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kurz und kn@pp news : Nr. 40
(2017)
Objectives: The aim of the study was to determine the time to, and risk factors for, triple-class virological failure (TCVF) across age groups for children and adolescents with perinatally acquired HIV infection and older adolescents and adults with heterosexually acquired HIV infection.
Methods: We analysed individual patient data from cohorts in the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). A total of 5972 participants starting antiretroviral therapy (ART) from 1998, aged < 20 years at the start of ART for those with perinatal infection and 15–29 years for those with heterosexual infection, with ART containing at least two nucleoside reverse transcriptase inhibitors (NRTIs) and a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (bPI), were followed from ART initiation until the most recent viral load (VL) measurement. Virological failure of a drug was defined as VL > 500 HIV-1 RNA copies/mL despite ≥ 4 months of use. TCVF was defined as cumulative failure of two NRTIs, an NNRTI and a bPI.
Results: The median number of weeks between diagnosis and the start of ART was higher in participants with perinatal HIV infection compared with participants with heterosexually acquired HIV infection overall [17 (interquartile range (IQR) 4–111) vs. 8 (IQR 2–38) weeks, respectively], and highest in perinatally infected participants aged 10–14 years [49 (IQR 9–267) weeks]. The cumulative proportion with TCVF 5 years after starting ART was 9.6% [95% confidence interval (CI) 7.0−12.3%] in participants with perinatally acquired infection and 4.7% (95% CI 3.9−5.5%) in participants with heterosexually acquired infection, and highest in perinatally infected participants aged 10–14 years when starting ART (27.7%; 95% CI 13.2−42.1%). Across all participants, significant predictors of TCVF were those with perinatal HIV aged 10–14 years, African origin, pre-ART AIDS, NNRTI-based initial regimens, higher pre-ART viral load and lower pre-ART CD4.
Conclusions: The results suggest a beneficial effect of starting ART before adolescence, and starting young people on boosted PIs, to maximize treatment response during this transitional stage of development.
Three new species of the genus Carychium O.F. Müller, 1773, Carychium hardiei Jochum & Weigand, sp. n., Carychium belizeense Jochum & Weigand, sp. n. and Carychium zarzaae Jochum & Weigand, sp. n. are described from the Southeastern United States, Belize and Panama, respectively. In two consecutive molecular phylogenetic studies of worldwide members of Carychiidae, the North and Central American morphospecies Carychium mexicanum Pilsbry, 1891 and Carychium costaricanum E. von Martens, 1898 were found to consist of several evolutionary lineages. Although the related lineages were found to be molecularly distinct from the two nominal species, the consequential morphological and taxonomic assessment of these lineages is still lacking. In the present paper, the shells of these uncovered Carychium lineages are assessed by comparing them with those of related species, using computer tomography for the first time for this genus. The interior diagnostic characters are emphasized, such as columellar configuration in conjunction with the columellar lamella and their relationship in context of the entire shell. These taxa are morphologically described and formally assigned their own names.
Introduction: For management of complicated retinal detachments, a pars plana vitrectomy with temporary silicone oil (SO) fill is the method of choice. According to literature, the retinal redetachment rate varies between <10% and >70% with around 36% in our own group (retrospective data analysis, n = 119 eyes).
Methods: The main goal was to reduce the retinal redetachment rate. Standard operating procedures (SOPs) and evaluation protocols (EVALPs) were developed to prospectively analyse risk factors. Lab analysis of SO was performed, and the role of surgical experience was evaluated and investigated with Eyesi®.
Results: We achieved a significant reduction of the retinal redetachment rate (to 6.80%, n = 101, p = 0.002). After surgery with SO injection, neither further membrane peeling (in 16.5%) nor retinal laser coagulation (in 100%) during revision surgery had a significant effect on the reattachment rate (p = 0.167, p = 0.23), while extensive additional laser coagulation reduced visual acuity (p = 0.01). A 3-port approach had to be set up to complete SO removal. A difference in success rate depending on surgical experience was confirmed, and the performance in Eyesi correlated with that in the patients' eye.
Conclusions: A SOP- and EVALP-based management and new strategies to secure the surgical performance seem to be essential for successful surgery.
We present results on transverse momentum (pT) and rapidity (y) differential production cross sections, mean transverse momentum and mean transverse momentum square of inclusive J/ψ and ψ(2S) at forward rapidity (2.5 < y < 4) as well as ψ(2S)-to-J/ψ cross section ratios. These quantities are measured in pp collisions at center of mass energies s√=5.02 and 13 TeV with the ALICE detector. Both charmonium states are reconstructed in the dimuon decay channel, using the muon spectrometer. A comprehensive comparison to inclusive charmonium cross sections measured at s√=2.76, 7 and 8 TeV is performed. A comparison to non-relativistic quantum chromodynamics and fixed-order next-to-leading logarithm calculations, which describe prompt and non-prompt charmonium production respectively, is also presented. A good description of the data is obtained over the full pT range, provided that both contributions are summed. In particular, it is found that for pT > 15 GeV/c the non-prompt contribution reaches up to 50% of the total charmonium yield.
We present an in-depth study of masses and decays of excited scalar and pseudoscalar q¯q states in the Extended Linear Sigma Model (eLSM). The model also contains ground-state scalar, pseudoscalar, vector and axial-vector mesons. The main objective is to study the consequences of the hypothesis that the f0(1790) resonance, observed a decade ago by the BES Collaboration and recently by LHCb, represents an excited scalar quarkonium. In addition we also analyse the possibility that the new a0(1950) resonance, observed recently by BABAR, may also be an excited scalar state. Both hypotheses receive justification in our approach although there appears to be some tension between the simultaneous interpretation of f0(1790)/a0(1950) and pseudoscalar mesons η(1295), π(1300), η(1440) and K(1460) as excited q¯q states.
This working paper gives insights on a theoretical perspective on class formation in the context of global financial markets and presents first empirical findings regarding the formation of a global financial class. It draws on numerous encounters with financial professionals that were inter- viewed in Frankfurt (Germany) and Sydney (Australia). As a preliminary conclusion from those inves- tigations on a micro-perspective, we state that acting on the market creates a sense of global socia- bility, whereby organizations only play a secondary role. Careers in finance follow internationally homogenized pathways. This process of global class formation is taking place prominently in global financial centers. Therefore we link the level of investigation on a micro-perspective (experience of financial professionals) with global city life and the fabric of the city. This results in empirical findings on a meso-level from an ethnography of the social and professional urban environment of finance in the two global cities. Symbolic struggles engraved in the built environment of Frankfurt and Sydney are traced and discussed against the background of every-day-practices of aspiration in the financial districts investigated.
Sozialräume der Global Financial Class : Untersuchungen in den Finanzzentren Frankfurt und Sydney
(2016)
Dieses Working Paper untersucht die Bedeutung von Global Cities für die Formierung einer globalen Finanzklasse anhand der Finanzzentren Frankfurt und Sydney. In einer vergleichenden Ethnographie dieser beiden Städte werden urbane Räume und soziale Kontexte erforscht, die durch die kulturellen Praktiken und stilistischen Gemeinsamkeiten der modernen Finanzklasse geprägt sind. Es werden dabei vier charakteristische kulturelle Muster identifiziert: Dies sind die Muster der Repräsentation, der Exklusivität, der Aspiration und der sozialen Durchlässigkeit.
Im Muster der Repräsentation verbindet sich das Finanzwesen auf eine symbolische Weise mit Politik und Gesellschaft, während im Muster der Exklusivität der Kern ökonomischer Praktiken dem Zugriff der Allgemeinheit entzogen wird. Das Muster der Aspiration ermöglicht Praktiken der Herstellung und des Austestens von Zugehörigkeit, während der Modus sozialer Durchlässigkeit eine Auseinandersetzung mit anderen gesellschaftlichen Gruppen und die Aufnahme fremder kultureller Muster durch Praktiken der cultural omnivorousness ermöglicht.
Die Praktiken, die diese vier typischen Muster konstituieren, nehmen dabei jeweils lokale Eigenhei- ten auf, die in einen global verlaufenden Klassenbildungsprozess eingespeist werden und diese glo- bale Klasse in den Städten verankern.
GPR116 (ADGRF5) and ELTD1 (ADGRL4) belong to different subfamilies of the adhesion G-protein-coupled receptor group but are both expressed in endothelial cells. We therefore analyzed their functions in mice lacking these receptors. While loss of GPR116 or ELTD1 alone had no obvious effect on cardiovascular or kidney function, mice lacking both, GPR116 and ELTD1, showed malformations of the aortic arch arteries and the cardiac outflow tract leading to perinatal lethality in about 50% of the mutants. In addition to cardiovascular malformations, surviving mice developed renal thrombotic microangiopathy as well as hemolysis and splenomegaly, and their lifespan was significantly reduced. Loss of GPR116 and ELTD1 specifically in endothelial cells or neural crest-derived cells did not recapitulate any of the phenotypes observed in GPR116-ELTD1 double deficient mice, indicating that loss of GPR116 and ELTD1 expressed by other cells accounts for the observed cardiovascular and renal defects.
Im Kontext der Diskussion zur „Globalisierung des Managements“ und der daraus entstandenen These einer transnationalen Klasse untersuchen wir in diesem Beitrag den Stellenwert internationaler Berufserfahrung bei Bankvorständen in Deutschland und weltweit. Bisherige Forschungen (etwa Pohlmann 2009) argumentieren, dass bei den Top-100- Industrieunternehmen in den USA, Ostasien und Deutschland Karriereverläufe im mittleren und Spitzenmanagement kaum internationalisiert sind und Hauskarrieren die Regel seien. Unsere eigene explorative Untersuchung legt die Vermutung nahe, dass die Situation im deutschen sowie im globalen Bankensektor anders aussieht. Vor allem in Deutschland verlaufen die Top-Karrieren im Unterschied zu Industrieunternehmen deutlich internationaler, was auf andere personelle Konstellation im Feld des global vernetzten Finanzsektors hinweist. Im deutschen wie im globalen Finanzsektor könnten wir es hierbei mit dem Phänomen einer „Transnationalisierung ohne Migration“ zu tun haben.
In methodischer Hinsicht macht unsere Studie auf die Grenzen quantitativer Forschungsdesigns bei der Untersuchung internationaler Berufserfahrung und internationalen Arbeitspraxen aufmerksam. Daher plädieren wir für ein an die Kategorien der Bourdieu‘schen Sozialtheorie angelehntes qualitatives Forschungsdesign für die Untersuchung der Herausbildung einer globalen Klasse auf den globalisierten Finanzmärkten.
Inhibition of the IκB kinase complex (IKK) has been implicated in the therapy of several chronic inflammatory diseases including inflammatory bowel diseases. In this study, using mice with an inactivatable IKKα kinase (IkkαAA/AA), we show that loss of IKKα function markedly impairs epithelial regeneration in a model of acute colitis. Mechanistically, this is caused by compromised secretion of cytoprotective IL-18 from IKKα-mutant intestinal epithelial cells because of elevated caspase 12 activation during an enhanced unfolded protein response (UPR). Induction of the UPR is linked to decreased ATG16L1 stabilization in IkkαAA/AA mice. We demonstrate that both TNF-R and nucleotide-binding oligomerization domain stimulation promote ATG16L1 stabilization via IKKα-dependent phosphorylation of ATG16L1 at Ser278. Thus, we propose IKKα as a central mediator sensing both cytokine and microbial stimulation to suppress endoplasmic reticulum stress, thereby assuring antiinflammatory function during acute intestinal inflammation.
Globale Finanzplätze im Vergleich : Frankfurt und Sydney zwischen Global City und lokaler Variation
(2015)
Frankfurt und Sydney sind international bedeutende Knotenpunkte des Global- Cities-Netzwerks. Als transnationale Finanzzentren erreichen sie im Global Financial Centres Index (GFCI) ähnliche Platzierungen. Populäre Rankings wie der GFCI entfalten ihre Wirkungsmacht in einem politischen Diskurs, der die Konkurrenz von Finanzzentren in einem hierarchischen Städtenetzwerk betont und so die Orientierung an den Champions der Finanzmetropolen forciert. Der hier vorgenommene kontrastive Vergleich Frankfurts und Sydneys zeigt hingegen, dass die stark von Globalisierungs- und Finanzialisierungstendenzen beeinflussten Städte sich nicht einfach einem Idealtypus von Global Cities angleichen. Vielmehr sorgt die Einbettung in unterschiedliche Entwicklungslinien – im Falle Frankfurts in die Tradition einer koordinierten Marktwirtschaft, im Falle Sydneys in die Tradition einer liberalen Marktwirtschaft – für die Ausbildung von Finanzsystemen mit unterschiedlichem Charakter und unterschiedlicher Reichweite. So weist der Finanzplatz Frankfurt im Vergleich mit Sydney eine starke globale Vernetzung auf, wenngleich die Merkmale der koordinierten Marktwirtschaft - geringere Börsenkapitalisierung der Unternehmen, einer primär kreditbasierten Unternehmensfinanzierung und geringere Finanzmarktorientierung der Bevölkerung nachwirken. Demgegenüber profitiert der Finanzstandort Sydney von einer durchwegs finanzialisierten Ökonomie, was sich in der Finanzmarktorientierung von Unternehmen und jener der allgemeinen Bevölkerung ausdrückt, weist aber eine stärkere Binnenorientierung, also die Fokussierung auf den nationalen Markt auf.
