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In meinem Vortrag geht es um Gastfreundschaft als kulturologisches Konzept. Mein Fokus wird sich auf die russische und sowjetische Konzeptualisierung der einer speziellen Art der Gastfreundschaft richten, bei der die für die Beziehung "Gastgeber - Gast" konstitutive "Fremdheit" durch eine Differenz im Lebensstil und nicht durch die Zugehörigkeit / Nichtzugehörigkeit zu Familie, sozialer Gruppe, Staat oder Ethnie definiert ist. Ich meine das Phänomen des "stranničestvo", d.h. einer für die russische Kultur spezifischen Form des wandernden, wohnsitzlosen Lebens, welches christlich-religiöse Ursprünge im Kontext des Altgläubigentums hatte, aber im Lauf der russischen Kulturgeschichte auch zahlreiche sozial motivierte Varianten herausgebildet hat. In der russischen nationalen Kulturgeschichtsschreibung des späteren 19. Jh.s wurde diesem Phänomen eine für den Verlauf der Nationalgeschichte, für die Herausbildung einer nationalen Identität und für die Konstituierung des russischen "Volkes" als Akteur der Nationalgeschichte zentrale Bedeutung zugeschrieben. Ich möchte der Frage nachgehen, welche Art von Gastfreundschaft im Zusammenhang dieser nationalen Konzeptualisierungen des "stranničestvo" entworfen wurde, welche Funktion dieser Gastfreundschaft als Komplement oder sogar Element dieses Verständnisses von "stranničestvo" zugeschrieben wurde und welche Bedeutung dies im Kontext der diskursiven Konzeptualisierung Russlands als Imperium hatte.
Background: The alpha7 nicotinic acetylcholine receptor (Chrna7) plays an essential anti-inflammatory role in immune homeostasis and was recently found on mast cells (MC). Psychosocial stress can trigger MC hyperactivation and increases pro-inflammatory cytokines in target tissues such as the skin. If the cholinergic system (CS) and Chrna7 ligands play a role in these cascades is largely unknown. Objective: To elucidate the role of the CS in the response to psychosocial stress using a mouse-model for stress-triggered cutaneous inflammatory circuits. Methods: Key CS markers (ACh, Ch, SLURP-1, SLURP-2, Lynx1, Chrm3, Chrna7, Chrna9, ChAT, VAChT, Oct3, AChE, and BChE) in skin and its MC (sMC), MC activation, immune parameters (TNFα, IL1β, IL10, TGFβ, HIF1α, and STAT3) and oxidative stress were analyzed in skin from 24 h noise-stressed mice and in cultured MC (cMC) from C57BL/6 or Chrna7-Knockout mice. Results: First, Chrna7 and SLURP-1 mRNA were exclusively upregulated in stressed skin. Second, histomorphometry located Chrna7 and SLURP-1 in nerves and sMC and demonstrated upregulated contacts and increased Chrna7+ sMC in stressed skin, while 5 ng/mL SLURP-1 degranulated cMC. Third, IL1β+ sMC were high in stressed skin, and while SLURP-1 alone had no significant effect on cMC cytokines, it upregulated IL1β in cMC from Chrna7-KO and in IL1β-treated wildtype cMC. In addition, HIF1α+ sMC were high in stressed skin and Chrna7-agonist AR-R 17779 induced ROS in cMC while SLURP-1 upregulated TNFα and IL1β in cMC when HIF1α was blocked. Conclusions: These data infer that the CS plays a role in the regulation of stress-sensitive inflammatory responses but may have a surprising pro-inflammatory effect in healthy skin, driving IL1β expression if SLURP-1 is involved.
Auf dem Workshop »Praxis trifft Forschung: Learning in a Digital World« hielt Prof. Susanne Weissman, Professorin für Psychologie an der Technischen Hochschule Nürnberg und dort als Vizepräsidentin verantwortlich u. a. für die Bereiche Hochschulentwicklung und Digitalisierungsstrategie, die Keynote zum Thema »Learning in a Digital World in Higher Education 2030«.
