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Bei der Ionenstrahltherapie bestimmt die Energie der Ionen die Eindringtiefe in das Gewebe und damit die Lage des Braggpeaks, in dem der größte Teil der Ionisationsenergie deponiert wird.
Um die gewünschte Dosis möglichst genau im Tumor zu lokalisieren, müssen in den aufeinanderfolgenden Extraktionen die gewünschten unterschiedlichen Energien möglichst genau sein.
In der Beschleunigungsphase werden die Magnetfelder der Magnete im Synchrotron bis zum vorgegebenen Exktraktionswert hochgefahren. Dieser bestimmt zusammen mit der Synchrotronfrequenz die Strahlenergie. Während und insbesondere am Ende dieser Phase, Rampe genannt, sollte das Magnetfeld daher sehr genau dem berechneten Sollwert folgen, um Strahlverluste zu minimieren und die geforderte Strahlqualität zu erreichen.
In der zeitlichen Steuerung der Magnetströme müssen magnetische Effekte, die hauptsächlich im Eisen der Magnete auftreten, wie Wirbelströme und die Hysterese berücksichtigt werden, da sie das Feld verfälschen und damit den Strahl in unerwünschter Weise beeinflussen. Die während der Rampe entstehenden Wirbelströme stören das Magnetfeld, so dass bisher vor der Extraktion des Strahls eine Wartezeit eingeführt wurde, bis die Wirbelströme abgeklungen waren.
Bei beliebig wählbaren Abfolgen der vordefinierten Zyklen kommt es durch die Hysterese des Eisens zu unterschiedlichen Remanenzfeldern, die das Magnetfeld verändern. Um dem vorzubeugen, durchliefen die Magnete eine vordefinierte Hystereseschleife. Ist die geforderte Energie des Strahls erreicht, wird das Magnetfeld konstant gehalten und die Teilchen aus dem Synchrotron extrahiert. Der Rest der Hystereseschleife wurde am Ende des Zyklus durchlaufen.
Die im Rahmen dieser Dissertation entwickelte dynamische Magnetfeldregelung misst das integrale Magnetfeld sehr genau und korrigiert die Feldfehler. Das integrale Magnetfeld folgt damit jederzeit seiner Vorgabe, unabhängig von den dynamischen Störeffekten. Die Wirbelströme und die Hysterese sind zwar immer noch vorhanden, die dadurch verursachten Feldfehler können aber durch eine Rückkopplung auf den Strom des Magneten korrigiert werden.
Es werden verschiedene Verfahren zur Messung der Magnetfelder untersucht. Am besten eignet sich für die dynamische Magnetfeldregelung die Kombination aus einer Hallsonden- und einer Induktionsspulenmessung. Die Messung muss das integrale Magnetfeld des Magneten BL, also das gesamte Feld entlang des Strahlwegs, bestimmen. Die Induktionsspule, oder Pickupspule, liegt deshalb entlang des Strahlrohrs im Magneten und liefert eine Spannung in Abhängigkeit von der Änderung des magnetischen Flusses. Durch die Integration dieser Spannung erhält man das integrale Feld des Magneten. Die Messung wird mit einer Hallsondenmessung zu Beginn des Beschleunigerzyklus auf einen absoluten Messwert geeicht.
Der Hauptteil dieser Arbeit beschäftigt sich mit der Entwicklung des sogenannten HIT Integrators, der die Integration der Pickupspulenspannung übernimmt. Bisher verfügbare Integratoren konnten die notwendigen Anforderungen an Genauigkeit, Echtzeitfähigkeit, automatische Kalibrierung, ständige Messbereitschaft, Temperaturunabhängigkeit und hohe Verfügbarkeit nicht erfüllen. Der neu entwickelte HIT Integrator wurde diesen Anforderungen entsprechend entwickelt. Der Integrator mit dem neuartigen Konzept der gleichzeitigen Messung und Kalibrierung in Echtzeit ist als Patent angemeldet worden. Neben der Entwicklung und Verwirklichung des Gesamtkonzepts war die numerische Integration des stark verrauschten Pickupspulensignals und die sofortige Umsetzung des integralen Werts in ein Steuersignal für die Dipolmagnetstromgeräte eine besondere technische Herausforderung.
Die elektronischen Schaltungen für die dynamische Magnetfeldregelung sind in der Baugruppe des HIT Integrators zusammengefasst. Die Ansteuerung der Hallsonde mit einer temperaturkompensierten Stromquelle, der Signalaufbereitung und Analog-Digital-Wandlung, sowie der Integrator und der Regler bilden eine technische Einheit.
Der HIT Integrator ist speziell für den Einsatz im bestehenden Beschleunigerkontrollsystem und den Magnetnetzgeräten entwickelt worden.
Die Regler der Magnetnetzgeräte wurden so verändert, dass sie einen Zusatzsollwert verarbeiten können, der auf den berechneten Sollwert der Datenversorgung addiert wird.
Die Magnetfeldregelung wurde in den Therapiebeschleuniger integriert, dazu wurde die Datenversorgung und das Kontrollsystem angepasst. Die Magnetfeldregelung stellt ein neues Gerät im Beschleuniger dar, das in die Netzgeräte der Synchrotronmagnete eingebaut worden ist. Die Datenversorgung dieser Geräte beinhaltet u.a. eine neue Methode der Kalibrierung.
Es konnte durch Messungen gezeigt werden, dass die Magnetfeldregelung mit hoher Genauigkeit funktioniert. Es wird eine Genauigkeit von besser als 10^{-4} des maximalen Feldes von 1.5 T erreicht, also weniger als 150uT, der dreifachen Stärke des Erdmagnetfelds. Vor allem die Bestrahlungszeit mit Protonen und die Bestrahlung bei niedrigen Energien profitiert von der Magnetfeldregelung, da hier das Extraktionsniveau der Magnete relativ gering ist und das Durchlaufen der vordefinierten Hystereseschleife prozentual mehr Zeit im Zyklus in Anspruch nimmt. Durch den Wegfall dieser Phase wird daher pro Zyklus mehr Zeit eingespart. Die Messungen zeigen, dass im Beschleunigerzyklus trotz der fehlenden Wartezeiten, die bis zu 24% betragen, eine gleichbleibend gute Strahlqualität erreicht wird. Dies wurde mit Vergleichsmessungen gezeigt, bei denen der Strahl mit und ohne Feldregelung vermessen wurde. Untersucht wurde eine große Stichprobenmenge aus dem Parameterraum, gegeben durch zwei Ionensorten mit jeweils 255 Strahlenergien, 10 verschiedenen Teilchenraten und 4 Strahlbreiten. Außerdem wurde die Energie des Strahls nachgemessen.
Für die Einführung in den Therapiebetrieb musste eine Impactanalyse gemacht werden, die mögliche Auswirkungen des neuen Verfahrens behandelt. Das Risiko für Patienten, Mitarbeiter und Dritte darf durch die Magnetfeldregelung nicht erhöht werden. Daraus entstand auch die Forderung nach einem redundanten System, das Fehler erkennt und die Bestrahlung abbricht.
Die mittlere Leistungsaufnahme des Beschleunigers des Heidelberger Ionenstrahltherapiezentrums liegt bei etwa 1 MW, bei einem Jahresenergieverbrauch von 8 GWh mit Kosten von etwa 1 Million Euro. Dies entspricht einer deutschen Kleinstadt mit 10000 Einwohnern. Die Verkürzung der Zykluszeiten wirkt sich direkt auf die Bestrahlungszeit und auf die Energiekosten aus. Würde man die Anlage durch die Zeiteinsparungen kürzer betreiben, würde man etwa 2 GWh pro Jahr sparen, was die Stromkosten um etwa 250000 Euro reduziert.
Zusätzlich zu den eingesparten Kosten wird auch die Bestrahlungszeit kürzer und damit auch die Zeit, die der Patient bei der Behandlung fixiert wird. Die Behandlung für die Patienten wird angenehmer. Man kann aber auch durch die eingesparte Bestrahlungszeit pro Patient entsprechend mehr Patienten behandeln. Das heißt man kann an Stelle von 700 Patienten im Jahr 910 Patienten mit einem Tumor behandeln. Dieser für die Patienten willkommene Effekt bedeutet auf der anderen Seite für HIT aber auch Mehreinnahmen von 4.2 Millionen Euro im Jahr.
