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In mammalian species, including humans, the hippocampal dentate gyrus (DG) is a primary region of adult neurogenesis. Aberrant adult hippocampal neurogenesis is associated with neurological pathologies. Understanding the cellular mechanisms controlling adult hippocampal neurogenesis is expected to open new therapeutic strategies for mental disorders. Microglia is intimately associated with neural progenitor cells in the hippocampal DG and has been implicated, under varying experimental conditions, in the control of the proliferation, differentiation and survival of neural precursor cells. But the underlying mechanisms remain poorly defined. Using fluorescent in situ hybridization we show that microglia in brain express the ADP-activated P2Y13 receptor under basal conditions and that P2ry13 mRNA is absent from neurons, astrocytes, and neural progenitor cells. Disrupting P2ry13 decreases structural complexity of microglia in the hippocampal subgranular zone (SGZ). But it increases progenitor cell proliferation and new neuron formation. Our data suggest that P2Y13 receptor-activated microglia constitutively attenuate hippocampal neurogenesis. This identifies a signaling pathway whereby microglia, via a nucleotide-mediated mechanism, contribute to the homeostatic control of adult hippocampal neurogenesis. Selective P2Y13R antagonists could boost neurogenesis in pathological conditions associated with impaired hippocampal neurogenesis.
Webportal Polyphonie. Mehrsprachigkeit_Kreativität_Schreiben http://www.polyphonie.at
Das Webportal Polyphonie. Mehrsprachigkeit_Kreativität_Schreiben ist 2012 aus dem gleichnamigen Forschungsprojekt entstanden, das 2009 von einer Gruppe von ForscherInnen aus Italien und Österreich ins Leben gerufen wurde. Das Projekt untersucht die vielfältigen Zusammenhänge zwischen Mehrsprachigkeit und Kreativität im Schreiben systematisch und aus interdisziplinärer Perspektive. Es setzt sich zum Ziel, den mehr oder weniger stringenten Zusammenhang von individueller oder gesellschaftlicher Mehrsprachigkeit und Kreativität im Allgemeinen bzw. literarischer Kreativität im Besonderen zu erforschen.
"Diachrone Interkulturalität". Tagung der Universität Luxemburg, 17.-19. November 2016
Ziel der Tagung "Diachrone Interkulturalität" war einerseits eine stärkere Anbindung der interkulturellen Forschung an ästhetische und literaturwissenschaftliche Fragestellungen, andererseits auch die Erweiterung eines bislang vorwiegend gegenwartszentrierten Theoriediskurses um die diachrone Betrachtungsweise: "Im aktuellen Theoriediskurs wird jedoch inzwischen häufiger darauf hingewiesen, dass eine Beschränkung der Interkulturalitätsforschung auf Globalisierungsphänomene zu kurz gegriffen ist und die Notwendigkeit einer Historisierung besteht. In diesem Sinne intendiert die Tagung eine Erweiterung des Forschungsfeldes im Zeichen des Diachron-Geschichtlichen und damit auch eine Komplexitätssteigerung eines häufig undifferenziert gedachten Interkulturalitätsbegriffes."
"Globale - Festival für grenzüberschreitende Literatur" in Bremen, 25. Oktober - 15. November 2016
(2016)
"Globale - Festival für grenzüberschreitende Literatur" in Bremen, 25. Oktober - 15. November 2016
Das Festival für grenzüberschreitende Literatur verwandelte auch dieses Jahr die Stadt Bremen drei wochenlang in einen Begegnungs- und Diskussionsort für alle literarisch Interessierten mit einem vielfältigen Programmangebot an Lesungen von Autoren und Autorinnen, die die Grenzüberschreitung verbindet. Denn die Intention des Festivals ist, wie die diesjährige Festivalleitung Prof. Dr. Elisabeth Arend und Libuše Černá im Vorwort des umfangreichen Programmhefts betonen, eine Literatur vorzustellen, die sich mit "den Federn fremder Herkünfte" schmückt, "viele Zungen" spricht und "dabei deutsch" ist.
"Vielfältige Konzepte - Konzepte der Vielfalt: Interkulturalität(en) weltweit". Internationale Tagung der Gesellschaft für interkulturelle Germanistik e.V. (GiG) in Ústí nad Labem und Prag, 04.-09. Oktober 2016
Vom 4. bis 9. Oktober 2016 fand in Ústí nad Labem und in Prag die Jahrestagung der GiG in Zusammenarbeit mit dem Tschechischen Germanistenverband unter der Schirmherrschaft des Kulturministers der Tschechischen Republik Mgr. Daniel Herman, des Regionspräsidenten von Ústí nad Labem Herrn Oldřich Bubeníček, des Rektors der J. E. Purkyně-Universität in Ústí nad Labem doc. RNDr. Martin Balej, Ph.D., der Oberbürgermeisterin der Stadt Ústí nad Labem Frau Ing. Věra Nechybová und der Stadträtin der Hauptstadt Prag Ing. Irena Ropková statt. Die wissenschaftliche Leitung hatten Dr. habil. Renata Cornejo (Ústí nad Labem), Prof. Dr. Manfred Weinberg (Prag) und Prof. Dr. Gesine Lenore Schiewer (Bayreuth) inne.
"Gewalt und Sprache". Internationale SUNG-Tagung an der Comenius-Universität in Bratislava, 30. Juni - 2. Juli 2016
Anlässlich des 25. Jahrestages seiner Gründung veranstaltete der Verband der Deutschlehrer und Germanisten der Slowakei (SUNG) eine Konferenz, die sich thematisch auf das Verhältnis von Gewalt und Sprache konzentrierte. Veranstaltungsort war die Philosophische Fakultät der Comenius-Universität, Mitveranstalter der dortige Lehrstuhl für Germanistik, Nederlandistik und Skandinavistik. Die Konferenz stellte zugleich die zwölfte Tagung des Verbandes dar.
Linguistik- und Literaturtage "Sprachen verbinden". 24. internationale GeSuS-Fachtagung an der Masaryk-Universität in Brno, 22.-24. Juni 2016
Die 24. internationale Fachtagung der Gesellschaft für Sprache und Sprachen (GeSuS) fand vom 22. bis 24. Juni 2016 statt. Als Ort wurde diesmal die Pädagogische Fakultät der Masaryk-Universität in Brno gewählt, die nicht nur einen Großteil der Organisation übernahm, sondern damit gleichzeitig auch ihr 70. Gründungsjubiläum feierte. Die internationale Tagung setzte sich zum Ziel, eine Plattform zur Präsentation neuer Forschungsergebnisse im Bereich der Germanistik zu schaffen und das Knüpfen neuer Kontakte zu ermöglichen.
"Grenzüberschreitungen: Migration und Literatur aus der Perspektive der Literatursoziologie". Tagung der Österreichischen Akademie der Wissenschaften in Wien, 20.-21. Juni 2016
Die zeitgenössische Literaturproduktion reagiert seit Längerem auf Thematiken wie Kulturkonflikte, Fremdheit, Einwanderung und Migration. Das Forschungsprojekt Literature on the Move untersuchte die Migration von Autor(inn)en nach Österreich und deren Möglichkeiten bzw. Schwierigkeiten beim Eintritt in das Feld der österreichischen Literatur. Es wurde der Versuch unternommen, die Rahmenbedingungen, die Struktur und die Konsequenzen literarischer Produktion miteinander in Beziehung zu bringen und mit Hinblick auf die literarischen Texte zu analysieren.
"Zentrum und Peripherie". Internationale Konferenz des Germanistenverbandes der Tschechischen Republik an der Schlesischen Universität in Opava, 25.-27. Mai 2016
Die internationale Tagung Zentrum und Peripherie wurde vom Germanistenverband der Tschechischen Republik und der Abteilung für Germanistik am Institut für Fremdsprachen der Schlesischen Universität in Opava veranstaltet. Das Organisationsteam aus Opava bestand aus Dr. habil. Gabriela Rykalová, Dr. habil. Veronika Kotůlková und Dr. Miroslav Urbanec. Fast hundert FachteilnehmerInnen aus der Tschechischen Republik, Deutschland, Österreich, Polen, der Slowakei, Spanien, der Türkei und Ungarn konnten in Opava begrüßt werden, außerdem VertreterInnen des DAAD, der Deutschen Welle, des Österreichischen Kulturforums Prag sowie Germanistikstudierende verschiedener Universitäten. Im Rahmen der Konferenz fand auch die Mitgliederversammlung des Germanistenverbands der Tschechischen Republik statt.
"Marie von Ebner-Eschenbach. Básnířka tří staletí / Dichterin dreier Jahrhunderte 1830 - 1916 - 2016". Internationale Tagung in Brno, 21.-23. April 2016
Über Fächer-, Sprach- und Landesgrenzen hinweg wurde bei der Konferenz Marie von Ebner-Eschenbach. Básnířka tři staletí/ Dichterin dreier Jahrhunderte (1830 - 1916 - 2016) in Brno (Brünn) vom 21. bis zum 23. April 2016 das Leben und Werk der in Mähren geborenen österreichischen Schriftstellerin beleuchtet. Vom sozialhistorischen Ansatz über die Werkanalyse bis hin zur Präsentation der Tagebücher war die Konferenz eine vielfältige Demonstration des regen Interesses an dem Forschungsgegenstand.
"Sinn - Unsinn - Wahnsinn. Beispiele zur österreichischen Kulturgeschichte". Tagung der Franz Werfel-Stipendiat(inn)en in Wien, 18.-19. März 2016
Das Franz Werfel-Stipendium des Österreichischen akademischen Austauschdienstes (OeAD) wendet sich an junge Germanist(inn)en und UniversitätslehrerInnen, die sich an ihren Heimatuniversitäten in der ganzen Welt schwerpunktmäßig mit der österreichischen Literatur beschäftigen. Als Plattform der ehemaligen sowie aktuellen Franz Werfel-Stipendiat(inn)en an den österreichischen Universitäten wird die alljährliche Franz Werfel-Tagung veranstaltet, die sich jeweils einem Thema aus der österreichischen Literatur widmet. Die Konferenz findet unter der Betreuung der Wiener Germanistin Konstanze Fliedl statt.
"Österreich - USA: Künstlerischer und interkultureller Dialog". Konferenz der Austrian Studies Association (ASA) an der Universität Wien, 14.-17. März 2016
Zum zweiten Mal seit Bestehen der 1961 ins Leben gerufenen Austrian Studies Association (ASA) fand die jährliche ASA-Konferenz in Europa, und zwar wieder in Wien, statt. Organisiert wurde sie von Pia Janke (Forschungsplattform Elfriede Jelinek, Universität Wien), Maria-Regina Kecht (Rice University) und Teresa Kovacs (Forschungsplattform Elfriede Jelinek, Universität Wien). Die Veranstaltung vernetzte durch ein vielfältiges Programm an wissenschaftlichen Vorträgen und künstlerischen Programmpunkten die Universität Wien mit anderen in Wien beheimateten Institutionen, die als Kooperationspartner fungierten, namentlich mit dem Wien Museum, dem Österreichischen Filmmuseum und dem Amerika-Haus.
"Raum Gefühl Heimat - Literarische Repräsentationen nach 1945". Internationale Tagung an der Universität des Baskenlandes in Vitoria-Gasteiz, 23.-25. September 2015
Nach einem einleitenden Vortrag von Thomas Anz (Marburg) über literarische Techniken der Emotionalisierung in der Repräsentation protoypischer Räume und Szenarien widmeten sich die Vortragenden aufbauend auf den theoretischen Grundlagen des Spatial und Emotional Turns aus verschiedenen Perspektiven und mit verschiedenen Foki dem Tagungsthema.
Für die deutsche Minderheit spielte die deutschsprachige Presse immer eine bedeutende Rolle. Über sie bewahrte man die deutsche Sprache und wurde es möglich, Informationen in der Muttersprache zu bekommen. Für die tschechoslowakischen Deutschen übernahmen diese Rolle seit 1951 zuerst die Blätter Aufbau und Frieden und seit 1964 die Prager Volkszeitung. Der vorliegende Aufsatz behandelt die Rolle der Prager Volkszeitung für die Identitätsbildung der deutschen Minderheit. Er befasst sich mit der historischen Entwicklung dieser Zeitung bis zu ihrer Einstellung im Jahr 2005 und verfolgt, wie in den einzelnen geschichtlichen Abschnitten, vor allem in jenem bis 1968, dann von 1968 bis 1989 und schließlich seit 1989 das genannte Blatt die Existenz der Deutschen beeinflusst bzw. widergespiegelt hat.
Zeit ihres Lebens bewegte sich Marie Luise Kaschnitz zwischen den Kulturen: denen des Nordens und des Südens, subtiler auch zwischen der deutschen (ihres familiären Ursprungs) und der österreichischen (ihres Ehemannes). In dem gefeierten lyrischen Prosatext Beschreibung eines Dorfes gelingt ihr gleichsam von der Peripherie aus, dem badischen Ort Bollschweil, ein durchaus interkultureller Weltentwurf. Seine tragende Mitte, das Haus Nr. 84, bleibt zwar weitgehend ausgespart, dennoch offenbart sich, welche Energien diese unbeschriebene Mitte des peripheren Dorfes in sich bündelt.
Ausgehend von der Verschränkung der aktuellen Diskurse von Spatial Turn und Emotional Turn wird in dem Beitrag der Frage nachgegangen, inwiefern der Begriff 'Heimat' als Raum des sozialen und symbolischen Handelns des Menschen bzw. dessen Emotionen in den Werken deutschsprachiger Gegenwartsautor(inn)en tschechischer Herkunft konstruiert wird. Während im Roman Die Fassade (Libuše Moníková) der Heimat eine symbolische Funktion eines externen Gedächtnisses zugesprochen wird, rückt in dem Roman Georgs Sorgen um die Vergangenheit… (Jan Faktor) die räumliche Komponente in den Vordergrund. Die Hauptfigur in Novemberfäden (Katja Fusek) konstruiert dagegen ihren Heimatbegriff aus der eigenen emotionsbeladenen Erinnerung heraus, wobei dessen Revision eine notwendige Voraussetzung für die eigene Identitätsbildung auf Grund der Konfrontation von 'Fiktion' und 'Realität' darstellt.