The family Gymnophthalmidae contains nearly 235 species with a distribution range from southern Mexico to central Argentina as well as in the Antilles. Among gymnophthalmids, the genus Colobosaura is a member of the tribe Iphisini, and currently is considered monotypic (C. modesta). The diversity of the tribe was studied recently, with the erection of several new genera. In this work genetic and morphological data of specimens of Colobosaura recently collected in Paraguay were analyzed. Genetic (16S barcode) data indicate that these samples are not conspecific with C. modesta and they are allocated to the nominal species C. kraepelini. Because the original primary type of the latter taxon is considered to be lost, a neotype (SMF 101370) is designated for this species and a redescription provided based on our material. Colobosaura kraepelini is distributed in the Humid Chaco, being the only member of the whole tribe in this ecoregion.
The ability to learn sequential behaviors is a fundamental property of our brains. Yet a long stream of studies including recent experiments investigating motor sequence learning in adult human subjects have produced a number of puzzling and seemingly contradictory results. In particular, when subjects have to learn multiple action sequences, learning is sometimes impaired by proactive and retroactive interference effects. In other situations, however, learning is accelerated as reflected in facilitation and transfer effects. At present it is unclear what the underlying neural mechanism are that give rise to these diverse findings. Here we show that a recently developed recurrent neural network model readily reproduces this diverse set of findings. The self-organizing recurrent neural network (SORN) model is a network of recurrently connected threshold units that combines a simplified form of spike-timing dependent plasticity (STDP) with homeostatic plasticity mechanisms ensuring network stability, namely intrinsic plasticity (IP) and synaptic normalization (SN). When trained on sequence learning tasks modeled after recent experiments we find that it reproduces the full range of interference, facilitation, and transfer effects. We show how these effects are rooted in the network’s changing internal representation of the different sequences across learning and how they depend on an interaction of training schedule and task similarity. Furthermore, since learning in the model is based on fundamental neuronal plasticity mechanisms, the model reveals how these plasticity mechanisms are ultimately responsible for the network’s sequence learning abilities. In particular, we find that all three plasticity mechanisms are essential for the network to learn effective internal models of the different training sequences. This ability to form effective internal models is also the basis for the observed interference and facilitation effects. This suggests that STDP, IP, and SN may be the driving forces behind our ability to learn complex action sequences.
Polytraumatisierte Patienten erleiden in ca. 40% der Fälle eine Verletzung des Thorax. Die Verletzung des Thorax erhöht die Dauer der Beatmungszeit, das Pneumonie-Risiko, die Intensiv- und Krankenhausverweildauer sowie das Letalitätsrisiko. Seit 2003 wurde im Universitätsklinikum Frankfurt am Main ein standardisiertes Behandlungsverfahren zur intensivmedizinischen Behandlung nach Polytrauma implementiert und weiterentwickelt. Eckpunkte des Konzeptes sind eine kinetische Therapie im Rotorest®Bett, eine initiale Beatmung mit einem PEEP von 15mbar, eine frühzeitige assistierte Spontanatmung und frühzeitige enterale Ernährung. In dieser Arbeit wurden die Auswirkungen der Weiterentwicklung des Behandlungsprotokolls, insbesondere die Auswirkungen der Ernährung und Sedierung auf die Leberfunktion und die Entwicklung einer Pneumonie, untersucht. Das Behandlungsprotokoll sah folgende Behandlungsstandards vor: 2003: Kontrollierte Beatmung und Therapie im Rotorest®Bett in den ersten Tagen, PEEP-Einstellung entsprechend der Oxygenierung, individuelle Entwöhnung von der Beatmung und der Rotorest®-Therapie. Der Kostaufbau überwiegend parenteral, Sedierung mit Propofol und Midazolam. 2006: 72h Beatmung mit einem PEEP von 15mbar, Rotorest®-Bett, zügige assistierte Beatmungsform. Individuelle Entwöhnung von der Beatmung und der Rotorest®-Therapie, der Kostaufbau parenteral und enteral, Sedierung überwiegend mit Midazolam. 2009: Reduktion der Rotorest®-Therapie mit einem PEEP von 15mbar auf 40 bis 48h, PEEP-Reduktionsprotokoll. Der Kostaufbau erfolgte primär enteral, die Sedierung mit vorwiegend Propofol und z. T. Midazolam.
Es konnten retrospektiv 108 Patienten (ISS 37+13) eingeschlossen werden. Bei 38,3% der Patienten lagen unvollständige Akten vor, oder die Rotorest® Therapie wurde erst nach 48h begonnen. Durch das Konzept konnten die Beatmungszeit von 17±15 auf 8±8 Tage und die intensivstationäre Verweildauer von 17±9 auf 10±9 Tage signifikant reduziert werden (p<0,001), die Krankenhausverweildauer blieb gleich. Die Pneumonierate fiel nicht signifikant von 25% in 2003 nach einem Anstieg auf 37% in 2006 auf 17% in 2009. Das Pneumonierisiko stieg mit der Höhe der aufgenommenen kcal/kgKG, der Gesamt-kcal/d bis Tag 7 sowie der Summe der kcal bis Tag 5 signifikant (p<0,05). Eine Leberdysfunktion erhöhte das Letalitätsrisiko signifikant (Rs 0,267; p<0,01). Die Rate an Leberdysfunktionen binnen der ersten 14 Tage fiel von 34,7% in 2003 nach einem Anstieg auf 43,4% im Jahr 2006 auf 22,1% in 2009 (p<0,001). Eine Leberdysfunktion korrelierte, bei Auftreten bis Tag 7, sowohl mit einer überwiegend parenteralen Ernährung bis Tag 5 (p=0,021) als auch der Höhe der parenteralen kcal (Rs 0,248; p=0,02) und der Höhe der Gesamt-kcal (Rs 0,201; p=0,038). Der Anteil an Patienten mit parenteraler Ernährung konnte von 92,2% (bis Tag 5) in 2003 und 97,5% in 2006 auf 65% in 2009 signifikant reduziert werden, ebenso wie die Gesamtmenge an verabreichten Kalorien bis Tag 7 (von 1210kcal/d auf 1113kcal/d und 2009 auf 851kcal/d; p<0,001). Keine Korrelation bestand zwischen der Entstehung einer Leberdysfunktion und der Beatmung, der Höhe des PEEP oder der Entwicklung einer Pneumonie. Im Gegensatz dazu erhöhte die verabreichte Menge von Midazolam in den ersten 7 Tagen (mg/kg/d) das Pneumonie-Risiko signifikant (p=0,024). Als unabhängige Risikofaktoren für die Entwicklung einer Pneumonie stellten sich die Transfusion von EKs (OR 3,646 95%CI 1,074-12,383), die Höhe der verabreichten Gesamtkalorien (>5000kcal) binnen der ersten fünf Tage (OR 3,219 95%Cl 1,033-10,034) und die Höhe des Beatmungsspitzendruckes (OR 1,135 95%Cl 1,010-1,275) dar.
Die Daten der vorliegenden Arbeit bestätigen den kritisch abzuwägenden Einsatz von Midazolam in der Intensivtherapie. Weiterhin zeigte sich ein signifikanter Einfluss der Ernährung auf die Morbidität der Patienten entsprechend der Literatur. Die vorliegenden Ergebnisse weisen weiter darauf hin, dass bei schwerverletzten Patienten auch die Gesamtkalorienzufuhr gering zu halten ist, um die Rate an Pneumonien zu reduzieren. Die Beatmung mit einem PEEP von 15mbar in den ersten Behandlungstagen unter PiCCO-Monitoring erscheint hierbei keine negativen Auswirkungen auf die Entwicklung einer Leberdysfunktion zu haben.
Zusammenfassend kann durch ein vorwiegend enterales Ernährungsschema, mit unter den Empfehlungen der AWMF liegenden Gesamtkalorien, das Auftreten von Leberdysfunktionen und die Rate an Pneumonien signifikant reduziert, durch ein strukturiertes Therapiekonzept mit u.a. reduziertem Einsatz von Midazolam eine signifikante Reduktion der Beatmungszeit sowie der Intensivverweildauer erreicht und eine Reduktion der Pneumonierate unterstützt werden.
A detailed study of the holotype of Sphecomyrma canadensis Wilson, 1985 (Hymenoptera: Formicidae) from Canadian amber has led to the conclusion that the specimen belongs to a new genus, here named Boltonimecia gen.n. Since the taxonomy of stem-group ants is not well understood, in order to find the taxonomic position of this genus, it is necessary to review the classifi cation of stem-group ants in a study of their relation to crown-group ants. In the absence of data for traditional taxonomic approaches, a statistical study was done based on a morphometric analysis of antennae. Scape elongation is believed to play an important role in the evolution of eusociality in ants; however, this hypothesis has never been confirmed statistically. The statistical analysis presented herein lends support to the view that antennal morphology reliably distinguishes stem-group ants from crown-group ants, to determine whether a species belongs to one or the other group. This, in turn, may indicate a relationship exists between eusociality and scape elongation. A review of Cretaceous records of ants is made and the higher classification of Formicidae with definitions of stem and crown groups is proposed. Newly obtained data are discussed focusing particularly on the origin, evolution and diversity of ants.
Dipropus tequesta Johnson new species (Coleoptera: Elateridae) is described from southern Florida. Dipropus fuscus (LeConte) is a new synonym of D. soleatus (Say), and D. granosus (Fall) is a new synonym of D. asper (LeConte). The fl ightless female of D. asper is described and provides the fi rst report of brachyptery and endogean habits in Dipropus. A key to the species of the eastern United States and a new checklist of species for the country are provided.
The primary types of Onciderini Thomson, 1860 (Coleoptera: Cerambycidae: Lamiinae) of the Museum of Comparative Zoology (MCZ), Harvard University, are catalogued and illustrated. Data on the original combination, current name, gender, and type locality are verifi ed and presented. There are 19 primary types of Onciderini including seven in Oncideres Lacordaire, 1830; two in Hesychotypa Thomson, 1868; and two in Hypsioma Audinet-Serville, 1835. Of the 19 primary types, 18 were described by L. S. Dillon and E. S. Dillon. A brief history of the Coleoptera collection at the MCZ is also presented.
Una nueva especie del género Eugnosta Hübner, E. lankinae n.sp. (Lepidoptera: Tortricidae), es descrita para la Provincia de Elqui, Chile. Se entregan los caracteres morfológicos del adulto y las fi guras de la genitalia masculina. Además se discute su posición sistemática con dos especies congéneres Neotropicales.
The taxonomic history of the rhinotragine genera Phygopoda Thomson, 1864 and Pseudophygopoda Tavakilian and Peñaherrera-Leiva, 2007 (Coleoptera: Cerambycidae: Cerambycinae) are discussed, and evidence is presented to suggest that some recent taxonomic changes made by Carelli and Monné (2015) were unjustified. Consequently, Phygopoda nigritarsis Gounelle, 1911 is moved to the genus Neophygopoda Melzer, 1933, creating the new combination Neophygopoda nigritarsis, the genera Panamapoda Clarke, 2014 and Paraphygopoda Clarke, 2014 are revalidated, and the species Paraphygopoda viridimicans (Fisher, 1952) and Paraphygopoda nappae Clarke, 2014 are also revalidated.
Digitale Technologien und ihre vielfältige Nutzung verändern normative Ordnungen auf politischer, rechtlicher und gesellschaftlicher Ebene. Das Internet bietet neue gesellschaftliche Räume, die soziale Interaktion strukturieren. Diese sind jedoch nur halb-öffentliche Räume, in denen die Dienstleistungsanbieter mit Verweis auf ihre AGBs die Möglichkeit haben, etwa politische Äußerungen zu zensieren oder gar zu löschen. Darüber hinaus kooperieren manche private Unternehmen auch mit Staaten in der Strafverfolgung, und treffen Entscheidungen darüber welche Daten sie weitergeben. Welche Normen stoßen im Rahmen der Digitalisierung aufeinander und inwieweit sollten und könnten diese per Gesetz reguliert werden? Können die Grundrechte der Nutzer/innen noch umfassend gewährleistet werden? Mit diesen hochaktuellen Fragen befasste sich am 06. und 07. Juli die interdisziplinäre Konferenz “Normative Orders of the Digital“ am Exzellenzcluster Normative Ordnungen der Goethe-Universität Frankfurt.
Atheism remains one of the most extreme taboos in Saudi Arabia. It is a red line that no one can cross. Atheists in Saudi Arabia have been suffering from imprisonment, maginalisation, slander, ostracisation and even execution. Indeed, atheists in Saudi are considered terrorists. Efforts for normalisation between those who believe and those who don’t remain bleak in the kingdom.
Despite constant warnings of Saudi religious authorities of “the danger of atheism”, which is, according to them, “equal to disbelieving in God”, many citizens in the kingdom are turning their back on Islam. Perhaps inter alia the Saudi dehumanising strict laws in the name of Islam, easy access to information and mass communication are the primary driving forces pushing Saudis to leave religion. Unfortunately, those who explicitly do, find themselves harshly punished or forced to live dual lives.
Ransomware wie WannaCry und Petya/NotPetya versetzten weltweit Unternehmen in Sorge und verursachen erheblichen Schaden. Dabei sind sie nur der sichtbare Teil einer unzureichenden Sicherheitskultur, die dringend ein Update benötigt.
Ransomware, auch Kryptotrojaner genannt, sind kein neues Phänomen, sondern die zunehmend sichtbare Begleiterscheinung kollektiver IT-Unsicherheit. Die Ransomware WannaCry infizierte Mitte Mai weltweit mindestens 220.000 Windows Rechner. Dabei verschaffte sich der Trojaner Zugang zu den Dateien der Computer und verschlüsseln diese um eine Lösegeldzahlung zu erpressen. Dies war möglich über die als EternalBlue bekannte Lücke, die seit dem Betriebssystem Windwos XP auftrat und erst in diesem Jahr im Februar durch Microsoft geschlossen wurde. EternalBlue war für eine unbekannte Zeit in den Händen der NSA bis sie Anfang dieses Jahres durch eine Hackergruppe namens Shadow Brokers von der NSA „gestohlen“ und veröffentlicht wurde. Und obwohl Microsoft eiligst einen Patch veröffentlichte, offenbarten die bisher folgenreichsten bekannte Kryptowurm das Dilemma, in dem sich die Cyber-Sicherheitskultur aktuell befindet: Es ist eine Kultur des Schweigens, die dazu führt, dass das Sammeln und der Missbrauch von Sicherheitslücken gefördert statt verhindert wird....