Das Konzept der Magnetfeldregelung kann auch an anderen Beschleunigeranlagen zum Einsatz kommen. Dazu müssen die Magnete mit den Sonden bestückt werden und die Magnetnetzgeräte einen Eingang für einen Zusatzsollwert bekommen. Das Beschleunigerkontrollsystem kann erweitert werden, damit es einen Sollwert mit allen notwendigen Kalibrierungen berechnen kann. Der HIT Integrator wird dann als eigenständiges Gerät in das Kontrollsystem eingebunden.
This thesis investigates how students with Cantonese (L1) and English (L2) backgrounds acquire German as a third language (L3), with a focus on the acquisition of the Vorfeld (fronting) constructions of German. In L3 studies, the roles played by mother tongue, L2 and developmental grammar may be distinguished. Previous L3 studies have suggested that the role of L2 seems to be prominent in L3 strategy building, including interlanguage transfer from L2 to L3. Pursuing a cognitive approach, we argue that incremental production and language processing strategies are significant factors in accounting for third language acquisition and production.
A total of 45 university students of German completed a questionnaire and submitted copies of their compositions, followed by picture elicitation tasks. Three typical fronting types were found to be common amongst the learners:
1. Für mich, jede Familie hat eigene Situation und Probleme.
2. Obwohl gibt es viele Probleme mit alten Leuten zusammen lebt, finde ich gut dafür.
3. Jetzt die meisterns haben schon nach Hong Kong zurückgekommen.
Type 1 is argued to reflect indirect transfer of native language function-form characteristics. Type two is argued to be an intralingual error in which the learners have overgeneralized the verb second (V2) rule, without acquiring the correct function of the Vorfeld construction. The third type shows that apart from the influence of English in adverb fronting constructions, adverbs of stance or perspective adverbs like ‘jetzt’ semantically do not form part of the proposition and they are therefore treated as “extra-sentential” constituents which do not affect the basic V2 construction.
The findings suggest that learners may have primarily acquired the topic function of German fronting, while failing to fully acquire the focus function. For the focus function, learners seem to prefer alternative constructions such as existential sentences using ‘es gibt’. Both of these findings implicate L1 Chinese influence.
As an overall perspective on the incipient field of third language acquisition research I propose a holistic and coherent view which encompasses syntax, semantics and pragmatics at all levels of language development. By probing an independent paradigm of L3 studies, we aim to contribute to a new dynamic research space as well to ongoing debates in the SLA field by attributing greater autonomy and consciousness to the learner, even on the level of grammatical interaction.
The ability of hematopoietic stem cells (HSCs) to self-renew is a prerequisite for the establishment of definitive hematopoiesis and life-long blood regeneration. Here, we report the single-stranded DNA-binding transcriptional regulator far upstream element (FUSE)-binding protein 1 (FUBP1) as an essential factor of HSC self-renewal. Functional inactivation of FUBP1 in two different mouse models resulted in embryonic lethal anemia at around E15.5 caused by severely diminished HSCs. Fetal and adult HSCs lacking FUBP1 revealed an HSC-intrinsic defect in their maintenance, expansion, and long-term blood reconstitution, but could differentiate into all hematopoietic lineages. FUBP1-deficient adult HSCs exhibit significant transcriptional changes, including upregulation of the cell-cycle inhibitor p21 and the pro-apoptotic Noxa molecule. These changes caused an increase in generation time and death of HSCs as determined by video-microscopy-based tracking. Our data establish FUBP1 and its recognition of single-stranded genomic DNA as an important element in the transcriptional regulation of HSC self-renewal.
It is estimated that a number between 27,000 and 31,000 foreign fighters have been flocking to Iraq and Syria since the breakout of the war in 2011.
An updated assessment of the flow of foreign fighters into Syria and Iraq shows that there is a significant increase in the number of foreign fighters travelling to Syria. Data provided by the Soufan Group in 2014 estimated that the identifiable number of foreign fighters is approximately 12,000 from 81 countries. It was also believed that the number of foreign Jihadists coming form Western countries does not exceed 3000: “Around 2,500 are from Western countries, including most members of the European Union, the United States, Canada, Australia, and New Zealand”, according to Soufan’s initial report on Foreign Fighters in Syria. Now the number exceeds 27,000 foreign fighters from at least 86 countries...
The global financial crisis and the ensuing criticism of macroeconomics have inspired researchers to explore new modeling approaches. There are many new models that deliver improved estimates of the transmission of macroeconomic policies and aim to better integrate the financial sector in business cycle analysis. Policy making institutions need to compare available models of policy transmission and evaluate the impact and interaction of policy instruments in order to design effective policy strategies. This paper reviews the literature on model comparison and presents a new approach for comparative analysis. Its computational implementation enables individual researchers to conduct systematic model comparisons and policy evaluations easily and at low cost. This approach also contributes to improving reproducibility of computational research in macroeconomic modeling. Several applications serve to illustrate the usefulness of model comparison and the new tools in the area of monetary and fiscal policy. They include an analysis of the impact of parameter shifts on the effects of fiscal policy, a comparison of monetary policy transmission across model generations and a cross-country comparison of the impact of changes in central bank rates in the United States and the euro area. Furthermore, the paper includes a large-scale comparison of the dynamics and policy implications of different macro-financial models. The models considered account for financial accelerator effects in investment financing, credit and house price booms and a role for bank capital. A final exercise illustrates how these models can be used to assess the benefits of leaning against credit growth in monetary policy.
Objective: Gestational diabetes mellitus (GDM) is associated with substantial morbidity for mothers and their offspring. While clinical and basic research activities on this important disease grow constantly, there is no concise analysis of global architecture of GDM research. Hence, it was the objective of this study to assess the global scientific performance chronologically, geographically and in relation to existing research networks and gender distribution of publishing authors.
Study design: On the basis of the New Quality and Quantity Indices in Science (NewQIS) platform, scientometric methods were combined with modern visualizing techniques such as density equalizing mapping, and the Web of Science database was used to assess GDM-related entries from 1900 to 2012.
Results: Twelve thousand five hundred four GDM-related publications were identified and analyzed. The USA (4295 publications) and the UK (1354 publications) dominated the field concerning research activity, overall citations and country-specific Hirsch-Index, which quantified the impact of a country’s published research on the scientific community. Semi-qualitative indices such as country-specific citation rates ranked New Zealand and the UK at top positions. Annual collaborative publications increased steeply between the years 1990 and 2012 (71 to 1157 respectively). Subject category analysis pointed to a minor interest of public health issues in GDM research. Gender analysis in terms of publication authorship revealed a clear dominance of the male gender until 2005; then a trend towards gender equity started and the activity of female scientists grew visibly in many countries. The country-specific gender analysis revealed large differences, i.e. female scientists dominated the scientific output in the USA, whereas the majority of research was published by male authors in countries such as Japan.
Conclusion: This study provides the first global sketch of GDM research architecture. While North-American and Western-European countries were dominating the GDM-related scientific landscape, a disparity exists in terms of research output between developed and low-resource countries. Since GDM is linked to considerable mortality and morbidity of mothers and their offspring and constitutes a tremendous burden for the healthcare systems in underserved countries, our findings emphasize the need to address disparities by fostering research endeavors, public health programs and collaborative efforts in these nations.