Der Beitrag versucht die Lektüre einer wenig bekannten Erzählung Oskar Panizzas unter machttheoretischen Aspekten. Mit ihrer Fokussierung auf Panizzas Kritik an der Hegemonie des wilhelminischen Kaiserreiches reproduziert die Panizza-Forschung ein Machtverständnis, das Macht als Besitz der Herrschenden konzipiert. Ein solches Verständnis verstellt den Blick auf die produktive Qualität und die performative Wirkung von Panizzas Texten. In Anlehnung an Michel Foucaults Konzept von Macht als produktivem Netz von Kräfteverhältnissen zeigt mein Beitrag, wie sich das Verhältnis zwischen Norm und Abweichung nicht in der zentralen Ausübung einer einzelnen Machtinstanz, sondern in dem dezentralen und produktiven Spiel der Kräfteverhältnisse beschreiben lässt. Vermittels literarischer Techniken inszeniert Panizzas Erzählung Ein scandalöser Fall ein solch dynamisches Machtverständnis und macht dabei die prekäre Beschaffenheit hegemonialer Konstellationen sichtbar.
"… die ehernen Blöcke männlichen Schaffens umkreisen" - Elfriede Jelinek queert Lessing und Goethe
(2016)
Der Beitrag verschränkt kommunikations-, informations-, kulturwissenschaftliche sowie philosophische Ansätze zur Störung mit gender- und queer theory, um Elfriede Jelineks 'Gattung' des Sekundärdramas analytisch zu beschreiben. Jelinek verfasst ihre Sekundärdramen zu kanonisierten Dramen des deutschsprachigen Raums und stellt über ihr typisches, intertextuelles Verfahren Bezug zu den Stücken her, fordert gleichzeitig aber auch die Kombination der Sekundärdramen mit ihren Bezugstexten im Moment der Inszenierung und geht damit über ihr bisheriges Verfahren hinaus. Ausgehend von der Feststellung, dass Jelineks Sekundärdramen in den Umsetzungen am Theater meist als weibliche Gegenschreibung interpretiert werden, will der vorliegende Beitrag zeigen, dass die Sekundärdramen vielmehr an einer Auflösung der Kategorien von 'Weiblichkeit' und 'Männlichkeit' arbeiten. Ein besonderes Augenmerk liegt dabei auf der Thematisierung des Inzests, der mit Judith Butler als vorhandene Ordnungen und Relationen verschiebendes Element gelesen werden kann.
Der Beitrag untersucht anhand von Amazon-Kundenrezensionen zu Werken Judith Hermanns die Beweggründe für deren Verwendung. Dabei wird ersichtlich, dass eine Abgrenzung zur professionellen Literaturkritik vorhanden ist und durch mindestens sechs folgende Gründe ergänzt werden muss: (1.) virtuelle Hilfsbereitschaft, (2.) Nacherzählung des Inhalts, (3.) Wertung und Kaufempfehlung, (4.) Beschreibung des Lektüreprozesses mit Empfehlung für Art und Weise des Lesens, (5.) Kommunikationsmittel zwischen Kunden und Autorin sowie (6.) vernichtender Umgang mit Hörbüchern.
Hinter dem kritischen und kommerziellen Erfolg literarischer Texte stehen nicht selten Autor(inn)en, verstanden als mächtige Akteure des literarischen Feldes sowie als Marken, die beim Publikum bestimmte Erwartungen erwecken und zur Gestaltung von entsprechenden Wertungsstrategien beitragen. Derartige Wertungen überschreiten nicht immer nationale Grenzen. Am Beispiel der polnischen Rezeption der deutschsprachigen Literatur kann bewiesen werden, dass die Macht der genannten Akteure kulturgeographisch begrenzt ist und dass sie im Kulturtransfer stereotypisiert werden. So lassen sich einzelne Rezeptionsfälle in Figuren ausdrücken: Metapher (Allgegenwart) - Günter Grass, Metonymie (Repräsentation) - Elfriede Jelinek, Litotes (Abwesenheit) - Daniel Kehlmann und Wolf Haas im polnischen Feld.
Das literarische Feld Deutschlands wurde lange durch eine Spaltung zwischen West und Ost geprägt, die man nun zu überwinden versucht. Seit der Wende wird nämlich an Mechanismen gearbeitet, die zu einer friedlichen Wiedervereinigung des Literaturbetriebs beitragen können, wie z. B. die Einführung zweier neuer Literaturpreise, und zwar des Deutschen Buchpreises und des Preises der Leipziger Buchmesse. Die beiden haben sich von Anfang an dank des Publikumserfolgs der ausgezeichneten Werke als kanonbildende Instanzen durchgesetzt, die die Richtlinien sowohl des Buchmarktes, als auch der Literaturkritik, stark beeinflussen. Es wird im folgenden Beitrag versucht, durch eine gründliche Analyse der Mechanismen dieser Preise, ihre Rolle als politisch-ökonomische Vorrichtungen, nämlich als 'agent in the cultural economy' (ENGLISH 2005), zu untersuchen. Darüber hinaus wird auch erforscht, wie diese zwei Ehrungen, die Aufnahme einzelner Werke in den herrschenden Kanon ermöglichen oder wesentlich erleichtern, indem sie als materielles Mittel eines 'invisible-hand Phänomens' (WINKO 2002) fungieren, und wie sie zur Produktion von Texten, die als 'Klassiker von heute' bezeichnet werden könnten, beitragen.
Dieser Beitrag versteht sich als Fallstudie zu den Aspekten der Macht und Aufmerksamkeit im literarischen Feld und untersucht beide im Kontext des Deutschen Buchpreises. Dieser Preis wurde während der letzten zehn Jahre zu einem mächtigen Marketingtool im deutschsprachigen Raum. Die Initiatoren und Organisatoren des Deutschen Buchpreises haben die Bedeutung von Aufmerksamkeit im literarischen Feld erkannt und versuchen, möglichst viele Akteure des Feldes an der durch den Preis generierten Aufmerksamkeit partizipieren zu lassen: Verlage, Autor(inn)en, den Buchhandel, den Börsenverein selbst, die Literaturkritik in ihren vielfältigen Erscheinungsformen. Problematisch dabei ist, dass diese Aufmerksamkeitsmaximierung im Rahmen von bestimmten Machtstrukturen erfolgt. Wer lenkt bei diesem Prozess die Aufmerksamkeit worauf und wie passiert das? Wer hat im Rahmen der Hierarchien des Feldes die Möglichkeit, diese Aufmerksamkeit zu nutzen bzw. daran zu partizipieren?
This paper presents an imaging radar system for structural health monitoring (SHM) of wind turbine blades. The imaging radar system developed here is based on two frequency modulated continuous wave (FMCW) radar sensors with a high output power of 30 dBm. They have been developed for the frequency bands of 24,05 GHz-24,25 GHz and 33.4 GHz-36.0 GHz, respectively. Following the successful proof of damage detection and localization in laboratory conditions, we present here the installation of the sensor system at the tower of a 2 MW wind energy plant at 95 m above ground. The realization of the SHM-system will be introduced including the sensor system, the data acquisition framework and the signal processing procedures. We have achieved an imaging of the rotor blades using inverse synthetic aperture radar techniques under changing environmental and operational condition. On top of that, it was demonstrated that the front wall and back wall radar echo can be extracted from the measured signals demonstrating the full penetration of wind turbine blades during operation.
Dysregulation of blood sphingolipids is an emerging topic in clinical science. The objective of this study was to determine preanalytical biases that typically occur in clinical and translational studies and that influence measured blood sphingolipid levels. Therefore, we collected blood samples from four healthy male volunteers to investigate the effect of storage conditions (time, temperature, long-term storage, freeze–thaw cycles), blood drawing (venous or arterial sampling, prolonged venous compression), and sample preparation (centrifugation, freezing) on sphingolipid levels measured by LC-MS/MS. Our data show that sphingosine 1-phosphate (S1P) and sphinganine 1-phosphate (SA1P) were upregulated in whole blood samples in a time- and temperature-dependent manner. Increased centrifugation at higher speeds led to lower amounts of S1P and SA1P. All other preanalytical biases did not significantly alter the amounts of S1P and SA1P. Further, in almost all settings, we did not detect differences in (dihydro)ceramide levels. In summary, besides time-, temperature-, and centrifugation-dependent changes in S1P and SA1P levels, sphingolipids in blood remained stable under practically relevant preanalytical conditions.
Innerhalb der Gentrifizierungsforschung analysiert die Rent‑Gap‑Theorie, wie kleinräumige Differenzen zwischen gegenwärtigen Verwertungsbedingungen einerseits sowie Erwartungen auf zukünftig steigende Mieten andererseits Verdrängungsprozesse antreiben. Dementgegen hat Eric Clark (2014) jüngst eingefordert, dass die Stadtforschung den Blick verstärkt darauf richten müsse, wie Verdrängung verhindert werden kann. Diesen Appell aufgreifend, zeigen wir bezogen auf den deutschen Kontext, inwiefern mietrechtliche Regularien, stadtplanerische Entscheidungen und die jeweilige Eigentümerstruktur wesentlich darüber entscheiden, ob sich ein immobilienwirtschaftlicher Verwertungsdruck auch tatsächlich in Verdrängungsprozesse übersetzt. Illustriert wird dies am Wandel der Eigentümerstruktur im Frankfurter Gallus seit den 1970er Jahren. Deutlich wird dabei, dass Gentrifizierung kein Naturgesetz darstellt, sondern ein zutiefst politischer Prozess ist, der sich effektiv verhindern lässt.
Far outside the surface of slabs, the exact exchange (EXX) potential vx falls off as −1/z , if z denotes the direction perpendicular to the surface and the slab is localized around z=0 . Similarly, the EXX energy density ex behaves as −n/(2z) , where n is the electron density. Here, an alternative proof of these relations is given, in which the Coulomb singularity in the EXX energy is treated in a particularly careful fashion. This new approach allows the derivation of the next-to-leading order contributions to the asymptotic vx and ex . It turns out that in both cases, the corrections are proportional to 1/z2 in general.
Acute graft-versus-host disease (GvHD) is still a major cause of treatment-related mortality after allogeneic stem cell transplantation. Allo-antigen recognition of donor T cells after transplantation account for the onset and persistence of this disease. MicroRNAs (miRNAs) are molecular regulators involved in numerous processes during T-cell development, homeostasis, and activation. Thus, miRNAs also contribute to pathological T-cell function during GvHD. Given their capacity of fine-tuning T-cell function, miRNAs have emerged as promising therapeutic targets to curtail acute GvHD, but simultaneously maintain T-cell-mediated graft-versus-tumor effects. Here, we review the role of key miRNAs contributing to the pathophysiology of GvHD. We focus on those miRNAs acting in T cells and for which a role in GvHD has been established in preclinical models. Finally, we provide an outlook for clinical application of this new therapeutic target for GvHD prevention and treatment.
Background: Bradykinin-mediated angioedema (Bk-AE) can be life-threatening and requires specific targeted therapies. Knowledge of its epidemiology may help optimize its management.
Methods: We systematically searched the medical literature to identify abstracts of interest indexed between 1948 and March, 2016. We used published national survey data on the proportion of the population treated with angiotensin-converting enzyme inhibitors (ACEI) to derive estimates of the population prevalence of ACEI-AE in the USA, Germany and France. For hereditary angioedema (C1-INH-HAE) and C1-inhibitor related acquired angioedema (C1-INH-AAE), publications had to contain original epidemiologic data collection within a defined geographical area. Hereditary angioedema with normal C1-INH was not included in the analysis due to lack of clearly defined criteria.
Results: We identified 4 relevant publications on the prevalence of ACEI-AE, 6 on the prevalence of C1-INH-HAE, and 1 on the prevalence of C1-INH-AAE. The 1st year cumulative incidence of ACEI-AE was estimated to vary between 0.12 (population-based analyses) and 0.30 (meta-analyses of clinical trials) per 100 patient-years. The population prevalence of ACEI-AE was modeled to vary between 7 and 26 in 100,000. The prevalence of C1-INH-HAE was estimated to vary between 1.1 and 1.6 per 100,000. The prevalence of C1-INH-AAE was estimated to be 0.15 per 100,000 in one epidemiological investigation of AAE in Denmark.
Conclusions: Epidemiological evidence on Bk-AE is limited to North America and Europe. ACEI-AE is more common than C1-INH-HAE (~ 10:1), which is more common than C1-INH-AAE (~ 10:1). More studies are needed to comprehensively assess the epidemiological burden of Bk-AE.
The bile acid activated transcription factor farnesoid X receptor (FXR) regulates numerous metabolic processes and is a rising target for the treatment of hepatic and metabolic disorders. FXR agonists have revealed efficacy in treating non-alcoholic steatohepatitis (NASH), diabetes and dyslipidemia. Here we characterize imatinib as first-in-class allosteric FXR modulator and report the development of an optimized descendant that markedly promotes agonist induced FXR activation in a reporter gene assay and FXR target gene expression in HepG2 cells. Differential effects of imatinib on agonist-induced bile salt export protein and small heterodimer partner expression suggest that allosteric FXR modulation could open a new avenue to gene-selective FXR modulators.
An empirical study of the per capita yield of science Nobel prizes : is the US era coming to an end?
(2018)
We point out that the Nobel prize production of the USA, the UK, Germany and France has been in numbers that are large enough to allow for a reliable analysis of the long-term historical developments. Nobel prizes are often split, such that up to three awardees receive a corresponding fractional prize. The historical trends for the fractional number of Nobelists per population are surprisingly robust, indicating in particular that the maximum Nobel productivity peaked in the 1970s for the USA and around 1900 for both France and Germany. The yearly success rates of these three countries are to date of the order of 0.2–0.3 physics, chemistry and medicine laureates per 100 million inhabitants, with the US value being a factor of 2.4 down from the maximum attained in the 1970s. The UK in contrast managed to retain during most of the last century a rate of 0.9–1.0 science Nobel prizes per year and per 100 million inhabitants. For the USA, one finds that the entire history of science Noble prizes is described on a per capita basis to an astonishing accuracy by a single large productivity boost decaying at a continuously accelerating rate since its peak in 1972.
