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Pain and pain chronification are incompletely understood and unresolved medical problems that continue to have a high prevalence. It has been accepted that pain is a complex phenomenon. Contemporary methods of computational science can use complex clinical and experimental data to better understand the complexity of pain. Among data science techniques, machine learning is referred to as a set of methods that can automatically detect patterns in data and then use the uncovered patterns to predict or classify future data, to observe structures such as subgroups in the data, or to extract information from the data suitable to derive new knowledge. Together with (bio)statistics, artificial intelligence and machine learning aim at learning from data. ...
Background: To prevent persistent post-surgery pain, early identification of patients at high risk is a clinical need. Supervised machine-learning techniques were used to test how accurately the patients’ performance in a preoperatively performed tonic cold pain test could predict persistent post-surgery pain.
Methods: We analysed 763 patients from a cohort of 900 women who were treated for breast cancer, of whom 61 patients had developed signs of persistent pain during three yr of follow-up. Preoperatively, all patients underwent a cold pain test (immersion of the hand into a water bath at 2–4 °C). The patients rated the pain intensity using a numerical ratings scale (NRS) from 0 to 10. Supervised machine-learning techniques were used to construct a classifier that could predict patients at risk of persistent pain.
Results: Whether or not a patient rated the pain intensity at NRS=10 within less than 45 s during the cold water immersion test provided a negative predictive value of 94.4% to assign a patient to the "persistent pain" group. If NRS=10 was never reached during the cold test, the predictive value for not developing persistent pain was almost 97%. However, a low negative predictive value of 10% implied a high false positive rate.
Conclusions: Results provide a robust exclusion of persistent pain in women with an accuracy of 94.4%. Moreover, results provide further support for the hypothesis that the endogenous pain inhibitory system may play an important role in the process of pain becoming persistent.
Hypoxia-induced miR-210 displays a pro-survival, cytoprotective and pro-angiogenic role in several in vitro systems. In vivo, we previously found that miR-210 inhibition increases ischemic damage. Here we describe the generation of a versatile transgenic mouse model allowing the evaluation of miR-210 therapeutic potential in ischemic cardiovascular diseases. We generated a Tet-On miR-210 transgenic mouse strain (TG-210) by targeted transgenesis in the ROSA26 locus. To functionally validate miR-210 transgenic mice, hindlimb ischemia was induced by femoral artery dissection. Blood perfusion was evaluated by power Doppler while tissue damage and inflammation were assessed by histological evaluation. We found that miR-210 levels were rapidly increased in TG-210 mice upon doxycycline administration. miR-210 overexpression was maintained over time and remained within physiological levels in multiple tissues. When hindlimb ischemia was induced, miR-210 overexpression protected from both muscular and vascular ischemic damage, decreased inflammatory cells density and allowed to maintain a better calf perfusion. In conclusion, we generated and functionally validated a miR-210 transgenic mouse model. Albeit validated in the context of a specific cardiovascular ischemic disease, miR-210 transgenic mice may also represent a useful model to assess the function of miR-210 in other physio-pathological conditions.
Different tissue engineering techniques are used to support rapid vascularisation. A novel technique is the use of platelet-rich fibrin (PRF), an autologous source of growth factors. This study was the first to investigate the influence of PRF matrices, isolated following different centrifugation protocols, on human dermal vascular endothelial cells (ECs) in mono-culture and co-culture with human primary fibroblasts (HFs) as an in vitro model for tissue regeneration. Focus was placed on vascular structure formation and growth factor release. HFs and ECs were cultivated with PRF prepared using a high (710 ×g) or low (44 ×g) relative centrifugation force (RCF) over 14 d. Immunofluorescence staining and immunohistochemistry were used to evaluate the microvascular formation. Cell culture supernatants were collected for evaluation of growth factor release. The results showed a PRF-mediated effect on the induction of angiogenesis in ECs. Microvessel-like structure formation was promoted when ECs were combined with low-RCF PRF as compared to high-RCF PRF or control group. The percentage of vascular lumen area was significantly higher in low-RCF PRF, especially at day 7, which coincided with statistically significantly higher growth factor [vascular endothelial factor (VEGF), transforming growth factor β1 (TGF-β1) and platelet derived growth factor (PDGF)] concentration measured in low-RCF PRF as compared to high-RCF PRF or control group. In conclusion, reducing the RCF according to the low-speed centrifugation concept (LSCC) resulted in increased growth factor release and angiogenic structure formation with EC mono-culture, suggesting that PRF may be a highly beneficial therapeutic tool for tissue engineering applications.
Background: Neonatal manifestation of life-threatening hyperammonemic encephalopathy in urea cycle disorders (UCD) is often misdiagnosed as neonatal sepsis, resulting in significantly delayed start of specific treatment and poor outcome. The major aim of this study was to identify specific initial symptoms or signs to clinically distinguish hyperammonemic encephalopathy in neonates from neonatal sepsis in order to identify affected individuals with UCD and to start metabolic therapy without delay. Furthermore, we evaluated the impact of diagnostic delay, peak plasma ammonium (NH4+) concentration, mode of emergency treatment and transfer to a tertiary referral center on the outcome.
Methods: Detailed information of 17 patients (born between 1994 and 2012) with confirmed diagnosis of UCD and neonatal hyperammonemic encephalopathy were collected from the original medical records.
Results: The initially suspected diagnosis was neonatal sepsis in all patients, but was not confirmed in any of them. Unlike neonatal sepsis and not previously reported blood pressure increased above the 95th percentile in 13 (81%) of UCD patients before emergency treatment was started. Respiratory alkalosis was found in 11 (65%) of UCD patients, and in 14 (81%) plasma NH4+concentrations further increased despite initiation of metabolic therapy.
Conclusion: Detection of high blood pressure could be a valuable parameter for distinguishing neonatal sepsis from neonatal manifestation of UCD. Since high blood pressure is not typical for neonatal sepsis, other reasons such as encephalopathy and especially hyperammonemic encephalopathy (caused by e.g. UCD) should be searched for immediately. However, our result that the majority of newborns with UCD initially present with high blood pressure has to be evaluated in larger patient cohorts.
Background: The number of Mesenchymal Stem/Stromal Cells (MSCs) in the human bone marrow (BM) is small compared to other cell types. BM aspirate concentration (BMAC) may be used to increase numbers of MSCs, but the composition of MSC subpopulations and growth factors after processing are unknown. The purpose of this study was to assess the enrichment of stem/progenitor cells and growth factors in BM aspirate by two different commercial concentration devices versus standard BM aspiration.
Methods: 120 mL of BM was aspirated from the iliac crest of 10 male donors. Each sample was processed simultaneously by either Emcyte GenesisCS® (Emcyte) or Harvest SmartPReP2 BMAC (Harvest) devices and compared to untreated BM aspirate. Samples were analyzed with multicolor flow cytometry for cellular viability and expression of stem/progenitor cells markers. Stem/progenitor cell content was verified by quantification of colony forming unit-fibroblasts (CFU-F). Platelet, red blood cell and total nucleated cell (TNC) content were determined using an automated hematology analyzer. Growth factors contents were analyzed with protein quantification assays. Statistical analyses were performed by ANOVA analysis of variance followed by Tukey’s multiple comparison test or Wilcoxon matched-pairs signed rank test with p < 0.05 for significance.
Results: Cell viability after processing was approximately 90% in all groups. Compared to control, both devices significantly enriched TNCs and platelets, as well as the CD45−CD73+ and CD45−CD73+CD90+ cell populations. Further, Harvest significantly concentrated CD45−CD10+, CD45−CD29+, CD45−CD90+, CD45−CD105+, CD45−CD119+ cells, and CD45dimCD90+CD271+ MSCs, whereas Emcyte significantly enriched CD45dimCD44+CD271+ MSCs. BM concentration also increased the numbers of CFU-F, platelet-derived growth factor, vascular endothelial growth factor, macrophage colony-stimulating factor, interleukin-1b, VCAM-1 and total protein. Neither system concentrated red blood cells, hematopoietic stem cells or bone morphogenetic proteins.
Conclusion: This data could contribute to the development of BMAC quality control assays as both BMAC systems concentrated platelets, growth factors and non-hematopoietic stem cell subpopulations with distinct phenotypes without loss of cell viability when compared to unprocessed BM.
Objective: To determine whether the performance of multiple sclerosis (MS) patients in the sound-induced flash illusion (SiFi), a multisensory perceptual illusion, would reflect their cognitive impairment.
Methods: We performed the SiFi task as well as an extensive neuropsychological testing in 95 subjects [39 patients with relapse-remitting MS (RRMS), 16 subjects with progressive multiple sclerosis (PMS) and 40 healthy control subjects (HC)].
Results: MS patients reported more frequently the multisensory SiFi than HC. In contrast, there were no group differences in the control conditions. Essentially, patients with progressive type of MS continued to perceive the illusion at stimulus onset asynchronies (SOA) that were more than three times longer than the SOA at which the illusion was already disrupted for healthy controls. Furthermore, MS patients' degree of cognitive impairment measured with a broad neuropsychological battery encompassing tests for memory, attention, executive functions, and fluency was predicted by their performance in the SiFi task for the longest SOA of 500 ms.
Conclusions: These findings support the notion that MS patients exhibit an altered multisensory perception in the SiFi task and that their susceptibility to the perceptual illusion is negatively correlated with their neuropsychological test performance. Since MS lesions affect white matter tracts and cortical regions which seem to be involved in the transfer and processing of both crossmodal and cognitive information, this might be one possible explanation for our findings. SiFi might be considered as a brief, non-expensive, language- and education-independent screening test for cognitive deficits in MS patients.
Anaerobic ammonium oxidation (anammox) is a major process in the biogeochemical nitrogen cycle in which nitrite and ammonium are converted to dinitrogen gas and water through the highly reactive intermediate hydrazine. So far, it is unknown how anammox organisms convert the toxic hydrazine into nitrogen and harvest the extremely low potential electrons (−750 mV) released in this process. We report the crystal structure and cryo electron microscopy structures of the responsible enzyme, hydrazine dehydrogenase, which is a 1.7 MDa multiprotein complex containing an extended electron transfer network of 192 heme groups spanning the entire complex. This unique molecular arrangement suggests a way in which the protein stores and releases the electrons obtained from hydrazine conversion, the final step in the globally important anammox process.
Fascial tissues form a ubiquitous network throughout the whole body, which is usually regarded as a passive contributor to biomechanical behavior. We aimed to answer the question, whether fascia may possess the capacity for cellular contraction which, in turn, could play an active role in musculoskeletal mechanics. Human and rat fascial specimens from different body sites were investigated for the presence of myofibroblasts using immunohistochemical staining for α-smooth muscle actin (n = 31 donors, n = 20 animals). In addition, mechanographic force registrations were performed on isolated rat fascial tissues (n = 8 to n = 18), which had been exposed to pharmacological stimulants. The density of myofibroblasts was increased in the human lumbar fascia in comparison to fasciae from the two other regions examined in this study: fascia lata and plantar fascia [H(2) = 14.0, p < 0.01]. Mechanographic force measurements revealed contractions in response to stimulation by fetal bovine serum, the thromboxane A2 analog U46619, TGF-β1, and mepyramine, while challenge by botulinum toxin type C3–used as a Rho kinase inhibitor– provoked relaxation (p < 0.05). In contrast, fascial tissues were insensitive to angiotensin II and caffeine (p < 0.05). A positive correlation between myofibroblast density and contractile response was found (rs = 0.83, p < 0.001). The hypothetical application of the registered forces to human lumbar tissues predicts a potential impact below the threshold for mechanical spinal stability but strong enough to possibly alter motoneuronal coordination in the lumbar region. It is concluded that tension of myofascial tissue is actively regulated by myofibroblasts with the potential to impact active musculoskeletal dynamics.
Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders with significant and often lifelong effects on social, emotional, and cognitive functioning. Influential neurocognitive models of ADHD link behavioral symptoms to altered connections between and within functional brain networks. Here, we investigate whether network-based theories of ADHD can be generalized to understanding variations in ADHD-related behaviors within the normal (i.e., clinically unaffected) adult population. In a large and representative sample, self-rated presence of ADHD symptoms varied widely; only eight out of 291 participants scored in the clinical range. Subject-specific brain-network graphs were modeled from functional MRI resting-state data and revealed significant associations between (non-clinical) ADHD symptoms and region-specific profiles of between-module and within-module connectivity. Effects were located in brain regions associated with multiple neuronal systems including the default-mode network, the salience network, and the central executive system. Our results are consistent with network perspectives of ADHD and provide further evidence for the relevance of an appropriate information transfer between task-negative (default-mode) and task-positive brain regions. More generally, our findings support a dimensional conceptualization of ADHD and contribute to a growing understanding of cognition as an emerging property of functional brain networks.
Mein Beitrag zeichnet im ersten Teil die Theoreme der Soziologie nach. Bis in die siebziger Jahre - die Palette reicht von Talcott Parsons über Erving Goffman bis zu Rollenanalyse als kritische Soziologie, das sich zu Alfred Schütz bekennt, und darüber hinaus - kann man verschiedene Stränge der Argumentation unterscheiden, allesamt bemüht, zu sozialen Rollen bzw. der Rollenhaftigkeit des sozialen Lebens etwas zu sagen, und bei einigen außerdem, die (idealisierende) Typisierung ins Visier zu nehmen. Im zweiten Teil wird der Gang des Theaters in den letzten Jahrzehnten skizziert. Seit es kein Stück und kein Publikum – also keine Rollen – mehr geben soll, sondern ein Skript genügen und eine Performance ausreichen soll, hat sich eine Theaterkultur entwickelt, die mit Blick auf Rollenrepertoire und Aufführungspraxis sich durch Wissenschaft begründet oder selbst eine "angewandte Theaterwissenschaft" sein will. Im dritten Teil wird das Verhältnis zwischen Rollen und Theater angesprochen. Nun wird die Typisierung zum Thema: Denn die Gesellschaft und die Bühne haben gemeinsam, dass eine Typisierung stattfindet, wenn in den sozialen Rollen, die das Leben verkörpern, oder dem Leben, das auf der Bühne nachempfunden oder gelegentlich beschworen wird, zwischen den Protagonisten etwas geschieht. Die Gesellschaft und die Bühne - im Blick auf Typisierung und Theater - kann man unter die Perspektive eines Dritten stellen, das sowohl eine Methode der Wissenschaft als auch ein Vorgang des Alltags ist - das Verstehen.
Während seines Aufenthaltes in Algerien hatte Pierre Bourdieu die eminente Bedeutung des Symbolischen erkannt. In der traditionellen Gesellschaft der Kabylei entdeckte er die relative Unabhängigkeit des Symbolischen (etwa der Ehre) gegenüber dem Ökonomischen. Mit Marx und Weber stimmte er darin überein, dass Sinnbeziehungen auf Machtbeziehungen beruhen. Während Marx in seiner antiidealistischen Haltung das Symbolische als eine bloße Widerspiegelung der ökonomisch- politischen Beziehungen betrachtete, unterstrich Bourdieu die Eigenlogik des Symbolischen, das nicht auf das Ökonomische im engeren Sinn reduziert werden kann. Der Begriff des symbolischen Kapitals wurde dann zu einer zentralen Kategorie des Theoriegebäudes von Bourdieu.
