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Vom 26. Juli bis 04. August 2015 veranstaltete die Akademie BURG FÜRSTENECK die 5. Hessische Schülerakademie für die Mittelstufe (Jgs. 7-9). Fünf Jahre Schülerakademie für die Mittelstufe – ein halbes Jahrzehnt Erfahrung und Entwicklung eines Projektes mit 12-15jährigen Schülerinnen und Schülern, hessischen Hochschullehrenden und Kulturschaffenden im Kontext von Engagement und überdurchschnittlicher Begabung!
Vom 27. Juli bis 05. August 2014 veranstaltete die Akademie BURG FÜRSTENECK die 4. Hessische Schülerakademie für die Mittelstufe (Jgs. 7-9). Es gibt nichts Schöneres als Ferien! Das dachten sicher auch die 60 zwölf- bis fünfzehnjährigen Schülerinnen und Schüler, die sich in den alten Burgmauern trafen. Allerdings entschieden sie sich nach einer aufwändigen Bewerbung dafür, einen Teil ihrer Sommerferien „ganz anders“ zu verbringen. Neugierig und voller Wissensdurst beschäftigten sich die vielfältig begabten jungen Menschen in den Hauptkursen mit folgenden Themen: Zaubern in der Chemie, geheimnisvollen Botschaften in der Mathematik, der Entdeckung des Lebensraums Baum in Biologie, überraschenden Experimenten in der Physik und den Facetten des Teenageralltags, dargestellt im Kurs Kunst und Kultur.
Vom 13. bis 22. Oktober 2013 veranstaltete die Akademie BURG FÜRSTENECK die 3. Hessische Schülerakademie für die Mittelstufe (Jgs. 7-9). In den alten Burgmauern trafen sich 60 wissensdurstige, neugierige und vielfältig begabte Schülerinnen und Schüler. Die Zwölf- bis Fünfzehnjährigen verbrachten ihre Herbstferien mit kniffligen Mathematikaufgaben zum perspektivischen Zeichnen, dem Bau von Energiesparhäusern und dem Lösen von Kriminalfällen anhand biologischer Spuren. Shakespeare geisterte durch die Burghallen und Gummibärchen wurden chemisch analysiert.
Vom 14. - 23. Oktober 2012 fand in der Hessischen Heimvolkshochschule BURG FÜRSTENECK die zweite Hessische Schülerakademie für die Mittelstufe (Jgs. 7 - 9) statt. 60 leistungsbereite, (hoch-)begabte Schülerinnen und Schüler nahmen während der Herbstferien an Haupt- und Wahlkursen aus Themenbereichen der Naturwissenschaften, Medienwissenschaft sowie Kunst und Kultur teil.
Erstmalig wurde im Jahr 2011 auf BURG FÜRSTENECK eine Hessische Schülerakademie für die Mittelstufe (7-9) durchgeführt. 60 Schülerinnen und Schüler nahmen während der Herbstferien für die Dauer von zehn Tagen an Haupt- und Wahlkursen aus Themenbereichen der Chemie, Biologie, Mathematik, Wirtschaftsethik sowie der Kulturwissenschaften und ästhetischen Bildung teil.
Die Hessische Schülerakademie 2014 stand ganz im Zeichen ihres 10jährigen Bestehens. Seit Gründung der Oberstufenakademie im Jahre 2004 durch Cynthia Hog-Angeloni und Wolfgang Metzler hat sich die "HSAKA" selbstverständlich verändert; das ist bei einem so ambitionierten Projekt auch gar nicht anders denkbar. Die Hessische Schülerakademie hat sich behauptet, indem sie immer wieder neue Impulse aufgenommen und sich beständig um Verbesserung bemüht hat – und sie ist gewachsen.
Bereits das Deckblatt dieser Dokumentation liefert den Hinweis auf eine wichtige personelle Veränderungbei der Hessischen Schülerakademie Oberstufe 2013: Nach neun erfolgreichen Jahren ist Wolfgang Metzler aus der Akademieleitung ausgeschieden. Seine beständige inhaltliche Mitarbeit und sein persönliches Engagement haben es seinem Nachfolger Peter Gorzolla jedoch ungemein erleichtert, sich erfolgreich in die neue Rolle einzufinden.
Die vorliegende Dokumentation der Hessischen Schülerakademie Oberstufe 2012 hat die bewährte Gliederung: Die Berichte über die Kurse entstehen aus Referaten der SchülerInnen, die von Studierenden betreut wurden. In aufsteigender Verantwortung werden sie von den Studierenden, der jeweiligen Kursleitung und der Akademieleitung gegengelesen, so dass ein möglichst fehlerfreies Ergebnis entsteht, welches überdies zur Lektüre einladen möchte. Wir hoffen, dass das auch diesmal gelungen ist.
Wenn Sie diese Dokumentation der Hessischen Schülerakademie Oberstufe 2011 in Händen halten, können wir ein 10-jähriges Jubiläum begehen. Im Jahr 2002 begann nämlich die Vorarbeit mit einem pädagogischen Ferienseminar, welches sich mit notwendigen Schritten nach dem Pisa-Schock und zu Beginn der Einführung neuer Studienstrukturen an den Hochschulen beschäftigte. Nach zwei Jahren intensiver Gespräche und Verabredungen konnte eine erste Hessische Schülerakademie 2004 realisiert werden; und nach weiteren zwei Jahren standen diese Akademien personell und finanziell auf sicheren Beinen. Sie wenden sich an begabte und interessierte SchülerInnen und fördern diese in einem integrierten Konzept aus wissenschaftlichen und musisch-kulturellen Inhalten, welches zugleich einen inhaltlichen Beitrag zu Lehrer- Aus- und Weiterbildung leistet. Alle Förderer betrachten "unsere" Akademien inzwischen als eins ihrer programmatischen "Highlights".
Die Hessischen Schülerakademien unterscheiden sich von manchen anderen Akademien dadurch, dass sie zugleich als Schulpraktika für Lehramtsstudierende durchgeführt werden, ferner, weil von derselben Schule mehrere SchülerInnen teilnehmen dürfen und dies nicht nur jeweils einmal. Dies sichert inhaltliche und persönliche Kontinuität, obwohl wir darauf achten, dass hinreichend viele Neulinge eine Chance zur Teilnahme erhalten. Etwa die Hälfte der SchülerInnen möchte sich nach einer Akademie sofort für die nächste anmelden, und auch unter den Studierenden steigt der Anteil an "Wiederholern", die den Praktikumsschein schon erworben haben. Eine solche Begeisterung ist kein schlechtes Zeichen für eine universitäre Lehrveranstaltung.
Die vorliegende Dokumentation der 4. "Hessischen Schülerakademie - Schulpraktische Veranstaltung für Lehramtsstudierende" L3 hat wiederum eine ähnliche Gliederung wie die vorangegangenen: Hauptteile bilden die Dokumentation der Kursinhalte und Berichte über die kursübergreifenden (musisch - kulturellen) Aktivitäten. Es folgen u.a. exemplarisch Auszüge aus den von Studierenden verfassten Praktikumsberichten, welche auf Grund der neuen Praktikumsordnung jetzt Pflicht sind.
1. Hessische Schülerakademie : schulpraktische Veranstaltung für Lehramtsstudierende : Dokumentation
(2004)
Die Studie untersucht die Frage, ob der Gesetzgeber des ARUG die Ziele erreicht hat, die mit der Reform des Rechts der Anfechtung von HVBeschlüssen verfolgt wurden. Darüber hinaus gehend soll die Entwicklung der Beschlußmängelklagen seit der letzten Studie der Verfasser hierzu nachgezeichnet werden. Unsere Studie zeigt, daß seit Inkrafttreten des ARUG ein deutlicher Rückgang der Beschlußmängelklagen und Freigabeverfahren zu verzeichnen ist. Dagegen ist der Anteil der von „Berufsklägern“ erhobenen Klagen und Nebeninterventionen gleich geblieben, wobei sich die Anzahl der Personen in der Gruppe der „Berufskläger“ nochmals vergrößert hat. Das ARUG hat insoweit keine erkennbare Wirkung gehabt...
Five books I liked in 2015
(2016)
Here are five books I read in 2015 that I particularly liked. Expect an eclectic mix of fiction and non-fiction, and not necessarily social-sciency. Although I tend to pick those books that end up having some social science-stuff / politics in them without explicitly looking for it. That, and books about spaceships...
Constitutionalization beyond the nation state can be observed as an evolutionary process that leads in two quite different directions: (1) constitutions evolve in transnational political processes outside the nation state; (2) simulta-neously, constitutions evolve outside international politics in global society’s ‘private’ sectors. What, however, is the specifically societal element in societal constitutionalism? This is currently the object of a controversy regarding the subjects of non-state constitutions, their origin, their legitimization, their scope, and their internal structures. This article interprets the controversy as a theme with a number of variations. What is the distinctive ‘compositional principle’ in each particular variation? Which problems become evident in its ‘development’? What are its most valuable ‘motifs’? The article starts with David Sciulli’s theme of societal constitutionalism. Then it presents six variations on Sciulli. In a first group, constitutionalization is perceived as the expansion of a single rationality into all spheres of society. In a second group, the motif of the unity of the consti-tution can still be heard, despite the essential pluralism of societal constitution-alism. In the final movement, three further variations will then reprise and devel-op further the most important motifs, in a resumption of the original theme.
p-process nucleosynthesis via proton-capture reactions in thermonuclear supernovae explosions
(2015)
Model calculations within the framework of the so-called γ process show an underproduction of the p nucleus with the highest isotopic abundace 92Mo. This discrepancy can be narrowed by taking into account the alternative production site of a type Ia supernova explosion. Here, the nucleus 92Mo can be produced by a sequence of proton-capture reactions. The amount of 92Mo nuclei produced via this reaction chain is most sensitive to the reactions 90Zr(p,γ) and 91Nb(p,γ). Both rates have to be investigated experimentally to study the impact of this nucleosynthesis aspect on the long-standing 92Mo-problem. We have already measured the proton-capture reaction on 90Zr using high-resolution in-beam γ-ray spectroscopy. In this contribution, we will present our preliminary results of the total cross sections as well as the partial cross sections. Furthermore, we plan to measure the 91Nb(p,γ) reaction soon. Due to the radioactive target material, the 91Nb nuclei have to be produced prior to the experiment. The current status of this production will be presented in this contribution.
Massive Open Online Courses
(2013)
Im englischsprachigen Raum verbreitete sich in den letzten Jahren ein Bildungsformat, die so genannten Massive Open Online Courses (MOOCs). So bezeichnete die New York Times beispielsweise das Jahr 2012 als „Das Jahr der MOOCs“ (Pappano 2012). Inzwischen hält das Format der offenen Online-Kurse mit großen Teilnehmerzahlen auch in Deutschland Einzug, wie verschiedene Presseartikel zum Jahresende 2012 zeigten (vgl. Dworschak 2013; Koller 2012; Mehnert 2012; Noack 2012a, 2012b). Ziel dieses Beitrags ist es, neben einer Begriffsklärung zu dem Phänomen einen Überblick über aktuelle Entwicklungen zu geben und die Erfahrungen mit zwei deutschsprachigen MOOCs zu dokumentieren.
Die Volkshochschulen sind der größte Bildungsanbieter in Deutschland. 2013 startete eine VHS-Initiative den vhsMOOC: eine offene Online-Veranstaltung zum Thema selbstbestimmtes Weblernen. Auf mehreren Plattformen wie Google+, Facebook und Twitter wurde gleichzeitig gepostet und kommentiert, auf YouTube entstanden 48 Videos zum vhsMOOC, in denen sich VHS-Mitarbeiterinnen und Mitarbeiter über Weblernen, neue Lehr- und Lernformate, unterstützende Tools und die Entwicklung der Volkshochschulen äußern. Der Band fasst den Verlauf, die Argumente und die Ergebnisse der achtwöchigen Online-Lehrveranstaltung zusammen. Passend zum offenen Format des vhsMOOC sind die Inhalte des Bandes auch auf wbv Open Access verfügbar.