The theory and practice of urban governance in recent years has undergone both a collaborative and participatory turn. The strong connection between collaboration and participation has meant that citizen participation in urban governance has been conceived in a very particular way: as varying levels of partnership between state actors and citizens. This over-focus on collaboration has led to: 1) a dearth of proposals in theory and practice for citizens to engage oppositionally with institutions; 2) the miscasting of agonistic opportunities for participation as forms of collaboration; 3) an inability to recognise the irruption of agonistic practices into participatory procedures. This article attempts to expand the conception of participatory urban governance by adapting Rosanvallon’s (2008) three democratic counter-powers—prevention, oversight and judgement—to consider options for institutionalising agonistic participatory practices. It argues that these counter-governance processes would more fully realise the inclusion agenda that underpins the participatory governance project.
By the fabrication of periodically arranged nanomagnetic systems it is possible to engineer novel physical properties by realizing artificial lattice geometries that are not accessible via natural crystallization or chemical synthesis. This has been accomplished with great success in two dimensions in the fields of artificial spin ice and magnetic logic devices, to name just two. Although first proposals have been made to advance into three dimensions (3D), established nanofabrication pathways based on electron beam lithography have not been adapted to obtain free-form 3D nanostructures. Here we demonstrate the direct-write fabrication of freestanding ferromagnetic 3D nano-architectures. By employing micro-Hall sensing, we have determined the magnetic stray field generated by our free-form structures in an externally applied magnetic field and we have performed micromagnetic and macro-spin simulations to deduce the spatial magnetization profiles in the structures and analyze their switching behavior. Furthermore we show that the magnetic 3D elements can be combined with other 3D elements of different chemical composition and intrinsic material properties.
Fluctuation spectroscopy measurements of quasi-two-dimensional organic charge-transfer salts (BEDT-TTF) 2 X are reviewed. In the past decade, the method has served as a new approach for studying the low-frequency dynamics of strongly correlated charge carriers in these materials. We review some basic aspects of electronic fluctuations in solids, and give an overview of selected problems where the analysis of 1/f -type fluctuations and the corresponding slow dynamics provide a better understanding of the underlying physics. These examples are related to (1) an inhomogeneous current distribution due to phase separation and/or a percolative transition; (2) slow dynamics due to a glassy freezing either of structural degrees of freedom coupling to the electronic properties or (3) of the electrons themselves, e.g., when residing on a highly-frustrated crystal lattice, where slow and heterogeneous dynamics are key experimental properties for the vitrification process of a supercooled charge-liquid. Another example is (4), the near divergence and critical slowing down of charge carrier fluctuations at the finite-temperature critical endpoint of the Mott metal-insulator transition. Here also indications for a glassy freezing and temporal and spatial correlated dynamics are found. Mapping out the region of ergodicity breaking and understanding the influence of disorder on the temporal and spatial correlated fluctuations will be an important realm of future studies, as well as the fluctuation properties deep in the Mott or charge-ordered insulating states providing a connection to relaxor or ordered ferroelectric states studied by dielectric spectroscopy.
Single nucleotide polymorphism (SNP) rs738409 C>G in the patatin‐like phospholipase domain containing 3 (PNPLA3) gene results in an amino acid exchange from isoleucin to methionine at position I148M of PNPLA3. The expression of this loss‐of‐function mutation leads to impaired hepatocellular triglyceride hydrolysis and is associated with the development of liver steatosis, fibrosis, and hepatocellular carcinoma. In contrast to these well‐established associations, the relationship of the PNPLA3 rs738409 variant with other metabolic traits is incompletely understood. We therefore assessed the association of the PNPLA3 rs738409 genotype with relevant metabolic traits in a prospective study of patients at high risk for cardiovascular events, i.e., patients undergoing coronary angiography. In a total of 270 patients, known associations of the PNPLA3 rs738409 GG genotype with nonalcoholic steatohepatitis and liver fibrosis were confirmed. In addition, we found an association of the PNPLA3 rs738409 G allele with the presence of diabetes (22% versus 28% versus 58% for CC versus CG versus GG genotype, respectively; P = 0.02). In contrast to its association with nonalcoholic fatty liver disease, liver fibrosis, and diabetes, the minor G allele of PNPLA3 rs738409 was inversely associated with total serum cholesterol and low‐density lipoprotein serum levels (P = 0.003 and P = 0.02, respectively). Finally, there was a trend toward an inverse association between the presence of the PNPLA3 rs738409 G allele and significant coronary heart disease. Comparable trends were observed for the transmembrane 6 superfamily member 2 (TM6SF2) 167 K variant, but the sample size was too small to evaluate this rarer variant. Conclusion: The PNPLA3 rs738409 G allele is associated with liver disease but also with a relatively benign cardiovascular risk profile.
The prediction of protein–ligand interactions and their corresponding binding free energy is a challenging task in structure-based drug design and related applications. Docking and scoring is broadly used to propose the binding mode and underlying interactions as well as to provide a measure for ligand affinity or differentiate between active and inactive ligands. Various studies have revealed that most docking software packages reliably predict the binding mode, although scoring remains a challenge. Here, a diverse benchmark data set of 99 matched molecular pairs (3D-MMPs) with experimentally determined X-ray structures and corresponding binding affinities is introduced. This data set was used to study the predictive power of 13 commonly used scoring functions to demonstrate the applicability of the 3D-MMP data set as a valuable tool for benchmarking scoring functions.
Background: Immigration has a strong impact on the development of health systems, medicine and science worldwide. Therefore, this article provides a descriptive study on the overall research output.
Methods: Utilizing the scientific database Web of Science, data research was performed. The gathered bibliometric data was analyzed using the established platform NewQIS, a benchmarking system to visualize research quantity and quality indices.
Findings: Between 1900 and 2016 a total of 6763 articles on immigration were retrieved and analyzed. 86 different countries participated in the publications. Quantitatively the United States followed by Canada and Spain were prominent regarding the article numbers. On comparing by additionally taking the population size into account, Israel followed by Sweden and Norway showed the highest performance. The main releasing journals are the Public Health Reports, the Journal of Immigrant and Minority Health and Social Science & Medicine. Over the decades, an increasing number of Public, Environmental & Occupational Health articles can be recognized which finally forms the mainly used subject area.
Conclusion: Considerably increasing scientific work on immigration cannot only be explained by the general increase of scientific work but is also owed to the latest development with increased mobility, worldwide crises and the need of flight and migration. Especially countries with a good economic situation are highly affected by immigrants and prominent in their publication output on immigration, since the countries’ publication effort is connected with the appointed expenditures for research and development. Remarkable numbers of immigrants throughout Europe compel medical professionals to consider neglected diseases, requires the public health system to restructure itself and finally promotes science.
Background: Cancer research is critically dependent on a continuous recruitment of junior research staff that devotes its academic life not only to clinical duties but also to basic and translational research. The present study aims to elucidate the success concerning gender equality in cancer research in the last decade (from 2008 to 2016) with lung cancer as the target parameter.
Materials and Methods: On the basis of the Gendermetrics Platform, a total of 19,724 articles related to lung cancer research were analyzed. The key method was the combined analysis of the proportion of female authorships and the female-to-male odds ratio for first, co- and last authorships. The distribution of prestigious authorships was measured by the Prestige Index.
Results: 31.3% of all authorships and 35.2% of the first, 32.2% of the co- and 22.1% of the last authorships were held by women. The corresponding female-to-male odds ratio is 1.22 (CI: 1.18–1.27) for first, 1.19 (CI: 1.16–1.23) for co- and 0.59 (CI: 0.57–0.61) for last authorships. Women are underrepresented at prestigious authorships compared to men (Prestige Index = −0.22). The female underrepresentation accentuates in articles with many authors that attract the highest citation rates.
Conclusions: While the current system promotes early career promotion of women, men still outnumber women in leadership positions. However, this male-female career dichotomy has been narrowed in the last decade and will likely be further reduced in the next decade.
The HCV NS5A protein plays multiple roles during viral replication, including viral genome replication and virus particle assembly. The crystal structures of the NS5A N-terminal domain indicated the potential existence of the NS5A dimers formed via at least two or more distinct dimeric interfaces. However, it is unknown whether these different forms of NS5A dimers are involved in its numerous functions. To address this question, we mutated the residues lining the two different NS5A dimer interfaces and determined their effects on NS5A self-interaction, NS5A-cyclophilin A (CypA) interaction, HCV RNA replication and infectious virus production. We found that the mutations targeting either of two dimeric interfaces disrupted the NS5A self-interaction in cells. The NS5A dimer-interrupting mutations also inhibited both viral RNA replication and infectious virus production with some genotypic differences. We also determined that reduced NS5A self-interaction was associated with altered NS5A-CypA interaction, NS5A hyperphosphorylation and NS5A subcellular localization, providing the mechanistic bases for the role of NS5A self-interaction in multiple steps of HCV replication. The NS5A oligomers formed via different interfaces are likely its functional form, since the residues at two different dimeric interfaces played similar roles in different aspects of NS5A functions and, consequently, HCV replication. In conclusion, this study provides novel insight into the functional significance of NS5A self-interaction in different steps of the HCV replication, potentially, in the form of oligomers formed via multiple dimeric interfaces.
The NF-κB-like velvet domain protein VosA (viability of spores) binds to more than 1,500 promoter sequences in the filamentous fungus Aspergillus nidulans. VosA inhibits premature induction of the developmental activator gene brlA, which promotes asexual spore formation in response to environmental cues as light. VosA represses a novel genetic network controlled by the sclB gene. Bfunction is antagonistic to VosA, because it induces the expression of early activator genes of asexual differentiation as flbC and flbD as well as brlA. The SclB controlled network promotes asexual development and spore viability, but is independent of the fungal light control. SclB interactions with the RcoA transcriptional repressor subunit suggest additional inhibitory functions on transcription. SclB links asexual spore formation to the synthesis of secondary metabolites including emericellamides, austinol as well as dehydroaustinol and activates the oxidative stress response of the fungus. The fungal VosA-SclB regulatory system of transcription includes a VosA control of the sclB promoter, common and opposite VosA and SclB control functions of fungal development and several additional regulatory genes. The relationship between VosA and SclB illustrates the presence of a convoluted surveillance apparatus of transcriptional control, which is required for accurate fungal development and the linkage to the appropriate secondary metabolism.
Five new species belonging to Hermatomyces (Hermatomycetaceae, Pleosporales) are described based on morphological investigations of specimens collected on rotten twigs and stems of various plants in Panama as well as phylogenetic analyses of sequence data of nuclear ribosomal and protein coding genes (EF1-α, RPB2, β-TUB). The new species are described as: Hermatomyces bifurcatus, H. constrictus, H. megasporus, H. sphaericoides, and H. verrucosus spp. nov. Previously described species such as H. sphaericus and H. tucumanensis were identified among the studied specimens. The new combination, H. reticulatus, is made for Subicularium reticulatum based on examination of the holotype and fresh collections. Hermatomyces subiculosus, originally described from Thailand, is reduced to synonymy with H. reticulatus; H. tectonae is synonymized under H. sphaericus based on morphological and molecular evidence; and H. chiangmaiensis and H. thailandicus are considered later synonyms of H. krabiensis and H. indicus, respectively. The type material of Scyphostroma mirum was found to be conspecific with H. tucumanensis and, therefore, the generic name Hermatomyces should be conserved or protected against the older name Scyphostroma and the binomial H. tucumanensis against S. mirum. Sixteen species of Hermatomyces are recognized, their distinctive characteristics are highlighted in line drawings and a key is provided for their identification. The peculiar morphology and consistent phylogeny of new and previously known Hermatomyces species supports the recognition of the recently introduced monotypic family Hermatomycetaceae as a well delimited monophyletic taxon within the order Pleosporales.
Leaf-stripe smuts on grasses are a highly polyphyletic group within Ustilaginomycotina, occurring in three genera, Tilletia, Urocystis, and Ustilago. Currently more than 12 Ustilago species inciting stripe smuts are recognised. The majority belong to the Ustilago striiformis-complex, with about 30 different taxa described from 165 different plant species. This study aims to assess whether host distinct-lineages can be observed amongst the Ustilago leaf-stripe smuts using nine different loci on a representative set. Phylogenetic reconstructions supported the monophyly of the Ustilago striiformis-complex that causes leaf-stripe and the polyphyly of other leaf-stripe smuts within Ustilago. Furthermore, smut specimens from the same host genus generally clustered together in well-supported clades that often had available species names for these lineages. In addition to already-named lineages, three new lineages were observed, and described as new species on the basis of host specificity and molecular differences: namely Ustilago jagei sp. nov. on Agrostis stolonifera, U. kummeri sp. nov. on Bromus inermis, and U. neocopinata sp. nov. on Dactylis glomerata.
Background: Recent epidemics have entailed global discussions on revamping epidemic control and prevention approaches. A general consensus is that all sources of data should be embraced to improve epidemic preparedness. As a disease transmission is inherently governed by individual-level responses, pathogen dynamics within infected hosts posit high potentials to inform population-level phenomena. We propose a multiscale approach showing that individual dynamics were able to reproduce population-level observations.
Methods: Using experimental data, we formulated mathematical models of pathogen infection dynamics from which we simulated mechanistically its transmission parameters. The models were then embedded in our implementation of an age-specific contact network that allows to express individual differences relevant to the transmission processes. This approach is illustrated with an example of Ebola virus (EBOV).
Results: The results showed that a within-host infection model can reproduce EBOV’s transmission parameters obtained from population data. At the same time, population age-structure, contact distribution and patterns can be expressed using network generating algorithm. This framework opens a vast opportunity to investigate individual roles of factors involved in the epidemic processes. Estimating EBOV’s reproduction number revealed a heterogeneous pattern among age-groups, prompting cautions on estimates unadjusted for contact pattern. Assessments of mass vaccination strategies showed that vaccination conducted in a time window from five months before to one week after the start of an epidemic appeared to strongly reduce epidemic size. Noticeably, compared to a non-intervention scenario, a low critical vaccination coverage of 33% cannot ensure epidemic extinction but could reduce the number of cases by ten to hundred times as well as lessen the case-fatality rate.