Die symbolische Dimension von Macht- und Herrschaftsverhältnissen galt Pierre Bourdieu als Schlüssel zum Verständnis sozialer Ungleichheit in demokratisch verfassten Gesellschaften. Wenngleich er die Bedeutung materieller Ressourcen nie in Frage stellte, sah er Strukturen sozialer Ungleichheit immer auch als Resultat von alltäglichen Bewertungskämpfen, in denen Klassifikationen und evaluative Praktiken eine zentrale Rolle spielen. Besonders anschaulich beschreibt Bourdieu diese Bewertungskämpfe im Feld der Musik. Denn die vermeintlich harmlosen und trivialen Vorlieben und Aversionen waren für Bourdieu nicht nur Ausdruck klassenspezifisch geprägter Lebensstile, sondern auch ein probates Mittel zur Legitimation und Reproduktion sozialer Herrschaftsverhältnisse.
In der Medien- und Filmwissenschaft, von deren semiologischen Ansätzen sich Pierre Bourdieu scharf abgrenzt, wird sein Konzept der symbolischen Herrschaft vergleichsweise wenig rezipiert. Darin selbst sind einige blinde Flecken, die von Bourdieu nicht reflektiert wurden. Zu den blinden Flecken gehören zum einen die Nichtberücksichtigung der darstellerischen, ästhetischen wie narrativen Eigenlogiken des Films, zum anderen die Nichtberücksichtigung der Eigensinnigkeit der ZuschauerInnen in der Rezeption und Aneignung filmischer Inhalte, zwei Aspekte, die die symbolische Herrschaft des oder im Film unterlaufen können. Da Bourdieu weder Filme inhaltlich analysiert noch Rezeptionsstudien durchführte, wird fälschlicherweise von der Form auf die Schichten der ZuschauerInnen geschlossen. Im Anschluss an die zentrale Thematik der symbolischen Herrschaft (symbolischen Gewalt, symbolischen Macht) lassen sich diese Konzepte allerdings gewinnbringend auf die verschiedensten Dimensionen und Instanzen der medialen Analyse an der Schnittstelle zwischen Medien- und Filmwissenschaft sowie der Filmsoziologie, im Folgenden insbesondere die Soziologie des Films respektive die Soziologie durch Film, anwenden.
Zunächst wird kurz in Bourdieus Konzept der symbolischen Herrschaft eingeführt und dessen Stellung im Kontext seiner Theorie der Praxis verdeutlicht. Da Bourdieu sein Verständnis der symbolischen Reproduktion des Sozialen insbesondere in Bezug auf die Sprache entfaltet, wird in einem zweiten Schritt auf seine sprachsoziologischen Arbeiten eingegangen. Dabei wird das Problem der Betonung der statischen Reproduktion sozialer Ordnungen adressiert. Im dritten Abschnitt erfolgt eine Kritik und Erweiterung von Bourdieus Perspektive im Anschluss an Judith Butler, die in "Haß spricht" eine Theorie zur Resignifikation sozialer Klassifikationen entwickelt hat und sich dabei von Bourdieus Sprachsoziologie abgrenzt. Sie betont im Unterschied zu Bourdieu die Möglichkeit der Verschiebung symbolischer Machtverhältnisse. Im Fazit werden die beiden Positionen vergleichend diskutiert und Ansätze einer Theorie sozialer Iterabilität herausgearbeitet.
Wenn in Frankreich, wie Curtius schreibt, die Literatur zum repräsentativen Ausdruck der Nation geworden war, so hatte das historische Gründe, die auf das Zeitalter der Klassik und der absoluten Monarchie zurückgehen. Im heutigen Frankreich ist in der Tat die Klassik, namentlich das Zeitalter Ludwigs XIV., die entscheidende kulturelle Referenz. Die wichtigen Werke dieser Zeit sind im kulturellen Gedächtnis der Franzosen präsent, bilden einen bedeutenden Teil eines lebendigen Erbes. Der Höhepunkt der politischen Macht unter Ludwig XIV. war gleichzeitig eine kulturelle Blütezeit. Die Kultur war schon seit der Renaissance in das nationale Leben integriert. Dieser Integrationsprozess verdichtete sich indes in der zweiten Hälfte des 17. Jahrhunderts. Peter Burke und Louis Marin haben aufgezeigt, wie alle Künste, die Literatur, die Malerei, die Bildhauerei und die Architektur, dazu beitrugen, die symbolische Macht der absoluten Monarchie zu konstituieren, und zwar im zentralen Bereich der Zeichen und der Imagination, eine Macht, die vor allem in der Re-Präsentation bestand. Man wird sich aber vor der Vorstellung hüten müssen, die Künste seien vom Sonnenkönig nur instrumentalisiert worden. Wegen ihrer Integration in die zentralen Sphären der Gesellschaft erreichten sie gleichzeitig einen bedeutenden sozialen Status. Wenn der König sein Zeitalter immer wieder mit demjenigen von Augustus vergleichen ließ, dann war das gleichzeitig ein Anstoß und eine Verpflichtung zur Förderung der Künste.
Pierre Bourdieu kannte seinen Kant. Er hatte ja auch Philosophie studiert und ein glänzendes Abschluss-Examen in diesem Fach abgelegt - als Bester seines Jahrganges in Frankreich. Er verfügte nach Jacques Bouveresse über eine breitere philosophische Kultur als viele Berufsphilosophen. Er kam immer wieder auf philosophische Fragestellungen zurück, die er aber glaubte mit den Instrumenten der Soziologie, zu der er in Algerien auf autodidaktischem Weg fand, besser beantworten zu können als mit denen einer kontext- und geschichtsvergessenen Philosophie. [...] Der Untertitel seines zentralen Werkes 'La distinction' (1979), 'Critique sociale du jugement' – was ich eher als "soziale Kritik der Urteilskraft" und nicht als "Kritik der gesellschaftlichen Urteilskraft" übersetzen würde -, versteht sich als Antwort auf Kants Kritik der Urteilskraft. Nach Kant beweist derjenige, der zu ästhetischen Urteilen über das Schöne fähig ist, Geschmack. Geschmacksurteile sind aber für ihn subjektiv. "Das Geschmacksurteil ist also kein Erkenntnisurteil, mithin nicht logisch, sondern ästhetisch, worunter man dasjenige versteht, dessen Bestimmungsgrund nicht anders als subjektiv sein kann." Die per se subjektiven Geschmacksurteile beanspruchen aber Allgemeingültigkeit, insofern sie "das Wohlgefallen an einem Gegenstand jedermann ansinnen". Nach Bourdieu sind indes auch Geschmacksurteile weder bloß subjektiv noch universell, sondern sozial bedingt. Gegensatzpaare wie Schönheit und Reiz, Wohlgefallen und Genuss oder Kultur und Zivilisation sublimierten indes diese soziale Bedingtheit, verdrängten die doppelte soziale Beziehung zum Hof (als Ort der der Kultur entgegengesetzten civilisation) und zum Volk (als dem Bereich der Natur und der Sinnlichkeit).
Präzise zeichnet Schillers bürgerliches Trauerspiel also die spezifischen absolutistischen Verhältnisse in einem deutschen Kleinstaat Ende des 18. Jahrhunderts: die Machtverschiebungen am Hof durch den Aufstieg einer gut ausgebildeten Verwaltungselite (Präsident), den Konkurrenzdruck innerhalb des dritten Standes, der sowohl aufstrebende Beamte hervorbrachte (Wurm) wie von Verelendung bedrohte Kleinbürger (Miller). Auffallend ist, wie differenziert Schiller dabei die soziale Verortung seiner Figuren besonders über Kleidungs-Codes regelt. Keine Farbe, kein Kleidungsstück, keine Requisite ist beliebig. An den unterschiedlichen Kleider-Zeichen, mit denen die beiden männlichen bürgerlichen Figuren, Miller und Wurm, markiert werden, wird dies anschaulich [...].
"À la mode", "Mode", "modisch", "alamodisch" (wie das Adjektiv noch bis ins frühe 18. Jahrhundert lautete): Schon die bloße Detektion danach in Titeln des Sprech- und Musiktheaters von Mitte des 18. bis ins erste Drittel des 19. Jahrhunderts lässt bemerkenswerte Schlüsse zu: "Mode", "modisch", etc. wurden als titelgebende Begriffe, also (vermutlich) auch als programmatische Motive eher in der Komödie und im Singspiel beziehungsweise der komischen Oper als in Schauspiel, Tragödie, Opera seria thematisiert; von den Autoren und Librettisten des komischen Alt- Wiener (Musik-)Theaters weitaus häufiger zur dramatischen oder thematisch-figurativen ‚Kristallisation‘ (Hermann Bausinger) herangezogen als von den Autoren des aufklärerischen, des sogenannten weinerlichen Lustspiels und des Rührstücks; und dies in besonderer Weise gehäuft im Dezennium zwischen 1765 und 1775 und dann wieder in den ersten beiden Jahrzehnten des 19. Jahrhunderts. Unter Ausschluss der nur vier begriffseinschlägigen, in diesem Zeitraum in Deutschland entstandenen und gespielten Lustspiele [...] ergibt sich ein Corpus von 15 in Wien entstandenen und vornehmlich in Wien und auf den Bühnen der Habsburger Monarchie gespielten dramatischen Erzeugnissen rund um die "Mode" und das "Modische".
Hundred Shades of Black : Inszenierungen des Herrenanzugs im Selbstbildnis des 20. Jahrhunderts
(2016)
Der Herrenanzug: Adrett, konservativ, angepasst? Gewagt, subversiv, gar revolutionär? Oder doch einfach nur todschick - und nichts weiter? Kaum ein Kleidungsstück kann einen so reichen Fundus an Attributen vorweisen wie der Anzug. Als treuer Begleiter des Mannes seit nunmehr fast zwei Jahrhunderten wurde und wird er mit den unterschiedlichsten Zuschreibungen bedacht, was angesichts seiner turbulenten Entstehungsgeschichte wenig überrascht. So spiegeln sich im Anzug wie in keinem anderen Kleidungsstück gesellschaftliche Entwicklungen, und das auf der Makroebene, denn die Formveränderungen des 'modernen Anzugs' fallen marginal aus.
Kleidung hat mehrere Aufgaben. Sie ist 'erstens' durch die biologisch gegebene Ausstattung des menschlichen Körpers bedingt. Der Mensch ist ein Lebewesen ohne Fell. Deshalb muss die biologisch bedingte Funktion der Kleidung darin bestehen, ihn vor Witterungseinflüssen zu schützen. Durch diese Funktion ist die notwendige Umhüllung des Körpers jedoch nicht zureichend bestimmt, vielmehr eröffnet sich damit ein breites Spektrum von Gestaltungsmöglichkeiten. Dazu zählt, dass Kleidung 'zweitens' der sozialen Distinktion dient. [...] Überlagert wird diese soziale Modekonkurrenz 'drittens' durch Verbergen bzw. Präsentieren von Körperpartien. Kleidung kann die sinnliche Präsenz eines Menschen steigern. "In der Kleidung" kann "sich ein erotisches Problem" erfüllen, nämlich "das des passiven aber dafür stetigen sinnlichen Werbens". Nur Menschen, die sich vom Eros verabschiedet haben, verzichten darauf; einen Extremfall stellen Nonnen und Mönche dar, die sich in weite Kutten hüllen.
Zu den Funktionen der Mode
(2016)
In der Literatur über die Mode herrscht Einvernehmen darüber, dass die Moden früher die oberen Schichten oder Stände von den nächstfolgenden abgrenzten; ging eine Mode erst einmal auf andere Schichten über, so musste eine neue Mode entwickelt, ein neues Abzeichen gefunden werden. Diese Bewegung gibt es, auch wenn die treffliche Charakterisierung durch den Rechtshistoriker Jhering von der "Hetzjagd der Standeseitelkeit" inzwischen überholt ist, noch immer. Auch in unserer Gesellschaft bietet die Mode - und zwar nicht nur die Kleidermode, sondern jede Form des modischen Konsums - die Möglichkeit, die Zugehörigkeit zu einem bestimmten Kreis, einer bestimmten Gruppe anzudeuten. Dies gilt im Hinblick auf die sozialen Schichten, so wenig diese im einzelnen definierbar sein mögen; es gilt aber auch im Blick auf andere Gruppierungen wie die Jugend, die heute ein ganz wesentlicher Ausgangspunkt für Moden ist, die sich von hier aus über die ganze Gesellschaft verbreiten. Die Jugendlichen bleiben so lange bei einer Mode, bis die anfängliche Barriere von den anderen übersprungen wird [...].
Background/Aims: Middle East respiratory syndrome coronavirus (MERS-CoV) and Marburg virus (MARV) are among the World Health Organization’s top 8 emerging pathogens. Both zoonoses share nonspecific early symptoms, a high lethality rate, and a reduced number of specific treatment options. Therefore, we evaluated extracorporeal virus and glycoprotein (GP) elimination by lectin affinity plasmapheresis (LAP).
Methods: For both MERS-CoV (pseudovirus) as well as MARV (GPs), 4 LAP devices (Mini Hemopurifiers, Aethlon Medical, San Diego, CA, USA) and 4 negative controls were tested. Samples were collected every 30 min and analyzed for reduction in virus infectivity by a flow cytometry-based infectivity assay (MERS-CoV) and in soluble GP content (MARV) by an immunoassay.
Results: The experiments show a time-dependent clearance of MERS-CoV of up to 80% within 3 h (pseudovirus). Up to 70% of MARV-soluble GPs were eliminated at the same time. Substantial saturation of the binding resins was detected within the first treatment hour.
Conclusion: MERS-CoV (pseudovirus) and MARV soluble GPs are eliminated by LAP in vitro. Considering the high lethality and missing established treatment options, LAP should be evaluated in vivo. Especially early initiation, continuous therapy, and timed cartridge exchanges could be of importance.
Chordomas are rare bone tumors with few therapeutic options. Here we show, using whole-exome and genome sequencing within a precision oncology program, that advanced chordomas (n = 11) may be characterized by genomic patterns indicative of defective homologous recombination (HR) DNA repair and alterations affecting HR-related genes, including, for example, deletions and pathogenic germline variants of BRCA2, NBN, and CHEK2. A mutational signature associated with HR deficiency was significantly enriched in 72.7% of samples and co-occurred with genomic instability. The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib, which is preferentially toxic to HR-incompetent cells, led to prolonged clinical benefit in a patient with refractory chordoma, and whole-genome analysis at progression revealed a PARP1 p.T910A mutation predicted to disrupt the autoinhibitory PARP1 helical domain. These findings uncover a therapeutic opportunity in chordoma that warrants further exploration, and provide insight into the mechanisms underlying PARP inhibitor resistance.
