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The Central Nigerian Nok Culture has been well known for its elaborate terracotta sculptures and evidence of iron metallurgy since its discovery by British archaeologist Bernard Fagg in the 1940s. With a date in the first millennium BCE, both, sculptures and ironworking, belong to the earliest of their kind in sub-Saharan Africa. After a period of destruction of Nok sites by looting, scientific research resumed in 2006, when a team of archaeologists from Goethe University in Germany started to explore different Nok Culture aspects, one of which focused on chronology. Establishing a chronology for the Nok Culture employed two approaches: a comprehensive pottery analysis based on decoration and form elements and a wealth of radiocarbon dates from a large number of excavated sites. This volume presents the radiocarbon dates and the methods, data and results of the chronological pottery analysis, conducted within the scope of a dissertation project completed in 2015. Combining the two strands of information, a chronology emerges, dividing the Nok Culture into three phases from the middle of the second millennium BCE to the last centuries BCE and defining seven pottery groups that can be arranged to some extent in a chronological order.
The degradation of cytosol-invading pathogens by autophagy, a process known as xenophagy, is an important mechanism of the innate immune system. Inside the host, Salmonella Typhimurium invades epithelial cells and resides within a specialized intracellular compartment, the Salmonella-containing vacuole. A fraction of these bacteria does not persist inside the vacuole and enters the host cytosol. Salmonella Typhimurium that invades the host cytosol becomes a target of the autophagy machinery for degradation. The xenophagy pathway has recently been discovered, and the exact molecular processes are not entirely characterized. Complete kinetic data for each molecular process is not available, so far. We developed a mathematical model of the xenophagy pathway to investigate this key defense mechanism. In this paper, we present a Petri net model of Salmonella xenophagy in epithelial cells. The model is based on functional information derived from literature data. It comprises the molecular mechanism of galectin-8-dependent and ubiquitin-dependent autophagy, including regulatory processes, like nutrient-dependent regulation of autophagy and TBK1-dependent activation of the autophagy receptor, OPTN. To model the activation of TBK1, we proposed a new mechanism of TBK1 activation, suggesting a spatial and temporal regulation of this process. Using standard Petri net analysis techniques, we found basic functional modules, which describe different pathways of the autophagic capture of Salmonella and reflect the basic dynamics of the system. To verify the model, we performed in silico knockout experiments. We introduced a new concept of knockout analysis to systematically compute and visualize the results, using an in silico knockout matrix. The results of the in silico knockout analyses were consistent with published experimental results and provide a basis for future investigations of the Salmonella xenophagy pathway.
Author Summary
Salmonellae are Gram-negative bacteria, which cause the majority of foodborne diseases worldwide. Serovars of Salmonella cause a broad range of diseases, ranging from diarrhea to typhoid fever in a variety of hosts. In the year 2010, Salmonella Typhi caused 7.6 million foodborne diseases and 52 000 deaths, and Salmonella enterica was responsible for 78.7 million diseases and 59 000 deaths. After invasion of Salmonella into host epithelial cells, a small fraction of Salmonella escapes from a specialized intracellular compartment and replicates inside the host cytosol. Xenophagy is a host defense mechanism to protect the host cell from cytosolic pathogens. Understanding how Salmonella is recognized and targeted for xenophagy is an important subject of current research. To the best of our knowledge, no mathematical model has been presented so far, describing the process of Salmonella Typhimurium xenophagy. Here, we present a manually curated and mathematically verified theoretical model of Salmonella Typhimurium xenophagy in epithelial cells, which is consistent with the current state of knowledge. Our model reproduces literature data and postulates new hypotheses for future investigations.
Recently a considerable amount of effort has been put into quantifying how interactions of the carbon and nitrogen cycle affect future terrestrial carbon sinks. Dynamic vegetation models, representing the nitrogen cycle with varying degree of complexity, have shown diverging constraints of nitrogen dynamics on future carbon sequestration. In this study, we use LPJ-GUESS, a dynamic vegetation model employing a detailed individual- and patch-based representation of vegetation dynamics, to evaluate how population dynamics and resource competition between plant functional types, combined with nitrogen dynamics, have influenced the terrestrial carbon storage in the past and to investigate how terrestrial carbon and nitrogen dynamics might change in the future (1850 to 2100; one representative "business-as-usual" climate scenario). Single-factor model experiments of CO2 fertilisation and climate change show generally similar directions of the responses of C–N interactions, compared to the C-only version of the model as documented in previous studies using other global models. Under an RCP 8.5 scenario, nitrogen limitation suppresses potential CO2 fertilisation, reducing the cumulative net ecosystem carbon uptake between 1850 and 2100 by 61%, and soil warming-induced increase in nitrogen mineralisation reduces terrestrial carbon loss by 31%. When environmental changes are considered conjointly, carbon sequestration is limited by nitrogen dynamics up to the present. However, during the 21st century, nitrogen dynamics induce a net increase in carbon sequestration, resulting in an overall larger carbon uptake of 17% over the full period. This contrasts with previous results with other global models that have shown an 8 to 37% decrease in carbon uptake relative to modern baseline conditions. Implications for the plausibility of earlier projections of future terrestrial C dynamics based on C-only models are discussed.
Raytracing und Szenegraphen
(2006)
Raytracing ist ein bekanntes Verfahren zur Erzeugung fotorealistischer Bilder. Globale Beleuchtungseffekte einer 3D-Szene werden durch das Raytracing-Verfahren physikalisch korrekt dargestellt. Erst aktuelle Forschungsarbeiten erm¨oglichen es, das sehr rechenintensive Verfahren bei interaktiven Bildraten in Echtzeit zu berechnen.
Komplexe 3D-Szenen, wie sie beispielsweise in 3D-Spielen oder Simulationen vorkommen, können durch einen Szenengraphen modelliert und animiert werden. Damit die Rendering-Ergebnisse eines Szenengraphen n¨aher an einem realen Bild liegen, ist es erforderlich das Raytracing-Verfahren in einen Szenengraphen einzugliedern.
In dieser Arbeit werden die Möglichkeiten zur Integration eines Echtzeit-Raytracers in eine Szenengraph-API untersucht. Ziel dieser Diplomarbeit ist die Darstellung dynamischer Szenen bei interaktiven Bildraten unter Verwendung des Raytracing-Verfahrens auf einem herk¨ommlichen PC. Zun¨achst m¨ussen bestehende Open Source Szenengraph-APIs und aktuelle Echtzeit-Raytracer auf ihre Eignung zur Integration hin überprüft werden.
Bei der Verarbeitung dynamischer Szenen spielt die verwendete Beschleunigungsdatenstruktur des Raytracers eine entscheidende Rolle. Da eine komplette Neuerstellung der Datenstruktur in jedem Bild zuviel Zeit in Anspruch nimmt, ist eine schnelle und kostengünstige Aktualisierung erforderlich. Die in [LAM01] vorgestellte Lösung, eine Hüllkörperhierarchie (BVH) als Beschleunigungsdatenstruktur zu verwenden, fügt sich sehr gut in das Konzept eines Szenengraphen ein. Dadurch wird eine einfache Aktualisierung ermöglicht.
Um das Ziel dieser Arbeit zu erreichen, ist es notwendig, die Parallelisierbarkeit des Raytracing-Verfahrens auszunutzen. Purcell zeigt in [Pur04], dass Grafikprozessoren (GPUs) neben ihrer eigentlichen Aufgabe auch für allgemeine, parallele Berechnungen wie das Raytracing verwendet werden können.
Die in bisherigen Arbeiten über GPU-basiertes Raytracing entwickelten Systeme können dynamische Szenen nicht bei interaktiven Bildraten darstellen. Aus diesem Grund wird in dieser Diplomarbeit ein neues System konzipiert und implementiert, das den in [TS05] entwickelten Raytracer erweitert und in die Open Source Szenengraph-API OGRE 3D integriert.
Das implementierte System ermöglicht die Darstellung statischer und dynamischer Szenen unter Verwendung einer Consumer-Grafikkarte bei interaktiven Bildraten. Durch seine Erweiterbarkeit bildet das System das Grundger¨ust für ein Realtime-High-Quality-Rendering-System.
We study the impact of higher capital requirements on banks’ balance sheets and its transmission to the real economy. The 2011 EBA capital exercise provides an almost ideal quasi-natural experiment, which allows us to identify the effect of higher capital requirements using a difference-in-differences matching estimator. We find that treated banks increase their capital ratios not by raising their levels of equity, but by reducing their credit supply. We also show that this reduction in credit supply results in lower firm-, investment-, and sales growth for firms which obtain a larger share of their bank credit from the treated banks.
This paper studies the role of the Community Reinvestment Act (CRA) in the recent US housing boom-bust cycle. Using a difference-in-differences matching estimation, I find that the enhancement of CRA enforcement in 1998 caused a 7.7 percentage points increase in annual growth rate of mortgage lending by CRA-regulated banks to CRA-eligible census tracts relative to a group of similar-income CRA-ineligible census tracts within the same state. Financial institutions which are not subject to the CRA, however, do not show any change in their mortgage supply between these two types of census tracts after 1998. I take advantage of this exogenous shift in mortgage supply within an instrumental variable framework to identify the causal effect of mortgage supply on housing prices. I find that every 1 percentage point higher annual growth rate of mortgage supply leads to 0.3 percentage points higher annual growth rate of housing prices. Reduced form regressions show that CRA-eligible neighborhoods experienced higher house price growth during the boom and sharper decline during the bust period. I use placebo tests to confirm that this effect is in fact channeled through the shift in mortgage supply by CRA-regulated banks and not by unobserved demand factors. Furthermore, my results indicate that CRA-induced mortgages went to borrowers with lower FICO scores, carried higher interest rates, and encountered more frequent delinquencies.
In order to better differentiate the drivers of corporations’ actions, in particular shareholder wealth and stakeholder interests, the paper explores the significance of the comply or explain-principle and its underlying enforcement mechanisms more generally. Against this background, compliance rates with specific provisions may shed a light on companies’ reasons for following the code. An analysis of these rates at the example of distinct provisions of the German Corporate Governance Code is therefore entered into. In light of the current corporate governance debate and the legitimacy problems that are raised, among the code provisions that exemplify these questions very well are those regulating incentive pay, severance pay caps, and age limits for supervisory board members. Their analysis will lay a basis for an answer to the question about what motivates companies to comply with the code. The motivation then paves the way to arrive at a further specification of the determinants of the regulatory evolution of the Code and the range of stakeholders and their concerns that enter into it.
owards their best performing products; and also extend the range of products sold to that market. We develop a theoretical model of multiproduct firms and derive the specific demand and cost conditions needed to generate these product-mix reallocations. Our theoretical model highlights how the increased competition from demand shocks in export markets - and the induced product mix reallocations - induce productivity changes within the firm. We then empirically test for this connection between the demand shocks and the productivity of multi-product firms exporting to those destinations. We find that the effect of those demand shocks on productivity are substantial - and explain an important share of aggregate productivity fluctuations for French manufacturing.
We use detailed data on exporters from Costa Rica, Ecuador and Uruguay as well as on their buyers to show that: aggregate exports are disproportionally driven by few multi-buyers exporters; and each multi-buyer exporter's foreign sales of any product are in turn accounted for by few dominant buyers. We propose an analytically solvable multi-country model of endogenous selection in which dominant exporters, dominant products and dominant buyers emerge in parallel as multi-product sellers with heterogeneous technologies compete for buyers with heterogeneous needs. The model not only provides an explanation of the existence of dominant buyers but also makes specific predictions on how the relative importance of dominant buyers should vary across export destinations depending on their market size and accessibility. We show that these predictions are borne out by our data and discuss their welfare implications in terms of gains from trade.
For the transport of high-intensity hadron beams in low-energy beam lines of linear accelerators, the compensation of space charge forces by the accumulation of particles of opposite charge is an important effect, reducing the required focusing strength and potentially the emittance growth due to space charge forces. In this thesis, space charge compensation was studied by including the secondary particles in particle-in-cell simulations.
For this purpose, a new electrostatic particle-in-cell code named bender was developed. The software was tested using known self-consistent solutions for an electron plasma confined in an external potential as well as for a KV distributed beam in a periodic focusing lattice. For the simulation of compensation, models for residual gas ionisation by proton and electron impact were implemented.
The compensation process was studied for a 120 keV, 100 mA proton beam transported through a short drift section. Various features in the particle distributions were identified, which can not explained by a uniform reduction in the electric field of the beam. These were tied to the presence of thermal electrons confined within the beam potential. Using the Poisson-Boltzmann equation, their distribution could be reproduced and their influence on the beam for a wider range of parameters studied. However, the observed temperatures show a significant numerical influence. The hypothesis was formed, that stochastical heating present in particle-in-cell simulations is the mechanism leading to the formation of the observed (partial) thermal equilibrium.
For the low-energy beam transport line of the Frankfurt neutron source FRANZ, bender was used to predict the pulse shaping in the novel ExB chopper system. The code was also used for the design and the study of an electron lens for the Integrable Optics Test Accelerator at Fermi National Accelerator Laboratory. Aberrations due to guiding center drifts and the strong electric field of the electron beam as well as the current limits in such a system were investigated.
This paper explores the impact of immigrants on the imports, exports and productivity of service- producing firms in the U.K. Immigrants may substitute for imported intermediate inputs (offshore production) and they may impact the productivity of the firm as well as its export behavior. The first effect can be understood as the re-assignment of offshore productive tasks to immigrant workers. The second can be seen as a productivity or cost cutting effect due to immigration, and the third as the effect of immigrants on specific bilateral trade costs. We test the predictions of our model using differences in immigrant inflows across U.K. labor markets, instrumented with an enclave-based instrument that distinguishes between aggregate and bilateral immigration, as well as immigrant diversity. We find that immigrants increase overall productivity in service-producing firms, revealing a cost cutting impact on these firms. Immigrants also reduce the extent of country-specific offshoring, consistent with a reallocation of tasks and, finally, they increase country-specific exports, implying an important role in reducing communication and trade costs for services.
In light of increasing division of labour in healthcare, the training and acquisition of both profession-specific and interprofessional competencies have been attributed growing significance, creating the need to test and establish specific teaching formats. Despite ever more complex and interconnected healthcare systems, an increase in patients’ active self-responsibility and innumerable pedagogical and technological innovations, educational systems have not reacted adequately to these new demands. Many authors, not lease the German Council of Science and Humanities, have therefore urged a rethinking of traditional medical education. Student-centred learning activities, such as problem-based and research-based learning, are becoming increasingly significant in view of the numbers of students achieving unsatisfactory levels of competence in critical thinking, communication and writing abilities and complex clinical decision making, for example. The Council of Science and Humanities arrived at a positive evaluation of the various model and reformed courses of study attempting to effectuate a comprehensive reorganisation of medical studies in content and structure as well as methods and didactics. The persistent pervasiveness of instructor-centred learning formats is not only to be found in medical education but in all of the health professions. Although alternative teaching and instruction formats have already been designed and their effectiveness deemed positive in empirical evaluation, the lecture remains the most practised means of transmitting knowledge. In its essence, however, learning is not a question of transmitting information but, moreover, a question of processing information. In traditional instruction units, referred to as “chalk and talk classes” by Becker and Watts, the teaching party presents material in the form of a lecture. As appropriate, questions may be permitted or short processing periods for the students may be integrated into the lecture. The knowledge-assimilating and most essential analysis of the lecture’s contents takes place in the subsequent self-instruction phase, in which the student works alone on concrete tasks. It is during the transfer of knowledge conveyed in the lectures, however, that most questions arise. Of further disadvantage in the traditional lecture is the low level of motivation among students to attend lectures as well as their often heterogeneous knowledge. The Inverted Classroom Model seems to be an eligible instrument for greater facilitation of student-centred and interprofessional learning.