Der Gyrus dentatus ist eine anatomische Region im Hippocampus und besitzt die einzigartige Fähigkeit auch im adulten Gehirn lebenslang neue Nervenzellen zu generieren. Dieser Prozess wird als adulte Neurogenese bezeichnet, stellt eine besondere Form struktureller Plastizität dar und es wurde gezeigt, dass adult neugebildete Körnerzellen im Gyrus dentatus essentiell am Prozess des hippocampalen Lernens und der Gedächtnisausbildung beteiligt sind. Es wird vermutet, dass neue Körnerzellen aufgrund ihrer charakteristischen Eigenschaften verstärkt auf neue Informationsmuster reagieren können und darauf spezialisiert sind Muster, die eine hohe Ähnlichkeit zueinander haben zu separieren und diese Unterschiede zu kodieren. Obwohl bereits eine Vielzahl von wissenschaftlichen Studien zum Verständnis der Entwicklung und Funktion adult neugebildeter Körnerzellen beitragen konnte, bestehen immer noch Unklarheiten darin, wie sich diese neuen Nervenzellen strukturell entwickeln, wann es zu einer funktionellen Integration kommt und wie diese beiden Prozesse miteinander zusammenhängen. In den vorliegenden Arbeiten wurde die strukturelle Entwicklung und synaptische Integration adult neugebildeter Körnerzellen in das bestehende hippocampale Netzwerk der Ratte und Maus unter in vivo Bedingungen untersucht. Zur Beantwortung dieser Fragen wurden Methoden aus der Anatomie, Histologie und in vivo Elektrophysiologie kombiniert. Der Nachweis neuer Körnerzellen erfolgte entweder durch immunhistologische Färbungen gegen spezifische Marker für unreife und reife Körnerzellen, Markierungen mit Bromdesoxyuridin oder retro- bzw. adenovirale intrazerebrale Injektionen und Expression von GFP. Es wurde eine in vivo Stimulation des Tractus perforans in der anästhesierten Ratte zur Langzeitpotenzierung der Körnerzellsynapsen und anschließend eine immunhistologische Analyse der Expression von synaptischen Aktivitäts- und Plastizitätsmarkern in neugebildeten und reifen Körnerzellen nach der Stimulation durchgeführt. Zusätzlich wurden detaillierte drei-dimensionale Rekonstruktion dendritischer Bäume erstellt und dendritische Dornenfortsätze an retroviral markierten Zellen analysiert.
Die vorliegenden Daten belegen den generellen Verlauf der Entwicklung neugeborener Körnerzellen in zwei unterschiedliche Phasen: eine frühe dendritische Reifung und eine späte funktionelle und synaptische Integration. Neugeborene Körnerzellen zeigten ein rasches dendritisches Auswachsen, dass innerhalb der ersten drei bis vier Wochen abgeschlossen war. Während dieses Wachstumsprozesses passieren Dendriten nacheinander die Körnerzellschicht und anschließend die innere, mittlere und äußere Molekularschicht. Dadurch sind sie innerhalb ihrer morphologischen Entwicklungsphasen anatomisch auf spezifische präsynaptische Partner limitiert. In der wissenschaftlichen Literatur wird eine transiente kritische Phase beschrieben, in der neugeborene Körnerzellen eine starke Plastizität und sensitivere synaptische Erregbarkeit aufweisen. Obwohl die vorliegenden Resultate keine direkten Hinweise auf eine stärkere bzw. sensitivere Plastizität neugeborener Körnerzellen liefern, konnte eine Phase zwischen vier und fünf Wochen identifiziert werden, in der neue Körnerzellen einen sprunghaften Anstieg in ihrer Fähigkeit zur Expression synaptischer Aktivitätsmarker (z.B. Arc und c-fos) und Ausbildung struktureller Plastizität (Dendriten und Dornenfortsätze) zeigten. Die präsentierten Resultate machen deutlich, dass Dornenfortsätze neuer Körnerzellen nach elf Wochen eine vergleichbare Dichte, Größenverteilung und Plastizität aufzeigen, die vergleichbar mit denen vorhandener Körnerzellen sind. Die Fähigkeit zur dendritischen Plastizität nach synaptischer Aktivierung zeigten jedoch nur neugeborene Körnerzellen zwischen der vierten und fünften Woche. Diese Ergebnisse implizieren, dass die Integration neugebildeter Körnerzellen kontinuierlich verläuft und obwohl die vorliegenden Daten die Existenz einer dendritischen Plastizität und einen sprunghaften Anstieg synaptischer Plastizität in der vierten und fünften Woche belegen, wurden keine weiteren Hinweise auf eine transiente kritische Phase gefunden. Des Weiteren zeigten dendritische Bäume von gereiften adult neugeborenen und reifen Körnerzellen Unterschiede, die daraufhin deuten, dass neue Körnerzellen eine eigene Subpopulation darstellen.
Earliest expansion of animal husbandry beyond the Mediterranean zone in the sixth millennium BC
(2017)
Since their domestication in the Mediterranean zone of Southwest Asia in the eighth millennium BC, sheep, goats, pigs and cattle have been remarkably successful in colonizing a broad variety of environments. The initial steps in this process can be traced back to the dispersal of farming groups into the interior of the Balkans in the early sixth millennium BC, who were the first to introduce Mediterranean livestock beyond its natural climatic range. Here, we combine analysis of biomolecular and isotopic compositions of lipids preserved in prehistoric pottery with faunal analyses of taxonomic composition from the earliest farming sites in southeast Europe to reconstruct this pivotal event in the early history of animal husbandry. We observe a marked divergence between the (sub)Mediterranean and temperate regions of Southeast Europe, and in particular a significant increase of dairying in the biochemical record coupled with a shift to cattle and wild fauna at most sites north of the Balkan mountain range. The findings strongly suggest that dairying was crucial for the expansion of the earliest farming system beyond its native bioclimatic zone.
Background: All European countries need to increase the number of health professionals in the near future. Most efforts have not brought the expected results so far. The current notion is that this is mainly related to the fact that female physicians will clearly outnumber their male colleagues within a few years in nearly all European countries. Still, women are underrepresented in leadership and research positions throughout Europe.
Objectives: The MedGoFem project addresses multiple perspectives with the participation of multiple stakeholders. The goal is to facilitate the implementation of Gender Equality Plans (GEP) in university hospitals; thereby, transforming the working conditions for women working as researchers and highly qualified physicians simultaneously. Our proposed innovation, a crosscutting topic in all research and clinical activities, must become an essential part of university hospital strategic concepts.
Methods: We capture the current status with gender-sensitive demographic data concerning medical staff and conduct Web-based surveys to identify cultural, country-specific, and interdisciplinary factors conducive to women’s academic success. Individual expectations of employees regarding job satisfaction and working conditions will be visualized based on “personal construct theory” through repertory grids. An expert board working out scenarios and a gender topic agenda will identify culture-, nation-, and discipline-specific aspects of gender equality. University hospitals in 7 countries will establish consensus groups, which work on related topics. Hospital management supports the consensus groups, valuates group results, and shares discussion results and suggested measures across groups. Central findings of the consensus groups will be prepared as exemplary case studies for academic teaching on research and work organization, leadership, and management.
Results: A discussion group on gender equality in academic medicine will be established on an internationally renowned open-research platform. Project results will be published in peer-reviewed journals with high-impact factors. In addition, workshops on gender dimension in research using the principles of Gendered Innovation will be held. Support and consulting services for hospitals will be introduced in order to develop a European consulting service.
Conclusions: The main impact of the project will be the implementation of innovative GEP tailored to the needs of university hospitals, which will lead to measurable institutional change in gender equality. This will impact the research at university hospitals in general, and will improve career prospects of female researchers in particular. Simultaneously, the gender dimension in medical research as an innovation factor and mandatory topic will be strengthened and integrated in each individual university hospital research activity. Research funding organizations can use the built knowledge to include mandatory topics for funding applications to enforce the use and implementation of GEP in university hospitals.
Background: PINK1 deficiency causes the autosomal recessive PARK6 variant of Parkinson’s disease. PINK1 activates ubiquitin by phosphorylation and cooperates with the downstream ubiquitin ligase PARKIN, to exert quality control and control autophagic degradation of mitochondria and of misfolded proteins in all cell types.
Methods: Global transcriptome profiling of mouse brain and neuron cultures were assessed in protein-protein interaction diagrams and by pathway enrichment algorithms. Validation by quantitative reverse transcriptase polymerase chain reaction and immunoblots was performed, including human neuroblastoma cells and patient primary skin fibroblasts.
Results: In a first approach, we documented Pink1-deleted mice across the lifespan regarding brain mRNAs. The expression changes were always subtle, consistently affecting “intracellular membrane-bounded organelles”. Significant anomalies involved about 250 factors at age 6 weeks, 1300 at 6 months, and more than 3500 at age 18 months in the cerebellar tissue, including Srsf10, Ube3a, Mapk8, Creb3, and Nfkbia. Initially, mildly significant pathway enrichment for the spliceosome was apparent. Later, highly significant networks of ubiquitin-mediated proteolysis and endoplasmic reticulum protein processing occurred. Finally, an enrichment of neuroinflammation factors appeared, together with profiles of bacterial invasion and MAPK signaling changes—while mitophagy had minor significance. Immunohistochemistry showed pronounced cellular response of Iba1-positive microglia and GFAP-positive astrocytes; brain lipidomics observed increases of ceramides as neuroinflammatory signs at old age.
In a second approach, we assessed PINK1 deficiency in the presence of a stressor. Marked dysregulations of microbial defense factors Ifit3 and Rsad2 were consistently observed upon five analyses: (1) Pink1 −/− primary neurons in the first weeks after brain dissociation, (2) aged Pink1 −/− midbrain with transgenic A53T-alpha-synuclein overexpression, (3) human neuroblastoma cells with PINK1-knockdown and murine Pink1 −/− embryonal fibroblasts undergoing acute starvation, (4) triggering mitophagy in these cells with trifluoromethoxy carbonylcyanide phenylhydrazone (FCCP), and (5) subjecting them to pathogenic RNA-analogue poly(I:C). The stress regulation of MAVS, RSAD2, DDX58, IFIT3, IFIT1, and LRRK2 was PINK1 dependent. Dysregulation of some innate immunity genes was also found in skin fibroblast cells from PARK6 patients.
Conclusions: Thus, an individual biomarker with expression correlating to progression was not identified. Instead, more advanced disease stages involved additional pathways. Hence, our results identify PINK1 deficiency as an early modulator of innate immunity in neurons, which precedes late stages of neuroinflammation during alpha-synuclein spreading.
Unequivocal international guidelines regarding the diagnosis and management of patients with acute appendicitis are lacking. The aim of the consensus meeting 2015 of the EAES was to generate a European guideline based on best available evidence and expert opinions of a panel of EAES members. After a systematic review of the literature by an international group of surgical research fellows, an expert panel with extensive clinical experience in the management of appendicitis discussed statements and recommendations. Statements and recommendations with more than 70 % agreement by the experts were selected for a web survey and the consensus meeting of the EAES in Bucharest in June 2015. EAES members and attendees at the EAES meeting in Bucharest could vote on these statements and recommendations. In the case of more than 70 % agreement, the statement or recommendation was defined as supported by the scientific community. Results from both the web survey and the consensus meeting in Bucharest are presented as percentages. In total, 46 statements and recommendations were selected for the web survey and consensus meeting. More than 232 members and attendees voted on them. In 41 of 46 statements and recommendations, more than 70 % agreement was reached. All 46 statements and recommendations are presented in this paper. They comprise topics regarding the diagnostic work-up, treatment indications, procedural aspects and post-operative care. The consensus meeting produced 46 statements and recommendations on the diagnostic work-up and management of appendicitis. The majority of the EAES members supported these statements. These consensus proceedings provide additional guidance to surgeons and surgical residents providing care to patients with appendicitis.
This paper examines the welfare implications of rising temperatures. Using a standard VAR, we empirically show that a temperature shock has a sizable, negative and statistically significant impact on TFP, output, and labor productivity. We rationalize these findings within a production economy featuring long-run temperature risk. In the model, macro-aggregates drop in response to a temperature shock, consistent with the novel evidence in the data. Such adverse effects are long-lasting. Over a 50-year horizon, a one-standard deviation temperature shock lowers both cumulative output and labor productivity growth by 1.4 percentage points. Based on the model, we also show that temperature risk is associated with non-negligible welfare costs which amount to 18.4% of the agent's lifetime utility and grow exponentially with the size of the impact of temperature on TFP. Finally, we show that faster adaptation to temperature shocks results in lower welfare costs. These welfare benefits become substantially higher in the presence of permanent improvements in the speed of adaptation.
Background: Clonidine effectively decreases perioperative mortality by reducing sympathetic tone. However, application of clonidine might also restrict anaemia tolerance due to impairment of compensatory mechanisms. Therefore, the influence of clonidine induced, short-term sympathicolysis on anaemia tolerance was assessed in anaesthetized pigs. We measured the effect of clonidine on anaemia tolerance and of the potential for macrohemodynamic alterations to constrain the acute anaemia compensatory mechanisms.