Background: To evaluate the current indications, resection strategies and short-term outcomes of surgery for benign goitre in a country with endemic goitre. Methods: Data of patients who underwent surgery for benign goitre were retrieved from the prospective StuDoQ/Thyroid registry and retrospectively analysed regarding the patient’s demographics, indications for surgery, surgical procedures, histology, and perioperative outcomes. Results: In a 15-month period, 12,888 patients from 83 departments underwent thyroid resections for benign conditions. Main indications for surgery were exclusion of malignancy (68%), compression symptoms (20.7%) and hyperthyroidism (9.7%). Preoperative fine needle aspiration cytology was performed in only 12.2% of patients with the indication "exclusion of malignancy". Thyroidectomy (49.8%) or hemithyroidectomy (36.9%) were performed in 86.7% of patients. Minimally invasive or alternative surgical techniques were applied in only 2.2%. Intraoperative neuromonitoring was used in 98.4% of procedures, in 97.5% of patients at least one parathyroid gland was visualized, and in 15.3% of patients parathyroid tissue was autografted, respectively. The rates of unilateral and bilateral transient recurrent nerve palsy were 3.6% and 0.07% of nerves at risk, the rate of transitory hypoparathyroidism was 15.3%. The rates of postoperative bleeding and wound infections requiring reoperation were 1.4% and 0.07%, respectively. Conclusions: The indication "exclusion of malignancy" is made too liberally, and there is a strong attitude to perform complete thyroid resections. Postoperative hypoparathyroidism is the major complication after surgery for benign thyroid disease, thus requiring more awareness.
Background: Computed tomography (CT) allows estimation of coronary artery calcium (CAC) progression. We evaluated several progression algorithms in our unselected, population-based cohort for risk prediction of coronary and cardiovascular events.
Methods: In 3281 participants (45–74 years of age), free from cardiovascular disease until the second visit, risk factors, and CTs at baseline (b) and after a mean of 5.1 years (5y) were measured. Hard coronary and cardiovascular events, and total cardiovascular events including revascularization, as well, were recorded during a follow-up time of 7.8±2.2 years after the second CT. The added predictive value of 10 CAC progression algorithms on top of risk factors including baseline CAC was evaluated by using survival analysis, C-statistics, net reclassification improvement, and integrated discrimination index. A subgroup analysis of risk in CAC categories was performed.
Results: We observed 85 (2.6%) hard coronary, 161 (4.9%) hard cardiovascular, and 241 (7.3%) total cardiovascular events. Absolute CAC progression was higher with versus without subsequent coronary events (median, 115 [Q1–Q3, 23–360] versus 8 [0–83], P<0.0001; similar for hard/total cardiovascular events). Some progression algorithms added to the predictive value of baseline CT and risk assessment in terms of C-statistic or integrated discrimination index, especially for total cardiovascular events. However, CAC progression did not improve models including CAC5y and 5-year risk factors. An excellent prognosis was found for 921 participants with double-zero CACb=CAC5y=0 (10-year coronary and hard/total cardiovascular risk: 1.4%, 2.0%, and 2.8%), which was for participants with incident CAC 1.8%, 3.8%, and 6.6%, respectively. When CACb progressed from 1 to 399 to CAC5y≥400, coronary and total cardiovascular risk were nearly 2-fold in comparison with subjects who remained below CAC5y=400. Participants with CACb≥400 had high rates of hard coronary and hard/total cardiovascular events (10-year risk: 12.0%, 13.5%, and 30.9%, respectively).
Conclusions: CAC progression is associated with coronary and cardiovascular event rates, but adds only weakly to risk prediction. What counts is the most recent CAC value and risk factor assessment. Therefore, a repeat scan >5 years after the first scan may be of additional value, except when a double-zero CT scan is present or when the subjects are already at high risk.
The on-surface synthesis of bisheptahelicene by Ullmann coupling of 9-bromoheptahelicene on Au(111) and its temperature-induced dehydrogenation is studied using temperature-programmed reaction spectroscopy and time-of-flight secondary ion mass spectrometry. Specific dehydrogenation products of bisheptahelicene after loss of 6, 8 and 10 hydrogen atoms are identified, corresponding to molecules having undergone Diels–Alder transformations and intramolecular C–C coupling reactions. By combining with atomic hydrogen produced by dehydrogenation, the Ullmann coupling side-product bromine desorbs as HBr. H2 desorption emerges only after all Br has desorbed. Such characteristic behavior is explained by a kinetic model which explicitly considers the coverage of transient atomic H on the surface. Heating experiments performed with saturated layers of different Br-containing molecules reveal that the onset of HBr desorption depends strictly on the dehydrogenation step and therefore on the structure of the molecules.
Der vorliegende Aufsatz ist eine Bestandsaufnahme zum Eurovision Song Contest (= ESC), der im Mai 2015 in Wien stattfand. Ihm liegt ein Vortrag zugrunde, der eine Woche vor der 60. Austragung des Komponistenwettstreits auf der Tagung Mode - Geschmack - Distinktion an der Karl-Franzens-Universität Graz diskutiert wurde. Die Aktualität des Vortrags wird auch im vorliegenden Aufsatz deutlich und erhält stellenweise eine Erweiterung. Als zeitlich gebundene Reflexion spiegeln die folgenden Zeilen den Sachverhalt wider, dass die Generierung von Moden ein vielschichtiges Merkmal in den Diskursen über Popmusik darstellt.
Unser Beitrag beleuchtet diese Entwicklung sowjetischer Mode- und Geschmacksdiskurse im Kontext von inter- und intrakulturellen Transfervorgängen in der Tauwetter- Periode, die nach dem Tod Stalins 1953 begann und über die Regierungszeit Chruščevs bis zum Machtantritt Brežnevs im Jahr 1964 dauerte, und bezieht Beispiele aus dem künstlerischen Diskurs dieser Zeit ein. Die ideologisch geprägten Definitionen von Mode, Stil und Geschmack und letztendlich die Strategien bei deren Umsetzung in der sozialistischen Alltagskultur der Tauwetter-Periode stehen im Zentrum des Beitrags. Hierfür wird das Konsumgut Kleidung als Beispiel genommen und anhand einiger Mode- und Frauenzeitschriften sowie anhand von Ratgeberliteratur analysiert. Zudem nutzen wir die wechselseitige Beeinflussung von Kunst und Realität - zumal der künstlerische Text, sei es als literarischer Text oder als Film, aus Zeichen besteht, die auch in der außerkünstlerischen Realität ihre Wirkmächtigkeit entfalten.
Sowohl die Abhängigkeit des Erfolgs von Sängern von der Mode, d. h. der Mode des Publikums, wie die Tatsache, dass gut singen zu können zwar nicht schadet, aber nicht essentiell für die Karriere von Sängern ist, widerspricht der These von John Rosselli, der in seinem maßgeblichen Buch über italienische Sänger der Meinung war, am Ende des 18. Jahrhunderts hätte sich für Sänger ein Markt herausgebildet, der nach dem Gesetz von Angebot und Nachfrage funktionierte. [...] Der Gesangs-Star verdankte seine Existenz schon im 19. Jahrhundert wiederum einem geschickten Marketing ("Reklame"), welches nicht zuletzt durch die ständigen Pressemeldungen möglich war, die nach Möglichkeit beeinflusst wurden. Sehr deutlich ist das an der spektakulären Affäre Lucca - Mallinger zu sehen.
Im Zentrum meiner Überlegungen stehen die beiden wichtigsten Beschreibungen der hessisch-nassauischen Badeorte Schwalbach und Schlangenbad aus dem 18. und 19. Jahrhundert. Der frühe Text erschien – ohne Autornennung – erstmals 1738 unter dem Titel "Amusemens des Eaux de Schwalbach, des Bains de Wisbaden et de Schlangenbad. Avec deux rélations curieuses; l'une de la Nouvelle Jerusalem et l'autre d'une partie de la Tartarie Indépendante"; weitere französischsprachige Auflagen kamen bereits in den beiden Folgejahren heraus. Schon 1739 lag auch eine deutsche Übersetzung vor: "Amusemens des Eaux de Schwalbach oder Zeitvertreibe Bey den Wassern zu Schwalbach, Denen Bädern zu Wisbaden, und dem Schlangenbade; Nebst Zweyen lesenswürdigen Erzehlungen: Darunter die eine von dem Neuen Jerusalem, Und die andere von einem Theil Der unter Niemandens Bothmäßigkeit stehenden Tartarey handelt".
Das Modische : Zu Entstehungsbedingungen und Funktionen einer bestimmten Art von Konformismus
(2016)
Das als "modisch" im engeren Sinn Bezeichnete, die Kleidung, ist durch kurzfristige Wandlungsprozesse charakterisiert und steht dem allgemeinen Verständnis nach im Gegensatz zu den Prinzipien der Dauer und der Beständigkeit, durch welche man die traditionellen Trachten bestimmt sieht. Aber wie ist es dann beispielsweise um die Sinnhaftigkeit der Rede von "Trachtenmode" bestellt? Und wie sehr sind die mit der Kleidermode verbundenen Begleitvorstellungen des Modischen für andere Bereiche des Lebens charakteristisch?
Sowohl unter VertreterInnen der Medien und der Sprachwissenschaft als auch unter sogenannten "SprachpflegerInnen" sind Sprachmoden ein durchaus frequentes - um nicht zu sagen "modernes" - Thema, wobei gerade Jugendliche und ihr Sprachgebrauch häufig zum Ausgangspunkt der Betrachtung gemacht werden: Lexikalische Auffälligkeiten und strukturelle Abweichungen im Sprachgebrauch der Jugendlichen zeigen starke Varianz und Fluktuation, die deutliche Indikatoren für sprachliche Modeerscheinungen sein können. Der folgende Beitrag soll Moden im Sprachgebrauch Jugendlicher in Österreich betrachten und der Frage nachgehen, ob diese nur kurzfristig bestehende Phänomene darstellen oder zu Sprachwandelprozessen führen können. Zu Beginn werden der Untersuchungsgegenstand "Jugend" näher betrachtet sowie wichtige Einflussfaktoren und Umstände in dessen Kontext angeführt. Anschließend sollen mögliche Sprachmoden in der Kommunikation unter Jugendlichen vorgestellt und erläutert werden. Die Ausführungen beziehen sich auf die im Projekt Jugendsprache(n) in Österreich erhobene Datengrundlage.
Apigenin (4′,5,7-trihydroxyflavone) (Api) is an important component of the human diet, being distributed in a wide number of fruits, vegetables and herbs with the most important sources being represented by chamomile, celery, celeriac and parsley. This study was designed for a comprehensive evaluation of Api as an antiproliferative, proapoptotic, antiangiogenic and immunomodulatory phytocompound. In the set experimental conditions, Api presents antiproliferative activity against the A375 human melanoma cell line, a G2/M arrest of the cell cycle and cytotoxic events as revealed by the lactate dehydrogenase release. Caspase 3 activity was inversely proportional to the Api tested doses, namely 30 μM and 60 μM. Phenomena of early apoptosis, late apoptosis and necrosis following incubation with Api were detected by Annexin V-PI double staining. The flavone interfered with the mitochondrial respiration by modulating both glycolytic and mitochondrial pathways for ATP production. The metabolic activity of human dendritic cells (DCs) under LPS-activation was clearly attenuated by stimulation with high concentrations of Api. Il-6 and IL-10 secretion was almost completely blocked while TNF alpha secretion was reduced by about 60%. Api elicited antiangiogenic properties in a dose-dependent manner. Both concentrations of Api influenced tumour cell growth and migration, inducing a limited tumour area inside the application ring, associated with a low number of capillaries.
Il existe sans doute peu d’histoire des relations entre deux aires culturelles qui suscite autant d’attention à l’heure actuelle que celle des relations entre « l’Occident » et le « monde musulman ». Elle montre particulièrement bien combien la période que nous qualifions communément de « Moyen Âge » influence les débats actuels. Certains phénomènes de cette histoire sont aujourd’hui si fortement enracinés dans l’imaginaire collectif qu’ils continuent à façonner de manière significative la représentation même de ces relations. C’est le cas en particulier de l’expansion arabo-musulmane, des croisades et de ce que l’on appelle la « Reconquista » : ces phénomènes n’évoquent pas seulement des images de fanatiques religieux, mais ils sont – les croisades notamment – ancrés si profondément dans notre pensée conceptuelle qu’ils sont considérés comme l’expression d’un antagonisme quasi épique entre deux civilisations, au fondement desquelles se trouvent une variante de monothéisme (chrétienté / islam) et une langue sur laquelle repose la vie intellectuelle (latin / arabe). ...
Latent tuberculosis infection (LTBI) is established in over 90% of persons infected with Mycobacterium tuberculosis (Mtb), from whom new active TB cases will arise. Understanding the spatio-temporal dynamics of host immune responses in LTBI granulomas is essential to designing effective post-exposure therapies that inhibit progression to TB. Information arising from cancer studies and other modalities – where local chronic inflammation leads to immunopathology – can help provide insights into the biological pathways at play in LTBI granulomas. Translational studies using patient material as well as LTBI+ donor-derived tissue samples are instrumental in understanding the various components of granuloma dynamics, immunological landscapes therein and how this could help to identify therapeutic targets. Deep sequencing technologies may aid to decipher the genetic changes in lung granuloma and blood samples from LTBI+ individuals associated with progression to active TB disease. This may lead to advancement of development of targeted Host-Directed Therapies (HDTs) and their evaluation as adjunct TB therapies for improving treatment outcomes for LTBI and pulmonary TB.
Zu einem Aspekt der Beziehungen zwischen lateinisch-christlicher und arabisch-islamischer Welt
(2011)
Wohl kaum eine Beziehungsgeschichte zwischen Kulturräumen zieht derzeit soviel Aufmerksamkeit auf sich wie die zwischen "dem Westen" und "der islamischen Welt". Gerade hier zeigt sich, wie sehr die Periode, die wir gemeinhin als "das Mittelalter" bezeichnen, heutige Diskurse beeinflusst. Einzelphänomene dieser Beziehungsgeschichte sind ein so fester Bestandteil der heutigen Vorstellungswelt, dass sie auch das Bild dieser Beziehungen bis heute maßgeblich prägen. Dies gilt insbesondere für die arabisch-islamische Expansion, die Kreuzzüge und die so genannte "Reconquista". Sie beschwören nicht nur Bilder von religiösen Fanatikern herauf, sondern sind – gerade die Kreuzzüge – so stark im konzeptuellen Denken verankert, dass sie für einen geradezu in epische Dimensionen reichenden Antagonismus zweier Kulturen stehen, für die eine Variante des Monotheismus (Christentum/Islam) und eine das Geistesleben bestimmende Sprache (Latein/Arabisch) grundlegend sind. ...
Introduction: Balanced fluid replacement solutions can possibly reduce the risks for electrolyte imbalances, for acid-base imbalances, and thus for renal failure. To assess the intraoperative change of base excess (BE) and chloride in serum after treatment with either a balanced gelatine/electrolyte solution or a non-balanced gelatine/electrolyte solution, a prospective, controlled, randomized, double-blind, dual centre phase III study was conducted in two tertiary care university hospitals in Germany.