Dieser Artikel beschreibt die Inverted-Classroom-Methode(ICM) im Sinne einer Einführung in die Thematik und soll als Praxisleitleitfaden für diejenigen dienen, die diese Methode in der medizinischen Aus-, Fort- und Weiterbildung einsetzen möchten. Es handelt sich bei der ICM um einen Blended-Learning-Methode, bei dem eine Selbstlernphase (individuelle Phase) vor die Präsenzunterrichtsphase gesetzt wird. In der Online-Phase wird Faktenwissen vermittelt, das als Grundlage für die Präsenzphase dient. Die Präsenzphase soll anschließend dafür genutzt werden, das erlernte Wissen zu vertiefen und anzuwenden. Dem gegenüber stehen die traditionellen Kurskonzepte, in denen das Faktenwissen beispielsweise in Vorlesungen oder in anderen Präsenzunterricht-Formaten vermittelt wird und die Vertiefung dieses Wissens durch die Studierenden im Anschluss daran im Selbststudium stattfinden soll. Das Ziel der ICM ist die Verschiebung des passiven Lernens hin zum aktivierenden Lernen, um das Lernen auf kognitiv anspruchvollen Ebenen wie Analyse, Synthese und Evaluation zu unterstützen. Dabei haben die gestiegene Produktion und Nutzung von Screencasts und Lernvideos, die „Bewegung“ der „Open Educational Resources“ und die verbreitete Nutzung von „Massive Open Online Courses“ (MOOCs) zu einer gestiegenen Verbreitung der Inverted-Classroom-Methode beigetragen. Der Artikel soll als Einführung in die Thematik dienen und dabei eine kurze Übersicht über wichtige Projekte und Forschungsergebnisse in der medizinischen Ausbildung und in weiteren Gesundheitsberufen geben. Außerdem werden die Vor- und Nachteile der Methode und ihr potentieller Nutzen für die zukünftige medizinische Aus- und Weiterbildung dargestellt.
Himaloaesalus gaoligongshanus Huang and Chen, new species (Coleoptera: Lucanidae: Aesalinae) is described from the Gaoligongshan Mts., Yunnan, China. It is the fi fth species of the genus Himaloaesalus Huang and Chen. This new species is similar to the Himalayan species Himaloaesalus himalayicus Kurosawa and H. saburoi Araya et al., from which it is distinguished. The male and female genitalia of all the known species of Himaloaesalus are illustrated. Dorcus yongreni Huang and Chen, new species (Coleoptera: Lucanidae: Lucaninae) is described from Ruili area, Yunnan, China. It belongs to the elegans group (Huang and Chen 2013). This new species is similar to the Indian species Dorcus apatani (Okuda and Maeda), new combination, originally described in Digonophorus Waterhouse. The male genitalia of both species are compared and illustrated.
El género Oogenius Solier, 1851, es revisado y ahora incluye siete especies: O. arrowi Gutiérrez (Argentina), O. castilloi Martínez y Peña (Chile), O. chilensis Ohaus (Chile), O. kuscheli Gutiérrez (Chile), O. lariosae Martínez (Argentina), O. penai Mondaca (Chile), y O. virens Solier (Chile). El género es redescrito, adultos macho y hembra de cada una de las especies son caracterizados, fotografi ados, y los caracteres morfológicos de valor diagnóstico ilustrados. Se incluye una clave de identifi cación, un mapa de distribución e información general sobre la biología de las especies. Basado en el estudio del material tipo, O. chilensis barrosi Gutiérrez, 1949, es considerado un nuevo sinónimo de O. chilensis Ohaus, 1905. Se designan lectotipos para Oogenius chilensis Ohaus, 1905 y Oogenius virens Solier, 1851.
Four species of the genus Enoclerus (Coleoptera: Cleridae) are reported to prey on chemically protected Coccinellidae in North America. The possibility that aposematically colored Enoclerus also mimic prey ladybird species is discussed, and the further possibility that clerid predators acquire chemical protection through sequestration of ladybird prey’s toxic alkaloids is suggested as an important avenue of investigation. The data presented are primarily based on photographs taken by non-specialists, discovered through Internet search. The crowdsourcing of natural history observations can reveal aspects of animal behavior heretofore unreported and even unsuspected.
Two new species of Eburiini (Coleoptera, Cerambycidae, Cerambycinae) are described from Mexico (Guerrero): Susuacanga boteroi; and Eburia (Eburia) girouxae. Both are included in previous keys.
The Republic of Panama currently has 300 recorded species of Trichoptera distributed among 14 families. Herein we add 42 new country records for Panama, including one new family (Anomalopsychidae) and three new genera (Anomalopsychidae: Contulma; Hydroptilidae: Byrsopteryx and Cerasmatrichia). The newly recorded caddisfly taxa increase Panama’s total known fauna to 342 species, distributed among 15 families and 50 genera. These results are part of an ongoing effort to characterize the caddisfly fauna of Panama, and to evaluate that country’s major watersheds (cuencas).
A new species of Neostenoptera (Diptera: Cecidomyiidae: Winnertziinae) from eastern North America
(2016)
A new species of paedogenetic gall midge, Neostenoptera appalachiensis sp. nov., (Diptera: Cecidomyiidae: Winnertziinae: Heteropezini) from the eastern United States is described and illustrated, and pertinent collection and biological data are also provided. It is compared to its congeners, N. kiefferi (Meunier), a subfossil described from African copal, and N. congoensis Gagné, from the Congo. This rare, exciting discovery is the first record of the genus Neostenoptera in the New World.
Parajulid milliped studies XI : Initial assessment of the tribe Gosiulini (Diplopoda: Julida)
(2016)
The parajulid milliped tribe Gosiulini (Diplopoda: Julida) comprises two genera – Gosiulus Chamberlin, with three projections on the posterior gonopod and two species in the southcentral/southwestern United States (US) [Arizona, Colorado, New Mexico, and Texas], and monotypic Minutissimiulus Shelley, n. gen., with two projections, in Nuevo León, Mexico. Gosiulus conformatus Chamberlin occupies the plains/fl atlands of Texas, while its congener inhabits high elevations to the west in all four US states. Both are anticipated in Mexico (Coahuila, Chihuahua, and Sonora), and G. conformatus is expected in southeastern Colorado, eastern New Mexico, and the Oklahoma panhandle. The eastern boundary of G. conformatus and the genus/tribe conforms to the western border of the Piney Woods biome in eastern Texas. As shown by the posterior gonopod drawing in the original description, Parajulus timpius Chamberlin, previously considered of “uncertain generic position or validity,” is unquestionably the oldest name for the western species. The anteriormost posterior gonopod projection, absent from Minutissimiulus, is considered the “prefemoral process,” while the “solenomere” and a third branch arise from a common base.
Because of positional homology with “process ‘C’” in Nesoressini, the last projection is accorded this name, which may also apply to the “prefemoral process” in Aniulini. Minutissimiulus biramus Shelley, n. sp., is proposed along with the following new subjective synonymies: Apacheiulus Loomis under Gosiulus; Ziniulus aethes and Z. medicolens, both by Chamberlin, and Z. ambiguus and Z. nati, both by Loomis, under G. conformatus; and A. pinalensis and A. guadelupensis, both by Loomis, under G. timpius, new combination. Ziniulus navajo Chamberlin becomes an objective synonym of P. timpius because its holotype is designated neotype of the latter. Minutissimiulus biramus Shelley is the fi rst Mexican gosiuline and “mainland” Mexican parajulid not in the tribe Parajulini.
Sandrart.net
(2014)
Sandrart.net describes itself as a ‘research platform for the history of art and culture of the 17th century’. It is a digital edition of Joachim von Sandrart’s magnum opus, the ‘Teutsche Academie’, published between 1675 and 1680 in a German and between 1680 and 1684 in a Latin version. Facsimiles and full texts for both publications are provided as well as a bibliography and additional texts. Browse and search functionalities allow for easy access. Particular emphasis lies on commenting the text and identifying entities such as places, works of art or persons, for which extensive dossiers are provided. These kind of information can also be downloaded as raw XML and as semantic data expressed in RDF. The project undoubtedly marks the state of the art in the critically digitizing and editing 17th century prints.
Es wird davon ausgegangen, dass das ehemalige Larven-Mikrohabitat der Asiatische Tigermücke Aedes albopictus (synonym: Stegomyia albopicta) die Phytotelmata in den Waldgebieten von Südostasien darstellte. In den letzten vier Jahrzehnten adaptierte sich die Art jedoch an urbanere Regionen und ihre Antrotelmata. Dank ihrer Eigenschaft, Eier mit einer gewissen Trocken- und Kältetoleranz zu produzieren, verbreitete sich die Art zusammen mit den international gehandelten Waren weltweit. Zudem ist Ae. albopictus ein theoretischer Vektor für mindestens 27 Viren sowie Parasiten und spielt eine Hauptrolle bei der Übertragung von Dengue-Viren und Chikungunya-Viren und Zika-Vieren. Daher wird die Art als große Gefahr für die öffentliche Gesundheit betrachtet.
Die vorliegende Arbeit thematisiert drei Untersuchungen zum Anpassungs- und Etablierungs-potential der invasiven Asiatischen Tigermücke.
In einem ersten Ansatz wurde das Problem behandelt, dass es lediglich zwei standardisierte toxikologische Testverfahren für Culicidae gab. Daher wurde ein Dosis-Wirkungs-Testsystem entwickelt, das den Weg für weitere biologische Endpunkte und ihre integrativen Parameter freimachte und dadurch ein besseres Verständnis für die Wirkweisen von Insektiziden ermöglicht. Hierdurch konnte nun der Frage nachgegangen werden, ob es Unterschiede in der ökotoxikologischen Reaktion zwischen der invasiven tropisch-subtropischen Asiatischen Tigermücke und der einheimischen nördlichen Hausstechmücke Culex pipiens auf das Insektizid λ-Cyhalothrin gibt. Weiter wurde der Einfluss von Temperatur und die Verfügbarkeit von Nahrung auf die Insektizidsensitivitäten der Arten getestet. Schließlich konnte in einer Risikobewertung festgestellt werden, dass bei falsch angewendeten Bekämpfungsmaßnahmen höhere Temperaturen sowie der Ausfall von aquatischen Top-Prädatoren zu Fitnessvorteilen für die Art führen können.
In einer zweiten Untersuchung wurde der Mechanismus der Kältetoleranz der Eier (Kälteakklimatisierung und Diapause) näher untersucht, da dieser für die erfolgreiche Invasion in gemäßigten Breitengraden verantwortlich gemacht wird. Nachdem eine lang vorherrschende Hypothese verworfen wurde, dass die Einlagerung von Polyolen die Frosttoleranz bewirken würde, war der aktuelle Stand der Wissenschaft, dass eine Verdickung der Wachsschicht des Chorions dafür verantwortlich sei. Jedoch lag keine detaillierte Evaluierung von Stechmücken-Eihüllen vor. Mittels einer transmissionselektronenmikroskopischen Studie konnte gezeigt werden, dass nicht nur die Wachsschicht nicht in der Serosa-Cuticula zu verorten ist, sondern im Endochorion und sie zudem im Zuge der Diapause in der Mächtigkeit schrumpft. Daher wird auf Basis der gewonnenen Erkenntnisse auf eine Kompaktierung der Schicht geschlossen.
Die dritte Untersuchung schließlich hatte das hohe Adaptationspotential in gemäßigten Breiten zum Gegenstand. Eine Adaptation auf genetischen Level gilt als unwahrscheinlich, da Gründerpopulationen in den neu besiedelten Gebieten eine niedrige genetische Diversität aufwiesen und ein regelmäßiger Neueintrag von Allelen unwahrscheinlich ist. Jedoch bietet das Konzept der epigenetischen Temperatur-Adaptation einen Erklärungsansatz für dieses Phänomen. Daher wurde die Frage gestellt, ob es möglich ist, eine vererbbare Diversifizierung dieses kältetoleranten Phänotyps nach einer randomisierten epigenetischen Behandlung der DNA zu detektieren. Es wurde eine transgenerationale Untersuchung der Effekte von zwei epigenetischen Agenzien (und einem Lösemittel) auf die Kältetoleranz der Eier durchgeführt. Die Ergebnisse zeigten ein Korrelationsmuster, das den durch die Agenzien veränderten Methylierungsgrad der DNA mit der Forsttoleranz verband, was die gestellte Hypothese unterstützte.
In Folge dieser drei Untersuchungen wurde festgestellt, dass Ae. albopictus ein hohes Potential hat, in weiteren Ländern – vor allem in gemäßigten Breiten – ein Gesundheitsrisiko darzustellen. Da die Art einerseits Fitnessvorteile durch falsche Bekämpfungsmaßnahmen und andererseits möglicherweise eine hohes epigenetisches Adaptationspotential besitzt, kann zusammenfassend empfohlen werden, dass der Fokus für weitere Forschung maßgeblich auf der Entwicklung von Impfstoffen für die übertragenen Viren und Pathogene liegen sollte. Dadurch kann die Bevölkerung geschützt werden, ohne Ökosysteme und ihre Dienstleistungen zu gefährden, und dies wäre zudem ökonomisch gesehen die effektivere Lösung.
When assessing global water resources with hydrological models, it is essential to know about methodological uncertainties. The values of simulated water balance components may vary due to different spatial and temporal aggregations, reference periods, and applied climate forcings, as well as due to the consideration of human water use, or the lack thereof. We analyzed these variations over the period 1901–2010 by forcing the global hydrological model WaterGAP 2.2 (ISIMIP2a) with five state-of-the-art climate data sets, including a homogenized version of the concatenated WFD/WFDEI data set. Absolute values and temporal variations of global water balance components are strongly affected by the uncertainty in the climate forcing, and no temporal trends of the global water balance components are detected for the four homogeneous climate forcings considered (except for human water abstractions). The calibration of WaterGAP against observed long-term average river discharge Q significantly reduces the impact of climate forcing uncertainty on estimated Q and renewable water resources. For the homogeneous forcings, Q of the calibrated and non-calibrated regions of the globe varies by 1.6 and 18.5 %, respectively, for 1971–2000. On the continental scale, most differences for long-term average precipitation P and Q estimates occur in Africa and, due to snow undercatch of rain gauges, also in the data-rich continents Europe and North America. Variations of Q at the grid-cell scale are large, except in a few grid cells upstream and downstream of calibration stations, with an average variation of 37 and 74 % among the four homogeneous forcings in calibrated and non-calibrated regions, respectively. Considering only the forcings GSWP3 and WFDEI_hom, i.e., excluding the forcing without undercatch correction (PGFv2.1) and the one with a much lower shortwave downward radiation SWD than the others (WFD), Q variations are reduced to 16 and 31 % in calibrated and non-calibrated regions, respectively. These simulation results support the need for extended Q measurements and data sharing for better constraining global water balance assessments. Over the 20th century, the human footprint on natural water resources has become larger. For 11–18% of the global land area, the change of Q between 1941–1970 and 1971–2000 was driven more strongly by change of human water use including dam construction than by change in precipitation, while this was true for only 9–13 % of the land area from 1911–1940 to 1941–1970.