Conclusions: Experimental data on the within-host infection have been able to capture upfront key transmission parameters of a pathogen; the applications of this approach will give us more time to prepare for potential epidemics. The population of interest in epidemic assessments could be modelled with an age-specific contact network without exhaustive amount of data. Further assessments and adaptations for different pathogens and scenarios to explore multilevel aspects in infectious diseases epidemics are underway.
In several tumor entities, transketolase-like protein 1 (TKTL1) has been suggested to promote the nonoxidative part of the pentose phosphate pathway (PPP) and thereby to contribute to a malignant phenotype. However, its role in glioma biology has only been sparsely documented. In the present in vitro study using LNT-229 glioma cells, we analyzed the impact of TKTL1 gene suppression on basic metabolic parameters and on survival following oxygen restriction and ionizing radiation. TKTL1 was induced by hypoxia and by hypoxia-inducible factor-1α (HIF-1α). Knockdown of TKTL1 via shRNA increased the cells’ demand for glucose, decreased flux through the PPP and promoted cell death under hypoxic conditions. Following irradiation, suppression of TKTL1 expression resulted in elevated levels of reactive oxygen species (ROS) and reduced clonogenic survival. In summary, our results indicate a role of TKTL1 in the adaptation of tumor cells to oxygen deprivation and in the acquisition of radioresistance. Further studies are necessary to examine whether strategies that antagonize TKTL1 function will be able to restore the sensitivity of glioma cells towards irradiation and antiangiogenic therapies in the more complex in vivo environment.
Background: Although mortality after cardiac surgery has significantly decreased in the last decade, patients still experience clinically relevant postoperative complications. Among others, atrial fibrillation (AF) is a common consequence of cardiac surgery, which is associated with prolonged hospitalization and increased mortality.
Methods: We retrospectively analyzed data from patients who underwent coronary artery bypass grafting, valve surgery or a combination of both at the University Hospital Muenster between April 2014 and July 2015. We evaluated the incidence of new onset and intermittent/permanent AF (patients with pre- and postoperative AF). Furthermore, we investigated the impact of postoperative AF on clinical outcomes and evaluated potential risk factors.
Results: In total, 999 patients were included in the analysis. New onset AF occurred in 24.9% of the patients and the incidence of intermittent/permanent AF was 59.5%. Both types of postoperative AF were associated with prolonged ICU length of stay (median increase approx. 2 days) and duration of mechanical ventilation (median increase 1 h). Additionally, new onset AF patients had a higher rate of dialysis and hospital mortality and more positive fluid balance on the day of surgery and postoperative days 1 and 2. In a multiple logistic regression model, advanced age (odds ratio (OR) = 1.448 per decade increase, p < 0.0001), a combination of CABG and valve surgery (OR = 1.711, p = 0.047), higher C-reactive protein (OR = 1.06 per unit increase, p < 0.0001) and creatinine plasma concentration (OR = 1.287 per unit increase, p = 0.032) significantly predicted new onset AF. Higher Horowitz index values were associated with a reduced risk (OR = 0.996 per unit increase, p = 0.012). In a separate model, higher plasma creatinine concentration (OR = 2.125 per unit increase, p = 0.022) was a significant risk factor for intermittent/permanent AF whereas higher plasma phosphate concentration (OR = 0.522 per unit increase, p = 0.003) indicated reduced occurrence of this arrhythmia.
Conclusions: New onset and intermittent/permanent AF are associated with adverse clinical outcomes of elective cardiac surgery patients. Different risk factors implicated in postoperative AF suggest different mechanisms might be involved in its pathogenesis. Customized clinical management protocols seem to be warranted for a higher success rate of prevention and treatment of postoperative AF.
Cardiac sarcoidosis is a rare immunologic disease causing heart involvement in 5% of patients. Cardiac sarcoidosis may manifest clinically as a cardiomyopathy with impaired left ventricular (LV) function or as tachyarrhythmias or bradyarrhythmias. On autopsy, cardiac granulomas can be found in approximately 25% of patients. The most common location for granulomas and scars is the LV free wall, followed by the intraventricular septum, often with involvement of the conduction system. ...
Temperature- and field-dependent 1H-, 19F-, and 79,81Br-NMR measurements together with zero - field 79,81Br-NQR measurements on polycrystalline samples of barlowite, Cu4(OH)6FBr are conducted to study the magnetism and possible structural distortions on a microscopic level. The temperature dependence of the 79,81Br-NMR spin-lattice relaxation rates 1/T1 indicate a phase transition at TN ≃ 15 K which is of magnetic origin, but with an unusually weak slowing down of fluctuations below TN. Moreover, 1/T1T scales linear with the bulk susceptibility which indicates persisting spin fluctuations down to 2 K. Quadupolare resonance (NQR) studies reveal a pair of zero-field NQR- lines associated with the two isotopes of Br with the nuclear spins of I = 3/2. Quadrupole coupling constants of vQ ≃ 28.5 MHz and 24.7 MHz for 79Br- and 81Br-nuclei are determined from Br-NMR and the asymmetry parameter of the electric field gradient was estimated to η ≃ 0.2. The Br-NQR lines are consistent with our findings from Br-NMR and they are relatively broad, even above TN. This broadening and the relative large η value suggests a symmetry reduction at the Br- site reflecting the presence of a local distortion in the lattice. Our density-functional calculations show that the displacements of Cu2 atoms located between the kagome planes do not account for this relatively large η. On the other hand, full structural relaxation, including the deformation of kagome planes, leads to a better agreement with the experiment.
Tubulogenesis is essential for the formation and function of internal organs. One such organ is the trachea, which allows gas exchange between the external environment and the lungs. However, the cellular and molecular mechanisms underlying tracheal tube development remain poorly understood. Here, we show that the potassium channel KCNJ13 is a critical modulator of tracheal tubulogenesis. We identify Kcnj13 in an ethylnitrosourea forward genetic screen for regulators of mouse respiratory organ development. Kcnj13 mutants exhibit a shorter trachea as well as defective smooth muscle (SM) cell alignment and polarity. KCNJ13 is essential to maintain ion homeostasis in tracheal SM cells, which is required for actin polymerization. This process appears to be mediated, at least in part, through activation of the actin regulator AKT, as pharmacological increase of AKT phosphorylation ameliorates the Kcnj13-mutant trachea phenotypes. These results provide insight into the role of ion homeostasis in cytoskeletal organization during tubulogenesis.
Background: Most smokers start smoking during their early adolescence, often with the idea that smoking is glamorous. Interventions that harness the broad availability of mobile phones as well as adolescents' interest in their appearance may be a novel way to improve school-based prevention. A recent study conducted in Germany showed promising results. However, the transfer to other cultural contexts, effects on different genders, and implementability remains unknown.
Objective: In this observational study, we aimed to test the perception and implementability of facial-aging apps to prevent smoking in secondary schools in Brazil in accordance with the theory of planned behavior and with respect to different genders.
Methods: We used a free facial-aging mobile phone app ("Smokerface") in three Brazilian secondary schools via a novel method called mirroring. The students’ altered three-dimensional selfies on mobile phones or tablets and images were "mirrored" via a projector in front of their whole grade. Using an anonymous questionnaire, we then measured on a 5-point Likert scale the perceptions of the intervention among 306 Brazilian secondary school students of both genders in the seventh grade (average age 12.97 years). A second questionnaire captured perceptions of medical students who conducted the intervention and its conduction per protocol.
Results: The majority of students perceived the intervention as fun (304/306, 99.3%), claimed the intervention motivated them not to smoke (289/306, 94.4%), and stated that they learned new benefits of not smoking (300/306, 98.0%). Only a minority of students disagreed or fully disagreed that they learned new benefits of nonsmoking (4/306, 1.3%) or that they themselves were motivated not to smoke (5/306, 1.6%). All of the protocol was delivered by volunteer medical students.
Conclusions: Our data indicate the potential for facial-aging interventions to reduce smoking prevalence in Brazilian secondary schools in accordance with the theory of planned behavior. Volunteer medical students enjoyed the intervention and are capable of complete implementation per protocol.
Background: Health care accessibility is known to differ geographically. With this study we focused on analysing accessibility of general and specialized obstetric units in England and Germany with regard to urbanity, area deprivation and neonatal outcome using routine data.
Methods: We used a floating catchment area method to measure obstetric care accessibility, the degree of urbanization (DEGURBA) to measure urbanity and the index of multiple deprivation to measure area deprivation.
Results: Accessibility of general obstetric units was significantly higher in Germany compared to England (accessibility index of 16.2 vs. 11.6; p < 0.001), whereas accessibility of specialized obstetric units was higher in England (accessibility index for highest level of care of 0.235 vs. 0.002; p < 0.001). We further demonstrated higher obstetric accessibility for people living in less deprived areas in Germany (r = − 0.31; p < 0.001) whereas no correlation was present in England. There were also urban–rural disparities present, with higher accessibility in urban areas in both countries (r = 0.37–0.39; p < 0.001). The analysis did not show that accessibility affected neonatal outcomes. Finally, our computer generated model for obstetric care provider demand in terms of birth counts showed a very strong correlation with actual birth counts at obstetric units (r = 0.91–0.95; p < 0.001).
Conclusion: In Germany the focus of obstetric care seemed to be put on general obstetric units leading to higher accessibility compared to England. Regarding specialized obstetric care the focus in Germany was put on high level units whereas in England obstetric care seems to be more balanced between the different levels of care with larger units on average leading to higher accessibility.
The identification of inhibitors of eukaryotic protein biosynthesis, which are targeting single translation factors, is highly demanded. Here we report on a small molecule inhibitor, gephyronic acid, isolated from the myxobacterium Archangium gephyra that inhibits growth of transformed mammalian cell lines in the nM range. In direct comparison, primary human fibroblasts were shown to be less sensitive to toxic effects of gephyronic acid than cancer-derived cells. Gephyronic acid is targeting the protein translation system. Experiments with IRES dual luciferase reporter assays identified it as an inhibitor of the translation initiation. DARTs approaches, co-localization studies and pull-down assays indicate that the binding partner could be the eukaryotic initiation factor 2 subunit alpha (eIF2α). Gephyronic acid seems to have a different mode of action than the structurally related polyketides tedanolide, myriaporone, and pederin and is a valuable tool for investigating the eukaryotic translation system. Because cancer derived cells were found to be especially sensitive, gephyronic acid could potentially find use as a drug candidate.
TEMPO spin labels protected with 2-nitrobenzyloxymethyl groups were attached to the amino residues of three different nucleosides: deoxycytidine, deoxyadenosine, and adenosine. The corresponding phosphoramidites could be incorporated by unmodified standard procedures into four different self-complementary DNA and two RNA oligonucleotides. After photochemical removal of the protective group, elimination of formic aldehyde and spontaneous air oxidation, the nitroxide radicals were regenerated in high yield. The resulting spin-labeled palindromic duplexes could be directly investigated by PELDOR spectroscopy without further purification steps. Spin–spin distances measured by PELDOR correspond well to the values obtained from molecular models.
Tight regulation of inflammation is very important to guarantee a balanced immune response without developing chronic inflammation. One of the major mediators of the resolution of inflammation is the transcription factor: the nuclear factor erythroid 2-like 2 (Nrf2). Stabilized following oxidative stress, Nrf2 induces the expression of antioxidants as well as cytoprotective genes, which provoke an anti-inflammatory expression profile, and is crucial for the initiation of healing. In view of this fundamental modulatory role, it is clear that both hyper- or hypoactivation of Nrf2 contribute to the onset of chronic diseases. Understanding the tight regulation of Nrf2 expression/activation and its interaction with signaling pathways, known to affect inflammatory processes, will facilitate development of therapeutic approaches to prevent Nrf2 dysregulation and ameliorate chronic inflammatory diseases. We discuss in this review the principle mechanisms of Nrf2 regulation with a focus on inflammation and autophagy, extending the role of dysregulated Nrf2 to chronic diseases and tumor development.
Proteins and glycolipids have been found to be decorated with phosphorylcholine (PC) both in protozoa and nematodes that parasitize humans and animals. PC epitopes can provoke various effects on immune cells leading to an immunomodulation of the host’s immune system that allows long-term persistence of the parasites. So far, only a limited number of PC-modified proteins, mainly from nematodes, have been identified. Infections caused by Leishmania spp. (e.g., L. infantum in southern Europe) affect about 12 million people worldwide and are characterized by a wide spectrum of clinical forms in humans, ranging from cutaneous to fatal visceral leishmaniasis. To establish and maintain the infection, these protozoa are dependent on the secretion of effector molecules into the host for modulating their immune system. In this project, we analyzed the PC modification of L. infantum promastigotes by 2D-gel based proteomics. Western blot analysis with the PC-specific antibody TEPC-15 revealed one PC-substituted protein in this organism, identified as eEF1α. We could demonstrate that the binding of eEF1α to one of its downstream effectors is dependent on its PC-modification. In this study we provide evidence that in this parasite the modification of eEF1α with PC may be essential for its function as an important virulence factor.
Mechanistic modeling of in vitro data generated from metabolic enzyme systems (viz., liver microsomes, hepatocytes, rCYP enzymes, etc.) facilitates in vitro–in vivo extrapolation (IVIV_E) of metabolic clearance which plays a key role in the successful prediction of clearance in vivo within physiologically-based pharmacokinetic (PBPK) modeling. A similar concept can be applied to solubility and dissolution experiments whereby mechanistic modeling can be used to estimate intrinsic parameters required for mechanistic oral absorption simulation in vivo. However, this approach has not widely been applied within an integrated workflow. We present a stepwise modeling approach where relevant biopharmaceutics parameters for ketoconazole (KTZ) are determined and/or confirmed from the modeling of in vitro experiments before being directly used within a PBPK model. Modeling was applied to various in vitro experiments, namely: (a) aqueous solubility profiles to determine intrinsic solubility, salt limiting solubility factors and to verify pKa; (b) biorelevant solubility measurements to estimate bile-micelle partition coefficients; (c) fasted state simulated gastric fluid (FaSSGF) dissolution for formulation disintegration profiling; and (d) transfer experiments to estimate supersaturation and precipitation parameters. These parameters were then used within a PBPK model to predict the dissolved and total (i.e., including the precipitated fraction) concentrations of KTZ in the duodenum of a virtual population and compared against observed clinical data. The developed model well characterized the intraluminal dissolution, supersaturation, and precipitation behavior of KTZ. The mean simulated AUC0–t of the total and dissolved concentrations of KTZ were comparable to (within 2-fold of) the corresponding observed profile. Moreover, the developed PBPK model of KTZ successfully described the impact of supersaturation and precipitation on the systemic plasma concentration profiles of KTZ for 200, 300, and 400 mg doses. These results demonstrate that IVIV_E applied to biopharmaceutical experiments can be used to understand and build confidence in the quality of the input parameters and mechanistic models used for mechanistic oral absorption simulations in vivo, thereby improving the prediction performance of PBPK models. Moreover, this approach can inform the selection and design of in vitro experiments, potentially eliminating redundant experiments and thus helping to reduce the cost and time of drug product development.
