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Goethe - Egmont
(2010)
Do you know what I think? asks Adrian Leverkuehn. "Musik ist die Zweideutigkeit als System." Music is Janus-faced by its very nature. It can move and paralyze. "What passion cannot music raise and quell," exclaims John Dryden in his Song for St. Cecilia's Day, 1687. Music is an expert in the use of opiates, asserts Settembrini in The Magic Mountain, and Nietzsche speaks of her dual, intoxicating and befogging, nature. Shakespeare's Desdemona "will sing the savageness out of a bear" (IV, i) and the merchants in Novalis' Heinrich von Ofterdingen tell the story of another Orpheus whose song so charms a sea "monster" that it saves the singer's life and returns his treasure to him. John Dryden's Thimotheus "to his breathing flute and sounding lyre, could swell the soul to rage, or kindle soft desire" (Alexander's Feast, 1697). "Musica Consolatrix" and "Musica Tremenda". She is the "Mysterium tremendum et fascinosum" in Kleist's novella about the power of music. While English late 17th and early 18th century literature offers a particularly rich harvest of poetry celebrating the contradictory qualities, or effects, of music, there is in fact testimony to this at all stages of our tradition.
Music
(2010)
The musical ending [of Goethe's Novelle] recalls the fascination with "music as metaphor", "the power of music", among recent and contemporary poets from Pope and Dryden and Collins to E.T.A. Hoffmann and Kleist and, of course to Goethe himself. Music saves Faust's life on Easter morning at the end of a dreadful night, and we'll encounter a similar role of music in his Trilogie der Leidenschaft which we'll read in this context.
A single mother and her grown children. A team now. The fathers have come and gone and are barely remembered. These are her children. By contrast, Matthew (27; 56) identifies an anonymous woman as "the mother of Zebedee's children." We'll talk about it, for what it may mean. More important is the fact that this group is headed by a dominant female. Let's see if it makes a difference. Demian, as you'll remember, was the product of matriarchy, as it were, and seemed to be none the worse for it. It wasn't even worth mentioning. Fifty years later, Edgar Wibeau of Plenzdorf's The New Sorrows of Young W. (1972), a modern version of Goethe's bestselling novel Werther written 200 years earlier, and one of the most brilliant pieces of theatre post-Brecht, does find it worth mentioning. He is "sick & tired" of being paraded as living proof that "a single mother can successfully raise a male."
At the beginning of The Judgment, we find Georg Bendemann, who has just finished a letter to his friend in Russia, reliving once more the agonizing decision to write the letter in the first place. The decision had not been easy. Like many of Kafka's characters, Georg Bendemann is obsessed with the idea of analysis, with the painstaking exploration of all sides of a given issue. "What could one write to such a man without hurting him?" had been the question. "On the other hand, by writing only casual gossip or not at all one would doubtless increase the friends isolation" had been the counter-argument. What follows now is an exercise in looking at alternatives that spawn new alternatives that leaves the reader dazzled. Each conclusion is in turn explored to its possible opposite implications, which are in turn qualified, which leads to more questions followed by more partial conclusions plus qualifications thereof. The process could continue ad infinitum, in fact, has gone on for years--we are merely presented with a condensed version of it.