Material and methods: 40 patients of both sexes, aged 18 to 90 years, who were scheduled to undergo elective abdominal surgery with assumed intraoperative volume requirement of at least 15 mL/kg body weight gelatine solution were included. Administration of study drug was performed intravenously according to patients need. The trigger for volume replacement was a central venous pressure (CVP) minus positive end-expiratory pressure (PEEP) <10 mmHg (CVP <10 mmHg). The crystalloid:colloid ratio was 1:1 intra- and postoperatively. The targets for volume replacement were a CVP between 10 and 14 mmHg minus PEEP after treatment with vasoactive agent and mean arterial pressure (MAP) > 65 mmHg.
Results: The primary endpoints, intraoperative changes of base excess –2.59 ± 2.25 (median: –2.65) mmol/L (balanced group) and –4.79 ± 2.38 (median: –4.70) mmol/L (non-balanced group)) or serum chloride 2.4 ± 1.9 (median: 3.0) mmol/L and 5.2 ± 3.1 (median: 5.0) mmol/L were significantly different (p = 0.0117 and p = 0.0045, respectively). In both groups (each n = 20) the investigational product administration in terms of volume and infusion rate was comparable throughout the course of the study, i.e. before, during and after surgery.
Discussion: Balanced gelatine solution 4% combined with a balanced electrolyte solution demonstrated significant smaller impact on blood gas analytic parameters in the primary endpoints BE and serum chloride when compared to a non-balanced gelatine solution 4% combined with NaCl 0.9%. No marked treatment differences were observed with respect to haemodynamics, coagulation and renal function.
Trial registration: ClinicalTrials.gov (NCT01515397) and clinicaltrialsregister.eu, EudraCT number 2010-018524-58.
Klaus Lichtblau - notice
(2012)
Klaus Lichtblau (né en 1951) étudie entre autres auprès de Niklas Luhmann à l’université de Bielefeld, sous la direction duquel il rédige son mémoire de sociologie en 1975. En 1980, toujours à Bielefeld, il soutient sa thèse de doctorat en philosophie, puis travaille dans un premier temps à l’université de Bielefeld, puis aux universités de Kassel et de Kiel. En 1996, il obtient son habilitation en sociologie à l’université de Kassel. Depuis 2004, Klaus Lichtblau est professeur de sociologie à l’Université de Francfort-sur-le-Main. Ses travaux de recherche s’axent autour de l’histoire des sciences sociales des XIXe et XXe siècles. Il porte un intérêt particulier aux classiques (Max Weber, Georg Simmel et Karl Mannheim, entre autres). Par ailleurs, il s’intéresse aux dimensions culturelles du social, à la fonction sociale de l’art, à la sociologie économique, etc.
Haloferax volcanii is a well-established model species for haloarchaea. Small scale RNomics and bioinformatics predictions were used to identify small non-coding RNAs (sRNAs), and deletion mutants revealed that sRNAs have important regulatory functions. A recent dRNA-Seq study was used to characterize the primary transcriptome. Unexpectedly, it was revealed that, under optimal conditions, H. volcanii contains more non-coding sRNAs than protein-encoding mRNAs. However, the dRNA-Seq approach did not contain any length information. Therefore, a mixed RNA-Seq approach was used to determine transcript length and to identify additional transcripts, which are not present under optimal conditions. In total, 50 million paired end reads of 150 nt length were obtained. 1861 protein-coding RNAs (cdRNAs) were detected, which encoded 3092 proteins. This nearly doubled the coverage of cdRNAs, compared to the previous dRNA-Seq study. About 2/3 of the cdRNAs were monocistronic, and 1/3 covered more than one gene. In addition, 1635 non-coding sRNAs were identified. The highest fraction of non-coding RNAs were cis antisense RNAs (asRNAs). Analysis of the length distribution revealed that sRNAs have a median length of about 150 nt. Based on the RNA-Seq and dRNA-Seq results, genes were chosen to exemplify characteristics of the H. volcanii transcriptome by Northern blot analyses, e.g. 1) the transcript patterns of gene clusters can be straightforward, but also very complex, 2) many transcripts differ in expression level under the four analyzed conditions, 3) some genes are transcribed into RNA isoforms of different length, which can be differentially regulated, 4) transcripts with very long 5’-UTRs and with very long 3’-UTRs exist, and 5) about 30% of all cdRNAs have overlapping 3’-ends, which indicates, together with the asRNAs, that H. volcanii makes ample use of sense-antisense interactions. Taken together, this RNA-Seq study, together with a previous dRNA-Seq study, enabled an unprecedented view on the H. volcanii transcriptome.
Depuis le milieu des années 1970, on assiste dans le monde entier à un retour en force des thématiques et problématiques relatives à la culture dans le champ de la sociologie. Ce regain d’intérêt va de pair avec le déclin croissant de la tradition, d’inspiration avant tout marxiste, de la théorie de la société, et s’inscrit dans un cultural turn global,qui a eu ces dernières années des répercussions sur la plupart des disciplines universitaires. ...
Epigenetic control of the angiotensin-converting enzyme in endothelial cells during inflammation
(2019)
The angiotensin-converting enzyme (ACE) plays a central role in the renin-angiotensin system, which is involved in the regulation of blood pressure. Alterations in ACE expression or activity are associated with various pathological phenotypes, particularly cardiovascular diseases. In human endothelial cells, ACE was shown to be negatively regulated by tumor necrosis factor (TNF) α. To examine, whether or not, epigenetic factors were involved in ACE expression regulation, methylated DNA immunoprecipitation and RNA interference experiments directed against regulators of DNA methylation homeostasis i.e., DNA methyltransferases (DNMTs) and ten-eleven translocation methylcytosine dioxygenases (TETs), were performed. TNFα stimulation enhanced DNA methylation in two distinct regions within the ACE promoter via a mechanism linked to DNMT3a and DNMT3b, but not to DNMT1. At the same time, TET1 protein expression was downregulated. In addition, DNA methylation decreased the binding affinity of the transcription factor MYC associated factor X to the ACE promoter. In conclusion, DNA methylation determines the TNFα-dependent regulation of ACE gene transcription and thus protein expression in human endothelial cells.
Multidrug-resistant TB (MDR-TB) is a major threat to global health security. In 2017, only 50% of patients with MDR-TB who received WHO-recommended treatment were cured. Most MDR-TB patients who recover continue to suffer from functional disability due to long-term lung damage. Whilst new MDR-TB treatment regimens are becoming available, conventional drug therapies need to be complemented with host-directed therapies (HDTs) to reduce tissue damage and improve functional treatment outcomes. This viewpoint highlights recent data on biomarkers, immune cells, circulating effector molecules and genetics which could be utilised for developing personalised HDTs. Novel technologies currently used for cancer therapy which could facilitate in-depth understanding of host genetics and the microbiome in patients with MDR-TB are discussed. Against this background, personalised cell-based HDTs for adjunct MDR-TB treatment to improve clinical outcomes are proposed as a possibility for complementing standard therapy and other HDT agents. Insights into the molecular biology of the mechanisms of action of cellular HDTs may also aid to devise non-cell-based therapies targeting defined inflammatory pathway(s) in Mtb-driven immunopathology.
Impaired alveolar formation and maintenance are features of many pulmonary diseases that are associated with significant morbidity and mortality. In a forward genetic screen for modulators of mouse lung development, we identified the non-muscle myosin II heavy chain gene, Myh10. Myh10 mutant pups exhibit cyanosis and respiratory distress, and die shortly after birth from differentiation defects in alveolar epithelium and mesenchyme. From omics analyses and follow up studies, we find decreased Thrombospondin expression accompanied with increased matrix metalloproteinase activity in both mutant lungs and cultured mutant fibroblasts, as well as disrupted extracellular matrix (ECM) remodeling. Loss of Myh10 specifically in mesenchymal cells results in ECM deposition defects and alveolar simplification. Notably, MYH10 expression is downregulated in the lung of emphysema patients. Altogether, our findings reveal critical roles for Myh10 in alveologenesis at least in part via the regulation of ECM remodeling, which may contribute to the pathogenesis of emphysema.
Early maternal care may counteract familial liability for psychopathology in the reward circuitry
(2018)
Reward processing is altered in various psychopathologies and has been shown to be susceptible to genetic and environmental influences. Here, we examined whether maternal care may buffer familial risk for psychiatric disorders in terms of reward processing. Functional magnetic resonance imaging during a monetary incentive delay task was acquired in participants of an epidemiological cohort study followed since birth (N = 172, 25 years). Early maternal stimulation was assessed during a standardized nursing/playing setting at the age of 3 months. Parental psychiatric disorders (familial risk) during childhood and the participants’ previous psychopathology were assessed by diagnostic interview. With high familial risk, higher maternal stimulation was related to increasing activation in the caudate head, the supplementary motor area, the cingulum and the middle frontal gyrus during reward anticipation, with the opposite pattern found in individuals with no familial risk. In contrast, higher maternal stimulation was associated with decreasing caudate head activity during reward delivery and reduced levels of attention deficit hyperactivity disorder (ADHD) in the high-risk group. Decreased caudate head activity during reward anticipation and increased activity during delivery were linked to ADHD. These findings provide evidence of a long-term association of early maternal stimulation on both adult neurobiological systems of reward underlying externalizing behavior and ADHD during development.
A body of research demonstrates convincingly a role for synchronization of auditory cortex to rhythmic structure in sounds including speech and music. Some studies hypothesize that an oscillator in auditory cortex could underlie important temporal processes such as segmentation and prediction. An important critique of these findings raises the plausible concern that what is measured is perhaps not an oscillator but is instead a sequence of evoked responses. The two distinct mechanisms could look very similar in the case of rhythmic input, but an oscillator might better provide the computational roles mentioned above (i.e., segmentation and prediction). We advance an approach to adjudicate between the two models: analyzing the phase lag between stimulus and neural signal across different stimulation rates. We ran numerical simulations of evoked and oscillatory computational models, showing that in the evoked case,phase lag is heavily rate-dependent, while the oscillatory model displays marked phase concentration across stimulation rates. Next, we compared these model predictions with magnetoencephalography data recorded while participants listened to music of varying note rates. Our results show that the phase concentration of the experimental data is more in line with the oscillatory model than with the evoked model. This finding supports an auditory cortical signal that (i) contains components of both bottom-up evoked responses and internal oscillatory synchronization whose strengths are weighted by their appropriateness for particular stimulus types and (ii) cannot be explained by evoked responses alone.
Background: While ICF-CY-based models of care are promising avenues for improving participation of children with chronic health conditions, feasible and valid instruments to assess participation as an outcome in routine are still needed. We aimed to validate a German parent-report version of the Child and Adolescent Scale of Participation (CASP) in children with chronic health conditions of different severity.
Methods: Cross-sectional data were collected in 327 children (mean age 7.8 years, 55% boys) from two paediatric centres (n = 112) and one population-based sample (n = 215). Cronbach’s alpha, factor analyses, face validity assessments, correlation analyses, receiver operating characteristics (ROC) curves, and parent-reported health-related quality of life (HRQoL: KINDL) were used to examine internal consistency, test-retest reliability, and capacity to differentiate between disease severity groups. Disease severity was operationalized according to ICD-diagnosis groups and/or parent-reports on health problems, medical and educational support, and medication. A newly developed item "overall perceived participation" was added to the CASP and evaluated.
Results: We found good to excellent content validity, excellent internal consistency, and good-to-excellent test-retest reliability of the instrument. While children with mild disease had a significantly greater extent of participation (higher CASP scores) than children with severe disease, they did not differ from healthy children. Children with mild compared to severe disease much more differed in participation as measured by the CASP compared to the KINDL (area under the ROC curve: 0.92 vs. 0.75). In addition, the item "overall perceived participation" was highly correlated (r = 0.86) with the CASP total score, indicating the potential value of this specific single item. Finally, we provided preliminary reference values for the CASP obtained in a population-based sample of children without chronic health conditions.
Conclusions: The German version of the CASP and the new item are efficient, valid and reliable measures of social participation in childhood. The CASP-measured participation focuses more on attendance than on involvement into social circumstances of everyday life. To detect children with a high burden of disease on everyday life, the CASP may be more accurate than HRQoL instruments such as the KINDL. As outcome measurement, the CASP may facilitate the implementation of patient-centred paediatric health care.
Clinically relevant immune responses against Cytomegalovirus : implications for precision medicine
(2019)
Immune responses to human cytomegalovirus (CMV) can be used to assess immune fitness in an individual. Further to its clinical significance in posttransplantation settings, emerging clinical and translational studies provide examples of immune correlates of protection pertaining to anti-CMV immune responses in the context of cancer or infectious diseases, e.g., tuberculosis. In this viewpoint, we provide a brief overview about CMV-directed immune reactivity and immune fitness in a clinical context and incorporate some of our own findings obtained from peripheral blood or tumour-infiltrating lymphocytes (TIL) from patients with advanced cancer. Observations in patients with solid cancers whose lesions contain both CMV and tumour antigen-specific T-cell subsets are highlighted, due to a possible CMV-associated "bystander" effect in amplifying local inflammation and subsequent tumour rejection. The role of tumour-associated antibodies recognising diverse CMV-derived epitopes is also discussed in light of anti-cancer immune responses. We discuss here the use of anti-CMV immune responses as a theranostic tool—combining immunodiagnostics with a personalised therapeutic potential—to improve treatment outcomes in oncological indications.
Bromodomains (BRDs) are conserved protein interaction modules which recognize (read) acetyl-lysine modifications, however their role(s) in regulating cellular states and their potential as targets for the development of targeted treatment strategies is poorly understood. Here we present a set of 25 chemical probes, selective small molecule inhibitors, covering 29 human bromodomain targets. We comprehensively evaluate the selectivity of this probe-set using BROMOscan and demonstrate the utility of the set identifying roles of BRDs in cellular processes and potential translational applications. For instance, we discovered crosstalk between histone acetylation and the glycolytic pathway resulting in a vulnerability of breast cancer cell lines under conditions of glucose deprivation or GLUT1 inhibition to inhibition of BRPF2/3 BRDs. This chemical probe-set will serve as a resource for future applications in the discovery of new physiological roles of bromodomain proteins in normal and disease states, and as a toolset for bromodomain target validation.
Background: Oral anticoagulants can cause potentially serious adverse events. Therefore, before prescribing oral anticoagulants for ischemic stroke prevention in patients with atrial fibrillation (AF), stroke risk assessment is required to identify patients that are likely to benefit from treatment. Current guidelines recommend the CHA2DS2-VASc-score for stroke risk assessment. The CHA2DS2-VASc-score is based on observational studies from different treatment settings and countries. As ischemic stroke risk differs by setting and region, the aim of this study is to estimate ischemic stroke risk (stratified by the CHA2DS2-VASc-score) for a broadly representative population with AF from southern Germany and compare them to results from previous studies.