Der vorliegende Artikel befasst sich mit der Rolle sogenannter „Massive Open Online Courses“ (MOOCs). Er diskutiert einerseits das Verhältnis von MOOCs zwischen dem ursprünglichen Anspruch auf Bildungsfreiheit als kostenlosem Freiheitsrecht, das andererseits kontrastiert wird durch die Konzeption von MOOCs als Konsumgut, das über die Nachfrage von Nutzern zu einem Marktpreis findet. Das fulminante Interesse, auf das solche MOOCs weltweit bei Bildungs- und Weiterbildungs-Interessenten stößt, ist eine Herausforderung für die Hochschulen – vor allem, wenn ihre Betreiber Unternehmer mit renditeträchtigem Geschäftsmodell sind.
Von April bis Juli 2012 fand der sogenannte OPCO12 statt, der offene (open) Online Course 2012. Inhaltlich befasste sich dieser MOOC (Massive Open Online Course) mit „Trends im E-Teaching“. Zum Zeitpunkt der Planung des OPCO12 stand das MOOC-Format im deutschsprachigen Kontext noch ganz am Anfang und dadurch im Erprobungs- und Experimentierstadium, was auch Einfluss auf die Themenwahl hatte: Um eine gewisse Teilnehmerzahl zu sichern und die Bekanntmachung des Kurses bei medienaffinen Teilnehmenden zu erleichtern, wurde – ähnlich wie in der Anfangsphase von MOOCs im nordamerikanischen Raum – für den OPCO12 ein eher selbstreferenzielles Thema gewählt, d.h. der Kurs behandelte die Themen Medien und Bildung. Im vorliegenden Beitrag befassen sich die Autorinnen vor allem mit der Frage, welche Schlussfolgerungen aus den Erfahrungen mit dem OPCO12 gezogen werden können. Nach einer Einordnung des Kurses in die (deutschsprachige) MOOC-Landschaft (Abschnitt 1) und einer Darstellung der zugrunde liegenden konzeptionellen Überlegungen (Abschnitt 2) werden ausgewählte Evaluationsergebnisse vorgestellt, darunter auch motivationale Faktoren (Abschnitt 3). Der Beitrag schließt mit einem perspektivischen Fazit (Abschnitt 4).
„Wir sind im Krieg mit Russland.“ Diese gleichermaßen lakonische wie wuchtige Bewertung des Journalisten Jan-Philipp Hein lässt den Leser unwillkürlich zusammenzucken, klingt sie doch wie ein aus der Zeit gefallenes Zitat einer längst überwundenen Ost-West-Konfrontation. Zudem erscheint sie verstörend irreal, da die sich in den Vordergrund drängenden aktuellen sicherheitspolitischen Herausforderungen wie islamistischer Terrorismus, anhaltend große (und vielfach unkontrollierte) Flüchtlingsströme und eng damit verknüpft ein Erstarken rechtsextremistischer Kräfte in den vergangenen Monaten die gesamte Aufmerksamkeit zu absorbieren schienen...
Triangles of groups have been introduced by Gersten and Stallings. They are, roughly speaking, a generalization of the amalgamated free product of two groups and occur in the framework of Corson diagrams. First, we prove an intersection theorem for Corson diagrams. Then, we focus on triangles of groups. It has been shown by Howie and Kopteva that the colimit of a hyperbolic triangle of groups contains a non-abelian free subgroup. We give two natural conditions, each of which ensures that the colimit of a non-spherical triangle of groups either contains a non-abelian free subgroup or is virtually solvable.
After the mass-vaccination campaign during the influenza A (H1N1) 2009 pandemic, a significant increase in narcolepsy incidence was observed initially in Scandinavia, later in other European countries and recently also in Canada. Narcolepsy is a sleep disease caused by the loss of hypocretin-producing cells in the hypothalamus. Almost all narcolepsy patients carry the HLA-DQB1*0602 allele, giving a link to an autoimmune-mediated process.
Most of the observed narcolepsy cases were correlated to the vaccination with Pandemrix, the most frequently used vaccine in the EU, and a slight connection to Arepanrix was also detected, which was distributed in Canada. Both vaccines were adjuvanted with AS03, suggesting a possible link between AS03 and narcolepsy. No narcolepsy cases were detected with MF59-adjuvanted or non-adjuvanted influenza vaccines. Recent studies reported differences between Pandemrix and Arepanrix and suggested the vaccine rather than the adjuvant as a suspect for narcolepsy development following vaccination. In addition, in China an increase of narcolepsy cases was reported to occur in absence of vaccination. Possible factors and potential additive effects that may have triggered narcolepsy after the pandemic vaccination are being reviewed in this paper.
Fossils are often anatomically and functionally compared to extant model taxa such as Pan, Gorilla, Pongo and modern Homo sapiens to put the respective fossils into the (taxonomical) context of human evolution. Therefore, knowledge of extant hominid anatomy is necessary as well as knowledge of which traits differ between sexes, populations, (sub-)species and taxa, and whether these differences are pronounced enough to separate respective groups. Dental and mandibular structures have been of particular interest in many paleoanthropological studies, simply due to the fact that these morphological structures are most abundant in the human fossil record.
Various studies have addressed questions regarding taxonomy, variation and sexual dimorphism of hominid taxa with regard to dental and mandibular size. Tooth size, however, has almost exclusively referred to crown size, with little focus on root size. The focus on tooth crowns is partly due to roots being embedded in mandibular bone which makes access difficult. With the help of micro-computed tomography (μCT) it is now possible to render virtual 3D models of dental roots and measure these models without harming the original specimens. In addition, measurements are much more precise using μCT data than previous techniques such as 2D x-rays. The present study used 3D models of 231 (first, second and third) molars and 80 mandibles of 53 Pan troglodytes verus (consisting of individuals form the Tai and Liberia populations), 14 Gorilla sp. and 13 Pongo sp. individuals to investigate molar and mandibular sizes within, and between, taxa and populations with regard to sexual dimorphism, variability and taxonomical value. Molar root size was assessed by applying 7 measurements to each molar. Mandibular size was investigated using three different measurements: overall mandibular size, mandibular robusticity (at each molar position) and 15 linear measurements. Overall mandibular size and root measurements were used to investigate the dental and mandibular size relationship. Furthermore, based on data acquired from great apes, how well fossil mandibles (including their dentition) of Australopithecus africanus, Paranthropus sp. and Homo sp. match one or multiple extant hominid taxa was examined Overall, molar root and mandibular metrics are suitable to differentiate between sexes, populations and taxa. Investigation of 40 (21 molar and 19 mandibular) different measure ments resulted in five common characteristics among Pan, Gorilla and Pongo only: firstly, molar root size sequence in root volume and root surface area (M3 < M1 < M2). Secondly, M2 as the molar with the largest cervical area, root volume, root surface area and mesial root lengths and thirdly, mandibular robusticity is larger in females than in males, yet the difference is not signifficant. Fourthly, mandibular length and premolar width are sexually dimorphic and fifthly, the best factors to discriminate between taxa are bicondyle width and molar root length. There is no generalized answer to the question which molar and/or measurement (dental or mandibular) is best to discriminate between sex or taxa in extant hominids. Moreover, size relationships differ among taxa, depending on the measurement. The overall trend, however, is that Pan is the taxa with the smallest, and Gorilla the largest, mean values. Among Pan populations, Liberian chimpanzees tend to have larger average values compared to Tai chimpanzees, with the exception of mandibular robusticity. The highest percentage of sexual dimorphic measurements is found in Pongo, yet only half of the measurements are statistically different between sexes. African apes are less sexually dimorphic compared to Pongo, and surprisingly, Gorilla is only slightly more dimorphic than Pan. The study also shows that statements and conclusions relating to \mandibular size" should not be generalized: whereas male and female Pongo do not differ significantly in overall mandibular size, they do differ in linear mandibular measurements. Moreover, Gorilla has the overall largest mandible, yet robusticity is higher in Pan, as are some linear measurements. Sexual dimorphism in overall mandibular size does not seem to reflect body mass dimorphism, whereas mandibular size appears to be related to body mass. The same was previously proposed for mandibular robusticity, yet Pan, the smallest taxa, has the most robust mandibular corpus (> Gorilla > Pongo). A substantial amount of molar measurements that positively correlate with (overall) mandibular size was found, but in African apes only. This contrasts with former studies which found no, or weak, correlations between dental and mandibular sizes. Given that the percentage of correlation is highest in Pan, and not present in Pongo, it is proposed that small jaws feature small teeth, rather than large jaws feature large teeth. This proposition assumes a size-threshold from which, when reached, dental and mandibular sizes no longer correlate, as has been previously proposed for the relationship between canine size and mandibular breadth. This assumption is further supported by the fact that the smaller and more robust Tai population shows more significant correlation compared to the less robust and larger Liberia population. Results show that fossil metrics are similar to one or multiple extant hominid taxa, depending on the measurement (dental or mandibular) used for comparison. Subsequently, the assignment to a specific sex depends on the earlier selected extant model taxa. Therefore the study questions whether choosing one model taxa for one fossil, or taxonomical group, is advisable. This study is the first to extensively investigate molar root size in extant hominids and to broadly describe differences in molar root sizes among and between taxa and therefore provides a solid database for future studies. The same applies to mandibular robusticity which has not been investigated as systematically or to such a great extent as in this work. The study specifically shows how complex the search for taxa or sex differentiating molar root and/or mandibular measurements is. Subsequently it shows that generalizations in relation to taxonomical values and statements about sexual dimorphism can be misleading.
In addition, the study contributes to the understanding of intra- and inter-population differences within Pan torglodytes verus. Furthermore, it could be demonstrated that results of a subspecies sample very likely depend on the sample composition, i.e. whether the sample consists of individuals from one or more populations. This study serves as a database for further studies investigating molar root sizes in great apes, whether these studies are investigating various relationships between taxa, population or sex, or as database to investigate functional adaptations or to examine mandibular robusticity and molar root relationships.
Biomedical data obtained during cell experiments, laboratory animal research, or human studies often display a complex distribution. Statistical identification of subgroups in research data poses an analytical challenge. Here were introduce an interactive R-based bioinformatics tool, called “AdaptGauss”. It enables a valid identification of a biologically-meaningful multimodal structure in the data by fitting a Gaussian mixture model (GMM) to the data. The interface allows a supervised selection of the number of subgroups. This enables the expectation maximization (EM) algorithm to adapt more complex GMM than usually observed with a noninteractive approach. Interactively fitting a GMM to heat pain threshold data acquired from human volunteers revealed a distribution pattern with four Gaussian modes located at temperatures of 32.3, 37.2, 41.4, and 45.4 °C. Noninteractive fitting was unable to identify a meaningful data structure. Obtained results are compatible with known activity temperatures of different TRP ion channels suggesting the mechanistic contribution of different heat sensors to the perception of thermal pain. Thus, sophisticated analysis of the modal structure of biomedical data provides a basis for the mechanistic interpretation of the observations. As it may reflect the involvement of different TRP thermosensory ion channels, the analysis provides a starting point for hypothesis-driven laboratory experiments.