RUCAM (Roussel Uclaf Causality Assessment Method) or its previous synonym CIOMS (Council for International Organizations of Medical Sciences) is a well established tool in common use to quantitatively assess causality in cases of suspected drug induced liver injury (DILI) and herb induced liver injury (HILI). Historical background and the original work confirm the use of RUCAM as single term for future cases, dismissing now the term CIOMS for reasons of simplicity and clarity. RUCAM represents a structured, standardized, validated, and hepatotoxicity specific diagnostic approach that attributes scores to individual key items, providing final quantitative gradings of causality for each suspect drug/herb in a case report. Experts from Europe and the United States had previously established in consensus meetings the first criteria of RUCAM to meet the requirements of clinicians and practitioners in care for their patients with suspected DILI and HILI. RUCAM was completed by additional criteria and validated, assisting to establish the timely diagnosis with a high degree of certainty. In many countries and for more than two decades, physicians, regulatory agencies, case report authors, and pharmaceutical companies successfully applied RUCAM for suspected DILI and HILI. Their practical experience, emerging new data on DILI and HILI characteristics, and few ambiguous questions in domains such alcohol use and exclusions of non-drug causes led to the present update of RUCAM. The aim was to reduce interobserver and intraobserver variability, to provide accurately defined, objective core elements, and to simplify the handling of the items. We now present the update of the well accepted original RUCAM scale and recommend its use for clinical, regulatory, publication, and expert purposes to validly establish causality in cases of suspected DILI and HILI, facilitating a straightforward application and an internationally harmonized approach of causality assessment as a common basic tool.
Die jüdisch-christliche Tradition, zu der im weiteren Sinn auch der Islam, der Gott als den gerechten Erbarmer kennt und bekennt, gehört, hat eine Intuition hervorgebracht, die in der Antike – sogar angesichts ihrer bewegenden Tragödienliteratur – einzigartig war. Diese Intuition hat ihren treffendsten Ausdruck im Evangelium des Matthäus (25,40) gefunden, einer jüdischen Schrift aus dem ersten Jahrhundert christlicher Zeitrechnung, in der sich der messianische König beim jüngsten Gericht so zu den Angeklagten äußert: "Was ihr getan habt einem unter diesen meinen geringsten Brüdern, das habt ihr mir getan." In der Ökumene der globalisierten Welt des 21. Jahrhunderts wird es auch darum gehen, diesem Gedanken vor dem Panorama der Erfahrungen des mörderischen 20. Jahrhunderts sozial-, geschichts- und erziehungswissenschaftlich gerecht zu werden.
Design typicality plays a major role in consumers’ reactions towards a product. Hence, assessing a product design’s typicality is vital to predicting consumers’ responses to a design. However, directly asking people for their subjective typicality experience may yield a biased measure as the rating arguably contains the overall aesthetic impression of the product. Against this background, we introduce four unbiased objective measures of design typicality (two based on feature points and two based on grids) and demonstrate their capability of capturing the subjective typicality experience. We validate the proposed measures in the context of automobile designs with ratings of aesthetic liking, processing fluency, and cumulative sales data by analysing 77 car models from four segments ranging from subcompact cars to SUVs. Our findings endorse the general notion that objective measures should be included in product design research; and the proposed objective approaches provide convenient means to easily assess design typicality.
Mit dem Konzept der Grundordnung verbindet sich eine vieldeutige Semantik, die das Zusammenspiel von Grund (als Boden/Territorium) mit dem Grund der Begründung betrifft, das für die Konstitution wie auch Geltungsbereich von Verfassungen eine wichtige Rolle spielt. Die kulturwissenschaftliche Perspektive der Frage nach Grundordnungen richtet sich auf jene Voraussetzungen, die im Zuge der juristischen Verengung des Begriffs ausgeschlossen worden sind. Damit gehen die Untersuchungen dieses Bandes hinter bzw. vor die juristische Semantik des Verfassungsbegriffs zurück. Untersucht werden die vielfältigen Übergänge zwischen Kultur, Religion und Gesetz und damit diejenigen Praktiken und Konzepte, mit denen das Selbstverständnis eines Volkes in konkrete politisch-juristische Grundsätze oder Grundrechte transformiert wird. "Mit der Frage nach der Grundordnung gehen die Untersuchungen dieses Bandes hinter bzw. vor die juristische Semantik des Verfassungsbegriffs zurück. Denn dieser ist, wie andere moderne Fachtermini auch, das Ergebnis einer Verengung. Die 'Verfassung', zunächst ein 'Erfahrungsbegriff', "der den politischen Zustand eines Staates umfassend wiedergibt", habe sich zum Begriff für den "rechtlich geprägten Zustand eines Staates" verengt und falle "nach dem Übergang zum modernen Konstitutionalismus mit Gesetz in eins", währenddessen der Begriff des Gesetzes nun "die Einrichtung und Ausrichtung der staatlichen Herrschaft regelt" und "damit selbst vom deskriptiven zum präskriptiven Begriff" wird, so Dieter Grimm, der die genannte Verengung damit erklärt, dass der Begriff der 'Verfassung' seine "nichtjuristischen Bestandteile zunehmend" abgestoßen habe. Diese nichtjuristischen Bestandteile aber sind Grundlage und Voraussetzung des Grundgesetzes, das sich eine Gemeinschaft gibt, um sich als politisch-rechtliches Gebilde zu konstituieren. Sie betreffen das Selbstverständnis eines politischen Gemeinwesens, ob Land, Staat oder Föderation, das tiefer und weiter zurück reicht als das Gesetz."
Die NADPH-Oxidasen stellen eine wichtige Quelle für reaktive Sauerstoffspezies (Reactive oxygen species; ROS) im Organismus dar. Hierbei dienen die NADPH-Oxidasen nicht nur der Pathogenabwehr, sondern haben einen Einfluss auf eine Vielzahl an oxidativen, physiologischen Prozessen. Unter den NADPH-Oxidasen ist NOX4 einzigartig, da es hauptsächlich im endoplasmatischen Retikulum (ER) lokalisiert ist, konstitutiv aktiv ist und Wasserstoffperoxid (H2O2) produziert. Wir vermuten, dass diese besonderen Eigenschaften eine Konsequenz aus der Interaktion mit bislang unentdeckten NOX4-interagiereden Proteinen ist.
Zweidimensionale blau-native Polyacrylamid-Gelelektrophorese (BN-PAGE) kombiniert mit SDS-PAGE zeigte NOX4 in makromolekularen Komplexen. Interagierende Proteine wurden durch eine quantitative SILAC (stable isotope labeling of amino acids in cell culture)-Co-immunopräzipitation (Co-IP) in NOX4-überexprimierenden HEK293-Zellen gescreent. Hierdurch konnten verschiedene interagierende Proteine identifiziert werden, wobei Calnexin die robusteste Interaktion aufwies. Calnexin konnte zudem in NOX4-haltigen Komplexen durch Complexome Profiling der BN-PAGE oder gleichzeitiger Antikörperfärbung nachgewiesen werden. Die Calnexin-NOX4-Interaktion konnte mittels reverser Co-IP und Proximity ligation assay bestätigt werden, während NOX1, NOX2 und NOX5 nicht mit Calnexin interagierten. Calnexin-Defizienz, untersucht in embryonalen Mausfibroblasten oder durch shRNA gegen Calnexin, reduzierte die NOX4-Proteinexpression und ROS-Bildung, wobei die mRNA-Expression unverändert blieb. Des Weiteren wurde untersucht, ob der bekannte Interaktionspartner von NADPH-Oxidasen, p22phox, wirklich essentiell für die Expression oder Aktivität von NOX4 ist, da es nur in manchen der NOX4-Co-IPs nachgewiesen wurde. Um den Einfluss von p22phox für NOX4 aufzuklären wurde ein CRISPR/Cas9 Knockdown in NOX4-überexprimierenden HEK293 Zellen etabliert. p22phox zeigte keinen Einfluss auf die NOX4-Expression, jedoch war die NOX4-abhängige ROS-Produktion in p22phox-Knockout Zellen verschwunden.
Unsere Ergebnisse deuten darauf hin, dass endogenes NOX4 makromolekulare Komplexe mit Calnexin ausbildet, welches für die korrekte Reifung, Prozessierung und Funktion von NOX4 im ER nötig ist. Darüber hinaus ist p22phox nicht für die Reifung von NOX4, aber für dessen Aktivität nötig. Diese Ergebnisse zeigen eine vielfältige Regulation von NOX4 auf Proteinebene.
In the body-centered cubic structure and in closest sphere-packings the atoms are arranged to give structures with equal densities. A measure of the packing density of atoms is derived. Several crystal structures of elements, including the bcc structure and the closest sphere packings, represent a state of maximum density in which the atomic volume is characteristic of each element. From any crystal structure of an element its atomic volume in this state can be calculated to a good approximation.
