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Kontingenz / Zufall
(2019)
Bis zum Jahr 2003, als Peter Vogt, auf dessen Habilitationsschrift "Kontingenz und Zufall. Eine Ideen- und Begriffsgeschichte" Verena Wirtz im Folgenden eingeht, Teil des von Hans Joas geleiteten Forschungsprojekts "Kontingenz und Moderne" wurde und der Begriff von der Peripherie ins Zentrum interdisziplinärer Forschung rückte, handelte es sich um eine noch nicht begriffene Geschichte. Dabei war 'Kontingenz' als Mode- und Schlagwort der klassischen Moderne längst zu einem Grundbegriff der Postmoderne avanciert. Zunächst und primär Gegenstand der Philosophie, dann Leitbegriff der Soziologie, Ökonomie und Politikwissenschaft, hat sich im vergangenen Jahrzehnt auch die kontingenzscheue Geschichtswissenschaft des Begriffs und Sachverhalts des Unverfügbaren in der Geschichte angenommen.
The endemic argan tree (Argania spinosa) populations in South Morocco are highly degraded due to their use as a biomass resource in dry years and illegal firewood extraction. The intensification and expansion of agricultural land lead to a retreat of the wooded area, while the remaining argan open woodlands are often overgrazed. Thus, canopy-covered areas decrease while areas without vegetation cover between the argan trees increase. In total, 36 rainfall simulation experiments as well as 60 infiltration measurements were conducted to investigate the potential difference between tree-covered areas and bare intertree areas. In addition, 60 soil samples were taken under the trees and in the intertree areas parallel to the contour lines. Significant differences using a t-test were found between tree and intertree areas for the studied parameters Ksat, Kh, pH, electric conductivity, percolation stability, total C-content, total N-content, K-content, Na-content, and Mg-content. Surface runoff and soil losses were not as conclusive but showed similar trends. The results showed that argan trees influence the soil underneath significantly, while the soil in intertree areas is less protected and more degraded. It is therefore reasonable to assume further degradation of the soil when intertree areas extend further due to lack of rejuvenation of argan trees.
Diversität: Bemerkungen zur Begriffsgeschichte der Diversität ausgehend von drei Sammelbänden
(2019)
Auffallend an der Geschichte des Begriffs der Diversität ist die Spannung zwischen der sehr langen Geschichte seines Gebrauchs und seinem dementsprechend sehr weiten Anwendungsbereich einerseits und der spezifischen Signalwirkung in der politisch-sozialen Sprache seit den 1980er Jahren andererseits. Bis zu dieser Zeit erscheint der Ausdruck in den großen deutschsprachigen Enzyklopädien meist nur mit einer kurzen Erläuterung seiner Bedeutung als "Verschiedenheit". Bereits in der Antike fungiert dieses Wort allerdings - ebenso wie die in seinem semantischen Umfeld stehenden Ausdrücke 'ποικiλία' und 'varietas' - als ein Wertbegriff, und zwar vor allem im Kontext der Ästhetik. Das Bunt-Schillernde, das die primäre Bedeutung von 'poikilia' im Griechischen ist, wird von Platon zwar noch abgelehnt, weil es etwas Oberflächliches sei, das nur für Kinder und Frauen Unterhaltung biete und von dem Eigentlichen, das in die Tiefe geht, ablenke. Später, besonders in der römischen Antike, avanciert die Darstellung von Vielfalt aber zu einem zentralen Prinzip der Ästhetik (so dass die Vielfalt ein "römisches Prinzip" genannt wurde). Erklärt wird dies mit politischen und kulturellen Entwicklungen wie der Verfasstheit des römischen Reiches als ein Vielvölkerstaat, der den vielfältigen Sinnenfreuden nicht abgeneigten römischen Alltagskultur (der Oberschicht) und nicht zuletzt dem Polytheismus. Auch in den christlichen Kontext wird die Vorliebe für Vielfalt übernommen und der eine Gott über die Vielfalt der Erscheinungen seiner Welt gepriesen. Dieser Hintergrund des Begriffsfeldes bildete eine Bedingung für die Konjunktur des Ausdrucks Diversität am Ende des 20. Jahrhunderts. Falko Schmieder beleuchtet anhand von drei in den letzten Jahren erschienenen Sammelbänden, wie diese Konjunktur sich entfaltete.
Zukunft
(2019)
In seiner Monographie zum Konzept der Zukunft hat sich Lucian Hölscher (Die Entdeckung der Zukunft, Göttingen 2016) einer Schlüsselkategorie aus dem Begriffsfeld der Zeit zugewandt, das im Wörterbuch der "Geschichtlichen Grundbegriffe" auffällig wenig bearbeitet ist. Das Thema der Zeitlichkeit ist dem Buch dabei selbst eingeschrieben, weil es sich hier um die aktualisierte und deutlich erweiterte Neuauflage einer Studie handelt, die erstmals im Jahre 1999 publiziert wurde. [...] Das Grundgerüst der Gliederung in vier größere Epochenabschnitte, beginnend mit dem Zeitraum von 1770 bis 1830, hat Hölscher beibehalten. Dem Themenschwerpunkt der vorliegenden FIB-Ausgabe entsprechend soll im Folgenden vor allem die Darstellung der Entwicklungen des 20. Jahrhunderts - also nach Hölschers Einteilung des Zeitraums von 1890 bis 1950 und der Zeit seit 1950 - betrachtet werden, denen etwa zwei Drittel des Buches gewidmet sind.
Innovation
(2019)
Der kanadische Wissenschaftshistoriker Benoît Godin legte im Jahre 2015 die erste umfassende Begriffsgeschichte von 'Innovation' vor, die sich im Wesentlichen auf englisch- und französischsprachige Quellen bezieht. Falko Schmieder beschäftigt sich nun mit der ersten begriffsgeschichtlichen Studie zur Verwendung von 'Innovation' im Deutschen, Susanna Webers "Innovation. Zur Begriffsgeschichte eines modernen Fahnenworts". Den aktuellen Ausgangspunkt bildet die Beobachtung einer enormen Reichweite und Expansion des Begriffs in den unterschiedlichsten gesellschaftlichen Bereichen.
Hegemonie
(2019)
Perry Andersons jüngstes Buch "Hegemonie. Konjunkturen eines Begriffs" ist ein Beleg für die internationale Konjunktur der Begriffsgeschichte und speziell für deren zunehmend globale Ausrichtung. Die Geschichte des Begriffs, die Anderson erzählt, berührt nämlich "acht oder neun verschiedene Nationalkulturen". Sie hat voneinander unabhängige Ursprünge, die in der griechischen Antike und in der noch älteren chinesischen Zhou-Dynastie liegen. Anderson hält fest, dass die lange und komplexe Bedeutungsgeschichte von 'Hegemonie' in den aktuellen Verwendungen zumeist ignoriert wird oder nicht mehr präsent ist; seine Überzeugung ist aber, dass wir diese Geschichte des Begriffs "verstehen müssen, um seine Bedeutung für die Gegenwart zu erfassen". [...] Die Gegenwart spielt für die Begriffsgeschichte aber auch deshalb eine besondere Rolle, weil der Begriff Hegemonie ungeachtet seiner langen Geschichte erst in jüngerer Zeit eine allgemeinere Bedeutung erlangt hat; im englischen Sprachraum liegt der große Sprung in den 1990er Jahren, in Deutschland dürfte das ähnlich sein. In dem "maßgeblichen Kompendium 'Geschichtliche Grundbegriffe'" hat der Begriff jedenfalls, so Anderson, "signifikanterweise keinen Eintrag" erhalten . Die möglichen Gründe dafür, über die Anderson nicht spekuliert, bringt Falko Schmieder hier zur Sprache.
Background: Accurate assessment of hepatic fibrosis in patients with chronic HBeAg-negative Hepatitis B is of crucial importance not only to predict the long-term clinical course, but also to evaluate antiviral therapy indication. The aim of this study was to prospectively assess the utility of point shear wave elastography (pSWE) for longitudinal non-invasive fibrosis assessment in a large cohort of untreated patients with chronic HBeAg-negative hepatitis B virus (HBV) infection.
Methods: 407 consecutive patients with HBeAg-negative HBV infection who underwent pSWE, transient elastography (TE) as well as laboratory fibrosis markers, including fibrosis index based on four factors (FIB-4), aspartate to platelet ratio index (APRI) and FibroTest, on the same day were prospectively followed up for six years. Patients were classified into one of the three groups: inactive carriers (IC; HBV-DNA <2000 IU/mL and ALT <40 U/L); grey zone group 1 (GZ-1; HBV DNA <2000 IU/mL and ALT >40 U/L); grey zone group 2 (GZ-2; HBV-DNA >2000 IU/mL and ALT <40 U/L).
Results: pSWE results were significantly correlated with TE (r = 0.29, p < 0.001) and APRI (r = 0.17; p = 0.005). Median pSWE values did not differ between IC, GZ-1 and GZ-2 patients (p = 0.82, p = 0.17, p = 0.34). During six years of follow-up, median pSWE and TE values did not differ significantly over time (TE: p = 0.27; pSWE: p = 0.05).
Conclusion: Our data indicate that pSWE could be useful for non-invasive fibrosis assessment and follow-up in patients with HBeAg-negative chronic HBV infection.
Heimat
(2019)
Heimat ist ein Begriff, der aktueller ist denn je. Die Süddeutsche Zeitung erklärte im April 2018: "Heimat ist der Debattenbegriff der Zeit." Im Kontext der weltweiten Migrationsbewegungen und der gleichzeitig erstarkenden rechtspopulistischen Tendenzen in Europa spielen 'Heimat' und verwandte Begriffe in den tagesaktuellen Diskussionen immer eine unterschwellige oder auch explizite Rolle: Vom Verlust der Heimat durch Krieg, Vertreibung oder wirtschaftliche Not über das 'Abendland' als konstruierte Heimat und die Angst vor ihrer Islamisierung bis hin zum seit 2018 um 'Heimat' erweiterten Namen des Bundesministeriums des Innern, für Bau und Heimat - es existieren viele Auslegungen und Bedeutungszuschreibungen für diesen Begriff. All diese gegenwärtigen Semantiken von 'Heimat' haben eine Geschichte und einen historischen Ursprung, denen die Sprachwissenschaftlerin Andrea Bastian in ihrer hier von Martin Schlüter besprochenen Untersuchung (Der Heimat-Begriff. Eine begriffsgeschichtliche Untersuchung in verschiedenen Funktionsbereichen der deutschen Sprache, Tübingen 1995) nachspürt.
Die Absicht von Johannes Rohbecks Beitrag ist eine kritische Würdigung der Geschichtstheorie von Reinhart Koselleck. Dabei konzentriert sich Rohbeck auf Kosellecks Untersuchungen über die Historiographie und Geschichtsphilosophie des 18. Jahrhunderts. [...] Zunächst beginnt Rohbeck mit den Verdiensten Kosellecks um die Geschichtsphilosophie der Aufklärung im 18. Jahrhundert. Da diese Leistung unbestritten ist, beschränkt er sich bei seiner Würdigung auf einige Hinweise. [...] Danach stellt Rohbeck einige begriffsgeschichtliche Behauptungen infrage; hier handelt es sich um philologische Korrekturen zu den Begriffen Fortschritt und Geschichte. Rohbeck zeigt außerdem, dass diese Korrekturen auf Kosellecks grundsätzliche Positionen verweisen. Sodann zielt seine Kritik auf allgemeine Einschätzungen zur neuzeitlichen Geschichtsphilosophie und Moderne, insbesondere auf die These von der 'Unverfügbarkeit der Geschichte'. Im Gegensatz zu Koselleck glaubt Rohbeck, dass es einige aktuelle und drängende Probleme gibt, die menschliches Handeln erfordern, um wenigstens teilweise in die Geschichte eingreifen zu können.
Globalisierung
(2019)
Wer denkt, Globalisierung habe etwas mit Marktwirtschaft zu tun, irrt nicht. Auf diesen kurzen Nenner ließe sich die ausführlichste begriffsgeschichtliche Studie bringen, die bislang zu 'Globalisierung' vorliegt. Doch wird man mit dieser verknappenden Formel weder dem Phänomen noch der von Olaf Bach 2013 veröffentlichten Studie "Die Erfindung der Globalisierung" gerecht. Denn zu Recht versteht er 'Globalisierung' nicht als einen ökonomischen Fachbegriff, sondern untersucht "Entstehung und Wandel eines zeitgeschichtlichen Grundbegriffs".
Begriffe 'nach dem Boom'
(2019)
Mit ihrem Essay "Nach dem Boom. Perspektiven auf die Zeitgeschichte seit 1970" haben Anselm Doering-Manteuffel und Lutz Raphael vor über zehn Jahren vielfältige Forschungen und Debatten zur Geschichte des 20. Jahrhunderts ausgelöst. Anders als Versuche, dieses Jahrhundert mit synthetischen Interpretationen wie der eines 'Weges nach Westen' oder eines Siegeszugs der liberalen Demokratie zu resümieren, beschrieb "Nach dem Boom" die drei Jahrzehnte seit 1970 als einen sozialen Wandel von revolutionärer Qualität. Dieser bis in die jüngste Gegenwart angenommene 'Strukturbruch' bündelt einschneidende ökonomische und sozialhistorische Zäsuren sowie politische und kulturelle Schwellen. Ernst Müller setzt sich im Folgenden mit dem von Ariane Leendertz und Wencke Meteling herausgegebenen Band "Die neue Wirklichkeit. Semantische Neuvermessungen und Politik seit den 1970er-Jahren, Frankfurt a. M./New York 2016" auseinander, der eine begriffsgeschichtliche Prüfung der 'Nach dem Boom-Thesen' vornimmt.
1967, im gleichen Jahr, in dem Richard Rorty seine Bestandsaufnahme zum 'linguistic turn' publiziert, hält Michel Foucault einen Vortrag über 'andere Räume'. Das 19. Jahrhundert, so Foucault, sei die Epoche der Geschichte und der Zeit gewesen, seine Themen waren "Entwicklung und Stillstand, Krise und Zyklus, die Akkumulation des Vergangenen". Das 20. Jahrhundert dagegen - für Foucault: die Gegenwart - sei als Epoche des Raumes zu begreifen: "Wir leben im Zeitalter der Gleichzeitigkeit, des Aneinanderreihens, des Nahen und des Fernen, des Nebeneinander und des Zerstreuten". Der Strukturalismus, so Foucault weiter, sei der Versuch, in diesem Sinne den Zusammenhang zwischen den Elementen nicht mehr als Abfolge, sondern als Ensemble von Relationen zu begreifen, als "Konfiguration". Der Raum, so könnte diese viel zitierte Passage gedeutet werden, wäre gegenüber der Sprache eine noch grundlegendere Kategorie; der 'linguistic turn' dann nur noch eine Variante des 'spatial turn'. In der Lesart von Stephan Günzel, dem Herausgeber des 2010 erschienenen interdisziplinären Handbuches "Raum", erscheint die Sprachwende in diesem Sinne als Teil der Vorgeschichte der späteren "Raumkehren". [...] David Kaldewey nimmt anhand des Handbuches eine über einzelne Autoren und Stichwortgeber hinausgehende Einschätzung der Bedeutung und Karriere des Raumbegriffs in verschiedenen Disziplinen und Forschungsfeldern vor.
Nichts ist so prekär wie die Kontinuität und Identität eines Zeichens. Gewiss, die Weiterverwendung eines tradierten Wortkörpers suggeriert Kontinuität auch auf der Inhaltsseite, und die Etablierung eines neuen Wortkörpers suggeriert Diskontinuität, wiewohl ein neuer Wortkörper einen etablieren Inhaltskomplex fortführen und ein alter einen grundstürzend neuen Inhaltskomplex etablieren kann. [...] Kurz und gut: Jegliche Verallgemeinerung über das, was die Leitbegriffe des 20. Jahrhunderts von denen des 19. Jahrhunderts unterscheidet, ist mit Vorsicht zu genießen. Was neu aussieht, muss nicht zur Gänze neu sein, und vice versa. Die ausdrucksseitigen Kodierungen sind selbst bisweilen strategisch, wir haben es mit einer öffentlichen Meinung zu tun, die zunehmend professionell produziert (und auch kurzfristig improvisiert) wird. [...] Es wird also zu fragen sein, ob sich nach dem Ansehensverlust der großen traditionellen 'Bewegungsbegriffe' (sagen wir) Stilmerkmale ausmachen lassen, die charakteristisch sind für die Macht-, Wissens- und Zustimmungspraktiken des 20. Jahrhunderts. [...] Als Sprach- und Kommunikationswissenschaftler versucht Clemens Knobloch, Veränderungen im Konnotationstransfer bei einigen 'modernen' Grundbegriffen auszuleuchten.