Emotional instability, difficulties in social adjustment, and disinhibited behavior are the most common symptoms of the psychiatric comorbidities in juvenile myoclonic epilepsy (JME). This psychopathology has been associated with dysfunctions of mesial-frontal brain circuits. The present work is a first direct test of this link and adapted a paradigm for probing frontal circuits during empathy for pain. Neural and psychophysiological parameters of pain empathy were assessed by combining functional magnetic resonance imaging (fMRI) with simultaneous pupillometry in 15 JME patients and 15 matched healthy controls. In JME patients, we observed reduced neural activation of the anterior cingulate cortex (ACC), the anterior insula (AI), and the ventrolateral prefrontal cortex (VLPFC). This modulation was paralleled by reduced pupil dilation during empathy for pain in patients. At the same time, pupil dilation was positively related to neural activity of the ACC, AI, and VLPFC. In JME patients, the ACC additionally showed reduced functional connectivity with the primary and secondary somatosensory cortex, areas fundamentally implicated in processing the somatic cause of another's pain. Our results provide first evidence that alterations of mesial-frontal circuits directly affect psychosocial functioning in JME patients and draw a link of pupil dynamics with brain activity during emotional processing. The findings of reduced pain empathy related activation of the ACC and AI and aberrant functional integration of the ACC with somatosensory cortex areas provide further evidence for this network's role in social behavior and helps explaining the JME psychopathology and patients' difficulties in social adjustment.
Treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute leukemia (Ph+ ALL) has been revolutionized with the advent of tyrosine kinase inhibitors (TKIs). Most patients with CML achieve long-term survival similar to individuals without CML due to treatment with TKIs not only in frontline but also in further lines of therapy. The third-generation TKI ponatinib has demonstrated efficacy in patients with refractory CML and Ph+ ALL. Ponatinib is currently the most potent TKI in this setting demonstrating activity against T315I mutant clones. However, ponatinib’s safety data revealed a dose-dependent, increased risk of serious cardiovascular (CV) events. Guidance is needed to evaluate the benefit–risk profile of TKIs, such as ponatinib, and safety measures to prevent treatment-associated CV events. An expert panel of German hematologists and cardiologists summarize current evidence regarding ponatinib’s efficacy and CV safety profile. We propose CV management strategies for patients who are candidates for ponatinib.
Systematic protein localization and protein-protein interaction studies to characterize specific protein functions are most effectively performed using tag-based assays. Ideally, protein tags are introduced into a gene of interest by homologous recombination to ensure expression from endogenous control elements. However, inefficient homologous recombination makes this approach difficult in mammalian cells. Although gene targeting efficiency by homologous recombination increased dramatically with the development of designer endonuclease systems such as CRISPR/Cas9 capable of inducing DNA double-strand breaks with unprecedented accuracy, the strategies still require synthesis or cloning of homology templates for every single gene. Recent developments have shown that endogenous protein tagging can be achieved efficiently in a homology independent manner. Hence, combinations between CRISPR/Cas9 and generic tag-donor plasmids have been used successfully for targeted gene modifications in mammalian cells. Here, we developed a tool kit comprising a CRISPR/Cas9 expression vector with several EGFP encoding plasmids that should enable tagging of almost every protein expressed in mammalian cells. By performing protein-protein interaction and subcellular localization studies of mTORC1 signal transduction pathway-related proteins expressed in HEK293T cells, we show that tagged proteins faithfully reflect the behavior of their native counterparts under physiological conditions.
Simple Summary: In patients with myeloproliferative neoplasms (MPN) and in patients with kidney dysfunction, a higher rate of thrombosis has been reported compared with the general population. Furthermore, MPN patients are more prone to develop kidney dysfunction. In our study, we assessed the importance of specific risk factors for kidney dysfunction and thrombosis in MPN patients. We found that the rate of thrombosis is correlated with the degree of kidney dysfunction, especially in myelofibrosis. Significant associations for kidney dysfunction included arterial hypertension, MPN treatment, and increased inflammation, and those for thrombosis comprised arterial hypertension, non-excessive platelet counts, and antithrombotic therapy. The identified risk factor associations varied between MPN subtypes. Our data suggest that kidney dysfunction in MPN patients is associated with an increased risk of thrombosis, mandating closer monitoring, and, possibly, early thromboprophylaxis.