Methods: After governmental approval, 14 anaesthetized pigs of either gender (Deutsche Landrasse, weight (mean ± SD) 24.1 ± 2.4 kg) were randomly assigned to intravenous saline or clonidine treatment (bolus: 20 μg · kg−1, continuous infusion: 15 μg · kg−1 · h−1). Thereafter, the animals were hemodiluted by exchange of whole blood for 6 % hydroxyethyl starch (MW 130.000/0.4) until the individual critical haemoglobin concentration (Hbcrit) was reached. Primary outcome parameters were Hbcrit and the exchangeable blood volume (EBV) until Hbcrit was reached.
Results: Hbcrit did not differ between both groups (values are median [interquartile range]: saline: 2.2 (2.0–2.5) g · dL−1 vs. clonidine: 2.1 (2.1–2.4) g · dL−1; n.s.). Furthermore, there was no difference in exchangeable blood volume (EBV) between both groups (saline: 88 (76–106) mL · kg−1 vs. clonidine: 92 (85–95) mL · kg−1; n.s.).
Conclusion: Anaemia tolerance was not affected by clonidine induced sympathicolysis. Consequently, perioperative clonidine administration probably has not to be omitted in view of acute anaemia.
We propose a 2-country asset-pricing model where agents' preferences change endogenously as a function of the popularity of internationally traded goods. We determine the effect of the time-variation of preferences on equity markets, consumption and portfolio choices. When agents are more sensitive to the popularity of domestic consumption goods, the local stock market reacts more strongly to the preferences of local agents than to the preferences of foreign agents. Therefore, home bias arises because home-country stock represents a better investment opportunity for hedging against future fluctuations in preferences. We test our model and find that preference evolution is a plausible driver of key macroeconomic variables and stock returns.
Abstract
Indoor air pollution with harmful particulate matter (PM) is mainly caused by cigarette smoke. Super-Slim-Size-Cigarettes (SSL) are considered a less harmful alternative to King-Size-Cigarettes (KSC) due to longer filters and relatively low contents. We ask if “Combined Mainstream and Sidestream Smoke” (CMSS)-associated PM levels of SSL are lower than of KSC and thus are potentially less harmful. PM concentrations in CMSS (PM10, PM2.5, and PM1) are measured from four cigarette types of the brand Vogue, using an “automatic-environmental-tobacco-smoke-emitter” (AETSE) and laser aerosol spectrometry: SSL-BLEUE, -MENTHE, -LILAS and KSC-La Cigarette and -3R4F reference. This analysis shows that SSL MENTHE emitted the highest amount of PM, and KSC-La Cigarette the lowest. 3R4F reference emitted PM in the middle range, exceeding SSL BLEUE and falling slightly below SSL LILAS. It emerged that PM1 constituted the biggest proportion of PM emission. The outcome shows significant type-specific differences for emitted PM concentrations. Our results indicate that SSL are potentially more harmful for passive smokers than the respective KSC. However, this study cannot give precise statements about the general influence of the size of a cigarette on PM. Alarming is that PM1 is responsible for the biggest proportion of PM pollution, since smaller particles cause more harmful effects.
We investigate how solvency and wholesale funding shocks to 84 OECD parent banks affect the lending of 375 foreign subsidiaries. We find that parent solvency shocks are more important than wholesale funding shocks for subsidiary lending. Furthermore, we find that parent undercapitalization does not affect the transmission of shocks, while wholesale shocks transmit to foreign subsidiaries of parents that rely primarily on wholesale funding. We also find that transmission is affected by the strategic role of the subsidiary for the parent and follows a locational, rather than an organizational pecking order. Surprisingly, liquidity regulation exacerbates the transmission of adverse wholesale shocks. We further document that parent banks tend to use their own capital and liquidity buffers first, before transmitting. Finally, we show that solvency shocks have higher impact on large subsidiary banks with low growth opportunities in mature markets.
Background: Although noise is one of the leading work-related health risk factors for teachers, many nursery schools lack sufficient noise reduction measures. Methods: This intervention study evaluated the noise exposure of nursery school teachers when dropping DUPLO toy bricks into storage cases. Sound analyses of the impact included assessment of the maximum sound pressure level (LAFmax) as well as frequency analyses with 1/3 octave band filter. For the purpose of standardization, a customized gadget was developed. Recordings were performed in 11 cases of different materials and designs to assess the impact on sound level reduction. Thereby, the acoustic effects of three damping materials (foam rubber, carpet, and PU-foam) were investigated. Results: The lowest LAFmax was measured in cases consisting of “metal grid” (90.71 dB) or of a woven willow “basket” (91.61 dB), whereas a case of “aluminium” (103.34 dB) generated the highest impact LAFmax. The frequency analyses determined especially low LAFmax in the frequency bands between 80 and 2500 Hz in cases designs “metal grid” and “basket”. The insertion of PU-foam achieved the most significant attenuation of LAFmax (−13.88 dB) and, in the frequency analyses, the best sound damping. Conclusion: The dropping of DUPLO bricks in cases contributes to the high noise level in nursery schools, but measured LAFmax show no evidence for the danger of acute hearing loss. However, continuous exposure may lead to functional impairment of the hair cells and trigger stress reactions. We recommend noise reduction by utilizing cases of woven “basket” with an insert of PU-foam.
We introduce an innovative approach to measure bank integration, based on the corporate culture of multinational banking conglomerates. The new measure, the Power Index, assesses the prevalence of a language of power and authority in the financial reports of global banks. We employ a two-step approach: as a first step, we investigate whether parent-bank or parent-country characteristics are more important for bank integration. In a second step, we analyze whether bank integration affects the transmission of shocks across borders. We find that the level of integration of global banks is determined by parent-bank-specific factors, as well as by the social centralization in the parent’s country: ethnically diverse and linguistically homogenous countries nurture decentralized corporate structures. Political and economic factors, such as corruption, political rights and economic development also affect bank integration. Furthermore, we find that organizational integration affects the transmission of exogenous shocks from parent banks to their subsidiaries: the more centralized a global bank is, the lower the lending of its subsidiaries after a solvency shock. Wholesale shocks do not appear to be transmitted through this channel. Also, past experience with solvency shocks reduces the integration between parents and subsidiaries.
We develop a state-space model to decompose bid and ask quotes of CDS into two components, fair default premium and liquidity premium. This approach gives a better estimate of the default premium than mid quotes, and it allows to disentangle and compare the liquidity premium earned by the protection buyer and the protection seller. In contrast to other studies, our model is structurally much simpler, while it also allows for correlation between liquidity and default premia, as supported by empirical evidence. The model is implemented and applied to a large data set of 118 CDS for a period ranging from 2004 to 2010. The model-generated output variables are analyzed in a difference-in-difference framework to determine how the default premium, as well as the liquidity premium of protection buyers and sellers, evolved during different periods of the financial crisis and to which extent they differ for financial institutions compared to non-financials.
The Gini index is a measure of the inequality of a distribution that can be derived from Lorenz curves. While commonly used in, e.g., economic research, it suffers from ambiguity via lack of Lorenz dominance preservation. Here, investigation of large sets of empirical distributions of incomes of the World’s countries over several years indicated firstly, that the Gini indices are centered on a value of 33.33% corresponding to the Gini index of the uniform distribution and secondly, that the Lorenz curves of these distributions are consistent with Lorenz curves of log-normal distributions. This can be employed to provide a Lorenz dominance preserving equivalent of the Gini index. Therefore, a modified measure based on log-normal approximation and standardization of Lorenz curves is proposed. The so-called UGini index provides a meaningful and intuitive standardization on the uniform distribution as this characterizes societies that provide equal chances. The novel UGini index preserves Lorenz dominance. Analysis of the probability density distributions of the UGini index of the World’s counties income data indicated multimodality in two independent data sets. Applying Bayesian statistics provided a data-based classification of the World’s countries’ income distributions. The UGini index can be re-transferred into the classical index to preserve comparability with previous research.
Background: The importance of the Internet as a medium for publishing and sharing health and medical information has increased considerably during the last decade. Nonetheless, comprehensive knowledge and information are scarce and difficult to find, especially for rare diseases. Additionally, the quality of health or medical information about rare diseases is frequently difficult to assess for the patients and their family members.
Objective: The aim of this study is to assess the quality of information on the Internet about rare diseases. Additionally, the study aims to evaluate if the quality of information on rare diseases varies between different information supplier categories.
Methods: A total of 13 quality criteria for websites providing medical information about rare diseases were transferred to a self-disclosure questionnaire. Identified providers of information on the Internet about rare diseases were invited to fill out the questionnaire. The questionnaire contained questions about the information provider in general (eg, supplier category, information category, language, use of quality certificates, and target group) and about quality aspects that reflect the 13 quality criteria. Differences in subgroup analyses were performed using t tests.
Results: We identified 693 websites containing information about rare diseases. A total of 123 questionnaires (17.7%) were completely filled out by the information suppliers. For the remaining identified suppliers (570/693, 82.3%), the questionnaires were filled out by the authors based on the information available on their website. In many cases, the quality of websites was proportionally low. Furthermore, subgroup analysis showed no statistically significant differences between the quality of information provided by support group/patient organization compared to medical institution (P=.19). The quality of information by individuals (patient/relative) was significantly lower compared to information provided by support group/patient organization (P=.001), medical institution (P=.009), and other associations and sponsoring bodies (P=.001) as well.
Conclusions: Overall, the quality of information on the Internet about rare diseases is low. Quality certificates are rarely used and important quality criteria are often not fulfilled completely. Additionally, some information categories are underrepresented (eg, information about psychosocial counseling, social-legal advice, and family planning). Nevertheless, due to the high amount of information provided by support groups, this study shows that these are extremely valuable sources of information for patients suffering from a rare disease and their relatives.
Objective: The aim of this study was to report the basic cerebrospinal fluid (CSF) profile in patients with primary progressive multiple sclerosis (PPMS).
Methods: The results of CSF analysis from 254 patients with PPMS were collected at four university hospitals in Germany. Routine CSF parameters and different indices of intrathecal immunoglobulin synthesis were evaluated. We assessed possible correlations between the various CSF parameters and the expanded disability status scale (EDSS) both at the time of lumbar puncture and during the course of the disease.
Results: The median cell count and albumin concentration in the CSF did not deviate from normal values. The CSF-serum albumin-quotient (QALB) was elevated in 29.6% of the patients, while intrathecal immunoglobulin G (IgG) oligoclonal bands (OCBs) were detected in 91.1% of the patients. CSF-lactate levels as well as local IgM- and IgA-synthesis were correlated with the yearly disease progression rate, as assessed by EDSS.
Conclusion: We present the results of the hitherto largest and most detailed CSF biomarker profile in a cohort of 254 patients with PPMS. As reported previously, OCBs are the most sensitive marker for intrathecal IgG synthesis. CSF-lactate concentrations are positively correlated with the progression rate, which might suggest that mitochondrial dysfunction plays a relevant role in PPMS. The negative correlation between intrathecally produced IgM and IgA and disease progression may indicate their hitherto unexplored protective role.
Non-lethal genotyping of Tribolium castaneum adults using genomic DNA extracted from wing tissue
(2017)
The red flour beetle Tribolium castaneum has become the second most important insect model organism and is frequently used in developmental biology, genetics and pest-associated research. Consequently, the methodological arsenal increases continuously, but many routinely applied techniques for Drosophila melanogaster and other insect species are still unavailable. For example, a protocol for non-lethal genotyping has not yet been adapted but is particularly useful when individuals with known genotypes are required for downstream experiments. In this study, we present a workflow for non-lethal genotyping of T. castaneum adults based on extracting genomic DNA from wing tissue. In detail, we describe a convenient procedure for wing dissection and a custom method for wing digestion that allows PCR-based genotyping of up to fifty adults in less than an afternoon with a success rate of about 86%. The amount of template is sufficient for up to ten reactions while viability and fertility of the beetles are preserved. We prove the applicability of our protocol by genotyping the white / scarlet gene pair alleles from the black-eyed San Bernadino wild-type and white-eyed Pearl recessive mutant strains spanning four generations. Non-lethal genotyping has the potential to improve and accelerate many workflows: Firstly, during the establishment process of homozygous cultures or during stock keeping of cultures that carry recessively lethal alleles, laborious test crossing is replaced by non-lethal genotyping. Secondly, in genome engineering assays, non-lethal genotyping allows the identification of appropriate founders before they are crossed against wild-types, narrowing the efforts down to only the relevant individuals. Thirdly, non-lethal genotyping simplifies experimental strategies, in which genotype and behavior should be correlated, since the genetic configuration of potential individuals can be determined before the actual behavior assays is performed.
Der "Regionalatlas Rhein-Main" wird zum 75-jährigen Jubiläum der "Rhein-Mainischen Forschung" veröffentlicht. Er verfolgt das Ziel,
- einne Überblick über die regionale Struktur des Rhein-Main-Gebietes zu verschaffen,
- Politik, Wirtschaft und Verwaltung Grundlagendaten in regionalisierter Form für ihre Entscheidungen an die Hand zu geben, und
- den im Rhein-Main-Gebiet lebenden Menschen die regionalen Strukturen ihres Lebensraumes näher zu bringen.
Background: Treatment of patients presenting with possible acute myocardial infarction (AMI) is based on timely diagnosis and proper risk stratification aided by biomarkers. We aimed at evaluating the predictive value of GDF-15 in patients presenting with symptoms suggestive of AMI.
Methods: Consecutive patients presenting with suspected AMI were enrolled in three study centers. Cardiovascular events were assessed during a follow-up period of 6 months with a combined endpoint of death or MI.