Up to now, very small protein-coding genes have remained unrecognized in sequenced genomes. We identified an mRNA of 165 nucleotides (nt), which is conserved in Bradyrhizobiaceae and encodes a polypeptide with 14 amino acid residues (aa). The small mRNA harboring a unique Shine-Dalgarno sequence (SD) with a length of 17 nt was localized predominantly in the ribosome-containing P100 fraction of Bradyrhizobium japonicum USDA 110. Strong interaction between the mRNA and 30S ribosomal subunits was demonstrated by their co-sedimentation in sucrose density gradient. Using translational fusions with egfp, we detected weak translation and found that it is impeded by both the extended SD and the GTG start codon (instead of ATG). Biophysical characterization (CD- and NMR-spectroscopy) showed that synthesized polypeptide remained unstructured in physiological puffer. Replacement of the start codon by a stop codon increased the stability of the transcript, strongly suggesting additional posttranscriptional regulation at the ribosome. Therefore, the small gene was named rreB (ribosome-regulated expression in Bradyrhizobiaceae). Assuming that the unique ribosome binding site (RBS) is a hallmark of rreB homologs or similarly regulated genes, we looked for similar putative RBS in bacterial genomes and detected regions with at least 16 nt complementarity to the 3′-end of 16S rRNA upstream of sORFs in Caulobacterales, Rhizobiales, Rhodobacterales and Rhodospirillales. In the Rhodobacter/Roseobacter lineage of α-proteobacteria the corresponding gene (rreR) is conserved and encodes an 18 aa protein. This shows how specific RBS features can be used to identify new genes with presumably similar control of expression at the RNA level.
The measurement of concentrations of drugs and endogenous substances is widely used in basic and clinical pharmacology research and service tasks. Using data science‐derived visualizations of laboratory data, it is demonstrated on a real‐life example that basic statistical exploration of laboratory assay results or advised standard visual methods of data inspection may fall short in detecting systematic laboratory errors. For example, data pathologies such as generating always the same value in all probes of a particular assay run may pass undetected when using standard methods of data quality check. It is shown that the use of different data visualizations that emphasize different views of the data may enhance the detection of systematic laboratory errors. A dotplot of single data in the order of assay is proposed that provides an overview on the data range, outliers and a particular type of systematic errors where similar values are wrongly measured in all probes.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers potential cure to acute myeloid leukemia (AML) patients. However, infections with commensal bacteria are an important cause for non-relapse mortality (NRM). We have previously described the impact of multidrug-resistant organism (MDRO) colonization on the survival of allo-HSCT patients. In the aforementioned publication, according to consensus, we there did not consider the opportunistic gram-negative bacterium Stenotrophomonas maltophilia (S. maltophilia) to be an MDRO. Since rate of S. maltophilia colonization is increasing, and it is not known whether this poses a risk for allo-HSCT patients, we here analyzed here its effect on the previously described and now extended patient cohort. We report on 291 AML patients undergoing allo-HSCT. Twenty of 291 patients (6.9%) were colonized with S. maltophilia. Colonized patients did not differ from non-colonized patients with respect to their age, remission status before allo-HSCT, donor type and HSCT-comorbidity index. S. maltophilia colonized patients had a worse overall survival (OS) from 6 months up to 60 months (85% vs. 88.1% and 24.7% vs. 59.7%; p = 0.007) due to a higher NRM after allo-HSCT (6 months: 15% vs. 4.8% and 60 months: 40.1% vs. 16.2% p = 0.003). The main cause of mortality in colonized patients was infection (46.2% of all deaths) and in non-colonized patients relapse (58.8% of all deaths). 5/20 colonized patients developed an invasive infection with S. maltophilia. The worse OS after allo-HSCT due to higher infection related mortality might implicate the screening of allo-HSCT patients for S. maltophilia and a closer observation of colonized patients as outpatients.
While interleukin (IL)-1β is a potent pro-inflammatory cytokine involved in host defense, high levels can cause life-threatening sterile inflammation including systemic inflammatory response syndrome. Hence, the control of IL-1β secretion is of outstanding biomedical importance. In response to a first inflammatory stimulus such as lipopolysaccharide, pro-IL-1β is synthesized as a cytoplasmic inactive pro-form. Extracellular ATP originating from injured cells is a prototypical second signal for inflammasome-dependent maturation and release of IL-1β. The human anti-protease alpha-1 antitrypsin (AAT) and IL-1β regulate each other via mechanisms that are only partially understood. Here, we demonstrate that physiological concentrations of AAT efficiently inhibit ATP-induced release of IL-1β from primary human blood mononuclear cells, monocytic U937 cells, and rat lung tissue, whereas ATP-independent IL-1β release is not impaired. Both, native and oxidized AAT are active, suggesting that the inhibition of IL-1β release is independent of the anti-elastase activity of AAT. Signaling of AAT in monocytic cells involves the lipid scavenger receptor CD36, calcium-independent phospholipase A2β, and the release of a small soluble mediator. This mediator leads to the activation of nicotinic acetylcholine receptors, which efficiently inhibit ATP-induced P2X7 receptor activation and inflammasome assembly. We suggest that AAT controls ATP-induced IL-1β release from human mononuclear blood cells by a novel triple-membrane-passing signaling pathway. This pathway may have clinical implications for the prevention of sterile pulmonary and systemic inflammation.
Bacterial pathogens exploit eukaryotic pathways for their own end. Upon ingestion, Salmonella enterica serovar Typhimurium passes through the stomach and then catalyzes its uptake across the intestinal epithelium. It survives and replicates in an acidic vacuole through the action of virulence factors secreted by a type three secretion system located on Salmonella pathogenicity island 2 (SPI-2). Two secreted effectors, SifA and SseJ, are sufficient for endosomal tubule formation, which modifies the vacuole and enables Salmonella to replicate within it. Two-color, superresolution imaging of the secreted virulence factor SseJ and tubulin revealed that SseJ formed clusters of conserved size at regular, periodic intervals in the host cytoplasm. Analysis of SseJ clustering indicated the presence of a pearling effect, which is a force-driven, osmotically sensitive process. The pearling transition is an instability driven by membranes under tension; it is induced by hypotonic or hypertonic buffer exchange and leads to the formation of beadlike structures of similar size and regular spacing. Reducing the osmolality of the fixation conditions using glutaraldehyde enabled visualization of continuous and intact tubules. Correlation analysis revealed that SseJ was colocalized with the motor protein kinesin. Tubulation of the endoplasmic reticulum is driven by microtubule motors, and in the present work, we describe how Salmonella has coopted the microtubule motor kinesin to drive the force-dependent process of endosomal tubulation. Thus, endosomal tubule formation is a force-driven process catalyzed by Salmonella virulence factors secreted into the host cytoplasm during infection.
Truffles (Tuber spp.) are the fruiting bodies of symbiotic fungi, which are prized food delicacies. The marked aroma variability observed among truffles of the same species has been attributed to a series of factors that are still debated. This is because factors (i.e. genetics, maturation, geographical location and the microbial community colonizing truffles) often co-vary in truffle orchards. Here, we removed the co-variance effect by investigating truffle flavour in axenic cultures of nine strains of the white truffle Tuber borchii. This allowed us to investigate the influence of genetics on truffle aroma. Specifically, we quantified aroma variability and explored whether strain selection could be used to improve human-sensed truffle flavour. Our results illustrate that aroma variability among strains is predominantly linked to amino acid catabolism through the Ehrlich pathway, as confirmed by 13C labelling experiments. We furthermore exemplified through sensory analysis that the human nose is able to distinguish among strains and that sulfur volatiles derived from the catabolism of methionine have the strongest influence on aroma characteristics. Overall, our results demonstrate that genetics influences truffle aroma much more deeply than previously thought and illustrate the usefulness of strain selection for improving truffle flavour.
Regulation of protein turnover allows cells to react to their environment and maintain homeostasis. Proteins can show different turnover rates in different tissue, but little is known about protein turnover in different brain cell types. We used dynamic SILAC to determine half-lives of over 5100 proteins in rat primary hippocampal cultures as well as in neuron-enriched and glia-enriched cultures ranging from <1 to >20 days. In contrast to synaptic proteins, membrane proteins were relatively shorter-lived and mitochondrial proteins were longer-lived compared to the population. Half-lives also correlate with protein functions and the dynamics of the complexes they are incorporated in. Proteins in glia possessed shorter half-lives than the same proteins in neurons. The presence of glia sped up or slowed down the turnover of neuronal proteins. Our results demonstrate that both the cell-type of origin as well as the nature of the extracellular environment have potent influences on protein turnover.
Many cancers have the tumor suppressor p53 inactivated by mutation, making reactivation of mutant p53 with small molecules a promising strategy for the development of novel anticancer therapeutics. The oncogenic p53 mutation Y220C, which accounts for approximately 100,000 cancer cases per year, creates an extended surface crevice in the DNA-binding domain, which destabilizes p53 and causes denaturation and aggregation. Here, we describe the structure-guided design of a novel class of small-molecule Y220C stabilizers and the challenging synthetic routes developed in the process. The synthesized chemical probe MB710, an aminobenzothiazole derivative, binds tightly to the Y220C pocket and stabilizes p53-Y220C in vitro. MB725, an ethylamide analogue of MB710, induced selective viability reduction in several p53-Y220C cancer cell lines while being well tolerated in control cell lines. Reduction of viability correlated with increased and selective transcription of p53 target genes such as BTG2, p21, PUMA, FAS, TNF, and TNFRSF10B, which promote apoptosis and cell cycle arrest, suggesting compound-mediated transcriptional activation of the Y220C mutant. Our data provide a framework for the development of a class of potent, non-toxic compounds for reactivating the Y220C mutant in anticancer therapy.
Natural sounds contain information on multiple timescales, so the auditory system must analyze and integrate acoustic information on those different scales to extract behaviorally relevant information. However, this multi-scale process in the auditory system is not widely investigated in the literature, and existing models of temporal integration are mainly built upon detection or recognition tasks on a single timescale. Here we use a paradigm requiring processing on relatively ‘local’ and ‘global’ scales and provide evidence suggesting that the auditory system extracts fine-detail acoustic information using short temporal windows and uses long temporal windows to abstract global acoustic patterns. Behavioral task performance that requires processing fine-detail information does not improve with longer stimulus length, contrary to predictions of previous temporal integration models such as the multiple-looks and the spectro-temporal excitation pattern model. Moreover, the perceptual construction of putatively ‘unitary’ auditory events requires more than hundreds of milliseconds. These findings support the hypothesis of a dual-scale processing likely implemented in the auditory cortex.
In 1957, Craig Mooney published a set of human face stimuli to study perceptual closure: the formation of a coherent percept on the basis of minimal visual information. Images of this type, now known as “Mooney faces”, are widely used in cognitive psychology and neuroscience because they offer a means of inducing variable perception with constant visuo-spatial characteristics (they are often not perceived as faces if viewed upside down). Mooney’s original set of 40 stimuli has been employed in several studies. However, it is often necessary to use a much larger stimulus set. We created a new set of over 500 Mooney faces and tested them on a cohort of human observers. We present the results of our tests here, and make the stimuli freely available via the internet. Our test results can be used to select subsets of the stimuli that are most suited for a given experimental purpose.
Effect of progesterone on Smad signaling and TGF-β/Smad-regulated genes in lung epithelial cells
(2018)
The effect of endogenous progesterone and/or exogenous pre- or postnatal progesterone application on lung function of preterm infants is poorly defined. While prenatal progesterone substitution may prevent preterm birth, in vitro and in vivo data suggest a benefit of postnatal progesterone replacement on the incidence and severity of bronchopulmonary dysplasia (BPD). However, the molecular mechanisms responsible for progesterone’s effects are undefined. Numerous factors are involved in lung development, airway inflammation, and airway remodeling: the transforming growth factor beta (TGF-β)/mothers against decapentaplegic homolog (Smad) signaling pathway and TGF-β-regulated genes, such as connective tissue growth factor (CTGF), transgelin (TAGLN), and plasminogen activator inhibitor-1 (PAI-1). These processes contribute to the development of BPD. The aim of the present study was to clarify whether progesterone could affect TGF-β1-activated Smad signaling and CTGF/transgelin/PAI-1 expression in lung epithelial cells. The pharmacological effect of progesterone on Smad signaling was investigated using a TGF-β1-inducible luciferase reporter and western blotting analysis of phosphorylated Smad2/3 in A549 lung epithelial cells. The regulation of CTGF, transgelin, and PAI-1 expression by progesterone was studied using a promoter-based luciferase reporter, quantitative real-time PCR, and western blotting in the same cell line. While progesterone alone had no direct effect on Smad signaling in lung epithelial cells, it dose-dependently inhibited TGF-β1-induced Smad3 phosphorylation, as shown by luciferase assays and western blotting analysis. Progesterone also antagonized the TGF-β1/Smad-induced upregulation of CTGF, transgelin, and PAI-1 at the promoter, mRNA, and/or protein levels. The present study highlights possible new molecular mechanisms involving progesterone, including inhibition of TGF-β1-activated Smad signaling and TGF-β1-regulated genes involved in BPD pathogenesis, which are likely to attenuate the development of BPD by inhibiting TGF-β1-mediated airway remodeling. Understanding these mechanisms might help to explain the effects of pre- or postnatal application of progesterone on lung diseases of preterm infants.