Non-neuronal acetylcholine plays a substantial role in the human skin by influencing adhesion, migration, proliferation and differentiation of keratinocytes. These processes are regulated by the Mitogen-Activated Protein (MAP) kinase cascade. Here we show that in HaCaT keratinocytes all five muscarinic receptor subtypes are expressed, but M1 and M3 are the subtypes involved in mitogenic signaling. Stimulation with the cholinergic agonist carbachol leads to activation of the MAP kinase extracellular signal regulated kinase, together with the protein kinase Akt. The activation is fully dependent on the transactivation of the epidermal growth factor receptor (EGFR), which even appears to be the sole pathway for the muscarinic receptors to facilitate MAP kinase activation in HaCaT cells. The transactivation pathway involves a triple-membrane-passing process, based on activation of matrix metalloproteases, and extracellular ligand release; whereas phosphatidylinositol 3-kinase, Src family kinases or protein kinase C do not appear to be involved in MAP kinase activation. Furthermore, phosphorylation, ubiquitination and endocytosis of the EGF receptor after cholinergic transactivation are different from that induced by a direct stimulation with EGF, suggesting that ligands other than EGF itself mediate the cholinergic transactivation.
Schätzwerte mittelfristiger Gleichgewichtszinsen mit der Methode nach Laubach und Williams (2003) werden inzwischen vielfach in der Diskussion um die Geld- und Fiskalpolitik zitiert. Unter anderem wurden sie von Summers (2014a) als Evidenz für eine säkulare Stagnation angeführt und von Yellen (2015) zur Rechtfertigung der Nullzinspolitik verwendet. In diesem Papier nehmen wir eine umfangreiche Untersuchung und Sensitivitätsanalyse dieser Schätzwerte für die Vereinigten Staaten, Deutschland und den Euro-Raum vor. Aufgrund der hohen Unsicherheit und Sensitivität, die mit den Schätzwerten mittelfristiger Gleichgewichtszinsen mit der Laubach-Williams-Methode und ähnlichen Ansätzen verbunden ist, sollten diese Schätzungen nicht den Ausschlag für entscheidende Weichenstellungen in der Geld- und Fiskalpolitik geben.
The increasing number of casting shows and talent contests in the media over the past years suggests a public interest in rating the quality of vocal performances. In many of these formats, laymen alongside music experts act as judges. Whereas experts' judgments are considered objective and reliable when it comes to evaluating singing voice, little is known about laymen's ability to evaluate peers. On the one hand, layman listeners–who by definition did not have any formal training or regular musical practice–are known to have internalized the musical rules on which singing accuracy is based. On the other hand, layman listeners' judgment of their own vocal skills is highly inaccurate. Also, when compared with that of music experts, their level of competence in pitch perception has proven limited. The present study investigates laypersons' ability to objectively evaluate melodies performed by untrained singers. For this purpose, laymen listeners were asked to judge sung melodies. The results were compared with those of music experts who had performed the same task in a previous study. Interestingly, the findings show a high objectivity and reliability in layman listeners. Whereas both the laymen's and experts' definition of pitch accuracy overlap, differences regarding the musical criteria employed in the rating task were evident. The findings suggest that the effect of expertise is circumscribed and limited and supports the view that laypersons make trustworthy judges when evaluating the pitch accuracy of untrained singers.
It is now accepted that heart failure (HF) is a complex multifunctional disease rather than simply a hemodynamic dysfunction. Despite its complexity, stressed cardiomyocytes often follow conserved patterns of structural remodelling in order to adapt, survive, and regenerate. When cardiac adaptations cannot cope with mechanical, ischemic, and metabolic loads efficiently or become chronically activated, as, for example, after infection, then the ongoing structural remodelling and dedifferentiation often lead to compromised pump function and patient death. It is, therefore, of major importance to understand key events in the progression from a compensatory left ventricular (LV) systolic dysfunction to a decompensatory LV systolic dysfunction and HF. To achieve this, various animal models in combination with an “omics” toolbox can be used. These approaches will ultimately lead to the identification of an arsenal of biomarkers and therapeutic targets which have the potential to shape the medicine of the future.
The Sonic Hedgehog (SHH) pathway plays a central role in the developing mammalian CNS. In our study, we aimed to investigate the spatiotemporal SHH pathway expression pattern in human fetal brains. We analyzed 22 normal fetal brains for Shh, Patched, Smoothened, and Gli1-3 expression by immunohistochemistry. In the telencephalon, strongest expression of Shh, Smoothened, and Gli2 was found in the cortical plate (CP) and ventricular zone. Patched was strongly upregulated in the ventricular zone and Gli1 in the CP. In the cerebellum, SHH pathway members were strongly expressed in the external granular layer (EGL). SHH pathway members significantly decreased over time in the ventricular and subventricular zone and in the cerebellar EGL, while increasing levels were found in more superficial telencephalic layers. Our findings show that SHH pathway members are strongly expressed in areas important for proliferation and differentiation and indicate a temporal expression gradient in telencephalic and cerebellar layers probably due to decreased proliferation of progenitor cells and increased differentiation. Our data about the spatiotemporal expression of SHH pathway members in the developing human brain serves as a base for the understanding of both normal and pathological CNS development.
Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis and, despite the larger estimated heritability for PsA, the majority of genetic susceptibility loci identified to date are shared with psoriasis. Here, we present results from a case-control association study on 1,962 PsA patients and 8,923 controls using the Immunochip genotyping array. We identify eight loci passing genome-wide significance, secondary independent effects at three loci and a distinct PsA-specific variant at the IL23R locus. We report two novel loci and evidence of a novel PsA-specific association at chromosome 5q31. Imputation of classical HLA alleles, amino acids and SNPs across the MHC region highlights three independent associations to class I genes. Finally, we find an enrichment of associated variants to markers of open chromatin in CD8(+) memory primary T cells. This study identifies key insights into the genetics of PsA that could begin to explain fundamental differences between psoriasis and PsA.
Objective: To evaluate two ultrafast cone-beam CT (UF-CBCT) imaging protocols with different acquisition and injection parameters regarding image quality and required contrast media during image-guided hepatic transarterial chemoembolization (TACE).
Methods: In 80 patients (male: 46, female: 34; mean age: 56.8 years; range: 33–83) UF-CBCT was performed during TACE for intraprocedural guidance. Imaging was performed using two ultrafast CBCT acquisition protocols with different acquisition and injection parameters (imaging protocol 1: acquisition time 2.54 s, and contrast 6 mL with 3 s delay; imaging protocol 2: acquisition time 2.72 s, and contrast 7 mL with 6 s delay). Image evaluation was performed with both qualitative and quantitative methods. Contrast injection volume and dose parameters were compared using values from the literature.
Results: Imaging protocol 2 provided significantly better (P < 0.05) image quality than protocol 1 at the cost of slightly higher contrast load and patient dose. Imaging protocol 1 provided good contrast perfusion but it mostly failed to delineate the tumors (P < 0.05). On the contrary, imaging protocol 2 showed excellent enhancement of hepatic parenchyma, tumor, and feeding vessels.
Conclusion: Tumor delineation, visualization of hepatic parenchyma, and feeding vessels are clearly possible using imaging protocol 2 with ultrafast CBCT imaging. A reduction of required contrast volume and patient dose were achieved due to the ultrafast CBCT imaging.
Animal experiments report contradictory findings on the presence of a behavioural and neuronal anisotropy exhibited in vertical and horizontal capabilities of spatial orientation and navigation. We performed a pointing experiment in humans on the imagined 3-D direction of the location of various invisible goals that were distributed horizontally and vertically in a familiar multilevel hospital building. The 21 participants were employees who had worked for years in this building. The hypothesis was that comparison of the experimentally determined directions and the true directions would reveal systematic inaccuracy or dimensional anisotropy of the localizations. The study provides first evidence that the internal representation of a familiar multilevel building was distorted compared to the dimensions of the true building: vertically 215% taller and horizontally 51% shorter. This was not only demonstrated in the mathematical reconstruction of the mental model based on the analysis of the pointing experiments but also by the participants’ drawings of the front view and the ground plan of the building. Thus, in the mental model both planes were altered in different directions: compressed for the horizontal floor plane and stretched for the vertical column plane. This could be related to human anisotropic behavioural performance of horizontal and vertical navigation in such buildings.
Abstract: Fine-scale temporal organization of cortical activity in the gamma range (∼25–80Hz) may play a significant role in information processing, for example by neural grouping ('binding') and phase coding. Recent experimental studies have shown that the precise frequency of gamma oscillations varies with input drive (e.g. visual contrast) and that it can differ among nearby cortical locations. This has challenged theories assuming widespread gamma synchronization at a fixed common frequency. In the present study, we investigated which principles govern gamma synchronization in the presence of input-dependent frequency modulations and whether they are detrimental for meaningful input-dependent gamma-mediated temporal organization. To this aim, we constructed a biophysically realistic excitatory-inhibitory network able to express different oscillation frequencies at nearby spatial locations. Similarly to cortical networks, the model was topographically organized with spatially local connectivity and spatially-varying input drive. We analyzed gamma synchronization with respect to phase-locking, phase-relations and frequency differences, and quantified the stimulus-related information represented by gamma phase and frequency. By stepwise simplification of our models, we found that the gamma-mediated temporal organization could be reduced to basic synchronization principles of weakly coupled oscillators, where input drive determines the intrinsic (natural) frequency of oscillators. The gamma phase-locking, the precise phase relation and the emergent (measurable) frequencies were determined by two principal factors: the detuning (intrinsic frequency difference, i.e. local input difference) and the coupling strength. In addition to frequency coding, gamma phase contained complementary stimulus information. Crucially, the phase code reflected input differences, but not the absolute input level. This property of relative input-to-phase conversion, contrasting with latency codes or slower oscillation phase codes, may resolve conflicting experimental observations on gamma phase coding. Our modeling results offer clear testable experimental predictions. We conclude that input-dependency of gamma frequencies could be essential rather than detrimental for meaningful gamma-mediated temporal organization of cortical activity.
Author Summary: Almost 350 years ago the physicist and polymath Christiaan Huygens first observed the synchronization between two pendulum clocks attached to a common support. Since then synchronization has been recognized as a universal phenomenon from astronomy to biology. The phase-locking (synchrony) and the phase-relation between the two pendulums are determined by two principal forces: the synchronization force exerted over the connection and the tendency to desynchronize due to frequency (speed) differences. We propose that gamma synchronization (25–80Hz) among oscillating cortical neurons in the brain can be understood according to the same principles—like a field of many connected pendula—with the critical addition that input changes the frequency of gamma oscillations, as shown by recent experimental studies. It has been assumed that input-dependent changes in oscillation frequency are detrimental for a meaningful role of gamma synchronization in neural processing. To the contrary, our theoretical analysis demonstrates that because input can change the frequency of the oscillation, phase-locking and phase-relations among neurons relate systematically to input. By analogy, it is because a local push to a pendulum will change its frequency, that resulting changes in phase-locking and phase-relation among the pendula can be used to derive the external force applied.
In vivo long-term monitoring of circulating tumor cells fluctuation during medical interventions
(2015)
The goal of this research was to study the long-term impact of medical interventions on circulating tumor cell (CTC) dynamics. We have explored whether tumor compression, punch biopsy or tumor resection cause dissemination of CTCs into peripheral blood circulation using in vivo fluorescent flow cytometry and breast cancer-bearing mouse model inoculated with MDA-MB-231-Luc2-GFP cells in the mammary gland. Two weeks after tumor inoculation, three groups of mice were the subject of the following interventions: (1) tumor compression for 15 minutes using 400 g weight to approximate the pressure during mammography; (2) punch biopsy; or (3) surgery. The CTC dynamics were determined before, during and six weeks after these interventions. An additional group of tumor-bearing mice was used as control and did not receive an intervention. The CTC dynamics in all mice were monitored weekly for eight weeks after tumor inoculation. We determined that tumor compression did not significantly affect CTC dynamics, either during the procedure itself (P = 0.28), or during the 6-week follow-up. In the punch biopsy group, we observed a significant increase in CTC immediately after the biopsy (P = 0.02), and the rate stayed elevated up to six weeks after the procedure in comparison to the tumor control group. The CTCs in the group of mice that received a tumor resection disappeared immediately after the surgery (P = 0.03). However, CTC recurrence in small numbers was detected during six weeks after the surgery. In the future, to prevent these side effects of medical interventions, the defined dynamics of intervention-induced CTCs may be used as a basis for initiation of aggressive anti-CTC therapy at time-points of increasing CTC number.
