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"Judith Müller"
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Futurism & Europe : the aesthetics of a new world
\"Futurism & Europe: The Aesthetics of a New World examines for the first time the many interconnections between Futurism and other European avant-gardes as varied as the Bauhaus in Germany, De Stijl in the Netherlands, Omega Workshops in Britain, Constructivism in Russia and Esprit Nouveau in France. Featuring over twenty essays by an international team of experts, this expansive book covers a range of topics and mediums including painting, sculpture, architecture, interior and stage designs, graphic work, fashion, theatre and cinema, as well as a diverse variety of functional objects from furniture and carpets to ceramics and toys. Spanning various avant-gardes from 1912 to 1939, artists featured include Italian futurists such as Giacomo Balla, Umberto Boccioni and Fortunato Depero, alongside other European artists including Sonia Delaunay, Le Corbusier, Fernand Léger, Walter Gropius, Alexander Rodchenko, Fritz Lang, László Moholy-Nagy, Wassily Kandinsky, Hans Arp, Duncan Grant, Natalia Goncharova and Vladimir Tatlin. Broad in scope, this pioneering book examines the intersections between Futurism and other European avant-garde movements in their shared quest for a new aesthetic, triggering a lively exchange of new ideas, friction and rivalry.\"-- Page 4 of cover.
Book
Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression
Posttranslational modifications of histones, such as methylation, regulate chromatin structure and gene expression
1
. Recently, lysine-specific demethylase 1 (LSD1)
2
, the first histone demethylase, was identified. LSD1 interacts with the androgen receptor and promotes androgen-dependent transcription of target genes by ligand-induced demethylation of mono- and dimethylated histone H3 at Lys 9 (H3K9)
3
only. Here, we identify the Jumonji C (JMJC)
4
domain-containing protein JMJD2C
5
,
6
as the first histone tridemethylase regulating androgen receptor function. JMJD2C interacts with androgen receptor
in vitro
and
in vivo
. Assembly of ligand-bound androgen receptor and JMJD2C on androgen receptor-target genes results in demethylation of trimethyl H3K9 and in stimulation of androgen receptor-dependent transcription. Conversely, knockdown of JMJD2C inhibits androgen-induced removal of trimethyl H3K9, transcriptional activation and tumour cell proliferation. Importantly, JMJD2C colocalizes with androgen receptor and LSD1 in normal prostate and in prostate carcinomas. JMJD2C and LSD1 interact and both demethylases cooperatively stimulate androgen receptor-dependent gene transcription. In addition, androgen receptor, JMJD2C and LSD1 assemble on chromatin to remove methyl groups from mono, di and trimethylated H3K9. Thus, our data suggest that specific gene regulation requires the assembly and coordinate action of demethylases with distinct substrate specificities.
Journal Article
Cell-free tumor DNA, CA125 and HE4 for the objective assessment of tumor burden in patients with advanced high-grade serous ovarian cancer
The present prospective study aimed at determining the impact of cell-free tumor DNA (ct-DNA), CA125 and HE4 from blood and ascites for quantification of tumor burden in patients with advanced high-grade serous epithelial ovarian cancer (EOC).
Genomic DNA was extracted from tumor FFPE and ct-DNA from plasma before surgery and on subsequent post-surgical days. Extracted DNA was subjected to hybrid-capture based next generation sequencing. Blood and ascites were sampled before surgery and on subsequent post-surgical days. 20 patients (10 undergoing complete resection (TR0), 10 undergoing incomplete resection (TR>0)) were included.
The minor allele frequency (MAF) of TP53 mutations in ct-DNA of all patients with TR0 decreased significantly, compared to only one patient with TR>0. It was not possible to distinguish between patients with TR0 and patients with TR>0, using CA125 and HE4 from blood and ascites.
Based upon the present findings, ct-DNA assessment in patients with high-grade serous EOC might help to better determine disease burden compared to standard tumor markers. Further studies should prospectively evaluate whether this enhancement of accuracy can help to optimize management of patients with EOC.
Journal Article
Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma
Increased expression of the Microphthalmia-associated transcription factor (MITF) contributes to melanoma progression and resistance to BRAF pathway inhibition. Here we show that the lack of MITF is associated with more severe resistance to a range of inhibitors, while its presence is required for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlate with the expression of several activated receptor tyrosine kinases, most frequently AXL. The MITF-low/AXL-high/drug-resistance phenotype is common among mutant BRAF and NRAS melanoma cell lines. The dichotomous behaviour of MITF in drug response is corroborated in vemurafenib-resistant biopsies, including MITF-high and -low clones in a relapsed patient. Furthermore, drug cocktails containing AXL inhibitor enhance melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas.