Intellektuelle
(2019)
Zumeist im Plural als 'die Intellektuellen', weniger häufig im Singular als 'der Intellektuelle' und kaum je in der weiblichen Form als 'die Intellektuelle', zählt der Begriff zu den Neuschöpfungen im frühen 20. Jahrhundert. Er ist von stark vagabundierender Bedeutung und steht immer auf dem Prüfstand. [...] Akademiker, Ideenträger, Geistesführer, das sind nur drei und dazu sehr unterschiedliche Bedeutungen, auf die der Begriff 'Intellektuelle' verweist, als er um 1900 in Deutschland zu zirkulieren beginnt. Diese Zirkulation wird im Folgenden entlang der neueren Intellektuellenforschung unter drei Aspekten betrachtet: Zuerst wird die in Deutschland einflussreiche 'Schimpfwortgeschichte' als Abwehrgeschichte französischer Traditionen aufgegriffen, es werden aber auch die mit Beginn des 20. Jahrhunderts für den deutschen Sprachraum nachweisbaren positiven Semantiken und Aneignungsformen betrachtet (I); im Anschluss werden Forschungswege der Soziologisierung wie der diskursanalytischen Behandlung des Intellektuellenthemas verzeichnet, zugleich wird noch einmal an Reinhart Kosellecks Konzept von Begriffsgeschichte und Sozialgeschichte erinnert (II); schließlich wird das gesteigerte Interesse an einer präzisierenden und differenzierenden Intellektuellengeschichte seit den 1970er Jahren beschrieben, um einige Linien zu gegenwärtigen Verwendungskontexten zu ziehen (III).
Netz / Netzwerk / Vernetzung
(2019)
Netz, Netzwerk und Vernetzung sind zu Schlüsselbegriffen für die Wissensorganisation der Gegenwart geworden. Wir begegnen uns im Netz, sind vom Netz gefangen, abhängig, begeistert und vor allem mit und durch Netzwerke verbunden; wir flirten, streiten, kaufen dort. Unsere Kühlschränke befinden sich in regem Austausch mit unseren Autos, Nachttischlampen, Kaffeemaschinen sowie den Firmen und Regierungen, die sich für diese Datenflut begeistern können. Dass wir vernetzt sind, würde gemeinhin niemand mehr bestreiten. Doch der Hang zur Vernetzung geht über den Cyberspace hinaus. Denn nebenbei betreiben wir fleißig Networking, halten Ausschau nach wertvollen Kontakten, begreifen das Netzwerk als effiziente wie raumrelativierende Kooperationsform und kartographieren komplexe Abläufe mithilfe feingliedriger Netzwerkmodelle. Dieser Umstand hat in den letzten Jahren viele geisteswissenschaftliche Arbeiten zur Reflexion angestoßen. Peter Fritz geht im Folgenden hauptsächlich auf zwei neuere Studien (Alexander Friedrich: Metaphorologie der Vernetzung. Zur Theorie kultureller Leitmetaphern, Paderborn 2015; Sebastian Gießmann: Die Verbundenheit der Dinge. Eine Kulturgeschichte der Netze und Netzwerke, Berlin 2016) ein, die die Dominanz von Netzen und Netzwerken in der Gegenwart als Ausgangsbeobachtung wählen, aber unterschiedlich mit dieser Gegenwartsdiagnose umgehen.
Editorial
(2019)
Diese Ausgabe des "Forum Interdisziplinäre Begriffsgeschichte" dient der Vorbereitung eines auf den deutschen Sprachraum bezogenen Lexikonprojekts zur politisch-sozialen und kulturellen Semantik im 20. Jahrhundert. In theoretisch-methodischer Hinsicht knüpft es an die vielen Debatten zur Neuausrichtung der Begriffsgeschichte an, zu denen vor allem Zeithistoriker*innen wichtige Beiträge geliefert haben.
Diese Ausgabe des "Forum Interdisziplinäre Begriffsgeschichte" dient der Vorbereitung eines auf den deutschen Sprachraum bezogenen Lexikonprojekts zur politisch-sozialen und kulturellen Semantik im 20. Jahrhundert. In theoretisch-methodischer Hinsicht knüpft es an die vielen Debatten zur Neuausrichtung der Begriffsgeschichte an, zu denen vor allem Zeithistoriker*innen wichtige Beiträge geliefert haben.
The photogrammetric acquisition of 3D object models can be achieved by Structure from Motion (SfM) computation of photographs taken from multiple viewpoints. All-around 3D models of small artefacts with complex geometry can be difficult to acquire photogrammetrically and the precision of the acquired models can be diminished by the generic application of automated photogrammetric workflows. In this paper, we present two versions of a complete rotary photogrammetric system and an automated workflow for all-around, precise, reliable and low-cost acquisitions of large numbers of small artefacts, together with consideration of the visual quality of the model textures. The acquisition systems comprise a turntable and (i) a computer and digital camera or (ii) a smartphone designed to be ultra-low cost (less than $150). Experimental results are presented which demonstrate an acquisition precision of less than 40 μm using a 12.2 Megapixel digital camera and less than 80 μm using an 8 Megapixel smartphone. The novel contribution of this work centres on the design of an automated solution that achieves high-precision, photographically textured 3D acquisitions at a fraction of the cost of currently available systems. This could significantly benefit the digitisation efforts of collectors, curators and archaeologists as well as the wider population.
Background and Aims: The IL-12/23 inhibitor ustekinumab (UST) opened up new treatment options for patients with Crohn’s disease (CD). Due to the recent approval, real-world German data on long-term efficacy and safety are lacking. This study aimed to assess the clinical course of CD patients under UST therapy and to identify potential predictive markers.
Methods: Patients with CD receiving UST treatment in three hospitals and two outpatient centers were included and retrospectively analyzed. Rates for short- and long-term remission and response were analyzed with the help of clinical (Harvey–Bradshaw Index (HBI)) and biochemical (C-reactive protein (CRP), Fecal calprotectin (fCal)) parameters for disease activity.
Results: Data from 180 patients were evaluated. One-hundred-and-six patients had a follow-up of at least eight weeks and were included. 96.2% of the patients were pre-exposed to anti- TNFα agents and 34.4% to both anti-TNFα and anti-integrin antibodies. The median follow-up was 49.1 weeks (95% CI 42.03-56.25). At week 8, 51 patients (54.8%) showed response to UST, and 24 (24.7%) were in remission. At week 48, 48 (51.6%) responded to UST, and 25 patients (26.9%) were in remission. Steroid-free response and remission at week eight was achieved by 30.1% and 19.3% of patients, respectively. At week 48, 37.6% showed steroid-free response to UST, and 20.4% of the initial patient population was in steroid-free remission.
Conclusion: Our study confirms short- and long-term UST effectiveness and tolerability in a cohort of multi-treatment-exposed patients.
(1) Background: Refractory acute graft-versus-host disease (R-aGvHD) remains a leading cause of death after allogeneic stem cell transplantation. Survival rates of 15% after four years are currently achieved; deaths are only in part due to aGvHD itself, but mostly due to adverse effects of R-aGvHD treatment with immunosuppressive agents as these predispose patients to opportunistic infections and loss of graft-versus-leukemia surveillance resulting in relapse. Mesenchymal stromal cells (MSC) from different tissues and those generated by various protocols have been proposed as a remedy for R-aGvHD but the enthusiasm raised by initial reports has not been ubiquitously reproduced.
(2) Methods: We previously reported on a unique MSC product, which was generated from pooled bone marrow mononuclear cells of multiple third-party donors. The products showed dose-to-dose equipotency and greater immunosuppressive capacity than individually expanded MSCs from the same donors. This product, MSC-FFM, has entered clinical routine in Germany where it is licensed with a national hospital exemption authorization. We previously reported satisfying initial clinical outcomes, which we are now updating. The data were collected in our post-approval pharmacovigilance program, i.e., this is not a clinical study and the data is high-level and non-monitored.
(3) Results: Follow-up for 92 recipients of MSC-FFM was reported, 88 with GvHD ≥°III, one-third only steroid-refractory and two-thirds therapy resistant (refractory to steroids plus ≥2 additional lines of treatment). A median of three doses of MSC-FFM was administered without apparent toxicity. Overall response rates were 82% and 81% at the first and last evaluation, respectively. At six months, the estimated overall survival was 64%, while the cumulative incidence of death from underlying disease was 3%.
(4) Conclusions: MSC-FFM promises to be a safe and efficient treatment for severe R-aGvHD.
Low-back pain is a major health problem exacerbated by the fact that most treatments are not suitable for self-management in everyday life. Particularly, interdisciplinary programs consist of intensive therapy lasting several weeks. Additionally, therapy components are rarely coordinated regarding reinforcing effects, which would improve complaints in persons with higher pain. This study assesses the effectiveness of a self-management program, firstly for persons suffering from higher pain and secondly compared to regular routines. Study objectives were treated in a single-blind multicenter controlled trial. A total of n = 439 volunteers (age 18–65 years) were randomly assigned to a twelve-week multidisciplinary sensorimotor training (3-weeks-center- and 9-weeks-homebased) or control group. The primary outcome pain (Chronic-Pain-Grade) as well as mental health were assessed by questionnaires at baseline and follow-up (3/6/12/24 weeks, M2-M5). For statistical analysis, multiple linear regression models were used. N = 291 (age 39.7 ± 12.7 years, female = 61.1%, 77% CPG = 1) completed training (M1/M4/M5), showing a significantly stronger reduction of mental health complaints (anxiety, vital exhaustion) in people with higher than those with lower pain in multidisciplinary treatment. Compared to regular routines, the self-management–multidisciplinary treatment led to a clinically relevant reduction of pain–disability and significant mental health improvements. Low-cost exercise programs may provide enormous relief for therapeutic processes, rehabilitation aftercare, and thus, cost savings for the health system.
Invasive plant species are increasingly altering species composition and the functioning of ecosystems from a local to a global scale. The grass species Pennisetum setaceum has recently raised concerns as an invader on different archipelagos worldwide. Among these affected archipelagos are the Canary Islands, which are a hotspot of endemism. Consequently, conservation managers and stakeholders are interested in the potential spreading of this species in the archipelago. We identify the current extent of the suitable habitat for P. setaceum on the island of La Palma to assess how it affects island ecosystems, protected areas (PAs), and endemic plant species richness. We recorded in situ occurrences of P. setaceum from 2010 to 2018 and compiled additional ones from databases at a 500 m × 500 m resolution. To assess the current suitable habitat and possible distribution patterns of P. setaceum on the island, we built an ensemble model. We projected habitat suitability for island ecosystems and PAs and identified risks for total as well as endemic plant species richness. The suitable habitat for P. setaceum is calculated to cover 34.7% of the surface of La Palma. In open ecosystems at low to mid elevations, where native ecosystems are already under pressure by land use and human activities, the spread of the invader will likely lead to additional threats to endemic plant species. Forest ecosystems (e.g., broadleaved evergreen and coniferous forests) are not likely to be affected by the spread of P. setaceum because of its heliophilous nature. Our projection of suitable habitat of P. setaceum within ecosystems and PAs on La Palma supports conservationists and policymakers in prioritizing management and control measures and acts as an example for the potential threat of this graminoid invader on other islands.
Often in climate system studies, linear and symmetric statistical measures are applied to quantify interactions among subsystems or variables. However, they do not allow identification of the driving and responding subsystems. Therefore, in this study, we aimed to apply asymmetric measures from information theory: the axiomatically proposed transfer entropy and the first principle-based information flow to detect and quantify climate interactions. As their estimations are challenging, we initially tested nonparametric estimators like transfer entropy (TE)-binning, TE-kernel, and TE k-nearest neighbor and parametric estimators like TE-linear and information flow (IF)-linear with idealized two-dimensional test cases along with their sensitivity on sample size. Thereafter, we experimentally applied these methods to the Lorenz-96 model and to two real climate phenomena, i.e., (1) the Indo-Pacific Ocean coupling and (2) North Atlantic Oscillation (NAO)–European air temperature coupling. As expected, the linear estimators work for linear systems but fail for strongly nonlinear systems. The TE-kernel and TE k-nearest neighbor estimators are reliable for linear and nonlinear systems. Nevertheless, the nonparametric methods are sensitive to parameter selection and sample size. Thus, this work proposes a composite use of the TE-kernel and TE k-nearest neighbor estimators along with parameter testing for consistent results. The revealed information exchange in Lorenz-96 is dominated by the slow subsystem component. For real climate phenomena, expected bidirectional information exchange between the Indian and Pacific SSTs was detected. Furthermore, expected information exchange from NAO to European air temperature was detected, but also unexpected reversal information exchange. The latter might hint to a hidden process driving both the NAO and European temperatures. Hence, the limitations, availability of time series length and the system at hand must be taken into account before drawing any conclusions from TE and IF-linear estimations.
Hepatic lipid deposition and inflammation represent risk factors for hepatocellular carcinoma (HCC). The mRNA-binding protein tristetraprolin (TTP, gene name ZFP36) has been suggested as a tumor suppressor in several malignancies, but it increases insulin resistance. The aim of this study was to elucidate the role of TTP in hepatocarcinogenesis and HCC progression. Employing liver-specific TTP-knockout (lsTtp-KO) mice in the diethylnitrosamine (DEN) hepatocarcinogenesis model, we observed a significantly reduced tumor burden compared to wild-type animals. Upon short-term DEN treatment, modelling early inflammatory processes in hepatocarcinogenesis, lsTtp-KO mice exhibited a reduced monocyte/macrophage ratio as compared to wild-type mice. While short-term DEN strongly induced an abundance of saturated and poly-unsaturated hepatic fatty acids, lsTtp-KO mice did not show these changes. These findings suggested anti-carcinogenic actions of TTP deletion due to effects on inflammation and metabolism. Interestingly, though, investigating effects of TTP on different hallmarks of cancer suggested tumor-suppressing actions: TTP inhibited proliferation, attenuated migration, and slightly increased chemosensitivity. In line with a tumor-suppressing activity, we observed a reduced expression of several oncogenes in TTP-overexpressing cells. Accordingly, ZFP36 expression was downregulated in tumor tissues in three large human data sets. Taken together, this study suggests that hepatocytic TTP promotes hepatocarcinogenesis, while it shows tumor-suppressive actions during hepatic tumor progression.
Scanning probe microscopy (SPM) has become an essential surface characterization technique in research and development. By concept, SPM performance crucially depends on the quality of the nano-probe element, in particular, the apex radius. Now, with the development of advanced SPM modes beyond morphology mapping, new challenges have emerged regarding the design, morphology, function, and reliability of nano-probes. To tackle these challenges, versatile fabrication methods for precise nano-fabrication are needed. Aside from well-established technologies for SPM nano-probe fabrication, focused electron beam-induced deposition (FEBID) has become increasingly relevant in recent years, with the demonstration of controlled 3D nanoscale deposition and tailored deposit chemistry. Moreover, FEBID is compatible with practically any given surface morphology. In this review article, we introduce the technology, with a focus on the most relevant demands (shapes, feature size, materials and functionalities, substrate demands, and scalability), discuss the opportunities and challenges, and rationalize how those can be useful for advanced SPM applications. As will be shown, FEBID is an ideal tool for fabrication/modification and rapid prototyping of SPM-tipswith the potential to scale up industrially relevant manufacturing.
(1) Background: A lesion within the dentato-rubro-olivary pathway (DROP) in the posterior fossa can cause secondary neurodegeneration of the inferior olivary nucleus: so-called hypertrophic olivary degeneration (HOD). The clinical syndrome of HOD occurs slowly over months and may be overlooked in progressive neuro-oncological diseases. Posterior fossa tumors are often located near these strategic structures. The goal of this study was to analyze the systematics of HOD occurrence in neuro-oncological patients.
(2) Methods: The neuroradiological database of the university healthcare center was scanned for HOD-related terms from 2010 to 2019. After excluding patients with other causes of HOD, 12 datasets from neuro-oncological patients were analyzed under predetermined criteria.
(3) Results: Patients received multimodal tumor treatments including neurosurgery, radiotherapy, and chemotherapy. HOD occurred both unilaterally (left n = 4; right n = 5) and bilaterally (n = 3). Though the mass effect of posterior fossa tumors had already affected strategic structures of the DROP, none of the patients showed signs of HOD on MRI until therapeutic measures including neurosurgery affecting the DROP were applied. HOD was visible on MRI within a median of 6 months after the neurosurgical intervention. In 67%, the presumed underlying surgical lesion in the DROP lay in the contralateral dentate nucleus.
(4) Conclusion: In a selected cohort of neuro-oncological patients, therapeutic lesions within the DROP were associated with HOD occurrence.