Methods: The study design is a retrospective cohort study on patients with atrial fibrillation based on secondary data. We calculated CHA2DS2-VASc-score based on patient’s diagnoses recorded in the year 2014 and assessed outcomes in 2015–2016. The primary outcome is hospitalization for ischemic stroke. The secondary outome is hospitalizations for any thromboembolic event, including ischemic stroke, transient ischemic attack, peripheral arterial embolism, pulmonary embolism, and mesenterial embolism. We estimated the incidence rates of the outcomes (and corresponding 95%-confidence intervals) stratified by CHA2DS2-VASc-score.
Results: The primary endpoint occurred in 961 of the 30,299 patients constituting the study population, resulting in a total incidence rate of 2.2 per 100 person-years. The secondary endpoint occurred in 1553 patients (3.6 per 100 person-years). Ischemic stroke rates stratified by the CHA2DS2-VASc-score tended to be lower than those reported previously. Thromboembolic event rates stratified tended to be similar to those reported previously.
Conclusions: Our results show that the performance of the CHA2DS2-VASc-score differs in the German population, as compared to internationally published data, with an overall trend towards lower risk of ischemic stroke in uncoagulated patients with AF. These results should not be practice changing, but they emphasize that stroke risk estimation in patients with atrial fibrillation should be further refined.
The mechanistic target of rapamycin (mTOR) is elevated in prostate cancer, making this protein attractive for tumor treatment. Unfortunately, resistance towards mTOR inhibitors develops and the tumor becomes reactivated. We determined whether epigenetic modulation by the histone deacetylase (HDAC) inhibitor, valproic acid (VPA), may counteract non-responsiveness to the mTOR inhibitor, temsirolimus, in prostate cancer (PCa) cells. Prostate cancer cells, sensitive (parental) and resistant to temsirolimus, were exposed to VPA, and tumor cell growth behavior compared. Temsirolimus resistance enhanced the number of tumor cells in the G2/M-phase, correlating with elevated cell proliferation and clonal growth. The cell cycling proteins cdk1 and cyclin B, along with Akt-mTOR signaling increased, whereas p19, p21 and p27 decreased, compared to the parental cells. VPA significantly reduced cell growth and up-regulated the acetylated histones H3 and H4. Cdk1 and cyclin B decreased, as did phosphorylated mTOR and the mTOR sub-complex Raptor. The mTOR sub-member Rictor and phosphorylated Akt increased under VPA. Knockdown of cdk1, cyclin B, or Raptor led to significant cell growth reduction. HDAC inhibition through VPA counteracts temsirolimus resistance, probably by down-regulating cdk1, cyclin B and Raptor. Enhanced Rictor and Akt, however, may represent an undesired feedback loop, which should be considered when designing future therapeutic regimens.
The Sleeping Beauty (SB) transposon system is a non-viral gene delivery platform that combines simplicity, inexpensive manufacture, and favorable safety features in the context of human applications. However, efficient correction of hematopoietic stem and progenitor cells (HSPCs) with non-viral vector systems, including SB, demands further refinement of gene delivery techniques. We set out to improve SB gene transfer into hard-to-transfect human CD34+ cells by vectorizing the SB system components in the form of minicircles that are devoid of plasmid backbone sequences and are, therefore, significantly reduced in size. As compared to conventional plasmids, delivery of the SB transposon system as minicircle DNA is ∼20 times more efficient, and it is associated with up to a 50% reduction in cellular toxicity in human CD34+ cells. Moreover, providing the SB transposase in the form of synthetic mRNA enabled us to further increase the efficacy and biosafety of stable gene delivery into hematopoietic progenitors ex vivo. Genome-wide insertion site profiling revealed a close-to-random distribution of SB transposon integrants, which is characteristically different from gammaretroviral and lentiviral integrations in HSPCs. Transplantation of gene-marked CD34+ cells in immunodeficient mice resulted in long-term engraftment and hematopoietic reconstitution, which was most efficient when the SB transposase was supplied as mRNA and nucleofected cells were maintained for 4–8 days in culture before transplantation. Collectively, implementation of minicircle and mRNA technologies allowed us to further refine the SB transposon system in the context of HSPC gene delivery to ultimately meet clinical demands of an efficient and safe non-viral gene therapy protocol.
The RNA-chaperone Hfq catalyses the annealing of bacterial small RNAs (sRNAs) with target mRNAs to regulate gene expression in response to environmental stimuli. Hfq acts on a diverse set of sRNA-mRNA pairs using a variety of different molecular mechanisms. Here, we present an unusual crystal structure showing two Hfq-RNA complexes interacting via their bound RNA molecules. The structure contains two Hfq6:A18 RNA assemblies positioned face-to-face, with the RNA molecules turned towards each other and connected via interdigitating base stacking interactions at the center. Biochemical data further confirm the observed interaction, and indicate that RNA-mediated contacts occur between Hfq-RNA complexes with various (ARN)X motif containing RNA sequences in vitro, including the stress response regulator OxyS and its target, fhlA. A systematic computational survey also shows that phylogenetically conserved (ARN)X motifs are present in a subset of sRNAs, some of which share similar modular architectures. We hypothesise that Hfq can co-opt RNA-RNA base stacking, an unanticipated structural trick, to promote the interaction of (ARN)X motif containing sRNAs with target mRNAs on a "speed-dating" fashion, thereby supporting their regulatory function.
In their study on "The modern anthropology of Southeast Asia", Victor King and William Wilder raise the question in how far the region can be taken as a field of anthropological enquiry. After their initial discussion of cultural and social trends as well as anthropological studies, they conclude that the common issue of the region is its diversity. They come to the rather pragmatic solution that "South-East Asia constitutes a convenient unit of study, ... but ... we should not think of it in terms of a bounded, unified and homogenous socio-cultural area" (King/Wilder 2003: 24). We doubt that there are homogenous socio-cultural areas anywhere else. These are usually constructed through the invention of traditions and ideological simulations. The interesting case with regards to Southeast Asia is, why no such homogeneity has been constructed, not even by anthropologists or sociologists. ...
Unweigerlich stellen sich lebensweltliche Assoziationen ein, wenn der Begriff der Mode verwendet wird – man denkt an Kleidung, Autos, Haarfarbe, Accessoires, alle möglichen Lifestyle-Attribute. Wenn man Mode über diesen naheliegenden Kontext hinausdenkt und das vertrackte Konzept auf andere Lebensbereiche anwenden will, stellen sich drei Fragen. Erstens: Wie kann man modische Trends von anderen Entwicklungen abgrenzen? Was ist bleibender oder nachhaltiger Wandel und was ist eine temporäre Modeerscheinung, die eine zeitliche Begrenzung aufweist: ein "Strohfeuer"? [...] Zweitens die Frage der Übertragbarkeit: Wo gibt es modische Erscheinungen jenseits der Textilien? Gibt es so etwas in Wissenschaft, Kunst, Politik, Management, Medien und anderen Bereichen? [...] Drittens die sich aufdrängende Frage der Intensivierung: Gibt es gute Gründe dafür anzunehmen, dass sich modische Prozesse in einer spätmodernen Gesellschaft verstärken oder verbreiten?
Die von 1934 bis 1938 bestehende Kleinkunstbühne 'ABC' genießt den Ruf eines subversiven Horts, wenn nicht gar einer widerständigen Vereinigung vornehmlich linker Kräfte. Bereits in Ingeborg Reisners 1961 erschienener, bis heute in vielen Teilen maßgeblicher Dissertation über die Wiener Kleinkunst vor dem Zweiten Weltkrieg umweht das 'ABC' eine Aura des Aufmüpfigen: "Das ABC stand eindeutig weit links und ließ dies auch erstaunlich klar erkennen, trotz 'Vaterländischer Front'. Das ABC war wohl sogar ziemlich direkt 'von illegalen Kommunisten beeinflußt'." Dass diese Beschreibung einen Zeitzeugenbericht wiedergibt und auf eine mündliche Äußerung Friedrich Torbergs zurückgeht, ist ein Charakteristikum der österreichischen Kabarettgeschichtsschreibung zur Zwischenkriegszeit. Allen voran haben nämlich die zu dieser Zeit vornehmlich als Autoren in Erscheinung tretenden Hans Weigel und Rudolf Weys mit ihren Lebenserinnerungen an die Kleinkunstszene der 1930er Jahre das Bild dieser Zeit geprägt.
In jedem Fall wurde die Zensur im Vormärz, im Kontrast zur Van Swietenschen Büchercensurs-Hofkommission des 18. Jahrhunderts, deutlich als direktes Instrument der Polizei betrachtet. So heißt es in einem Vortrag des Polizeipräsidenten Josef von Sedlnitzky schon 1821, dass die Bücherzensur "keine gelehrte oder Bildungssondern eine reine Polizei-Anstalt" sei. Diese Haltung wird umso klarer, wenn man bedenkt, dass die Zensur des Theaters und der Zeitschriften aufgrund ihrer politischen Unmittelbarkeit und Aktualität direkt der Polizeidirektion und nicht den dieser untergeordneten Zensoren der Zensurbehörden überlassen war. Gleichzeitig erschließt sich aus der Korrespondenz der Zeit jedoch auch eine weniger unmittelbar restriktive und deshalb moderner wirkende Methode der Kontrolle öffentlicher Meinung, nämlich eine der direkten oder indirekten Diskurssteuerung mittels finanzieller Methoden, Personalpolitik oder direkter Intervention.
On July 10, 1798, the German ensemble at the Vienna court theater presented the premiere performance of 'Die Hochzeit des Figaro', the first production of Mozart and Da Ponte's 'Le nozze di Figaro' – and indeed of any Mozart-Da Ponte work – at the court theater since Mozart's death and Da Ponte's departure from the imperial capital. A few months later, on December 11, 1798, a new production of Don Giovanni, titled Don Juan, arrived at the court theater stage. On September 19, 1804, a production of Così fan tutte followed, under the title 'Mädchentreue'. Although the productions were not extraordinarily successful in terms of performance numbers, they represented important trends in the Viennese reception of Mozart's operas that were to continue throughout the early nineteenth century. In particular, these productions left behind numerous records about the convoluted processes through which theatrical works were approved, re-approved, and revised before reaching the stage in Vienna around 1800. Particularly prominent among these processes was censorship. Yet, as this article shows, Viennese censors worked in tandem with numerous private and public agents who likewise contributed to the final shape of pre-existing works' adaptations. An examination of the censorial approaches to Mozart's Don Giovanni and Così fan tutte in Vienna around 1800 shows that late Enlightenment censorship was contradictory and multidirectional and should be considered not as a force of restriction but as an element that affected artworks in ways similar to other social, political, and cultural factors, such as patronage, audience structure, and various social and political ideologies.
Zu den wertenden Klassifikationen, die bereits zu einem frühen Zeitpunkt unter den Vorzeichen politischer Korrektheit thematisiert und problematisiert wurden, gehört die "Rasse". Im Folgenden soll es um Dimensionen des Sagbaren in einem Diskursfeld gehen, das unmittelbar an diese Klassifikation anschließt, nämlich das Diskursfeld des "Fremden", "Anderen", "Ausländischen", und zwar bezogen auf die Tagesproduktion des deutschsprachigen Theaters des 19. Jahrhunderts als einer spezifischen medialen Konstellation. Es lässt sich zeigen, dass sich innerhalb weniger Jahrzehnte erhebliche Verschiebungen hinsichtlich der Frage vollzogen, was und wie über Fremde und die Ferne im populären, also auf ein Massenpublikum zielenden Theater gesprochen werden könne. Diese Verschiebungen waren nicht das Resultat von konkreten, im Theater wirksamen staatlichen Zensurbestimmungen oder -maßnahmen. Sie reflektierten vielmehr grundsätzliche Entwicklungen der politischen Ideologie.
Politische Korrektheit ist kein Rechtsbegriff, der in irgendeiner gesetzlichen Regelung definiert wird. Primär geht es – und dieses Verständnis wird den folgenden Überlegungen zugrunde gelegt – darum, Ausdrücke und Handlungen zu vermeiden, die Gruppen von Menschen kränken oder beleidigen können, vor allem bezogen auf Geschlecht oder Herkunft. Ebenso soll eine Diskriminierung hintangehalten werden. Der Begriff ist zweifellos vielschichtiger, als er hier kurz zunächst als Ausgangspunkt für die folgenden Überlegungen beschrieben wurde. Folgt man dieser oberflächlichen Begriffsbestimmung, dann stehen Formen des Zusammenlebens von Menschen im Vordergrund. Mitmenschen nicht zu beleidigen oder zu kränken, ist für das Zusammenleben zweifellos von Wert. Auch das Strafrecht betrifft das Zusammenleben von Menschen, indem Rechtsgüter durch Einwirkung auf menschliches Verhalten geschützt werden. Gerade hinsichtlich des Beleidigens gibt es mehrere in Betracht kommende Strafnormen. Kränkungen können auf vielerlei Weise entstehen, einzelne Formen sind strafrechtlich verboten. Da das Strafrecht wohl die schärfste Waffe des Staates ist, um ein Zusammenleben von Menschen durch Verhaltensregeln zu ermöglichen oder zu erleichtern, wird diese Waffe nur rudimentär eingesetzt, um ihre (theoretische) Wirkung nicht zu vermindern. Strafrecht soll daher nicht zu oft eingesetzt werden, sondern nur, wenn es keine andere Möglichkeit gibt ("ultima ratio"). Die Anforderungen an das Verhalten sollen dabei klar und eindeutig sein, strafrechtliche Normen müssen dementsprechend sehr bestimmt sein.
Hier soll [...] der Versuch einer sprachwissenschaftlichen Beschreibung des Genderns unternommen werden, um die Sachlage zu klären und zwischen Ärger und sprachlicher Funktionalität einen wissenschaftlich vertretbaren Standpunkt zu finden. Angesichts der komplexen Datenlage ist das nur ein Essay, beschränkt auf eine kleine Zusammenstellung von Daten und auf eine kleine, doch bewusst ausgewählte wissenschaftliche Literatur. Hin und wieder möge man mir einen eigenen Zugang zur Diskussion, kleine stilistische Wagnisse und einige persönliche Bemerkungen gestatten; durchwegs wird aber auf Belegbarkeit und Überprüfbarkeit geachtet.
Die Zensur und das politisch Korrekte spielen für das Theater keine oder nur eine sehr untergeordnete Rolle. Das Politische, namentlich das politische Theater, ist gut belegt und weitgehend aufgearbeitet, ich habe kein Interesse, das zu wiederholen. Ich hatte vor, einen kleinen Spaziergang entlang der politischen Grenzen des jetzigen Theaters zu machen und die eine oder andere Aufführung zu streifen, die ich gesehen habe. Dabei hatte ich die Zensur keiner Betrachtung wert gefunden, und das politisch Korrekte habe ich im Zusammenhang des Theaters für eine Arabeske gehalten, die ein bißchen bizarr, ein bißchen unverständlich, meist als Anekdote an den Rändern der Theaterpraxis auftaucht. Seit voriger Woche weiß ich, daß ich das falsch beurteilt habe. Vorige Woche habe ich beim Berliner Theatertreffen eine Aufführung aus Leipzig gesehen, die nach dem PC-Gesichtspunkt zensiert war. Ich habe dann mit den Recherchen im Internet begonnen und bin auf eine Plattform gestoßen, die sich Bühnenwatch nennt und die seit 2012 verschiedene Theater wegen Rassismus attackiert hat (Problem Blackfacing). Es gibt auf der Plattform sehr ausführliche Statements zu Aufführungspraxis und Struktur des Theaterwesens, die ich sehr mühsam zu lesen finde, weil sie unentwegt zwischen Richtigem und Falschem, Vernünftigem und Überzogenem mäandern. Ich werde darauf zu sprechen kommen. Ich möchte aber zunächst meinen Spaziergang antreten, vorne, am Anfang, wie ich es geplant hatte, entlang der Begriffe unseres Themas – allerdings in entgegengesetzter Richtung.