Network graphs have become a popular tool to represent complex systems composed of many interacting subunits; especially in neuroscience, network graphs are increasingly used to represent and analyze functional interactions between multiple neural sources. Interactions are often reconstructed using pairwise bivariate analyses, overlooking the multivariate nature of interactions: it is neglected that investigating the effect of one source on a target necessitates to take all other sources as potential nuisance variables into account; also combinations of sources may act jointly on a given target. Bivariate analyses produce networks that may contain spurious interactions, which reduce the interpretability of the network and its graph metrics. A truly multivariate reconstruction, however, is computationally intractable because of the combinatorial explosion in the number of potential interactions. Thus, we have to resort to approximative methods to handle the intractability of multivariate interaction reconstruction, and thereby enable the use of networks in neuroscience. Here, we suggest such an approximative approach in the form of an algorithm that extends fast bivariate interaction reconstruction by identifying potentially spurious interactions post-hoc: the algorithm uses interaction delays reconstructed for directed bivariate interactions to tag potentially spurious edges on the basis of their timing signatures in the context of the surrounding network. Such tagged interactions may then be pruned, which produces a statistically conservative network approximation that is guaranteed to contain non-spurious interactions only. We describe the algorithm and present a reference implementation in MATLAB to test the algorithm’s performance on simulated networks as well as networks derived from magnetoencephalographic data. We discuss the algorithm in relation to other approximative multivariate methods and highlight suitable application scenarios. Our approach is a tractable and data-efficient way of reconstructing approximative networks of multivariate interactions. It is preferable if available data are limited or if fully multivariate approaches are computationally infeasible.
The bug Gyaclavator kohlsi Wappler, Guilbert, Wedmann et Labandeira, gen. et sp. nov., represents a new extinct genus of lace bugs (Insecta: Heteroptera: Tingidae) occurring in latest early Eocene deposits of the Green River Formation, from the southern Piceance Basin of Northwestern Colorado, in North America. Gyaclavator can be placed within the Tingidae with certainty, perhaps it is sistergroup to Cantacaderinae. If it belongs to Cantacaderinae, it is the first fossil record of this group for North America. Gyaclavator has unique, conspicuous antennae bearing a specialized, highly dilated distiflagellomere, likely important for intra- or intersex reproductive competition and attraction. This character parallels similar antennae in leaf-footed bugs (Coreidae), and probably is associated with a behavioral convergence as well.
At the sensor level many aspects, such as spectral power, functional and effective connectivity as well as relative-power-ratio ratio (RPR) and spatial resolution have been comprehensively investigated through both electroencephalography (EEG) and magnetoencephalography (MEG). Despite this, differences between both modalities have not yet been systematically studied by direct comparison. It remains an open question as to whether the integration of EEG and MEG data would improve the information obtained from the above mentioned parameters. Here, EEG (64-channel system) and MEG (275 sensor system) were recorded simultaneously in conditions with eyes open (EO) and eyes closed (EC) in 29 healthy adults. Spectral power, functional and effective connectivity, RPR, and spatial resolution were analyzed at five different frequency bands (delta, theta, alpha, beta and gamma). Networks of functional and effective connectivity were described using a spatial filter approach called the dynamic imaging of coherent sources (DICS) followed by the renormalized partial directed coherence (RPDC). Absolute mean power at the sensor level was significantly higher in EEG than in MEG data in both EO and EC conditions. At the source level, there was a trend towards a better performance of the combined EEG+MEG analysis compared with separate EEG or MEG analyses for the source mean power, functional correlation, effective connectivity for both EO and EC. The network of coherent sources and the spatial resolution were similar for both the EEG and MEG data if they were analyzed separately. Results indicate that the combined approach has several advantages over the separate analyses of both EEG and MEG. Moreover, by a direct comparison of EEG and MEG, EEG was characterized by significantly higher values in all measured parameters in both sensor and source level. All the above conclusions are specific to the resting state task and the specific analysis used in this study to have general conclusion multi-center studies would be helpful.
Adult neurogenesis is frequently studied in the mouse hippocampus. We examined the morphological development of adult-born, immature granule cells in the suprapyramidal blade of the septal dentate gyrus over the period of 7–77 days after mitosis with BrdU-labeling in 6-weeks-old male Thy1-GFP mice. As Thy1-GFP expression was restricted to maturated granule cells, it was combined with doublecortin-immunolabeling of immature granule cells. We developed a novel classification system that is easily applicable and enables objective and direct categorization of newborn granule cells based on the degree of dendritic development in relation to the layer specificity of the dentate gyrus. The structural development of adult-generated granule cells was correlated with age, albeit with notable differences in the time course of development between individual cells. In addition, the size of the nucleus, immunolabeled with the granule cell specific marker Prospero-related homeobox 1 gene, was a stable indicator of the degree of a cell's structural maturation and could be used as a straightforward parameter of granule cell development. Therefore, further studies could employ our doublecortin-staging system and nuclear size measurement to perform investigations of morphological development in combination with functional studies of adult-born granule cells. Furthermore, the Thy1-GFP transgenic mouse model can be used as an additional investigation tool because the reporter gene labels granule cells that are 4 weeks or older, while very young cells could be visualized through the immature marker doublecortin. This will enable comparison studies regarding the structure and function between young immature and older matured granule cells.
Background: From 2008–2013, the European indication for panitumumab required that patients' tumor KRAS exon 2 mutation status was known prior to starting treatment. To evaluate physician awareness of panitumumab prescribing information and how physicians prescribe panitumumab in patients with metastatic colorectal cancer (mCRC), two European multi-country, cross-sectional, observational studies were initiated in 2012: a physician survey and a medical records review. The first two out of three planned rounds for each study are reported.
Methods: The primary objective in the physician survey was to estimate the prevalence of KRAS testing, and in the medical records review, it was to evaluate the effect of test results on patterns of panitumumab use. The medical records review study also included a pathologists' survey.
Results: In the physician survey, nearly all oncologists (299/301) were aware of the correct panitumumab indication and the need to test patients' tumor KRAS status before treatment with panitumumab. Nearly all oncologists (283/301) had in the past 6 months of clinical practice administered panitumumab correctly to mCRC patients with wild-type KRAS status. In the medical records review, 97.5% of participating oncologists (77/79) conducted a KRAS test for all of their patients prior to prescribing panitumumab. Four patients (1.3%) did not have tumor KRAS mutation status tested prior to starting panitumumab treatment. Approximately one-quarter of patients (85/306) were treated with panitumumab and concurrent oxaliplatin-containing chemotherapy; of these, 83/85 had confirmed wild-type KRAS status prior to starting panitumumab treatment. All 56 referred laboratories that participated used a Conformité Européenne-marked or otherwise validated KRAS detection method, and nearly all (55/56) participated in a quality assurance scheme.
Conclusions: There was a high level of knowledge amongst oncologists around panitumumab prescribing information and the need to test and confirm patients' tumors as being wild-type KRAS prior to treatment with panitumumab, with or without concurrent oxaliplatin-containing therapy.
Synaptic vesicles (SVs) undergo a cycle of biogenesis and membrane fusion to release transmitter, followed by recycling. How exocytosis and endocytosis are coupled is intensively investigated. We describe an all-optical method for identification of neurotransmission genes that can directly distinguish SV recycling factors in C. elegans, by motoneuron photostimulation and muscular RCaMP Ca2+ imaging. We verified our approach on mutants affecting synaptic transmission. Mutation of genes affecting SV recycling (unc-26 synaptojanin, unc-41 stonin, unc-57 endophilin, itsn-1 intersectin, snt-1 synaptotagmin) showed a distinct ‘signature’ of muscle Ca2+ dynamics, induced by cholinergic motoneuron photostimulation, i.e. faster rise, and earlier decrease of the signal, reflecting increased synaptic fatigue during ongoing photostimulation. To facilitate high throughput, we measured (3–5 times) ~1000 nematodes for each gene. We explored if this method enables RNAi screening for SV recycling genes. Previous screens for synaptic function genes, based on behavioral or pharmacological assays, allowed no distinction of the stage of the SV cycle in which a protein might act. We generated a strain enabling RNAi specifically only in cholinergic neurons, thus resulting in healthier animals and avoiding lethal phenotypes resulting from knockdown elsewhere. RNAi of control genes resulted in Ca2+ measurements that were consistent with results obtained in the respective genomic mutants, albeit to a weaker extent in most cases, and could further be confirmed by opto-electrophysiological measurements for mutants of some of the genes, including synaptojanin. We screened 95 genes that were previously implicated in cholinergic transmission, and several controls. We identified genes that clustered together with known SV recycling genes, exhibiting a similar signature of their Ca2+ dynamics. Five of these genes (C27B7.7, erp-1, inx-8, inx-10, spp-10) were further assessed in respective genomic mutants; however, while all showed electrophysiological phenotypes indicative of reduced cholinergic transmission, no obvious SV recycling phenotypes could be uncovered for these genes.
An individual's choices are shaped by its experience, a fundamental property of behavior important to understanding complex processes. Learning and memory are observed across many taxa and can drive behaviors, including foraging behavior. To explore the conditions under which memory provides an advantage, we present a continuous-space, continuous-time model of animal movement that incorporates learning and memory. Using simulation models, we evaluate the benefit memory provides across several types of landscapes with variable-quality resources and compare the memory model within a nested hierarchy of simpler models (behavioral switching and random walk). We find that memory almost always leads to improved foraging success, but that this effect is most marked in landscapes containing sparse, contiguous patches of high-value resources that regenerate relatively fast and are located in an otherwise devoid landscape. In these cases, there is a large payoff for finding a resource patch, due to size, value, or locational difficulty. While memory-informed search is difficult to differentiate from other factors using solely movement data, our results suggest that disproportionate spatial use of higher value areas, higher consumption rates, and consumption variability all point to memory influencing the movement direction of animals in certain ecosystems.
Magnetic resonance imaging (MRI) provides non-invasive, repetitive measures in the same individual, allowing the study of a physio-pathological event over time. In this study, we tested the performance of 7 Tesla multi-parametric MRI to monitor the dynamic changes of mouse skeletal muscle injury and regeneration upon acute ischemia induced by femoral artery dissection. T2-mapping (T2 relaxation time), diffusion-tensor imaging (Fractional Anisotropy) and perfusion by Dynamic Contrast-Enhanced MRI (K-trans) were measured and imaging results were correlated with histological morphometric analysis in both Gastrocnemius and Tibialis anterior muscles. We found that tissue damage positively correlated with T2-relaxation time, while myofiber regeneration and capillary density positively correlated with Fractional Anisotropy. Interestingly, K-trans positively correlated with capillary density. Accordingly, repeated MRI measurements between day 1 and day 28 after surgery in ischemic muscles showed that: 1) T2-relaxation time rapidly increased upon ischemia and then gradually declined, returning almost to basal level in the last phases of the regeneration process; 2) Fractional Anisotropy dropped upon ischemic damage induction and then recovered along with muscle regeneration and neoangiogenesis; 3) K-trans reached a minimum upon ischemia, then progressively recovered. Overall, Gastrocnemius and Tibialis anterior muscles displayed similar patterns of MRI parameters dynamic, with more marked responses and less variability in Tibialis anterior. We conclude that MRI provides quantitative information about both tissue damage after ischemia and the subsequent vascular and muscle regeneration, accounting for the differences between subjects and, within the same individual, between different muscles.