Several oxoplatinates (IV) and -rhenates (VII) with isolated PtO6 or ReO6 octahedra respectively surrounded by lithium, sodium, magnesium, calcium, strontium and barium atoms were prepared. From infrared spectra (KBr pellet technique) force constants were calculated. The values varied. depending on an inductive field effect caused by the alcaline and alcaline earth atoms, which increased in the following order: Ba<Sr<Ca ≈ ≪ Mg. By means of bond order it can be predicted that for central atoms with d0 or d10 configuration and with an oxidation state lower than six only such hexaoxometallates will be formed in which the alcaline or alcaline earth atoms intensity the force constant by a strong inductive effect. PtO6 requires an additional force which lowers the symmetry of PtO6 and stabilizes the hexaoxoplatinates (IV).
It is shown that in the case of metals connected by a first order conductor the decomposition of formic acid is less at the element of lower work function while it is more at the element of higher work function. The metals used were Ni, Cd, Zn. The results correspond to the investigations of other authors 1 who showed that the activation energy on alloys depends on how far the concentration of electrons is from full saturation of the lattice type. This effect is explicable in terms of the development of a contact potential, the conditions in the case of metals being similar to those in the case of alloys
Mitochondrien aus Rattenleber (RL) und Rinderherzmuskel (BH) erzeugen bei Behandlung mit O2 eine schwache Chemilumineszenz in dem Spektralbereich zwischen 400 und 650 mµ, deren Intensität bei RL-Mitochondrien durch vorheriges Einfrieren und Auftauen wie durch Ultraschallbehandlung größer wird. Bei beiden Arten verursacht Zusatz von Acridinorange eine wesentliche Verstärkung der Lumineszenz, gleichzeitig wird die O2-Aufnahme gehemmt. RL-Mitochondrien erzeugen unter diesen Bedingungen eine kurzzeitige, BH-Mitochondrien eine langsam ansteigende langandauernde Strahlung; das gleiche Verhalten zeigen aus BH-Mitochondrien gewonnene „electrontransfer-particles“ (ETP). Der zeitliche Ablauf und die Beeinflußbarkeit durch Effektoren der Atmungskette ist andersartig als bei der von VLADIMIROV gefundenen Chemilumineszenz von RL-Mitochondrien. Als Träger der Lumineszenz wird angeregter O2 diskutiert.
Untersuchungen an uv-bestrahlten Schwimmhäuten von Fröschen und Rückenhäuten von Mäusen ergaben, daß mit Hilfe der Nadi - Reaktion (GRÄFF) Oxydationspotentiale an der Bestrahlungsstelle nachgewiesen werden können. Kurzwelliges UV unter λ = 300 mμ hat hierbei die beste Wirkung. Die Stellen stärkster Oxydationskraft liegen bei Schwimmhäuten an den Melanophoren des Corium, bei Mäuserücken-Häuten verteilt im Corium. Bei den Froschhäuten kann zusätzlich bei unphysiologischem pH 4,2 Oxydationswirkung in der Epidermis nachgewiesen werden. Strukturelle Veränderungen an der Schwimmhaut werden polarisationsoptisch deutlich.
Triphenylphosphane 1, its oxide 2 and sulfide 3 undergo one-electron reduction at a mercury cathode in DMF to yield the corresponding radical anions. ESE analysis of the paramagnetic species is facilitated by deuteration and suggests a pyramidal geometry of the radicals. Reduction with potassium metal in DME at low temperature yields also radical anions for 2 and 3. The phosphane 1, however, reacts under phenyl cleavage and potassiumphenyl-assisted ring closure to the dianion of 5H-dibenzophosphole 4. This radical 4· ⊖⊖ is also obtainod by alkali metal reduction of P-phenyldibenzophosphole o, and its spin distribution is compared to iso-.-π-electronic radicals containing CH, N, O, S, or Se links instead of the phosphorus atom.
A thermodynamic interpretation of the liquidus curves of some methyltrichloro-respectively dimethyldichlorosilane/lutidine-systems is given. Based on certain approximations it was possible to fit thermodynamic functions to the experimental results to obtain the excess datas of binary systems. A comparison between the models of Redlich-Kister, Wilson and the NRTL-formalism for the free excess enthalpy of binary mixtures is given.
A phase equilibrium study of the systems dimethyldichlorosilane with 2.4-lutidine and 2.6-lutidine is presented with evidence for the existence of the incongruently melting compounds 2.6-lutidine · Me2SiCl2, (2.6-lutidine)2 · Me2SiCl2 and the congruently melting compound 2.4-lutidine · Me2SiCl2.
The phase diagrams of the systems of trimethylbromosilane and the isomeric lutidines are shown. The existence of the congruently melting addition compounds (CH3)3SiBr ∙ (3,4-lutidine), (CH3)3SiBr (3,5-lutidine) and the incongruently melting addition compounds (CH3)3SiBr • (2,3-lutidine)2, (CH3)3SiBr • (2,3-lutidine), (CH3)3SiBr (2,4-lutidine), ((CH3)3SiBr)2 • (2,4-lutidine), (CH3)3SiBr • (2,5-lutidine)2, (CH3)3SiBr • (2,5-lutidine), (CH3)3SiBr (2,6-lutidine)2 could be proved.
Es wird versucht, Beweise für die indirekte Strahlenwirkung zu erbringen und die einzelnen Reaktionsschritte, die bei Röntgenstrahlen-Wirkung auf wäßrige Lysinlösungen ablaufen, zu erkennen. Zur Untersuchung der durch HO2 oder OH-Radikale ausgelösten Wirkungen wurden 2 Versuchsreihen durchgeführt:
1. Bestrahlung bei Anwesenheit von Sauerstoff,
2. Bestrahlung bei Sauerstoffmangel.
Außerdem wurde der Einfluß der Dosis, Dosisleistung, Temperatur und verschiedener Substrat-Konzentrationen untersucht.
Schließlich wurde versucht, die experimentell gewonnenen Ergebnisse mit Hilfe von Radikalwirkungen, die sich auf
a) Decarboxylierungen,
b) Desaminierungen,
c) und Veränderungen des Kohlenstoff-Gerüstes erstrecken, zu deuten.
Rezension zu: Mathias Rohe (Hrsg.), Mouhanad Khorchide (Hrsg.), Havva Engin (Hrsg.), Hansjörg Schmid (Hrsg.), Ömer Özsoy (Hrsg.), Eugen-Biser-Stiftung (Hrsg.): Handbuch Christentum und Islam in Deutschland. Grundlagen, Erfahrungen und Perspektiven des Zusammenlebens, Freiburg 2015, Verlag Herder, ISBN: 978-3-451-31188-8, zwei Bände, 1297 Seiten, 48 Euro.
Seit seinen Anfängen ist das Christentum alles andere als einheitlich oder homogen. Mit dem Aufstieg zur Staatsreligion im Römischen Reich und dem Wunsch des Kaisertums, seine Herrschaft zu legitimieren, wuchs der Druck zur Vereinheitlichung. Diese Bemühungen ziehen sich wie ein roter Faden durch die mittelalterliche Geschichte. Doch die Alltags-, Gesellschafts- und Kulturgeschichte verweist in der mittelalterlichen Gesellschaft auf eine große Vielfalt der Ausprägungen des Christentums.
Wirtszellreaktivierung chemisch induzierter Letalschäden im DNS-haltigen Serratia-Phagen Kappa
(1965)
After treating free phage Kappa with nitrous acid, triethylenemelamine, ethylmethanesulfonate, or hydroxylamin and using these phages for infecting Serratia H Y wildtype cells, at least 20% of the lethal damage in the phage-DNA can be reactivated by the host ( = host cell reactivation). It is known that all lethal agents tested so far attack the primary structure of the D N A in different ways. Therefore, we assume that the target for the host cell reactivation consists of some damage in the secondary structure of the DNA, because there is probably some coincidence in the action of all agents. The hypothesis that in the DNA changes of thymine are a prerequisite for host cell reactivation has been disproved by the experiments with nitrous acid and ethylmethanesulfonate because both substances do not act on thymine.