Peptidyl arginine deiminase 4 (PAD4) is a nuclear enzyme that converts arginine residues to citrulline. Although increasingly implicated in inflammatory disease and cancer, the mechanism of action of PAD4 and its functionally relevant pathways remains unclear. E2F transcription factors are a family of master regulators that coordinate gene expression during cellular proliferation and diverse cell fates. We show that E2F-1 is citrullinated by PAD4 in inflammatory cells. Citrullination of E2F-1 assists its chromatin association, specifically to cytokine genes in granulocyte cells. Mechanistically, citrullination augments binding of the BET (bromodomain and extra-terminal domain) family bromodomain reader BRD4 (bromodomain-containing protein 4) to an acetylated domain in E2F-1, and PAD4 and BRD4 coexist with E2F-1 on cytokine gene promoters. Accordingly, the combined inhibition of PAD4 and BRD4 disrupts the chromatin-bound complex and suppresses cytokine gene expression. In the murine collagen-induced arthritis model, chromatin-bound E2F-1 in inflammatory cells and consequent cytokine expression are diminished upon small-molecule inhibition of PAD4 and BRD4, and the combined treatment is clinically efficacious in preventing disease progression. Our results shed light on a new transcription-based mechanism that mediates the inflammatory effect of PAD4 and establish the interplay between citrullination and acetylation in the control of E2F-1 as a regulatory interface for driving inflammatory gene expression.
A revised annotated checklist for the butterfly family Lycaenidae (Lepidoptera) of Trinidad is presented, updating nomenclature, and indicating synonyms from earlier lists and papers. The checklist includes 131 species of Lycaenidae, comprising 127 species of 49 genera of Eumaeini, Theclinae, and four species of three genera of Polyommatinae.
There are more than 30 new island records. No lycaenid species is endemic to Trinidad, and the fauna consists primarily of widespread species (71%) that occur from Central America to the Amazon Basin. However, the primary biogeographic affi nity is the Amazon Region, where 94% of the Trinidad lycaenid fauna also occurs.
Corrections are made to the literature cited in the first author’s earlier checklists on other Trinidad butterflies.
The genus Rhinolaemus Steel is revised. A new island and a new country record are presented for the type species, R. maculatus Steel. A new species, R. niueensis Thomas, new species, is described from Niue, and Rhinolaemus tuberculatus (Grouvelle), new combination, is transferred from Laemophloeus (sens. lat.). The members of the genus are illustrated and a key to their identification is presented.
Epimelitta Bates, 1870 (Coleoptera, Cerambycidae) is redescribed with two species: Epimelitta scoparia (Klug, 1825) and Epimelitta rufiventris Bates, 1870; Epimelitta meliponica Bates, 1870 syn. nov. and Epimelitta acutipennis Fisher, 1947 syn. nov. are considered junior synonyms of E. scoparia. Exepimelitta gen. nov. is described with five species: Exepimelitta mimica (Bates, 1873), Ex. nigerrima (Bates, 1892), Ex. consobrina (Melzer, 1931) (=Epimelitta nigerrima var. flavipubescens Fisher, 1947, syn. nov.), Ex. lestradei (Peñaherrera-Leiva and Tavakilian, 2003) and Ex. windsori sp. nov. Charisia Champion, 1892 is revalidated and redescribed with six species: Charisia euphrosyne (Newman, 1840), C. mneme (Newman, 1841), C. melanaria Gounelle, 1911, C. ornaticollis Zajciw, 1973, C. bleuzeni (Peñaherrera-Leiva and Tavakilian, 2003) and C. durantoni (Peñaherrera-Leiva and Tavakilian, 2003).
Erratamelitta gen. nov. is described with two species: Erratamelitta erato (Newman, 1840) (= Epimelitta bicolor (Bates, 1873), syn. nov.) and Er. eliasi sp. nov.. Adepimelitta gen. nov. is described with two species: Adepimelitta debilis (Gounelle, 1911) and Ad. eupheme (Lameere, 1884). A brief synopsis of the genus Acorethra Bates, 1873 is presented, with two species included: Acorethra chrysaspis Bates, 1873, revalidated, and Ac. aureofasciata Gounelle, 1911. All species are illustrated (including genitalia when available); and keys to the genera, and their species, are provided.
Seven specimens of Sybra alternans (Wiedemann) (Cerambycidae: Lamiinae: Apomecynini) were captured with a UV light trap and by beating branches of trees in the urban area of Easter Island (Chile) during 2011–2016, representing the fi rst record of the species in this Chilean insular territory, but not continental Chile.
Sybra alternans is native to Southeast Asia and has been introduced accidentally to Hawaii and Florida in the United States of America. Data are presented from the literature on this species’ distribution, host plants, and biological information.
Taxonomic supplement (2001 to 2015) to the catalogue of New Zealand Carabidae (Insecta: Coleoptera)
(2016)
A supplement to the “Carabidae (Insecta: Coleoptera): catalogue” published by Larochelle and Larivière (2001; Fauna of New Zealand 43), is provided. A total of 99 genera and 547 species and subspecies belonging to 21 tribes and 8 subfamilies of Carabidae (including Cicindelini and Rhysodini), is recorded for New Zealand. Endemism is high, with 93% of the species and subspecies as well as 62% of the genera recorded from this country only. Changes to the 2001 catalogue are documented. The synonymy and type locality of taxa described between 2001 and 2015 are also provided.
The description of a new species of Kessleria (Lepidoptera: Yponomeutidae) is presented, based on male and female specimens obtained from laboratory rearing of material collected on their host, Maytenus boaria, of the central region of Chile.
Andaspis recurrens Takagi and Kawai, Hypaspidiotus jordani (Kuwana), Lepidosaphes kamakurensis (Kuwana) and Selenomphalus distylii Takagi from warm temperate forests are newly documented in the Korean fauna of armored scale insects (Hemiptera: Diaspididae). Characteristics of these species are briefl y given and illustrative photographs and information on their distribution and hosts are provided.
Nine new species of Hydroptilidae (Trichoptera) are described and illustrated from the western United States, Canada, Mexico, and Belize: Seven new species in the genus Neotrichia Morton, N. buenoi, N. chihuaha, N. contrerasi, N. maya, N. palitla, N. pinnacles, and N. sandersoni, one new species in the genus Oxyethira Eaton, O. pembertonensis, and one new species in the genus Metrichia Ross, M. mastelleri. As well, new records for N. mobilensis and Mayatrichia tuscaloosa and new illustrations of the male genitalia of Neotrichia jarochita Bueno-Soria and Mayatrichia tuscaloosa Harris and Sykora are provided.
The Iranian fauna of Cucujidae, Laemophloeidae, and Silvanidae (Coleoptera: Cucujoidea) are summarized in this paper. In total 2 species of Cucujidae (1 genus: Pediacus Shuckard), 6 species of Laemophloeidae (3 genera: Cryptolestes Ganglbauer, Laemophloeus Dejean, and Placonotus MacLeay) and 7 species of Silvanidae (6 genera: Uleiota Latreille, Psammoecus Latreille, Ahasverus Gozis, Nausibius Lentz, Oryzaephilus Ganglbauer, Psammoecus Latreille, and Silvanus Latreille) are listed in this paper. Synonymies and distribution data are given.
The previously published list of Coleoptera holotypes in the Museo de Historia Natural, Noel Kempff Mercado (MNKM), Santa Cruz, Bolivia is updated to include those deposited in the Museo since then though the end of 2015. Literature citations for the original descriptions of each listed holotype are also provided along with summary comments regarding family composition and authorship of included species. Photographs of collector, authors, habitats, and major Bolivian type repositories are provided.
Descriptions or diagnoses are given for 36 species of New World Eremoleon including 12 new species:
Eremoleon attenuatus, E. durangoensis, E. jacumba, E. jamaica, E. inca, E. monagas, E. morazani, E. pygmaeus, E. samne, E. tanya, E. tepuyiensis and E. venezolanus. A neotype is designated for Hesperoleon atomarius Navás 1933.
The larvae of 25 species are described and keyed. Keys to the adults and larvae are given, and biological notes are provided. Twenty-five species were reared from larvae found in cave mouths, rock overhangs, or other less common habitats; for example, E. nigribasis were found in deep recesses of mammal burrows, E. gracile were reared from reptile holes in the ground, E. punctipennis were found in beetle frass beneath logs, and E. femoralis in small twig holes or abandoned termite galleries in termite frass. Many new bombyliid and chalcidid parasites are listed.
Die Empfehlung des Corporate Governance-Kodex (Ziff. 5.4.2), „dem Aufsichtsrat soll eine nach seiner Einschätzung angemessene Anzahl unabhängiger Mitglieder angehören“, wirft in der Praxis nach wie vor Fragen auf. Im Folgenden sollen einige Thesen zur Auslegung dieser Empfehlung aufgestellt werden. Eine rechtspolitische Auseinandersetzung mit ihr und Änderungsvorschläge sind an dieser Stelle nicht beabsichtigt.
André Prüm has asked me to talk about “La Théorie de l´organe” supposing that this is a German invention. Well, we cannot claim the authorship or copyright for that, but it is true that this doctrine is still dominating German doctrinal thinking in company law. Let me first look at the historical development and background of this theory and then ask for its actual meaning and practical consequences.
„Corporate groups are a fact of life“.1 This was the starting point for a group of renowned European experts to deliver a report on a possible Directive on corporate group law in 2000.2 We all know that no such Directive has been issued.3 However, these days a fresh group of eminent experts has started, among other things, to develop an initiative „on groups of companies“.4 One reason for a European regulation to take its time might be the enormous national differences in dealing with group situations. While some countries, notably the UK,5 rely on general company law to deal with corporate groups, others provide most detailed rules specifically for groups of companies.6 German law provides an example for the latter. Do we need a law of corporate groups? Most countries regulate one or another aspect of group law.7
This is probably most common for tax and for accounting law. Insolvency law will often take group situations into account and the same is true for labour law. Regulatory oversight for financial institutions or insurance companies usually includes a group dimension. Competition law necessarily does so as well. However, in what follows when we speak about „group law“ we will focus on regulation more specifically tuned to genuine questions of company law such as the protection of minority shareholders or creditors, the standards for managerial behavior and the „enabling“ function of legal structures.
Capital maintenance rules are part of a legal capital regime that consists of rules on raising capital and rules on maintaining it. The function of these rules is the protection of the corporation’s creditors. This is evidenced by the fact that in public as well as private companies the provisions on legal capital are not open to disapplication or variation even with unanimous shareholder consent. Thus, providing the company with a minimum of funding and ensuring equal treatment of shareholders are mere reflexes of creditor protection or, at best, ancillary purposes of legal capital. Legal capital is part of a corporation’s equity. The key feature of equity is that it ranks behind the claims of other stakeholders in the distribution of a corporation’s assets. Consequently, equity will also be the first part of a corporation’s funds to be depleted by losses. Capital maintenance rules seek to enforce this order of priority of different groups of stakeholders by restricting distributions to shareholders. Such restrictions are not unique to legal systems that have adopted a legal capital regime. A prominent example of a statute that has eliminated mandatory legal capital is the Delaware General Corporation Law. § 154 DCGL leaves it up to the directors to decide whether any part of the consideration received by the corporation for its shares shall be attributed to capital. Thus, a Delaware corporation need not have any stated capital. This has significant impact on the funds available for distribution to shareholders. Pursuant to § 170 (a) DGCL dividends may only be paid out of surplus or, in the absence of surplus, out of net profits of the current or the preceding fiscal year. § 154 DGCL defines surplus as the excess of a corporation’s net assets over the amount of its capital, and net assets as the amount by which total assets exceed total liabilities. A corporation without stated capital may, therefore, distribute all of its net assets to its shareholders and continue business without any equity on its balance sheet. This highlights the difference between the different approaches to creditor protection in Germany and the U.S. Both legal systems acknowledge the priority of creditors over shareholders in corporate distributions. However, German law seeks to give creditors additional comfort by requiring companies to raise and maintain additional layers of assets above and beyond those corresponding to the company’s liabilities that may not be depleted by way of distributions to shareholders. While private companies must merely raise and maintain their stated capital, public companies are required to raise and maintain additional equity accounts unavailable for distributions to shareholders such as the share premium account1 and the legal reserve.2
In recent years a number of objections have been raised against this concept of creditor protection. Critics argue that contractual arrangements are a more efficient means for protecting the interests of creditors.3 Capital maintenance does not prevent creditors from negotiating for more stringent protection of their claims such as collateral or financial covenants. It does, however, provide a minimum standard of protection for the benefit of creditors who lack the commercial experience or the bargaining power or who, like tort victims, are simply unable to negotiate for contractual safeguards. Capital maintenance ensures that their protection against excessive distributions does not depend on large creditors who are free to waive covenants that, in effect, benefit all creditors in exchange for individual arrangements that work exclusively in their favour.
Anleihen werden in der Regel in zahlreiche Teilschuldverschreibungen aufgespalten und diese an verschiedene Investoren verkauft. Dies begründet, der Zahl der umlaufenden Teilschuldverschreibungen entsprechend, jeweils unterschiedliche Schuldverhältnisse zwischen dem Emittenten und dem jeweiligen Investor. Hält ein Investor mehrere Teilschuldverschreibungen, so entstehen dementsprechend mehrere rechtlich voneinander zu unterscheidende Schuldverhältnisse mit gleichem Inhalt.1 Diese können jeweils ein unterschiedliches rechtliches Schicksal haben, z. B. getrennt voneinander übertragen werden. Sie können auch, von atypischen Gestaltungen abgesehen, je einzeln vom Gläubiger gekündigt werden, wenn die Anleihebedingungen insoweit keine Vorkehrungen treffen. Die folgenden Bemerkungen dazu befassen sich zunächst mit der umstrittenen Frage, ob auch eine Kündigung aus wichtigem Grund seitens eines Gläubigers gemäß §§ 490 Abs. 1, 314 BGB in Betracht kommt (im Folgenden I. - VII.)
Coccolithophores are an abundant phytoplankton group that exhibit remarkable diversity in their biology, ecology, and calcitic exoskeletons (coccospheres). Their extensive fossil record is testament to their important biogeochemical role and is a valuable archive of biotic responses to environmental change stretching back over 200 million years. However, to realise the potential of this archive requires an understanding of the physiological processes that underpin coccosphere architecture. Using culturing experiments on four modern coccolithophore species (Calcidiscus leptoporus, Calcidiscus quadriperforatus, Helicosphaera carteri and Coccolithus braarudii) from three long-lived families, we investigate how coccosphere architecture responds to shifts from exponential (rapid cell division) to stationary (slowed cell division) growth phases as cell physiology reacts to nutrient depletion. These experiments reveal statistical differences in cell size and the number of coccoliths per cell between these two growth phases, specifically that cells in exponential-phase growth are typically smaller with fewer coccoliths, whereas cells experiencing growth-limiting nutrient depletion have larger coccosphere sizes and greater numbers of coccoliths per cell. Although the exact numbers are species-specific, these growthphase
shifts in coccosphere geometry demonstrate that the core physiological responses of cells to nutrient depletion results in increased cell sizes and coccoliths per cell across four different coccolithophore families (Calcidiscaceae, Coccolithaceae, Isochrysidaceae, Helicosphaeraceae), a representative diversity of this phytoplankton group. Building on this, direct comparison of coccosphere geometries in modern and fossil coccolithophores enables a proxy for growth phase to be developed that allows growth responses to environmental change to be investigated throughout their evolutionary history. Our data also shows that changes in growth rate and coccoliths per cell associated with growth-phase shifts can substantially alter cellular calcite production. Coccosphere geometry is therefore a valuable tool for accessing growth information in the fossil record that provides unprecedented insights into the biotic responses of species to environmental change and its potential biogeochemical consequences.