The immune system makes use of major histocompatibility complex class I (MHC I) molecules to present peptides to other immune cells, which can evoke an immune response. Within this process of antigen presentation, the MHC I peptide loading complex, consisting of a transporter associated with antigen processing TAP, MHC I, and chaperones, is key to the initiation of immune response by shuttling peptides from the cytosol into the ER lumen. However, it is still enigmatic how the flux of antigens is precisely coordinated in time and space, limiting our understanding of antigen presentation pathways. Here, we report on the development of a synthetic viral TAP inhibitor that can be cleaved by light. This photo-conditional inhibitor shows temporal blockade of TAP-mediated antigen translocation, which is unleashed upon illumination. The recovery of TAP activity was monitored at single-cell resolution both in human immune cell lines and primary cells. The development of a photo-conditional TAP inhibitor thus expands the repertoire of chemical intervention tools for immunological processes.
Purpose: To evaluate if repeat Descemet membrane endothelial keratoplasty (DMEK) is appropriate to achieve functional improvements in patients with corneal decompensation from secondary graft failure after primary DMEK.
Methods: This is a retrospective monocentric cohort study including 13 eyes of 13 patients with repeat DMEK for corneal decompensation following primary DMEK. Eyes with primary DMEK only and comparable preoperative corrected distance visual acuity (CDVA) served as control. Main outcome parameter was CDVA. Secondary outcome measures were central corneal thickness (CCT), endothelial cell density, and rebubbling rate (RR).
Results: The average time interval (±SD) between primary and secondary DMEK was 12.5±6 months. Preoperative CDVA (logMAR) was 1.97±0.90 in the repeat DMEK group and 1.38±0.92 in the primary DMEK group. At 6 months, both groups showed significant improvement in visual acuity (repeat DMEK group, 0.49±0.35, P<0.01 and primary DMEK group, 0.40±0.36, P<0.01). CDVA did not differ significantly between both groups at all time points examined (1, 3, and 6 months postoperatively). Mean CCT values at 3 and 6 months postoperatively did not differ significantly between the two groups (P>0.05). The RR was
23% (n=3) in both groups.
Conclusion: Repeat DMEK is a useful therapeutic approach in the setting of corneal decompensation following primary DMEK. Functional results of repeat DMEK, visual acuity in particular, are comparable to patients with single DMEK only.
The treatment of patients with advanced breast cancer has developed further in recent years. In addition to therapeutic progress in the established subgroups (hormone receptor and HER2 status), there are now therapies which are geared to individual molecular characteristics, such as PARP inhibitor therapy in BRCA-mutated patients. In addition to this, tests are being developed which are intended to establish additional markers within subgroups in order to predict the efficacy of a therapy. PI3K mutation testing in HER2-negative, hormone-receptor-positive tumours and PD-L1 testing of immune cells in triple-negative tumours are expected to become established in clinical practice in order to select patients for the respective therapies. With new therapeutic approaches, new adverse effects also appear. The management of these adverse effects, just as those of classical therapy (supportive therapy), is essential with the introduction of new treatments in order to preserve patientsʼ quality of life. Knowledge regarding measures to preserve and improve quality of life has significantly increased in recent years. Lifestyle factors should be taken into account, as should modern therapeutic methods. This review summarises the latest studies and publications and evaluates them in regard to the relevance for clinical practice.
Die Behandlung von Patientinnen mit fortgeschrittenem Mammakarzinom hat sich in den letzten Jahren weiterentwickelt. Zusätzlich zum Therapiefortschritt in den etablierten Subgruppen (Hormonrezeptor- und HER2-Status) gibt es nun Therapien, die sich an einzelnen molekularen Charakteristika orientieren, wie zum Beispiel die PARP-Inhibitortherapie bei BRCA-mutierten Patientinnen. Zusätzlich dazu sind Tests in der Entwicklung, die innerhalb von Subgruppen weitere Marker etablieren sollen, um die Wirksamkeit einer Therapie vorherzusagen. Die PI3K-Mutationstestung bei HER2-negativen, hormonrezeptorpositiven Tumoren, und die PD-L1-Testung von Immunzellen bei triple-negativen Tumoren werden voraussichtlich in der klinischen Praxis etabliert, um Patientinnen für die jeweiligen Therapien auszuwählen. Mit neuen Therapieansätzen treten auch neue Nebenwirkungen auf. Das Management dieser Nebenwirkungen ebenso wie die der klassischen Therapien (supportive Therapie) ist mit der Einführung neuer Behandlungen essenziell, um die Lebensqualität der Patientinnen zu erhalten. Das Wissen über Maßnahmen zur Erhaltung und Verbesserung der Lebensqualität hat in den letzten Jahren deutlich zugenommen. Lifestyle-Faktoren sollten dabei ebenso Berücksichtigung finden wie moderne Therapieverfahren. Diese Übersichtsarbeit fasst die neuesten Studien und Veröffentlichungen zusammen und bewertet sie in Bezug auf die Relevanz für die klinische Praxis.
For many years, small but significant advancements have been made time and again in the prevention and treatment of early breast cancer. The so-called panel gene analyses are becoming more and more important in prevention, since the risk due to the tested genes is better understood and as a result, concepts for integration in health care can be developed. In the adjuvant situation, the first study in the so-called post-neoadjuvant situation was able to demonstrate a clear improvement in the prognosis with an absent pathological complete remission following trastuzumab or pertuzumab + trastuzumab. Additional studies with this post-neoadjuvant therapeutic concept are still being conducted at present. The CDK4/6 inhibitors which had shown a significant improvement in progression-free survival in a metastatic situation are currently being tested in the adjuvant situation in large therapeutic studies. These and other new data for the treatment or prevention of primary breast cancer are presented in this review against the backdrop of current studies.
In der Prävention und Behandlung des frühen Mammakarzinoms sind über die Jahre immer wieder kleine, aber bedeutsame Fortschritte gemacht worden. In der Prävention gewinnen die sogenannten Panel-Gen-Analysen immer mehr an Bedeutung, da das durch die getesteten Gene bedingte Risiko immer besser verstanden wird und somit Konzepte für die Integration in die Krankenversorgung erarbeitet werden können. In der adjuvanten Situation konnte die erste Studie in der sogenannten postneoadjuvanten Situation bei fehlender pathologischer Komplettremission nach Trastuzumab oder Pertuzumab + Trastuzumab eine deutliche Verbesserung der Prognose zeigen. Weitere Studien mit diesem postneoadjuvanten Therapiekonzept werden zurzeit noch durchgeführt. Die CDK4/6-Inhibitoren, die in der metastasierten Situation eine deutliche Verbesserung des progressionsfreien Überlebens gezeigt hatten, werden zurzeit in der adjuvanten Situation in großen Therapiestudien getestet. Diese und weitere neue Daten zur Behandlung oder Prävention des primären Mammakarzinoms werden in dieser Übersichtsarbeit vor dem Hintergrund aktueller Studien vorgestellt.
Objective: The mortality associated with sepsis remains unacceptably high, despite modern high-quality intensive care. Based on the results from previous studies, anaemia and its management in patients with sepsis appear to impact outcomes; however, the transfusion policy is still being debated, and the ideal approach may be extremely specific to the individual. This study aimed to investigate the long-term impact of anaemia requiring red blood cell (RBC) transfusion on mortality and disease severity in patients with sepsis. We studied a general surgical intensive care unit (ICU) population, excluding cardiac surgery patients. 435 patients were enrolled in this observational study between 2012 and 2016.
Results: Patients who received RBC transfusion between 28 days before and 28 days after the development of sepsis (n = 302) exhibited a significantly higher 90-day mortality rate (34.1% vs 19.6%; P = 0.004, Kaplan–Meier analysis). This association remained significant after adjusting for confounders in the multivariate Cox regression analysis (hazard ratio 1.68; 95% confidence interval 1.03–2.73; P = 0.035). Patients who received transfusions also showed significantly higher morbidity scores, such as SOFA scores, and ICU lengths of stay compared to patients without transfusions (n = 133). Our results indicate that anaemia and RBC transfusion are associated with unfavourable outcomes in patients with sepsis.
LILBID and nESI : different native mass spectrometry techniques as tools in structural biology
(2018)
Native mass spectrometry is applied for the investigation of proteins and protein complexes worldwide. The challenge in native mass spectrometry is maintaining the features of the proteins of interest, such as oligomeric state, bound ligands, or the conformation of the protein complex, during transfer from solution to gas phase. This is an essential prerequisite to allow conclusions about the solution state protein complex, based on the gas phase measurements. Therefore, soft ionization techniques are required. Widely used for the analysis of protein complexes are nanoelectro spray ionization (nESI) mass spectrometers. A newer ionization method is laser induced liquid bead ion desorption (LILBID), which is based on the release of protein complexes from solution phase via infrared (IR) laser desorption. We use both methods in our lab, depending on the requirements of the biological system we are interested in. Here we benchmark the performance of our LILBID mass spectrometer in comparison to a nESI instrument, regarding sample conditions, buffer and additive tolerances, dissociation mechanism and applicability towards soluble and membrane protein complexes.
Que doit nous apporter une histoire culturelle (Kulturgeschichte) du politique ? Elle ne doit pas se laisser réduire à une science sectorielle, découpée sur le modèle du camembert statistique, mais nous ouvrir, au contraire, une perspective vers le global. Ce « global », que l’on peut assimiler de façon assez vague au politique, elle ne doit pas seulement le présenter sous un autre éclairage, mais aussi l’expliquer de façon plus satisfaisante que les approches conventionnelles. Et elle devrait s’aventurer dans les domaines plus « durs » de l’histoire politique et de l’histoire constitutionnelle, c’est-à-dire des processus macro. C’est à un tel processus macro-historique, qui appartient de surcroît aux thèmes classiques de l’histoire politique et de l’histoire constitutionnelle, que je m’intéresserai : à la formation de l’État, plus exactement, à la formation de l’État au niveau provincial, et particulièrement à ce que l’on pourrait appeler l’intégration territoriale, soit l’annexion de territoires nouvellement acquis. Cette intégration territoriale est un processus fondamental dans une histoire marquée par la régression du nombre d’États en Europe à l’époque moderne : des plus de 500 entités politiques indépendantes que comptait l’Europe au début de l’époque moderne, il n’en restait plus que 25 en 19001. Les autres, soit tout de même quelques centaines d’États, ont été « avalés » par les vainqueurs dans cette course à la résorption étatique : tout d’abord prise de possession par mariage, héritage ou conquête, puis intégration dans les structures du système de domination existant. Mais le fonctionnement de cette intégration n’a guère été étudié pour le début de l’époque moderne. A fortiori, la littérature disponible sur ce thème ne propose aucun modèle permettant d’expliquer ces processus à leurs différents niveaux. La responsabilité en revient à un modèle micro-macro classique, que l’on ne peut résoudre, telle est ma thèse, que par une histoire culturelle du politique, plus exactement par l’élargissement de la recherche conventionnelle grâce au concept de culture politique. ...
The circumventricular organs (CVOs) in the central nervous system (CNS) lack a vascular blood-brain barrier (BBB), creating communication sites for sensory or secretory neurons, involved in body homeostasis. Wnt/β-catenin signaling is essential for BBB development and maintenance in endothelial cells (ECs) in most CNS vessels. Here we show that in mouse development, as well as in adult mouse and zebrafish, CVO ECs rendered Wnt-reporter negative, suggesting low level pathway activity. Characterization of the subfornical organ (SFO) vasculature revealed heterogenous claudin-5 (Cldn5) and Plvap/Meca32 expression indicative for tight and leaky vessels, respectively. Dominant, EC-specific β-catenin transcription in mice, converted phenotypically leaky into BBB-like vessels, by augmenting Cldn5+ vessels, stabilizing junctions and by reducing Plvap/Meca32+ and fenestrated vessels, resulting in decreased tracer permeability. Endothelial tightening augmented neuronal activity in the SFO of water restricted mice. Hence, regulating the SFO vessel barrier may influence neuronal function in the context of water homeostasis.
Birgit Emich
(2008)
Birgit Emich ist Gastprofessorin am Max-Weber-Kolleg für kultur- und sozialwissenschaftliche Studien Erfurt. 1999 promovierte sie an der Universität Freiburg mit einer Arbeit über Nepotismus und Behördenalltag. Politik, Verwaltung und Patronage unter Papst Paul V. (1605–1621). Studien zur frühneuzeitlichen Mikropolitik in Rom. Mit der Arbeit Territoriale Integration in der Frühen Neuzeit. Ferrara und der Kirchenstaat, für die sie den Akademiepreis der Heidelberger Akademie der Wissenschaften sowie den Jahrespreis der Wissenschaftlichen Gesellschaft in Freiburg i.B. erhielt, habilitierte sie 2002. ...
In ischemic vascular diseases, leukocyte recruitment and polarization are crucial for revascularization and tissue repair. We investigated the role of vasodilator-stimulated phosphoprotein (VASP) in vascular repair. After hindlimb ischemia induction, blood flow recovery, angiogenesis, arteriogenesis, and leukocyte infiltration into ischemic muscles in VASP−/− mice were accelerated. VASP deficiency also elevated the polarization of the macrophages through increased signal transducer and activator of transcription (STAT) signaling, which augmented the release of chemokines, cytokines, and growth factors to promote leukocyte recruitment and vascular repair. Importantly, VASP deletion in bone marrow–derived cells was sufficient to mimic the increased blood flow recovery of global VASP−/− mice. In chemotaxis experiments, VASP−/− neutrophils/monocytes were significantly more responsive to M1-related chemokines than wild-type controls. Mechanistically, VASP formed complexes with the chemokine receptor CCR2 and β-arrestin-2, and CCR2 receptor internalization was significantly reduced in VASP−/− leukocytes. Our data indicate that VASP is a major regulator of leukocyte recruitment and polarization in postischemic revascularization and support a novel role of VASP in chemokine receptor trafficking.
Introduction: The Retro-IDEAL (ILUVIEN Implant for chronic DiabEtic MAcuLar edema) study is a retrospective study designed to assess real-world outcomes achieved with the ILUVIEN® (0.19 mg fluocinolone acetonide (FAc)) in patients with chronic diabetic macular edema (DME) in clinical practices in Germany.