Die Geschichte der frühen Christenverfolgung wird in Hollywoodstreifen wesentlich dramatischer dargestellt, als sie in der jüngeren Forschung beurteilt wird. Auch andere Kulte wurden unterdrückt, denn es bestand kein Recht auf Religionsfreiheit. Die Gründe für solche Maßnahmen lagen nicht in Glaubensvorstellungen, sondern in Handlungen, die als gefährlich für das Gemeinwesen galten. So fürchtete man, dass die Weigerung der Christen, Opfer darzubringen, den Zorn der Götter heraufbeschwören könne oder ein Zeichen mangelnder Loyalität sei. Vor diesem Hintergrund forderten Christen Religionsfreiheit von den Heiden, doch wurde diese auch im später christlichen spätantiken Reich nicht praktiziert.
In ihrem Gespräch beschäftigen sich Prof. Dr. Bekim Agai, geschäftsführender Direktor des Instituts für Studien der Kultur und Religion des Islam, und Ulrike Jaspers, Redakteurin von "Forschung Frankfurt", mit dem Wahrheitsanspruch der Religionen, der Debattenkultur in Deutschland, der jungen islamischen Theologie, den fundamentalistischen Strömungen und anderem mehr.
Als Reaktion auf die von islamischen Extremisten begangenen Terroranschläge sowie auf das Wüten des IS in Syrien und im Irak werden diese Forderungen immer lauter: Muslime müssen selbstkritisch nach dem Zusammenhang von islamischer Religion und Gewalt fragen. Bloße Distanzierungen seien nicht ausreichend, so die Kritik von außen, aber zunehmend auch innerhalb der muslimischen Gemeinschaften. Wie setzt sich die islamische Theologie, wie sie u. a. in Frankfurt betrieben wird, damit auseinander?
In the pyrolysis of 1,2,3-benzoselenodiazole using a short-distance furnace, a short-lived intermediate is detected photoelectron spectroscopically. Mass spectra recorded under similar conditions suggest an isomer C6H4Se rearranging to the more stable final product 6-fulveneselone. The ionization pattern obtained by computerized spectra stripping is assigned to benzselenirene by molecular radical cation state comparison based on MNDO calculations.
Der Islam befindet sich in einer Phase fundamentaler Veränderungen, die neue progressive Spielarten, aber auch beunruhigende Formen religiösen Extremismus hervorbringt. In Deutschland diskutieren Muslime, ob es sinnvoll sei, einen spezifisch deutschen oder europäischen Islam zu entwickeln oder ob die herkunftsorientierte Religion der Moschee-Gemeinschaften beibehalten werden sollte.
Der Streit um das Kopftuch : vom Umgang mit religiösen Geltungsansprüchen in liberalen Ordnungen
(2016)
Im Streit um das Kopftuch geht es um mehr als ein beliebiges Rechtsproblem. Welche Rolle soll die Religion im öffentlichen Leben spielen? Wie geht eine liberale Gesellschaft mit der religiösen Vielfalt um? In Deutschland – im Gegensatz zu Frankreich – orientiert sich das Verfassungsrecht am Modell einer "positiven Neutralität": Der Staat weist die Religion nicht vollständig von sich ab, sondern gibt ihr aktiv Raum zur Entfaltung. Muss dieses Modell hinterfragt werden, wenn Gruppen mit starkem religiösen Geltungsanspruch die Bühne betreten und Religion wieder für gesellschaftlichen Konfliktstoff sorgt?
Gehört Religionsunterricht in den Fächerkanon einer staatlichen Schule? In Deutschland wird dies sogar im Grundgesetz bejaht. Während atheistische Kreise die Abschaffung dieses Grundrechts fordern, sehen Politik und Wissenschaft darin eine Chance, auch Kindern aus muslimischen Familien religiöses Wissen näherzubringen, sie auf diese Weise besser zu integrieren und vielleicht sogar gegen fundamentalistische Hasslehren zu wappnen. In Hessen erhalten Grundschüler seit dem Schuljahr 2013 / 2014 bekenntnisorientierten islamischen Religionsunterricht; die Justus-Liebig-Universität Gießen und künftig auch die Goethe-Universität bilden Lehrer aus.
Kennt die Nächstenliebe Grenzen? : wie christliche Ethik über die aktuelle Migration nachdenkt
(2016)
In der Flüchtlingsdebatte geht es auch um die moralische Frage: Dürfen wir Menschen in Not abweisen? Einfache Antworten sind unseriös. Verschiedenste soziale, kulturelle und religiöse Aspekte müssen berücksichtigt werden. Die christliche Ethik kann zu dieser Diskussion u. a. ihr Handlungsmotiv der "Nächstenliebe" beisteuern, das allerdings auch der Interpretation bedarf.
Sehnsucht nach absoluter Wissenschaft : die moderne Esoterik will nicht glauben, sondern wissen
(2016)
Esoterische Weltanschauungen versprechen "höhere", "ganzheitliche" Einsichten statt kalter, "materialistischer" Erkenntnis. Damit stellen sie sich in ein bewusstes, wenn auch aussichtsloses Konkurrenzverhältnis zu den akademischen Wissenschaften. Dennoch hat sich der esoterische Diskurs immer wieder gerade im Umfeld und im Schatten der gesellschaftlich anerkannten universitären Wissenschaften konstituiert, zumindest in reflexiver Abhängigkeit von ihren normativen Ansprüchen.
Religion und Gesellschaft
(2016)
Religion und Gesellschaft
(2016)
Kaufen macht Spaß, hat aber einen schlechten Ruf. Schnell ist vom "Tanz um das goldene Kalb" die Rede, womit das religiös motivierte Register noch lang nicht erschöpft ist. Parallelen zwischen Konsum und Gottesglauben sind in der Tat nicht von der Hand zu weisen. Aber lässt sich unser Umgang mit den Waren wirklich auf die Suche nach Erlösung reduzieren?
Religiöse Vielfalt und Differenz gehören zu den zentralen Erfahrungen des Judentums. Im Zentrum stehen dabei einerseits konkurrierende Interpretationen des Jüdischen, aber auch die Auseinandersetzung mit Christentum und Islam. Was lässt sich für den aktuellen Dialog der Religionen daraus lernen? Der Religionsphilosoph Martin Buber plädiert für eine echte Zwiesprache, die die eigene Position ebenso ernst nimmt wie die dialogische Verwiesenheit religiöser Traditionen aufeinander. Aber auch tief greifende Differenzen sollten nicht verschwiegen werden.
Religion sei "das Opium des Volks", das einem herz- und geistlosen "Jammertal" einen Heiligenschein verleihe. Der werde verschwinden, wenn "die Kritik des Jammertals" zur "Wahrheit des Diesseits" geführt habe, so Karl Marx 1844. Und heute: Die Religion existiert weiter, eine "wahre" Gesellschaft ist nicht verwirklicht. Im Gespräch mit vier Frankfurter Professoren erkundet der Philosoph und Publizist Rolf Wiggershaus, wie Religionsexperten das aktuelle Verhältnis von Religion und Gesellschaft sehen.
"Toleranz kommt vor Glückseligkeit" : eine Zeitreise mit der Tugend des gegenseitigen Respekts
(2016)
Toleranz ist gerade da nötig, wo sie besonders schwerfällt. Das war schon vor gut 300 Jahren so, als Denker wie der französische Philosoph Pierre Bayle in Zeiten religiöser Auseinandersetzungen den Grundstein für ein fortschrittliches Toleranz-Verständnis legten. Warum der Begriff gerade heute wieder Konjunktur hat und wie umstritten er noch immer ist, erläutert der politische Philosoph Rainer Forst im Gespräch mit Bernd Frye.
Phenology is the study of periodic life cycle events of living organisms and how these are influenced by environmental factors. Late phenological phases such as the timing of seed release and subsequent seed dispersal considerably affect ecology and evolution in plants. Since plants are mostly sessile organisms, seed dispersal is a crucial life cycle event for the ecology and evolution of plants. In fact, long-distance seed dispersal (LDD) is a very complex process in plant biology and significantly shapes the spatial and temporal dynamics of plant populations. For example, wind dispersal in plants is influenced by a variety of factors such as plant traits, habitat type and environmental conditions (e.g. wind speed). Considering the variability of wind conditions throughout the year, the timing of seed release and dispersal is known to have considerable effects on LDD. Even though late phenologies such as ripening duration and timing of seed release and subsequent dispersal are vital in estimating ecologically highly relevant LDD, these phenologies are not appropriately addressed in ecological research. The aim of this thesis is to gain insights into the factors that shape late plant phenologies. In particular, we address the following questions: which ecologically or evolutionary parameters drive the ripening process of plant species? How does the seasonal variability of wind affect the seed release phenology of plant species? How do these factors interact for plant species in different habitat types?