Increased expression of MITF transcription factor is thought to promote melanoma progression and kinase inhibitor resistance. Here Muller
et al
. show that MITF loss is also common in melanomas and confers kinase inhibitor resistance due to upregulation of AXL and other receptor tyrosine kinases.
Journal Article
Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity and prostate cancer growth
Prostate cancer (PCa) growth depends on de novo lipogenesis controlled by the mitochondrial pyruvate dehydrogenase complex (PDC). In this study, we identify lysine methyltransferase (KMT)9 as a regulator of PDC activity. KMT9 is localized in mitochondria of PCa cells, but not in mitochondria of other tumor cell types. Mitochondrial KMT9 regulates PDC activity by monomethylation of its subunit dihydrolipoamide transacetylase (DLAT) at lysine 596. Depletion of KMT9 compromises PDC activity, de novo lipogenesis, and PCa cell proliferation, both in vitro and in a PCa mouse model. Finally, in human patients, levels of mitochondrial KMT9 and DLAT K596me1 correlate with Gleason grade. Together, we present a mechanism of PDC regulation and an example of a histone methyltransferase with nuclear and mitochondrial functions. The dependency of PCa cells on mitochondrial KMT9 allows to develop therapeutic strategies to selectively fight PCa.
Prostate cancer growth depends on de novo lipogenesis controlled by the mitochondrial pyruvate dehydrogenase complex (PDC). Here the authors find that a histone methyltransferase KMT9 is localized in the mitochondria of prostate cancer cells to regulate PDC activity by methylating its subunit DLAT.
Journal Article
Lysine-specific demethylase 1 regulates hematopoietic stem cell expansion and myeloid cell differentiation
The lysine-specific demethylase 1 (LSD1) regulates hematopoietic stem cell differentiation and has been identified as a therapeutic target in hematological disorders. LSD1 demethylates mono and dimethylated histones 3 at lysine 4 and 9. In addition, it acts as a scaffold for the formation of chromatin-modifying complexes that regulates the transcription of myeloid-lineage-specific genes in complex with GFI1, a transcriptional repressor. While both enzymatic and non-enzymatic functions of LSD1 have been well defined, the relative importance of these two functions in hematopoiesis remains incompletely understood. Here, we investigated the contribution of enzymatic and non-enzymatic functions of LSD1 to myelopoiesis. We show that myeloid differentiation is independent of the enzymatic functions of LSD1 but requires the non-enzymatic, scaffolding function, which directs GFI1 binding to target sequences. In the absence of the LSD1 protein, GFI1 DNA binding is diminished, and myeloid cell differentiation arrests at an immature, myelomonocytic-like cell stage, which overexpresses
Prtn3
. We provide functional data implicating
Prtn3
as an effector of the stem cell expansion and myeloid maturation block caused by the loss of LSD1.
Journal Article
Deregulated MYC expression induces dependence upon AMPK-related kinase 5
Oncogenic levels of MYC, the deregulation of which is implicated in many human tumours, are shown to establish a dependence on ARK5, offering insights into potential therapeutic strategies.
Alternative target in MYC-related cancers
Deregulated expression of the
MYC
oncogene is characteristic of many cancers. In an RNA interference screen designed to uncover genes that are crucial for cell survival specifically in MYC-driven tumour cells, Martin Eilers and colleagues have identified the kinase ARK5 as an important factor in MYC-mediated transformation. This is attributable to metabolic stress in MYC-expressing cells in which ARK5 is shown to be crucial for metabolic homeostasis and hence cell survival. ARK5 is also crucial in a MYC-driven mouse model of liver cancer. As a transcriptional regulator, MYC is difficult to target therapeutically, so ARK5 might prove to be an alternative target.
Deregulated expression of the MYC oncoprotein contributes to the genesis of many human tumours, yet strategies to exploit this for a rational tumour therapy are scarce. MYC promotes cell growth and proliferation, and alters cellular metabolism to enhance the provision of precursors for phospholipids and cellular macromolecules
1
,
2
. Here we show in human and murine cell lines that oncogenic levels of MYC establish a dependence on AMPK-related kinase 5 (ARK5; also known as NUAK1) for maintaining metabolic homeostasis and for cell survival. ARK5 is an upstream regulator of AMPK and limits protein synthesis via inhibition of the mammalian target of rapamycin 1 (mTORC1) signalling pathway. ARK5 also maintains expression of mitochondrial respiratory chain complexes and respiratory capacity, which is required for efficient glutamine metabolism. Inhibition of ARK5 leads to a collapse of cellular ATP levels in cells expressing deregulated MYC, inducing multiple pro-apoptotic responses as a secondary consequence. Depletion of ARK5 prolongs survival in MYC-driven mouse models of hepatocellular carcinoma, demonstrating that targeting cellular energy homeostasis is a valid therapeutic strategy to eliminate tumour cells that express deregulated MYC.