Epigenetic marks critically control gene expression and thus the cellular activity state. The functions of many epigenetic modifiers in the vascular system have not yet been studied. We screened for histone modifiers in endothelial cells and observed a fairly high expression of the histone plant homeodomain finger protein 8 (PHF8). Given its high expression, we hypothesize that this histone demethylase is important for endothelial cell function. Overexpression of PHF8 catalyzed the removal of methyl-groups from histone 3 lysine 9 (H3K9) and H4K20, whereas knockdown of the enzyme increased H3K9 methylation. Knockdown of PHF8 by RNAi also attenuated endothelial proliferation and survival. As a functional readout endothelial migration and tube formation was studied. PHF8 siRNA attenuated the capacity for migration and developing of capillary-like structures. Given the impact of PHF8 on cell cycle genes, endothelial E2F transcription factors were screened, which led to the identification of the gene repressor E2F4 to be controlled by PHF8. Importantly, PHF8 maintains E2F4 but not E2F1 expression in endothelial cells. Consistently, chromatin immunoprecipitation revealed that PHF8 reduces the H3K9me2 level at the E2F4 transcriptional start site, demonstrating a direct function of PHF8 in endothelial E2F4 gene regulation. Conclusion: PHF8 by controlling E2F4 expression maintains endothelial function.
Background: Chronic ethanol (EtOH) abuse worsens pathophysiological derangements after hemorrhagic shock and resuscitation (H/R) that induce hepatic injury and strong inflammatory changes via JNK and NF-κB activation. Inhibiting JNK with a cell-penetrating, protease-resistant peptide D-JNKI-1 after H/R in mice with healthy livers ameliorated these effects. Here, we studied if JNK inhibition by D-JNKI-1 in chronically EtOH-fed mice after hemorrhagic shock prior to the onset of resuscitation also confers protection.
Methods: Male mice were fed a Lieber-DeCarli diet containing EtOH or an isocaloric control (ctrl) diet for 4 weeks. Animals were hemorrhaged for 90 min (32 ± 2 mm Hg) and randomly received either D-JNKI-1 (11 mg/kg, intraperitoneally, i. p.) or sterile saline as vehicle (veh) immediately before the onset of resuscitation. Sham animals underwent surgical procedures without H/R and were either D-JNKI-1 or veh treated. Two hours after resuscitation, blood samples and liver tissue were harvested.
Results: H/R induced hepatic injury with increased systemic interleukin (IL)-6 levels, and enhanced local gene expression of NF-κB-controlled genes such as intercellular adhesion molecule (ICAM)-1 and matrix metallopeptidase (MMP)9. c-Jun and NF-κB phosphorylation were increased after H/R. These effects were further increased in EtOH-fed mice after H/R. D-JNKI-1 application inhibited the proinflammatory changes and reduced significantly hepatic injury after H/R in ctrl-fed mice. Moreover, D-JNKI-1 reduces in ctrl-fed mice the H/R-induced c-Jun and NF-κB phosphorylation. However, in chronically EtOH-fed mice, JNK inhibition did not prevent the H/R-induced hepatic damage and proinflammatory changes nor c-Jun and NF-κB phosphorylation after H/R.
Conclusions: These results indicate, that JNK inhibition is protective only in not pre-harmed liver after H/R. In contrast, the pronounced H/R-induced liver damage in mice being chronically fed with ethanol cannot be prevented by JNK inhibition after H/R and seems to be under the control of NF-κB.
Introduction: Interferon alpha (IFNα) is routinely used in the clinical practice for adjuvant systemic melanoma therapy. Understanding the molecular mechanism of IFNα effects and prediction of response in the IFNα therapy regime allows initiation and continuation of IFNα treatment for responder and exclusion of non-responder to avoid therapy inefficacy and side-effects. The transporter protein associated with antigen processing-1 (TAP1) is part of the MHC class I peptide-loading complex, and important for antigen presentation in tumor and antigen presenting cells. In the context of personalized medicine, we address this potential biomarker TAP1 as a target of IFNα signalling.
Results: We could show that IFNα upregulates TAP1 expression in peripheral blood mononuclear cells (PBMCs) of patients with malignant melanoma receiving adjuvant high-dose immunotherapy. IFNα also induced expression of TAP1 in mouse blood and tumor tissue and suppressed the formation of melanoma metastasis in an in vivo B16 tumor model. Besides its expression, TAP binding affinity and transport activity is induced by IFNα in human monocytic THP1 cells. Furthermore, our data revealed that IFNα clearly activates phosphorylation of STAT1 and STAT3 in THP1 and A375 melanoma cells. Inhibition of Janus kinases abrogates the IFNα-induced TAP1 expression. These results suggest that the JAK/STAT pathway is a crucial mediator for TAP1 expression elicited by IFNα treatment.
Conclusion: We suppose that silencing of TAP1 expression provides tumor cells with a mechanism to escape cytotoxic T-lymphocyte recognition. The observed benefit of IFNα treatment could be mediated by the shown dual effect of TAP1 upregulation in antigen presenting cells on the one hand, and of TAP1 upregulation in ‘silent’ metastatic melanoma cells on the other hand. In conclusion, this work contributes to a better understanding of the mode of action of IFNα which is essential to identify markers to predict, assess and monitor therapeutic response of IFNα treatment in the future.
A fundamental question in evolutionary genetics concerns the extent to which adaptive phenotypic convergence is attributable to convergent or parallel changes at the molecular sequence level. Here we report a comparative analysis of hemoglobin (Hb) function in eight phylogenetically replicated pairs of high- and low-altitude waterfowl taxa to test for convergence in the oxygenation properties of Hb, and to assess the extent to which convergence in biochemical phenotype is attributable to repeated amino acid replacements. Functional experiments on native Hb variants and protein engineering experiments based on site-directed mutagenesis revealed the phenotypic effects of specific amino acid replacements that were responsible for convergent increases in Hb-O2 affinity in multiple high-altitude taxa. In six of the eight taxon pairs, high-altitude taxa evolved derived increases in Hb-O2 affinity that were caused by a combination of unique replacements, parallel replacements (involving identical-by-state variants with independent mutational origins in different lineages), and collateral replacements (involving shared, identical-by-descent variants derived via introgressive hybridization). In genome scans of nucleotide differentiation involving high- and low-altitude populations of three separate species, function-altering amino acid polymorphisms in the globin genes emerged as highly significant outliers, providing independent evidence for adaptive divergence in Hb function. The experimental results demonstrate that convergent changes in protein function can occur through multiple historical paths, and can involve multiple possible mutations. Most cases of convergence in Hb function did not involve parallel substitutions and most parallel substitutions did not affect Hb-O2 affinity, indicating that the repeatability of phenotypic evolution does not require parallelism at the molecular level.
The swine plasma metabolome chronicles "many days" biological timing and functions linked to growth
(2016)
The paradigm of chronobiology is based almost wholly upon the daily biological clock, or circadian rhythm, which has been the focus of intense molecular, cellular, pharmacological, and behavioral, research. However, the circadian rhythm does not explain biological timings related to fundamental aspects of life history such as rates of tissue/organ/body size development and control of the timing of life stages such as gestation length, age at maturity, and lifespan. This suggests that another biological timing mechanism is at work. Here we focus on a "many days" (multidien) chronobiological period first observed as enigmatic recurring growth lines in developing mammalian tooth enamel that is strongly associate with all adult tissue, organ, and body masses as well as life history attributes such as gestation length, age at maturity, weaning, and lifespan, particularly among the well studied primates. Yet, knowledge of the biological factors regulating the patterning of mammalian life, such as the development of body size and life history structure, does not exist. To identify underlying molecular mechanisms we performed metabolome and genome analyses from blood plasma in domestic pigs. We show that blood plasma metabolites and small non-coding RNA (sncRNA) drawn from 33 domestic pigs over a two-week period strongly oscillate on a 5-day multidien rhythm, as does the pig enamel rhythm. Metabolomics and genomics pathway analyses actually reveal two 5-day rhythms, one related to growth in which biological functions include cell proliferation, apoptosis, and transcription regulation/protein synthesis, and another 5-day rhythm related to degradative pathways that follows three days later. Our results provide experimental confirmation of a 5-day multidien rhythm in the domestic pig linking the periodic growth of enamel with oscillations of the metabolome and genome. This association reveals a new class of chronobiological rhythm and a snapshot of the biological bases that regulate mammalian growth, body size, and life history.
We describe a new large-sized species of hypercarnivorous hyainailourine–Kerberos langebadreae gen. & sp. nov.–from the Bartonian (MP16) locality of Montespieu (Tarn, France). These specimens consist of a skull, two hemimandibles and several hind limb elements (fibula, astragalus, calcaneum, metatarsals, and phalanges). Size estimates suggest K. langebadreae may have weighed up to 140 kg, revealing this species as the largest carnivorous mammal in Europe at that time. Besides its very large size, K. langebadreae possesses an interesting combination of primitive and derived features. The distinctive skull morphology of K. langebadreae reflects a powerful bite force. The postcranial elements, which are rarely associated with hyainailourine specimens, indicate an animal capable of a plantigrade stance and adapted for terrestrial locomotion. We performed the first phylogenetic analysis of hyainailourines to determine the systematic position of K. langebadreae and to understand the evolution of the group that includes other massive carnivores. The analysis demonstrates that Hemipsalodon, a North American taxon, is a hyainailourine and is closely related to European Paroxyaena. Based on this analysis we hypothesize the biogeographic history of the Hyainailourinae. The group appeared in Africa with a first migration to Europe during the Bartonian that likely included the ancestors of Kerberos, Paroxyaena and Hemipsalodon, which further dispersed into North America at this time. We propose that the hyainailourines dispersed into Europe also during the Priabonian. These migrants have no ecological equivalent in Europe during these intervals and likely did not conflict with the endemic hyaenodont proviverrines. The discovery of K. langebadreae shows that large body size appears early in the evolution of hyainailourines. Surprisingly, the late Miocene Hyainailouros shares a more recent common ancestor with small-bodied hyainailourines (below 15 kg). Finally, our study supports a close relationship between the Hyainailourinae and Apterodontinae and we propose the new clade: Hyainailouridae.
During the last decade, Bayesian probability theory has emerged as a framework in cognitive science and neuroscience for describing perception, reasoning and learning of mammals. However, our understanding of how probabilistic computations could be organized in the brain, and how the observed connectivity structure of cortical microcircuits supports these calculations, is rudimentary at best. In this study, we investigate statistical inference and self-organized learning in a spatially extended spiking network model, that accommodates both local competitive and large-scale associative aspects of neural information processing, under a unified Bayesian account. Specifically, we show how the spiking dynamics of a recurrent network with lateral excitation and local inhibition in response to distributed spiking input, can be understood as sampling from a variational posterior distribution of a well-defined implicit probabilistic model. This interpretation further permits a rigorous analytical treatment of experience-dependent plasticity on the network level. Using machine learning theory, we derive update rules for neuron and synapse parameters which equate with Hebbian synaptic and homeostatic intrinsic plasticity rules in a neural implementation. In computer simulations, we demonstrate that the interplay of these plasticity rules leads to the emergence of probabilistic local experts that form distributed assemblies of similarly tuned cells communicating through lateral excitatory connections. The resulting sparse distributed spike code of a well-adapted network carries compressed information on salient input features combined with prior experience on correlations among them. Our theory predicts that the emergence of such efficient representations benefits from network architectures in which the range of local inhibition matches the spatial extent of pyramidal cells that share common afferent input.