Methods: This study was conducted across 16 sites in Germany and involved 81 eyes (63 patients) with persistent or recurrent DME and a prior suboptimal response to a first-line intravitreal therapy (primarily anti-VEGF intravitreal therapies).
Results: Patients were followed-up for 30.8 ± 11.3 months (mean ± standard deviation) and had a mean age of 68.0 ± 10.4 years. Best-recorded visual acuity (BRVA) improved by +5.5 letters at month 9 (P ⩽ 0.005, n=56; from a baseline of 49 letters) and this was maintained through to month 30 (P ⩽ 0.05, n = 42). There was a concurrent improvement in central macular thickness with a reduction from 502 µm at baseline to 338 µm at year 1 (P ⩽ 0.0001, n = 43). This effect was sustained to year 3 (i.e. 318 µm; P ⩽ 0.0001, n = 29). Mean intraocular pressure (IOP) remained constant between baseline and year 3 with a peak change of 1.9 mm Hg occurring at year 1. Elevated IOP was observed in a similar percentage of patients prior to (22.2% of cases) and following (27.2%) treatment with the FAc implant. In the majority of cases, these elevations were managed effectively with IOP medications.
Conclusions: Despite substantial amounts of prior intravitreal treatments – primarily with anti–vascular endothelial growth factor (VEGF) drugs – this real-world study showed that sustained structural and functional improvements can last for up to 3 years with a single FAc implant.
BIAM switch assay coupled to mass spectrometry identifies novel redox targets of NADPH oxidase 4
(2019)
Aim: NADPH oxidase (Nox) -derived reactive oxygen species have been implicated in redox signaling via cysteine oxidation in target proteins. Although the importance of oxidation of target proteins is well known, the specificity of such events is often debated. Only a limited number of Nox-oxidized proteins have been identified thus far; especially little is known concerning redox-targets of the constitutively active NADPH oxidase Nox4.
In this study, HEK293 cells with tetracycline-inducible Nox4 overexpression (HEK-tet-Nox4), as well as podocytes of WT and Nox4-/- mice, were utilized to identify Nox4-dependent redox-modified proteins.
Results: TGFβ1 induced an elevation in Nox4 expression in podocytes from WT but not Nox4-/- mice. Using BIAM based redox switch assay in combination with mass spectrometry and western blot analysis, 142 proteins were identified as differentially oxidized in podocytes from wild type vs. Nox4-/- mice and 131 proteins were differentially oxidized in HEK-tet-Nox4 cells upon Nox4 overexpression. A predominant overlap was found for peroxiredoxins and thioredoxins, as expected. More interestingly, the GRB2-associated-binding protein 1 (Gab1) was identified as being differentially oxidized in both approaches. Further analysis using mass spectrometry-coupled BIAM switch assay and site directed mutagenesis, revealed Cys374 and Cys405 as the major Nox4 targeted oxidation sites in Gab1.
Innovation & conclusion: BIAM switch assay coupled to mass spectrometry is a powerful and versatile tool to identify differentially oxidized proteins in a global untargeted way. Nox4, as a source of hydrogen peroxide, changes the redox-state of numerous proteins. Of those, we identified Gab1 as a novel redox target of Nox4.
Last week’s printed edition of Focus had a piece about how Germany’s politicians are using social media. It made the dubious claim that 61% of Green top candidate Katrin Göring-Eckardt’s Twitter followers could have been bought.
Let’s actually instead try to get to grips with what is going on here, and try to draw some conclusions. ...
Background: Aortic valve stenosis has gained increasingly more importance due to its high prevalence in elderly people. More than two decades ago, transcatheter aortic valve replacement emerged for patients who were denied surgery, and its noninferiority has been demonstrated in numerous studies. Oxidative stress has generated great interest because of its sensitivity to cell damage and the possibility of offering early hints of clinical outcomes. The aim of the present study was to investigate whether there is a significant difference between transcatheter (TAVR) or surgical aortic valve replacement (SAVR) in terms of the changes in oxidation-reduction potential (ORP) and antioxidant capacity. Therefore, we investigated perioperative oxidative stress levels and their influence on clinical outcomes.
Methods: A total of 72 patients (50% TAVR versus 50% SAVR) were included in the present study. Static oxidation-reduction potential (sORP) and antioxidant capacity were measured using the RedoxSys™ Diagnostic System (Luoxis Diagnostics, USA) in serum samples drawn before and after surgery, as well as on the first postoperative day. In addition, clinical data were obtained to evaluate the clinical outcome of each case.
Results: TAVR patients had higher preoperative sORP levels compared to the SAVR patients and more severe comorbidities. Unlike the TAVR cohort, patients in the SAVR group showed a significant difference in sORP from the pre- to postoperative levels. Capacity demonstrated higher preoperative levels in the SAVR cohort and also a greater difference postoperatively compared to the TAVR cohort. Regression analysis revealed a significant correlation between pre- and postoperative capacity levels (r = -0.9931, p < 0.0001), providing a method of predicting postoperative capacity levels by knowing the preoperative levels. According to the multivariable analysis, both sORP and antioxidant capacity are dependent on time point, baseline value, and type of surgery, with the largest variations observed for time effect and surgery method.
Conclusion: A high preoperative sORP level correlated to more severe illness in the TAVR patients. As the TAVR patients did not show significant differences in their preoperative levels, we assume that there was a smaller production of oxidative agents during TAVR due to the less invasive nature of the procedure. Baseline values and development of antioxidant capacity values strengthen this hypothesis. The significant correlation of pre- and postoperative capacity levels might allow high risk patients to be detected more easily and might provide more adequate and individualized therapy preoperatively. This trial is registered with clinicaltrials.gov, identifier: NCT 02488876.
Background: There are no blood-based molecular biomarkers of temporal lobe epilepsy (TLE) to support clinical diagnosis. MicroRNAs are short noncoding RNAs with strong biomarker potential due to their cell-specific expression, mechanistic links to brain excitability, and stable detection in biofluids. Altered levels of circulating microRNAs have been reported in human epilepsy, but most studies collected samples from one clinical site, used a single profiling platform or conducted minimal validation.
Method: Using a case-control design, we collected plasma samples from video-electroencephalogram-monitored adult TLE patients at epilepsy specialist centers in two countries, performed genome-wide PCR-based and RNA sequencing during the discovery phase and validated findings in a large (>250) cohort of samples that included patients with psychogenic non-epileptic seizures (PNES).
Findings: After profiling and validation, we identified miR-27a-3p, miR-328-3p and miR-654-3p with biomarker potential. Plasma levels of these microRNAs were also changed in a mouse model of TLE but were not different to healthy controls in PNES patients. We determined copy number of the three microRNAs in plasma and demonstrate their rapid detection using an electrochemical RNA microfluidic disk as a prototype point-of-care device. Analysis of the microRNAs within the exosome-enriched fraction provided high diagnostic accuracy while Argonaute-bound miR-328-3p selectively increased in patient samples after seizures. In situ hybridization localized miR-27a-3p and miR-328-3p within neurons in human brain and bioinformatics predicted targets linked to growth factor signaling and apoptosis.
Interpretation: This study demonstrates the biomarker potential of circulating microRNAs for epilepsy diagnosis and mechanistic links to underlying pathomechanisms.
Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAFcases = 0.431, MAFcontrols = 0.368) upstream of MIR579 was associated with panic disorder in patients (pallelic = 0.004, ncases = 506, ncontrols = 506) and with higher trait anxiety in healthy individuals (pASI = 0.029, pACQ = 0.047, n = 3112). Compared to the major (A)-allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p = 0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270) = 5.47, p = 0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.
Memory enables us to use information from our past experiences to guide new behaviours, calling for the need to integrate or form inference across multiple distinct episodic experiences. Here, we compared children (aged 9–10 years), adolescents (aged 12–13 years), and young adults (aged 19–25 years) on their ability to form integration across overlapping associations in memory. Participants first encoded a set of overlapping, direct AB- and BC-associations (object-face and face-object pairs) as well as non-overlapping, unique DE-associations. They were then tested on these associations and inferential AC-associations. The experiment consisted of four such encoding/retrieval cycles, each consisting of different stimuli set. For accuracy on both unique and inferential associations, young adults were found to outperform teenagers, who in turn outperformed children. However, children were particularly slower than teenagers and young adults in making judgements during inferential than during unique associations. This suggests that children may rely more on making inferences during retrieval, by first retrieving the direct associations, followed by making the inferential judgement. Furthermore, young adults showed a higher correlation between accuracy in direct (AB, BC) and inferential AC-associations than children. This suggests that, young adults relied closely on AB- and BC-associations for making AC decisions, potentially by forming integrated ABC-triplets during encoding or retrieval. Taken together, our findings suggest that there may be an age-related shift in how information is integrated across experienced episodes, namely from relying on making inferences at retrieval during middle childhood to forming integrated representations at different memory processing stages in adulthood.
Here we present a comprehensive attempt to correlate aragonitic Na / Ca ratios from Lophelia pertusa, Madrepora oculata and a caryophylliid cold-water coral (CWC) species with different seawater parameters such as temperature, salinity and pH. Living CWC specimens were collected from 16 different locations and analyzed for their Na / Ca content using solution-based inductively coupled plasma-optical emission spectrometry (ICP-OES) measurements. The results reveal no apparent correlation with salinity (30.1–40.57 g/kg) but a significant inverse correlation with temperature (−0.31 mmol/mol/°C). Other marine aragonitic organisms such as Mytilus edulis (inner aragonitic shell portion) and Porites sp. exhibit similar results highlighting the consistency of the calculated CWC regressions. Corresponding Na / Mg ratios show a similar temperature sensitivity to Na / Ca ratios, but the combination of two ratios appear to reduce the impact of vital effects and domain-dependent geochemical variation. The high degree of scatter and elemental heterogeneities between the different skeletal features in both Na / Ca and Na / Mg however limit the use of these ratios as a proxy and/or make a high number of samples necessary. Additionally, we explore two models to explain the observed temperature sensitivity of Na / Ca ratios for an open and semi-enclosed calcifying space based on temperature sensitive Na and Ca pumping enzymes and transport proteins that change the composition of the calcifying fluid and consequently the skeletal Na / Ca ratio.
In einer diachronen Vergleichsstudie sollen die Probleme des frühneuzeitlichen Seehandels Dänemarks und der Hansestädte gegenüber den Barbaresken beschrieben und verschiedene Lösungsmodelle wie auch die Implementierung derselben herausgearbeitet werden. Die Gefährdung der Schifffahrt auf dem vogelperspektivisch konzipierten Raum Meer mit einem nach Süden hin steigenden Risiko führte zu einer kartographischen Einteilung von Risikozonen. Die institutionelle Antwort auf diese Entwicklung kann mit den Begriffen Sklavenkasse und Türkenpässe idealtypisch zusammengefasst werden.
Prescribing practice of pregabalin/gabapentin in pain therapy : an evaluation of German claim data
(2019)
Objectives: To analyse the prevalence and incidence of pregabalin and gabapentin (P/G) prescriptions, typical therapeutic uses of P/G with special attention to pain-related diagnoses and discontinuation rates.
Design: Secondary data analysis.
Setting: Primary and secondary care in Germany.
Participants: Four million patients in the years 2009–2015 (anonymous health insurance data).
Intervention: None.
Primary and secondary outcome measures: P/G prescribing rates, P/G prescribing rates associated with pain therapy, analysis of pain-related diagnoses leading to new P/G prescriptions and the discontinuation rate of P/G.
Results: In 2015, 1.6% of insured persons received P/G prescriptions. Among the patients with pain first treated with P/G, as few as 25.7% were diagnosed with a typical neuropathic pain disorder. The remaining 74.3% had either not received a diagnosis of neuropathic pain or showed a neuropathic component that was pathophysiologically conceivable but did not support the prescription of P/G. High discontinuation rates were observed (85%). Among the patients who had discontinued the drug, 61.1% did not receive follow-up prescriptions within 2 years.
Conclusion: The results show that P/G is widely prescribed in cases of chronic pain irrespective of neuropathic pain diagnoses. The high discontinuation rate indicates a lack of therapeutic benefits and/or the occurrence of adverse effects.
Electron cryo-microscopy analyzes the structure of proteins and protein complexes in vitrified solution. Proteins tend to adsorb to the air-water interface in unsupported films of aqueous solution, which can result in partial or complete denaturation. We investigated the structure of yeast fatty acid synthase at the air-water interface by electron cryo-tomography and single-particle image processing. Around 90% of complexes adsorbed to the air-water interface are partly denatured. We show that the unfolded regions face the air-water interface. Denaturation by contact with air may happen at any stage of specimen preparation. Denaturation at the air-water interface is completely avoided when the complex is plunge-frozen on a substrate of hydrophilized graphene.
An accelerating Brewer-Dobson circulation (BDC) is a robust signal of climate change in model predictions but has been questioned by trace gas observations. We analyze stratospheric mean age of air and the full age spectrum as measures for the BDC and its trend. Age of air is calculated with the Chemical Lagrangian Model of the Stratosphere (CLaMS) driven by ERA-Interim, JRA-55 and MERRA-2 reanalysis data to assess the robustness of the representation of the BDC in current generation meteorological reanalyses. We find that climatological mean age significantly depends on the reanalysis, with JRA-55 showing the youngest and MERRA-2 the oldest mean age. Consideration of the age spectrum indicates that the older age for MERRA-2 is related to a stronger spectrum tail, likely related to weaker tropical upwelling and stronger recirculation. Seasonality of stratospheric transport is robustly represented in reanalyses, with similar mean age variations and age spectrum peaks. Long-term changes over 1989–2015 turn out to be similar for the reanalyses with mainly decreasing mean age accompanied by a shift of the age spectrum peak towards shorter transit times, resembling the forced response in climate model simulations to increasing greenhouse gas concentrations. For the shorter periods 1989–2001 and 2002–2015 age of air changes are less robust. Only ERA-Interim shows the hemispheric dipole pattern in age changes during 2002–2015 as viewed by recent satellite observations. Consequently, the representation of decadal variability of the BDC in current generation reanalyses appears less robust and a major uncertainty of modelling the BDC.
Cysteinyl leukotriene receptor 1 antagonists (CysLT1RA) are frequently used as add-on medication for the treatment of asthma. Recently, these compounds have shown protective effects in cardiovascular diseases. This prompted us to investigate their influence on soluble epoxide hydrolase (sEH) and peroxisome proliferator activated receptor (PPAR) activities, two targets known to play an important role in CVD and the metabolic syndrome. Montelukast, pranlukast and zafirlukast inhibited human sEH with IC50 values of 1.9, 14.1, and 0.8 μM, respectively. In contrast, only montelukast and zafirlukast activated PPARγ in the reporter gene assay with EC50 values of 1.17 μM (21.9% max. activation) and 2.49 μM (148% max. activation), respectively. PPARα and δ were not affected by any of the compounds. The activation of PPARγ was further investigated in 3T3-L1 adipocytes. Analysis of lipid accumulation, mRNA and protein expression of target genes as well as PPARγ phosphorylation revealed that montelukast was not able to induce adipocyte differentiation. In contrast, zafirlukast triggered moderate lipid accumulation compared to rosiglitazone and upregulated PPARγ target genes. In addition, we found that montelukast and zafirlukast display antagonistic activities concerning recruitment of the PPARγ cofactor CBP upon ligand binding suggesting that both compounds act as PPARγ modulators. In addition, zafirlukast impaired the TNFα triggered phosphorylation of PPARγ2 on serine 273. Thus, zafirlukast is a novel dual sEH/PPARγ modulator representing an excellent starting point for the further development of this compound class.