Amorphous formulation technologies to improve oral absorption of poorly soluble active pharmaceutical ingredients (APIs) have become increasingly prevalent. Currently, polymer-based amorphous formulations manufactured by spray drying, hot melt extrusion (HME), or co-precipitation are most common. However, these technologies have challenges in terms of the successful stabilization of poor glass former compounds in the amorphous form. An alternative approach is mesoporous silica, which stabilizes APIs in non-crystalline form via molecular adsorption inside nano-scale pores. In line with these considerations, two poor glass formers, haloperidol and carbamazepine, were formulated as polymer-based solid dispersion via HME and with mesoporous silica, and their stability was compared under accelerated conditions. Changes were monitored over three months with respect to solid-state form and dissolution. The results were supported by solid-state nuclear magnetic resonance spectroscopy (SS-NMR) and scanning electron microscopy (SEM). It was demonstrated that mesoporous silica was more successful than HME in the stabilization of the selected poor glass formers. While both drugs remained non-crystalline during the study using mesoporous silica, polymer-based HME formulations showed recrystallization after one week. Thus, mesoporous silica represents an attractive technology to extend the formulation toolbox to poorly soluble poor glass formers.
Immunosuppressive compounds affect the fungal growth and viability of defined aspergillus species
(2019)
Immunosuppressive drugs are administered to a number of patients; e.g., to allogeneic hematopoietic stem cell transplant recipients. Immunosuppressive drugs impair the immune system and thus increase the risk of invasive fungal disease, but may exhibit antifungal activity at the same time. We investigated the impact of various concentrations of three commonly used immunosuppressive compounds—cyclosporin A (CsA), methylprednisolone (mPRED), and mycophenolic acid (MPA)—on the growth and viability of five clinically important Aspergillus species. Methods included disc diffusion, optical density of mycelium, and viability assays such as XTT. MPA and CsA had a species-specific and dose-dependent inhibitory effect on the growth of all Aspergillus spp. tested, although growth inhibition by MPA was highest in A. niger, A. flavus and A. brasiliensis. Both agents exhibited species-specific hyphal damage, which was higher when the immunosuppressants were added to growing conidia than to mycelium. In contrast, mPRED increased the growth of A. niger, but had no major impact on the growth and viability of any of the other Aspergillus species tested. Our findings may help to better understand the interaction of drugs with Aspergillus species and ultimately may have an impact on individualizing immunosuppressive therapy.
Colorectal cancer (CRC) is one of the most common cancers that is characterized by a high mortality due to the strong metastatic potential of the primary tumor and the high rate of therapy resistance. Hereby, evasion of apoptosis is the primary underlying cause of reduced sensitivity of tumor cells to chemo- and radiotherapy. Using RNA affinity chromatography, we identified the tripartite motif-containing protein 25 (TRIM25) as a bona fide caspase-2 mRNA-binding protein in colon carcinoma cells. Loss-of-function and gain-of-function approaches revealed that TRIM25 attenuates the protein levels of caspase-2 without significantly affecting caspase-2 mRNA levels. In addition, experiments with cycloheximide revealed that TRIM25 does not affect the protein stability of caspase-2. Furthermore, silencing of TRIM25 induced a significant redistribution of caspase-2 transcripts from RNP particles to translational active polysomes, indicating that TRIM25 negatively interferes with caspase-2 translation. Functionally, the elevation in caspase-2 upon TRIM25 depletion significantly increased the sensitivity of colorectal cells to drug-induced intrinsic apoptosis as implicated by increased caspase-3 cleavage and cytochrome c release. Importantly, the apoptosis-sensitizing effects by transient TRIM25 knockdown were rescued by concomitant silencing of caspase-2, demonstrating a critical role of caspase-2. Inhibition of caspase-2 by TRIM25 implies a survival mechanism that critically contributes to chemotherapeutic drug resistance in CRC.
Since hyperactivity of the protein kinase DYRK1A is linked to several neurodegenerative disorders, DYRK1A inhibitors have been suggested as potential therapeutics for Down syndrome and Alzheimer’s disease. Most published inhibitors to date suffer from low selectivity against related kinases or from unfavorable physicochemical properties. In order to identify DYRK1A inhibitors with improved properties, a series of new chemicals based on [b]-annulated halogenated indoles were designed, synthesized, and evaluated for biological activity. Analysis of crystal structures revealed a typical type-I binding mode of the new inhibitor 4-chlorocyclohepta[b]indol-10(5H)-one in DYRK1A, exploiting mainly shape complementarity for tight binding. Conversion of the DYRK1A inhibitor 8-chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one into a corresponding Mannich base hydrochloride improved the aqueous solubility but abrogated kinase inhibitory activity.
Regorafenib CSF penetration, efficacy, and MRI patterns in recurrent malignant glioma patients
(2019)
(1) Background: The phase 2 Regorafenib in Relapsed Glioblastoma (REGOMA) trial indicated a survival benefit for patients with first recurrence of a glioblastoma when treated with the multikinase inhibitor regorafenib (REG) instead of lomustine. The aim of this retrospective study was to investigate REG penetration to cerebrospinal fluid (CSF), treatment efficacy, and effects on magnetic resonance imaging (MRI) in patients with recurrent high-grade gliomas.
(2) Methods: Patients were characterized by histology, adverse events, steroid treatment, overall survival (OS), and MRI growth pattern. REG and its two active metabolites were quantified by liquid chromatography/tandem mass spectrometry in patients’ serum and CSF.
(3) Results: 21 patients mainly with IDH-wildtype glioblastomas who had been treated with REG were retrospectively identified. Thirteen CFS samples collected from 3 patients of the cohort were available for pharmacokinetic testing. CSF levels of REG and its metabolites were significantly lower than in serum. Follow-up MRI was available in 19 patients and showed progressive disease (PD) in all but 2 patients. Two distinct MRI patterns were identified: 7 patients showed classic PD with progression of contrast enhancing lesions, whereas 11 patients showed a T2-dominant MRI pattern characterized by a marked reduction of contrast enhancement. Median OS was significantly better in patients with a T2-dominant growth pattern (10 vs. 27 weeks respectively, p = 0.003). Diffusion restrictions were observed in 13 patients.
(4) Conclusion: REG and its metabolites were detectable in CSF. A distinct MRI pattern that might be associated with an improved OS was observed in half of the patient cohort. Treatment response in the total cohort was poor.
Background: Ataxia-telangiectasia (A-T) is a multisystem disorder with progressive cerebellar ataxia, immunodeficiency, chromosomal instability, and increased cancer susceptibility. Cellular immunodeficiency is based on naïve CD4+ and CD8+ T-cell lymphopenia. Hematopoietic stem cell transplantation (HSCT) offers a potential to cure immunodeficiency and cancer due to restoration of the lymphopoietic system. The aim of this investigation was to analyze the effect of HSCT on naïve CD4+ as well as CD8+ T-cell numbers in A-T.
Methods: We analyzed total numbers of peripheral naïve (CD45RA+CD62L+) and memory (CD45RO+CD62L−) CD4+ and CD8+ T-cells of 32 A-T patients. Naïve (CD62LhighCD44low) and memory (CD62LlowCD44high) T-cells were also measured in Atm-deficient mice before and after HSCT with GFP-expressing bone marrow derived hematopoietic stem cells. In addition, we analyzed T-cells in the peripheral blood of two A-T patients after HLA-identic allogeneic HSCT.
Results: Like in humans, naïve CD4+ as well as naïve CD8+ lymphocytes were decreased in Atm-deficient mice. HSCT significantly inhibited thymic lymphomas and increased survival time in these animals. Donor cell chimerism increased up to more than 50% 6 months after HSCT accompanied by a significant increase of naïve CD4 and CD8 T-cell subpopulations, but not of memory T-cells. This finding was also identified in the blood of the A-T patients after HSCT.
Conclusion: HSCT seems to be a feasible strategy to overcome immunodeficiency and might be a conceivable strategy to avoid T-cell driven cancer in A-T at higher risk for malignancy. Naïve CD4 and CD8 T-cells counts are suitable markers for monitoring immune reconstitution post-HSCT. However, risks and benefits of HSCT in A-T have to be properly weighted.
Brain metastases are the most common intracranial tumor in adults and are associated with poor patient prognosis and median survival of only a few months. Treatment options for brain metastasis patients remain limited and largely depend on surgical resection, radio- and/or chemotherapy. The development and pre-clinical testing of novel therapeutic strategies require reliable experimental models and diagnostic tools that closely mimic technologies that are used in the clinic and reflect histopathological and biochemical changes that distinguish tumor progression from therapeutic response. In this study, we sought to test the applicability of magnetic resonance (MR) spectroscopy in combination with MR imaging to closely monitor therapeutic efficacy in a breast-to-brain metastasis model. Given the importance of radiotherapy as the standard of care for the majority of brain metastases patients, we chose to monitor the post-irradiation response by magnetic resonance spectroscopy (MRS) in combination with MR imaging (MRI) using a 7 Tesla small animal scanner. Radiation was applied as whole brain radiotherapy (WBRT) using the image-guided Small Animal Radiation Research Platform (SARRP). Here we describe alterations in different metabolites, including creatine and N-acetylaspartate, that are characteristic for brain metastases progression and lactate, which indicates hypoxia, while choline levels remained stable. Radiotherapy resulted in normalization of metabolite levels indicating tumor stasis or regression in response to treatment. Our data indicate that the use of MR spectroscopy in addition to MRI represents a valuable tool to closely monitor not only volumetrical but also metabolic changes during tumor progression and to evaluate therapeutic efficacy of intervention strategies. Adapting the analytical technology in brain metastasis models to those used in clinical settings will increase the translational significance of experimental evaluation and thus contribute to the advancement of pre-clinical assessment of novel therapeutic strategies to improve treatment options for brain metastases patients.
Music listening has become a highly individualized activity with smartphones and music streaming services providing listeners with absolute freedom to listen to any kind of music in any situation. Until now, little has been written about the processes underlying the selection of music in daily life. The present study aimed to disentangle some of the complex processes among the listener, situation, and functions of music listening involved in music selection. Utilizing the experience sampling method, data were collected from 119 participants using a smartphone application. For 10 consecutive days, participants received 14 prompts using stratified-random sampling throughout the day and reported on their music-listening behavior. Statistical learning procedures on multilevel regression models and multilevel structural equation modeling were used to determine the most important predictors and analyze mediation processes between person, situation, functions of listening, and music selection. Results revealed that the features of music selected in daily life were predominantly determined by situational characteristics, whereas consistent individual differences were of minor importance. Functions of music listening were found to act as a mediator between characteristics of the situation and music-selection behavior. We further observed several significant random effects, which indicated that individuals differed in how situational variables affected their music selection behavior. Our findings suggest a need to shift the focus of music-listening research from individual differences to situational influences, including potential person-situation interactions.
Alterations in the autophagosomal–lysosomal pathway are a major pathophysiological feature of CLN3 disease, which is the most common form of childhood-onset neurodegeneration. Accumulating autofluorescent lysosomal storage material in CLN3 disease, consisting of dolichols, lipids, biometals, and a protein that normally resides in the mitochondria, subunit c of the mitochondrial ATPase, provides evidence that autophagosomal–lysosomal turnover of cellular components is disrupted upon loss of CLN3 protein function. Using a murine neuronal cell model of the disease, which accurately mimics the major gene defect and the hallmark features of CLN3 disease, we conducted an unbiased search for modifiers of autophagy, extending previous work by further optimizing a GFP-LC3 based assay and performing a high-content screen on a library of ~2000 bioactive compounds. Here we corroborate our earlier screening results and identify expanded, independent sets of autophagy modifiers that increase or decrease the accumulation of autophagosomes in the CLN3 disease cells, highlighting several pathways of interest, including the regulation of calcium signaling, microtubule dynamics, and the mevalonate pathway. Follow-up analysis on fluspirilene, nicardipine, and verapamil, in particular, confirmed activity in reducing GFP-LC3 vesicle burden, while also demonstrating activity in normalizing lysosomal positioning and, for verapamil, in promoting storage material clearance in CLN3 disease neuronal cells. This study demonstrates the potential for cell-based screening studies to identify candidate molecules and pathways for further work to understand CLN3 disease pathogenesis and in drug development efforts.
Preeclampsia (PE) remains a leading cause of maternal and perinatal mortality and morbidity worldwide. Its pathogenesis has not been fully elucidated and no causal therapy is currently available. It is of clinical relevance to decipher novel molecular biomarkers. RITA (RBP-J (recombination signal binding protein J)-interacting and tubulin-associated protein) has been identified as a negative modulator of the Notch pathway and as a microtubule-associated protein important for cell migration and invasion. In the present work, we have systematically studied RITA’s expression in primary placental tissues from patients with early- and late-onset PE as well as in various trophoblastic cell lines. RITA is expressed in primary placental tissues throughout gestation, especially in proliferative villous cytotrophoblasts, in the terminally differentiated syncytiotrophoblast, and in migrating extravillous trophoblasts. RITA’s messenger RNA (mRNA) level is decreased in primary tissue samples from early-onset PE patients. The deficiency of RITA impairs the motility and invasion capacity of trophoblastic cell lines, and compromises the fusion ability of trophoblast-derived choriocarcinoma cells. These data suggest that RITA may play important roles in the development of the placenta and possibly in the pathogenesis of PE.
Flesh flies (Sarcophagidae) are necrophagous insects initially colonizing on a corpse. The species-specific developmental data of the flies collected from a death scene can be used to estimate the minimum postmortem interval (PMImin). Thus, the first crucial step is to correctly identify the fly species. Because of the high similarity among species of flesh flies, DNA-based identification is considered more favorable than morphology-based identification. In this study, we demonstrated the effectiveness of combined sequences (2216 to 2218 bp) of cytochrome c oxidase subunit I and II genes (COI and COII) for identification of the following 14 forensically important flesh fly species in Thailand: Boettcherisca nathani Lopes, Fengia ostindicae (Senior-White), Harpagophalla kempi (Senior-White), Liopygia ruficornis (Fabricius), Lioproctia pattoni (Senior-White), Lioproctia saprianovae (Pape & Bänziger), Parasarcophaga albiceps (Meigen), Parasarcophaga brevicornis (Ho), Parasarcophaga dux (Thomson), Parasarcophaga misera (Walker), Sarcorohdendorfia antilope (Böttcher), Sarcorohdendorfia inextricata (Walker), Sarcorohdendorfia seniorwhitei (Ho) and Seniorwhitea princeps (Wiedemann). Nucleotide variations of Thai flesh flies were evenly distributed throughout the COI-COII genes. Mean intra- and interspecific variations ranged from 0.00 to 0.96% and 5.22% to 12.31%, respectively. Using Best Match (BM) and Best Close Match (BCM) criteria, identification success for the combined genes was 100%, while the All Species Barcodes (ASB) criterion showed 76.74% success. Maximum Likelihood (ML) and Bayesian Inference (BI) phylogenetic analyses yielded similar tree topologies of monophyletic clades between species with very strong support values. The achieved sequences covering 14 forensically important flesh fly species including newly submitted sequences for B. nathani, F. ostindicae and S. seniorwhitei, can serve as a reliable reference database for further forensic entomological research in Thailand and in other areas where those species occur.
Antagonistic and mutualistic species interactions provide important ecosystem functions affecting plant population dynamics and distribution. Many of these functions are important for the regeneration of plants, either by limiting or facilitating successful transition between life stages. Interactions can occur across the whole geographical range of a species and thereby encompass different environmental gradients, such as changes in temperature or water availability. Understanding the joint effects of species interactions and environmental factors on the regeneration of plants is key for understanding plant population dynamics under global change and could provide important recommendations for managing and conservation efforts.
My thesis aimed at advancing the knowledge of how species interactions depend on environmental conditions and jointly affect plant recruitment along the elevational distribution of plants. This thesis includes three chapters in which I studied the effects of animal seed deposition, seed predation, mycorrhizal and pathogenic fungi occurrences as well as abiotic and biotic environmental factors on the recruitment of Swiss stone pine (Pinus cembra). I conducted fieldwork in the Swiss Alps across the entire elevational distribution of the pine (1850 – 2250 m a.s.l). Over a period of three years, I recorded animal seed deposition by spotted nutcrackers (Nucifraga caryocatactes) and conducted seed translocation experiments. Further, I assessed fungal communities using DNA metabarcoding. I measured abiotic environmental factors such as temperature, water and light availability, pH, as well as biotic environmental factors such as distance to conspecific adults and ground vegetation cover. In my thesis, I used a broad range of community ecology approaches, from seed dispersal ecology to experimental plant ecology and microbial ecology.
First, I investigated the effects of environmental factors on four recruitment processes (i.e. seed deposition, seed predation, seed germination, seedling survival) of Swiss stone pine. Further, I aimed at identifying the most important recruitment processes potentially limiting pine regeneration across its elevational range. To investigate pine recruitment, I firstly tested how seed deposition, seed predation, seed germination and seedling survival were affected by the microhabitat characteristics ultimately determining where a seed arrives in the environment (i.e. canopy cover & ground vegetation cover). Secondly, I applied a sensitivity analysis to investigate which of the four recruitment processes poses limitation to the pines’ regeneration across its range. My results reveal that the importance of particular recruitment processes varies along the pines’ elevational range. I found that at the lower range margin and the distribution centre seed germination and seedling survival were the main limiting factors, whereas animal-mediated seed dispersal became especially important at the upper range margin. My study contributes to the field with a new approach for disentangling the relative importance of recruitment processes across environmental gradients and thereby could help to project how plant recruitment might respond to future changes in environmental conditions.