Tumor hypoxia and nutrient starvation are common phenomena in cancerous tissue. Cells that resist this hostile environment are selected for a more aggressive phenotype, usually accompanied by therapy resistance. The hypoxia inducible factors HIF-1a and HIF-2a play a key role in the adaptive homeostatic responses to these challenging conditions inducing a number of target genes that are involved in the regulation of a variety of cellular processes such as angiogenesis, proliferation, metabolism, self-renewal and cell death/cycle arrest. Thus, the HIF pathway encompasses opposing adaptive responses on tumor growthgrowth promoting abilities on the one hand and growth inhibiting on the other. A recent study in our lab uncovered that this switch between cell death and cell survival critically depends on HIF-2a protein levels. Since PHDs (HIF prolyl hydroxylases) are the main regulators of HIF protein abundance and hypoxia drives the malignant phenotype of tumors, we wanted to characterize HIF regulatory functions of PHDs under hypoxic conditions. Our intention was to reveal the importance of PHD contribution to the opposing functions of HIFs under hypoxia. Characterization of PHD1-4 mRNA and protein expression levels under normoxic and hypoxic conditions in glioblastoma cell lines led to the identification of PHD2 and PHD3 as hypoxia inducible PHD isoforms and highlighted their predominant function under hypoxia. Mechanistically, we demonstrated that HIF mediates the hypoxic induction of PHD2 and 3 within a negative feedback loop, promoting its own degradation during prolonged hypoxia. The functional impact of PHD2 and 3 abundance on cell viability under hypoxic conditions was analyzed by disrupting PHD2 and PHD3 function either through a siRNA mediated approach or by application of the PHD inhibitor DMOG. These experiments uncovered that PHD2 and 3 are protective under hypoxic conditions and that PHD inhibition expedites cell death. Combined HIF and PHD suppression under hypoxic conditions abrogated this increased susceptibility to cell death, clearly showing that PHD2 and 3 act in a negative feedback regulatory loop to limit the HIF response under prolonged hypoxia. With respect to possible future therapeutical applications we co-treated cells with a PHD inhibitor and pro-apoptotic agents staurosporine or TRAIL. Co-challenging tumor cells even potentiated the cell death response, indicating a more widespread protective function of PHD. Taken together PHD2 and 3 protect tumor cells from cell death induction, functioning in a negative feedback regulatory loop to constrain the HIF dependent cell death responses under hypoxia. Interestingly, however, when assessing the role of PHD2 and PHD3 in in vivo tumor growth using an intracranial tumor model, we identified an exclusive tumor suppressor function for PHD3. Loss of PHD3 function enhanced tumor growth whereas increased PHD3 expression diminished the tumor burden. The accelerated tumor growth following PHD3 loss could be attributed to a decrease in the induction of apoptosis and an increase in proliferation. Tumor cells are frequently exposed to temporary and spatial depletion of nutrients. Interestingly, PHD3 loss conferred a growth advantage under growth factor deprivation. The growth regulatory function of PHD3 was isoform specific, HIF independent and importantly, did not require the hydroxylase function of PHD3. Previous reports have uncovered a regulatory function of the PHD system in NF-kB signaling. However, our results demonstrated that NF- kB signaling remained unaffected by alteration in the PHD3 status of the cell. Additionally, the PHD3 tumor suppressor function proved to be independent of two putative PHD3 downstream effectors, ATF4 and KIF1Bb. Mechanistically, PHD3 suppression reduced EGFR internalization, enhancing the amount of EGFR expressed on the cell surface. We further showed that the impaired EGFR internalization during PHD3 loss resulted in receptor hyperactivation under stimulated and growth factor deprived conditions. Importantly, PHD3 physcially associated with the EGFR complex as evidenced by co-immunoprecpitation. Consequently, this extended EGFR activation in PHD3 deficient cells resulted in enhanced downstream activation of EGFR signaling and increased proliferation. Consistent with the interpretation that PHD3 loss is beneficial for tumor growth, we found PHD3 promoter methylation in glioblastoma cell lines, hinting at a epigenetic mechanism to finetune PHD3 expression on top of the hypoxic driven gene regulation. Finally, we demonstrated that PHD3 tumor suppressor function is not restricted to glioblastomas since PHD3 suppression in lung adenocarcinoma accelerated subcutaneous tumor growth. With these findings, we expand the knowledge of PHD3 action from its oxygen sensing role to a regulatory function in growth factor signaling. This clearly discriminates PHD3 from the other isoforms and supports the exclusive tumor suppressor function in glioblastoma. Taken together our results identify a complex role of PHD signaling in cancer and delineate HIF dependent and HIF independent functions of the PHD system. We think that the HIF dependent protective effect of PHD2 and 3 and the HIF independent PHD3 tumor suppressor function are not mutually exclusive, but might be activated according to the heterogeneous intra-tumoral conditions. However, PHD3 hydroxylase activity is dispensable for its HIFindependent tumor suppressor function in glioma. This uncouples PHD3 function from co-factor and co-substrate requirements and allows it to act over a broader physiological range, since its influence on cellular processes is not constrained by the availability of rate limiting factors. It might explain, why the enzymatic independent functions of PHD3 predominate in vivo. Thus, therapeutic modulation of the PHD system to inhibit tumor growth has to be based on these contrasting functions of the PHD system. However, their differential dependence on the hydroxylase activity may facilitate a therapeutic strategy to specifically inhibit or promote the protective versus suppressive functions of the PHD system.