Die sog. Business Judgment Rule wurde durch Art. 1 Nr. 1a des UMAG1 auf entsprechende Vorschläge im Schrifttum2 als neuer § 93 Abs. 1 Satz 2 in das Aktiengesetz eingefügt. Der Sache nach war sie bereits zuvor in Rechtsprechung3 und Lehre4 anerkannt. Nach gängigem Verständnis soll die Business Judgment Rule einen „sicheren Hafen“ bieten, der Organmitglieder davor schützt, dass unternehmerische Misserfolge auf der Grundlage nachträglicher besserer Erkenntnis als Sorgfaltspflichtverstöße sanktioniert werden. Nach ganz überwiegen-der Auffassung beschränkt sich die Bedeutung von § 93 Abs. 1 Satz 2 AktG nicht darauf, durch ausdrückliche Regelung von Elementen der Sorgfaltspflicht klarzustellen, dass das Gesetz mit dem strengen Sorgfaltsmaßstab des ordentlichen und gewissenhaften Geschäftslei-ters nicht etwa eine Erfolgshaftung statuiert. Die Business Judgment Rule wird vielmehr als Privilegierung gegenüber dem ansonsten geltenden Haftungsmaßstab des § 93 Abs. 1 Satz 1 AktG verstanden. Ausdrückliche Stellungnahmen zur Wirkungsweise dieses Privilegs reichen von der Annahme eines der richterlichen Nachprüfung entzogenen unternehmerischen Ermes-sensspielraums5 über die Einordnung als unwiderlegliche Vermutung objektiv rechtmäßigen Verhaltens6 bis hin zu der Annahme, dass im Anwendungsbereich der Business Judgment Rule eine Haftung gegenüber der Gesellschaft nur ab der Grenze der groben Fahrlässigkeit in Betracht komme.7 Aber auch die zahlreichen Stellungnahmen, die sich nicht ausdrücklich zur Frage der Haftungserleichterung äußern, setzen eine privilegierende Wirkung der Business Judgment Rule voraus. Anderenfalls hätten die eingehenden Überlegungen zur Abgrenzung unternehmerischer von anderen, insbesondere rechtlich gebundenen Entscheidungen, für die offenbar ein strengerer Sorgfalts- und Haftungsmaßstab gelten soll, keinerlei praktische Bedeutung.
1.Hinsichtlich der Haftung von Organmitgliedern gegenüber der Gesellschaft für Fehlein-schätzungen der Rechtslage gilt kein anderer Maßstab als hinsichtlich der Haftung für Fehler bei unternehmerischen Entscheidungen (dazu sogleich, II).
2.Die Business Judgment Rule des § 93 Abs. 1 Satz 2 AktG enthält kein Haftungsprivileg; insbesondere stellt sie Organmitglieder nicht grundsätzlich von der Haftung für grobe Fahr-lässigkeit frei. Sie konkretisiert vielmehr lediglich die Sorgfaltsanforderungen an einen or-dentlichen und gewissenhaften Geschäftsleiter und stellt klar, dass dessen Haftung nicht mit nachträglicher besserer Erkenntnis begründet werden kann. Aus diesem Grund ist es unbe-denklich, dass sich die Haftung für unternehmerische, rechtliche und sonstige Fehler nach einheitlichen Haftungsgrundsätzen richtet (dazu unten, III.).
In der Experimentierhalle der Physik am Campus Riedberg der Goethe – Universität wird gegenwärtig die Beschleunigeranlage FRANZ aufgebaut. FRANZ steht für Frankfurter Neutronenquelle am Stern-Gerlach-Zentrum. Die Anlage bietet vielfältige Experimentiermöglichkeiten in der Untersuchung intensiver, gepulster Protonenstrahlen. Ein Forschungsschwerpunkt an den sekundären Neutronenstrahlen sind Messungen zur nuklearen
Astrophysik. Die Neutronen werden durch einen 2 MeV Protonenstrahl mittels der Reaktion 7Li (p, n) 7Be erzeugt. Die geplanten Experimente erfordern sowohl eine hier weltweit erstmals realisierte Pulsrepetitionsrate von bis zu 250 kHz bei Pulsströmen im 100 mA – Bereich als auch eine extreme Pulskompression auf eine Nanosekunde bei dann auftretenden Pulsströmen im Ampere – Bereich. Daneben ist auch ein Dauerstrich – Strahlbetrieb im mA – Strombereich möglich. Auch viele einzelne Beschleunigerkomponenten wie die Ionenquelle, der Chopper zur Pulsformung, die hochfrequent gekoppelte RFQ-IH-Kombination, der Rebuncher in Form einer CH – Struktur und der Bunchkompressor sind Neuentwicklungen. Mittlere Strahlleistungen von bis zu 24 kW treten im Niederenergiestrahltransportbereich auf, da die Ionenquelle grundsätzlich im Dauerstrich zu betreiben ist, auch bei Hochstrom mit hohen Pulsrepetitionsraten. Der Personen- und Geräteschutz spielt damit auch eine wesentliche Rolle bei der Auslegung des Kontrollsystems für FRANZ. Der Aufbau von FRANZ und seine wesentlichen Komponenten werden in Kapitel 2 erläutert. Die vielen unterschiedlichen Komponenten wie Hochspannungsbereich, Magneten, Hochfrequenzbauteile und Kavitäten, Vakuumbauteile, Strahldiagnose und Detektoren machen plausibel, dass auch das Kontrollsystem für eine solche Anlage speziell ausgelegt werden muss. In Kapitel 4 werden zum Vergleich die Konzepte zur Steuerung und Regelung aktueller, großer Beschleunigerprojekte aufgezeigt, nämlich für die „European Spallation Source ESS“ und für die „Facility for Antiproton and Ion Research FAIR“. In der vorliegenden Arbeit wurde die Ionenquelle als komplexe Beschleunigerkomponente ausgewählt, um Entwicklungen zur Steuerung und Regelung durchzuführen und zu testen. Zum Anfahren und Betreiben der Ionenquelle wurde ein Flussdiagramm (Abb. 5.15) entwickelt und realisiert. Im Detail wurden Untersuchungen zur Abhängigkeit der Heizkathodenparameter von der Betriebsdauer gemacht. Daraus konnte ein Algorithmus zur Vorhersage eines rechtzeitigen Filamentaustausches abgeleitet werden. Weiterhin konnte die Nachregelung des Kathodenheizstromes automatisiert werden, um damit die Bogenentladungsspannung innerhalb eines Intervalls von ± 0.5 V zu stabilisieren. Das Anfahren des Filamentstroms wurde ebenfalls automatisiert. Dazu wird die Vakuumdruckänderung in Abhängigkeit der Filamentstromerhöhung gemessen, ausgewertet und daraus der nächste erlaubte Stromerhöhungsschritt abgeleitet. Auf diese Weise wird der Betriebszustand schneller und kontrollierter erreicht als bei manuellem Hochfahren. Das Ziel eines unbemannten Ionenquellenbetriebs ist damit näher gerückt. In einem ersten Test zur Komponentensteuerung und zur Datenaufnahme wurde ein Ionenstrahl extrahiert und durch den ersten Fokussierungsmagneten – einen Solenoiden – transportiert. Es wurde der Erregungsstrom des Solenoiden sowie die Strahlenergie automatisch durchgefahren, die Daten abgespeichert und daraus ein Kontourplot zum gemessenen Strahlstrom hinter der Fokussierlinse erstellt (Abb. 5). Die vorliegende Arbeit beschäftigt sich nur mit den „langsamen“ Steuerungs- und Regelungsprozessen, während die schnellen Prozesse im Hochfrequenzregelungssystem unabhängig geregelt werden. Neben der Überwachung des Betriebszustandes aller Komponenten werden auch alle für den Service und die Personensicherheit benötigten Daten weggeschrieben. Das System basiert auf MNDACS (Mesh Networked Data Acquisition and Control System) und ist in JAVA geschrieben. MNDACS besteht aus einem Kernel, welcher die Komponententreiber-Software sowie den Netzwerkserver und das graphische Netzwerkinterface (GUI) betreibt. Weterhin gehört dazu das Driver Abstraction Layer (DAL), welches den Zugang zu weiteren Computern oder zu lokalen Treibern ermöglicht. CORBA stellt die Middleware für Netzwerkkommunikation dar. Dadurch wird Kommunikation mit externer Software geregelt, weiterhin wird die Umlegung von Kommunikation im Fall von Leitungsunterbrechungen oder einem lokalen Computerabsturz festgelegt. Es gibt bei FRANZ zwei Kontrollebenen: Über Ethernet läuft die „High Level Control“ und die Datenverarbeitung. Über die „Low Level Control“ läuft das Interlock – und Sicherheitssystem. Die Netzwerkverbindungen laufen über 1 Gb Ethernet Links, womit ein schneller Austausch auch bei lokalen Netzwerkstörungen noch möglich ist. Um bei Stromausfällen das Computersystem am Laufen zu halten, wurde im Rahmen dieser Arbeit ein „Uninterruptable Power Supply“ UPS beschafft und erfolgreich am Hochspannungsterminal getestet.
Ribosomes are the central cellular assembly lines for protein synthesis. To cope with the translational needs, a proliferating mammalian cell can produce up to 7500-ribosomes per minute. However, under growth limiting conditions, such as nutrient depletion, ribosome synthesis is rapidly shut down exemplifying the importance of a tight coordination between ribosome supply and cellular energy status. In addition to the quantitative regulation, a strict quality control of ribosome synthesis is equally important, because alterations in the composition or function of ribosomes can lead to a variety of pathologies. To cope with these challenges a highly regulated, multi-step pathway of ribosome biogenesis has evolved. In mammals this pathway generates the mature 80S ribosomes that comprise the large 60S and the small 40S subunits. Together they contain around 80 ribosomal proteins and the 28S, 18S, 5.8S and 5S rRNAs. The 28S, 5.8S and 5S rRNAs are assembled into the large subunit, while the 18S rRNA is part of the small subunit. The pathway of ribosome biogenesis is a multi-step cellular process, where specific stages occur in distinct subcellular compartments. Transcription of the 47S rRNA, which is the precursor for the 28S, 18S and 5.8S species, occurs in the nucleolus. Modification of distinct bases and early processing of this precursor also take place in the nucleolus. Subsequently, the 40S and 60S pre-ribosomes take separate maturation routes through the nucleoplasm before their export and final assembly in the cytoplasm. The various stages of preribosomal maturation require the constant and sequential action of a large number of non-ribosomal proteins, known as trans-acting factors. These factors coordinate the delicate remodeling of the pre-ribosomal intermediates and thereby ensure proper progression of the maturation process. The remodeling events largely depend on the dynamics of post-translational modifications, such as phosphorylation or SUMOylation. This requires that the enzymes controlling these modifications are properly targeted to their sites of activity as they fulfill their functions within specific compartments. Here we studied the regulatory principles that govern the subcellular partitioning of the SUMO-specific isopeptidase SENP3 and its associated factor PELP1. Previous work from our laboratory has delineated the importance of the SUMO system for proper ribosome biogenesis in mammalian cells. In particular, we have shown that SENP3 is critically involved in 28S rRNA formation, which is a key step for pre-60S subunit maturation. A critical involvement of SENP3 at this stage of the maturation process is in agreement with the observed enrichment of SENP3 in the nucleolus, since 28S rRNA processing is considered to occur in the nucleolus. Our subsequent work identified the nucleolar scaffold protein NPM1 and the ribosomal trans-acting factor PELP1 as bona fide substrates of SENP3. For both proteins we could demonstrate modification by SUMO2/3 and define SENP3 as the demodifying enzyme. Depletion of SENP3 enhanced the conjugation of SUMO to both proteins and concomitantly reduced conversion of the 32S pre-rRNA to the mature 28S rRNA. PELP1 is part of a larger protein complex consisting of the core components PELP1, TEX10 and WDR18. We could show that the balanced SUMOylation/deSUMOylation of PELP1 controls the nucleolar/nucleoplasmic distribution of this complex. Enhanced SUMOylation, which is observed in the absence of SENP3, triggers the nucleolar release of the complex suggesting that SENP3-mediated deSUMOylation controls the dynamics of nucleolar trans-acting factors. Based on these findings we first wanted to understand, in which cellular compartment(s) SENP3 exerts its function on 28S maturation. Next, we wanted to tackle the question how the subcellular distribution of SENP3 is controlled. Finally
we addressed the question how the SUMOylation of PELP1 determines the subnuclear distribution of the PELP1 complex. This work initially revealed that the nucleolar localization of SENP3 is crucial for proper 28S rRNA formation and 60S ribosome maturation. Importantly, we could demonstrate that the nucleolar compartmentalization of SENP3 depends on its direct physical interaction with NPM1. Further, we could show that the amino-terminal region of SENP3 is necessary for its binding to NPM1 and nucleolar recruitment. Strikingly, this interaction requires the phosphorylation of SENP3, which is brought about by the mTOR kinase. By in-vitro kinase assays and mass-spectrometric approaches we identified five serine/threonine residues within the amino-terminal region of SENP3 that are targeted by mTOR (S/T 25, 26, 141, 142, 143). We could further demonstrate by mutagenesis that these sites in SENP3 are in fact critical for the phospho-dependent binding of SENP3 to NPM1 and its nucleolar recruitment.
Consistent with these data, we found that chemical inhibitors of the mTOR kinase trigger the nucleolar release of SENP3 and impair its interaction with NPM1. Strikingly, this goes along with severe 28S rRNA maturation defects demonstrating the physiological importance of mTOR signaling in the regulation SENP3 function and rRNA processing. By specifically depleting components of the either mTORC1 or mTORC2, we could attribute the observed effects to signaling by mTORC1 rather than mTORC2. In an attempt to find the negative regulators of SENP3 phosphorylation, we identified PP1-γ as the candidate phosphatase in this pathway. We found a strong physical interaction of SENP3 with PP1-γ and observed a loss of SENP3 nucleolar localization upon ectopic expression of PP1-γ. Thus we could define mTOR/PP1-γ mediated phosphorylation/dephosphorylation of SENP3 as an important
mechanism in the control of ribosome maturation. Given that mTOR activity is controlled by nutrient availability, SENP3 functions as a sensor that couples ribosome synthesis with nutrient availability. The second part of this work delineated the role of SUMOylated PELP1 in nucleoplasmic partitioning of the SENP3-PELP1 complex. It was revealed that the AAA-ATPase MDN1 binds preferentially to SUMO modified PELP1 and likely segregates SUMOylated PELP1 from nucleolar pre-60S particles. We initially found that the PELP1 complex associates with MDN1, a factor known to be involved in the 28S rRNA maturation. Notably, depletion of MDN1 led to an enhanced accumulation of the PELP1 complex in the nucleolus and a strong association of PELP1 with pre-60S particles, suggesting that MDN1 is required for the release of this complex from the pre-ribosomes. Intriguingly, the interaction of PELP1 with MDN1 requires SUMO2/3 and SUMOylated PELP1 shows enhanced binding to MDN1 when compared to unmodified PELP1. Taken together this work provides new insights in the control of the SENP3-PELP1 complex dynamics. We could define several layers for the coordinated spatial regulation of SENP3 and the PELP1 complex. This work therefore underscores the crucial importance of dynamic post-translational modifications for the control of ribosome maturation.
The prevalence of food allergies has increased in the westernized countries during the past decades. Clinical manifestations of food allergies involve the skin (e.g. atopic dermatitis), the respiratory tract (e.g. rhinitis, and asthma), the ocular area (e.g. conjunctivitis), the gastrointestinal tract (e.g. food-protein-induced enterocolitis syndrome, food-induced proctocolitis, and eosinophilic gastroenteropathies), and the cardiovascular system (e.g. anaphylaxis). A curative treatment of these diseases has not been established yet. Oral immunotherapy (OIT) has gained attention as a potential therapy for food allergies. Continuous feeding of allergenic diet applied in the model described here mirrors to a certain extent an OIT treatment. It might be therefore useful to investigate efficacy and safety of OIT pre-clinically.