The second aim of my study was to investigate how abiotic and biotic environmental factors affect the occurrence of Swiss stone pine-associated pathogenic and mutualistic fungi by combining field measurements of environmental factors with a DNA metabarcoding approach. I identified potentially important fungal interaction partners of the pine and determined drivers shaping their occurrences. My results reveal that generalist fungi were not affected by abiotic and biotic environmental factors. However, specialist pathogens showed patterns according to the Janzen-Connell framework (i.e. accumulation of pathogen close to adult plants). Interestingly, I found evidence for an “inverse” Janzen-Connell effect, i.e. high abundance of a specialist mutualist close to adult plants, potentially mitigating effects of soil pathogens close to parent trees. Further, I found that pine-associated fungi are distributed widely within and beyond the range of their host plant, adding knowledge on how mutualisms and antagonisms might be affected when plants move their distributional range upwards.
Finally, I investigated how known and unknown plant-associated fungi affect the regeneration of Swiss stone pine in an environmental context. My results suggest that seedling establishment was most strongly affected by abiotic environmental factors, such as light availability and maximum summer temperature. Further, the results indicate that seedling survival was affected by biotic environmental factors, i.e. fungal agents, with high abundances of a known fungal pathogen co-occurring with low seedling survival rates. My results also reveal that known mycorrhizal partners as well as a large number of unknown fungal operational taxonomic units (OTUs) were associated with the survival of seedlings. My findings highlight the importance of plant-fungal interactions for plant recruitment and offer a feasible approach for the identification of hidden plant-fungal associations in highly complex DNA metabarcoding datasets. This approach offers a valuable tool for investigating plant-microbe interactions, ultimately helping to understand plant population dynamics.
My dissertation adds to a deeper understanding on the linkage between plant regeneration and species interactions, especially on how plant-animal and plant-fungal interactions in concert with environmental factors shape plant recruitment. My study reveals the importance of animal-mediated seed dispersal and fungal pathogens in plant recruitment with consequences for potential range shifts of plant species. My thesis has important implications for conservation and management efforts by informing on key species interactions under environmental change.
The diffusive behavior of macromolecules in solution is a key factor in the kinetics of macromolecular binding and assembly, and in the theoretical description of many experiments. Experiments on high-density protein solutions have found that a slow down of the diffusion dynamics is larger than expected from colloidal theory for non-interaction hard-spheres. It has also been shown that the rotational diffusion anisotropy in high-density protein solutions is larger than in dilute ones. High-density protein solutions are a complex fluid that is different from the neat fluid assumption used in the hydrodynamic theory. It is therefore important to have methods to accurately calculate the translational and rotational diffusion tensor from simulations as well as simulation algorithms to explore high-density solutions.
Simulations provide a powerful tool to study diffusion in complex fluids. They can be used to study the macroscopic and microscopic effects of complex fluids on the diffusive behavior. There has been already a lot of work done to accurately simulate diffusion and to determine the diffusion coefficients from simulations.
The translational diffusion of molecules in simple and complex liquids can be determined with high accuracy from simulations. This is not yet the case for rotational diffusion. Existing algorithms to calculate the rotational diffusion coefficients from simulations make assumptions about the shape of the protein or only work at short times. For the simulation of diffusive behavior of macromolecules two options exist today. An all-atom integrator with explicit solvent molecules or coarse-grained (CG) simulations with an implicit solvent. CG simulations of dynamic behavior with implicit solvent are also called Brownian dynamics (BD) simulations. For the CG simulations the Ermak-McCammon algorithm is often used to solve the underlying Langevin equation. The algorithm is an extension of the Euler-Maruyama integrator to include translation and rotation in three dimensions. This algorithm only correctly reproduces the equilibrium probability for short time-steps and the error depends linearly on the time-step. It has been shown that Monte Carlo based algorithms can produce BD for translational dynamics, when appropriately parametrized. The advantage of Monte Carlo based algorithm is that they will reproduce the correct equilibrium distribution independent of the chosen time-step. This in return allows choosing larger time-steps in simulations. The aim of this thesis is to develop novel´methods to accurately determine the rotational diffusion coefficient from simulations and extend existing Monte Carlo algorithms to include rotational dynamics.
The first project addresses the question of how to accurately determine the rotational diffusion coefficients from simulations. We develop a quaternion based method to calculate the rotational diffusion tensor from simulations and a theory for the effects of periodic boundary conditions (PBC) on the rotational diffusion coefficient in simulations.
Our method for calculating rotational diffusion coefficients is based on the quaternion covariances from Favro for a freely rotating rigid molecule. The covariances as formulated by Favro are only valid in the principal coordinate system (PCS) of the rotation diffusion tensor. The covariances can be generalized for an arbitrary reference coordinate system (RCS), i.e., a simulation, given the principle axes of the rotational diffusion tensor in the RCS. We show that no prior knowledge of the diffusion tensor and its principal axes is required to calculate the generalized covariances from simulations using common root-mean-square distance (RMSD) procedures. We develop two methods to fit the covariances calculated from simulations to our generalized equations to fit the rotational diffusion tensor. In the first method we minimize the sum of the squared error deviations between model and simulation data. For this six dimensional optimization we use a simulated annealing algorithm. Alternatively the rotational diffusion tensor can also be determined from a eigenvalue decomposition of covariance after integration. To minimize the effects of sampling noise in the integration we first apply a Laplace-transformation to smooth the covariances at large times. For ideal sampling the resulting rotational diffusion coefficient should be independent of the value of the Laplace variable. In practice, however, the best results are achieved using a value close to the inverse autocorrelation time of the rotational motion.
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In dieser Dissertation wird die Parametrisierung von subgitterskaligen (SGS) Prozessen in Atmosphärenmodellen untersucht. Die Arbeit befasst sich mit den stochastisch angetriebenen Flachwassergleichungen, im ersten Teil in einer räumlichen Dimension und im zweiten Teil in zwei Dimensionen. Die Einteilung in aufgelöste und SGS-Variable erfolgt in beiden Fällen über lokale räumliche Mittel der Ursprungsvariable und deren Abweichungen vom lokalen Mittel.
Im eindimensionalen Fall liegt zwischen den Variablen eine deutliche Separation der charakteristischen Zeitskalen vor, wodurch die Anwendung der stochastischen Moden Reduktion (SMR) ermöglicht wird. Die SMR generiert ein reduziertes Modell der aufgelösten Variable mit einer stochastischen SGS-Parametrisierung, im Folgenden auch Schließung genannt. Die SMR-Schließung basiert auf den Grundgleichungen des Flachwassermodells und ist numerisch effizient einsetzbar, da sie nur eine geringe Anzahl von benachbarten Zellen koppelt. Sie verbessert die Ergebnisse des reduzierten Modells und übertrifft die Ergebnisse zweier zum Vergleich untersuchter empirischer stochastischer Schließungen. Den größten Zugewinn liefert sie im Energiespektrum, insbesondere für kleine Skalen. Das Ergebnis der SMR-Schließung kann verbessert werden, indem die Amplitude der stochastischen Schließungskomponente gedämpft wird. Die SMR-Schließung ist skalenabhängig im Sinne der räumlichen Modellauflösung. Untersucht wird die Schließung bei Halbierung und Viertelung der räumlichen Auflösung, wo sie ihre Überlegenheit gegenüber den empirischen Schließungen wiederholt bestätigt.
Im Unterschied zum eindimensionalen Fall ist in zwei Dimensionen auch die Corioliskraft enthalten und eine räumliche Divergenz der Schwerewellen möglich. Zwischen der aufgelösten und der SGS-Variable kommt es erneut zu einer Separation der charakteristischen Zeitskalen. Die Separation ist allerdings weniger stark ausgeprägt als im eindimensionalen Fall. Grund hierfür ist das Auftreten einer lang korrelierten geostrophisch balancierten Mode, welche auch auf die SGS-Variable projiziert. Das Vorgehen zur Bestimmung der SMR-Schließung für das zweidimensionale Modell verläuft analog zum eindimensionalen Fall. Es werden die Ergebnisse des hoch aufgelösten Referenzmodells und zweier Modelle ohne SGS-Schließung verglichen.
The members of the multidrug/oligosaccharidyl-lipid/polysaccharide (MOP) transporter superfamily mediate export of a wealth of molecules of physiological and pharmacological importance. According to the Transporter Classification Database (TCDB), the MOP superfamily is mainly categorized into six distantly related families functionally characterized families: the multidrug and toxic compound extrusion (MATE), the polysaccharide transporter (PST), the oligosaccharidyl-lipid flippase (OLF), the mouse virulence factor (MVF) the agrocin 84 antibiotic exporter (AgnG), and the progressive ankylosis (Ank) family. Among these, the multidrug resistance MATE family transporters are most ubiquitous, being present in all domains of life: Archaea, Bacteria and Eukarya. As secondary active transporters, they utilize transmembrane electrochemical ion gradients of Na+ and/or H+ in order to drive the efflux of xenobiotics or cytotoxic metabolic waste products with specificity mainly for polyaromatic and cationic substrates. Active efflux of drugs and toxic compounds carried out by multidrug transporters is one of the strategies developed by bacterial pathogens to confer multidrug resistance. MATE proteins provide resistance to, e.g., fluoroquinolone, aminoglycoside antibiotics, and anticancer chemotherapeutical agents, thus serving as promising pharmacological targets for tackling a severe global health issue. Based on their amino acid sequence similarity, the MATE family members are classified into the NorM, the DNA-damage-inducible protein F (DinF), and the eukaryotic subfamilies. Structural information on the alternate conformational states and knowledge of the detailed mechanism of the MATE transport are of great importance for the structure-aided drug design. Over the past decade, the crystal structures of representative members of the NorM, DinF and eukaryotic subfamilies have been presented. They all share similar overall architecture comprising 12 transmembrane helices (TMs) divided into two domains, the N-terminal domain (TMs 1-6) and the C-terminal domain (TMs 7-12), connected by a cytoplasmic loop between TM6 and TM7 (Fig. II.1). Since all available MATE family structures are known only in V-shaped outward-facing states with the central binding cavity open towards the extracellular side, a detailed understanding of the complete transport cycle has remained elusive. In order to elucidate the underlying steps of the MATE transport mechanism, structures of distinct intermediates, particularly inward-facing conformation, are required.In my PhD project, structural and functional studies have been performed on a MATE family (DinF subfamily) transporter, PfMATE, from the hyperthermophilic and anaerobic archaeon Pyrococcus furiosus. This protein was produced homologously in Pyrococcus furiosus as well as heterologously in Escherichia coli, and used for the subsequent purification and crystallization trials by the vapor diffusion (VD) and lipidic cubic phase (LCP) method. To the best of my knowledge, PfMATE is the first example of a successful homologous production of a membrane protein in P. furiosus. Due to the very low final amount of the purified protein from the native source, the heterologously produced PfMATE samples were typically used for the extensive structural studies. Crystal structures of PfMATE have been previously determined in an outward-facing conformation in two distinct states (bent and straight) defined on the arrangement of TM1. A pH dependent conformational transition of this helix regulated by the protonation state of the conserved aspartate residue Asp41 was proposed. However, it has been discussed controversially, leading to the hypothesis about TM1 bending to be rather affected by interactions with exogenous lipids (monoolein) present under the crystallization conditions. Based on these open questions, an experimental approach to investigate the role of lipids as structural and functional modulators of PfMATE has been taken in the course of my PhD project. The interplay between membrane proteins and lipids can affect membrane protein topology, structure and function. Considering differences between archaeal and bacterial lipid composition, cultivation of P. furiosus cells and extraction of its lipids was followed by the mass spectrometry (MS) based lipidomics for identification of individual lipid species in the archaeal extract. In order to assess the effects of lipids on PfMATE, different lipid molecules were used for co-purification and co-crystallization trials. This dissertation presents a workflow leading to the structure determination of a MATE transporter in the long sought-after inward-facing state, which has been achieved upon purification and crystallization of the heterologously produced PfMATE in the presence of lipids from its native source P. furiosus. Also, the PfMATE outward-facing state obtained from the crystals grown at the acidic pH conditions sheds light on the previously proposed pH-dependent structural alterations within TM1. It is interesting to note that the inward and outward-facing states of PfMATE were obtained from the crystals grown under similar conditions, but in the presence and absence of native lipids, respectively. This observation supports the hypothesis about physiologically relevant lipids to act as conformational modulators or/and a new class of substrates, expanding the substrate spectrum of the MATE family transporters. Comparative analysis of two PfMATE states reveals that transition from the outward to the inward-facing state involves rigid body movements of TMs 2-6 and 8-12 to form an inverted V, facilitated by a loose binding of TMs 1 and 7 to their respective bundles and their conformational flexibility. Local fluctuations within TM1 in the inward-facing structure, including bending and unwinding in the intracellular half of the helix, invoke its highly flexible nature, which is suitable for ion and substrate gating.
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Food allergies are defined as an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food. The prevalence of food allergies has increased in the past decade. Epidemiologic studies involving controlled food challenges for the diagnosis of food allergies indicated that between 1 % to 10.8 % of the population have immunemediated non-toxic food hypersensitivity.
Despite the increasing prevalence, no curative treatment has been established for food allergies so far except the complete avoidance of the elicited food. To establish safe and effective immunotherapy for food allergies, it is of crucially importance to elucidate pathological mechanism of such diseases.
Food allergies are classified into IgE-mediated and non-IgE mediated (T-cell mediated) allergies, depending on the immunologic pathways and the role of the IgE on the pathogenesis of the disease. Allergic enteritis (AE) is a gastrointestinal form of food allergy. It is classified as non-IgE-mediated food allergy. However, patients with AE often develop IgE and high levels of IgE have been associated with development of persistent AE. The gastrointestinal symptoms of AE are nonspecific, resulting in the fact that a broad differential diagnoses including diagnostic approaches for allergic diseases are necessary to rule out other gastrointestinal pathologies. Biopsies of patients with allergic enteritis have shown infiltration of inflammatory cells (e.g. mast cells, eosinophils, neutrophils, and T cells) in the lamina propria, disruption of intestinal villi, edema, and presence of goblet cells in the intestine...
Aim: To assess outcomes in patients with advanced adenocarcinoma non-small-cell lung cancer who received nintedanib plus docetaxel after progression on prior chemotherapy followed by immune checkpoint inhibitor (ICI) therapy. Patients & methods: VARGADO is a prospective, noninterventional study. We describe initial data from a cohort of 22 patients who received nintedanib plus docetaxel after chemotherapy and ICI therapy. Results: Median progression-free survival with nintedanib plus docetaxel was 5.5 months (95% CI: 1.9–8.7 months). The objective response rate was 7/12 (58%) and the disease control rate was 10/12 (83%). Data for overall survival rate 12 months after the start of treatment (primary end point) are not yet mature and are not reported. Of 22 patients, 73% experienced drug-related adverse events; adverse events led to treatment discontinuation in 32% of patients. Conclusion: These data highlight the potential clinical benefit of nintedanib plus docetaxel in patients who failed prior ICI therapy.
Trial registration number: NCT02392455
This dissertation contains two chapters. Each chapter covers a unique topic within RNA science and is divided in two sub sections, part A and B. Each chapter contains an introduction.
Chapter 1 gives an insight into challenges encountered during sample design and preparation for single molecule Förster energy transfer (smFRET) spectroscopy and offers a solution via a newly establishedestablished workflow to obtain accurate smFRET constructs. Following this workflow, a FRET network could be generated, which allowed a detailed structural dynamics study on H/ACA RNP during catalysis with smFRET spectroscopy. This led to detailed mechanistic insights into H/ACA RNPs dynamics during catalysis.
Chapter 2 deals with RNA synthetic biology whereby a novel eclectic design strategy for RNA of interest (ROI) release platform is presented, which allows to release a diverse ROI sequences with single nucleotide precision triggered by an external stimulus. This design strategy was used to establish a ROI release system and its powerful performance in in vitro and in vivo applications was shown.
Die vorliegende kumulative, publikationsbasierte Disserationsschrift zum Thema „Diversität und Zoogeographie metazoischer Fischparasiten aus dem Südpolarmeer“ gibt einen zusammenfassenden Überblick über die von mir verfasseten ausgewählten drei (ISI-)Publiaktionen. Diese sind im Anhang (Kapitel 6) in chronologischer Reihenfolge aufgeführt. Die Verweise zu den Publikationen sind im Text mit den römischen Ziffern I-III (s.u.) gekennzeichnet. Die für die Promotion relevanten Publikationen wurden wie folgt publiziert:
I Münster J, Kochmann J, Klimpel S, Klapper R, Kuhn T (2016) Parasite fauna of Antarctic Macrourus whitsoni (Gadiformes: Macrouridae) in comparison with closely related macrourids. Parasites & Vectors 9:403
II Münster J, Kochmann J, Grigat J, Klimpel S, Kuhn T (2017) Parasite fauna of the Antarctic dragonfish Parachaenichthys charcoti (Perciformes: Bathydraconidae) and closely related Bathydraconidae from the Antarctic Peninsula, Southern Ocean. Parasites & Vectors 10:235
III Kuhn T, Zizka VMA, Münster J, Klapper R, Mattiucci S, Kochmann J, Klimpel S (2018) Lighten up the dark: metazoan parasites as indicators for the ecology of Antarctic crocodile icefish (Channichthyidae) from the north-west Antarctic Peninsula. PeerJ 6, e4638
Diese drei Publikationen sind im Ergebnisteil (Kapitel 2) separat zusammengefasst und folgend im gemeinsamen Kontext diskutiert (Kapitel 3).