In order to address these questions, we applied different methodological approaches, ranging from fieldwork and monitoring phenology to computational simulation studies and statistical modeling. To study the ripening process of species, we monitored the flowering, ripening and seed release phenology of more than 100 Central European plant species. We conducted computational simulation studies for estimating LDD by wind to study the phenology of seed release and the parameters determining LDD by wind. In conjunction with phenological data from literature, we used the obtained simulation results to investigate evidence for the existence of phenological adaptations towards LDD in 165 plant species. Further, we used the results from simulation studies of LDD by wind to disentangle the effects of species, habitat types and meteorological conditions and their interactions on the spatial spread of plant species.
The results of the relationship between plant traits, phylogeny, the ripening process and climatic factors provide insights into the basic understanding of the ripening process of plants. We identified ecological factors that shape species’ ripening phenology and seed release timing. In particular, we suggest that the species’ seed weight, life form and phylogeny shapes ripening and seed release phenology. With the statistical models on species’ temperature demands for reproduction, we introduce data that that are well suitable for parametrization and further development of plant dispersal models. The results from the simulation study based on a seasonal perspective showed that heavier seeded tree species with medium wind dispersal potential (including genera Abies, Acer, Fraxinus and Larix) have a clear synchronisation of seed abscission with periods favouring LDD. These species, which are both ecologically and economically important, showed significant synchronisation of the highest rate of seed release with high wind-speed that promoted LDD by wind in wintertime. For the tree species mentioned, we suggest strong seasonal synchronisation as evidence for phenological adaptations in order to match favourable conditions during seed release. With a closer look at the wind conditions that promote LDD by wind, our results showed considerable differences in how specific wind conditions affect LDD in different species and habitat types. We suggest that LDD by wind in species from open habitats with high wind dispersal potential is likely to be driven by thermal updrafts that are mainly driven by the sun providing energy to the ground. By contrast, LDD of heavier-seeded species from open and forested habitats is more likely to be driven by storms that produce shear-driven turbulence. The results from this thesis contribute to an increased understanding of the complete dispersal process of plants and to making more realistic projections of (future) plant distribution.
The results obtained on factors driving ripening and release phenology provide valuable insights into their ecological and phylogenetic factor constraints. The implementation of more realistic assumptions in assessing species’ dispersal potential throughout the year could help considerably in improving landscape management (e.g. timing of mowing) and in the conservation of plant populations. The evidence found for phenological adaptations towards LDD in plants is an important step in understanding the evolutionary basis of LDD in these species.
Telecommunications companies traditionally offer several tariffs from which their customers can choose the tariff that best suits their preferences. Yet, customers sometimes make choices that are not optimal for them because they do not minimize their bill for a certain usage amount. We show in this paper that companies should be very concerned about choices in which customers pick tariffs that are too small for them because they lead to a significant increase in customers churn. In contrast, this is not the case if customers choose tariffs that are too big for them. The reason is that in particular flat-rates provide customers with the additional benefit that they guarantee a constant bill amount that consumption can be enjoyed more freely because all costs are already accounted for.
Correlated activity of cortical neurons survives extensive removal of feedforward sensory input
(2016)
A fundamental property of brain function is that the spiking activity of cortical neurons is variable and that some of this variability is correlated between neurons. Correlated activity not due to the stimulus arises from shared input but the neuronal circuit mechanisms that result in these noise correlations are not fully understood. Here we tested in the visual system if correlated variability in mid-level area V4 of visual cortex is altered following extensive lesions of primary visual cortex (V1). To this end we recorded longitudinally the neuronal correlations in area V4 of two behaving macaque monkeys before and after a V1 lesion while the monkeys fixated a grey screen. We found that the correlations of neuronal activity survived the lesions in both monkeys. In one monkey, the correlation of multi-unit spiking signals was strongly increased in the first week post-lesion, while in the second monkey, correlated activity was slightly increased, but not greater than some week-by-week fluctuations observed. The typical drop-off of inter-neuronal correlations with cortical distance was preserved after the lesion. Therefore, as V4 noise correlations remain without feedforward input from V1, these results suggest instead that local and/or feedback input seem to be necessary for correlated activity.
Infections are an important cause for morbidity and mortality in pediatric acute myeloid leukemia (AML). We therefore characterized infectious complications in children treated according to the trial AML-BFM 2004. Patients with Down syndrome were excluded from the analysis. Data were gathered from the medical records in the hospital where the patients were treated. A total of 405 patients (203 girls; median age 8.4 years) experienced 1326 infections. Fever without identifiable source occurred in 56.1% of the patients and clinically and microbiologically documented infections in 17.5% and 32.4% of the patients, respectively. In all, 240 Gram-positive (112 viridans group streptococci) and 90 Gram-negative isolates were recovered from the bloodstream. Invasive fungal infection was diagnosed in 3% of the patients. Three children each died of Gram-negative bacteremia and invasive aspergillosis, respectively. As compared with the results of AML-BFM 93 with lower dose intensity, infection-related morbidity was slightly higher in AML-BFM 2004 (3.3. versus 2.8 infections per patient), whereas infection-related mortality significantly decreased (1.5% versus 5.4%; P=0.003). Specific anti-infective recommendations included in the treatment protocol, regular training courses for pediatric hematologists and increasing experience may be the reason for reduced infection-related mortality in children with AML. Further studies are needed to decrease infection-related morbidity.
A complex aberrant karyotype consisting of multiple unrelated cytogenetic abnormalities is associated with poor prognosis in patients with acute myeloid leukemia (AML). The European Leukemia Net classification and the UK Medical Research Council recommendation provide prognostic categories that differ in the definition of unbalanced aberrations as well as the number of single aberrations. The aim of this study on 3526 AML patients was to redefine and validate a cutoff for karyotype complexity in AML with regard to adverse prognosis. Our study demonstrated that (1) patients with a pure hyperdiploid karyotype have an adverse risk irrespective of the number of chromosomal gains, (2) patients with translocation t(9;11)(p21~22;q23) have an intermediate risk independent of the number of additional aberrations, (3) patients with greater than or equal to4 abnormalities have an adverse risk per se and (4) patients with three aberrations in the absence of abnormalities of strong influence (hyperdiploid karyotype, t(9;11)(p21~22;q23), CBF-AML, unique adverse-risk aberrations) have borderline intermediate/adverse risk with a reduced overall survival compared with patients with a normal karyotype.
DNA methylation is a major regulatory process of gene transcription, and aberrant DNA methylation is associated with various diseases including cancer. Many compounds have been reported to modify DNA methylation states. Despite increasing interest in the clinical application of drugs with epigenetic effects, and the use of diagnostic markers for genome-wide hypomethylation in cancer, large-scale screening systems to measure the effects of drugs on DNA methylation are limited. In this study, we improved the previously established fluorescence polarization-based global DNA methylation assay so that it is more suitable for application to human genomic DNA. Our methyl-sensitive fluorescence polarization (MSFP) assay was highly repeatable (inter-assay coefficient of variation = 1.5%) and accurate (r2 = 0.99). According to signal linearity, only 50–80 ng human genomic DNA per reaction was necessary for the 384-well format. MSFP is a simple, rapid approach as all biochemical reactions and final detection can be performed in one well in a 384-well plate without purification steps in less than 3.5 hours. Furthermore, we demonstrated a significant correlation between MSFP and the LINE-1 pyrosequencing assay, a widely used global DNA methylation assay. MSFP can be applied for the pre-screening of compounds that influence global DNA methylation states and also for the diagnosis of certain types of cancer.