Abstract: Inflammation-induced thrombosis represents a severe complication in patients with myeloproliferative neoplasms (MPN) and in those with kidney dysfunction. Overlapping disease-specific attributes suggest common mechanisms involved in MPN pathogenesis, kidney dysfunction, and thrombosis. Data from 1420 patients with essential thrombocythemia (ET, 33.7%), polycythemia vera (PV, 38.5%), and myelofibrosis (MF, 27.9%) were extracted from the bioregistry of the German Study Group for MPN. The total cohort was subdivided according to the calculated estimated glomerular filtration rate (eGFR, (mL/min/1.73 m2)) into eGFR1 (≥90, 21%), eGFR2 (60–89, 56%), and eGFR3 (<60, 22%). A total of 29% of the patients had a history of thrombosis. A higher rate of thrombosis and longer MPN duration was observed in eGFR3 than in eGFR2 and eGFR1. Kidney dysfunction occurred earlier in ET than in PV or MF. Multiple logistic regression analysis identified arterial hypertension, MPN treatment, increased uric acid, and lactate dehydrogenase levels as risk factors for kidney dysfunction in MPN patients. Risk factors for thrombosis included arterial hypertension, non-excessive platelet counts, and antithrombotic therapy. The risk factors for kidney dysfunction and thrombosis varied between MPN subtypes. Physicians should be aware of the increased risk for kidney disease in MPN patients, which warrants closer monitoring and, possibly, early thromboprophylaxis.
Autophagy is the highly conserved catabolic process, which enables the survival of a cell under unfavorable environmental conditions. In a constantly changing environment, cells must be capable of dynamically oscillating between anabolism and catabolism in order to maintain cellular homeostasis. In this context, the activity of the mechanistic Target Of Rapamycin Complex 1 (mTORC1) is of major importance. As a central signaling node, it directly controls the process of macroautophagy and thus cellular metabolism. Thereby, the control of mTORC1 is equally crucial as the regulation of cellular homeostasis itself, whereby particular importance is attributed to amino acid sensory proteins. In this review, we describe the recent findings of macroautophagy and mTORC1 regulation by upstream amino acid stimuli in different subcellular localizations. We highlight in detail which proteins of the sensor complexes play a specific role in this regulation and point out additional non-canonical functions, e.g. in the regulation of macroautophagy, which have received little attention so far.
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell diseases leading to an insufficient formation of functional blood cells. Disease-immanent factors as insufficient erythropoiesis and treatment-related factors as recurrent treatment with red blood cell transfusions frequently lead to systemic iron overload in MDS and AML patients. In addition, alterations of function and expression of proteins associated with iron metabolism might are increasingly recognized to be pathogenetic factors and potential vulnerabilities of these diseases. Iron is known to be involved in multiple intracellular and extracellular processes. It is essential for cell metabolism as well as for cell proliferation and closely linked to the formation of reactive oxygen species. Therefore, iron can influence the course of clonal myeloid disorders, the leukemic environment and the occurrence as well as the defense of infections. Imbalances of iron homeostasis may induce cell death of normal but also of malignant cells. New potential treatment strategies utilizing the importance of the iron homeostasis include iron chelation, modulation of proteins involved in iron metabolism, induction of leukemic cell death via ferroptosis and exploitation of iron proteins for the delivery of antileukemic drugs.
Here, we provide a summary of some of the latest findings about the function, the prognostic impact and potential treatment strategies of iron in patients with MDS and AML.
Despite a high clinical need for the treatment of colorectal carcinoma (CRC) as the second leading cause of cancer-related deaths, targeted therapies are still limited. The multifunctional enzyme Transglutaminase 2 (TGM2), which harbors transamidation and GTPase activity, has been implicated in the development and progression of different types of human cancers. However, the mechanism and role of TGM2 in colorectal cancer are poorly understood. Here, we present TGM2 as a promising drug target.
In primary patient material of CRC patients, we detected an increased expression and enzymatic activity of TGM2 in colon cancer tissue in comparison to matched normal colon mucosa cells. The genetic ablation of TGM2 in CRC cell lines using shRNAs or CRISPR/Cas9 inhibited cell expansion and tumorsphere formation. In vivo, tumor initiation and growth were reduced upon genetic knockdown of TGM2 in xenotransplantations. TGM2 ablation led to the induction of Caspase-3-driven apoptosis in CRC cells. Functional rescue experiments with TGM2 variants revealed that the transamidation activity is critical for the pro-survival function of TGM2. Transcriptomic and protein–protein interaction analyses applying various methods including super-resolution and time-lapse microscopy showed that TGM2 directly binds to the tumor suppressor p53, leading to its inactivation and escape of apoptosis induction.