Eukaryotische Zellen sind durch, aus Lipiddoppelschichten bestehenden, Membranen in Kompartimente mit unterschiedlichen Funktionen eingeteilt. Um einen Transport von Molekülen über die Membranen hinweg zu gewährleisten, werden Kanälen und Transporter benötigt. Eine Familie von Transportern sind die ATP-binding cassette (ABC) Transporter, die in allen Lebewesen, von Bakterien bis zum Menschen, vorkommen. Ein Mitglied dieser Familie ist der transporter associated with antigen processing-like (TAPL oder ABCB9). TAPL ist ein lysosomaler Polypeptidtransporter der per ATP-Hydrolyse Peptide von 6 – 59 Aminosäuren Länge vom Zytosol in das Lumen der Lysosomen transportiert. Hierbei kann TAPL, das ein Homodimer ist, in zwei funktionale Domänen geteilt werden. Der Teil des Komplexes, der für den Transport zuständig ist, wird als coreTAPL bezeichnet. Dieser beinhaltet die zytosolischen nucleotide binding domains (NBDs), die ATP binden und hydrolysieren können, und die Transmembrandomänen (TMDs), die Peptide binden und sie durch konformationelle Änderungen auf der anderen Membranseite freilassen. Die zweite Domäne ist eine N-terminale TMD, die als TMD0 bezeichnet wird. Dieser, aus vier Transmembranhelices (TMHs) bestehende Teil des Proteins, ist für die Lokalisation von TAPL in der lysosomalen Membran verantwortlich, sowie für die Interaktion mit den dort lokalisierten Membranproteinen LAMP-1 und LAMP-2. CoreTAPL ohne die TMD0s erreicht nicht die Lysosomen, sondern liegt in der Plasmamembran (PM) der Zelle vor. Die TMD0 hingegen benötigt coreTAPL nicht um korrekt in der lysosomalen Membran lokalisiert zu sein.
Die korrekte Lokalisation in der Zelle ist ein kritischer Punkt für ein Protein, um seine Funktion ausüben zu können. Die Transportprozesse vom Ort der Synthese des Proteins, dem Endoplasmatischem Reticulum (ER), zum Organell wo es seine Funktion ausüben soll, umfassen dutzende Proteine und Proteinkomplexe und ein komplexes Zusammenspiel zwischen Proteinen und den einzigartigen Lipidzusammensetzungen der Membranen verschiedener Organellen. Auf das Einfachste heruntergebrochen benötigt ein Transmembranprotein eine kurze Aminosäuresequenz auf der zytosolischen Seite, die Signalsequenz. Diese Sequenz wird von sogenannten Adapterproteinen erkannt, die wiederum andere Bestandteile der zellulären Maschinerie rekrutieren, die letztlich Vesikelbildung, Transport und Fusion mit der Zielorganelle vermitteln. Allerdings weisen nicht alle lysosomalen Transmembranproteine eine solche Signalsequenz auf, sondern besitzen unkonventionelle Zieldeterminanten, wie posttranslationale Modifikationen, oder sie interagieren mit anderen Proteinen, die wiederum die Interaktion mit den Adapterproteinen vermitteln.
Der Fokus der vorliegenden Arbeit liegt in der erfolgreichen Entwicklung von vier neuen Methoden zur Darstellung von Sulfonen und von einer neuen Methode zur Synthese von N-Aminosulfonamiden. Dabei sollen die Strukturmotive von Sulfonen und Sulfonamiden aus stabilen Startmaterialien in einer einfachen Durchführung, vorzugsweise in einer Eintopf-Synthese oder Multikomponenten-Reaktion, aufgebaut und der Reaktionsmechanismus weitestgehend experimentell aufgeklärt werden. In diesem Rahmen konnte die Lücke einer Nickel-katalysierten Darstellung von Diarylsulfonen sowohl unter thermischen als auch unter photochemischen Bedingungen gefüllt werden. Zusätzlich konnten im Bereich der SO2-Fixierung Sulfonylradikale mittels Diaryliodoniumsalzen und sichtbaren Licht erzeugt werden, die mit dem entsprechenden Quencher zum Sulfonamid oder Sulfon weiter reagieren konnten.
The adult mammalian heart is a non-regenerative organ that fails to recover neither functionally nor structurally after insults. Although, reports show that the presences of mitotic nuclei after pathological or physiological cardiac stress in humans, it is widely accepted that the regenerative capacity of the human heart is immensely inadequate to restore the loss of cardiomyocytes (CMs) (Beltrami et al., 2001; Kajstura et al., 1998). Consequently, myocardial infarctions (MIs) are the primary cause of cardiovascular morbidity and mortality. MIs is the irreversible loss of cardiac myocytes due to prolonged myocardial ischemia caused by an imbalance of the metabolic demand of the myocardium and myocardial blood flow (Whelan et al., 2010). Patients with MIs often die prematurely because of heart failure, resulting from irreversible scar formation on the ventricular wall and undermined heart function (Jessup and Brozena, 2003). Despite early intervention and advancements of medical devices for prevention, MIs are still untreatable, unless the heart transplantation approach considered, which is very limited by heart donation (Augoustides and Riha, 2009). Therefore, there is a high demand for standard therapy for heart failure that can restore the loss of CMs, prompt myocardial regeneration, and eventually, reduce morbidity and mortality rate of the disease.
Contrary to the adult mammalian heart, zebrafish display an extraordinary capacity for heart regeneration after the cardiac insult (Poss et al., 2002). This regenerative response relies on the ability of CMs to proliferate and replenish the lost tissue. Zebrafish is indeed one of the most commonly used experimental models for developmental and regenerative biology studies (Gemberling et al., 2013; Gonzalez-Rosa et al., 2017). For decades, the process of cardiac regeneration has been investigated using various cardiac injury models. The most commonly used and well-established injury methods are ventricular apical resection (Poss et al., 2002; Raya et al., 2003), cryoinjury (Chablais et al., 2011; Schnabel et al., 2011), as well as genetic and chemical ablation of heart cells (Curado et al., 2007; Wang et al., 2011). The origin of new cells is one of the most fundamental questions to be addressed during organ regeneration in any regenerative organism, and understanding of such phenomenon is crucial to design effective therapeutic strategies for non-regenerative organisms (Gonzalez-Rosa et al., 2017; Tanaka and Reddien, 2011).
Despite the robust cardiac regenerative potential, to date, only a handful of lineage tracing experiments have been reported in zebrafish heart regeneration. It was proposed that the cellular source of the renewed cardiac tissue might arise from progenitor or stem cells (Lepilina et al., 2006), through CMs dedifferentiation (Jopling et al., 2010; Kikuchi et al., 2010), transdifferentiation from other cell types in the heart tissue, and/or direct proliferation of the existing CMs (Kikuchi and Poss, 2012). Fate-mapping studies using transgenic lines driven by the myl7 promoter have shown that pre-existing CMs contribute to myocardial regeneration. However, myl7 expression is activated at early developmental stages in cardiac progenitor cells and hence precluding the identification of genuinely mature CMs in adult stages. Therefore, the cellular origin of the regenerating CMs remains elusive. Moreover, CM heterogeneity in the developing and adult zebrafish heart has never been explored to provide full insight into the process of regeneration. Therefore, I set out to identify genes exclusively expressed by either immature or mature CMs, generate promoter-driven reporter and CreERT2 lines to characterize the reporters during zebrafish heart development, and regeneration, and eventually to determine the contribution of the immature CMs to the regenerating CMs....
Diese Ausgabe der Interjekte präsentiert erstmals ein vollständiges Verzeichnis von Karlheinz Barcks Schriften. Der 1934 in Quedlinburg geborene Karlheinz "Carlo" Barck gehörte zu den wenigen Romanisten aus der DDR, die schon vor dem Fall der Mauer internationale Wertschätzung genossen. Seine literaturgeschichtlichen Beiträge zur spanischen und französischen Moderne, zur Geschichte der Literaturwissenschaft und zur Theorie ästhetischen Denkens wurden international rezipiert. Als Mitarbeiter am Zentralinstitut für Literaturgeschichte der Akademie der Wissenschaften der DDR (dem Vorgängerinstitut des ZfL) gehörte er zu den maßgeblichen Initiatoren des Wörterbuchprojekts der "Ästhetischen Grundbegriffe". Bis zu seinem Tod 2012 prägte er mit seiner enzyklopädischen Gelehrsamkeit, seiner intellektuellen Neugierde und Gesprächsbereitschaft die Arbeit am ZfL.
The aim of this essay is to provide an analysis of Foucault's use of the notion of revolution in the reports he wrote for "Il Corriere della Sera" during his two trips to Iran in September and November 1978. Foucault critically frames the historical and philosophical concept of revolution, in order to oppose it to the spreading revolts against the Shah, which embody the simple and negative opening of the possibility of a transformation in history. Yet is it possible to reactivate the notion of revolution in a nonrestrictive sense in order to think about the role and the possibility of political revolts and freedom today?
Reversion: lyric time(s) II
(2019)
Is a 'history' of the lyric even conceivable? What would a 'lyric' temporality look like? With a focus on Rainer Maria Rilke's decision not to translate, but rather to rewrite Dante's "Vita nova" (1293–1295) in the first of his "Duineser Elegien" (1912), the essay deploys 'reversion' (as turning back, return, coming around again), alongside 're-citation', as a keyword that can unlock the transhistorical operations of the lyric as the re-enactment of selected gestures under different circumstances.
Restrain
(2019)
The re- of 'restrain' - not the more common iterative 're-' but a mere, if semantically obscure intensifier - marks a temporal paradox: the restraint that prevents a force from reaching its 'telos' is not only a delay, but the intervention of a separate, autonomous, and anti-teleological regime of time. The article reads the biblical figure of the 'katéchon', 'the withholder', as an expression of this paradox and as symptomatic of a political-theological ambivalence essential to the foundation of Western political thought. If the 'secular order' or 'worldly government' has the function of withholding both the ultimate salvation and the final outbreak of chaos, then it sustains itself only by postponing any determination of its value or effect.
Resolution
(2019)
Many parodies operate through temporal strategies that distort the narrative proportions of their targets. This essay discusses two texts that manipulate time for parodic purposes: the contemporary animated sitcom "Bojack Horseman" and the twelfth-century romance "Ipomedon". Their shared method involves the absurd prolongation of narrative structures of resolution and satisfaction in order to reveal these structures' arbitrary nature. But this method, in turn, shows that resolution - a retrospective determination of shape and meaning - can never be avoided entirely, even if it can be deferred.
Resistance
(2019)
The term 'resistance', as it appears in the writings of Walter Benjamin, marks the attempt to think a politics that emerges out of a certain experience of history and time. This entry shows that 'Widerstand' is conceived here principally as a resistance against the course of a catastrophic history - a desire for time to cease its flow and come to a standstill.
Resistance II
(2019)
Resistance I
(2019)
In an essay on Peter Weiss, W. G. Sebald remarked that 'the grotesque deformities of our inner lives have their background and origin in collective social history'. Weiss's works explore the relationships between writing and action, aesthetics and politics. This short essay discusses some fragments of texts by Weiss, asking how subjects formed and (grotesquely) deformed by history can continue to resist or intervene to alter its course.
Repetition
(2019)
Repetition
(2019)
This article explores the creative value of the notion of 'repetition' in Michel Foucault's texts from the 1960s and early 1970s. Re-enacting Gilles Deleuze's philosophy, Foucault implicitly refers to the Freudian repetition mechanisms in order to distort and reverse them. Foucault's repetition is de-psychologized, affectively de-individualizing, and temporally erratic, using the power of a senseless repetition to create new possibilities for the future.
Repetition
(2019)
Serial texts must repeat, so that they can be recognized, but they must also change, so that they can remain interesting. Unusual temporal manipulations can emerge in such texts in order to balance these contradictory demands. This essay studies two serial texts whose need for self-extension produces a suspension of historical time: the contemporary animated sitcom "The Simpsons", and medieval romance as theorized by the twelfth-century poet Wace. I suggest that we might name this temporal constraint fiction.
Renewal
(2019)
Interruptions and discontinuity are the very essence of Aby Warburg's conception of the temporality that affects art objects. Beneath the seemingly immobilized expressive gesture, the Hamburg scholar recognizes the vitality of the "Pathosformeln" that convey the intricacy of human multi-layered temporality, made of interruptions, resumptions, inversions, regressions, stops, accelerations, and survivals (Nachleben). In this sense, Warburg's idea of 'renewal', which he developed from his well-known investigation of the Italian Renaissance, does not quite overlap with the notion of rebirth: an expressive gesture can re-emerge and be renewed in a different time without dying and being born a second time with a different form.
Rehabilitation II
(2019)
Rehabilitation I
(2019)
By distancing it from historical revival (i.e., 'Living History'), reenactment is here understood as artistic strategy as well as curatorial practice, and therefore as critical method. As artistic strategy it implies the reactivation (over time) and remediation (on different supports) of images stemming from a vast visual repertoire that artists - especially those working with time-based media (film, video, performance) - appropriate in order to give them new meanings. As curatorial practice and critical method, reenactment regards the remaking of impermanent artworks and the restaging of temporary exhibitions to possibly offer an understanding of (art) history that gives preference to a visual and performative, sometimes immersive, approach.
Recovery
(2019)
Despite the increasing incidence of eating disorders, very few films have addressed these conditions in particular. What's more, most of the US-American mainstream fiction films that deal with eating disorders tend to be built on anachronistic clichés, hardly depicting their broad array. Furthermore, the traditional narrative structure of beginning, middle, and (happy) end misrepresents the erratic temporality of eating disorder symptoms as well as the nonlinear phases of recovery and relapse.
Recitation : lyric time(s) I
(2019)
What is the time of the lyric? For Augustine, the recitation of a hymn illustrates the workings of time in the human mind; for Giorgio Agamben, the poem itself exemplifies the structure of what he defines as 'messianic time'. By focusing on Dante's sonnet 'Tanto gentile e tanto onesta pare' and looking at the double act of the recitation of the poem and the "re-citation" of prior gestures, the temporality of both the single poem and lyric discourse will come into focus.
The text considers recirculation as a process through which both visual and cultural imagery are put in motion over and over again in the current information age, especially in the context of post-Internet art. Hito Steyerl's writings and thoughts on the 'poor image', namely the low-resolution digital image bound to a perpetual wandering or 'circulationism', here serve as major reference points for the development of the argument.
Recherche II : anamnesis
(2019)
The temporal loop of Proust's "Recherche" complicates the unidirectional understanding of anamnesis in psychoanalysis, which, in turn, allows for a renewed reading of the temporality of the "Recherche", highlighting the intrinsic link between artistic 'research' and unconscious affect - at the same time origin, motif, and destination.
Recherche I
(2019)
Recherche, (re-)search: do I research to find something not yet found or do I re-search back to find something that has been lost? These two directionalities structure Proust's "À la recherche du temps perdu" and are reflected in its reception. But what if they only seem mutually exclusive, yet really are one and the same thing?
Preface
(2019)
What's in a prefix? How to read a prefix as short as 're-'? Does 're-' really signify? Can it point into a specific direction? Can it reverse? Can it become the shibboleth of a 'postcritical' reboot? At first glance transparent and directional, 're-' complicates the linear and teleological models commonly accepted as structuring the relations between past, present, and future, opening onto errant temporalities.
Albumin, the most abundant plasma protein, not only controls osmotic blood pressure, but also serves as a carrier for various small molecules, including pharmaceuticals. Its impact on pharmacological properties of many drugs has been extensively studied over decades. Here, we focus on its interaction with the following mobilizing agents: Granulocyte-colony stimulating factor (G-CSF) and AMD3100, where such analyses are lacking. These compounds are widely used for hematopoietic stem cell mobilization of healthy donors or patients. Using albumin-deficient (Alb−/−) mice, we studied the contribution of albumin to mobilization outcomes. Mobilization with the bicyclam CXCR4 antagonist AMD3100 was attenuated in Alb−/− mice compared to wild-type littermates. By contrast, mobilization with recombinant human G-CSF (rhG-CSF), administered twice daily over a five-day course, was significantly increased in Alb−/− mice. In terms of a mechanism, we show that rhG-CSF bioavailability in the bone marrow is significantly improved in Alb−/− mice, compared to wild-type (WT) littermates, where rhG-CSF levels dramatically drop within a few hours of the injection. These observations likely explain the favorable mobilization outcomes with split-dose versus single-dose administration of rhG-CSF to healthy donors.