Mouse models have been widely used to analyse novel treatment approaches. Unfortunately, most of them have focussed on IgE-mediated hyperreactivity. Only a limited number of mouse models presenting mixed IgE- and non-IgE-mediated gastrointestinal symptoms and inflammation upon allergen-challenge are available. To study the mechanisms underlying the induction of food-induced gastrointestinal inflammation and subsequent oral tolerance induction, a mouse model of food-induced gastrointestinal allergy was established. BALB/c mice were sensitised with Ovalbumin (OVA) plus ALUM and subsequently challenged by feeding a diet containing egg white (EW diet). During the first seven days on EW diet, OVA-sensitised mice (OVA/ALUM EW mice) developed gastrointestinal symptoms (e.g. weight loss, ruffed fur, soft stool and less mobility) and inflammation in the small intestines accompanied by a strong induction of OVA-specific IgE antibodies and mouse mast cell protease-1 (mMCP-1). Proliferation of CD4+ T cells from spleen of OVA/ALUM EW mice was reduced compared controls. The result indicated that feeding EW diet induced T cell tolerance systemically. In contrast, CD4+ T cells isolated from MLN of OVA/ALUM EW mice showed stronger proliferation upon OVA stimulation in vitro than mice OVA-sensitised but fed a conventional diet, indicating that tolerance was not induced by short-term EW diet. Histological analysis of the small intestinal tissue of OVA/ALUM EW mice revealed strong inflammation present in the duodenum, jejunum and ileum at this time point.
Interestingly, the observed symptoms in OVA/ALUM EW mice resolved spontaneously after 7 days on EW diet, if the feeding was continued. In the next steps the CD4+ T cell-mediated immune response after 28 days continuous EW diet was assessed and revealed that tolerance was induced systemically as well as locally. This was shown by reduced proliferation and cytokine secretion of CD4+ T cells from MLN of OVA/ALUM EW mice after long-term EW diet. However, the inflammation in the jejunum was aggravated instead of resolved at this time point of allergenic diet. Our results suggest that application of OIT in food-allergic patients with gastrointestinal inflammation may need to be reconsidered, since continuous administration of allergenic food may aggravate inflammation in the local tissue. Interestingly, only the jejunum was affected by a worsened condition, whereas duodenum and ileum resolved inflammation. In accordance to the observed jejunal inflammation mMCP-1 levels in the sera were not changed. Allergen-specific IgE levels did not reach baseline level after long-term EW diet, although they were reduced compared to levels in mice after 7 days on EW diet. This result suggests that residual OVA-specific IgE antibodies would promote the jejunal inflammation by sustained activation of mast cells. Furthermore, our results suggest that IL-4 produced by activated Th2 cells could be an effector molecule to induce intestinal inflammation.
The second part of this thesis was aimed at verifying the hypothesis that IgE-mediated mast cell activation is a major effector mechanism in induction of chronic inflammation induced by long-term EW diet. For that mice deficient for FcεRI, a high affinity IgE receptor, were used. These mice were sensitised with OVA and fed EW diet as described for WT mice. Although FcεRI-deficient mice showed an intact Th2 immunity with IgE production, weight loss in the receptor-deficient mice was moderately induced by EW diet compared to WT mice, suggesting that this clinical symptom during the acute phase of allergic response is associated with IgE-mediated mechanisms. Surprisingly, the deficient mice presented comparable intestinal inflammation on day seven of EW diet as WT mice did. However, if EW diet was continued, recovery of intestinal inflammation was observed in FcεRI-deficient mice in contrast to WT mice. These results suggest that the induction of intestinal inflammation is not IgE-dependent. Nevertheless, this does not rule out a potential role of mast cells in the inflammation, because of their IgE-independent activation pathways. It also suggests the involvement of T cell-mediated mechanisms during induction of jejunal inflammation. Interestingly, the aggravated inflammation seen after long-term EW diet in WT mice seems to be IgE-dependent, considering that it was not observed in FcεRI-deficient mice. The elevated number of mast cells in the intestine of WT mice further led to a hypothesis that their continuous activation might be responsible for the chronification of allergic inflammation observed after long-term EW diet. In the context of OIT it further implies that IgE might be a poor prognostic factor for recovery of intestinal inflammation during and after an OIT treatment. In the third part of this thesis regulatory mechanisms employed by the immune system were analysed. Initial results from CD4+ T cells isolated from MLN from OVA/ALUM EW mice showed elevated IL-10 levels in their supernatants after short-term EW diet. IL-10-deficient mice were used to analyse the effect of this immunosuppressive cytokine in the mouse model presented here. However, IL-10-deficient mice tend to develop a strong Th1-dominated immune response. Nevertheless, an accelerated weight loss and slight inflammation of the jejunum was observed after short-term EW diet. Analysis of OVA-specific proliferation and cytokine production CD4+ T cells from Spleen and MLN of IL-10-deficient mice on EW diet suggested that systemic as well as local tolerance was induced after short-term and long-term EW diet feeding, respectively. The result suggests that IL-10 is dispensable for induction of T cell tolerance in our mouse model.
However, the presence of functionally active Tregs was observed during this study in WT mice fed short-term EW diet, suggesting that Tregs might have an important role in regulating the systemic or local immune response. T cell deletion as an alternative immune regulatory mechanism was also observed. Additionally, the efficacy of continuous EW diet (mirroring to a certain extent an OIT treatment) in induction of permanent tolerance was assessed. In OVA-sensitised WT mice continuous allergenic diet was stopped after resolution of clinical symptoms and reintroduced after a defined period on conventional diet. Evaluating the weight development showed that reintroduction of EW diet induced weight loss again, but not as pronounced as seen after short-term EW diet. Also the CD4+ T cell-mediated response was elevated again upon allergen stimulation in vitro. The results suggested that permanent tolerance was not induced in the chosen feeding regime.
The mouse model established and analysed here was used to investigate inflammatory and regulatory mechanisms underlying food-induced gastrointestinal allergy. It presents clinical symptoms and intestinal inflammation (Burggraf et al., 2011). This model is easy to be reproduced in different laboratories, and is useful for testing novel therapy approaches (Schülke et al., 2011; Bohnen et al., 2013). It further provides an opportunity to investigate basic mechanisms underlying OIT. This therapy approach is currently extensively investigated and our mouse model would help to understand the therapeutic mechanism of OIT.
Während des Zellzykluses werden spezifische regulatorische Proteine, die Cycline exprimiert, die mit ihren spezifischen CDK (Cyclin Dependent Kinases) interagieren und sie hierdurch aktivieren. So interagiert in der frühen G1 Phase Cyclin D1 mit CDK4 und CDK6. Die D-Cyclin kontrollieren gemeinsam mit Cyclin E den G1 Restriktionspunkt. Rb wird durch diese D-Cycline und die assoziierten Kinasen CDK4/6 mehrfach phosphoryliert und kann nun Transkriptionsfaktoren wie E2F nicht mehr inhibieren und die nun freie E2F/ DP-Untereinheit ( = DNS-Bindungsprotein) kann Promotoraktivierung vermitteln und Gene aktivieren, die die S-Phase einleiten. Hiermit wird der Zelle der Fortschritt durch den Zellzyklus ermöglicht bis Rb gegen Ende des Zellzyklus durch Phosphatasen dephoshoryliert wird und die aus der Mitose hervorgegangenen Tochterzellen nach Ende der M-Phase erneut in der G1-Phase sind. CDK-Inhibitoren (CDKI) können diese Cyclin/CDK Komplexe in jeder Zellzyklusphase hemmen und Zellzyklusarrest auslösen. In der vorliegenden Arbeit sollte die Expression von Cyclin D1 und Retinoblastomgens immunhistochemisch untersucht werden. Es wurde versucht, mit der Avidin-Biotin-Enzymkomplexmethode die Proteinexpression des Retinoblastomgens mit einem monoklonalem Antikörper in Probeexzisionen von Mammakarzinomen der Jahre 1983 bis 1987 dazustellen, die in Paraffinum eingebettet waren. Trotz vielfacher Versuchswiederholungen gelang es nicht, eine Kernfärbung hervorzubringen, die wissenschaftlichem Standard genügte. Zum damaligen Zeitpunkt stand noch nicht viel know-how bezüglich der Kernfärbung mittels Antikörpern zur Verfügung. Vor allem nicht bei Präparaten, die bis zu 15 Jahre in Paraffinum eingebetet waren. Somit konnte eine verwertbare Kernfärbung der Gewebeschnitte, das Retinoblastomgen betreffend, nicht nachgewiesen werden und damit war es bedauerlicherweise auch nicht möglich, eine Korrelation zwischen Cyclin D1 und Retinoblastomgen im Mammakarzinom nachzuweisen. Bei der nun verbliebenen Analyse des Cyclin D1 wiesen von 198 Tumoren 10,6% (21 Präparate) eine positive Kernfärbung auf. Hierbei wurden die Präparate, die bei der lichtmikroskopischen Beurteilung der immunhistochemisch gefärbten Zellen einen Prozentsatz von 10% oder größer aufwiesen, wurden als positiv gewertet.13 von den 198 Tumoren zeigten eine Färbbarkeit zwischen 1%-10% auf und wurden per definitionem als negativ gewertet. Hieraus folgt, dass bei 164 Tumoren überhaupt keine Zellkernfärbung stattfand. Es zeigte sich, dass aufgrund der niedrigen positiven Fallzahlen nur schwer eine statische Signifikanz erreichbar sein würde. Das spiegelte unter anderem die Korrelation mit dem Menopausenstatus wieder, die einen p-Wert von 0,273 aufwies und sich hiermit einer statistischen Signifikanz entzog. Auch beim Vergleich von Cyclin D1 mit dem Ostrogen/Progesteron- Rezeptorstatus ist ein verwertbares Ergebnis nicht erreichbar (p=0,08) Eine prognostische Signifikanz des TNM-Stagings konnte bei T:p= 0,496; N:p=0,052 und M:p=0,720 nicht bestätigt werden. Zwar zeigte sich bei der Cyclin D1-Expression der Lymphknoten primär ein grenzwertig positiver Wert von p=0,047. Dieser wurde jedoch durch den kontrollierenden Fisher Exact-Test nicht bestätigt (p=0,052). Ebenfalls konnte keine signifikante Beziehung zum histologischen Tumortyp (p=0,553) und zum Differenzierungsgrad (p=0,575) nachgewiesen werden. Bei den Kaplan-Meier-Analysen in Bezug auf das rezidivfreie Intervall
(p=0,934), das metastasenfreie Intervall (p=0,386) sowie das krankheitsfreie Intervall (p=0,709), konnte kein signifikanter Parameter erhoben werden. Der Einfluss von Cyclin D1 auf das Gesamtüberleben spiegelt letztendlich auch keinen signifikanten Zusammenhang wider (p=0,830). Insgesamt zeigte sich bei keinem Parameter ein signifikanter Bezug. Dies ist wohl, wie auch bei der Versuchsreihe mit dem Retinoblastom, bei dem es ja zu überhaupt keiner verwertbaren Kernfärbung kam, auf das Alter der Probeexcisionen und der damals noch in Entwicklung befindlichen Verfahren zu erklären. Wobei hier nur gemutmaßt werden kann. Eine etablierte Methode jedoch, stand noch nicht zur Verfügung. In den letzten Jahren ist zunehmend wenig Augenmerk dem Gebiet der Cycline und des Retinoblastomgens, besonders im Hinblick auf das Mammakarzinom, gelegt worden. Vielleicht lässt sich mit den jetzigen etablierten Methoden eine Renaissance dieser interessanten Forschungsrichtung erwecken.
On October the 2nd the Colombian people rejected the peace agreement between the government and the FARC in a referendum with a very thin majority of 0.4%. With this unexpected rejection, the referendum was in some ways similar to the Brexit referendum, for the results of which David Cameron was as little prepared as Juan Manuel Santos for his rejection; there was obviously no Plan B. In the last weeks, the government undertook ten changes to the agreement, but it will not go through a referendum again. Santos, as he said, has learned his lesson from the rejection and will seek to have the amended peace agreement approved in Congress. This will likely lead to the implementation of the peace agreement and the furtherance of its goals, such as a DDR process, land reforms, a transitional justice process and reparations for victims, just to mention a few. But this progress in peace will be seen as being at odds with popular opinion. Many of the “no” voters are still not satisfied with the adjustments made by the government and the FARC, and neither are the sectors of the opposition mainly responsible for the rejection. Nevertheless, the government and the FARC are progressing with the implementation, and peace talks with the second-largest – and now the last standing – guerrilla group, the ELN, are scheduled to start in 2017. The prospects for 2018 and onwards, when the presidency election will be held, are more questionable.
The constantly increasing memory density and performance of recent Field Programmable Gate Arrays (FPGA) has boosted a usage in many technical applications such as particle accelerators, automotive industry as well as defense and space. Some of these fields of interest are characterized by the presence of ionizing radiation as caused by natural decay or artificial excitation processes. Unfortunately, this type of radiation affects various digital circuits, including transistors forming Static Random Access Memory (SRAM) storage cells that constitute the technology node for high performance FPGAs. Various digital misbehavior in temporal or permanent manner as well as physical destruction of transistors are the consequence. Therefore, the mitigation of such effects becomes an essential design rule when using SRAM FPGAs in ionizing radiation environments. Tolerance against soft errors can be handled across various layers of modern FPGA design, starting with the most basic silicon manufacturing process, towards configuration, firmware, and system design, until finally ending up with application and software engineering. But only a highly optimized, joint concept of system-wide fault tolerance provides sufficient resilience against ionizing radiation effects without losing too much valuable device resources to the safety approach. This concept is introduced, analyzed, improved and validated in the present work. It includes, but is not limited to, static configuration scrubbing, various firmware redundancy approaches, dynamic memory conservation as well as state machine protection. Guidelines are given to improve manual design practices concerning fault tolerance and tools are shown to reduce necessary efforts. Finally, the SysCore development platform has been maintained to support the recommended design methods and act as Device Under Test (DUT) for all particle irradiation experiments that prove the efficiency of the proposed concept of system-wide fault tolerance for SRAM FPGAs in ionizing radiation environments.
Recently, several magnetic resonance imaging contrast mechanisms have been shown to distinguish cortical substructure corresponding to selected cortical layers. Here, we investigate cortical layer and area differentiation by automatized unsupervised clustering of high-resolution diffusion MRI data. Several groups of adjacent layers could be distinguished in human primary motor and premotor cortex. We then used the signature of diffusion MRI signals along cortical depth as a criterion to detect area boundaries and find borders at which the signature changes abruptly. We validate our clustering results by histological analysis of the same tissue. These results confirm earlier studies which show that diffusion MRI can probe layer-specific intracortical fiber organization and, moreover, suggests that it contains enough information to automatically classify architecturally distinct cortical areas. We discuss the strengths and weaknesses of the automatic clustering approach and its appeal for MR-based cortical histology.
The Radical Pair Model proposes that the avian magnetic compass is based on spin-chemical processes: since the ratio between the two spin states singlet and triplet of radical pairs depends on their alignment in the magnetic field, it can provide information on magnetic directions. Cryptochromes, blue light-absorbing flavoproteins, with flavin adenine dinucleotide as chromophore, are suggested as molecules forming the radical pairs underlying magnetoreception. When activated by light, cryptochromes undergo a redox cycle, in the course of which radical pairs are generated during photo-reduction as well as during light-independent re-oxidation. This raised the question as to which radical pair is crucial for mediating magnetic directions. Here, we present the results from behavioural experiments with intermittent light and magnetic field pulses that clearly show that magnetoreception is possible in the dark interval, pointing to the radical pair formed during flavin re-oxidation. This differs from the mechanism considered for cryptochrome signalling the presence of light and rules out most current models of an avian magnetic compass based on the radical pair generated during photo-reduction. Using the radical pair formed during re-oxidation may represent a specific adaptation of the avian magnetic compass.