Results: From the 1818 enrolled patients (m/f = 1208/610), 413 (22.7%) had an acute MI and 63 patients reached the combined endpoint. Patients with MI and patients with adverse outcome had higher GDF-15 levels compared with non-MI patients (967.1pg/mL vs. 692.2 pg/L, p<0.001) and with event-free patients (1660 pg/mL vs. 756.6 pg/L, p<0.001). GDF-15 levels were lower in patients with SYNTAX score ≤ 22 (797.3 pg/mL vs. 947.2 pg/L, p = 0.036). Increased GDF-15 levels on admission were associated with a hazard ratio of 2.1 for death or MI (95%CI: 1.67–2.65, p<0.001) in a model adjusted for age and sex and of 1.57 (1.13–2.19, p = 0.008) adjusted for the GRACE score variables. GDF-15 showed a relevant reclassification with regards to the GRACE score with an overall net reclassification index (NRI) of 12.5% and an integrated discrimination improvement (IDI) of 14.56% (p = 0.006).
Conclusion: GDF-15 is an independent predictor of future cardiovascular events in patients presenting with suspected MI. GDF-15 levels correlate with the severity of CAD and can identify and risk-stratify patients who need coronary revascularization.
In mammals, acoustic communication plays an important role during social behaviors. Despite their ethological relevance, the mechanisms by which the auditory cortex represents different communication call properties remain elusive. Recent studies have pointed out that communication-sound encoding could be based on discharge patterns of neuronal populations. Following this idea, we investigated whether the activity of local neuronal networks, such as those occurring within individual cortical columns, is sufficient for distinguishing between sounds that differed in their spectro-temporal properties. To accomplish this aim, we analyzed simple pure-tone and complex communication call elicited multi-unit activity (MUA) as well as local field potentials (LFP), and current source density (CSD) waveforms at the single-layer and columnar level from the primary auditory cortex of anesthetized Mongolian gerbils. Multi-dimensional scaling analysis was used to evaluate the degree of “call-specificity” in the evoked activity. The results showed that whole laminar profiles segregated 1.8-2.6 times better across calls than single-layer activity. Also, laminar LFP and CSD profiles segregated better than MUA profiles. Significant differences between CSD profiles evoked by different sounds were more pronounced at mid and late latencies in the granular and infragranular layers and these differences were based on the absence and/or presence of current sinks and on sink timing. The stimulus-specific activity patterns observed within cortical columns suggests that the joint activity of local cortical populations (as local as single columns) could indeed be important for encoding sounds that differ in their acoustic attributes.
QCD matter is expected to exist in different phases, when heated to high temperatures and getting highly compressed. Each phase could be characterized by distinct properties. A way to access extreme phases of matter in the laboratory are heavy-ion collisions at (ultra-)relativistic energies. During the collision, the temperature and density is evolving and reaches a maximum temperature and density far beyond the ground state of matter. The matter properties depend on the incident collision energy. Typically, a collision is separated into three collisions stages, namely first chance collisions (I), hot and dense stage (II) and freeze-out stage (III). Out of those, the second one is of major interest, since the extreme states of matter are generated within. For this reason, the most prominent change of the hadrons is expected to appear there in. Those changes are caused by i.e. modification of the hadronic spectral function. However, to retrieve such information is complicated. Hadrons are strongly interacting particles and therefore, carry little information about the hot and dense stage. For that purpose, decays of hadrons (low-mass vector mesons) to e+e- pairs via a virtual photon, so-called dielectrons, are an ideal probe. Electrons and positrons do not interact strongly and transport the information about the hot and dense stage nearly undisturbed to the detector. Unfortunately, the production of dielectrons is suppressed by a branching ratio of ≈ 10^(-5) and requires a precise lepton identification. Nonetheless, previous experiments have extracted a dilepton signal and observed in the low-mass range an excess over the hadronic cocktail. Latter one is expected to be caused by thermal radiation induced by the medium. Up to now, experiments conducted dilepton measurements with a focus on larger collision energies and large collision systems. Measurements of dielectrons at collision energies of around 1-2A GeV were only conducted for small and medium size collision systems. HADES continued the systematic studies by a measurement of Au+Au collisions at 1.23A GeV.
The detection of dielectrons requires detectors that handle high data rates and specific detectors for a high purity lepton identification. In HADES, the strongest separation of electrons or positrons from the hadronic background is provided by a ring imaging Cherenkov detector (RICH). Its electron identification is based on Cherenkov photons, that are emitted in ring like patterns. In this work a new approach, using the time-of-flight information to preselect electrons and the reconstructed particle trajectory to estimate ring positions, is utilized to improve the lepton identification. The concept of the so-called backtracking algorithm will be explained and applied to e+e- identification in Au+Au collisions. The whole analysis chain comprises single lepton identification, pair reconstruction and correction for efficiency and acceptance losses. The final pair spectra will be presented in form of their invariant mass, pt, mt and helicity distributions. Subsequently, transport model calculations as well as results from the recently developed coarse-grained transport approach will be compared to the dielectron spectra. Moreover, the centrality dependence of the excess yield and true (not "blue-shifted") temperature of the fireball will be presented. The results will be put in context to measurements of lighter collisions systems and at higher energies.
Im Folgenden wird Herders wechselseitiger Entwurf von Mensch und Natur in ein Verhältnis zur Klimakonzeption Kants gesetzt, wie dieser sie im Kontext seiner naturphilosophischen Überlegungen entwickelt. Dabei wird es nicht darum gehen, eine der beiden Positionen gegen die andere auszuspielen, sondern darum, die Denk- und Darstellbarkeit klimatischer Natur – noch vor ihrer Repräsentation in Diagrammen oder dem Versuch der Klimaprognose - auf den Grundlagen von zwei verschiedenen theoretischen Positionen zu rekonstruieren. Ein Hauptaugenmerk gilt der Frage, ob und inwiefern bei der Darstellung klimatischer Natur für beide Autoren Modelle eine Rolle spielen, und zwar in zwei Hinsichten: Erstens gilt die Aufmerksamkeit der Verwendung von Modellen, die rückwirkend als solche identifiziert werden können, von den Autoren aber nicht unbedingt als "Modell" bezeichnet wurden; zweitens der Verbindung zwischen den Darstellungsweisen klimatischer Natur in den Texten und ihrer Reflexion auf den Einsatz von Modellen, die sowohl bei Kant als auch bei Herder in der expliziten Beschäftigung mit der Funktion der Analogie zu finden ist.
In diversen Wissenschaftsdisziplinen ist derzeit eine Konjunktur der Begriffe Modell und Modellierung zu beobachten. Darunter sind auch solche Disziplinen, die Begriff wie Praxis des Modells bislang nicht zu ihrem methodischen Kernbereich zählten. Die Aktualität des Begriffs wie die Notwendigkeit einer Arbeit mit Modellen zeigt sich beispielsweise im Kontext sogenannter 'global challenges' wie klimatischer oder ökonomischer Krisen, die immer schon die Zuständigkeit einzelner Wissenschaften überschreiten und eine interdisziplinäre Zusammenarbeit verlangen. Eine zunehmende Resonanz modellhaften Denkens lässt sich indessen auch dort erkennen, wo kanonische Themen aus dem Geltungsbereich der Geistes- und Kulturwissenschaften zur Diskussion stehen. Es liegt daher die Vermutung nahe, der Modellbegriff erweise sein Potenzial nicht nur hinsichtlich der Analyse und Prognose komplexer dynamischer Systeme, sondern auch im Hinblick auf die interdisziplinäre Untersuchung tradierter Gegenstände wie literarischer Formen und Epochen, deren geschichtlicher Wandel beleuchtet werden soll. Die neue Anschlussfähigkeit für literatur- und kulturwissenschaftliche Ansätze ist u. a. der jüngeren Modelltheorie zu verdanken, welche das Modell bzw. den Modellierungsvorgang selbst im Modell erfasst und zugleich auf die 'aktiven Potenziale' sowie auf die Grenzen von Modellen hinsichtlich ihres epistemischen Status oder ihrer Materialität hingewiesen hat.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic, Th17-derived cytokine thought to critically contribute to the pathogenesis of diverse autoimmune diseases, including rheumatoid arthritis and psoriasis. Treatment with monoclonal antibodies that block GM-CSF activity is associated with favorable therapeutic effects in patients with rheumatoid arthritis. We evaluated the role of GM-CSF as a potential target for therapeutic interference in psoriasis using a combined pharmacologic and genetic approach and the mouse model of imiquimod-induced psoriasiform dermatitis (IMQPD). Neutralization of murine GM-CSF by an anti-GM-CSF antibody ameliorated IMQPD. In contrast, genetic deficiency in GM-CSF did not alter the course of IMQPD, suggesting the existence of mechanisms compensating for chronic, but not acute, absence of GM-CSF. Further investigation uncovered an alternative pathogenic pathway for IMQPD in the absence of GM-CSF characterized by an expanded plasmacytoid dendritic cell population and release of IFNα and IL-22. This pathway was not activated in wild-type mice during short-term anti-GM-CSF treatment. Our investigations support the potential value of GM-CSF as a therapeutic target in psoriatic disease. The discovery of an alternative pathogenic pathway for psoriasiform dermatitis in the permanent absence of GM-CSF, however, suggests the need for monitoring during therapeutic use of long-term GM-CSF blockade.
Die vorliegende Arbeit leistet einen Beitrag zur Debatte über den Schriftspracherwerb mehrsprachiger Kinder in der Grundschule. Motiviert wird dieses Thema durch den Forschungsstand hinsichtlich der Erwerbsprozesse unter den Bedingungen der Mehrsprachigkeit sowie durch die Relevanz von Schreibkompetenzentwicklung in den früheren Schuljahren für die gesamte schulische Laufbahn der Kinder. Das Forschungsinteresse des Promotionsprojektes richtet sich auf die Rekonstruktion von Schreibprozessen der mehrsprachigen SchülerInnen mit Sprachförderbedarf im Sprachunterricht der Schuleingangsphase. Die Arbeit stellt einen ersten Versuch dar, die Schreibpraktiken der Schüler im interaktiven Kontext systematisch zu erfassen.
Treatment with tyrosine kinase inhibitors is the standard of care for Philadelphia chromosome positive leukemias. However the eradication of leukemia initiating cells remains a challenge. Circumstantial evidence suggests that the cytokine microenvironment may play a role in BCR-ABL mediated leukemogenesis and in imatinib resistance. Gene expression analyses of BCR-ABL positive ALL long-term cultured cells revealed strong reduction of SOCS mRNA expression after imatinib treatment, thereby demonstrating a strong inhibition of cytokine signaling. In this study we employed SOCS1—a strong inhibitor of cytokine signaling—as a tool to terminate external cytokine signals in BCR-ABL transformed cells in vitro and in vivo. In colony formation assays with primary bone marrow cells, expression of SOCS1 decreased colony numbers under pro-proliferative cytokines, while it conferred growth resistance to anti-proliferative cytokines. Importantly, co-expression of SOCS1 with BCR-ABL led to the development of a MPD phenotype with a prolonged disease latency compared to BCR-ABL alone in a murine bone marrow transplantation model. Interestingly, SOCS1 co-expression protected 20% of mice from MPD development. In summary, we conclude that under pro-proliferative cytokine stimulation at the onset of myeloproliferative diseases SOCS1 acts as a tumor suppressor, while under anti-proliferative conditions it exerts oncogenic function. Therefore SOCS1 can promote opposing functions depending on the cytokine environment.
Protein kinases are highly tractable targets for drug discovery. However, the biological function and therapeutic potential of the majority of the 500+ human protein kinases remains unknown. We have developed physical and virtual collections of small molecule inhibitors, which we call chemogenomic sets, that are designed to inhibit the catalytic function of almost half the human protein kinases. In this manuscript we share our progress towards generation of a comprehensive kinase chemogenomic set (KCGS), release kinome profiling data of a large inhibitor set (Published Kinase Inhibitor Set 2 (PKIS2)), and outline a process through which the community can openly collaborate to create a KCGS that probes the full complement of human protein kinases.
Die "Digitalisierung" ist ein gesamtgesellschaftlicher und globaler Trend, der nahezu alle Bereiche der Lebens- und Arbeitswelt durchzieht und insofern auch das Studieren an (allen) Hochschulen betrifft. Das Schlagwort "Digitalisierung" verweist auch auf alle Varianten der Nutzung von digitalen Technologien im Bereich Studium und Lehre. Lange Zeit stand vor allem das E-Learning im Vordergrund der Diskussion und damit die Nutzung von digitalen Technologien im engeren Lehr-Lernkontext zur Unterstützung der Interaktion von Lehrenden und Studierenden. Heute werden an den Hochschulen zunehmend die weiteren Möglichkeiten der digitalen Technik für Studium und Lehre erkannt und immer mehr in der Praxis an Hochschulen genutzt: Von der Werbung um Studierende bis hin zur Ansprache von Alumni können sie die Qualität, die Leistungsfähigkeit, die Öffnung, Vermarktung und Internationalisierung der Hochschullehre unterstützen (Kerres 2013, Bischof und von Stuckrad 2013); und einige Hochschulen nutzen die Digitalisierung von Lehre und Studium zur Profilbildung und zur besseren Positionierung im nationalen und internationalen Wettbewerb zwischen Hochschulen. ...
The future heavy-ion experiment CBM (FAIR/GSI, Darmstadt, Germany) will focus on the measurements of very rare probes, which require the experiment to operate under extreme interaction rates of up to 10 MHz. Due to high multiplicity of charged particles in heavy-ion collisions, this will lead to the data rates of up to 1 TB/s. In order to meet the modern achievable archival rate, this data ow has to be reduced online by more than two orders of magnitude.
The rare observables are featured with complicated trigger signatures and require full event topology reconstruction to be performed online. The huge data rates together with the absence of simple hardware triggers make traditional latency limited trigger architectures typical for conventional experiments inapplicable for the case of CBM. Instead, CBM will employ a novel data acquisition concept with autonomous, self-triggered front-end electronics.