Understanding factors that structure regional biodiversity is important for linking ecological and biogeographic processes. Our objective was to explore regional patterns in riverine benthic invertebrate assemblages in relation to their broad positioning along the river network and examine differences in composition, biodiversity (alpha and beta diversity), and environmental drivers. We up-scaled methods used to examine patterns in metacommunity structure (Elements of Metacommunity Structure framework) to examine faunal distribution patterns at the regional extent for 168 low-mountain stream invertebrate assemblages in central Germany. We then identified the most influential environmental factors using boosted regression trees. Faunal composition patterns were compartmentalised (Clementsian or quasi-Clementsian), with little difference from headwaters to large rivers, potentially reflecting the regional scale of the study, by crossing major catchment boundaries and incorporating different species pools. While idealised structures did not vary, environmental drivers of composition varied considerably between river sections and with alpha diversity. Prediction was substantially weaker, and the importance of space was greater, in large rivers compared to other sections suggesting a weakening in species sorting downstream. Further, there was a stronger transition in composition than for alpha diversity downstream. The stronger links with regional faunal composition than with richness further emphasises the importance of considering the alternative ways in which anthropogenic stressors are operating to affect biodiversity patterns. Our approach allowed bridging the gap between local (or metacommunity) and regional scales, providing key insights into drivers of regional biodiversity patterns.
Long-term potentiation (LTP) and long-term depression (LTD) are widely accepted to be synaptic mechanisms involved in learning and memory. It remains uncertain, however, which particular activity rules are utilized by hippocampal neurons to induce LTP and LTD in behaving animals. Recent experiments in the dentate gyrus of freely moving rats revealed an unexpected pattern of LTP and LTD from high-frequency perforant path stimulation. While 400 Hz theta-burst stimulation (400-TBS) and 400 Hz delta-burst stimulation (400-DBS) elicited substantial LTP of the tetanized medial path input and, concurrently, LTD of the non-tetanized lateral path input, 100 Hz theta-burst stimulation (100-TBS, a normally efficient LTP protocol for in vitro preparations) produced only weak LTP and concurrent LTD. Here we show in a biophysically realistic compartmental granule cell model that this pattern of results can be accounted for by a voltage-based spike-timing-dependent plasticity (STDP) rule combined with a relatively fast Bienenstock-Cooper-Munro (BCM)-like homeostatic metaplasticity rule, all on a background of ongoing spontaneous activity in the input fibers. Our results suggest that, at least for dentate granule cells, the interplay of STDP-BCM plasticity rules and ongoing pre- and postsynaptic background activity determines not only the degree of input-specific LTP elicited by various plasticity-inducing protocols, but also the degree of associated LTD in neighboring non-tetanized inputs, as generated by the ongoing constitutive activity at these synapses.
Even in the absence of sensory stimulation the brain is spontaneously active. This background “noise” seems to be the dominant cause of the notoriously high trial-to-trial variability of neural recordings. Recent experimental observations have extended our knowledge of trial-to-trial variability and spontaneous activity in several directions: 1. Trial-to-trial variability systematically decreases following the onset of a sensory stimulus or the start of a motor act. 2. Spontaneous activity states in sensory cortex outline the region of evoked sensory responses. 3. Across development, spontaneous activity aligns itself with typical evoked activity patterns. 4. The spontaneous brain activity prior to the presentation of an ambiguous stimulus predicts how the stimulus will be interpreted. At present it is unclear how these observations relate to each other and how they arise in cortical circuits. Here we demonstrate that all of these phenomena can be accounted for by a deterministic self-organizing recurrent neural network model (SORN), which learns a predictive model of its sensory environment. The SORN comprises recurrently coupled populations of excitatory and inhibitory threshold units and learns via a combination of spike-timing dependent plasticity (STDP) and homeostatic plasticity mechanisms. Similar to balanced network architectures, units in the network show irregular activity and variable responses to inputs. Additionally, however, the SORN exhibits sequence learning abilities matching recent findings from visual cortex and the network's spontaneous activity reproduces the experimental findings mentioned above. Intriguingly, the network's behaviour is reminiscent of sampling-based probabilistic inference, suggesting that correlates of sampling-based inference can develop from the interaction of STDP and homeostasis in deterministic networks. We conclude that key observations on spontaneous brain activity and the variability of neural responses can be accounted for by a simple deterministic recurrent neural network which learns a predictive model of its sensory environment via a combination of generic neural plasticity mechanisms.
Leaky integrate-and-fire (LIF) network models are commonly used to study how the spiking dynamics of neural networks changes with stimuli, tasks or dynamic network states. However, neurophysiological studies in vivo often rather measure the mass activity of neuronal microcircuits with the local field potential (LFP). Given that LFPs are generated by spatially separated currents across the neuronal membrane, they cannot be computed directly from quantities defined in models of point-like LIF neurons. Here, we explore the best approximation for predicting the LFP based on standard output from point-neuron LIF networks. To search for this best “LFP proxy”, we compared LFP predictions from candidate proxies based on LIF network output (e.g, firing rates, membrane potentials, synaptic currents) with “ground-truth” LFP obtained when the LIF network synaptic input currents were injected into an analogous three-dimensional (3D) network model of multi-compartmental neurons with realistic morphology, spatial distributions of somata and synapses. We found that a specific fixed linear combination of the LIF synaptic currents provided an accurate LFP proxy, accounting for most of the variance of the LFP time course observed in the 3D network for all recording locations. This proxy performed well over a broad set of conditions, including substantial variations of the neuronal morphologies. Our results provide a simple formula for estimating the time course of the LFP from LIF network simulations in cases where a single pyramidal population dominates the LFP generation, and thereby facilitate quantitative comparison between computational models and experimental LFP recordings in vivo.
Allergy against birch pollen is among the most common causes of spring pollinosis in Europe and is diagnosed and treated using extracts from natural sources. Quality control is crucial for safe and effective diagnosis and treatment. However, current methods are very difficult to standardize and do not address individual allergen or isoallergen composition. MS provides information regarding selected proteins or the entire proteome and could overcome the aforementioned limitations. We studied the proteome of birch pollen, focusing on allergens and isoallergens, to clarify which of the 93 published sequence variants of the major allergen, Bet v 1, are expressed as proteins within one source material in parallel. The unexpectedly complex Bet v 1 isoallergen composition required manual data interpretation and a specific design of databases, as current database search engines fail to unambiguously assign spectra to highly homologous, partially identical proteins. We identified 47 non-allergenic proteins and all 5 known birch pollen allergens, and unambiguously proved the existence of 18 Bet v 1 isoallergens and variants by manual data analysis. This highly complex isoallergen composition raises questions whether isoallergens can be ignored or must be included for the quality control of allergen products, and which data analysis strategies are to be applied.
The flow-responsive transcription factor Krüppel-like factor 2 (KLF2) maintains an anti-coagulant, anti-inflammatory endothelium with sufficient nitric oxide (NO)-bioavailability. In this study, we aimed to explore, both in vitro and in human vascular tissue, expression of the NO-transporting transmembrane pore aquaporin-1 (AQP1) and its regulation by atheroprotective KLF2 and atherogenic inflammatory stimuli. In silico analysis of gene expression profiles from studies that assessed the effects of KLF2 overexpression in vitro and atherosclerosis in vivo on endothelial cells, identifies AQP1 as KLF2 downstream gene with elevated expression in the plaque-free vessel wall. Biomechanical and pharmaceutical induction of KLF2 in vitro is accompanied by induction of AQP1. Chromosome immunoprecipitation (CHIP) confirms binding of KLF2 to the AQP1 promoter. Inflammatory stimulation of endothelial cells leads to repression of AQP1 transcription, which is restrained by KLF2 overexpression. Immunohistochemistry reveals expression of aquaporin-1 in non-activated endothelium overlying macrophage-poor intimae, irrespective whether these intimae are characterized as being plaque-free or as containing advanced plaque. We conclude that AQP1 expression is subject to KLF2-mediated positive regulation by atheroprotective shear stress and is downregulated under inflammatory conditions both in vitro and in vivo. Thus, endothelial expression of AQP1 characterizes the atheroprotected, non-inflamed vessel wall. Our data provide support for a continuous role of KLF2 in stabilizing the vessel wall via co-temporal expression of eNOS and AQP1 both preceding and during the pathogenesis of atherosclerosis.
Different highly effective interferon-free treatment options for chronic hepatitis C virus (HCV) infection are currently available. Pre-existence of resistance associated variants (RAVs) to direct antiviral agents (DAAs) reduces sustained virologic response (SVR) rates by 3–53% in hepatitis C virus (HCV) genotype 1 infected patients depending on different predictors and the DAA regimen used. Frequencies of single and combined resistance to NS3, NS5A and NS5B inhibitors and consequences for the applicability of different treatment regimens are unknown. Parallel population based sequencing of HCV NS3, NS5A and NS5B genes in 312 treatment-naïve Caucasian HCV genotype 1 infected patients showed the presence of major resistant variants in 20.5% (NS3), 11.9% (NS5A), and 22.1% (NS5B) with important differences for HCV subtypes. In NS3, Q80K was observed in 34.7% and 2.1% of subtype 1a and 1b patients, respectively while other RAVs to second generation protease inhibitors were detected rarely (1.4%). Within NS5A RAVs were observed in 7.1% of subtype 1a and 17.6% in subtype 1b infected patients. RAVs to non-nucleoside NS5B inhibitors were observed in 3.5% and 44.4% of subtype 1a and 1b patients, respectively. Considering all three DAA targets all subtype 1a and 98.6% of subtype 1b infected patients were wildtype for at least one interferon free DAA regimen currently available. In conclusion, baseline resistance testing allows the selection of at least one RAVs-free treatment option for nearly all patients enabling a potentially cost- and efficacy-optimized treatment of chronic hepatitis C.
Tumour hypoxia plays a pivotal role in cancer therapy for most therapeutic approaches from radiotherapy to immunotherapy. The detailed and accurate knowledge of the oxygen distribution in a tumour is necessary in order to determine the right treatment strategy. Still, due to the limited spatial and temporal resolution of imaging methods as well as lacking fundamental understanding of internal oxygenation dynamics in tumours, the precise oxygen distribution map is rarely available for treatment planing. We employ an agent-based in silico tumour spheroid model in order to study the complex, localized and fast oxygen dynamics in tumour micro-regions which are induced by radiotherapy. A lattice-free, 3D, agent-based approach for cell representation is coupled with a high-resolution diffusion solver that includes a tissue density-dependent diffusion coefficient. This allows us to assess the space- and time-resolved reoxygenation response of a small subvolume of tumour tissue in response to radiotherapy. In response to irradiation the tumour nodule exhibits characteristic reoxygenation and re-depletion dynamics which we resolve with high spatio-temporal resolution. The reoxygenation follows specific timings, which should be respected in treatment in order to maximise the use of the oxygen enhancement effects. Oxygen dynamics within the tumour create windows of opportunity for the use of adjuvant chemotherapeutica and hypoxia-activated drugs. Overall, we show that by using modelling it is possible to follow the oxygenation dynamics beyond common resolution limits and predict beneficial strategies for therapy and in vitro verification. Models of cell cycle and oxygen dynamics in tumours should in the future be combined with imaging techniques, to allow for a systematic experimental study of possible improved schedules and to ultimately extend the reach of oxygenation monitoring available in clinical treatment.
Introduction: Aim of this study was to reduce blood loss caused by diagnostic blood sampling and to minimize the development of anemia in a high-risk group of mechanically ventilated medical intensive care patients. We therefore implemented a “blood-saving bundle” (BSB) combining a closed-loop arterial blood sampling system, smaller sampling tubes, reduced frequency of blood drawings, and reduced sample numbers.