We present the prototype of a regional climate system model based on the COSMO-CLM regional climate model coupled with several model components, analyze the performance of the couplings and present a strategy to find an optimum configuration with respect to computational costs and time to solution.
The OASIS3-MCT coupler is used to couple COSMO-CLM with two land surface models (CLM and VEG3D), a regional ocean model for the Mediterranean Sea (NEMO-MED12), two ocean models for the North and Baltic Sea (NEMO-NORDIC and TRIMNP+CICE) and the atmospheric component of an earth system model (MPI-ESM). We present a unified OASIS3-MCT interface which handles all couplings in a similar way, minimizes the model source code modifications and describes the physics and numerics of the couplings. Furthermore, we discuss solutions for specific regional coupling problems like handling of different domains, multiple usage of MCT interpolation library and efficient exchange of 3D fields.
A series of real-case simulations over Europe has been conducted and the computational performance of the couplings has been analyzed. The usage of the LUCIA tool of the OASIS3-MCT coupler enabled separation of the direct costs of: coupling, load imbalance and additional computations. The resulting limits for time to solution and costs are shown and the potential of further improvement of the computational efficiency is summarized for each coupling.
It was found that the OASIS3-MCT coupler keeps the direct coupling costs of communication and horizontal interpolation small in comparison with the costs of the additional computations and load imbalance for all investigated couplings. For the first time this could be demonstrated for an exchange of approximately 450 2D fields per time step necessary for the atmosphere-atmosphere coupling between COSMO-CLM and MPI-ESM.
A procedure for finding an optimum configuration for each of the couplings was developed considering the time to solution and costs of the simulations. The optimum configurations are presented for sequential and concurrent coupling layouts. The procedure applied can be regarded as independent on the specific coupling layout and coupling details.
Background: Bacteria within the genus Photorhabdus maintain mutualistic symbioses with nematodes in complicated lifecycles that also involves insect pathogenic phases. Intriguingly, these bacteria are rich in biosynthetic gene clusters that produce compounds with diverse biological activities. As a basis to better understand the life cycles of Photorhabdus we sequenced the genomes of two recently discovered representative species and performed detailed genomic comparisons with five publically available genomes.
Results: Here we report the genomic details of two new reference Photorhabdus species. By then conducting genomic comparisons across the genus, we show that there are several highly conserved biosynthetic gene clusters. These clusters produce a range of bioactive small molecules that support the pathogenic phase of the integral relationship that Photorhabdus maintain with nematodes.
Conclusions: Photorhabdus contain several genetic loci that allow them to become specialist insect pathogens by efficiently evading insect immune responses and killing the insect host.
Background: Lung ultrasound has become an emerging tool in acute and critical care medicine. Combined theoretical and hands-on training has been required to teach ultrasound diagnostics. Current computer technology allows for display, explanation, and animation of information in a remote-learning environment.
Objective: Development and assessment of an e-learning program for lung ultrasound.
Methods: An interactive online tutorial was created. A prospective learning success study was conducted with medical students using a multiple-choice test (Trial A). This e-learning program was used as preparation for a certified course followed by an evaluation of trained doctors (Trial B) by linear analogue scales. Pretests were compared with postcourse tests and sustainability tests as well as a posttest of a one-day custom classroom training.
Results: In Trial A, during the learning success study (n = 29), the increase of correct answers was 11.7 to 17/20 in the post-test and to 16.6/20 in the sustainability test (relative change 45.1%, P < 0.0001). E-learning almost equalled scores of classroom-based training regarding gain and retention of factual knowledge. In Trial B, nineteen participating doctors found a 79.5% increase of knowledge (median, 95% CI: 69%; 88%).
Conclusion: The basics of lung ultrasound can be taught in a highly effective manner using e-learning.
A record number of 39 209 HSCT in 34 809 patients (14 950 allogeneic (43%) and 19 859 autologous (57%)) were reported by 658 centers in 48 countries to the 2013 survey. Trends include: more growth in allogeneic than in autologous HSCT, increasing use of sibling and unrelated donors and a pronounced increase in haploidentical family donors when compared with cord blood donors for those patients without a matched related or unrelated donor. Main indications were leukemias, 11 190 (32%; 96% allogeneic); lymphoid neoplasias, 19 958 (57%; 11% allogeneic); solid tumors, 1543 (4%; 4% allogeneic); and nonmalignant disorders, 1975 (6%; 91% allogeneic). In patients without a matched sibling or unrelated donor, alternative donors are used. Since 2010 there has been a marked increase of 96% in the number of transplants performed from haploidentical relatives (802 in 2010 to 1571 in 2013), whereas the number of unrelated cord blood transplants has slightly decreased (789 in 2010 to 666 in 2013). The use of donor type varies greatly throughout Europe.
Ruijs-Aalfs syndrome is a segmental progeroid syndrome resulting from mutations in the SPRTN gene. Cells derived from patients with SPRTN mutations elicit genomic instability and people afflicted with this syndrome developed hepatocellular carcinoma. Here we describe the molecular mechanism by which SPRTN contributes to genome stability and normal cellular homeostasis. We show that SPRTN is a DNA-dependent mammalian protease required for resolving cytotoxic DNA-protein crosslinks (DPCs)— a function that had only been attributed to the metalloprotease Wss1 in budding yeast. We provide genetic evidence that SPRTN and Wss1 function distinctly in vivo to resolve DPCs. Upon DNA and ubiquitin binding, SPRTN can elicit proteolytic activity; cleaving DPC substrates and itself. SPRTN null cells or cells derived from patients with Ruijs-Aalfs syndrome are impaired in the resolution of covalent DPCs in vivo. Collectively, SPRTN is a mammalian protease required for resolving DNA-protein crosslinks in vivo whose function is compromised in Ruijs-Aalfs syndrome patients.
Ataxin-2 (Atxn2)-knock-out mice show branched chain amino acids and fatty acids pathway alterations
(2016)
Human Ataxin-2 (ATXN2) gene locus variants have been associated with obesity, diabetes mellitus type 1,and hypertension in genome-wide association studies, whereas mouse studies showed the knock-out of Atxn2 to lead to obesity, insulin resistance, and dyslipidemia. Intriguingly, the deficiency of ATXN2 protein orthologs in yeast and flies rescues the neurodegeneration process triggered by TDP-43 and Ataxin-1 toxicity. To understand the molecular effects of ATXN2 deficiency by unbiased approaches, we quantified the global proteome and metabolome of Atxn2-knock-out mice with label-free mass spectrometry. In liver tissue, significant downregulations of the proteins ACADS, ALDH6A1, ALDH7A1, IVD, MCCC2, PCCA, OTC, together with bioinformatic enrichment of downregulated pathways for branched chain and other amino acid metabolism, fatty acids, and citric acid cycle were observed. Statistical trends in the cerebellar proteome and in the metabolomic profiles supported these findings. They are in good agreement with recent claims that PBP1, the yeast ortholog of ATXN2, sequestrates the nutrient sensor TORC1 in periods of cell stress. Overall, ATXN2 appears to modulate nutrition and metabolism, and its activity changes are determinants of growth excess or cell atrophy.
The German postgraduate degree program in ecotoxicology (SETAC GLB and GDCh) : a success story
(2016)
This article gives a comprehensive overview on the strategy, the development and the progress of the German postgraduate degree program in ecotoxicology (SETAC GLB and GDCh). The program soon prompted positive results: more than 10 years now the courses had an average enrolment rate of 90 %, and employment-seeking graduates from the first courses mostly succeeded in quickly finding employment relevant to their training. With over 450 students enrolled to date, the degree program contributes significantly to the field of Environmental Chemistry and Ecotoxicology.
Purpose: Subcutaneous allergen-specific immunotherapy (SCIT) is a well-established and clinically effective method to treat allergic diseases, such as rhinitis and asthma. It remains unclear how soon after initiation of an ultra-short course of grass pollen immunotherapy adjuvanted with monophosphoryl lipid A (MPL)-specific bronchial tolerance can be induced.
Methods: In a prospective study of 69 children double-sensitized to birch and grass pollens (51 males, average age 11.1 years), development of bronchial tolerance after 1 cycle of SCIT for grass was evaluated. In all the patients, the bronchial allergen provocation test (BAP) was performed before and after treatment. According to the results of the first BAP, the patients were divided into 2 groups: those showing a negative BAP with a decrease in FEV1 of <20% (seasonal allergic rhinitis [SAR] group, n=47); and those showing a positive BAP with a decrease in FEV1 of ≥20% (SAR with allergic asthma [SAR and Asthma] group, n=22). All the patients received MPL-adjuvanted, ultra-short course immunotherapy for birch, but only those with a positive BAP to grass received MPL-SCIT for grass.
Results: After the pollen season, the BAP in the SAR group remained unchanged, while it was improved in the SAR and Asthma group (decrease in FEV1 of 28.8% vs 12.5%, P<0.01). The IgG4 levels increased after SCIT (median before SCIT 0.34 to 11.4 after SCIT), whereas the total and specific IgE levels remained unchanged.
Conclusions: After 1 cycle of MPL-SCIT, specific bronchial tolerance may be significantly induced, whereas in patients without SCIT, bronchial hyperactivity may remain unchanged.
Ubiquitination plays a critical role in the activation of host immune responses to infection and serves as a signal for pathogen delivery to phagophores along the xenophagy pathway. We recently performed systematic ubiquitination site profiling of epithelial cells infected with Salmonella Typhimurium. Our findings specifically highlight components of the NFKB, membrane trafficking pathways and RHO GTPase systems as ubiquitination hubs during infection. In addition, a broad spectrum of bacterial effectors and several outer membrane proteins are ubiquitinated in infected cells. This comprehensive resource of ubiquitinome dynamics during Salmonella infection enables further understanding of the complex host-pathogen interplay and may reveal novel targets for the inhibition of Salmonella invasion and inflammation.
Purpose: The Action Plan for Medication Safety by the German Federal Ministry of Health introduced a standardized medication plan (MP), a printable document for the patient. The practical handling needs to be tested before the nationwide implementation in Germany. Therefore, the aims of our study were 1) to develop an instrument to evaluate the usage of the standardized MP, 2) to assess if patients can locate, and 3) understand important information. Moreover, we explored patients’ opinion and suggestions regarding the standardized MP template.
Patients and methods: We conducted a cross-sectional study to evaluate the practical handling of the standardized MP. We interviewed 40 adult patients in seven community pharmacies in Germany, who took at least five medicines regularly and gave their written informed consent. The interview consisted of questions regarding finding and understanding information provided on a mock-up MP, patients’ opinion and the execution of the information on the MP by filling pill boxes. We eventually developed a new evaluation method to quantify the practical handling of the MP by rating the pill boxes filled by the patients.
Results: Overall, the participants rated the MP positively. Thirty-nine (98%) participants found important information on a mock-up standardized MP. Patients were questioned to identify if they understood information on medical intake as it relates to meals. In particular, they were questioned about medicine intake "1 hour before a meal", which 98% (n=39) interpreted correctly, and "during a meal", which 100% (n=40) interpreted correctly. The less precise advice of "before a meal" was interpreted correctly by 73% (n=29), and only 15% (n=6) correctly interpreted the term "after the meal". The evaluation of the filled pill boxes resulted in the "Evaluation Tool to test the handling of the Medication Plan" (ET-MP) – a weighted scoring system.
Conclusion: The standardized MP is clearly arranged, and patients are able to find important information. The findings of this study resulted in minor but important revisions of the standardized MP template. The developed evaluation tool ET-MP may serve as an objective instrument to assess patients’ ability to transfer written information on the MP into practical handling of medicines.
Premise of the study: Polymorphic microsatellite markers were developed for the lichen species Cetraria aculeata (Parmeliaceae) to study fine-scale population diversity and phylogeographic structure.
Methods and Results: Using Illumina HiSeq and MiSeq, 15 fungus-specific microsatellite markers were developed and tested on 81 specimens from four populations from Spain. The number of alleles ranged from four to 13 alleles per locus with a mean of 7.9, and average gene diversities varied from 0.40 to 0.73 over four populations. The amplification rates of 10 markers (CA01– CA10) in populations of C. aculeata exceeded 85%. The markers also amplified across a range of closely related species, except for locus CA05, which did not amplify in C. australiensis and C. "panamericana," and locus CA10 which did not amplify in C. australiensis.
Conclusions: The identified microsatellite markers will be used to study the genetic diversity and phylogeographic structure in populations of C. aculeata in western Eurasia.
Background: n-Butanol can serve as an excellent gasoline substitute. Naturally, it is produced by some Clostridia species which, however, exhibit only limited suitability for industrial n-butanol production. The yeast Saccharomyces cerevisiae would be an ideal host due to its high robustness in fermentation processes. Nevertheless, n-butanol yields and titers obtained so far with genetically engineered yeast strains are only low.
Results: In our recent work, we showed that n-butanol production via a clostridial acetoacetyl-CoA-derived pathway in engineered yeast was limited by the availability of coenzyme A (CoA) and cytosolic acetyl-CoA. Increasing their levels resulted in a strain producing up to 130 mg/L n-butanol under anaerobic conditions. Here, we show that under aerobic conditions. this strain can even produce up to 235 mg/L n-butanol probably due to a more efficient NADH re-oxidation. Nevertheless, expression of a bacterial water-forming NADH oxidase (nox) significantly reduced n-butanol production although it showed a positive effect on growth and glucose consumption. Screening for an improved version of an acetyl-CoA forming NAD+-dependent acetylating acetaldehyde dehydrogenase, adhEA267T/E568K/R577S, and its integration into n-butanol-producing strain further improved n-butanol production. Moreover, deletion of the competing NADP+-dependent acetaldehyde dehydrogenase Ald6 had a superior effect on n-butanol formation. To increase the endogenous supply of CoA, amine oxidase Fms1 was overexpressed together with pantothenate kinase coaA from Escherichia coli, and could completely compensate the beneficial effect on n-butanol synthesis of addition of pantothenate to the medium. By overexpression of each of the enzymes of n-butanol pathway in the n-butanol-producing yeast strain, it turned out that trans-2-enoyl-CoA reductase (ter) was limiting n-butanol production. Additional overexpression of ter finally resulted in a yeast strain producing n-butanol up to a titer of 0.86 g/L and a yield of 0.071 g/g glucose.
Conclusions: By further optimizing substrate supply and redox power in the form of coenzyme A, acetyl-CoA and NADH, n-butanol production with engineered yeast cells could be improved to levels never reached before with S. cerevisiae via an acetoacetyl-CoA-derived pathway in synthetic medium. Moreover, our results indicate that the NAD+/NADH redox balance and the trans-2-enoyl-CoA reductase reaction seem to be bottlenecks for n-butanol production with yeast.