Journal Article
Detection of viral antibodies in camel sera using magnetic particle spectroscopy
Pandemics like SARS-Cov-2 very frequently have their origin in different animals and in particular herds of camels could be a source of zoonotic diseases. This study took advantage on a highly sensitive and adaptable method for the fast and reliable detection of viral antibodies in camels using low-cost equipment. Magnetic nanoparticles (MNP) have high variability in their functionalization with different peptides and proteins. We confirm that 3-aminopropyl triethoxysilane (APTES)-coated MNP could be functionalized with viral proteins. The protein loading could be confirmed by simple loading controls using FACS-analysis (p < 0.05). Complementary combination of antigen and antibody yields in a significant signal increase could be proven by both FACS and COMPASS. However, COMPASS needs only a few seconds for the measurement. In COMPASS, the phase φn on selected critical point of the fifth higher harmonic (n = 5th). Here, positive sera display highly significant signal increase over the control or negative sera. Furthermore, a clear distinction could be made in antibody detection as an immune response to closely related viruses (SARS-CoV2 and MERS). Using modified MNPs along with COMPASS offers a fast and reliable method that is less cost intensive than current technologies and offers the possibility to be quickly adapted in case of new occurring viral infections.Key points• COMPASS (critical offset magnetic particle spectroscopy) allows the fast detection of antibodies.• Magnetic nanoparticles can be adapted by exchange of the linked bait molecule.• Antibodies could be detected in camel sera without washing steps within seconds.
Journal Article
CYCLOPS, a mediator of symbiotic intracellular accommodation
The initiation of intracellular infection of legume roots by symbiotic rhizobia bacteria and arbuscular mycorrhiza (AM) fungi is preceded by the induction of calcium signatures in and around the nucleus of root epidermal cells. Although a calcium and calmodulin-dependent kinase (CCaMK) is a key mediator of symbiotic root responses, the decoding of the calcium signal and the molecular events downstream are only poorly understood. Here, we characterize Lotus japonicus cyclops mutants on which microbial infection was severely inhibited. In contrast, nodule organogenesis was initiated in response to rhizobia, but arrested prematurely. This arrest was overcome when a deregulated CCaMK mutant version was introduced into cyclops mutants, conferring the development of full-sized, spontaneous nodules. Because cyclops mutants block symbiotic infection but are competent for nodule development, they reveal a bifurcation of signal transduction downstream of CCaMK. We identified CYCLOPS by positional cloning. CYCLOPS carries a functional nuclear localization signal and a predicted coiled-coil domain. We observed colocalization and physical interaction between CCaMK and CYCLOPS in plant and yeast cell nuclei in the absence of symbiotic stimulation. Importantly, CYCLOPS is a phosphorylation substrate of CCaMK in vitro. Cyclops mutants of rice were impaired in AM, and rice CYCLOPS could restore symbiosis in Lotus cyclops mutants, indicating a functional conservation across angiosperms. Our results suggest that CYCLOPS forms an ancient, preassembled signal transduction complex with CCaMK that is specifically required for infection, whereas organogenesis likely requires additional yet-to-be identified CCaMK interactors or substrates.
Journal Article
central role of Arabidopsis thaliana ovate family proteins in networking and subcellular localization of 3-aa loop extension homeodomain proteins
The organization of living cells is based on networks of interacting molecules. Systematic analysis of protein interactions of 3-aa loop extension (TALE) homeodomain proteins, fundamental regulators of plant meristem function and leaf development, revealed a highly connected, complex network. The network includes nine members of Arabidopsis thaliana ovate family proteins (AtOFPs), a plant-specific protein family, indicating a close functional connection to TALE homeodomain proteins. Evidence is provided that AtOFP1 is an essential pleiotropic developmental regulator. AtOFP1 and AtOFP5 are shown to associate with the cytoskeleton and to regulate subcellular localization of TALE homeodomain proteins, suggesting a previously unrecognized control mechanism in plant development.
Journal Article