While in conventional experiments with event-by-event processing the association of detector hits with corresponding physical event is known a priori, it is not true for the CBM experiment, where the reconstruction algorithms should be modified in order to process non-event-associated data. At the highest interaction rates the time difference between hits belonging to the same collision will be larger than the average time difference between two consecutive collisions. Thus, events will overlap in time. Due to a possible overlap of events one needs to analyze time-slices rather than isolated events.
The time-stamped data will be shipped and collected into a readout buffer in a form of a time-slice of a certain length. The time-slice data will be delivered to a large computer farm, where the archival decision will be obtained after performing online reconstruction. In this case association of hit information with physical events must be performed in software and requires full online event reconstruction not only in space, but also in time, so-called 4-dimensional (4D) track reconstruction.
Within the scope of this work the 4D track finder algorithm for online reconstruction has been developed. The 4D CA track finder is able to reproduce performance and speed of the traditional event-based algorithm. The 4D CA track finder is both vectorized (using SIMD instructions) and parallelized (between CPU cores). The algorithm shows strong scalability on many-core systems. The speed-up factor of 10.1 has been achieved on a CPU with 10 hyper-threaded physical cores.
The 4D CA track finder algorithm is ready for the time-slice-based reconstruction in the CBM experiment.
The Facility for Antiproton and Ion Research (FAIR) at GSI Darmstadt will provide unprecedented intensities of protons and heavy ions up to uranium at energies of up to 29 GeV for protons and 2.7 GeV/u for Uranium 28+. To achieve high intensities in the synchrotron accelerators, high beam currents have to be provided by the injector linear accelerators. High current heavy ion beams are provided by the Universal Linear Accelerator (UNILAC), which in its current state will not be able to provide the required FAIR beam currents. This thesis deals with the development of upgrades for the UNILAC to ensure its high current capability. The first improvement is a matching section (MEBT) for the interface between the RFQ and the IH-DTL of the existing high current injector HSI at the UNILAC. With this new MEBT section, particle losses are eliminated and the overall beam quality is improved. As a second improvement, a complete replacement of the existing Alvarez-DTL is presented. A combination of efficient IH-type cavities and KONUS beam dynamics results in a reduction of the linac length from about 60 m (Alvarez) to just 23 m (new IH-DTL) while providing the same energy and fulfilling FAIR requirements of a high beam current and beam quality. This thesis contains a detailed beam dynamics design of the new linac including some fundamental investigations of the KONUS beam dynamics concept. A cross-check of the beam dynamics design was performed with two independent multi-particle simulation codes. Detailed error studies were conducted to investigate the influence of manufacturing, alignment and operating errors on the beam dynamics performance. Additionally, all five linac cavities were designed, optimized, and their RF parameters including power requirements calculated to provide a comprehensive linac design.
Diese Untersuchung beschäftigt sich mit der Morphosyntax pronominaler Partitivanaphern im kontinentalwestgermanischen Dialektkontinuum im Allgemeinen und im deutschen (insbesondere hessischen) Sprachraum im Speziellen. Schwerpunkte sind dabei die sprachgeografische Verteilung, die morphosyntaktische Variation und die strukturelle Analyse pronominaler Ausdrucksmittel der unbestimmten Teilmenge. Es werden traditionell dialektologische Erkenntnisinteressen (Raumstruktur syntaktischer Variablen und Verlauf syntaktischer Isoglossen) mit Fragestellungen der (theoretisch orientierten) Syntaxforschung verbunden. Außerdem erfolgt erstmals eine wirklich sprachübergreifende Behandlung der verschiedenen Systeme pronominaler Partitivität, zum einen innerhalb der (West-)Germania, zum anderen durch den Einbezug (zentral-)romanischer Sprachen, um Unterschiede und Gemeinsamkeiten auf der Mikro- und Mesoebene herauszuarbeiten. Die gewählte Methode ist nicht nur kontrastiv, sondern auch geolinguistisch fundiert, insofern als morphologische Formen und syntaktische Variation im Raum abgebildet werden, wodurch nicht zuletzt auch interessante Korrelationen und Anti-Korrelationen in den Daten bestätigt bzw. entdeckt werden konnten.
Nach einer Gegenstandsbestimmung der morphosyntaktischen Variable und ihrer Varianten (Inventarisierung und Typisierung) sowie des Variationsrahmens (areal-horizontal, vertikal, morphosyntaktisch, historisch, idiolektal etc.) wird zunächst das DFG-Projekt „Syntax hessischer Dialekte“ (SyHD) vorgestellt, das die empirische Basis zur Untersuchung lieferte. Dabei werden generelle und spezifische Fragen der Datengewinnung (multivariate Methode mit indirekten und direkten Elementen) sowie der Datenanalyse und -interpretation (Instrument der Kartierung) diskutiert. Den Hauptteil der Arbeit bildet die diatopische, diachrone und distributionell-syntaktische Variation der Systeme pronominaler Partitivität. Als die vier Hauptstrategien zum Ausdruck partitiv-anaphorischer Referenz innerhalb des deutschsprachigen Gebiets finden sich das konservative System versteinerter Pronominalgenitive wie „(d)(e)r(e)“, „s(e)n“ und „es“ (vor allem in einem mitteldeutschen Streifen und randdialektal) - Relikte eines ehemals umfassenderen genitivbasierten Systems der Partitivität -, das sprachgeschichtlich junge und typologisch auffällige indefinit-partitive Pronomen „welch-“/„we(l)k-“ (im Nieder-/Norddeutschen und in der Standardsprache) sowie schließlich die innovativen Systeme der Null-Anapher (im Alemannischen bzw. Südwesten) und des generalisierten Indefinitpronomens „ein-“ (im Bairischen bzw. Südosten). Wenngleich sich diese areale Distribution im zentral gelegenen und daher unter dem Einfluss nahezu aller Strategien stehenden Hessen als Kleinraum bestätigt - mit Ausnahme der weitgehenden Abwesenheit des „ein“-Systems -, so zeigen sich doch einige überraschende Ergebnisse wie beispielsweise ein kategorialer Unterschied nach Numerus und zum Teil Genus bei der Vitalität der Genitivpartikeln. Sprachhistorisch können zwei Arten von Wandel beim Genitiv-System identifiziert werden: systeminterne Veränderungen (durch Merkmals- oder Formverlust) und systemexterne Verdrängungsprozesse (durch Ausbreitung der innovativen Ausdrucksformen, was in einem Dialekt bzw. intraindividuell zu konkurrierenden oder Mischsystemen führen kann). Darüber hinaus sind mit Blick auf die Art und Weise der Veränderungen für Sprachwandelprozesse allgemein typische zyklische Abfolgen von Abschwächung und Verstärkung erkennbar. In Bezug auf die syntaktische Distribution werden insbesondere die Genitivanaphern auf ihre Kompatibilität mit nominalen Modifikatoren wie Numeralien/(schwachen) Quantoren, „flektierten“ Zahlwörtern (Schwa), Adjektiven, verschiedenen Arten von Präpositionalphrasen sowie Relativ- vs. Komplementsätzen hin untersucht und - funktional wie formal - mit ihrem niederländischen partitiven/quantitativen Äquivalent „er“ sowie den romanischen, in ein partitives System integrierten Pronomina fr. „en“/it. „ne“ verglichen. Für die deutschen Partitivanaphern ergibt sich daraus Evidenz für zwei unterschiedliche Pronominalisierungsebenen. Abschließend wird das Phänomen in die allgemeine Diskussion um nominale Ellipsen eingebettet (Elision und Pronominalisierung). Aufgrund der Evaluation der in der Literatur diskutierten Lizenzierungsansätze anhand neuer dialektaler und typologischer Daten wird hier ein flexions-/kongruenzbasierter Ansatz favorisiert (Rolle von Adjektivmorphologie bzw. generell von unterschiedlichen Flexionssystemen, etwa im Deutschen vs. Englischen).
In this thesis, we study some features of the quantum chromodynamics (QCD) phase diagram at purely imaginary chemical potential using lattice techniques. This is one of the possible methodologies to get insights about the situation at finite density, where the sign problem prevents direct investigations from first principles.
We focus, in particular, on the Roberge-Weiss plane, where the phase structure with two degenerate flavours is studied both in the light and in the heavy quark mass limit. On the lattice, any result is affected by cut-off effects and so are the positions of the two tricritical points m_{tric}^{1,2} separating the second-order intermediate mass region from the first-order triple light and heavy mass regions. Therefore, changing the lattice spacing 'a', the values of m_{tric}^1 and m_{tric}^2 will change. In order to find their position in the continuum limit – i.e. for 'a' going to 0 – they have to be located on finer and finer lattices. Typically, in lattice QCD (LQCD) simulations, the temperature T is tuned through the bare coupling β, on which 'a' depends, while keeping Nt fixed. Hence, it is common to implicitly refer to how fine the lattice is just mentioning its temporal extent.
Using both Wilson and staggered fermions, we simulate Nf=2 QCD on Nt=6 lattices, varying the quark bare mass from the chiral (m_{u,d} going to 0) to the quenched (m_{u,d} going to infinity) limit. For each quark mass, a thorough finite scaling analysis is carried out, taking advantage of two different but consistent methods. In this way we identify the order of the phase transition locating, then, the position of the tricritical points. In order to convert our measurements to physical units we fix the scale measuring the lattice spacing as well as the pion mass corresponding to the quark bare mass used. This allows a comparison between different discretisation, getting a first idea of how serious are cut-off effects.
To be able to make a comparison between two different discretisations, we added an RHMC algorithm with staggered fermions to the CL2QCD software, a GPU code based on OpenCL, which we released in 2014. A considerable part of our work has been invested in ameliorating and optimising CL2QCD, as well as in developing new analysis tools regularly used next to it. Just to mention one, the multiple histogram method has been implemented in a completely general way and we took advantage of it in order to obtain more precise results. Finally, in order to efficiently handle and monitor the hundreds of simulations that are typically concurrently run in finite temperature LQCD, a completely new Bash library of tools has been developed. We plan to release it as a byproduct of CL2QCD in the near future.
We explore space improvements in LRP, a polymorphically typed call-by-need functional core language. A relaxed space measure is chosen for the maximal size usage during an evaluation. It Abstracts from the details of the implementation via abstract machines, but it takes garbage collection into account and thus can be seen as a realistic approximation of space usage. The results are: a context lemma for space improving translations and for space equivalences; all but one reduction rule of the calculus are shown to be space improvements, and the exceptional one, the copy-rule, is shown to increase space only moderately.
Several further program transformations are shown to be space improvements or space equivalences, in particular the translation into machine expressions is a space equivalence. These results are a step Forward in making predictions about the change in runtime space behavior of optimizing transformations in callbyneed functional languages.
Wassergefiltertes Infrarot A (wIRA) als spezielle Form der Wärmestrahlung mit hohem Eindringvermögen in das Gewebe bei geringer thermischer Oberflächenbelastung kann die Heilung akuter und chronischer Wunden sowohl über thermische und temperaturabhängige als auch über nicht-thermische und temperaturunabhängige Effekte verbessern. wIRA steigert Temperatur (+2,7°C in 2 cm Gewebetiefe) und Sauerstoffpartialdruck im Gewebe (+32% in 2 cm Gewebetiefe) sowie die Gewebedurchblutung. Diese drei Faktoren sind entscheidend für eine ausreichende Versorgung des Gewebes mit Energie und Sauerstoff und deshalb auch für Wundheilung und Infektionsabwehr.
wIRA vermag Schmerzen deutlich zu mindern (ausnahmslos bei 230 Bestrahlungen) mit bemerkenswert niedrigerem Analgetikabedarf (52–69% niedriger in den Gruppen mit wIRA verglichen mit den Kontrollgruppen) und eine erhöhte Wundsekretion und Entzündung herabzusetzen sowie positive immunmodulierende Effekte zu zeigen. Die Gesamtbeurteilung des Effekts der Bestrahlung wie auch die Wundheilung und das kosmetische Ergebnis (erhoben mittels visueller Analogskalen) waren in der Gruppe mit wIRA wesentlich besser verglichen mit der Kontrollgruppe. wIRA kann sowohl bei akuten als auch bei chronischen Wunden einschließlich infizierter Wunden die Wundheilung beschleunigen (Abnahme der Wundfläche im Median um 90% bei schwerbrandverletzten Kindern bereits nach 9 Tagen in der Gruppe mit wIRA verglichen mit 13 Tagen in der Kontrollgruppe; im Durchschnitt 18 versus 42 Tage bis zum kompletten Wundschluss bei chronischen venösen Unterschenkelulzera) oder bei stagnierender Wundheilung verbessern (mit Erreichen eines kompletten Wundschlusses und Normalisierung des thermographischen Bildes bei zuvor therapierefraktären chronischen venösen Unterschenkelulzera). Nach großen abdominalen Operationen zeigte sich ein Trend zugunsten der wIRA-Gruppe hin zu einer niedrigeren Rate von Wundinfektionen insgesamt (7% versus 15%) einschließlich später Infektionen nach der Entlassung aus dem Krankenhaus (0% versus 8%) und ein Trend hin zu einem kürzeren postoperativen Krankenhausaufenthalt (9 versus 11 Tage).
Selbst der normale Wundheilungsprozess kann verbessert werden.
Die erwähnten Effekte wurden in 6 prospektiven Studien belegt, die meisten mit einem Evidenzgrad von Ia/Ib.
wIRA stellt eine wertvolle Therapieoption dar und kann generell für die Therapie von akuten und chronischen Wunden empfohlen werden.
Ultrafast protein dynamics are of great interest for understanding the molecular basis of biochemical function. One method to study structural changes with highest time-resolution starting in the femtosecond regime is 2D-IR spectroscopy. However its application to investigate protein dynamics both with high temporal and spatial resolution is currently limited to few biological systems with intrinsic chromophores. Spectral congestion, the contribution of many similar oscillators to the same signals, makes it difficult to draw conclusions about local structural dynamics in most other proteins.