This study was designed to characterize morphologic stages during neuroma development post amputation with an eye toward developing better treatment strategies that intervene before neuromas are fully formed. Right forelimbs of 30 Sprague Dawley rats were amputated and limb stumps were collected at 3, 7, 28, 60 and 90 Days Post Amputation (DPA). Morphology of newly formed nerves and neuromas were assessed via general histology and neurofilament protein antibody staining. Analysis revealed six morphological characteristics during nerve and neuroma development; 1) normal nerve, 2) degenerating axons, 3) axonal sprouts, 4) unorganized bundles of axons, 5) unorganized axon growth into muscles, and 6) unorganized axon growth into fibrotic tissue (neuroma). At early stages (3 & 7 DPA) after amputation, normal nerves could be identified throughout the limb stump and small areas of axonal sprouts were present near the site of injury. Signs of degenerating axons were evident from 7 to 90 DPA. From day 28 on, variability of nerve characteristics with signs of unorganized axon growth into muscle and fibrotic tissue and neuroma formation became visible in multiple areas of stump tissue. These pathological features became more evident on days 60 and 90. At 90 DPA frank neuroma formation was present in all stump tissue. By following nerve regrowth and neuroma formation after amputation we were able to identify 6 separate histological stages of nerve regrowth and neuroma development. Axonal regrowth was observed as early as 3 DPA and signs of unorganized axonal growth and neuroma formation were evident by 28 DPA. Based on these observations we speculate that neuroma treatment and or prevention strategies might be more successful if targeted at the initial stages of development and not after 28 DPA.
Background and aims: Expression of carbonic anhydrase IX (CA9), an enzyme expressed in response to hypoxia, acidosis and oncogenic alterations, is reported to be a prognostic factor in HCC patients. Here we evaluated serum CA9 levels in HCC and cirrhosis patients.
Methods: HCC and cirrhosis patients were prospectively recruited and CA9 levels were determined. CA9 levels were compared to stages of cirrhosis and HCC stages. The association of the CA9 levels and overall survival (OS) was assessed. Furthermore, immunohistochemical CA9 expression in HCC and cirrhosis was evaluated.
Results: 215 patients with HCC were included. The median serum CA9 concentration in patients with HCC was 370 pg/ml and significantly higher than in a healthy cohort. Patients with advanced cancer stages (BCLC and ALBI score) had hid significant higher levels of CA9 in the serum. HCC patients with high serum CA9 concentrations (>400 pg/ml) had an increased mortality risk (hazard ratio (HR) 1.690, 95% confidence interval (CI) 1.017–2.809, P = 0.043). Serum CA9 concentration in cirrhotic patients did not differ significantly from HCC patients. Higher CA9 levels in cirrhotic patients correlated with portal hypertension and esophageal varices. Patients with ethanol induced cirrhosis had the highest CA9 levels in both cohorts. Levels of CA9 did not correlate with immunohistochemical expression.
Conclusions: We conclude that a high CA9 level is a possible prognostic indicator for a poor outcome in HCC patients. The high CA9 levels are probably mainly associated with portal hypertension. Ductular reactions might be a possible source of serum CA9.
Transmission of temporally correlated spike trains through synapses with short-term depression
(2018)
Short-term synaptic depression, caused by depletion of releasable neurotransmitter, modulates the strength of neuronal connections in a history-dependent manner. Quantifying the statistics of synaptic transmission requires stochastic models that link probabilistic neurotransmitter release with presynaptic spike-train statistics. Common approaches are to model the presynaptic spike train as either regular or a memory-less Poisson process: few analytical results are available that describe depressing synapses when the afferent spike train has more complex, temporally correlated statistics such as bursts. Here we present a series of analytical results—from vesicle release-site occupancy statistics, via neurotransmitter release, to the post-synaptic voltage mean and variance—for depressing synapses driven by correlated presynaptic spike trains. The class of presynaptic drive considered is that fully characterised by the inter-spike-interval distribution and encompasses a broad range of models used for neuronal circuit and network analyses, such as integrate-and-fire models with a complete post-spike reset and receiving sufficiently short-time correlated drive. We further demonstrate that the derived post-synaptic voltage mean and variance allow for a simple and accurate approximation of the firing rate of the post-synaptic neuron, using the exponential integrate-and-fire model as an example. These results extend the level of biological detail included in models of synaptic transmission and will allow for the incorporation of more complex and physiologically relevant firing patterns into future studies of neuronal networks.
Background: The progression of mild cognitive impairment (MCI) to Alzheimer’s disease (AD) dementia can be predicted by cognitive, neuroimaging, and cerebrospinal fluid (CSF) markers. Since most biomarkers reveal complementary information, a combination of biomarkers may increase the predictive power. We investigated which combination of the Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR)-sum-of-boxes, the word list delayed free recall from the Consortium to Establish a Registry of Dementia (CERAD) test battery, hippocampal volume (HCV), amyloid-beta1–42 (Aβ42), amyloid-beta1–40 (Aβ40) levels, the ratio of Aβ42/Aβ40, phosphorylated tau, and total tau (t-Tau) levels in the CSF best predicted a short-term conversion from MCI to AD dementia.
Methods: We used 115 complete datasets from MCI patients of the "Dementia Competence Network", a German multicenter cohort study with annual follow-up up to 3 years. MCI was broadly defined to include amnestic and nonamnestic syndromes. Variables known to predict progression in MCI patients were selected a priori. Nine individual predictors were compared by receiver operating characteristic (ROC) curve analysis. ROC curves of the five best two-, three-, and four-parameter combinations were analyzed for significant superiority by a bootstrapping wrapper around a support vector machine with linear kernel. The incremental value of combinations was tested for statistical significance by comparing the specificities of the different classifiers at a given sensitivity of 85%.
Results: Out of 115 subjects, 28 (24.3%) with MCI progressed to AD dementia within a mean follow-up period of 25.5 months. At baseline, MCI-AD patients were no different from stable MCI in age and gender distribution, but had lower educational attainment. All single biomarkers were significantly different between the two groups at baseline. ROC curves of the individual predictors gave areas under the curve (AUC) between 0.66 and 0.77, and all single predictors were statistically superior to Aβ40. The AUC of the two-parameter combinations ranged from 0.77 to 0.81. The three-parameter combinations ranged from AUC 0.80–0.83, and the four-parameter combination from AUC 0.81–0.82. None of the predictor combinations was significantly superior to the two best single predictors (HCV and t-Tau). When maximizing the AUC differences by fixing sensitivity at 85%, the two- to four-parameter combinations were superior to HCV alone.
Conclusion: A combination of two biomarkers of neurodegeneration (e.g., HCV and t-Tau) is not superior over the single parameters in identifying patients with MCI who are most likely to progress to AD dementia, although there is a gradual increase in the statistical measures across increasing biomarker combinations. This may have implications for clinical diagnosis and for selecting subjects for participation in clinical trials.
Many new strategies for the reconstruction of peripheral nerve injuries have been explored for their effectiveness in supporting nerve regeneration. However only a few of these materials were actually clinically evaluated and approved for human use. This open, mono-center, non-randomized clinical study summarizes the 12-month follow-up of patients receiving reconstruction of the sural nerve biopsy defect by the collagen-based nerve guide Neuromaix. Neuromaix was implanted as a micro-structured, two-component scaffold bridging 20–40 mm nerve defects after sural nerve biopsy in twenty patients (eighteen evaluated, two lost in follow-up). Safety of the material was evaluated by clinical examination of wound healing. Performance was assessed by sensory testing of modalities, pain assessment, and palpation for the Hoffmann–Tinel’s sign as well as demarcating the asensitive area at each follow-up visit. Every patient demonstrated uneventful wound healing during the complete 12-month time course of the study. Two patients reported complete return of sensation, whereas eleven out of eighteen patients reported a positive Hoffmann–Tinel’s sign at the lower leg with simultaneous reduction of the asensitive area by 12 months. Our data show that Neuromaix can be implanted safely in humans to bridge sural nerve gaps. No procedure-related, adverse events, or severe adverse events were reported. These first clinical data on Neuromaix provide promising perspectives for the bridging of larger nerve gaps in combined nerves, which should be investigated more through extensive, multi-center clinical trials in the near future.
Cortex-wide BOLD fMRI activity reflects locally-recorded slow oscillation-associated calcium waves
(2017)
Spontaneous slow oscillation-associated slow wave activity represents an internally generated state which is characterized by alternations of network quiescence and stereotypical episodes of neuronal activity - slow wave events. However, it remains unclear which macroscopic signal is related to these active periods of the slow wave rhythm. We used optic fiber-based calcium recordings of local neural populations in cortex and thalamus to detect neurophysiologically defined slow calcium waves in isoflurane anesthetized rats. The individual slow wave events were used for an event-related analysis of simultaneously acquired whole-brain BOLD fMRI. We identified BOLD responses directly related to onsets of slow calcium waves, revealing a cortex-wide BOLD correlate: the entire cortex was engaged in this specific type of slow wave activity. These findings demonstrate a direct relation of defined neurophysiological events to a specific BOLD activity pattern and were confirmed for ongoing slow wave activity by independent component and seed-based analyses.
Evoked potentials (EPs) are well established in clinical practice for diagnosis and prognosis in multiple sclerosis (MS). However, their value is limited to the assessment of their respective functional systems. Here, we used transcranial magnetic stimulation (TMS) coupled with electroencephalography (TMS-EEG) to investigate cortical excitability and spatiotemporal dynamics of TMS-evoked neural activity in MS patients. Thirteen patients with early relapsing–remitting MS (RRMS) with a median Expanded Disability Status Scale (EDSS) of 1.0 (range 0–2.5) and 16 age- and gender-matched healthy controls received single-pulse TMS of left and right primary motor cortex (L-M1 and R-M1), respectively. Resting motor threshold for L-M1 and R-M1 was increased in MS patients. Latencies and amplitudes of N45, P70, N100, P180, and N280 TMS-evoked EEG potentials (TEPs) were not different between groups, except a significantly increased amplitude of the N280 TEP in the MS group, both for L-M1 and R-M1 stimulation. Interhemispheric signal propagation (ISP), estimated from the area under the curve of TEPs in the non-stimulated vs. stimulated M1, also did not differ between groups. In summary, findings show that ISP and TEPs were preserved in early-stage RRMS, except for an exaggerated N280 amplitude. Our findings indicate that TMS-EEG is feasible in testing excitability and connectivity in cortical neural networks in MS patients, complementary to conventional EPs. However, relevance and pathophysiological correlates of the enhanced N280 will need further study.
Background: The recurrence rate in lumbar disc herniations (LDH) has been reported between 5 and 25%. There are only few data about this phenomenon that occurs within days of the initial operation. We analyse early recurrent LDH by analysis of data from the German Spine register.
Methods: Data from patients undergoing disc herniation surgery in the lumbar region were extracted from the German Spine Registry between 1st January 2012 and 31st December 2016. Patients with early recurrent LDH within days of initial surgery were separately analysed.
Results: A total of 9310 surgeries for LDH were documented in the German Spine Register. From these patients 115 (1.2%) presented an early recurrent disc surgeries within days of the initial surgery. The mean age was 70 ± 2.50 years. Most affected segment was L4/5 (47 cases, 41%), followed by L3/4 (45 cases, 39%). The most of our patients showed a normal or overweight Body Mass Index. Surgery for early recurrent LDH was associated with a high rate of incidental durotomies (20 cases, 17.6%). In 3 cases (2.6%) therapy with a lumbar drain was necessary.
Conclusions: The rate of early recurrent LDH within days of surgery is 1.2%. Age seems to be an important factor in early recurrent LDH while obesity does not. The data of the German Spine Register seems to have a reliable data collection system that can perform multicentre data analysis. The databases from this Register could be used in the future for various purposes, such as the evaluation of multicentre surgical techniques, results in patients with various surgical procedures and basic research in spine surgery.
Background: Juvenile dermatomyositis (JDM) is the most common inflammatory myopathy in childhood and a major cause of morbidity among children with pediatric rheumatic diseases. The management of JDM is very heterogeneous. The JDM working group of the Society for Pediatric Rheumatology (GKJR) aims to define consensus- and practice-based strategies in order to harmonize diagnosis, treatment and monitoring of JDM.
Methods: The JDM working group was established in 2015 consisting of 23 pediatric rheumatologists, pediatric neurologists and dermatologists with expertise in the management of JDM. Current practice patterns of management in JDM had previously been identified via an online survey among pediatric rheumatologists and neurologists. Using a consensus process consisting of online surveys and a face-to-face consensus conference statements were defined regarding the diagnosis, treatment and monitoring of JDM. During the conference consensus was achieved via nominal group technique. Voting took place using an electronic audience response system, and at least 80% consensus was required for individual statements.
Results: Overall 10 individual statements were developed, finally reaching a consensus of 92 to 100% regarding (1) establishing a diagnosis, (2) case definitions for the application of the strategies (moderate and severe JDM), (3) initial diagnostic testing, (4) monitoring and documentation, (5) treatment targets within the context of a treat-to-target strategy, (6) supportive therapies, (7) explicit definition of a treat-to-target strategy, (8) various glucocorticoid regimens, including intermittent intravenous methylprednisolone pulse and high-dose oral glucocorticoid therapies with tapering, (9) initial glucocorticoid-sparing therapy and (10) management of refractory disease.
Conclusion: Using a consensus process among JDM experts, statements regarding the management of JDM were defined. These statements and the strategies aid in the management of patients with moderate and severe JDM.
