hohe Anzahl an Derivaten zuließ, welche Aussagen über den Bindemodus der Kinase erlaubten. Besonders Verbindung 142 hob sich durch eine hohe Bindeaffinität zu MKK4 (POC = 26) hervor, welche sich im gleichen Bereich wie Vemurafenib bewegt und ist trotz bekanntem Imidazol Strukturmotiv eine neue Substanzklasse zur Inhibition von MKK4. Diese Ergebnisse ebenen den Weg für die Entwicklung neuer Leitstrukturen zur Adressierung von MKK4
Design and synthesis of novel fluorescently labeled analogs of vemurafenib targeting MKK4
Somatostatin receptor based PET/CT in patients with the suspicion of cardiac sarcoidosis: an initial comparison to cardiac MRI
Diagnosis of cardiac sarcoidosis is often challenging. Whereas cardiac magnetic resonance imaging (CMR) and positron emission tomography/computed tomography (PET/CT) with F-fluorodeoxyglucose (FDG) are most commonly used to evaluate patients, PET/CT using radiolabeled somatostatin receptor (SSTR) ligands for visualization of inflammation might represent a more specific alternative. This study aimed to investigate the feasibility of SSTR–PET/CT for detecting cardiac sarcoidosis in comparison to CMR.
15 patients (6 males, 9 females) with sarcoidosis and suspicion on cardiac involvement underwent SSTR-PET/CT imaging and CMR. Images were visually scored. The AHA 17-segment model of the left myocardium was used for localization and comparison of inflamed myocardium for both imaging modalities. In semi-quantitative analysis, mean (SUV) and maximum standardized uptake values (SUV) of affected myocardium were calculated and compared with both remote myocardium and left ventricular (LV) cavity.
SSTR-PET was positive in 7/15, CMR in 10/15 patients. Of the 3 CMR+/PET- subjects, one patient with minor involvement (<25% of wall thickness in CMR) was missed by PET. The remaining two CMR+/PET- patients displayed no adverse cardiac events during follow-up.
In the 17-segment model, PET/CT yielded 27 and CMR 29 positive segments. Overall concordance of the 2 modalities was 96.1% (245/255 segments analyzed). SUV and SUV in inflamed areas were 2.0±1.2 and 2.6±1.2, respectively. The lesion-to-remote myocardium and lesion-to-LV cavity ratios were 1.8±0.2 and 1.9±0.2 for SUV and 2.0±0.3 and 1.7±0.3 for SUV, respectively.
Detection of cardiac sarcoidosis by SSTR-PET/CT is feasible. Our data warrant further analysis in larger prospective series
Imaging of C-X-C motif chemokine receptor CXCR4 expression after myocardial infarction with [68Ga]Pentixafor-PET/CT in correlation with cardiac MRI
Detection of cardiac amyloidosis with 18F-Florbetaben-PET/CT in comparison to echocardiography, cardiac MRI and DPD-scintigraphy
Imaging of C-X-C Motif Chemokine Receptor CXCR4 Expression After Myocardial Infarction With [68Ga]Pentixafor-PET/CT in Correlation With Cardiac MRI
Myocardial infarction triggers cardioprotective antigen-specific T helper cell responses
T cell autoreactivity is a hallmark of autoimmune diseases but can also benefit self-maintenance and foster tissue repair. Here, we investigated whether heart-specific T cells exert salutary or detrimental effects in the context of myocardial infarction (MI), the leading cause of death worldwide. After screening more than 150 class II–restricted epitopes, we found that myosin heavy chain α (MYHCA) was a dominant cardiac antigen triggering post-MI CD4+ T cell activation in Balb/c mice. Transferred MYHCA 614–629-specific CD4+ T cells (TCR-M cells) selectively accumulated in the myocardium and mediastinal lymph nodes (med-LNs) of infarcted mice, acquired a Treg phenotype with a distinct prohealing gene expression profile, and mediated cardioprotection. Myocardial Tregs were also detected in autopsy samples from patients who had had a MI. Noninvasive PET/CT imaging using a CXCR4 radioligand revealed enlarged med-LNs with increased cellularity in patients with MI. Notably, the med-LN alterations observed in MI patients correlated with the infarct size and cardiac function. Taken together, the results obtained in our study provide evidence that MI context induces prohealing T cell autoimmunity in mice and confirm the existence of an analogous heart/med-LN/T cell axis in patients with MI
Bipolar-associated miR-499-5p controls neuroplasticity by downregulating the Cav1.2 subunit CACNB2
Bipolar disorder (BD) is a chronic mood disorder characterized by manic and depressive episodes. Dysregulation of neuroplasticity and calcium homeostasis are frequently observed in BD patients, but the underlying molecular mechanisms are largely unknown. Here, we show that miR-499-5p regulates dendritogenesis and cognitive function by downregulating the BD risk gene CACNB2. miR-499-5p expression is increased in peripheral blood of BD patients, as well as in the hippocampus of rats which underwent juvenile social isolation. In rat hippocampal neurons, miR-499-5p impairs dendritogenesis and reduces surface expression and activity of the L-type calcium channel Cav1.2. We further identified CACNB2, which encodes a regulatory beta-subunit of Cav1.2, as a direct functional target of miR-499-5p in neurons. miR-499-5p overexpression in the hippocampus in vivo induces short-term memory impairments selectively in rats haploinsufficient for the Cav1.2 pore forming subunit Cacna1c. In humans, miR-499-5p expression is negatively associated with gray matter volumes of the left superior temporal gyrus, a region implicated in auditory and emotional processing. We propose that stress-induced miR-499-5p overexpression contributes to dendritic impairments, deregulated calcium homeostasis, and neurocognitive dysfunction in BD.ISSN:1469-221XISSN:1469-317