We investigated the implications of string theory in the high-precision regime of quantum mechanics. In particular, we examined a quantum field theoretical propagator which was derived from string theory when compactified at the T-duality self-dual radius and which is closely related to the path integral duality. Our focus was on the hydrogen ground state energy and the 1S1/2−2S1/2 transition frequency, as they are the most precisely explored properties of the hydrogen atom. The T-duality propagator alters the photon field dynamics leading to a modified Coulomb potential. Thus, our study is complementary to investigations where the electron evolution is modified, as in studies of a minimal length in the context of the generalized uncertainty principle. The first manifestation of the T-duality propagator arises at fourth order in the fine-structure constant, including a logarithmic term. For the first time, constraints on the underlying parameter, the zero-point length, are presented. They reach down to 3.9×10−19m and are in full agreement with previous studies on black holes.
Convective shower characteristics simulated with the convection-permitting climate model COSMO-CLM
(2019)
This paper evaluates convective precipitation as simulated by the convection-permitting climate model (CPM) Consortium for Small-Scale Modeling in climate mode (COSMO-CLM) (with 2.8 km grid-spacing) over Germany in the period 2001–2015. Characteristics of simulated convective precipitation objects like lifetime, area, mean intensity, and total precipitation are compared to characteristics observed by weather radar. For this purpose, a tracking algorithm was applied to simulated and observed precipitation with 5-min temporal resolution. The total amount of convective precipitation is well simulated, with a small overestimation of 2%. However, the simulation underestimates convective activity, represented by the number of convective objects, by 33%. This underestimation is especially pronounced in the lowlands of Northern Germany, whereas the simulation matches observations well in the mountainous areas of Southern Germany. The underestimation of activity is compensated by an overestimation of the simulated lifetime of convective objects. The observed mean intensity, maximum intensity, and area of precipitation objects increase with their lifetime showing the spectrum of convective storms ranging from short-living single-cell storms to long-living organized convection like supercells or squall lines. The CPM is capable of reproducing the lifetime dependence of these characteristics but shows a weaker increase in mean intensity with lifetime resulting in an especially pronounced underestimation (up to 25%) of mean precipitation intensity of long-living, extreme events. This limitation of the CPM is not identifiable by classical evaluation techniques using rain gauges. The simulation can reproduce the general increase of the highest percentiles of cell area, total precipitation, and mean intensity with temperature but fails to reproduce the increase of lifetime. The scaling rates of mean intensity and total precipitation resemble observed rates only in parts of the temperature range. The results suggest that the evaluation of coarse-grained (e.g., hourly) precipitation fields is insufficient for revealing challenges in convection-permitting simulations.
Focused electron and ion beam-induced deposition (FEBID/FIBID) are direct-write techniques with particular advantages in three-dimensional (3D) fabrication of ferromagnetic or superconducting nanostructures. Recently, two novel precursors, HCo 3 Fe(CO) 12 and Nb(NMe 3 ) 2 (N-t-Bu), were introduced, resulting in fully metallic CoFe ferromagnetic alloys by FEBID and superconducting NbC by FIBID, respectively. In order to properly define the writing strategy for the fabrication of 3D structures using these precursors, their temperature-dependent average residence time on the substrate and growing deposit needs to be known. This is a prerequisite for employing the simulation-guided 3D computer aided design (CAD) approach to FEBID/FIBID, which was introduced recently. We fabricated a series of rectangular-shaped deposits by FEBID at different substrate temperatures between 5 ∘ C and 24 ∘ C using the precursors and extracted the activation energy for precursor desorption and the pre-exponential factor from the measured heights of the deposits using the continuum growth model of FEBID based on the reaction-diffusion equation for the adsorbed precursor.
To improve and focus preclinical testing, we combine tumor models based on a decellularized tissue matrix with bioinformatics to stratify tumors according to stage-specific mutations that are linked to central cancer pathways. We generated tissue models with BRAF-mutant colorectal cancer (CRC) cells (HROC24 and HROC87) and compared treatment responses to two-dimensional (2D) cultures and xenografts. As the BRAF inhibitor vemurafenib is—in contrast to melanoma—not effective in CRC, we combined it with the EGFR inhibitor gefitinib. In general, our 3D models showed higher chemoresistance and in contrast to 2D a more active HGFR after gefitinib and combination-therapy. In xenograft models murine HGF could not activate the human HGFR, stressing the importance of the human microenvironment. In order to stratify patient groups for targeted treatment options in CRC, an in silico topology with different stages including mutations and changes in common signaling pathways was developed. We applied the established topology for in silico simulations to predict new therapeutic options for BRAF-mutated CRC patients in advanced stages. Our in silico tool connects genome information with a deeper understanding of tumor engines in clinically relevant signaling networks which goes beyond the consideration of single drivers to improve CRC patient stratification.
The sources and critical enrichment processes for granite related tin ores are still not well understood. The Erzgebirge represents one of the classical regions for tin mineralization. We investigated the four largest plutons from the Western Erzgebirge (Germany) for the geochemistry of bulk rocks and autocrystic zircons and relate this information to their intrusion ages. The source rocks of the Variscan granites were identified as high-grade metamorphic rocks based on the comparison of Hf-O isotope data on zircons, the abundance of xenocrystic zircon ages as well as Nd and Hf model ages. Among these rocks, restite is the most likely candidate for later Variscan melts. Based on the evolution with time, we could reconstruct enrichment factors for tin and tungsten starting from the protoliths (575 Ma) that were later converted to high-grade metamorphic rocks (340 Ma) and served as sources for the older biotite granites (323–318 Ma) and the tin granites (315–314 Ma). This evolution involved a continuous enrichment of both tin and tungsten with an enrichment factor of ~15 for tin and ~7 for tungsten compared to the upper continental crust (UCC). Ore level concentrations (>10–100 times enrichment) were achieved only in the greisen bodies and dykes by subsequent hydrothermal processes.
CCR8 leads to eosinophil migration and regulates neutrophil migration in murine allergic enteritis
(2019)
Allergic enteritis (AE) is a gastrointestinal form of food allergy. This study aimed to elucidate cellular and molecular mechanisms of AE using a murine model. To induce AE, BALB/c wild type (WT) mice received intraperitoneal sensitization with ovalbumin (an egg white allergen) plus ALUM and feeding an egg white (EW) diet. Microarray analysis showed enhanced gene expression of CC chemokine receptor (CCR) 8 and its ligand, chemokine CC motif ligand (CCL) 1 in the inflamed jejunum. Histological and FACS analysis showed that CCR8 knock out (KO) mice exhibited slightly less inflammatory features, reduced eosinophil accumulation but accelerated neutrophil accumulation in the jejunums, when compared to WT mice. The concentrations of an eosinophil chemoattractant CCL11 (eotaxin-1), but not of IL-5, were reduced in intestinal homogenates of CCR8KO mice, suggesting an indirect involvement of CCR8 in eosinophil accumulation in AE sites by inducing CCL11 expression. The potential of CCR8 antagonists to treat allergic asthma has been discussed. However, our results suggest that CCR8 blockade may promote neutrophil accumulation in the inflamed intestinal tissues, and not be a suitable therapeutic target for AE, despite the potential to reduce eosinophil accumulation. This study advances our knowledge to establish effective anti-inflammatory strategies in AE treatment.
Glioblastome (GB) sind die häufigsten bösartigen primären Hirntumore im Erwachsenenalter. Das Therapiekonzept bei Erstdiagnose besteht aus einer maximalen Tumorresektion, gefolgt von einer Strahlentherapie mit konkomitanter und anschließend adjuvanter Chemotherapie mit dem Alkylanz Temozolomid in Zyklusform. Zusätzlich zur adjuvanten Chemotherapie werden inzwischen für supratentorielle GBs auch Tumortherapiefelder empfohlen, die über elektromagnetische Wechselfelder die Tumorzellteilung hemmen sollen. Trotz multimodaler Therapiekonzepte und Fortschritte im Verständnis der GB-Biologie ist die Prognose der Patienten bei einer 5-Jahresüberlebensrate von unter 5% sehr ernüchternd. Eine mögliche Ursache für den ausbleibenden Erfolg neuer GB-Medikamente könnten die besonderen metabolischen Bedingungen des Tumormikromilieus sein. Unter diesen kann eine therapeutische zielgerichtete Inhibition bestimmter Kinasen, wie des Epidermalen Wachstumsfaktorrezeptors (EGFR) oder mammalian Target of Rapamycin (mTOR), unerwünschte Tumorzell-protektive Effekte entfalten, da bereits gezeigt werden konnte, dass sich Tumorzellen durch Suppression der mTORC1 abhängigen Signalkaskade an Energiemangelbedingungen, wie sie im Tumormikromilieu zu finden sind, anpassen, um zu überleben. Ziel dieses Projektes war es den physiologischen mTORC1-Inhibitor DNAdamage-inducible transcript 4 (DDIT4) als möglichen intrinsischen Resistenzmechanismus gegenüber Strahlen- und Chemotherapie in GBs zu untersuchen. In verschiedenen GB-Zelllinien konnte eine Induktion von DDIT4 teilweise durch Bestrahlung, Temozolomid und generell durch die im Tumormikromilieu vorherrschende Hypoxie nachgewiesen werden. Dies gelang sowohl auf transkriptioneller Ebene als auch auf Proteinniveau. Zur Beurteilung der Relevanz dieses zellulären Anpassungsmechanismus wurden Zellen mit DDIT4 Gensuppression generiert und charakterisiert. Hier zeigte sich in klonalen Überlebensanalysen eine gesteigerte Sensibilität der Zellen mit verminderter DDIT4 Expression gegenüber Temozolomid und Strahlentherapie. Darüber hinaus waren diese Zellen gegenüber Hypoxie-induziertem Zelltod sensibilisiert. Umgekehrt führte eine stabile oder Doxycyclin- induzierte DDIT4 Überexpression zu einer signifikanten Resistenz gegenüber Strahlentherapie, Temozolomid und Hypoxie-induziertem Zelltod.
Zusammenfassend beschreiben unsere Ergebnisse DDIT4 als Mediator von Therapieresistenz gegenüber den etablierten Komponenten der GBErstlinientherapie und zudem als Anpassungsmechanismus an das hypoxische Tumormikromilieu. DDIT4 stellt somit einen möglichen Angriffspunkt für eine therapeutische Inhibition beim GB dar.
Human beings are supposed to possess an approximate number system (ANS) dedicated to extracting and representing approximate numerical magnitude information as well as an object tracking system (OTS) for the rapid and accurate enumeration of small sets. It is assumed that the OTS and the ANS independently contribute to the acquisition of more elaborate numerical concepts. Chinese children have been shown to exhibit more elaborate numerical concepts than their non-Chinese peers, but it is still an open question whether similar cross-national differences exist with regard to the underlying systems, namely the ANS and the OTS. In the present study, we investigated this question by comparing Chinese and German preschool children with regard to their performance in a non-symbolic numerical magnitude comparison task (assessing the ANS) and in an enumeration task (assessing the OTS). In addition, we compared children’s counting skills. To ensure that possible between-group differences could not be explained by differences in more general performance factors, we also assessed children’s reasoning ability and processing speed. Chinese children showed a better counting performance and a more accurate performance in the non-symbolic numerical magnitude comparison task. These differences in performance could not be ascribed to differences in reasoning abilities and processing speed. In contrast, Chinese and German children did not differ significantly in the enumeration of small sets. The superior counting performance of Chinese children was thus found to be reflected in the ANS but not in the OTS.
Aquesta tesi doctoral estudia la construcció de la notícia sobre esdeveniments del procés polític català en els mitjans de comunicació escrits alemanys. El període d’anàlisi s’estèn del 2010 al 2015, quan el procés ha passat de la societat civil a l’agenda política catalana i s’ha internacionalitzat. En aquest context, l’opinió publicada alemanya es considera un referent.
La tesi analitza dotze fets clau a partir d’una doble metodologia, quantitativa i qualitativa. Es duu a terme una anàlisi d’Agenda i de Frames, també s’aplica una Anàlisi del Discurs i es complementa la recerca amb entrevistes a periodistes i polítics. La metodologia ha estat provada i validada per set analistes germanòfons.
Els resultats de la recerca, exposats a més en quaranta-nou taules i figures, mostren l’establiment de l’agenda i els enquadraments dels temes i actors del procés català, la relació entre discurs, poder i legitimació, així com la construcció de l’opinió publicada alemanya.
In this work we provided additional insights into our understanding of bulk QCD matter through the study of the transport coeffcients which govern the non-equilibrium microscopical processes of statistical ensembles. Specically, we focused on the low energy regime corresponding to the hadron gas, as the properties of this region of the phase diagram are still relatively unknown, and existing calculations for the transport coeffcients are either scarce, contradictory, or somewhat limited in scope; this thesis' main goal was thus to shed some light on this by providing new independent calculations of these quantities.
We subsequently presented two formalisms which can be used to calculate transport coeffcients. The first one (which also was the main tool we used in the following chapters to produce our results) relies on the development of so-called Green-Kubo formulas, which relate non-equilibrium dissipative fluctuations with transport coeffcients; notably, the off-diagonal components of the energy-momentum tensor are shown to be related to the shear viscosity, its diagonal components to the bulk viscosity and fluctuations in the electric current can be related to the electric conductivity. We additionally introduced two new conductivities, namely the baryon-electric and strange electric conductivities, which we dubbed, together with the already known electric one, the "cross-conductivity", which encodes information about how electric fluctuations are correlated to changes in electric, baryonic or strange currents, or vice-versa. The second way of calculating transport coeffcient which we discussed consists in linearizing the collision term of the Boltzmann equation through the Chapman-Enskog formalism. While in principle providing direct semi-analytical results for the transport coeffcients, this approach is complicated to implement when more than a few species are considered, and as such was then mostly used as a tool to calibrate our Green-Kubo calculations.
The hadron gas model that we used for all calculations, namely the transport approach SMASH, was then presented. The main features of the model were explained, such as the collision criterion, the considered degrees of freedom and the specific way in which they microscopically interact with each other. It was verified that SMASH does reproduce analytical results of the Boltzmann equation in an expanding universe scenario, thus showing the equivalence of this transport approach and the associated kinetic theory results. A special care was taken to detail the ways in which a state of thermal and chemical equilibrium (which is necessary for Green-Kubo relations to be valid) can be reached and described using SMASH.
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Ziel dieser Arbeit war es, eine vergleichende Bewertung der Erkennbarkeit der apikalen Aufhellung in den dreidimensionalen DVT-Aufnahmen und den konventionellen Panoramaschichtaufnahmen im Oberkiefer unter den folgenden Gesichtspunkten vorzunehmen:
Werden die apikalen Aufhellungen sowohl bei zwei- als auch bei dreidimensionalen Aufnahmen gleichermaßen erkannt?
Spielt die Stärke der Kompakta eine Rolle in der radiologischen Diagnose einer apikalen Aufhellung?
Zu diesem Zweck wurden 351 Patienten aus der Datenbank einer privaten Praxis in Stuttgart ausgewählt. Davon erfüllten 199 Patienten die Einschlusskriterien. Es wurden insgesamt 2223 Zähne durch den Untersucher ausgewertet. Es konnten 144 apikale Aufhellungen mittels der DVT diagnostiziert werden, wovon lediglich 23 (15,9 %) mittels der OPT erkannt wurden. Die Ergebnisse dieser Studie zeigen insgesamt einen signifikanten Unterschied zwischen den DVT- und den OPG-Befunden hinsichtlich der Sichtbarkeit der apikalen Aufhellungen im Oberkiefer. Andere Parameter wie die Tiefe, die Breite und die Länge der apikalen Aufhellungen wurden ebenfalls untersucht. Die Messungen erfolgten mittels der Software i-CatVision 2008 für die DVT-Aufnahmen und mittels DBSWIN von Dürr Dental für die OPG- Aufnahmen. Es ergab sich daraus, dass die apikalen Läsionen, die im OPG und in der DVT sichtbar waren, signifikant größere Breiten hatten als die, die nur in der DVT sichtbar waren. Es zeigte sich hierbei ein signifikanter Unterschied (U- Test, p =0,018). Dies weist daraufhin, dass insbesondere schmale apikale Läsionen nicht sicher in OPG-Aufnahmen diagnostiziert werden, während sie in der DVT nachweisbar sind. Des Weiteren wurde in der Studie die Kompaktadicke gemessen. Es bestand kein signifikanter Zusammenhang zwischen der Sichtbarkeit der apikalen Aufhellung und der Kompaktadicke. Zusammenfassend lässt sich anhand der Ergebnisse der vorliegenden Arbeit feststellen, dass die Kompaktadicke keine Rolle bei der Sichtbarkeit der apikalen Läsionen spielt und dass die OPT im Nachweis apikaler Läsionen der DVT eindeutig unterlegen ist. Es wurden dadurch nur 19 % der apikalen 64 Aufhellungen diagnostiziert und damit ist eine Unterdiagnose sehr wahrscheinlich.