Testicular germ cell cancer in a metastatic state is curable with a cisplatin‑based first line chemotherapy. However, 10‑15% of these patients are resistant to first line chemotherapy and are thus left with only palliative options. Immunotherapies and inhibition of angiogenesis used in multiple types of cancer; however, the molecular context of angiogenesis and immune checkpoints in the development and progression of testicular cancers is still unknown. Therefore, the present study performed tissue micro array based analysis of 84 patients with immunohistochemistry of programmed cell death protein 1 (PD‑1), programmed cell death ligand 1 (PD‑L1) and vascular endothelial growth factor receptor 2 (VEGFR2) of testicular cancer and corresponding normal appearing testis tissue, matching the results with clinical data. The results demonstrated that PD‑L1 was significantly upregulated in testicular tumors and that PD‑1 positive cells significantly infiltrated the testicular tumor when compared with normal testicular tissue. VEGFR2 was significantly upregulated in testicular cancer. It was indicated that PD‑1 expressing cytotoxic cells may require pathologic tumor vessels to pass the blood‑testis‑barrier in order to migrate into the tumor. Notably, when matching the clinical data for PD‑1, PD‑L1 and VEGFR2 there were no differences in expression in the different International Germ Cell Cancer Collaborative Group stages of non‑seminoma. These data suggested that the anti‑PD‑1/PD‑L1 immunotherapy and the anti‑angiogenic therapy, sequentially or in combination, may be a promising option in the treatment of testicular cancer.
According to embodied cognition accounts, viewing others’ facial emotion can elicit the respective emotion representation in observers which entails simulations of sensory, motor, and contextual experiences. In line with that, published research found viewing others’ facial emotion to elicit automatic matched facial muscle activation, which was further found to facilitate emotion recognition. Perhaps making congruent facial muscle activity explicit produces an even greater recognition advantage. If there is conflicting sensory information, i.e., incongruent facial muscle activity, this might impede recognition. The effects of actively manipulating facial muscle activity on facial emotion recognition from videos were investigated across three experimental conditions: (a) explicit imitation of viewed facial emotional expressions (stimulus-congruent condition), (b) pen-holding with the lips (stimulus-incongruent condition), and (c) passive viewing (control condition). It was hypothesised that (1) experimental condition (a) and (b) result in greater facial muscle activity than (c), (2) experimental condition (a) increases emotion recognition accuracy from others’ faces compared to (c), (3) experimental condition (b) lowers recognition accuracy for expressions with a salient facial feature in the lower, but not the upper face area, compared to (c). Participants (42 males, 42 females) underwent a facial emotion recognition experiment (ADFES-BIV) while electromyography (EMG) was recorded from five facial muscle sites. The experimental conditions’ order was counter-balanced. Pen-holding caused stimulus-incongruent facial muscle activity for expressions with facial feature saliency in the lower face region, which reduced recognition of lower face region emotions. Explicit imitation caused stimulus-congruent facial muscle activity without modulating recognition. Methodological implications are discussed.
Optogenetics offers a unique method to regulate the activity of select neural circuits. However, the electrophysiological consequences of targeted optogenetic manipulation upon the entire circuit remain poorly understood. Analysis of the sensory-CNS-motor circuit in Drosophila larvae expressing eHpHR and ChR2-XXL revealed unexpected patterns of excitability. Optical stimulation of motor neurons targeted to express eNpHR resulted in inhibition followed by excitation of body wall contraction with repetitive stimulation in intact larvae. In situ preparations with direct electrophysiological measures showed an increased responsiveness to excitatory synaptic activity induced by sensory stimulation within a functional neural circuit. To ensure proper function of eNpHR and ChR2-XXL they were expressed in body wall muscle and direct electrophysiological measurements were obtained. Under eNpHR induced hyperpolarization the muscle remained excitable with increased amplitude of excitatory postsynaptic synaptic potentials. Theoretical models to explain the observations are presented. This study aids in increasing the understanding of the varied possible influences with light activated proteins within intact neural circuits.
Cervical spine injuries are frequent and often caused by a blunt trauma mechanism. They can have severe consequences, with a high mortality rate and a high rate of neurological lesions.Diagnosis is a three-step process: 1) risk assessment according to the history and clinical features, guided by a clinical decision rule such as the Canadian C-Spine rule; 2) imaging if needed; 3) classification of the injury according to different classification systems in the different regions of the cervical spine.The urgency of treatment is dependent on the presence of a neurological lesion and/or instability. The treatment strategy depends on the morphological criteria as defined by the classification.
Sprifermin (rhFGF18) enables proliferation of chondrocytes producing a hyaline cartilage matrix
(2017)
Objective: Fibroblast growth factor (FGF) 18 has been shown to increase cartilage volume when injected intra-articularly in animal models of osteoarthritis (OA) and in patients with knee OA (during clinical development of the recombinant human FGF18, sprifermin). However, the exact nature of this effect is still unknown. In this study, we aimed to investigate the effects of sprifermin at the cellular level.
Design: A combination of different chondrocyte culture systems was used and the effects of sprifermin on proliferation, the phenotype and matrix production were evaluated. The involvement of MAPKs in sprifermin signalling was also studied.
Results: In monolayer, we observed that sprifermin promoted a round cell morphology and stimulated both cellular proliferation and Sox9 expression while strongly decreasing type I collagen expression. In 3D culture, sprifermin increased the number of matrix-producing chondrocytes, improved the type II:I collagen ratio and enabled human OA chondrocytes to produce a hyaline extracellular matrix (ECM). Furthermore, we found that sprifermin displayed a ‘hit and run’ mode of action, with intermittent exposure required for the compound to fully exert its anabolic effect. Finally, sprifermin appeared to signal through activation of ERK.
Conclusions: Our results indicate that intermittent exposure to sprifermin leads to expansion of hyaline cartilage-producing chondrocytes. These in vitro findings are consistent with the increased cartilage volume observed in the knees of OA patients after intra-articular injection with sprifermin in clinical studies.
Global change effects on biodiversity and human wellbeing call for improved long-term environmental data as a basis for science, policy and decision making, including increased interoperability, multifunctionality, and harmonization. Based on the example of two global initiatives, the International Long-Term Ecological Research (ILTER) network and the Group on Earth Observations Biodiversity Observation Network (GEO BON), we propose merging the frameworks behind these initiatives, namely ecosystem integrity and essential biodiversity variables, to serve as an improved guideline for future site-based long-term research and monitoring in terrestrial, freshwater and coastal ecosystems. We derive a list of specific recommendations of what and how to measure at a monitoring site and call for an integration of sites into co-located site networks across individual monitoring initiatives, and centered on ecosystems. This facilitates the generation of linked comprehensive ecosystem monitoring data, supports synergies in the use of costly infrastructures, fosters cross-initiative research and provides a template for collaboration beyond the ILTER and GEO BON communities.
Background: Conversion from calcineurin inhibitor (CNI) therapy to everolimus within 6 months after kidney transplantation improves long-term graft function but can increase the risk of mild biopsy-proven acute cellular rejection (BPAR). We performed a post-hoc analysis of histological data from a randomized trial in order to further analyze histologic information obtained from indication and protocol biopsies up to 5 years after transplantation.
Methods: Biopsy samples obtained up to 5 years post-transplant were analyzed from the randomized ZEUS study, in which kidney transplant patients were randomized at month 4.5 to switch to everolimus (n = 154) or remain on cyclosporine (CsA)-based immunosuppression (n = 146). All patients received mycophenolate and steroids.
Results: At least one investigator-initiated biopsy was undertaken in 53 patients in each group between randomization and year 5, with a mean (SD) of 2.6 (1.7) and 2.2 (1.4) biopsies per patient in the everolimus and CsA groups, respectively. In the everolimus and CsA groups, investigator-initiated biopsies showed (i) BPAR in 12.3 and 7.5% (p = 0.182) of patients, respectively, with episodes graded mild in 22/24 and 18/20 cases (ii) CsA toxicity lesions in 4.5 and 10.3% of patients (p = 0.076) (iii) antibody-mediated rejection in 0.6 and 2.7% of patients (p = 0.204), respectively.
Conclusions: This analysis of histological findings in the ZEUS study to 5 years after kidney transplantation shows no increase in antibody-mediated rejection under everolimus-based therapy with a lower rate of CNI-related toxicity compared to a conventional CsA-based regimen, and confirms the preponderance of mild BPAR seen in the main study after the early switch to CsA-free everolimus therapy.
Trial registration: ClinicalTrials.gov NCT00154310. Date of registration: September 12, 2005.
Background: Subdural hematoma (SDH) is a common disease associated with high morbidity, which is becoming more prominent due to the increasing incidence. Decision for a surgical evacuation is made depending on the clinical appearance and the volume of SDH, wherefore it is important to have a simple ‘bedside’ method to measure and compare the volume of SDH.
Objective: The aim of the study was to verify the accuracy of the simplified ABC/2 volumetric formula to determine a valuable tool for the clinical practice.
Methods: Preoperative CT-scans of 83 patients with SDHs were used for the computer-assisted volumetric measurement via BrainLab® as well as the ABC/2 volumetric measurement. A = largest length (anterior to posterior) of the SDH; B = maximum width (lateral to midline) 90° to A; C = maximum height (coronal plane or multiplication of slices) of the hematoma. These measurements were performed by two independent clinicians in a blinded fashion. Both volumes were compared by linear regression analysis of Pearson and Bland-Altman regression analysis.
Results: Among 100 SDHs, 53% were under an 47% were over 100cm3 showing a well distribution of the hematoma sizes. There was an excellent correlation between computer-assisted volumetric measurement and ABC/2 (R2 = 0.947, p<0.0001) and no undesirable deviation and trend were detected (p = 0.101; p = 0.777). A 95% tolerance region of the ratios of both methods was [0.805–1.201].
Conclusion: The ABC/2 method is a simple and fast bedside formula for the measurement of SDH volume in a timely manner without limited access through simple adaption, which may replace the computer-assisted volumetric measurement in the clinical and research area. Reason for the good accuracy seems to be the spherical form of SDH, which has a similarity to a half ellipsoid.
Descent of testes from a position near the kidneys into the lower abdomen or into the scrotum is an important developmental process that occurs in all placental mammals, with the exception of five afrotherian lineages. Since soft-tissue structures like testes are not preserved in the fossil record and since key parts of the placental mammal phylogeny remain controversial, it has been debated whether testicular descent is the ancestral or derived condition in placental mammals. To resolve this debate, we used genomic data of 71 mammalian species and analyzed the evolution of two key genes (relaxin/insulin-like family peptide receptor 2 [RXFP2] and insulin-like 3 [INSL3]) that induce the development of the gubernaculum, the ligament that is crucial for testicular descent. We show that both RXFP2 and INSL3 are lost or nonfunctional exclusively in four afrotherians (tenrec, cape elephant shrew, cape golden mole, and manatee) that completely lack testicular descent. The presence of remnants of once functional orthologs of both genes in these afrotherian species shows that these gene losses happened after the split from the placental mammal ancestor. These “molecular vestiges” provide strong evidence that testicular descent is the ancestral condition, irrespective of persisting phylogenetic discrepancies. Furthermore, the absence of shared gene-inactivating mutations and our estimates that the loss of RXFP2 happened at different time points strongly suggest that testicular descent was lost independently in Afrotheria. Our results provide a molecular mechanism that explains the loss of testicular descent in afrotherians and, more generally, highlight how molecular vestiges can provide insights into the evolution of soft-tissue characters.
Since its founding in 1993 the International Long-term Ecological Research Network (ILTER) has gone through pronounced development phases. The current network comprises 44 active member LTER networks representing 700 LTER Sites and ~ 80 LTSER Platforms across all continents, active in the fields of ecosystem, critical zone and socio-ecological research. The critical challenges and most important achievements of the initial phase have now become state-of-the-art in networking for excellent science. At the same time increasing integration, accelerating technology, networking of resources and a strong pull for more socially relevant scientific information have been modifying the mission and goals of ILTER. This article provides a critical review of ILTER's mission, goals, development and impacts. Major characteristics, tools, services, partnerships and selected examples of relative strengths relevant for advancing ILTER are presented. We elaborate on the tradeoffs between the needs of the scientific community and stakeholder expectations. The embedding of ILTER in an increasingly collaborative landscape of global environmental observation and ecological research networks and infrastructures is also reflected by developments of pioneering regional and national LTER networks such as SAEON in South Africa, CERN/CEOBEX in China, TERN in Australia or eLTER RI in Europe. The primary role of ILTER is currently seen as a mechanism to investigate ecosystem structure, function, and services in response to a wide range of environmental forcings using long-term, place-based research. We suggest four main fields of activities and advancements for the next decade through development/delivery of a: (1) Global multi-disciplinary community of researchers and research institutes; (2) Strategic global framework and strong partnerships in ecosystem observation and research; (3) Global Research Infrastructure (GRI); and (4) a scientific knowledge factory for societally relevant information on sustainable use of natural resources.
The marine hydrocarbonoclastic bacterium Alcanivorax borkumensis is well known for its ability to successfully degrade various mixtures of n-alkanes occurring in marine oil spills. For effective growth on these compounds, the bacteria possess the unique capability not only to incorporate but also to modify fatty intermediates derived from the alkane degradation pathway. High efficiency of both these processes provides better competitiveness for a single bacteria species among hydrocarbon degraders. To examine the efficiency of A. borkumensis to cope with different sources of fatty acid intermediates, we studied the growth rates and membrane fatty acid patterns of this bacterium cultivated on diesel, biodiesel and rapeseed oil as carbon and energy source. Obtained results revealed significant differences in both parameters depending on growth substrate. Highest growth rates were observed with biodiesel, while growth rates on rapeseed oil and diesel were lower than on the standard reference compound (hexadecane). The most remarkable observation is that cells grown on rapeseed oil, biodiesel, and diesel showed significant amounts of the two polyunsaturated fatty acids linoleic acid and linolenic acid in their membrane. By direct incorporation of these external fatty acids, the bacteria save energy allowing them to degrade those pollutants in a more efficient way. Such fast adaptation may increase resilience of A. borkumensis and allow them to strive and maintain populations in more complex hydrocarbon degrading microbial communities.