The aim of this thesis is to extend the application of 2D-IR spectroscopy to a wider range of proteins by introducing unnatural amino acids (UAAs) with azide or nitrile groups as site-specific vibrational probes, which absorb in the free spectral window between 1800 to 3000 cm-1 by using methods from chemical biology.
In a comparative experimental study using FTIR and 2D-IR spectroscopy of single amino acids azidohomoalanine (Aha), a methionine analogue, was identified as preferred label. To demonstrate the application potential of UAAs as site-specific probes, Aha was then incorporated into different positions in a small globular protein. By using both FTIR and ultrafast 2D-IR it was shown, that indeed the local microenvironment as well as conformational fluctuations on picosecond timescale could be monitored with high spatial information. The azide moiety shows a shift of its absorption frequency depending on the polarity of its surrounding. Using this approach, different subensembles for the protein conformations with more polar and less polar environment around the vibrational probe can be distinguished.
A second major application of site-specific labels is the study of vibrational energy transfer processes (VET), predicted to be relevant for allosteric communication in protein domains such as the PDZ domain. VET can be tracked with high spatial resolution using time-resolved IR spectroscopy by exciting a localized vibrational mode and probing separate modes in a two-colour 2D-IR experiment. To extend this kind of experiment to proteins, a specific donor-acceptor pair of two UAAs was introduced. It uses an azulene moiety as donor that can be excited in the visible range but deposits the excess energy by internal conversion into the vibrational modes of the ground state. In small peptides this VET pair was applied successfully, showing a distance-dependent energy transfer induced signal for VET through covalent bonds. These findings bare great promise for the direct observation of vibrational energy flow in proteins in real-time.
Overall this thesis is the basis for extending the usability of 2D-IR spectroscopy to study structural dynamics in a wide range of proteins systems both with high temporal and spatial resolution.
The efficacy of cisplatin-based chemotherapy in cancer is limited by the occurrence of innate and acquired drug resistance. In order to better understand the mechanisms underlying acquired cisplatin resistance, we have compared the adenocarcinoma-derived non-small cell lung cancer (NSCLC) cell line A549 and its cisplatin-resistant sub-line A549rCDDP2000 with regard to cisplatin resistance mechanisms including cellular platinum accumulation, DNA-adduct formation, cell cycle alterations, apoptosis induction and activation of key players of DNA damage response. In A549rCDDP2000 cells, a cisplatin-induced G2/M cell cycle arrest was lacking and apoptosis was reduced compared to A549 cells, although equitoxic cisplatin concentrations resulted in comparable platinum-DNA adduct levels. These differences were accompanied by changes in the expression of proteins involved in DNA damage response. In A549 cells, cisplatin exposure led to a significantly higher expression of genes coding for proteins mediating G2/M arrest and apoptosis (mouse double minute 2 homolog (MDM2), xeroderma pigmentosum complementation group C (XPC), stress inducible protein (SIP) and p21) compared to resistant cells. This was underlined by significantly higher protein levels of phosphorylated Ataxia telangiectasia mutated (pAtm) and p53 in A549 cells compared to their respective untreated control. The results were compiled in a preliminary model of resistance-associated signaling alterations. In conclusion, these findings suggest that acquired resistance of NSCLC cells against cisplatin is the consequence of altered signaling leading to reduced G2/M cell cycle arrest and apoptosis.
Na+/H+ exchange is essential for survival of all organisms, having a role in the regulation of the intracellular Na+ concentration, pH and cell volume. Furthermore, Na+/H+ exchangers were shown to be involved in the virulence of the bacterium Yersinia pestis, indicating they might be potential targets for novel antibiotic treatments. The model system for Na+/H+ exchangers is the NhaA transporter from Escherichia coli, EcNhaA. Therefore, the general transport mechanism of NhaA exchangers is currently well characterized. However, much less is known about NhaB exchangers, with only a limited number of studies available. The pathogen Klebsiella pneumoniae, which is a major source of nosocomial infection, possesses three electrogenic Na+/H+ exchangers, KpNhaA1, KpNhaA2 and KpNhaB, none of which have been previously investigated. Our aim in this study was to functionally characterize KpNhaB using solid supported membrane-based electrophysiology as the main investigation technique, and thus provide the first electrophysiological investigation of an NhaB Na+/H+ exchanger. We found that NhaB can be described by the same competition-based mechanism that was shown to be valid for electrogenic NhaA and NapA, and for electroneutral NhaP Na+/H+ exchangers. For comparison we also characterized the activity of KpNhaA1 and KpNhaA2 and found that the three exchangers have complementary activity profiles, which is likely a survival advantage for K. pneumoniae when faced with environments of different salinity and pH. This underlines their importance as potential antibiotic drug targets.
Nach dem zweiten Weltkrieg war das Stadtzentrum Frankfurt am Main fast vollkommen zerstört worden. In den Nachkriegsjahren war nun fraglich, wie die Stadt von den Trümmermassen befreit werden sollte. Der Straßenraum musste von Schutt geräumt werden, Krankenhäuser und Versorgungseinrichtungen mussten wiederhergestellt werden und es musste neuer Wohnraum geschaffen werden. Es herrschte großer Baumaterialmangel, dass damals als großes Problem galt. Über eine Wiederverwertung des Trümmerschutts und die Verarbeitung zu neuen Baustoffen machte sich der damals amtierende Bürgermeister Kurt Blaum im Sommer 1945 die ersten Gedanken. Am 18. Oktober 1945 beschloss man in einer geheimen Sitzung die Gründung der Trümmerverwertungsgesellschaft. Die Aufgaben der Trümmerverwertungsgesellschaft wurde klar festgehalten: 1) Abbruch von Gefahrenstellen, Leitung der Trümmergewinnung und Transport zur Verwertungsanlage 2) Forschung zur Verwertung von Trümmerschutt 3) Errichtung und Betrieb der Aufbereitungsanlage sowie das Betonwerks.
Auf einem 10 Hektar großen Baugelände im Frankfurter Riederwald wurde die Trümmerverwertungsanlage gebaut. Zunächst wurde eine provisorische Aufbereitungsanlage gebaut, die 1947 in Betrieb war. Nach der Fertigstellung der Aufbereitungs- und Sinteranlage sowie das Betonwerk im Jahr 1950, wurde die provisorische Anlage zurückgebaut.
Die Philipp Holzmann AG war einer ihrer Gründer und trug ihren Teil zum Wiederaufbau der Stadt bei.
In this doctoral thesis the transformation from relativistic hydrodynamics to transport and vice versa is studied. Approximations made by hybrid (hydrodynamics + transport) simulations of relativistic heavy ion collisions are discussed and their reliability is assessed at intermediate collision energies. A new method to simulate heavy ion collisions is suggested, based on the forced thermalization in high-density regions.
Im Rahmen einer Zusammenarbeit zwischen der Thüringer Landesanstalt für Umwelt und Geologie und der Goethe-Universität Frankfurt fand in Kooperation mit dem Deutschen Wetterdienst (DWD) eine umfassende Studie zum konvektiven Unwetterpotential über Thüringen statt. Unwetterereignisse, die durch konvektive Prozesse in der Atmosphäre verursacht werden, besitzen ein nicht unerhebliches Schadenspotential, obwohl sie oftmals eine räumlich eng begrenzte Ausdehnung aufweisen. Aufgrund ihrer Charakteristik ist sowohl die Vorhersage solcher Ereignisse, als auch eine vollständige, systematische Erfassung für eine detaillierte Auswertung längerer Zeitreihen noch immer eine Herausforderung. Zusätzliches Interesse besteht in der Abschätzung der durch den Klimawandel abhängigen Entwicklung des zukünftigen Gefährdungspotentials konvektiver Unwetter. Für eine gezielte Untersuchung des Themenkomplexes ist eine Vielzahl unterschiedlicher Daten und Methoden verwendet worden. Mit Hilfe von Fernerkundungsdatensätzen wird ein räumlich differenziertes Gefährdungspotential über Thüringen nachgewiesen. Bedingt durch das Relief ist das Auftreten von Konvektion am häufigsten und intensivsten über dem südlichen Thüringer Wald und dessen Ostrand zu beobachten, während Nordthüringen eine deutlich geringere Aktivität solcher Unwetterereignisse aufweist. Eine Abschätzung mittels globaler Klimamodelle und daraus abgeleiteten Wetterlagen zeigt unter Berücksichtigung des RCP8.5 Klimaszenarios für die nahe Zukunft (2016-2045) eine Zunahme des Gefährdungspotentials durch konvektive Unwetter. Aufgrund des Anstiegs feuchter Wetterlagen (49 % auf 82 %) erhöht sich die Zunahme der Gefährdung für den Zeitraum 2071-2100 noch deutlicher. Im Vergleich zu diesem statistischen Ansatz nimmt die projizierte Gefährdung durch extreme Ereignisse erheblich zu (Faktor 6), wenn die Ergebnisse expliziter Simulationen konvektiver Ereignisse mit einem regionalen Klimamodell (mit horizontaler Gitterdistanz von 1 km) und eine Zunahme der Tage mit konvektiven Extremereignissen berücksichtigt werden. Ein Anstieg der Gefährdung durch konvektive Unwetter in der Zukunft ist wahrscheinlich. Eine Quantifizierung bleibt jedoch unsicher.
Transforming the current rather centralized electricity generating system into a climate neutral system based on renewable energy is an important approach to reduce greenhouse gas emissions and thus mitigate climate change. Stakeholders have each of them their own perception of the best strategies to achieve such a transformation. All perspectives are equally legitimate and needed for developing a specific transformation strategy suited for the region in focus....
National Model United Nations New York 2015 : Delegation der Goethe-Universität Frankfurt am Main
(2015)
Seit ihrer Gründung im Jahr 1945 sind die Vereinten Nationen zur bedeutendsten und einflussreichsten internationalen Organisation geworden. Als völkerrechtlicher Zusammenschluss verschiedenster Staaten haben die Vereinten Nationen eine generelle Zuständigkeit in Fragen von Frieden, Sicherheit und internationalem Zusammenleben. Unter den sechs Hauptorganen der Vereinten Nationen sind besonders der Sicherheitsrat und die Generalversammlung hervorzuheben. Letztere ist mit Vertretern aus allen 193 Mitgliedsstaaten die weltweit größte, regelmäßige Zusammenkunft von offiziellen Staatsvertretern. ...
National Model United Nations New York 2014 : Delegation der Goethe-Universität Frankfurt am Main
(2014)
Seit ihrer Gründung im Jahr 1945 sind die Vereinten Nationen auf internationaler Ebene zu einer Schlüsselorganisation geworden, der hohe Problemlösungskompetenzen zugeschrieben werden. Mittlerweile arbeiten 193 Mitgliedsstaaten gemeinsam an dem ehrgeizigen Ziel, den Weltfrieden und die internationale Sicherheit zu wahren. Der in der Charta der Vereinten Nationen verankerte Grundsatz des Verzichts auf Gewaltanwendung und der friedlichen Beilegung aller Streitigkeiten, macht sie zu einer weltweit einzigartigen Organisation. ...
Despite various policy and management responses, biodiversity continues to decline worldwide. We must redouble our efforts to halt biodiversity loss. The current lack of policy action can be partly linked to an insufficient knowledge base regarding the conservation and sustainable use of biodiversity. Biodiversity research needs to incorporate both social and ecological factors to gain a deeper understanding of the interrelations between society and nature that affect biodiversity. A transdisciplinary research approach is crucial to fulfilling these requirements. It aims to produce new insights by integrating scientific and nonscientific knowledge. Several measures need to be taken to strengthen transdisciplinary social-ecological biodiversity research: Within the science community: firstly, scientists themselves must promote transdisciplinarity; secondly, the reward system for scientists must be brought into line with transdisciplinary research processes; and thirdly, academic training needs to advocate transdisciplinarity. As for research policies, research funding priorities need to be linked to large scale biodiversity policy frameworks, and funding for transdisciplinary social-ecological research on biodiversity must be increased significantly.
CGC aktuell 01/2017
(2017)
Multicellular organisms require that cells adhere to each other. This cell-cell adhesion is indispensable for the formation and the integrity of epithelial structures, tissues and organs. Mammals have developed four different cell-cell adhesion structures, the adhering junctions, which ensure the tight contact between cells but are also important platforms for communication and exchange in tissues. Two of these adhering junctions are cadherin based, the belt-like adherens junctions and the spot-like desmosomes. Both structures have in common that they are composed of single membrane spanning proteins, the cadherins, which accomplish adhesion in a calcium-dependent manner. The intracellular parts of classical as well as desmosomal cadherins bind to different adaptor proteins of the armadillo-protein family and others which build a protein plaque underneath the membrane and link the cadherins to the actin or intermediate filament cytoskeleton.
Desmosomes are of special importance for tissues that have to withstand mechanical stress. Although they are essential to stabilize tissues they have to be highly flexible and dynamic structures, as processes like wound healing or tissue remodeling require that adhesive interactions can be modulated. The molecular dynamics within desmosomes are not jet understood in detail, but it is assumed that two different membrane associated pools of desmosomal cadherins exist in cells. Cadherins that are incorporated in mature desmosomes are part of the junctional pool, whereas cadherins that are not associated with firm desmosomes and the intermediate filament cytoskeleton belong to the non-junctional pool. Lateral movements between the two pools results in a dynamic equilibrium and allows for example the exchange of old cadherins. Little is known about the breakdown of desmosomal cadherins. Several studies found that desmosome assembly or endocytosis are cholesterol dependent processes and claimed that membrane microdomains play a role in the regulation of desmosome dynamics. Moreover, membrane rafts may be involved in the pathomechanism of the desmosome associated disease pemphigus, were autoantibodies bind to the cadherin desmoglein-3 and trigger its internalization which results in a loss of adhesion in skin cells.