Schlussfolgernd scheint die DVT ein zuverlässiges diagnostisches Mittel bezüglich des Erkennens der apikalen Läsionen zu sein. Mehrere Studien bezeichnen die DVT als Goldstandard und ziehen sie für die Diagnose der apikalen Aufhellungen den konventionellen Röntgenbildern vor. Dieses Vorgehen widerspricht jedoch dem Bestreben nach einer möglichst geringen Strahlenexposition gemäß dem ALARA-Prinzips. Damit bleibt die DVT derzeit eine Ergänzung zur konventionellen Bildgebung.
Der VEGF-neutralisierende Antikörper Bevacizumab ist ein wichtiger Bestandteil der modernen Tumortherapie. Auch in der Glioblastom Therapie wird Bevacizumab eingesetzt, da in klinischen Studien eine Verlängerung des progressionsfreien Überlebens beobachtet wurde. Leider entwickeln sich schnell Resistenzen und das Gesamtüberleben konnte durch Bevacizumab in der Erstlinientherapie von Glioblastomen nicht verlängert werden.
Die genaue Wirkungsweise von Bevacizumab und somit auch die Resistenzentwicklung sind nur teilweise bekannt. Es wird vermutet, dass es durch Gefäßveränderungen zu einer Mangelsituation und zu Hypoxie kommt. Einige Studien deuten darauf hin, dass es neben der Wiedererlangung einer VEGF-unabhängigen Gefäßversorgung auch zu Resistenz gegen das durch Bevacizumab hervorgerufene, von Sauerstoffmangel gekennzeichnete Mikromilieu kommt. So konnte gezeigt werden, dass Bevacizumab-resistente Tumoren einen stark glykolytischen, sauerstoff-unabhängigen Zellmetabolismus aufweisen und vermehrt Laktat produzieren. Darüber hinaus wurde in Folge der Bevacizumab-Behandlung eine Fehlfunktion von Mitochondrien beobachtet. Unklar ist noch, ob die beschriebenen metabolischen Veränderungen ein Epiphänomen der Nährstoffmangelsituation sind oder ob sie kausal mit der Resistenzentwicklung in Zusammenhang stehen.
In der vorliegenden Arbeit sollte deshalb geprüft werden, ob die metabolische Umstellung hin zu einem glykolytischen, anaeroben Phänotyp eine hinreichende Bedingung zur Entwicklung einer Hypoxie- und Bevacizumabresistenz darstellt.
Hierzu wurden Glioblastomzellen (LNT229) derart verändert, dass sie keine oxidative Phosphorylierung durchführen konnten und rein auf die glykolytische Energiegewinnung angewiesen waren (rho0-Zellen). Diese Veränderung führte in-vitro zu einer Hypoxieresistenz der Zellen. Außerdem waren rho0-Zellen empfindlicher gegenüber Glukoseentzug und einer Behandlung mit dem Glykolyse-Inhibitor 2-Deoxyglucose (2DG). Des Weiteren waren im Mausmodell intrakranielle rho0-Tumorxenografts resistent gegenüber Bevacizumab. Diese Resistenz konnte durch zusätzliche Therapie mit 2DG wieder aufgehoben werden.
Somit konnte in der vorliegenden Arbeit gezeigt werden, dass die Hemmung der oxidativen Phosphorylierung zu einem glykolytischen Phänotyp führt, der hinreichend ist, um eine Hypoxieresistenz und in Folge dessen eine Bevacizumabresistenz in Glioblastomzellen zu verursachen. Dies lässt einen kausalen Zusammenhang zwischen bereits in anderen Studien beschriebenen metabolischen Veränderungen und einer Bevacizumabresistenz in Tumoren vermuten. Der zelluläre Glukosestoffwechsel ist damit ein vielversprechender therapeutischer Angriffspunkt zur Vermeidung und Überwindung einer Bevacizumabresistenz.
Das Strukturgleichungsmodell (SEM) wird in den Sozial- und Verhaltenswissenschaften oft verwendet, um die Beziehung zwischen latenten Variablen zu modellieren. In der Analyse dieser Modelle spielt die Bewertung der Modellgüte eine wesentliche Rolle, wobei geprüft werden soll, ob das untersuchte Modell (Zielmodell) zu den erhobenen Daten passt. Dafür werden verschiedene inferenzstatistische und deskriptive Gütemaße verwendet. In nichtlinearen SEM, in denen nichtlineare Effekte, wie beispielsweise Interaktionseffekte, modelliert werden, gibt es bisher allerdings keine Verfahren, um die Modellgüte ausreichend prüfen zu können. Insbesondere der χexp2-Test ist für verschiedene nichtlineare SEM nicht geeignet (vgl. Klein & Schermelleh-Engel, 2010; Mooijaart & Satorra, 2009).
In dieser Arbeit werden zwei unterschiedliche nichtlineare SEM betrachtet. Das erste dieser Modelle wird für die Analyse von Interaktions- und quadratischen Effekten verwendet (quadratisches SEM, QSEM). Das zweite Modell ist das Heterogene Wachstumskurvenmodell (HGM; Klein & Muthén, 2006). In diesem Modell wird das latente Wachstumskurvenmodell (LGM), mit dem individuelle Wachstumsverläufe modelliert werden können, um eine heterogene Varianzkomponente des Slope-Faktors erweitert. Diese Heterogenität des Slope-Faktors ist abhängig von den Ausgangswerten und Kovariaten.
Ziel dieser Arbeit war es, die Bewertung der Modellgüte für das QSEM und das HGM zu verbessern. Für das QSEM und das HGM wurde jeweils ein globaler Modelltest entwickelt („Quasi-Likelihood-Ratio-Test“; QLRT). Darüber hinaus wurden Differenztests für diese Art der Modelle diskutiert. Außerdem wurde für beide Modelle je ein Gütemaß bereitgestellt, um fehlende Nichtlinearität, wie fehlende nichtlineare Terme bzw. fehlende Heterogenität der Slope-Varianzen, aufdecken zu können (der Homoscedastic Fit Index, HFI, für das QSEM und der hhet-Test für das HGM).
Die Entwicklung der neuen Gütemaße ist im Wesentlichen von der verwendeten Schätzmethode abhängig. Für beide Modelle, das QSEM und das HGM, wurde in dieser Arbeit die Quasi-Maximum-Likelihood-Methode (Quasi-ML-Methode; Wedderburn, 1974) ausgewählt, mit der für beide betrachteten Modelle geeignete Schätzungen erzielt werden können (Klein & Muthén, 2006, 2007). Die Quasi-ML-Methode ist vergleichbar mit der Maximum-Likelihood-Methode, berücksichtigt allerdings Fehlspezifikationen der LogLikelihood-Funktion, wie beispielsweise kleinere Abweichungen von der angenommenen Verteilung. Für das QSEM wurde im Rahmen der Entwicklung der Modelltests eine zur Schätzung von QSEM entwickelte Quasi-ML-Methode (QML-Methode; Klein & Muthén, 2007) vereinfacht zu der „simplified QML“-Methode (sQML-Methode; Büchner & Klein, 2019). Für die sQML-Methode ist es erheblich einfacher als für die QML-Methode einen globalen Modelltest zu entwickeln. In einer Simulationsstudie konnte gezeigt werden, dass die sQML-Methode ähnlich gute Schätzeigenschaften wie die QML-Methode aufweist.
Die Idee der neuen globalen Modelltests für das QSEM und das HGM besteht darin, statt des für das lineare SEM verwendeten χexp2-Tests, der ein Likelihood-Quotienten-Test („Likelihood Ratio Test“, LRT) ist, einen Quasi-LRT (QLRT) zu verwenden, der auf der Quasi-ML-Methode basiert (Büchner & Klein, 2019; Büchner, Klein & Irmer, 2019). Wie für den χexp2-Test soll das Zielmodell mit einem unbeschränkten Vergleichsmodell verglichen werden. Ist der Unterschied zwischen den Modellen groß, wird darauf geschlossen, dass das Zielmodell nicht gut zu den Daten passt. Die Schwierigkeit bei der Entwicklung solcher QLRT liegt dabei in der Definition eines Vergleichsmodells. Die hier verwendete Idee für solche Vergleichsmodelle besteht darin, wie im χexp2-Test, die Beschränkungen durch das Zielmodell im Vergleichsmodell aufzuheben. Eine weitere Herausforderung ist die Bestimmung der asymptotischen Verteilung der QLRT-Statistiken, die nicht, wie viele LRT-Statistiken, asymptotisch χexp2-verteilt sind. Deshalb wurde die korrekte asymptotische Verteilung dieser Teststatistiken bestimmt, die das Ermitteln von p-Werten ermöglicht.
Globale Modelltests sind zwar geeignet, wichtige Aussagen zur Passung des Modells zu machen, ermöglichen aber keine direkte Aussage über den Vergleich zweier konkurrierender Modelle. Ein solcher Modellvergleich ist aber wichtig, um ein möglichst sparsames Modell zu erhalten. Zum Vergleich ineinander geschachtelter Modelle werden häufig Differenztests verwendet. Diese werden auch in der Arbeit mit dem QSEM und dem HGM empfohlen. Allerdings ist zu beachten, dass die Teststatistiken für mit der Quasi-MLMethode geschätzten Modelle nicht χexp2-verteilt sind. Im Rahmen dieser Arbeit wurde eine korrekte asymptotische Verteilung angegeben. Im Speziellen wurde der Differenztest für den Vergleich zwischen einem HGM und einem LGM vorgestellt, mit dem getestet wird, ob die im HGM modellierten heterogenen Slope-Varianzen notwendig sind.
Ein weiteres Ziel bestand darin, fehlende Nichtlinearität, die nicht in einem Modell berücksichtigt ist, aufzudecken. Dafür wurde ein Test für Regressionsmodelle, der hhet-Test (Klein, Gerhard, Büchner, Diestel & Schermelleh-Engel, 2016), angepasst. Für das SEM wurde dieser Test zu einem Fit-Index, dem HFI (Gerhard, Büchner, Klein & SchermellehEngel, 2017), weiterentwickelt und darin die Verteilung der Residuen der abhängigen Variable bewertet. Der HFI deckt dabei Veränderungen in der Verteilung auf, die durch fehlende nichtlineare Terme verursacht sind. Für das LGM wird der hhet-Test verwendet, um fehlende heterogene Entwicklungsverläufe aufzudecken. Es wird die Verteilung der mit dem LGM standardisierten beobachteten Variablen geprüft.
Für alle vorgeschlagenen Gütemaße wurden Simulationsstudien durchgeführt, um ihre Eignung für die Bewertung des QSEMs bzw. des HGMs zu prüfen. Die α-Fehler-Raten waren meistens nahe an dem erstrebten 5%-Niveau. Für den QLRT für das QSEM bei kleinen Stichproben und für den HFI bei komplexeren Modellen waren sie allerdings erhöht. Darüber hinaus zeigten die Tests insgesamt eine gute Teststärke für das Aufdecken von Fehlspezifikationen. Wie in allen statistischen Tests muss dafür die Stichprobengröße ausreichend groß sein. Die praktische Anwendbarkeit der beiden QLRTs, des hhet-Tests und des Differenztests für das HGM wurde anhand von empirischen Beispielen aufgezeigt.
Background: Approximately every third surgical patient is anemic. The most common form, iron deficiency anemia, results from persisting iron‐deficient erythropoiesis (IDE). Zinc protoporphyrin (ZnPP) is a promising parameter for diagnosing IDE, hitherto requiring blood drawing and laboratory workup.
Study design and methods: Noninvasive ZnPP (ZnPP‐NI) measurements are compared to ZnPP reference determination of the ZnPP/heme ratio by high‐performance liquid chromatography (ZnPP‐HPLC) and the analytical performance in detecting IDE is evaluated against traditional iron status parameters (ferritin, transferrin saturation [TSAT], soluble transferrin receptor–ferritin index [sTfR‐F], soluble transferrin receptor [sTfR]), likewise measured in blood. The study was conducted at the University Hospitals of Frankfurt and Zurich.
Results: Limits of agreement between ZnPP‐NI and ZnPP‐HPLC measurements for 584 cardiac and noncardiac surgical patients equaled 19.7 μmol/mol heme (95% confidence interval, 18.0–21.3; acceptance criteria, 23.2 μmol/mol heme; absolute bias, 0 μmol/mol heme). Analytical performance for detecting IDE (inferred from area under the curve receiver operating characteristics) of parameters measured in blood was: ZnPP‐HPLC (0.95), sTfR (0.92), sTfR‐F (0.89), TSAT (0.87), and ferritin (0.67). Noninvasively measured ZnPP‐NI yielded results of 0.90.
Conclusion: ZnPP‐NI appears well suited for an initial IDE screening, informing on the state of erythropoiesis at the point of care without blood drawing and laboratory analysis. Comparison with a multiparameter IDE test revealed that ZnPP‐NI values of 40 μmol/mol heme or less allows exclusion of IDE, whereas for 65 μmol/mol heme or greater, IDE is very likely if other causes of increased values are excluded. In these cases (77% of our patients) ZnPP‐NI may suffice for a diagnosis, while values in between require analyses of additional iron status parameters.
Glioblastoma (GB) is the most common and aggressive primary brain tumor in adults and currently incurable. Despite multimodal treatment regimens, median survival in unselected patient cohorts is <1 year, and recurrence remains almost inevitable. Escape from immune surveillance is thought to contribute to the development and progression of GB. While GB tumors are frequently infiltrated by natural killer (NK) cells, these are actively suppressed by the GB cells and the GB tumor microenvironment. Nevertheless, ex vivo activation with cytokines can restore cytolytic activity of NK cells against GB, indicating that NK cells have potential for adoptive immunotherapy of GB if potent cytotoxicity can be maintained in vivo. NK cells contribute to cancer immune surveillance not only by their direct natural cytotoxicity which is triggered rapidly upon stimulation through germline-encoded cell surface receptors, but also by modulating T-cell mediated antitumor immune responses through maintaining the quality of dendritic cells and enhancing the presentation of tumor antigens. Furthermore, similar to T cells, specific recognition and elimination of cancer cells by NK cells can be markedly enhanced through expression of chimeric antigen receptors (CARs), which provides an opportunity to generate NK-cell therapeutics of defined specificity for cancer immunotherapy. Here, we discuss effects of the GB tumor microenvironment on NK-cell functionality, summarize early treatment attempts with ex vivo activated NK cells, and describe relevant CAR target antigens validated with CAR-T cells. We then outline preclinical approaches that employ CAR-NK cells for GB immunotherapy, and give an overview on the ongoing clinical development of ErbB2 (HER2)-specific CAR-NK cells currently applied in a phase I clinical trial in glioblastoma patients.
Charge states and energy loss of heavy ions after passing an inductively coupled plasma target
(2019)
In various kinds of fields such as accelerator physics, warm dense matter, high energy density physics, and inertial confinement fusion, heavy ions beam-plasma interaction plays an important role, and abundant investigations have been and are being carried out. Taking advantage of a good level of understanding on the interaction between a swift heavy ions beam and a hydrogen gas discharge plasma, an engineering application of a spherical theta-pinch device as a plasma stripper for FAIR (facility for antiproton and ion research) and a scientific application of a swift heavy ions beam as a novel plasma diagnostic tool are proposed and investigated.
The spherical theta-pinch device is manufactured, improved, and comprehensively tested for its application as a plasma stripper. The device is mainly composed of an evacuated glass vessel that can be filled with gas (for example: hydrogen) and a LRC circuit including a capacitors bank and a set of coils. Discharging the device at an initial hydrogen pressure in the glass vessel and an operation voltage for the capacitors bank, a circuit current oscillates in the LRC circuit. The oscillating circuit current in the set of coils induces a corresponding alternating magnetic field inside the glass vessel to ignite and maintain a hydrogen plasma.
Based on the built setup of circuit and plasma diagnostics, the measurements of circuit current, plasma light emission, plasma shape, and hydrogen Balmer series are carried out. The recorded signals of the circuit current and the plasma light emission of many consecutively repetitive discharges overlap perfectly, which indicate a very good reproducibility of the parameters of the LRC circuit during discharge and the generated plasma. From the measured circuit current, a real energy transfer efficiency is calculated by our proposed new model, which shows its overall tendency varying with the hydrogen pressure and the operation voltage, including the maximum value of 25% occurring at an initial hydrogen pressure of around 25 Pa and a maximum operation voltage of 14 kV. So, the discharge at an initial hydrogen pressure of 20 Pa and an operation voltage of 14 ...