The taxanes are effective microtubule-stabilizing chemotherapy drugs that inhibit mitosis, induce apoptosis, and produce regression in a fraction of cancers that arise at many sites including the ovary. Novel therapeutic targets that augment taxane effects are needed to improve clinical chemotherapy response in CCNE1-amplified high grade serous ovarian cancer (HGSOC) cells. In this study, we conducted an siRNA-based kinome screen to identify modulators of mitotic progression in CCNE1-amplified HGSOC cells that may influence clinical paclitaxel response. PLK1 is overexpressed in many types of cancer, which correlates with poor prognosis. Here, we identified a novel synthetic lethal interaction of the clinical PLK1 inhibitor BI6727 and the microtubule-targeting drug paclitaxel in HGSOC cell lines with CCNE1-amplification and elucidated the underlying molecular mechanisms of this synergism. BI6727 synergistically induces apoptosis together with paclitaxel in different cell lines including a patient-derived primary ovarian cancer culture. Moreover, the inhibition of PLK1 reduced the paclitaxel-induced neurotoxicity in a neurite outgrowth assay. Mechanistically, the combinatorial treatment with BI6727/paclitaxel triggers mitotic arrest, which initiates mitochondrial apoptosis by inactivation of anti-apoptotic BCL-2 family proteins, followed by significant loss of the mitochondrial membrane potential and activation of caspase-dependent effector pathways. This conclusion is supported by data showing that BI6727/paclitaxel-co-treatment stabilizes FBW7, a component of SCF-type ubiquitin ligases that bind and regulate key modulators of cell division and growth including MCL-1 and Cyclin E. This identification of a novel synthetic lethality of PLK1 inhibitors and a microtubule-stabilizing drug has important implications for developing PLK1 inhibitor-based combination treatments in CCNE1-amplified HGSOC cells.
The photoregulation of nucleic acids by azobenzene photoswitches has recently attracted considerable interest in the context of emerging biotechnological applications. To understand the mechanism of photoinduced isomerisation and conformational control in these complex biological environments, we employ a Quantum Mechanics/Molecular Mechanics (QM/MM) approach in conjunction with nonadiabatic Surface Hopping (SH) dynamics. Two representative RNA–azobenzene complexes are investigated, both of which contain the azobenzene chromophore covalently attached to an RNA double strand via a β-deoxyribose linker. Due to the pronounced constraints of the local RNA environment, it is found that trans-to-cis isomerization is slowed down to a time scale of ∼10–15 picoseconds, in contrast to 500 femtoseconds in vacuo, with a quantum yield reduced by a factor of two. By contrast, cis-to-trans isomerization remains in a sub-picosecond regime. A volume-conserving isomerization mechanism is found, similarly to the pedal-like mechanism previously identified for azobenzene in solution phase. Strikingly, the chiral RNA environment induces opposite right-handed and left-handed helicities of the ground-state cis-azobenzene chromophore in the two RNA–azobenzene complexes, along with an almost completely chirality conserving photochemical pathway for these helical enantiomers.
Drug-induced liver injury (DILI) has become a major problem for patients and for clinicians, academics and the pharmaceutical industry. To date, existing hepatotoxicity test systems are only poorly predictive and the underlying mechanisms are still unclear. One of the factors known to amplify hepatotoxicity is the tumor necrosis factor alpha (TNFα), especially due to its synergy with commonly used drugs such as diclofenac. However, the exact mechanism of how diclofenac in combination with TNFα induces liver injury remains elusive. Here, we combined time-resolved immunoblotting and live-cell imaging data of HepG2 cells and primary human hepatocytes (PHH) with dynamic pathway modeling using ordinary differential equations (ODEs) to describe the complex structure of TNFα-induced NFκB signal transduction and integrated the perturbations of the pathway caused by diclofenac. The resulting mathematical model was used to systematically identify parameters affected by diclofenac. These analyses showed that more than one regulatory module of TNFα-induced NFκB signal transduction is affected by diclofenac, suggesting that hepatotoxicity is the integrated consequence of multiple changes in hepatocytes and that multiple factors define toxicity thresholds. Applying our mathematical modeling approach to other DILI-causing compounds representing different putative DILI mechanism classes enabled us to quantify their impact on pathway activation, highlighting the potential of the dynamic pathway model as a quantitative tool for the analysis of DILI compounds.
Background: Prolonged immunosuppression or delayed T-cell recovery may favor Epstein-Barr virus (EBV) infection or reactivation after allogeneic hematopoietic stem cell transplantation (HSCT), which can lead to post-transplant lymphoproliferative disease (PTLD) and high-grade malignant B-cell lymphoma. Cytokine-induced killer (CIK) cells with dual specific anti-tumor and virus-specific cellular immunity may be applied in this context.
Methods: CIK cells with EBV-specificity were generated from peripheral blood mononuclear cells (PBMCs), expanded in the presence of interferon-γ, anti-CD3, interleukin (IL)-2 and IL-15 and were pulsed twice with EBV consensus peptide pool. CIK cells with EBV-specificity and conventional CIK cells were phenotypically and functionally analyzed. Additionally, CIK cells with EBV-specificity were applied to a patient with EBV-related PTLD rapidly progressing to highly aggressive B-cell lymphoma on a compassionate use basis after approval and agreement by the regulatory authorities.
Results: Pre-clinical analysis showed that generation of CIK cells with EBV-specificity was feasible. In vitro cytotoxicity analyses showed increased lysis of EBV-positive target cells, enhanced proliferative capacity and increased secretion of cytolytic and proinflammatory cytokines in the presence of EBV peptide-displaying target cells. In addition, 1 week after infusion of CIK cells with EBV-specificity, the patient's highly aggressive B-cell lymphoma persistently disappeared. CIK cells with EBV-specificity remained detectable for up to 32 days after infusion and infusion did not result in acute toxicity.
Discussion: The transfer of both anti-cancer potential and T-cell memory against EBV infection provided by EBV peptide-induced CIK cells might be considered a therapy for EBV-related PTLD.
The emotional state of being moved, though frequently referred to in both classical rhetoric and current language use, is far from established as a well-defined psychological construct. In a series of three studies, we investigated eliciting scenarios, emotional ingredients, appraisal patterns, feeling qualities, and the affective signature of being moved and related emotional states. The great majority of the eliciting scenarios can be assigned to significant relationship and critical life events (especially death, birth, marriage, separation, and reunion). Sadness and joy turned out to be the two preeminent emotions involved in episodes of being moved. Both the sad and the joyful variants of being moved showed a coactivation of positive and negative affect and can thus be ranked among the mixed emotions. Moreover, being moved, while featuring only low-to-mid arousal levels, was experienced as an emotional state of high intensity; this applied to responses to fictional artworks no less than to own-life and other real, but media-represented, events. The most distinctive findings regarding cognitive appraisal dimensions were very low ratings for causation of the event by oneself and for having the power to change its outcome, along with very high ratings for appraisals of compatibility with social norms and self-ideals. Putting together the characteristics identified and discussed throughout the three studies, the paper ends with a sketch of a psychological construct of being moved.
Stories can elicit powerful emotions. A key emotional response to narrative plots (e.g., novels, movies, etc.) is suspense. Suspense appears to build on basic aspects of human cognition such as processes of expectation, anticipation, and prediction. However, the neural processes underlying emotional experiences of suspense have not been previously investigated. We acquired functional magnetic resonance imaging (fMRI) data while participants read a suspenseful literary text (E.T.A. Hoffmann's "The Sandman") subdivided into short text passages. Individual ratings of experienced suspense obtained after each text passage were found to be related to activation in the medial frontal cortex, bilateral frontal regions (along the inferior frontal sulcus), lateral premotor cortex, as well as posterior temporal and temporo-parietal areas. The results indicate that the emotional experience of suspense depends on brain areas associated with social cognition and predictive inference.
Emotional competence has an important influence on development in school. We hypothesized that reading and discussing children’s books with emotional content increases children’s emotional competence. To examine this assumption, we developed a literature-based intervention, named READING and FEELING, and tested it on 104 second and third graders in their after-school care center. Children who attended the same care center but did not participate in the emotion-centered literary program formed the control group (n = 104). Our goal was to promote emotional competence and to evaluate the effectiveness of the READING and FEELING program. Emotional competence variables were measured prior to the intervention and 9 weeks later, at the end of the program. Results revealed significant improvements in the emotional vocabulary, explicit emotional knowledge, and recognition of masked feelings. Regarding the treatment effect for detecting masked feelings, we found that boys benefited significantly more than girls. These findings underscore the assumption that children’s literature is an appropriate vehicle to support the development of emotional competence in middle childhood.
This psychophysiological study is the first to examine the relationship between emotional tears and emotional piloerection (i.e., goosebumps). Although both phenomena have been related to peak states of being moved, details about their temporal occurrence and the associated levels of physiological arousal have remained unknown. In our study, we used emotionally powerful film scenes that were self-selected by participants. Our findings show that even within peak moments of emotional arousal, a gradation of intensity is possible. The overlap of tears and goosebumps signifies a maximal climax within peak moments. On the side of the stimulus, we found that displays of prosocial behavior play a crucial role in the elicitation of tears and goosebumps. Finally, based on the results of a formal film analysis of the tears-eliciting clips provided by our participants, as compared to randomly extracted, equally long control clips from the same films, we show how the technical and artistic making of the clips was optimized for the display of social interaction and emotional expressions.
The present paper aims to elucidate the conceptual structure of the aesthetics of literature.Following Fechner's "aesthetics from below" (1876) and adopting a method introduced by Jacobsen, Buchta, Kohler, and Schroeger (2004), we asked 1544 German-speaking research participants to list adjectives that they use to label aesthetic dimensions of literature in general and of individual literary forms and genres in particular (novels, short stories, poems, plays, comedies). According to our analyses of frequency, mean list rank, and the Cognitive Salience Index, beautiful and suspenseful rank highest across all target categories. For plays/comedies, funny and sad turned out to be the most relevant terms; for novels and short stories, suspenseful, interesting and romantic; and for poetry romantic, along with the music-related terms harmonious, rhythmic, and melodious. A comparison of our results with analogous studies for visual aesthetics and music yielded a comprehensive map of the distribution of aesthetic appeal dimensions across sensory modalities and aesthetic domains, with poetry and music showing the greatest overlap.
This study explored the organization of the semantic field and the conceptual structure of moving experiences by investigating German-language expressions referring to the emotional state of being moved. We used present and past participles of eight psychological verbs as primes in a free word-association task, as these grammatical forms place their conceptual focus on the eliciting situation and on the felt emotional state, respectively. By applying a taxonomy of basic knowledge types and computing the Cognitive Salience Index, we identified joy and sadness as key emotional ingredients of being moved, and significant life events and art experiences as main elicitors of this emotional state. Metric multidimensional scaling analyses of the semantic field revealed that the core terms designate a cluster of emotional states characterized by low degrees of arousal and slightly positive valence, the latter due to a nearly balanced representation of positive and negative elements in the conceptual structure of being moved.
The emotional power of poetry: neural circuitry, psychophysiology and compositional principles
(2017)
It is a common experience—and well established experimentally—that music can engage us emotionally in a compelling manner. The mechanisms underlying these experiences are receiving increasing scrutiny. However, the extent to which other domains of aesthetic experience can similarly elicit strong emotions is unknown. Using psychophysiology, neuroimaging and behavioral responses, we show that recited poetry can act as a powerful stimulus for eliciting peak emotional responses, including chills and objectively measurable goosebumps that engage the primary reward circuitry. Importantly, while these responses to poetry are largely analogous to those found for music, their neural underpinnings show important differences, specifically with regard to the crucial role of the nucleus accumbens. We also go beyond replicating previous music-related studies by showing that peak aesthetic pleasure can co-occur with physiological markers of negative affect. Finally, the distribution of chills across the trajectory of poems provides insight into compositional principles of poetry.
Der Frankfurter Botaniker Martin Dürer (1842–1921) hinterließ umfangreiche Notizen zur Frankfurter Pflanzenwelt gegen Ende des 19. Jahrhunderts. Diese Daten wurden mit dem heutigen Zustand verglichen, dabei stand der Wandel von 6 Kalkgebieten in Frankfurt im Vordergrund. In allen Gebieten kam es zu einem massiven Artenschwund. Selbst in den Schutzgebieten "Am Berger Hang" und "Berger Warte" sind bis zu 50% der Arten im Laufe der letzten 120 Jahre verschwunden. Der größte Artenschwund hat am Lohrberg stattgefunden. Hier konnten von ehemals 44 Arten nur noch 2 Arten wiedergefunden werden. Hauptgrund für den Artenschwund sind Landnutzungsänderungen. Zum einen wurden einige Gebiete direkt bebaut und in Wohngebiete umgewandelt. Zum anderen änderte sich in den heute unbebauten Gebieten die Bewirtschaftung, etwa von Wein- zu Obstbau oder von Obstbau zu Grünlandnutzung. Von einstigen Kalkmagerrasen am Lerchesberg oder Bornheimer Hang ist heute nichts mehr erhalten. Die schönsten Kalkmagerrasen befinden sich heute in den Schutzgebieten, sind aber weiterhin durch Nährstoffeintrag oder Flächenverlust bedroht.
Die Flechte Cladonia stygia (Fr.) Ruoss wurde anlässlich einer Bestandsaufnahme der Rentierflechten 2009 erstmals aus Hessen gemeldet. Da die Unterscheidung von der ähnlichen C. rangiferina (L.) F. H. Wigg. anhand morphologischer Merkmale oft unsicher ist, wurden molekulargenetische Daten zur Identifizierung der hessischen Belege der Art herangezogen. Phylogenetische Stammbäume auf der Grundlage von sechs mitochondrialen und nuklearen Genloci untermauern die Abgrenzung beider Arten. Nur zwei von sieben gemeldeten hessischen Vorkommen gehören nach diesen Ergebnissen zu C. stygia, die übrigen zu C. rangiferina. Eine gezielte Suche nach C. stygia und eine durch molekulargenetische Daten untermauerte Bestimmung der Belege erscheint notwendig, um den Status der Art in Hessen zuverlässig beurteilen zu können.
Im Jahre 2014 wurde eine umfassende Bestandsaufnahme der hessischen Vorkommen der Sumpf-Platterbse (Lathyrus palustris) durchgeführt. Dabei konnten zahlreiche Vorkommen südlich des Mains nicht mehr bestätigt werden, während die individuen- und flächenmäßig größten Bestände nördlich des Mains in der Wetterau gefunden wurden. Im Vergleich zu allen von früher bekannten Vorkommen ist ein erheblicher Rückgang der Sumpf-Platterbse festzustellen. Für die verbliebenen Bestände werden Vorschläge zur Sicherung und Erhaltung gemacht sowie Anregungen zur Entwicklung gegeben.