Das natürlich vorkommende Polyphenol Resveratrol (3,4‘,5-(E)-Trihydroxystilben) ist eine potente chemopräventive Substanz, die in vielen verschiedenen Krebszelllinien wirksam ist. Außerdem verfügt sie über anti-inflammatorische, anti-oxidative und pro-apoptotische Wirkungen. Da Resveratrol auch in Tiermodellen des Typ-2-Diabetes und der nicht-alkoholischen Fettlebererkrankung gute Effekte gezeigt hat, wird in Erwägung gezogen es zur Prävention und Behandlung von metabolischen Erkrankungen einzusetzen. Allerdings liegen, aufgrund von schneller Metabolisierung und geringer Bioverfügbarkeit, die wirksamen Konzentrationen im mikromolaren Bereich. Eine geeignete Strategie, um die anti-tumorale Wirkung und die Bioverfügbarkeit von Resveratrol zu verbessern, scheint die Methylierung der freien Hydroxylgruppen zu sein. Allerdings liefern einige Studien Hinweise darauf, dass diese strukturelle Modifikation der Stilbengrundstruktur zu einer Veränderung des antiproliferativen Wirkmechanismus der methylierten Substanzen führt. Daher führten wir im ersten Teil dieser Arbeit genauere Untersuchungen durch, um die Veränderungen der biologischen Wirkung, die durch die Methylierung der freien Hydroxylgruppen von (E)- und (Z)-Resveratrol verursacht werden, zu charakterisieren. Einen Schwerpunkt bildete die Bestimmung der metabolischen Effekte der methylierten Substanzen. Dabei sollte aufgeklärt werden, ob die Analoga noch immer in der Lage sind bekannte Resveratrol-Targets, wie AMPK, SIRT1 und Phosphodiesterasen, zu modulieren. Zunächst bestätigten wir, dass die methylierten Resveratrolanaloga ST911 (3,4‘,5-Z)-Trimethoxystilben) und ST912 (3,4‘,5-(E)-Trimethoxystilben) einen starken antiproliferativen Effekt auf verschiedene Krebszelllinien ausüben. Wie bereits zuvor beschrieben, konnten wir beobachten, dass ST911 und ST912 das Wachstum von Tumorzellen stärker beeinflussen, als die hydroxylierten Substanzen (E)- und (Z)-Resveratrol. Dies, in Verbindung mit einer vernachlässigbaren zytotoxischen Wirkung und einer deutlich geringeren antiproliferativen Wirkung auf Primärzellen, legt nahe, dass ST911 als potentielles neues Chemotherapeutikum weiter untersucht werden sollte. Zudem zeigten ST911 und ST912 signifikante pro-apoptotische Wirkungen in CaCo-2-Zellen. Auch Resveratrol konnte in diesen Zellen Apoptose auslösen, allerdings erst nach Behandlung mit deutlich höheren Konzentrationen, verglichen mit ST911 und ST912. Eine genauere Charakterisierung der antitumoralen Wirkung von ST911 in HT-29-Zellen zeigte, dass ST911 die Polymerisation von Tubulin zu Mikrotubuli beeinflusst und einen Arrest des Zellzyklus in der Mitose-Phase auslöst. Im Gegensatz dazu führt Resveratrol zu einem Zellzyklus-Arrest in der S-Phase und beeinflusst die Tubulinpolymerisation nicht. Diese Beobachtungen verstärkten die Annahme, dass ST911 ein Mitosehemmer ist und betonten noch einmal die mechanistischen Unterschiede zwischen Resveratrol und den methylierten Analoga. Interessanterweise konnte ST911 die hepatische Fettakkumulation in einem in-vitro-Steatosemodell nicht beeinflussen, während eine Behandlung mit Resveratrol zu einer signifikanten Reduktion der intrahepatischen Triglyzeride führte. Dieses Experiment lässt vermuten, dass die stärkere antiproliferative Wirkung von ST911, keine erhöhte Aktivität in metabolischen Krankheitsmodellen nach sich zieht. Die beobachteten Unterschiede im Steatosemodell führten zu der Frage, ob die methylierten Analoga noch immer in der Lage sind die gleichen metabolischen Targetgene zu modulieren, die in der Literatur für Resveratrol beschrieben sind. Vor kurzem wurden Phosphodiesterasen (PDEs) als direkte Targets von Resveratrol identifiziert. Die Inhibition von PDEs durch Resveratrol führt zu einem Anstieg der intrazellulären cAMP-Konzentration. Diese wiederum aktiviert die bekannten Resveratrol-Targetgene AMPK und SIRT1. Unsere Experimente zeigten, dass ST911 und ST912 keinen Einfluss auf die intrazelluläre cAMP-Konzentration haben. Zusätzlich konnten wir keine AMPK- oder SIRT1-abhängigen Veränderungen der Genexpression beobachten. Dies ist ein Hinweis darauf, dass die Substanzen ihre zellulären Effekte vermutlich nicht über eine Modulation von PDEs, AMPK oder SIRT1 vermitteln. Zusammenfassend liefert der erste Teil der Arbeit Beweise dafür, dass ST911 keine positiven Effekte in metabolischen Krankheitsmodellen ausübt. Dies liegt vermutlich in einem Aktivitätsverlust gegenüber den metabolischen Targetgenen von Resveratrol begründet. Des Weiteren unterstützen unsere Ergebnisse frühere Arbeiten, die zeigen konnten, dass ST911 an Tubulin bindet und die Polymerisation zu Mikrotubuli verhindert. Weiterhin bestätigen unsere Daten, dass die Methylierung von Resveratrol zu einer grundlegenden Veränderung des Wirkmechanismus dieser Substanzen führt, die von einem kompletten Verlust der metabolischen Aktivität begleitet wird. Dies sollte bei zukünftigen Leitstrukturoptimierungen mit Resveratrol berücksichtigt werden. Im ersten Teil dieser Arbeit konnte außerdem gezeigt werden, dass Resveratrol die Gentranskription des nukleären Rezeptors SHP (aus dem Englischen: small heterodimer partner) stark induziert. Der Mechanismus dieser Induktion scheint von der Aktivität von AMPK und SIRT1 abhängig zu sein. Diese Ergebnisse konnten unser Verständnis der vielseitigen biologischen Wirkungen von Resveratrol erweitern. Dennoch sollte die Relevanz der SHP-Induktion für die Effekte von Resveratrol auf metabolische Krankheiten und Tumorwachstum noch weiter untersucht werden. Während der Experimente für den ersten Teil der Arbeit stellten wir fest, dass der AMPK-Inhibitor Compound C (CC) in der Lage war, die wachstumshemmende Wirkung von ST911 signifikant zu reduzieren. Die Untersuchung dieses sogenannten „Rescue-Effektes“ wird durch die Tatsache bestärkt, dass eine steigende Anzahl von Tumoren resistent gegenüber Chemotherapeutika ist. Außerdem fehlen spezifische Antidota für akute Intoxikationen mit Mitosehemmern. Daher zielten die folgenden Experimente darauf ab den Rescue-Effekt näher zu charakterisieren und die zugrundeliegenden Wirkmechanismen aufzuklären. Zunächst zeigten Knockdown-Experimente, dass der Rescue-Effekt unabhängig von der AMPK-inhibierenden Wirkung von CC vermittelt wird. Da CC ein ATP-kompetitiver Inhibitor der AMPK ist und zuvor bereits gezeigt wurde, dass es auch eine große Zahl anderer Kinasen inhibieren kann, vermuteten wir, dass der Rescue-Effekt mit diesen Off-Target-Effekten von CC zusammenhängt. Als nächstes testeten wir, ob die wachstumshemmenden Effekte von anderen Mitosehemmern auch durch CC aufgehoben werden können. Wir wählten verschiedene etablierte Substanzen, die dafür bekannt sind mit Mikrotubuli zu interagieren: Colchicin, das Vinca-Alkaloid Vinblastin, Disorazol A und das aus Taxus-Arten isolierte Paclitaxel. Die ersten drei dieser Substanzen haben eine depolymerisierende Wirkung auf die Mikrotubuli, während Paclitaxel zu einer stärkeren Polymerisierung führt. Zudem binden diese Substanzen an drei verschiedenen Bindestellen am Tubulin. Interessanterweise zeigten unsere Versuche, dass CC die antiproliferative Wirkung aller getesteten Mitosehemmer auf HT-29-Zellen, unabhängig von der Bindestelle, abschwächen kann. Des Weiteren konnte CC die Wirkung der pro-apoptotischen Substanz Staurosporin nicht reduzieren. Diese Ergebnisse weisen darauf hin, dass eher die tubulinbindenden, als die pro-apoptotischen Eigenschaften, von ST911 für den Rescue-Effekt verantwortlich sind. Um zu untersuchen, ob der Rescue-Effekt mit einer kompetitiven Bindung von CC und Mitosehemmern an Mikrotubuli erklärt werden kann, führten wir eine Immunfluoreszenzfärbung von ?-Tubulin durch. Wir konnten beobachten, dass die Tubulinpolymerisation und die Funktion des Spindelapparates in Zellen, die mit Mitosehemmern behandelt wurden, deutlich eingeschränkt waren. Außerdem stellten wir fest, dass CC nicht in der Lage ist die Zerstörung des Tubulingerüstes durch die Mitosehemmer zu verhindern. Eine Einzelbehandlung mit CC hatte keine Wirkung auf die Polymerisation des Tubulin zu Mikrotubuli. Insgesamt legen diese Daten nahe, dass CC nicht direkt an Mikrotubuli binden kann, um mit den Mitosehemmern um eine Bindung zu kompetitieren. Um diese Hypothese zu stärken, führten wir, in Kooperation mit Dr. Jennifer Herrmann (Helmholtz Institut für Pharmazeutische Forschung, Saarbrücken) SPR-Experimente mit Chips durch, auf denen Tubulin immobilisiert wurde. Die Messungen zeigten, das CC nicht in der Lage war gebundenes Disorazol A von der Bindestelle am Tubulin zu verdrängen. Dies zeigte nun deutlich, dass der Rescue-Effekt nicht auf einer Kompetition von CC und Mitosehemmern um Tubulinbindestellen beruht. Zellzyklusanalysen zeigten, dass die kombinierte Behandlung mit ST911 und CC zu einer Abschwächung des durch ST911 verursachten G2/M-Arrestes führt. Da wir zuvor bereits eine Beeinflussung der direkten Targets von CC und Mitosehemmern, AMPK oder Tubulin, ausgeschlossen hatten, schlussfolgerten wir, dass CC vermutlich mit anderen zellulären Signalwegen interagiert, die zu den beschriebenen Veränderungen des Zellwachstums und der Zellzyklusprogression führen. Eine Literaturrecherche ergab, dass ein erhöhter intrazellulärer Polyaminspiegel, die Aktivierung des PI3K/Akt-Signalweges oder eine erhöhte Aktivität des Transkriptionsfaktors c-Myc zu einer Abschwächung eines G2/M-Arrestes führen können. Daher fokussierten wir die weiteren Experimente auf die Untersuchung einer möglichen Beteiligung dieser Targets an der Vermittlung des Rescue-Effektes. Wir zeigten, dass CC die Expression der Spermidin/Spermin-N1-Acetyltransferase (SSAT) erhöhen kann. Die SSAT ist ein Enzym, das an der Biosynthese der Polyamine beteiligt ist. Zusätzlich beobachteten wir, dass die Behandlung mit CC nach 4 h zu einer Erhöhung von phosphoryliertem und damit aktiviertem Akt (pAkt) führt. Die zusätzliche Behandlung mit Wortmannin, einer Substanz, welche die Phosphorylierung von Akt hemmen kann, führte zu einer Abschwächung des Rescue-Effektes. Insgesamt weisen diese Ergebnisse darauf hin, dass eine Aktivierung von Akt-Signalwegen und ein Einfluss auf die Polyaminbiosynthese, zumindest teilweise, mit dem Rescue-Effekt zusammenhängen können. Die Überexpression von c-Myc, einem Transkriptionsfaktor, der eng mit dem Akt-Signalweg und der Biosynthese von Polyaminen zusammenhängt, ist oft mit einer erhöhten Zellproliferation verbunden. Wir untersuchten die zellulären Proteinmengen von c-Myc mittels Western Blot und entdeckten, dass nach der Behandlung mit Mitosehemmern zusätzliche Banden für c-Myc auf den Blots auftauchten. Diese Ergebnisse geben einen Hinweis auf eine posttranslationale Modifikation von c-Myc nach der Behandlung mit Mitosehemmern. Durch Kombination mit CC wurden die zusätzlichen Banden abgeschwächt und die Gesamtmenge an c-Myc-Protein nahm nach längeren Inkubationszeiten rapide ab. Dies legt nahe, dass die posttranslationale Modifikation von c-Myc zum Abbau des Proteins führt und, dass CC dies abschwächen kann. Verschiedene Arbeiten zeigten bereits, dass c-Myc phosphoryliert wird und nach Konjugation mit Ubiquitin vom Proteasom abgebaut wird. Daher überprüften wir, ob eine Inhibition des Proteasoms mit MG-132 zu einem ähnlichen Rescue-Effekt führt wie mit CC. Tatsächlich führte die Behandlung mit ST911 in Kombination mit MG-132 zu einer Zunahme der Zellproliferation, wie sie vorher bereits für CC beobachtet wurde. Dies bestärkte die Theorie, dass der proteasomale Abbau von c-Myc eine Rolle beim Rescue-Effekt spielen kann. Als nächstes untersuchten wir die Phosphorylierungen von c-Myc am Ser62 und Thr58. Diese Phosphorylierungen spielen eine wichtige Rolle beim Abbau von c-Myc, indem Sie das Protein für die Konjugation mit Ubiquitin markieren. Die densitometrische Auswertung der Western Blots ergab, dass die Behandlung mit ST911 initial zu einem Anstieg von phospho-c-Myc führt, dem eine schnelle Abnahme zu späteren Zeitpunkten folgt. Außerdem konnte gezeigt werden, dass dieser Anstieg von phospho-c-Myc durch Kombination mit CC reduziert wurde. Dies unterstützt die Hypothese, dass ST911 den proteasomalen Abbau von c-Myc begünstigt und CC dies verhindern kann. Dies ist eine mögliche Erklärung für die erhöhte Zellproliferation, die für die durch CC „geretteten“ Zellen beobachtet wurde. Allerdings konnte das direkte Target, das für die Vermittlung des Rescue-Effektes durch CC verantwortlich ist, bisher nicht identifiziert werden. DYRKs (aus dem Englischen: Dual-specificity tyrosine-phosphorylation-regulated kinases) sind wichtige Regulatoren von Proteinstabilität und –abbau während der Zellzyklusprogression. Vor kurzem wurde gezeigt, dass DYRK1A und DYRK2 c-Myc am Ser62 phosphorylieren können und es dadurch für den proteasomalen Abbau markieren. Interessanterweise wurde CC bereits in einer früheren Publikation als potenter Inhibitor verschiedener DYRKs beschrieben. Allerdings wurde die Hemmung der DYRKs durch CC in diesem Artikel nur in einer einzelnen Konzentration getestet. Daher bestimmten wir in einem in-vitro-Kinaseassay in Kooperation mit Dr. Matthias Engel (Universität des Saarlandes, Saarbrücken) die IC50-Werte für CC gegenüber DYRK1A, DYRK1B und DYRK2. Unsere Ergebnisse zeigten deutlich, dass CC ein bevorzugter Inhibitor von DYRK1A und DYRK1B (IC50-Wert von etwa 1 µM) ist, aber auch DYRK2 hemmen kann (IC50-Wert von etwa 5 µM). Da sich die vermutete Bindestelle von CC in der stark konservierten Kinasedomäne befindet, ist eine unspezifische Inhibition verschiedener DYRKs nicht überraschend. Genexpressionsanalysen zeigten, dass HT-29 und HepG2 vergleichbare Mengen an DYRK1A exprimieren, während DYRK1B und DYRK2 deutlich weniger in HepG2 vorhanden sind. Vorige Experimente hatten gezeigt, dass HepG2 weniger sensitiv für ST911 und den durch CC vermittelten Rescue-Effekt waren. Wir schlussfolgerten, dass die unterschiedliche Expression der DYRK-Formen eine mögliche Erklärung für diese Unterschiede sein könnte. Daher entschieden wir uns für eine nähere Untersuchung von DRK1B und DYRK2. Experimente mit verschiedenen Inhibitoren der DYRKs zeigten, dass diese Substanzen, ähnlich wie CC, in der Lage waren die antiproliferative Wirkung von ST911 abzuschwächen. Diese Ergebnisse wurden in nachfolgenden Knockdown-Experimenten bestätigt. Dies legt nahe, dass die DYRKs zumindest teilweise für die Vermittlung des Rescue-Effektes verantwortlich sind. Zusammenfassend man kann sagen, dass der Rescue-Effekt vermutlich mit der Biosynthese von Polyaminen, dem Akt-Signalweg und dem proteasomalen Abbau von c-Myc zusammenhängt. Des Weiteren scheint die direkte Inhibition von DYRKs durch CC ein vielversprechender Ansatz für die Erklärung des Effektes zu sein. Allerdings konnte in keinem der Experimente eine kompletten Aufhebung des Rescue-Effektes durch CC gezeigt werden. Daher gehen wir davon aus, dass verschiedene Targets in die Vermittlung des Rescue-Effektes involviert sind. Dies ist höchstwahrscheinlich auf eine unspezifische, ATP-kompetitive Hemmung verschiedener Kinasen durch CC zurückzuführen. Nichtsdestotrotz, sind eine nähere Untersuchung von DYRKs im Rahmen der Therapieresistenz von Tumoren und eine genauere Aufklärung der am Rescue-Effekt beteiligten Signalwege eine interessantes Feld für weitere Untersuchungen.