The mitochondrial cascade hypothesis of dementia assumes mitochondrial dysfunction leading to reduced energy supply, impaired neuroplasticity, and finally cell death as one major pathomechanism underlying the continuum from brain aging over mild cognitive impairment to initial and advanced late onset Alzheimer's disease. Accordingly, improving mitochondrial function has become an important strategy to treat the early stages of this continuum. The metabolic enhancer piracetam has been proposed as possible prototype for those compounds by increasing impaired mitochondrial function and related aspects like mechanisms of neuroplasticity. We here report that piracetam at therapeutically relevant concentrations improves neuritogenesis in the human cell line SH-SY5Y over conditions mirroring the whole spectrum of age-associated cognitive decline. These effects go parallel with improvement of impaired mitochondrial dynamics shifting back fission and fusion balance to the energetically more favorable fusion site. Impaired fission and fusion balance can also be induced by a reduction of the mitochondrial permeability transition pore (mPTP) function as atractyloside which indicates the mPTP has similar effects on mitochondrial dynamics. These changes are also reduced by piracetam. These findings suggest the mPTP as an important target for the beneficial effects of piracetam on mitochondrial function.
The general assumption that brain size differences are an adequate proxy for subtler differences in brain organization turned neurobiologists toward the question why some groups of mammals such as primates, elephants, and whales have such remarkably large brains. In this meta-analysis, an extensive sample of eutherian mammals (115 species distributed in 14 orders) provided data about several different biological traits and measures of brain size such as absolute brain mass (AB), relative brain mass (RB; quotient from AB and body mass), and encephalization quotient (EQ). These data were analyzed by established multivariate statistics without taking specific phylogenetic information into account. Species with high AB tend to (1) feed on protein-rich nutrition, (2) have a long lifespan, (3) delayed sexual maturity, and (4) long and rare pregnancies with small litter sizes. Animals with high RB usually have (1) a short life span, (2) reach sexual maturity early, and (3) have short and frequent gestations. Moreover, males of species with high RB also have few potential sexual partners. In contrast, animals with high EQs have (1) a high number of potential sexual partners, (2) delayed sexual maturity, and (3) rare gestations with small litter sizes. Based on these correlations, we conclude that Eutheria with either high AB or high EQ occupy positions at the top of the network of food chains (high trophic levels). Eutheria of low trophic levels can develop a high RB only if they have small body masses.
G protein coupled receptors (GPCRs) constitute the largest family of cell-surface receptors in mammals and are key players in signal transduction. By responding to a plethora of extracellular stimuli ranging from photons to amines to fatty acids to peptides and proteins, these receptors trigger intracellular signalling cascades and regulate a variety of cellular responses. Approximately 800 genes in humans encode GPCRs which are classified according to sequence conservation into rhodopsin-like, glutamate, adhesion, frizzled/taste2 and secretin receptors. GPCRs share a seven transmembrane domain fold undergoing a conformational change upon ligand binding which is translated to the intracellular surface of the receptor thereby allowing a heterotrimeric G protein to couple. Heterotrimeric G proteins consist of a Ga, Gb and Gg subunit and dissociate into their Ga and Gbg entities upon activation by a GPCR. Subsequently, distinct signalling cascades are triggered by each G protein protomer.
Membrane proteins and GPCRs in particular, are highly important targets in drug design and development as currently approximately 60% of all marketed drugs target membrane proteins. Although these classes of proteins are of high therapeutic interest, our understanding of their mechanism of action and structure remains limited. The first structure of a human GPCR was determined in 2007 and required the development of protein engineering and innovative crystallisation techniques. Since then, approximately 130 GPCR structures of less than 40 individual receptors have been determined providing insights into the structural arrangement of the transmembrane helices, ligand binding pockets and G protein interactions. Combined with spectroscopic methods, these studies allowed a more detailed understanding of the molecular aspects of GPCR activation and signalling. Despite the tremendous advances in GPCR structural biology, certain aspects of GPCR function still remain poorly understood. Due to their size and inherent flexibility, the interaction of protein and peptide ligands with their receptors remains a challenging aspect in the structural characterisation of GPCRs. Moreover, structural information on subtype selectivity of peptide ligands continues to be scarce. To contribute functional and structural information on the molecular mechanisms of peptide interactions with GPCRs, this thesis focused on characterising receptors from the chemoattractant cluster using radioligand binding assays as well as NMR spectroscopy.
The chemoattractant cluster mainly groups the kinin, angiotensin, anaphylatoxin chemotactic complement and apelin receptors according to conserved residues in their ligand binding cavities. All receptors in this cluster bind to peptide ligands deriving from high molecular weight protein precursors upon proteolytic processing. Comparable to the conserved binding pocket of the chemoattractant receptors, the peptide ligands display a certain sequence conservation although they differ strongly in size. The largest ligands used in this thesis are the anaphylatoxins complement 3a and 5a, comprising 77 or 74 residues, respectively. Due to their size and complex fold involving three intramolecular disulphide bonds, solid phase synthesis is impossible, which prompted us to develop a modified cell-free expression system to produce these ligands in tritiated form for subsequent functional characterisation of the complement receptors. To demonstrate the versatility of the developed system, it was applied to another disulphidebond containing peptide ligand, the 21 amino acid endothelin-1. We describe a reliable and multifaceted tool to generate custom labelled peptide ligands for the structural and functional characterisation of GPCRs. The system allows the production of custom radioligands, peptides labelled for NMR studies or with fluorescent amino acids.
Apart from the modulation of GPCR activity by orthosteric ligands, GPCR signalling has long been described to be regulated by allosteric ligands including peptides, small molecules and ions. In this thesis, the influence of sodium ions on the activity state of the chemoattractant cluster receptors and in particular on the apelin, bradykinin 2 and angiotensin II type 1 receptors was examined. In recent high resolution crystal structures an allosteric sodium ion pocket beneath the orthosteric ligand binding cavity was identified and residues contributing to the coordination of sodium ions are conserved throughout the chemoattractant cluster receptors. This allosteric sodium ion coordinated within the transmembrane domain bundle has been described to negatively influence the affinity of agonists but not of antagonists. It was found that sodium ions have distinct influences on the affinity state as well as the available number of binding sites of the chemoattractant receptors. In case of the apelin and bradykinin 2 receptors, sodium ions drastically reduced the number of available binding sites whereas the affinity of peptide ligands to the bradykinin 2 receptors remained constant and the ligand binding affinities to the apelin receptor were completely abolished. In contrast, the angiotensin II type 1 receptor affinity state towards the endogenous peptide ligand angiotensin II is highly dependent on the presence of sodium ions, whereas binding of the synthetic peptide antagonist Sar1-Ile8-angiotensin II remained unaffected by the sodium ion concentration. As differential effects irrespective of the efficacy class but dependent on the amino acid composition of the applied ligands are observed, it can be concluded that electrostatic interactions between charged residues of the peptide ligands and amino acids on the extracellular surface of the receptors are influenced by sodium ions thereby adding another layer of complexity on GPCR signalling.
To elucidate the structure-function relationship of ligand selectivity between the kinin receptors, the structure of desArg10-kallidin (DAK) bound to the bradykinin 1 receptor was determined using solid state NMR (SSNMR) in the course of this thesis. The kinin peptides DAK and bradykinin bind with high affinity and high selectivity to either the bradykinin 1 or bradykinin 2 receptor, respectively. The binding pockets of the receptors are highly conserved and the two peptide ligands only differ in one amino acid at their N- and C-termini whereas the remaining eight amino acids are fully conserved. DAK adopts a U-shaped structure when bound to the bradykinin 1 receptor which resembles a horse shoe-like conformation. Using 2D TEDOR spectroscopy it could furthermore be demonstrated that positively charged residues at the N-terminal part of the peptide engage in ionic interactions with negatively charged amino acids on the extracellular surface of the bradykinin 1 receptor. In contrast, bradykinin displays a distinct b-turn at the C-terminus and an S-shaped conformation of the N-terminal segment when bound to the bradykinin 2 receptor. By using SSNMR to study the binding mode of DAK on the bradykinin 1 receptor we could determine that subtype selectivity between the kinin receptors is conferred by distinct conformational restraints within the peptide ligands and by the formation of specific ionic interaction between charged residues on the peptide and receptor, respectively.