We demonstrate here that TGM2 is an essential survival factor in CRC, highlighting the therapeutic potential of TGM2 inhibitors in CRC patients with high TGM2 expression. The inactivation of p53 by TGM2 binding indicates a general anti-apoptotic function, which may be relevant in cancers beyond CRC.
Eines der zentralen Konzepte, auf das sich die Sowjetunion in ihrem Selbstverständnis als neue Zivilisation berief, war das Konzept der "Völkerfreundschaft" (družba narodov). Über den naheliegenden Zusammenhang mit der sowjetischen Nationalitätenpolitik (insbesondere stalinscher Prägung) hinaus verweist es auf die propagierte sowjetische Ethik – die Gleichheit aller Sowjetbürger nach der Abschaffung der Klassengesellschaft. Nach dem Zerfall der Sowjetunion wird dieses Modell des gemeinschaftlichen Zusammenlebens bezogen auf den Raum der Sowjetkultur vor allem als machtpolitische Strategie bzw. in seiner mythenhaften Dimension betrachtet. Anliegen des Workshops ist es, ausgehend vom sowjetischen Freundschaftsbegriff unterschiedliche Facetten und Implikationen der Freundschaft im interkulturellen Vergleich zu diskutieren. So haben Länder und Regionen im Süden und Osten Europas (wie Georgien) beispielsweise die Gastfreundschaft als kulturelle Praktik zu ihrem "Markenzeichen" erklärt. Die Art und Weise, wie die Gastfreundschaft in Literatur und Kunst verhandelt bzw. repräsentiert wird, ist ein Indiz für die nachhaltige Bedeutung des Paradigmas, das bis in aktuelle Konflikte und juristische Diskurse (wie etwa die Frage nach dem Gastrecht oder das ethnisch begründete Restitutionsgesetz im heutigen Abchasien) hineinreicht. Gefragt wird u.a. nach den politischen Implikationen des Freundschaftsbegriffs, nach der Übertragung des interpersonellen Konzepts Freundschaft auf Völker im (sowjetischen) Konzept der Völkerfreundschaft, nach Politisierungsstrategien, nach unterschiedlichen Praktiken der (Gast-)Freundschaft (u.a. im Kontext der Derridaschen Ethik oder der Positionen von C. Schmitt, P. Klossowski oder M. Mauss) oder etwa nach der Bildung formeller und informeller Netzwerke in unterschiedlichen kulturellen und historischen Kontexten. Schwerpunktmäßig im 20. und 21. Jahrhundert angesiedelt, wird im Rahmen des Workshops auch die Genese der (sowjetischen) Konzepte und Praktiken der Freundschaft aus der Antike bzw. der Vormoderne thematisiert.
Polo-like kinase 1 regulates the stability of the mitotic centromere-associated kinesin in mitosis
(2014)
Proper bi-orientation of chromosomes is critical for the accurate segregation of chromosomes in mitosis. A key regulator of this process is MCAK, the mitotic centromere-associated kinesin. During mitosis the activity and localization of MCAK are regulated by mitotic key kinases including Plk1 and Aurora B. We show here that S621 in the MCAK’s C-terminal domain is the major phosphorylation site for Plk1. This phosphorylation regulates MCAK’s stability and facilitates its recognition by the ubiquitin/proteasome dependent APC/CCdc20 pathway leading to its D-box dependent degradation in mitosis. While phosphorylation of S621 does not directly affect its microtubule depolymerising activity, loss of Plk1 phosphorylation on S621 indirectly enhances its depolymerization activity in vivo by stabilizing MCAK, leading to an increased level of protein. Interfering with phosphorylation at S621 causes spindle formation defects and chromosome misalignments. Therefore, this study suggests a new mechanism by which Plk1 regulates MCAK: by regulating its degradation and hence controlling its turnover in mitosis.