Elucidating the immune evasion mechanisms of borrelia mayonii, the causative agent of lyme disease
(2019)
Borrelia (B.) mayonii sp. nov. has recently been reported as a novel human pathogenic spirochete causing Lyme disease (LD) in North America. Previous data reveal a higher spirochaetemia in the blood compared to patients infected by LD spirochetes belonging to the B. burgdorferi sensu lato complex, suggesting that this novel genospecies must exploit strategies to overcome innate immunity, in particular complement. To elucidate the molecular mechanisms of immune evasion, we utilized various methodologies to phenotypically characterize B. mayonii and to identify determinants involved in the interaction with complement. Employing serum bactericidal assays, we demonstrated that B. mayonii resists complement-mediated killing. To further elucidate the role of the key regulators of the alternative pathway (AP), factor H (FH), and FH-like protein 1 (FHL-1) in immune evasion of B. mayonii, serum adsorption experiments were conducted. The data revealed that viable spirochetes recruit both regulators from human serum and FH retained its factor I-mediated C3b-inactivating activity when bound to the bacterial cells. In addition, two prominent FH-binding proteins of approximately 30 and 18 kDa were detected in B. mayonii strain MN14-1420. Bioinformatics identified a gene, exhibiting 60% identity at the DNA level to the cspA encoding gene of B. burgdorferi. Following PCR amplification, the gene product was produced as a His-tagged protein. The CspA-orthologous protein of B. mayonii interacted with FH and FHL-1, and both bound regulators promoted inactivation of C3b in the presence of factor I. Additionally, the CspA ortholog counteracted complement activation by inhibiting the alternative and terminal but not the classical and Lectin pathways, respectively. Increasing concentrations of CspA of B. mayonii also strongly affected C9 polymerization, terminating the formation of the membrane attack complex. To assess the role of CspA of B. mayonii in facilitating serum resistance, a gain-of-function strain was generated, harboring a shuttle vector allowing expression of the CspA encoding gene under its native promotor. Spirochetes producing the native protein on the cell surface overcame complement-mediated killing, indicating that CspA facilitates serum resistance of B. mayonii. In conclusion, here we describe the molecular mechanism utilized by B. mayonii to resists complement-mediated killing by capturing human immune regulators.
Background: The DIAMOND study of de novo liver transplant patients showed that prolonged-release tacrolimus exposure in the acute post-transplant period maintained renal function over 24 weeks of treatment. To assess these findings further, we performed a post-hoc analysis in patients according to baseline kidney function, Model for End-stage Liver Disease [MELD] scores, and donor age.
Material/Methods: Patients received prolonged-release tacrolimus (initial-dose, Arm 1: 0.2 mg/kg/day, Arm 2: 0.15-0.175 mg/kg/day, Arm 3: 0.2 mg/kg/day delayed until Day 5), mycophenolate mofetil and 1 steroid bolus. Arms 2 and 3 also received basiliximab. The recommended tacrolimus target trough levels to Day 42 post-transplantation were 5-15 ng/mL in all arms. In this post-hoc analysis, change in renal outcome, based on estimated glomerular filtration rate (eGFR), Modified Diet in Renal Disease-4 (MDRD4), values from baseline to Week 24 post-transplantation, were assessed according to baseline patient factors: eGFR (≥60 and ˂60 mL/min/1.73 m²), MELD score (˂25 and ≥25) and donor age (˂50 and ≥50 years).
Results: Baseline characteristics were comparable (Arms 1-3: n=283, n=287, n=274, respectively). Patients with baseline renal function, eGFR ≥60 mL/min/1.73 m², experienced a decrease in eGFR in all tacrolimus treatment arms. In patients with lower baseline renal function (eGFR ˂60 mL/min/1.73 m²), an advantage for renal function was observed with both the early lower-dose and delayed higher-dose tacrolimus regimens compared with the early introduction of higher-dose tacrolimus. At Week 24, renal function was higher in the early-lower tacrolimus arm with older donors, and the delayed higher-dose tacrolimus arm with younger donors, both compared with early higher-dose tacrolimus.
Conclusions: Pre-transplantation factors, such as renal function and donor age, could guide the choice of prolonged-release tacrolimus regimen following liver transplantation.
The thrombopoietin receptor agonist eltrombopag was successfully used against human cytomegalovirus (HCMV)-associated thrombocytopenia refractory to immunomodulatory and antiviral drugs. These effects were ascribed to the effects of eltrombopag on megakaryocytes. Here, we tested whether eltrombopag may also exert direct antiviral effects. Therapeutic eltrombopag concentrations inhibited HCMV replication in human fibroblasts and adult mesenchymal stem cells infected with six different virus strains and drug-resistant clinical isolates. Eltrombopag also synergistically increased the anti-HCMV activity of the mainstay drug ganciclovir. Time-of-addition experiments suggested that eltrombopag interfered with HCMV replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-negative cells, and the addition of Fe3+ prevented the anti-HCMV effects, indicating that it inhibits HCMV replication via iron chelation. This may be of particular interest for the treatment of cytopenias after hematopoietic stem cell transplantation, as HCMV reactivation is a major reason for transplantation failure. Since therapeutic eltrombopag concentrations are effective against drug-resistant viruses, and synergistically increase the effects of ganciclovir, eltrombopag is also a drug-repurposing candidate for the treatment of therapy-refractory HCMV diseas.
We study the Wigner function for massive spin-1/2 fermions in electromagnetic fields. The Wigner function is analytically solved in five cases when electromagnetic fields are constants. For a general space-time dependent field configuration, we use the method of semi-classical expansion and solved the Wigner function at linear order in the Planck's constant. At the same order, we obtained a generalized Boltzmann equation for particle distribution, and a generalized BMT equation for spin polarization. Using the Wigner function, we calculated some physical quantities in a thermal equilibrium system.
Nina Kühnle wendet sich in ihrer Untersuchung in erster Linie sozialgeschichtlichen Fragestellungen zu. Im Eingangskapitel wirft sie die zentrale Ausgangsfrage ihrer Arbeit auf: Handelt es sich bei der sog. "Ehrbarkeit" in Württemberg tatsächlich um eine "ständegeschichtlich einzigartige Sondergruppe" unter den städtischen Oberschichten in Deutschland (8), die man in dieser Form tatsächlich nur in Württemberg antrifft? Und handelt es sich bei dieser "Ehrbarkeit" um einen halbwegs abgrenzbaren stadtbürgerlichen Stand, der sich von den Patriziaten anderer, zumal süddeutscher Städtelandschaften in signifikanter Weise unterscheidet? Eben dies war die mittlerweile allerdings überholte These des württembergischen Landeshistorikers Hansmartin Decker-Hauff: Ihm zufolge bildete die württembergische Ehrbarkeit einen ganz spezifischen Stand, der sich dadurch ausgezeichnet habe, dass bei ihm allein die ausgeübten Ämter und Funktionen die Standeszugehörigkeit begründet hätten. In der eingehenden Auseinandersetzung mit dieser These zeigt die Verf. sodann deren Schwachstellen auf (12–17), wobei sie an die Kritik von Gabriele Haug-Moritz anknüpft, die in ihrer Monographie über die württembergische Ehrbarkeit von Decker-Hauffs Konzept nicht mehr viel übrig gelassen hat: Die Ehrbarkeit bestand nicht – das dürfte mittlerweile feststehen – aus der Gruppe der Amtsinhaber; letztere kamen vielmehr zu Amt und Würden, weil sie aus der Ehrbarkeit stammten (17). "Ehrbarkeit" ergab sich demzufolge nicht aus einem Amt, sondern umgekehrt aus der Zugehörigkeit zu einer bestimmten Gesellschaftsschicht. Angesichts dessen spricht die Verf. in ihrer Arbeit auch nicht von "der Ehrbarkeit", sondern von "städtischen Führungsgruppen" oder der "Stadtelite" (26f.), hier im Anschluss an die neuere Sozialgeschichte, die bekanntlich seit geraumer Zeit eine besondere Vorliebe für das Wort "Elite" entwickelt hat. ...
Neuroblastoma (NB) is the most common solid extracranial tumor in childhood. Despite therapeutic progress, prognosis in high-risk NB is poor and innovative therapies are urgently needed. Therefore, we addressed the potential cytotoxic capacity of interleukin (IL)-activated natural killer (NK) cells compared to cytokine-induced killer (CIK) cells for the treatment of NB. NK cells were isolated from peripheral blood mononuclear cells (PBMCs) by indirect CD56-enrichment or CD3/CD19-depletion and expanded with different cytokine combinations, such as IL-2, IL-15, and/or IL-21 under feeder-cell free conditions. CIK cells were generated from PBMCs by ex vivo stimulation with interferon-γ, IL-2, OKT-3, and IL-15. Comparative analysis of expansion rate, purity, phenotype and cytotoxicity was performed. CD56-enriched NK cells showed a median expansion rate of 4.3-fold with up to 99% NK cell content. The cell product after CD3/CD19-depletion consisted of a median 43.5% NK cells that expanded significantly faster reaching also 99% of NK cell purity. After 10–12 days of expansion, both NK cell preparations showed a significantly higher median cytotoxic capacity against NB cells relative to CIK cells. Remarkably, these NK cells were also capable of efficiently killing NB spheroidal 3D culture in long-term cytotoxicity assays. Further optimization using a novel NK cell culture medium and a prolonged culturing procedure after CD3/CD19-depletion for up to 15 days enhanced the expansion rate up to 24.4-fold by maintaining the cytotoxic potential. Addition of an IL-21 boost prior to harvesting significantly increased the cytotoxicity. The final cell product consisted for the major part of CD16−, NCR-expressing, poly-functional NK cells with regard to cytokine production, CD107a degranulation and antitumor capacity. In summary, our study revealed that NK cells have a significantly higher cytotoxic potential to combat NB than CIK cell products, especially following the synergistic use of IL-15 and IL-21 for NK cell activation. Therefore, the use of IL-15+IL-21 expanded NK cells generated from CD3/CD19-depleted apheresis products seems to be highly promising as an immunotherapy in combination with haploidentical stem cell transplantation (SCT) for high-risk NB patients.
Background: Patients with acutely decompensated cirrhosis (AD) may or may not develop acute-on-chronic liver failure (ACLF). ACLF is characterized by high-grade systemic inflammation, organ failures (OF) and high short-term mortality. Although patients with AD cirrhosis exhibit distinct clinical phenotypes at baseline, they have low short-term mortality, unless ACLF develops during follow-up. Because little is known about the association of profile of systemic inflammation with clinical phenotypes of patients with AD cirrhosis, we aimed to investigate a battery of markers of systemic inflammation in these patients.
Methods: Upon hospital admission baseline plasma levels of 15 markers (cytokines, chemokines, and oxidized albumin) were measured in 40 healthy controls, 39 compensated cirrhosis, 342 AD cirrhosis, and 161 ACLF. According to EASL-CLIF criteria, AD cirrhosis was divided into three distinct clinical phenotypes (AD-1: Creatinine<1.5, no HE, no OF; AD-2: creatinine 1.5–2, and or HE grade I/II, no OF; AD-3: Creatinine<1.5, no HE, non-renal OF).
Results: Most markers were slightly abnormal in compensated cirrhosis, but markedly increased in AD. Patients with ACLF exhibited the largest number of abnormal markers, indicating “full-blown” systemic inflammation (all markers). AD-patients exhibited distinct systemic inflammation profiles across three different clinical phenotypes. In each phenotype, activation of systemic inflammation was only partial (30% of the markers). Mortality related to each clinical AD-phenotype was significantly lower than mortality associated with ACLF (p < 0.0001 by gray test). Among AD-patients baseline systemic inflammation (especially IL-8, IL-6, IL-1ra, HNA2 independently associated) was more intense in those who had poor 28-day outcomes (ACLF, death) than those who did not experience these outcomes.
Conclusions: Although AD-patients exhibit distinct profiles of systemic inflammation depending on their clinical phenotypes, all these patients have only partial activation of systemic inflammation. However, those with the most extended baseline systemic inflammation had the highest the risk of ACLF development and death.
MicroRNAs (miRs) significantly contribute to the regulation of gene expression, by virtue of their ability to interact with a broad, yet specific set of target genes. MiRs are produced and released by almost every cell type and play an important role in horizontal gene regulation in the tumor microenvironment (TME). In the TME, both tumor and stroma cells cross-communicate via diverse factors including miRs, which are taking central stage as a therapeutic target of anti-tumor therapy. One of the immune escape strategies adopted by tumor cells is to release miRs as a Trojan horse to hijack circulating or tumor-localized monocytes/macrophages to tune them for pro-tumoral functions. On the other hand, macrophage-derived miRs exert anti-tumor functions. The transfer of miRs from host to recipient cells depends on the supramolecular structure and composition of miR carriers, which determine the distinct uptake mechanism by recipient cells. In this review, we provide a recent update on the miR-mediated crosstalk between tumor cells and macrophages and their mode of uptake in the TME.
EDTA is commonly used as an efficient chelator of metal ion enzyme cofactors. It is highly soluble, optically inactive and does not interfere with most chemicals used in standard buffers making EDTA a common choice to generate metal-free conditions for biochemical and biophysical investigations. However, the controversy in the literature on metal-free enzyme activities achieved using EDTA or by other means called our attention to a putative effect of EDTA beyond chelation. Here, we show that EDTA competes for the nucleotide binding site of the nucleotide hydrolase dUTPase by developing an interaction network within the active site similar to that of the substrate. To achieve these findings, we applied kinetics and molecular docking techniques using two different dUTPases. Furthermore, we directly measured the binding of EDTA to dUTPases and to two other dNTPases, the Taq polymerase and MutT using isothermal titration calorimetry. EDTA binding proved to be exothermic and mainly enthalpy driven with a submicromolar dissociation constant considerably lower than that of the enzyme:substrate or the Mg:EDTA complexes. Control proteins, including an ATPase, did not interact with EDTA. Our findings indicate that EDTA may act as a selective inhibitor against dNTP hydrolyzing enzymes and urge the rethinking of the utilization of EDTA in enzymatic experiments.
Yellow fever virus (YFV) represents a re-emerging zoonotic pathogen, transmitted by mosquito vectors to humans from primate reservoirs. Sporadic outbreaks of YFV occur in endemic tropical regions, causing a viral hemorrhagic fever (VHF) associated with high mortality rates. Despite a highly effective vaccine, no antiviral treatments currently exist. Therefore, YFV represents a neglected tropical disease and is chronically understudied, with many aspects of YFV biology incompletely defined including host range, host–virus interactions and correlates of host immunity and pathogenicity. In this article, we review the current state of YFV research, focusing on the viral lifecycle, host responses to infection, species tropism and the success and associated limitations of the YFV-17D vaccine. In addition, we highlight the current lack of available treatments and use publicly available sequence and structural data to assess global patterns of YFV sequence diversity and identify potential drug targets. Finally, we discuss how technological advances, including real-time epidemiological monitoring of outbreaks using next-generation sequencing and CRISPR/Cas9 modification of vector species, could be utilized in future battles against this re-emerging pathogen which continues to cause devastating disease.
As the prognosis of invasive aspergillosis remains unacceptably poor in patients undergoing hematopoietic stem cell transplantation (HSCT), there is a growing interest in the adoptive transfer of antifungal effector cells, such as Natural Killer (NK) cells. Because immunosuppressive agents are required in most HSCT recipients, knowledge of the impact of these compounds on the antifungal activity of NK cells is a prerequisite for clinical trials. We, therefore, assessed the effect of methylprednisolone (mPRED), cyclosporin A (CsA) and mycophenolic acid (MPA) at different concentrations on proliferation, apoptosis/necrosis, and the direct and indirect anti-Aspergillus activity of human NK cells. Methylprednisolone decreased proliferation and increased apoptosis of NK cells in a significant manner. After seven days, a reduction of viable NK cells was seen for all three immunosuppressants, which was significant for MPA only. Cyclosporin A significantly inhibited the direct hyphal damage by NK cells in a dose-dependent manner. None of the immunosuppressive compounds had a major impact on the measured levels of interferon-γ, granulocyte-macrophage colony-stimulating factor and RANTES (regulated on activation, normal T cell expressed and secreted; CCL5). Our data demonstrate that commonly used immunosuppressive compounds have distinct effects on proliferation, viability and antifungal activity of human NK cells, which should be considered in designing studies on the use of NK cells for adoptive antifungal immunotherapy.
Objective: Many cancer patients complain about cognitive dysfunction. While cognitive deficits have been attributed to the side effects of chemotherapy, there is evidence for impairment at disease onset, prior to cancer-directed therapy. Further debated issues concern the relationship between self-reported complaints and objective test performance and the role of psychological distress.
Method: We assessed performance on neuropsychological tests of attention and memory and obtained estimates of subjective distress and quality of life in 27 breast cancer patients and 20 healthy controls. Testing in patients took place shortly after the initial diagnosis, but prior to subsequent therapy.
Results: While patients showed elevated distress, cognitive performance differed on a few subtests only. Patients showed slower processing speed and poorer verbal memory than controls. Objective and self-reported cognitive function were unrelated, and psychological distress correlated more strongly with subjective complaints than with neuropsychological test performance.
Conclusion: This study provides further evidence of limited cognitive deficits in cancer patients prior to the onset of adjuvant therapy. Self-reported cognitive deficits seem more closely related to psychological distress than to objective test performance.