Selection and prioritization of patients with HCC for LT are based on pretransplant imaging diagnostic, taking the risk of incorrect diagnosis. According to the German waitlist guidelines, imaging has to be reported to the allocation organization (Eurotransplant) and pathology reports have to be submitted thereafter. In order to assess current procedures we performed a retrospective multicenter analysis in all German transplant centers with focus on accuracy of imaging diagnostic and tumor classification. 1168 primary LT for HCC were conducted between 2007 and 2013 in Germany. Patients inside the Milan, UCSF, and up-to-seven criteria were misclassified with definitive histologic results in 18%, 15%, and 11%, respectively. Patients pretransplant outside the Milan, UCSF, and up-to-seven criteria were otherwise misclassified in 34%, 43%, and 41%. Recurrence-free survival correlated with classification by posttransplant histological report, but not pretransplant imaging diagnostic. Univariate analysis revealed tumor size, vascular invasion, and grading as significant parameters for outcome, while tumor grading was the only parameter persisting by multivariate testing. Conclusion. There was a relevant percentage (15-40%) of patients misclassified by imaging diagnosis at a time prior to LI-RADS and guidelines to improve imaging of HCC. Outcome analysis showed a good correlation to histological, in contrast poor correlation to imaging diagnosis, suggesting an adjustment of the LT selection and prioritization criteria.
Background: Hepatitis C virus (HCV) is currently classified into 8 genotypes and 86 subtypes. The objective of this study was to characterize novel HCV subtypes and to investigate the impact of subtypes on treatment outcome.
Methods: Full-genome sequencing was performed on HCV plasma samples with <85% sequence homology of NS3, NS5A, and/or NS5B to HCV genotype (GT) 1–8 reference strains.
Results: A total of 14 653 patients with GT1–6 HCV infection were enrolled in clinical studies of sofosbuvir-based regimens. For the majority of the patients, a specific subtype could be assigned based on a close genetic relationship to previously described subtypes. However, for 19 patients, novel subtypes were identified with <85% homology compared with previously described subtypes. These novel subtypes had the following genotypes: 9 in GT2, 5 in GT4, 2 in GT6, and 1 each in GT1, GT3, and GT5. Despite the presence of polymorphisms at resistance-associated substitution positions, 18 of the 19 patients treated with sofosbuvir-containing therapy achieved SVR12.
Conclusions: Nineteen novel HCV subtypes were identified, suggesting an even greater genetic diversity of HCV subtypes than previously recognized.
Background: Task switch protocols are frequently used in the assessment of cognitive control, both in clinical and non-clinical populations. These protocols frequently confound task switch and attentional set shift. The current study investigated the ability of adult ADHD patients to shift attentional set in the context of switching tasks.
Method: We tested 38 adults with ADHD and 39 control adults with an extensive diagnostic battery and a task switch protocol without proactive interference. The experiment combined orthogonally task-switch vs. repetition, and attentional set shift vs. no shift. Each experimental stimulus had global and local features (Hierarchical/"Navon" stimuli), associated with corresponding attentional sets.
Results: ADHD patients were slower than controls in task switch trials with a simultaneous shift of attention between global/local attentional sets. This also correlated significantly with diagnostic scales for ADHD symptoms. The patients had more variable reaction times, but when the attentional set was kept constant neither were they significantly slower nor showed higher task switch costs.
Conclusion: ADHD is associated with a deficit in flexible deployment of attention to varying sources of stimulus information.
Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders with significant and often lifelong effects on social, emotional, and cognitive functioning. Influential neurocognitive models of ADHD link behavioral symptoms to altered connections between and within functional brain networks. Here, we investigate whether network-based theories of ADHD can be generalized to understanding variations in ADHD-related behaviors within the normal (i.e., clinically unaffected) adult population. In a large and representative sample, self-rated presence of ADHD symptoms varied widely; only eight out of 291 participants scored in the clinical range. Subject-specific brain-network graphs were modeled from functional MRI resting-state data and revealed significant associations between (non-clinical) ADHD symptoms and region-specific profiles of between-module and within-module connectivity. Effects were located in brain regions associated with multiple neuronal systems including the default-mode network, the salience network, and the central executive system. Our results are consistent with network perspectives of ADHD and provide further evidence for the relevance of an appropriate information transfer between task-negative (default-mode) and task-positive brain regions. More generally, our findings support a dimensional conceptualization of ADHD and contribute to a growing understanding of cognition as an emerging property of functional brain networks.
B-cell development and function depend on stage-specific signaling through the B-cell antigen receptor (BCR). Signaling and intracellular trafficking of the BCR are connected, but the molecular mechanisms of this link are incompletely understood. Here, we investigated the role of the endosomal adaptor protein and member of the LAMTOR/Ragulator complex LAMTOR2 (p14) in B-cell development. Efficient conditional deletion of LAMTOR2 at the pre-B1 stage using mb1-Cre mice resulted in complete developmental arrest. Deletion of LAMTOR2 using Cd19-Cre mice permitted analysis of residual B cells at later developmental stages, revealing that LAMTOR2 was critical for the generation and activation of mature B lymphocytes. Loss of LAMTOR2 resulted in aberrant BCR signaling due to delayed receptor internalization and endosomal trafficking. In conclusion, we identify LAMTOR2 as critical regulator of BCR trafficking and signaling that is essential for early B-cell development in mice.
Short Summary: Extracellular vesicles (EVs), released during tissue/cell injury, contain a "barcode" indicating specific microRNAs (miRs) that can uncover their origin. We examined whether systemic EVs possessing hepatic miR-signatures would indicate ongoing liver injury and clinical complications in trauma patients (TP). We grouped the patients of alcoholic drinkers into "alcohol-drinkers with liver injury (LI)" (EtOH with LI) or "alcohol-drinkers without LI" (EtOH w/o LI) and we compared these groups to "non-drinkers" (no EtOH). When we examined patient blood from the EtOH with LI group we found the total number of EVs to be increased, along with an increase in miR-122 and let7f—two EV-associated miRNAs—and several inflammation-associating cytokines, such as interleukin (IL)-6 and IL-33. In contrast, all of the aforementioned readouts were found to be decreased in the EtOH w/o LI group. These novel data demonstrate that hepatocyte damage in alcohol-intoxicated trauma patients presenting with liver injury can be reflected by an increase in circulating serum EVs, their specific miR-"barcode" and the concomitant increase of systemic inflammatory markers IL-6 and IL-33. Anti-inflammatory effect of alcohol-drinking in EtOH w/o LI can be presented by a reduced number of hepato-derived EVs, no upregulation of IL-6 and IL-33, and a miR "barcode" different from patients presenting with liver injury.
Background: Alcohol abuse is associated with (neuro)protective effects related to (head) injuries, and with negative effects regarding infection rates and survival in severely injured trauma patients (TP). Extracellular vesicles (EVs), which are released during tissue and/or cell injury, can contain a "barcode" including specific microRNAs (miRs) that uncover their origin. We examined whether EVs with a hepatic miR signature can be systemically measured, and whether they can indicate ongoing liver injury in alcohol-intoxicated TP and foretell clinical complications.
Patients/Methods: We enrolled 35 TP and measured blood EVs, IL-6, TNF-alpha, IL-1beta, IL-10 and IL-33, alcohol (ethanol, EtOH) concentration (BAC), GLDH, GGT, AST, ALT, leukocytes, platelets, and bilirubin. Within circulating EVs we measured the expression levels of miR-122, let7f, miR21, miR29a, miR-155, and miR-146a. Patients of alcohol-drinkers were grouped into "alcohol drinkers with liver injury (LI)" (EtOH with LI) or "alcohol drinkers without LI" (EtOH w/o LI) and compared to "non-drinkers" (no EtOH). We assessed systemic injury characteristics and the outcome of hospitalization with regard to sepsis, septic shock, pneumonia, or mortality.
Results: EtOH with LI patients had significantly increased rates of pneumonia vs. the EtOH w/o LI group. EVs, IL-6, and IL-33 levels were significantly increased in EtOH with LI vs. EtOH w/o LI group (p < 0.05). EV number correlated positively with ALT and IL-6 (p < 0.0001). Two miRs, miR-122 and let7f, were increased only in the blood EVs from the EtOH with LI group (p < 0.05). Five miRs, miR-122, let7f, miR-21, miR-29a, and miR-146a, were reduced in the blood EVs from the EtOH w/o LI group, vs. no EtOH (p < 0.05). Notably miR-122 correlated significantly with increased bilirubin levels in the EtOH with LI group (p < 0.05).
Conclusions: Liver injury in alcohol-intoxicated TP is reflected by increased EV numbers, their specific miR barcode, and the correlated increase of systemic inflammatory markers IL-6 and IL-33. Interestingly, severely injured TP without liver injury were found to have a reduced number of liver-derived EVs, no observed inflammatory infiltration and reduced specific miR "barcode."
Aim: Reactive oxygen species (ROS) produced by enzymes of the NADPH oxidase family serve as second messengers for cellular signaling. Processes such as differentiation and proliferation are regulated by NADPH oxidases. In the intestine, due to the exceedingly fast and constant renewal of the epithelium both processes have to be highly controlled and balanced. Nox1 is the major NADPH oxidase expressed in the gut, and its function is regulated by cytosolic subunits such as NoxO1. We hypothesize that the NoxO1-controlled activity of Nox1 contributes to a proper epithelial homeostasis and renewal in the gut.
Results: NoxO1 is highly expressed in the colon. Knockout of NoxO1 reduces the production of superoxide in colon crypts and is not subsidized by an elevated expression of its homolog p47phox. Knockout of NoxO1 increases the proliferative capacity and prevents apoptosis of colon epithelial cells. In mouse models of dextran sulfate sodium (DSS)-induced colitis and azoxymethane/DSS induced colon cancer, NoxO1 has a protective role and may influence the population of natural killer cells.
Conclusion: NoxO1 affects colon epithelium homeostasis and prevents inflammation.
Objectives: Large-scale clinical studies investigating associations between intestinal microbiota signatures and human diseases usually rely on stool samples. However, the timing of repeated stool sample collection cannot be predefined in longitudinal settings. Rectal swabs, being straightforward to obtain, have the potential to overcome this drawback. Therefore, we assessed the usability of rectal swabs for microbiome sampling in a cohort of hematological and oncological patients.
Study design: We used a pipeline for intestinal microbiota analysis from deep rectal swabs which was established and validated with test samples and negative controls. Consecutively, a cohort of patients from hematology and oncology wards was established and weekly deep rectal swabs taken during their admissions and re-admissions.
Results: Validation of our newly developed pipeline for intestinal microbiota analysis from rectal swabs revealed consistent and reproducible results. Over a period of nine months, 418 rectal swabs were collected longitudinally from 41 patients. Adherence to the intended sampling protocol was 97%. After DNA extraction, sequencing, read pre-processing and filtering of chimeric sequences, 405 of 418 samples (96.9%) were eligible for further analyses. Follow-up samples and those taken under current antibiotic exposure showed a significant decrease in alpha diversity as compared to baseline samples. Microbial domination occurred most frequently by Enterococcaceae (99 samples, 24.4%) on family level and Enterococcus (90 samples, 22.2%) on genus level. Furthermore, we noticed a high abundance of potential skin commensals in 99 samples (24.4%).
Summary: Deep rectal swabs were shown to be reliable for microbiome sampling and analysis, with practical advantages related to high sampling adherence, easy timing, transport and storage. The relatively high abundance of putative skin commensals in this patient cohort may be of potential interest and should be further investigated. Generally, previous findings on alpha diversity dynamics obtained from stool samples were confirmed.
Tolerizing CTL by sustained hepatic PD-L1 expression provides a new therapy spproach in mouse sepsis
(2019)
Cytotoxic T lymphocyte (CTL) activation contributes to liver damage during sepsis, but the mechanisms involved are largely unknown. Understanding the underlying principle will permit interference with CTL activation and thus, provide a new therapeutic option.
Methods: To elucidate the mechanism leading to CTL activation we used the Hepa1-6 cell line in vitro and the mouse model of in vivo polymicrobial sepsis, following cecal-ligation and -puncture (CLP) in wildtype, myeloid specific NOX-2, global NOX2 and NOX4 knockout mice, and their survival as a final readout. In this in vivo setting, we also determined hepatic mRNA and protein expression as well as clinical parameters of liver damage - aspartate- and alanine amino-transaminases. Hepatocyte specific overexpression of PD-L1 was achieved in vivo by adenoviral infection and transposon-based gene transfer using hydrodynamic injection.
Results: We observed downregulation of PD-L1 on hepatocytes in the murine sepsis model. Adenoviral and transposon-based gene transfer to restore PD-L1 expression, significantly improved survival and reduced the release of liver damage, as PD-L1 is a co-receptor that negatively regulates T cell function. Similar protection was observed during pharmacological intervention using recombinant PD-L1-Fc. N-acetylcysteine blocked the downregulation of PD-L1 suggesting the involvement of reactive oxygen species. This was confirmed in vivo, as we observed significant upregulation of PD-L1 expression in NOX4 knockout mice, following sham operation, whereas its expression in global as well as myeloid lineage NOX2 knockout mice was comparable to that in the wild type animals. PD-L1 expression remained high following CLP only in total NOX2 knockouts, resulting in significantly reduced release of liver damage markers.
Conclusion: These results suggest that, contrary to common assumption, maintaining PD-L1 expression on hepatocytes improves liver damage and survival of mice during sepsis. We conclude that administering recombinant PD-L1 or inhibiting NOX2 activity might offer a new therapeutic option in sepsis.
Site-specific cleavage of RNAs derived from the PIM1 3′-UTR by a metal-free artificial ribonuclease
(2019)
Oligonucleotide conjugates of tris(2-aminobenzimidazole) have been reported previously to cleave complementary RNA strands with high levels of sequence and site specificity. The RNA substrates used in these studies were oligonucleotides not longer than 29-mers. Here we show that ~150–400-mer model transcripts derived from the 3′-untranslated region of the PIM1 mRNA reacted with rates and specificities comparable to those of short oligonucleotide substrates. The replacement of DNA by DNA/LNA mixmers further increased the cleavage rate. Tris(2-aminobenzimidazoles) were designed to interact with phosphates and phosphate esters. A cell, however, contains large amounts of phosphorylated species that may cause competitive inhibition of RNA cleavage. It is thus important to note that no loss in reaction rates was observed in phosphate buffer. This opens the way to in-cell applications for this type of artificial nuclease. Furthermore, we disclose a new synthetic method giving access to tris(2-aminobenzimidazoles) in multigram amounts.