In brief, this thesis contributes structural and functional data on the binding mechanisms and binding mode of different peptide-ligand GPCRs helping to understand subtype selectivity and allosteric modulation of the chemoattractant cluster receptors. In addition, a versatile cell-free expression system was developed that allows the custom synthesis of isotopically labelled peptides containing disulphide bonds for the functional characterisation of GPCRs.
Melt segregation inside the earth consists of two different processes: 1) Generation of partially molten rock and 2) separation of melt, produced from partially molten rock, from the solid residual matrix. This thesis focuses on the later process. The 2 phase flow dynamics combines the study of flow dynamics of melt and matrix. Several studies have given the background theoretical frameworks for the flow dynamics of melt inside the earth. [McKenzie, 1984] summarizes the studies of [Ahern and Turcotte, 1979; Frank, 1968; Sleep, 1975] and gives a complete set of governing equations for the 2-phase flow problem.
[Bercovici et al., 2001] gives a general formulation considering the univariate system of equations related to matrix and melt flow which includes the interfacial surface force. The assumption of melt having negligible viscosity compare to the matrix has been abandoned. Therefore, based on these formulations, we have constructed our numerical model and thereafter a fortran code PERCOL2D to get an insight of melt percolation process through porous media. Additionally, we have used the Helmhotz decomposition, which splits a smooth and rapidly decaying vector field into an irrotational vector field and an incompressible vector field [Srámek, 2007], for matrix and fluid viscosity in order to lower the number of linearly independent variables to minimize the computational complications. The melt residing at inter-granular areas of lithosphere, forms an interconnected network even at low porosity. Therefore, being less dense than the matrix, melt moves up through porous media due to its buoyancy. Compaction of matrix, which occurs to compensate the melt separation, is considered in this thesis, where the effective bulk and shear viscosity of matrix are function of melt fraction. We have effective bulk viscosity of matrix as inversely proportional to melt fraction. Porosity dependence of effective bulk and shear viscosity leads to stronger melt focusing in highly porous region like mid ocean ridges [Katz, 2008] since the ratio of bulk and shear viscosity is smaller (< 10) than the constant viscosity case for the porous waves having non dimensional amplitude 5% or higher. Moreover, it is observed in [Richard et al., 2012] that the solitary wave formed in porosity dependent viscous matrix settings are steeper than the one formed in the constant matrix viscosity setting.
Firstly some 1D numerical experiments with PERCOL2D have been carried out using fixed and periodic boundary conditions for zero source term (i.e. no melting or no freezing) and negligible surface tension.
3 series of model setups with different initial conditions have been carried out varying the width, non-dimensional amplitude and the background porosity value of the initial input of porous wave.
A mathematical derivation for 1D solitary wave solution for the two phase flow through porosity dependent compacting media, is obtained in this thesis which is different than the study of [Barcilon and Lovera, 1989; Barcilon and Richter, 1986; Scott and Stevenson, 1984; Spiegelman, 1993a,b] as the effective viscosity of matrix is constant there.
Although [Simpson and Spiegelman, 2011] gives the solitary wave solutions in 1D, 2D and 3D considering the porosity dependent effective viscosity of the matrix, but using the small background porosity approximation, they neglect the background porosity (i.e φ0) and therefore the effect of variation of compaction lengths, which causes variation in the shape and dynamics of the solitary wave. Therefore, the study [This thesis, Richard et al., 2012] can be used for more general purpose. Solitary waves in varying viscous medium, are steeper (cf fig.5.1) compared to the one in constant viscous medium and their speed decreases as an inverse function of the background porosity. Additionally, this analytical solution is used in our code PERCOL2D and also in FDCON for numerical benchmarking (1D) of PERCOL2D.
The role of melt grain contiguity is considered in the revised viscosity formulation [Schmeling et al., 2012] based on elastic moduli theory of a fluid filled poro-elastic medium. This formulation is used in this thesis to produce a comparative dispersion relationship between speed of the wave and the non dimensional amplitude of porous wave, based on both the viscosity formulations (fig. 6.20) where one can see that the model based on [Bercovici et al., 2001] formulation, converges to the same dispersion relationship obtained from [Simpson and Spiegelman, 2011]. Whereas, the dispersion relationship using [Schmeling et al., 2012] formulations, shows time-dependent decrease of phase velocity with increasing amplitude and it is not yet clear that whether these solutions converge to steady state porosity waves before the porosity becomes 1.
Amid increasing regulation, structural changes of the market and Quantitative Easing as well as extremely low yields, concerns about the market liquidity of the Eurozone sovereign debt markets have been raised. We aim to quantify illiquidity risks, especially such related to liquidity dry-ups, and illiquidity spillover across maturities by examining the reaction to illiquidity shocks at high frequencies in two ways:
a) the regular response to shocks using a variance decomposition and,
b) the response to shocks in the extremes by detecting illiquidity shocks and modeling those as ultivariate Hawkes processes.
We find that:
a) market liquidity is more fragile and less predictable when an asset is very illiquid and,
b) the response to shocks in the extremes is structurally different from the regular response.
In 2015 long-term bonds are less liquid and the medium-term bonds are liquid, although we observe that in the extremes the medium-term bonds are increasingly driven by illiquidity spillover from the long-term titles.
Most defined contribution pension plans pay benefits as lump sums, yet the US Treasury has recently encouraged firms to protect retirees from outliving their assets by converting a portion of their plan balances into longevity income annuities (LIA). These are deferred annuities which initiate payouts not later than age 85 and continue for life, and they provide an effective way to hedge systematic (individual) longevity risk for a relatively low price. Using a life cycle portfolio framework, we measure the welfare improvements from including LIAs in the menu of plan payout choices, accounting for mortality heterogeneity by education and sex. We find that introducing a longevity income annuity to the plan menu is attractive for most DC plan participants who optimally commit 8-15% of their plan balances at age 65 to a LIA that starts paying out at age 85. Optimal annuitization boosts welfare by 5-20% of average retirement plan accruals at age 66 (assuming average mortality rates), compared to not having access to the LIA. We also compare the optimal LIA allocation versus two default options that plan sponsors could implement. We conclude that an approach where a fixed fraction over a dollar threshold is invested in LIAs will be preferred by most to the status quo, while enhancing welfare for the majority of workers.
Am 27. Dezember 2015 verabschiedete der Ständige Ausschuss des Nationalen Volkskongresses das erste Antiterrorgesetz in der Geschichte der Volksrepublik China (VRC). Damit wurde eine über 25 Jahre erarbeitete umfangreiche Antiterrorstrategie zu Papier gebracht und mit ihr endlich eine verbindliche rechtliche Definition von „Terrorismus.“ Bereits gängige Praktiken wie öffentliche Medienzensur oder die Verpflichtung von Telekommunikationsunternehmen und Internetprovidern zur Bereitstellung von Inhaltsdaten wurden formalisiert und verschärft, sowie auch die Mobilisierung zivilgesellschaftlicher Organisationen auf eine rechtliche Grundlage gestellt. Allerdings stellt das Gesetz nur den finalen, formalen Schritt einer fünfundzwanzigjährigen Entwicklung dar. Tatsächlich kämpft Beijing seit Anfang der 1990er Jahre in der Provinz Xinjiang mit einer Mischung aus separatistisch und islamistisch motivierter politischer Gewalt, an deren Spitze seit spätestens 2008 das East Turkestan Independence Movement (ETIM) steht. ETIM weist ideell und organisatorisch eine Nähe zu Al Qaeda auf, und arbeitet transnational mit der Islamischen Bewegung Usbekistans, Tehrik-i-Taliban (Pakistan) und der al-Nusra Front (Syrien) zusammen...
Systemic co-jumps
(2016)
The simultaneous occurrence of jumps in several stocks can be associated with major financial news, triggers short-term predictability in stock returns, is correlated with sudden spikes of the variance risk premium, and determines a persistent increase (decrease) of stock variances and correlations when they come along with bad (good) news. These systemic events and their implications can be easily overlooked by traditional univariate jump statistics applied to stock indices. They are instead revealed in a clearly cut way by using a novel test procedure applied to individual assets, which is particularly effective on high-volume stocks.