Methods: The study included all patients from our medical ICU who were ventilated for more than 72 hours. Exclusion criteria were: acute or chronic anemia on admission, bleeding episode(s) during the ICU stay, or end-of-life therapy. The BSB was introduced in 2009 with training and educational support. Patients treated in 2008, before the introduction of the BSB, served as a control group (n = 41, 617 observation days), and were compared with patients treated in 2010 after the introduction of the BSB (BSB group, n = 50, 559 observation days). Primary endpoints were blood loss per day, and development of anemia. Secondary endpoints were numbers of blood transfusions, number of days on mechanical ventilation, and length of the ICU stay.
Results: Mean blood loss per ICU day was decreased from 43.3 ml (95% CI: 41.2 to 45.3 ml) in the controls to 15.0 ml (14.3 to 15.7 ml) in the BSB group (P < 0.001). The introduction of a closed-loop arterial blood sampling system was the major contributor to this effect. Mean hemoglobin concentrations showed no significant differences in both groups during the ICU stay. Hemoglobin values <9 g/dl, however, were recorded in 21.2% of observation days in the controls versus 15.4% in the BSB group (P = 0.01). Units of transfused red blood cells per 100 observation days decreased from 7 to 2.3 (P < 0.001). The mean number of ventilation days was 7.1 days (6.1 to 8.3 days) in the controls and 7.5 days (6.6 to 8.5 days) in the BSB group (P = NS). In total, patients in the BSB group stayed in ICU for a mean of 9.9 days (8.6 to 11.3 days), compared to a mean ICU stay of 13.0 days (10.9 to 15.4 days) in the control group (P = 0.014). Due to the longitudinal study design, however, we cannot exclude uncontrolled confounders affecting the transfusion frequency and mean ICU stay.
Conclusion: Our BSB could be easily implemented and was able to reduce diagnostic blood loss.
In the last decades, natural products from lichens have gained more interest for pharmaceutical application due to the broad range of their biological activity. However, isolation of the compounds of interest directly from the lichen is neither feasible nor sustainable due to slow growth of many lichens. In order to develop a pipeline for heterologous expression of lichen biosynthesis gene clusters and thus the sustainable production of their bioactive compounds we have identified and characterized the phosphopantheteinyl transferase (PPTase) EppA from the lichen Evernia prunastri. The Sfp-type PPTase EppA was functionally characterized through heterologous expression in E. coli using the production of the blue pigment indigoidine as readout and by complementation of a lys5 deletion in S. cerevisiae.
In most habitats, vegetation provides the main structure of the environment. This complexity can facilitate biodiversity and ecosystem services. Therefore, measures of vegetation structure can serve as indicators in ecosystem management. However, many structural measures are laborious and require expert knowledge. Here, we used consistent and convenient measures to assess vegetation structure over an exceptionally broad elevation gradient of 866–4550m above sea level at Mount Kilimanjaro, Tanzania. Additionally, we compared (human)-modified habitats, including maize fields, traditionally managed home gardens, grasslands, commercial coffee farms and logged and burned forests with natural habitats along this elevation gradient. We distinguished vertical and horizontal vegetation structure to account for habitat complexity and heterogeneity. Vertical vegetation structure (assessed as number, width and density of vegetation layers, maximum canopy height, leaf area index and vegetation cover) displayed a unimodal elevation pattern, peaking at intermediate elevations in montane forests, whereas horizontal structure (assessed as coefficient of variation of number, width and density of vegetation layers, maximum canopy height, leaf area index and vegetation cover) was lowest at intermediate altitudes. Overall, vertical structure was consistently lower in modified than in natural habitat types, whereas horizontal structure was inconsistently different in modified than in natural habitat types, depending on the specific structural measure and habitat type. Our study shows how vertical and horizontal vegetation structure can be assessed efficiently in various habitat types in tropical mountain regions, and we suggest to apply this as a tool for informing future biodiversity and ecosystem service studies.
Aging of biological systems is accompanied by degeneration of mitochondrial functions. Different pathways are active to counteract the processes which lead to mitochondrial dysfunction. Mitochondrial dynamics, the fission and fusion of mitochondria, is one of these quality control pathways. Mitophagy, the controlled degradation of mitochondria, is another one. Here we show that these pathways are linked. A double deletion mutant of Saccharomyces cerevisiae in which two essential components of the fission and fusion machinery, Dnm1 and Mgm1, are simultaneously ablated, contain wild-type like filamentous mitochondria, but are characterized by impaired respiration, an increased sensitivity to different stressors, increased mitochondrial protein carbonylation, and a decrease in mitophagy and replicative lifespan. These data show that a balanced mitochondrial dynamics and not a filamentous mitochondrial morphotype per se is the key for a long lifespan and demonstrate a cross-talk between two different mitochondrial quality control pathways.
Background: In vertebrates, several anatomical regions located within the nasal cavity mediate olfaction. Among these, the main olfactory epithelium detects most conventional odorants. Olfactory sensory neurons, provided with cilia exposed to the air, detect volatile chemicals via an extremely large family of seven-transmembrane chemoreceptors named odorant receptors. Their genes are expressed in a monogenic and monoallelic fashion: a single allele of a single odorant receptor gene is transcribed in a given mature neuron, through a still uncharacterized molecular mechanism known as odorant receptor gene choice.
Aim: Odorant receptor genes are typically arranged in genomic clusters, but a few are isolated (we call them solitary) from the others within a region broader than 1 Mb upstream and downstream with respect to their transcript's coordinates. The study of clustered genes is problematic, because of redundancy and ambiguities in their regulatory elements: we propose to use the solitary genes as simplified models to understand odorant receptor gene choice.
Procedures: Here we define number and identity of the solitary genes in the mouse genome (C57BL/6J), and assess the conservation of the solitary status in some mammalian orthologs. Furthermore, we locate their putative promoters, predict their homeodomain binding sites (commonly present in the promoters of odorant receptor genes) and compare candidate promoter sequences with those of wild-caught mice. We also provide expression data from histological sections.
Results: In the mouse genome there are eight intact solitary genes: Olfr19 (M12), Olfr49, Olfr266, Olfr267, Olfr370, Olfr371, Olfr466, Olfr1402; five are conserved as solitary in rat. These genes are all expressed in the main olfactory epithelium of three-day-old mice. The C57BL/6J candidate promoter of Olfr370 has considerably varied compared to its wild-type counterpart. Within the putative promoter for Olfr266 a homeodomain binding site is predicted. As a whole, our findings favor Olfr266 as a model gene to investigate odorant receptor gene choice.
Attractive growth cone turning requires Igf2bp1-dependent local translation of β-actin mRNA in response to external cues in vitro. While in vivo studies have shown that Igf2bp1 is required for cell migration and axon terminal branching, a requirement for Igf2bp1 function during axon outgrowth has not been demonstrated. Using a timelapse assay in the zebrafish retinotectal system, we demonstrate that the β-actin 3’UTR is sufficient to target local translation of the photoconvertible fluorescent protein Kaede in growth cones of pathfinding retinal ganglion cells (RGCs) in vivo. Igf2bp1 knockdown reduced RGC axonal outgrowth and tectal coverage and retinal cell survival. RGC-specific expression of a phosphomimetic Igf2bp1 reduced the density of axonal projections in the optic tract while sparing RGCs, demonstrating for the first time that Igf2bp1 is required during axon outgrowth in vivo. Therefore, regulation of local translation mediated by Igf2bp proteins may be required at all stages of axon development.
Responding to studies on prejudice in the Greco-Roman world, E. Gruen argues that Greeks and Romans had more nuanced and complex opinions about foreigners than often recognized. G. observes that the Greek and Romans could discover or invent links with these other societies through cultural appropriations of the past. These connections, G. contends, show that the Greeks and Romans cannot be ‘blanketed’ with xenophobia, ethnocentrism, and “let alone racism” (p. 3). G. argues that the Greeks and Romans were more interested in drawing connections with the other through cultural appropriation. G. contends that this approach reveals a positive outlook which does not reject or degrade the foreign other.
„The importance of the Epic Cycle in relation to the Iliad and Odyssey on the one hand, and on the other to lyric poetry, tragedy, and mythography, can hardly be overstated. Yet it has never been the object of a thorough commentary, and not often of a comprehensive study.“ Mit diesen Worten leitet M. L. West seinen Kommentar ein (V). Zwar hat M. Davies zu Beginn seiner ‚Epicorum Graecorum fragmenta‘ (1988) einen entsprechenden Kommentar angekündigt, erschienen ist dieser bislang aber nicht. Desto erfreulicher ist es, dass ein anerkannter Spezialist wie M. L. West sich dieses Unternehmens angenommen hat, nachdem bereits 2003 eine zweisprachige Ausgabe von ihm vorgelegt wurde...
Introduction: The Helicopter Emergency Medical Service (HEMS) was established for the prehospital trauma care of patients. Improved rescue times and increased coverage areas are discussed as specific advantages of HEMS. We recently found evidence that HEMS exerts beneficial effects on outcomes for severely injured patients. However, it still remains unknown which group of trauma patients might benefit most from HEMS rescue. Consequently, the unique aim of this study was to reveal which patients might benefit most from HEMS rescue.
Methods: Trauma patients (ISS ≥9) primarily treated by HEMS or ground emergency medical services (GEMS) between 2002 and 2012 were analysed using the TraumaRegister DGU. A multivariate regression analysis was used to reveal the survival benefit between different trauma populations.
Results: The study included 52 281 trauma patients. Of these, 68.8% (35 974) were rescued by GEMS and 31.2% (16 307) by HEMS. HEMS patients were more severely injured compared to GEMS patients (ISS: HEMS 24.8±13.5 vs. GEMS 21.7±18.0) and more frequently suffered traumatic shock (SBP sys <90mmHg: HEMS 18.3% vs. GEMS 14.8%). However, logistic regression analysis revealed that HEMS rescues resulted in an overall survival benefit compared to GEMS (OR 0.81, 95% CI [0.75–0.87], p<0.001, Nagelkerke's R squared 0.526, area under the ROC curve 0.922, 95% CI [0.919–0.925]). Analysis of specific subgroups demonstrated that patients aged older than 55 years (OR 0.62, 95% CI [0.50–0.77]) had the highest survival benefit after HEMS treatment. Furthermore, HEMS rescue had the most significant impact after ‘low falls’ (OR 0.68, 95% CI [0.55–0.84]) and in the case of minor severity injuries (ISS 9–15) (OR 0.66, 95% CI [0.49–0.88]).
Conclusions: In general, trauma patients benefit from HEMS rescue with in-hospital survival as the main outcome parameter. Focusing on special subgroups, middle aged and older patients, low-energy trauma, and minor severity injuries had the highest survival benefit when rescued by HEMS. Further studies are required to determine the potential reasons of this benefit.
Die erste Auflage dieser Einführung in die griechische Religion hat sich innerhalb der Forschung schnell zum Standardwerk entwickelt und kann inzwischen als Klassiker bezeichnet werden, da sie nicht nur die antiken Phänomene beschrieb und zu deuten suchte, sondern dies mit zum Teilen neuen wissenschaftlichen Herangehensweisen unternahm, die sich inzwischen vielfach bewährt haben. Seit ihrem Erscheinen im Jahre 1977 ist die Monographie in die englische (1985), griechische (1993), portugiesische (1993), spanische (2007), italienische (3. Auflage 2010) und französische (2011) Sprache übersetzt worden, wobei Burkert (meist zusammen mit den entsprechenden Übersetzern) jeweils die Chance genutzt hat, gewisse Teile dem neuesten Forschungsstand anzupassen. Erfreulicherweise gilt dies auch für die zweite deutsche Auflage...