RITA, the RBP‐J interacting and tubulin‐associated protein, has been reported to be related to tumor development, but the underlying mechanisms are not understood. Since RITA interacts with tubulin and coats microtubules of the cytoskeleton, we hypothesized that it is involved in cell motility. We show here that depletion of RITA reduces cell migration and invasion of diverse cancer cell lines and mouse embryonic fibroblasts. Cells depleted of RITA display stable focal adhesions (FA) with elevated active integrin, phosphorylated focal adhesion kinase, and paxillin. This is accompanied by enlarged size and disturbed turnover of FA. These cells also demonstrate increased polymerized tubulin. Interestingly, RITA is precipitated with the lipoma‐preferred partner (LPP), which is critical in actin cytoskeleton remodeling and cell migration. Suppression of RITA results in reduced LPP and α‐actinin at FA leading to compromised focal adhesion turnover and actin dynamics. This study identifies RITA as a novel crucial player in cell migration and invasion by affecting the turnover of FA through its interference with the dynamics of actin filaments and microtubules. Its deregulation may contribute to malignant progression.
Adipose-derived mesenchymal stem cells (ASCs) are considered to be a useful tool for regenerative medicine, owing to their capabilities in differentiation, self-renewal, and immunomodulation. These cells have become a focus in the clinical setting due to their abundance and easy isolation. However, ASCs from different depots are not well characterized. Here, we analyzed the functional similarities and differences of subcutaneous and visceral ASCs. Subcutaneous ASCs have an extraordinarily directed mode of motility and a highly dynamic focal adhesion turnover, even though they share similar surface markers, whereas visceral ASCs move in an undirected random pattern with more stable focal adhesions. Visceral ASCs have a higher potential to differentiate into adipogenic and osteogenic cells when compared to subcutaneous ASCs. In line with these observations, visceral ASCs demonstrate a more active sonic hedgehog pathway that is linked to a high expression of cilia/differentiation related genes. Moreover, visceral ASCs secrete higher levels of inflammatory cytokines interleukin-6, interleukin-8, and tumor necrosis factor α relative to subcutaneous ASCs. These findings highlight, that both ASC subpopulations share multiple cellular features, but significantly differ in their functions. The functional diversity of ASCs depends on their origin, cellular context and surrounding microenvironment within adipose tissues. The data provide important insight into the biology of ASCs, which might be useful in choosing the adequate ASC subpopulation for regenerative therapies.
Function of p21 (Cip1/Waf1/CDKN1A) in migration and invasion of cancer and trophoblastic cells
(2019)
Tumor progression and pregnancy have several features in common. Tumor cells and placental trophoblasts share many signaling pathways involved in migration and invasion. Preeclampsia, associated with impaired differentiation and migration of trophoblastic cells, is an unpredictable and unpreventable disease leading to maternal and perinatal mortality and morbidity. Like in tumor cells, most pathways, in which p21 is involved, are deregulated in trophoblasts of preeclamptic placentas. The aim of the present study was to enlighten p21’s role in tumorigenic choriocarcinoma and trophoblastic cell lines. We show that knockdown of p21 induces defects in chromosome movement during mitosis, though hardly affecting proliferation and cell cycle distribution. Moreover, suppression of p21 compromises the migration and invasion capability of various trophoblastic and cancer cell lines mediated by, at least partially, a reduction of the extracellular signal-regulated kinase 3, identified using transcriptome-wide profiling, real-time PCR, and Western blot. Further analyses show that downregulation of p21 is associated with reduced matrix metalloproteinase 2 and tissue inhibitor of metalloproteinases 2. This work evinces that p21 is involved in chromosome movement during mitosis as well as in the motility and invasion capacity of trophoblastic and cancer cell lines.
Adipose-derived mesenchymal stem cells (ASCs) have crucial functions, but their roles in obesity are not well defined. We show here that ASCs from obese individuals have defective primary cilia, which are shortened and unable to properly respond to stimuli. Impaired cilia compromise ASC functionalities. Exposure to obesity-related hypoxia and cytokines shortens cilia of lean ASCs. Like obese ASCs, lean ASCs treated with interleukin-6 are deficient in the Hedgehog pathway, and their differentiation capability is associated with increased ciliary disassembly genes like AURKA. Interestingly, inhibition of Aurora A or its downstream target the histone deacetylase 6 rescues the cilium length and function of obese ASCs. This work highlights a mechanism whereby defective cilia render ASCs dysfunctional, resulting in diseased adipose tissue. Impaired cilia in ASCs may be a key event in the pathogenesis of obesity, and its correction might provide an alternative strategy for combating obesity and its associated diseases.