In addition to infectious viral particles, hepatitis B virus-replicating cells secrete high amounts of SVPs, which are ssembled by HBsAg in the shape of spheres and filaments but lack any capsid and genome. Filaments are characterized by a much higher amount of the surface protein LHBs as compared to spheres. Spheres are
released via the constitutive secretory pathway, while viral particles are ESCRT-dependently released via MVBs. The interaction of virions with the ESCRT machinery is mediated by α-taxilin that connects the PreS1 domain of LHBs with the ESCRT-component tsg101. Since viral particles and filaments contain a significant amount of LHBs, it is unclear whether filaments are secreted as spheres or released like viral particles. To study the release pathways of HBV filaments in the absence of viral particles, A core-deficient
HBV mutant (1.2×HBVΔCore) was generated by site-directed mutagenesis based on wt1.2x HBV. The start codon of core protein was mutated into stop codon, which was confirmed by DNA sequencing. Data from HBsAg ELISA, Western blot, immunofluorescence microscopy and immunoelectron microscopy showed that the lack of core protein did neither affect the production nor the secretion of HBV SVPs. The intracellular distribution of
LHBs and SHBs showed no difference between wtHBV and the core-deficient mutant expressing cells. Therefore, this system is suitable to investigate the release pathway of HBV filaments in the absence of viral particles. Confocal microscopy analysis of cells cotransfected core-deficient mutants with peYFPRab7 as marker for the endosomal/MVB pathway or with pGalT-eGFP as marker for the trans Golgi apparatus showed that YFP-Rab7, but not GalT-GFP, partially colocalized with LHBs. Furthermore, LHBs could be found in dilated MVBs by immune electron microscopy of ultrathin sections. This was confirmed by isolation of MVBs by cell fractionation using discontinuous sucrose gradient ultracentrifugation and percoll-based linear gradient ultracentrifugation, indicating that filaments enter MVBs in the absence of virion formation. Moreover, inhibition of MVB biogenesis by the small molecular inhibitor U18666A significantly abolished the release of filaments in a dose-dependent manner, but no inhibition could be observed in the production. In contrast, no inhibition on the secretion and production of spheres could be
detected. Inhibition of ESCRT-functionality by coexpression of transdominant negative mutants (Vps4A, Vps4B, CHMP3) abolished the release of filaments while secretion of spheres was not affected. These data indicate that in contrast Abstract 73 to spheres while are secreted via the secretory pathway, filaments are released via ESCRT/MVB pathway like infectious viral particles.
Im Folgenden werden die wichtigsten Fragen und Probleme, die die Genealogie der modernen Lesarten und 'rewritings' der Fesselung Isaaks aufwirft, sowie einige interessante Funde, die ich in meiner Studie skizziert habe, vorgestellt. Zum Schluss soll eine zentrale Frage erhoben werden: Wann genau wurde Isaak, das Möchtegern-Opfer im Buch Genesis, "der Grundpfeiler unseres religiösen Bundes" in Yehoshuas Worten, als Grundpfeiler des sog. modernen säkularen Nationalismus wiedererfunden?
Background and Aims. Biliary complications are the most frequent complications after common liver surgeries. In this study, accuracy of hepatobiliary scintigraphy (HBS) and impact of hyperbilirubinemia were evaluated. Methods. Between November 2007 and February 2016, 131 patients underwent hepatobiliary scintigraphy after having liver surgery. 39 patients with 42 scans after LTX (n=13) or hepatic resection (n=26) were evaluated in the study; 27 were male, with mean age 60 years. The subjects underwent hepatobiliary scintigraphy with Tc-99m labeled Mebrofenin. The results were compared to ERCP as gold standard performed within one month after HBS. We calculated sensitivity, specificity, PPV, and NPV. We compared LTX patients to patients with other liver surgeries. Furthermore the influence of hyperbilirubinemia on HBS scans was evaluated. Results. HBS always provided the correct diagnosis in cases of bile leak in the liver-resected group (14/14). Overall diagnostic accuracy was 76% (19/25) in this group and 54% (7/13) in the LTX group. False negative (FN) diagnoses occurred more often among LTX patients (p=0.011). Hyperbilirubinemia (>5 mg/dL) significantly influenced the excretion function of the liver, prolonging HBS’s time-activity-curve (p=0.001). Conclusions. Hepatobiliary scintigraphy is a reliable tool to detect biliary complications, but reduced accuracy must be considered after LTX.
Mantle cell lymphoma (MCL) is a unique type of B-cell non-Hodgkin's lymphoma, which very rarely exhibits skin involvement. We herein describe the case of a 55-year-old woman, who initially presented with a nodular mass of the right infraorbital region. On histological analysis of the subcutaneous tissue, a diffuse neoplastic cell infiltration was identified, composed of medium‑sized lymphoid cells with irregular nuclei, which was diagnosed as MCL. The tumor cells were positive for CD5, CD20, CD79a, cyclin D1 and sex‑determining region Y-box 11, but negative for CD10 and CD23. Our patient received six cycles of R‑CHOP chemotherapy and intrathecal methotrexate as central nervous system prophylaxis. However, the patient relapsed 1 year later and was treated with two cycles of R‑DHAP and one cycle of intrathecal methotrexate. After achieving partial remission, the patient was consolidated with peripheral blood stem cell transplantation using the BEAM conditioning regime. While prior case studies suggest that skin invasion by MCL is associated with a poor prognosis, our patient remains alive almost 4 years after the initial presentation. Skin involvement as a first sign of systemic MCL is very rare and must be considered.
Study of hard core repulsive interactions in an hadronic gas from a comparison with lattice QCD
(2016)
We study the influence of hard-core repulsive interactions within the Hadron-Resonace Gas model in comparison to first principle calculation performed on a lattice. We check the effect of a bag-like parametrization for particle eigenvolume on flavor correlators, looking for an extension of the agreement with lattice simulations up to higher temperatures, as was yet pointed out in an analysis of hadron yields measured by the ALICE experiment. Hints for a flavor depending eigenvolume are present.
Zielsetzung. Diese Pilotstudie untersucht den therapeutischen Effekt des RelaxBogens in Bezug auf Bruxismus und Symptome einer kraniomandibulären Dysfunktion (CMD).
Probanden und Methoden. Untersucht wurde eine Gruppe von 10 Probanden. Auswahlkriterien waren ein vorliegender Bruxismus und erste Symptome einer CMD. Dies wurde durch die Anwendung einer Brux-Checker®-Folie für 2 Nächte und eine Schmerzanamnese verifiziert. Eingangs wurden neben einer ausführlichen zahnärztlichen Anamnese folgende CMDParameter erhoben: SL-NRS-Fragebogen sowie Palpation von 42 Muskeln im Kopf-HalsNacken-Bereich und der 6 Austrittspunkte des N. trigeminus. Nach der Voruntersuchung wurde der RelaxBogen mindestens 10 Wochen getragen. Danach wurden die genannten Parameter erneut erhoben und miteinander verglichen.
Ergebnisse. Die Vor- und Nachuntersuchungen zeigten starke Tendenzen der Reduktion sowohl der allgemeinen Symptomatik als auch der Schmerzempfindung im Kieferbereich. Nach dem Tragen des RelaxBogens konnte eine eindeutige Reduktion des durch Palpation ausgelösten, muskulären Schmerzes beobachtet werden. Ebenfalls deutlich positive Tendenzen ließen sich bei der Verbesserung des allgemeinen Wohlbefindens finden. Die Ergebnisse legen nahe, dass bei einer größeren Stichprobe eine statistische Signifikanz zu erwarten ist.
Schlussfolgerung. Der RelaxBogen führt nach den Ergebnissen dieser Pilotstudie bei Patienten, die unter Bruxismus- und CMD-Symptomen leiden, zu einer deutlichen Reduktion der Schmerzwahrnehmung sowie einer eindeutigen Steigerung des Wohlbefindens. Neben der Verringerung des Schmerzempfindens und einem reduzierten Spannungsgefühl in den großen Kiefermuskeln konnten auch positive Tendenzen im Bereich der Hals-, Nacken- und Schultermuskulatur festgestellt werden.
This is the last post in the blog series „Movements and Institutions“. Check out the introductory post for more information on the series and click here for all contributions.
This blog series reflected on the interactions between social movements and institutions. These interactions have proven to be among the most complicated areas of social movement research, especially because causality is very hard to establish: (how) do movements influence formal political institutions – and vice versa? How to study, understand and explain the consequences of the institutionalization of social movements? The difficulties of addressing these questions are also related to definitional problems as social movements and institutions can be understood and defined in various ways. All authors contributing to this blog series highlight the importance of studying interactions between social movements from one perspective or another.
Die Geschichte der Folter und die der Märtyrer, das zeigt nicht erst Gallonio, gehen Hand in Hand. Bereits im Mittelalter bezeichnete 'cruciatus' auch die Folter und die Pein, ebenso wie das mhd. 'Marter' aus dem Leiden Christi über das Blutzeugnis die Bedeutung Folter entwickelt hat. Rein begrifflich landeten somit die Passion und das Martyrium wieder dort, wo sie ihren Ausgang genommen hatten: in der Geschichte des Rechts und seiner Zeugen. Im Martyrium ist immer schon ein gewisser Juridismus am Werk: Es beginnt mit einer Konfrontation vor Gericht, vollzieht sich in einer spezifischen Verbindung von Zwang und Zeugenschaft und bezeugt zuletzt, in seiner eschatologischen Dimension, die Hoffnung auf eine weltgeschichtliche Wiederherstellung des Rechts. Vergleichbar aber sind Folter und Martyrium auch darin, dass sie beide 'diskursive Praktiken' im strengen Sinn darstellen: Beide bestehen in einem Sprechakt, der durch einen Akt körperlicher Gewalt beglaubigt werden muss. Erst unter der Folter kommt das Bekenntnis oder Geständnis ganz zu sich, und so sehr die Marter und das Martyrium gerade über die sprachlose Evidenz der Schmerzen 'sprechen' machen, so sehr produzieren sie weitere Diskurse: Zuvorderst entstehen Protokolle der peinlichen Befragung oder des Bekenntnisses; und zuletzt wird ein rechtsgültiges Urteil oder aber die kanonische Beurteilung darüber zu den Akten genommen, ob es sich um einen Pseudomärtyrer, um ein gescheitertes Martyrium oder um einen wahren Blutzeugen gehandelt hat. In beiden Fällen sind es Schmerzen oder Leiden, die positiviert und - nach Maßgabe einer weltlichen oder geistlichen Macht - in einer Wahrheit aufgehoben werden. Somit ist selbst jene Selbstautorisierung, die die 'confessores' der ersten Stunde auszeichnet, nur von Gnaden einer Diskursgewalt, welche rechtsgültige Verbrecher 'ex post' in Leidende ('pathontes') und diese in Zeugen ('martyres') verwandelt. Im Archiv der Märtyrer lässt sich dieses Zusammenwirken unterschiedlicher Diskurspraktiken schon am Grundstock der frühchristlichen Märtyrerakten studieren: Zuweilen als Briefe verfasst und als solche an die gesamte expandierende Christenheit adressiert, vermischen sie Augenzeugenberichte und Dokumente, Urkunden und Fälschungen, Glaubensunterweisungen und Erzählungen, Protokolle und authentische Textzeugen. Stets präsentieren sie eine juristische Fallgeschichte und statuieren aus ihr ein heilsgeschichtliches Exempel. Als Gallonios Kollegen an der Wende zum 17. Jahrhundert die Märtyrerakten historisch-kritisch bearbeiteten, vereinigten sie die verstreuten Textzeugnisse und brachten die diskursive Ordnung der Blutzeugnisse auf den neuesten Stand. Martyrologie ist so gesehen immer auch eine fortlaufend aktualisierte Ableitung der Heils- aus der Rechtsgeschichte.
Die Krisenproteste in Frankfurt am Main und insb. das Blockupy-Bündnis und dessen Praxen zwischen 2012 und 2015 stehen im Mittelpunkt der folgenden Auseinandersetzung. Insgesamt stellt Blockupy den wohl breitesten Versuch dar, in Deutschland Widerstand gegen das „europäische Krisenregime“ zu organisieren. Hierfür trat das Bündnis 2012 und 2013 mit Aktionen des zivilen Ungehorsams in Frankfurt, im Mai 2014 mit dezentralen Aktionen in ganz Europa sowie der Mobilisierung gegen die Eröffnungsfeier des Neubaus der EZB im Frankfurter Ostend 2015 in Erscheinung. In dichter Form werden die Ereignisse skizziert und abschließend bewertet. Zentralgestellt werden in der Auseinandersetzung mit Blockupy dessen Praxen des Widerspruchs, die Aktionsformen sowie die Prozesse der Bündnisbildung. Gefragt wird nach Blockupys Organisation, den vollzogenen Lernprozessen sowie den inhaltlichen und praxisbezogenen Verschiebungen. Herausgearbeitet wird, dass Blockupy zunächst stark auf die Kritik an „Banken und Konzernen“ abzielte, dann aber immer expliziter auf die EZB fokussierte und eine antikapitalistische Position entwickelte. Immer stärker wird auch die internationale Ausrichtung des Bündnisses, womit die Zielsetzung der Etablierung eines ‚Europas von unten‘ entgegen der ‚autoritären EU von oben‘ einherging.
The future heavy-ion experiment CBM (FAIR/GSI, Darmstadt, Germany) will focus on measurement of very rare probes at interaction rates up to 10 MHz with data flow of up to 1 TB/s. The beam will provide free stream of beam particles without bunch structure. That requires full online event reconstruction and selection not only in space, but also in time, so-called 4D event building and selection.
The FLES (First-Level Event Selection) reconstruction and selection package consists of several modules: track finding, track fitting, short-lived particles finding, event building and event selection. A time-slice is reconstructed in parallel between cores within a same CPU, thus minimizing the communication between CPUs. After all tracks are found and fitted in 4D, they are collected into clusters of tracks originated from common primary vertices, which then are fitted, thus identifying 4D interaction points registered within the time-slice. Secondary tracks are associated with primary vertices according to their estimated production time. After that, short-lived particles are found and the full event building process is finished. The last stage of the FLES package is the selection of events according to the requested trigger signatures.