Um terminologische Klarheit zu schaffen, muss mit der funktionalen Beschreibung der Kunst zunächst geklärt werden, in welcher Form die Identität im Werke Richard Wagners (1813 – 1883) gestiftet wird, wobei verständlicherweise auch der situative Kontext Erwähnung finden muss. Aus diesem Grunde kann sich diese Analyse nicht rein mit der performativen Leistung des Wagnerschen Schauspiels auseinandersetzen, ohne nicht zumindest in skizzenhafter Art und Weise die gesellschaftlichen Verhältnisse des 19. Jahrhunderts nachzuzeichnen. Dabei wird sich diese Skizze nicht in allgemeinen Analysen erschöpfen, sondern immer an die Person Wagners gebunden sein und dabei vor allem jene geistigen Zeitströmungen herausarbeiten, die ihn als „philosophisch-theologische[n] Denker“ zu erkennen geben, dessen theoretische Denkmodelle, obwohl in modifizierter Form, sich sehr eindrücklich auf intentionaler Ebene der attischen Tragödie verpflichtet fühlen...
“Shades” of Postmortem Personal Identity: ψυχή καὶ εἴδωλον in the Dream Passage (Il. 23.103-104)
(2013)
In a recent contribution entitled, “Homer’s Challenge to Philosophical Psychology,” Fred Miller proposes an “aporetic approach” to the Homeric poems. That is to say, a close reading of the epics reveals “serious aporiai,” at least insofar as philosophical consistency is concerned. Homeric readers, ancient and modern alike, have found irreconcilably-different answers to our perennial questions about humanity and divinity, fate and free will. To his credit, Miller rightly relieves Homer of an undue burden – viz., that of addressing the philosophical problems of later generations. “The analysis of concepts and the resolution of aporiai”: these are, as Miller notes, definitively not the priorities of an epic bard. Instead, such poets, working freely within the parameters of their oral traditions, understandably use language in ways not strictly-philosophical. Ultimately, Miller wants to argue that the ambiguities of Homer’s poetic language hastened Greece’s philosophical awakening...
Die politischen Beziehungsgeflechte im Alten Rom – neudeutsch: „Netzwerke“ – bildeten für John Nicols schon früh einen zentralen Ansatzpunkt seiner wissenschaftlichen Interessen. Ein formal klar abgrenzbarer Teilbereich dieses breiten Forschungsfeldes betrifft das patrocinium publicum („civic patronage“ bzw. „Stadtpatronat“), also das offizielle und formelle Patronat über Gemeinden, aber auch größere Gebiete wie etwa Provinzen im Imperium Romanum. Eine umfassende Untersuchung zu diesem Thema ist seit der immer noch wichtigen Arbeit von L. Harmand aus dem Jahr 1957 und seit der Freiburger Dissertation von F. Engesser aus demselben Jahr zum Stadtpatronat in Italien und im Westen des römischen Reiches trotz einer Reihe von regionalen Teilstudien oder solchen zu Einzelfällen nicht wieder vorgelegt worden. Hier schließt das Buch von Nicols eine Lücke auf aktuellem Stand. Ergänzt wird es durch eine Datenbank mit einem Corpus von ca. 900 Inschriften, Abbildungen und zusätzlichen Materialien, die auf einer bei der University of Oregon geführten Website hinterlegt ist und vorwiegend für den Spezialisten von Interesse sein dürfte. Bereits in der Vergangenheit hat sich Nicols wiederholt mit grundlegenden Aspekten des Themas auseinandergesetzt, was nicht wenige Beiträge aus seiner Feder vor allem aus den letzten beiden Jahrzehnten des vergangenen Jahrhunderts, dann aber auch wieder der jüngeren Vergangenheit dokumentieren...
Kathrin Jaschke hat eine mustergültige wirtschaftsgeschichtliche Analyse des antiken Puteoli vorgelegt. Ziel der Studie ist es, das Wirtschaftsleben der Stadt zur Gänze darzustellen: „Die meist allgemein getroffene Aussage der außergewöhnlichen Bedeutung der Stadt soll detailliert beleuchtet werden“ (7). Hierfür stellt sie verschiedene Fragen: Inwieweit wurde die Wirtschaft Puteolis durch die Einführung der annona beeinflusst? Wie waren die Verbindungen zwischen dem privaten Handel und der stadtrömischen Getreideversorgung? Hat die annona-Einfuhr die anderen Wirtschafts- und Handelszweige verändert? Wie gestalteten sich die Handelsbeziehungen nach Westen und Osten? Welche Personengruppen partizipierten an dem Handel? Welche Güter wurden in der Stadt und im Umland produziert? ...
Wim Broekaert, der bereits durch mehrere Aufsätze die Erforschung der kaiserzeitlichen Wirtschaftsgeschichte bereichert hat1, hat nun seine umfängliche Dissertation zu Schiffern und Kaufleuten/Händlern im lateinischen Westen vorgelegt. Das Buch ist eine prosopographische Arbeit, die es sich – wie Broekaert in der Einleitung (S. 6-8) formuliert – zum Ziel setzt, die sozialökonomische Organisation des wirtschaftlichen Handels zu beleuchten. Zu Recht wird einleitend bemerkt, dass eine Zusammenstellung des inschriftlichen Materials, das Aussagen über die sozialen Verknüpfungen und Strukturen, die wirtschaftlichen Handlungen zugrundliegen, bisher nicht erfolgt ist. Prospographische Untersuchungen als Bestandteil der Forschungen zur antiken Wirtschaft wurden gleichfalls bisher nicht unternommen. Broekaerts Untersuchung, das darf vorab gesagt werden, zeigt jedoch eindringlich den Mehrwert und das Potenzial der Prosopographie für die Erforschung der antiken Wirtschaft...
Rezension zu: Philip Matyszak, Legionär in der römischen Armee. Der ultimative Karriereführer
(2014)
Überblicksdarstellungen zum römischen Militärwesen erfreuen sich steter Beliebtheit. Meist wird dabei die Armee als Institution in ihrer Gesamtheit in den Blick genommen. Studien, die sich primär mit der Lebenswelt der Soldaten beschäftigen, finden sich hingegen selten, stattdessen tauchen sie in der Regel als Unterkapitel in den o.g. Überblicksdarstellungen auf. Philip Matyszak richtet in dem vorliegenden Buch den Blick ausschließlich auf den einfachen Soldaten und stellt dessen Alltagsleben in der römischen Armee dar. Das im Untertitel humorvoll als „Karriereführer“ bezeichnete Werk bietet eine Momentaufnahme des Dienstalltags in der Zeit um 100 n. Chr...
„Die Publikationen zum antiken Mythos sind fast unüberschaubar“ (5), bemerkt U. Reinhardt in der kurzen Einführung des mit „Der antike Mythos“ betitelten ersten Bandes seines zweiteiligen Werkes zum Komplex Mythos – Sagen – Märchen. Er selbst möchte sich von diesen abheben, indem er sich nicht nur mit dem Phänomen Mythos beschäftigt, sondern ausführlich diskutiert, was überhaupt unter diesem Begriff zu verstehen ist bzw. verstanden werden kann. Darüber hinaus behandelt Reinhardt auch die Ursprünge und konstitutiven Grund- sowie die wesentlichen Zusatzkategorien des frühgriechischen Mythos, um zuletzt die kulturhistorische Gesamtentwicklung darzulegen. Diesem Vorhaben sind insgesamt fünf Hauptkapitel und sechs Exkurse gewidmet. Zu Recht kann man somit von einem „systematischen Handbuch“ sprechen, welches sich deutlich abhebt von Lexika wie Roschers siebenbändigem „Ausführlichen Lexikon der griechischen und römischen Mythologie“ (1884-1937) und eher ‚erzählenden‘ Handbüchern wie Gantz’ zweiteiligem „Early Greek Myth: A Guide to Literary and Artistic Sources“ (1993)...
Die hier angezeigte Sammlung Kleiner Schriften des Althistorikers Gustav Adolf Lehmann enthält einen Großteil seiner publizierten Artikel und Rezensionen. Insgesamt 56 Beiträge, darunter eine Monographie, 46 fachliche Aufsätze, fünf Rezensionen, zwei biographische Beiträge zu Eduard Meyer, ein Nachruf auf Jochen Bleicken sowie eine Laudatio auf Hans Erich Stier, verteilen sich auf zwei Bände mit einem Gesamtumfang von 1074 Seiten. Die Anordnung der Schriften erfolgt in chronologischer Reihenfolge der behandelten Themen in insgesamt fünf großen Kapiteln: von der frühgriechischen Geschichte und derjenigen des Alten Orients bis zum frühen Principat (1-795). Im Anschluss folgen Beiträge zur antiken Historiographie (797-979) und zur Wissenschaftsgeschichte (981-1047). Den Beiträgen vorangestellt ist ein kurzes Vorwort (V-VI). Ein Schriftenverzeichnis (1049-1059) sowie ein Index (1061-1074, mit den erwähnten Namen und Orten), der „nur eine erste grobe Orientierung“ (V-VI) ermöglichen soll, beschließen den Doppelband...
Der von STEFFEN DIEFENBACH und GERNOT MICHAEL MÜLLER herausgegebene Tagungsband (zugleich Band 43 der Millenium-Studien) beschäftigt sich mit dem Westen des römischen Reichs in der Spätantike und fokussiert sich auf die tiefgreifenden Veränderungen vom frühen 5. bis zum ausgehenden 6. Jahrhundert, die zeitgleich, aber nicht unbedingt synchron abliefen und so gerade in der älteren Forschung den Eindruck eines katastrophischen Niedergangs aufkommen ließen. In der Einleitung plädieren DIEFENBACH und MÜLLER dafür, diese Zeit als einen „Strukturwandel mittlerer Reichweite“ anzusehen und erörtern die relevanten Aspekte wie die sichverändernden Formen der Herrschaftsbildung und der politischen sowie kulturellen Vergemeinschaftung, die Widerstand hervorrufende staatliche Durchdringung z.B. von ländlichen Regionen und die neuen kirchlichen Strukturen (S. 1)...
Rezension zu: Sara Stöcklin-Kaldewey, Kaiser Julians Gottesverehrung im Kontext der Spätantike
(2014)
Von einem nachlassendem Interesse an der Gestalt des letzten Kaisers der konstantinischen Dynastie, der sich vom Christentum abwandte, kann wahrlich nicht gesprochen werden. Erst im vergangenen Jahr (2013) ist die Arbeit von Th. Nesselrath erschienen, die nach den Konzepten und Vorbildern der Repaganisierung des Reiches fragte. Nun hat S. Stöcklin-Kaldewey eine Dissertation vorgelegt, die von M. Wallraff (Universität Basel, Kirchen- und Theologiegeschichte; evang.) betreut wurde und die allein schon durch ihren Umfang (456 Seiten) beeindruckt. Die Biographie des Kaisers wird nur ganz sporadisch behandelt, seine politischen Maßnahmen werden ausgeblendet (vgl. S. 13). Umso mehr ist das Buch für Philosophen und Religionswissenschaftler eine anspruchsvolle, aber auch höchst bereichernde Lektüre. Die große Zahl an Werken, die aus der Feder des Kaisers erhalten ist, bietet zweifellos eine hervorragende Basis, die die Vf. im besten Sinne genutzt hat für ihre Frage nach Julians Gottesverehrung im Kontext der Spätantike. Wer das Buch gründlich liest, wird schnell feststellen, dass ihm hier mehr geboten wird, als der Titel vermuten lässt. Die Vf. sieht in Julian mit Recht „eine Schlüsselfigur für das Verständnis der religiösen Kultur der Spätantike“ (S.2) mit ihrer „wechselseitigen Durchdringung verschiedener religiöser Sphären“ (S.4)...