Membrane rafts are cholesterol dependent nanoscale structures of cellular membranes that are able to regulate the distribution of proteins within the plasma membrane and thus form platforms for cell signaling and membrane trafficking. Flotillins are proteins that are associated with membrane rafts and are reported to be involved in processes like endocytosis, endosomal sorting and a multitude of different signaling events. We could recently show that the membrane raft associated proteins flotillin-1 and flotillin-2 bind directly to the armadillo protein y-catenin which can be part of both, the adherens junction and the desmosome. The aim of this study was to eluciadate a possible role of flotillins in the regulation of desmosomes.
HaCaT keratinocytes were chosen as the main cell system for this study and at first the association of desmosomal components with flotillins was analyzed in detail. It was found that flotillins are clearly associated with desmosomal proteins. They colocalize with desmoglein-3 at cell borders and precipitate the other desmogleins. Further binding assays revealed that both flotillins bind to all desmogleins and the long isoforms of the second class of desmosomal cadherins, the desmocollins. The interaction is a direct one and was mapped to the ICS sequence within the cadherins. This close association rendered the question whether flotillins are functionally implicated in desmosome regulation. To address this issue, stable flotillin knockdown HaCaT cells were analyzed in detail. The molecular morphology of desmoglein-3, desmoglein-1 and two plaque proteins was clearly altered in the absence of flotillins. The membrane staining of all tested desmosomal proteins was derailed and disordered. Furthermoore, the loss of flotillins had an impact on the adhesive capacity of HaCaT keratinocytes. The cell-cell adhesion was weakened in the absence of flotillins, which was monitored by an increased fragmentation of knockdown cells in a cell dissociation assay.
In order to find out the mechanism by which flotillins influence the membrane morphology and the adhesiveness in keratinocytes, the association of desmosomal proteins with membrane microdomains was examined, at first. A predominant part of desmoglein-3 is associated with membrane rafts in HaCaT keratinocytes, whereas only a minor part of desmoglein-1 is found there. However, the raft-association of none of the examined proteins was altered in the absence of flotillins. Furthermore, flotillin depletion did not change the distribution of desmogleins with the two different cadherin pools. Less desmoglein-3 is found in the junctional pool of the flotillin depleted cells compared to the control cells, but this is due to an overall diminished desmoglein-3 protein level in these cells.
Flotillins are involved in endocytic processes but their exact role there is under debate. The endocytic uptake of desmosomal cadherins requires intact membrane rafts, but the precise mechanism is still unknown. A possible involvement of flotillins on the endocytosis of desmoglein-3 was addressed next. It is known that the internalization of desmoglein-2 is dependent on the GTPase dynamin, arguing for an involvement of dynamin in the endocytosis of desmoglein-3 as well. When dynamin and thus desmoglein-3 endocytosis was inhibited using chemical compounds, the mislocalization of desmoglein-3 that was observed in flotillin knockdown cells was restored. This suggest that inhibition of desmoglein-3 endocytosis enhances the amount and/or availability of desmoglein-3 at the plasma membrane, which then normalizes the morphological alterations caused by a knockdown of flotillins. Furthermore the morphological alterations in the flotillin knockdown HaCaT cells were found to be similar to the localization of desmoglein-3 that was observed upon treatment of keratinocytes with PV IgG These structures have been described before as linear arrays and are assumed to be sites of endocytic uptake. This strengthens the idea that enhanced desmoglein-3 internalization takes place in the absence of flotillins, which then results in a weakened adhesion.
Altogether this study revealed flotillins as novel players in desmosome mediated cell-cell adhesion processes. By binding to desmosomal cadherins and desmosomal plaque proteins, flotillins stabilize desmosomes at the plasma membrane and are required for a proper cell-cell adhesion.
Psoriasis is a frequent and often severe inflammatory skin disease, characterized by altered epidermal homeostasis. Since we found previously that Akt/mTOR signaling is hyperactivated in psoriatic skin, we aimed at elucidating the role of aberrant mTORC1 signaling in this disease. We found that under healthy conditions mTOR signaling was shut off when keratinocytes switch from proliferation to terminal differentiation. Inflammatory cytokines (IL-1β, IL-17A, TNF-α) induced aberrant mTOR activity which led to enhanced proliferation and reduced expression of differentiation markers. Conversely, regular differentiation could be restored if mTORC1 signaling was blocked. In mice, activation of mTOR through the agonist MHY1485 also led to aberrant epidermal organization and involucrin distribution. In summary, these results not only identify mTORC1 as an important signal integrator pivotal for the cells fate to either proliferate or differentiate, but emphasize the role of inflammation-dependent mTOR activation as a psoriatic pathomechanism.
Two theories address the origin of repeating patterns, such as hair follicles, limb digits, and intestinal villi, during development. The Turing reaction–diffusion system posits that interacting diffusible signals produced by static cells first define a prepattern that then induces cell rearrangements to produce an anatomical structure. The second theory, that of mesenchymal self-organisation, proposes that mobile cells can form periodic patterns of cell aggregates directly, without reference to any prepattern. Early hair follicle development is characterised by the rapid appearance of periodic arrangements of altered gene expression in the epidermis and prominent clustering of the adjacent dermal mesenchymal cells. We assess the contributions and interplay between reaction–diffusion and mesenchymal self-organisation processes in hair follicle patterning, identifying a network of fibroblast growth factor (FGF), wingless-related integration site (WNT), and bone morphogenetic protein (BMP) signalling interactions capable of spontaneously producing a periodic pattern. Using time-lapse imaging, we find that mesenchymal cell condensation at hair follicles is locally directed by an epidermal prepattern. However, imposing this prepattern’s condition of high FGF and low BMP activity across the entire skin reveals a latent dermal capacity to undergo spatially patterned self-organisation in the absence of epithelial direction. This mesenchymal self-organisation relies on restricted transforming growth factor (TGF) β signalling, which serves to drive chemotactic mesenchymal patterning when reaction–diffusion patterning is suppressed, but, in normal conditions, facilitates cell movement to locally prepatterned sources of FGF. This work illustrates a hierarchy of periodic patterning modes operating in organogenesis.
Pertusarialean lichens include more than 300 species belonging to several independent phylogenetic lineages. Only some of these phylogenetic clades have been comprehensively sampled for molecular data, and formally described as genera. Here we present a taxonomic treatment of a group of pertusarialean lichens formerly known as "Pertusaria amara-group", "Monomurata-group", or "Variolaria-group", which includes widespread and well-known taxa such as P. amara, P. albescens, or P. ophthalmiza. We generated a 6-locus data set with 79 OTUs representing 75 species. The distinction of the Variolaria clade is supported and consequently, the resurrection of the genus Lepra is followed. Thirty-five new combinations into Lepra are proposed and the new species Lepra austropacifica is described from mangroves in the South Pacific. Lepra is circumscribed to include species with disciform ascomata, a weakly to non-amyloid hymenial gel, strongly amyloid asci without clear apical amyloid structures, containing 1 or 2, single-layered, thin-walled ascospores. Chlorinated xanthones are not present, but thamnolic and picrolichenic acids occur frequently, as well as orcinol depsides. Seventy-one species are accepted in the genus. Although the distinction of the genus from Pertusaria is strongly supported, the relationships of Lepra remain unresolved and the genus is tentatively placed in Pertusariales incertae sedis.
Tagungsbericht: Unter dem Titel 'National - postnational - transnational? Neuere Perspektiven auf die deutschsprachige Gegenwartsliteratur aus Mittel- und Osteuropa' fand vom 10. bis 13. Mai 2012 in Ústí nad Labem eine internationale Tagung statt, die von Renata Cornejo vom Lehrstuhl für Germanistik an der dortigen Jan Evangelista Purkynĕ-Universität in Zusammenarbeit mit Sławomir Piontek von der Adam Mickiewicz-Universität in Poznań (Polen) und Sandra Vlasta von der Universität Wien (Österreich) veranstaltet wurde. In zahlreichen Vorträgen wurde das Werk von AutorInnen, die aus unterschiedlichen Gründen zu verschiedenen Zeitpunkten in ihrem Leben in den deutschsprachigen Raum eingewandert sind und die Deutsch, obwohl nicht ihre Erstsprache, als ihre Literatursprache gewählt haben, untersucht. Der Schwerpunkt lag dabei auf AutorInnen aus Mittel- und Osteuropa, die zur Entwicklung der deutschsprachigen Gegenwartsliteratur der letzten Jahrzehnte mit wichtigen Impulsen beigetragen haben.
We have reported previously that Short Interspersed Degenerate Retroposons of the SIDER2 subfamily, largely located within 3'UTRs of Leishmania transcripts, promote rapid turnover of mRNAs through endonucleolytic cleavage within the highly conserved second tandem 79-nt hallmark sequence (79-nt SII). Here, we used site-directed mutagenesis and in silico RNA structural studies to delineate the cis-acting requirements within 79-nt SII for cleavage and mRNA degradation. The putative cleavage site(s) and other nucleotides predicted to alter the RNA secondary structure of 79-nt SII were either deleted or mutated and their effect on mRNA turnover was monitored using a gene reporter system. We found that short deletions of 8-nt spanning the two predicted cleavage sites block degradation of SIDER2-containing transcripts, leading to mRNA accumulation. Furthermore, single or double substitutions of the dinucleotides targeted for cleavage as well as mutations altering the predicted RNA secondary structure encompassing both cleavage sites also prevent mRNA degradation, confirming that these dinucleotides are the bona fide cleavage sites. In line with these results, we show that stage-regulated SIDER2 inactivation correlates with the absence of endonucleolytic cleavage. Overall, these data demonstrate that both cleavage sites within the conserved 79-nt SII as well as RNA folding in this region are essential for SIDER2-mediated mRNA decay, and further support that SIDER2-harboring transcripts are targeted for degradation by endonucleolytic cleavage.
Zwischen "öffentlicher" und "kommerzieller" Kultur besteht ein Spannungsverhältnis. Durchzieht diese Feststellung fast alle Arbeiten, die sich mit öffentlicher Kulturpolitik befassen, so gilt sie für Frankfurt doch in ganz besonderem Maße: Die Stadt verkörpert zugleich eine richtungsweisende Kulturpolitik, von der Impulse für die gesamte Bundesrepublik ausgingen wie auch eine von den wirtschaftlichen Interessen des Finanzsektors dominierte Kommunalpolitik. In "Kultur für alle", einem Buch, dessen Autor Hilmar Hoffman nicht nur viele Jahre lang Kulturdezernent der Stadt war, sondern das sich auch maßgeblich aus den Erfahrungen dieser Zeit speist, ist beispielsweise von einer "im Kern antagonistischen Beziehung" die Rede. Kultur und Arbeit stünden in einem "krassen Mißverhältnis" und als "noch weitgehend vorbelastet muß auch das gestörte Verhältnis der öffentlichen Kulturarbeit zur Kulturindustrie gelten, obschon die Überschneidungsflächen erheblich an Terrain gewonnen haben, zum Beispiel im Bereich von Film und Kino oder in den Großveranstaltungen mit populärer Musik nach dem Motto 'Umsonst und open air'" (Hoffmann 1981: 22). ...
Dendrites form predominantly binary trees that are exquisitely embedded in the networks of the brain. While neuronal computation is known to depend on the morphology of dendrites, their underlying topological blueprint remains unknown. Here, we used a centripetal branch ordering scheme originally developed to describe river networks—the Horton-Strahler order (SO)–to examine hierarchical relationships of branching statistics in reconstructed and model dendritic trees. We report on a number of universal topological relationships with SO that are true for all binary trees and distinguish those from SO-sorted metric measures that appear to be cell type-specific. The latter are therefore potential new candidates for categorising dendritic tree structures. Interestingly, we find a faithful correlation of branch diameters with centripetal branch orders, indicating a possible functional importance of SO for dendritic morphology and growth. Also, simulated local voltage responses to synaptic inputs are strongly correlated with SO. In summary, our study identifies important SO-dependent measures in dendritic morphology that are relevant for neural function while at the same time it describes other relationships that are universal for all dendrites.
In light of the global sea-level rise and climate change of the 21th century, it is important to look back into the recent past in order to understand what the future might hold. A multi-proxy data set was compiled to evaluate the influence of geomorphological and environmental factors, such as antecedent topography, subsidence, sea level and climate, on reef, sand apron and lagoon development in modern carbonate platforms through the Holocene. Therefore, a combination of remote sensing and morphological data from 122 modern carbonate platforms and atolls in the Atlantic, Indian and Pacific Oceans were conducted, along with a case study from the oceanic (Darwinian) barrier-reef system of Bora Bora, French Polynesia, South Pacific.
The influence of antecedent topography and platform size as factors controlling Holocene sand apron development and extension in modern atolls and carbonate platforms is hypothesized. Antecedent topography describes the elevation and relief of the underlying Pleistocene topography (karst) and determines the distance from the sea floor to the rising postglacial sea level. Maximum lagoon depth and marginal reef thickness, when available in literature, were used as proxies for antecedent topography. Sand apron proportions of 122 atolls and carbonate platforms from the Atlantic, Indian and Pacific Oceans were quantified and correlated to maximum lagoon depth, total platform area and marginal reef thickness. This study shows that sand apron proportions increase with decreasing lagoon depths. Sand apron proportions also increase with decreasing platform area. The interaction of antecedent topography and Holocene sea-level rise is responsible for variations in accommodation space and at least determines the extension of the lateral expansion of sand aprons. In general, sand apron formation started when marginal reefs approached relative sea level. Spatial and regional variations in sea-level history let sand apron formation start earlier in the Indo-Pacific region (transgressive-regressive) than in the Western Atlantic Ocean (transgressive).
The influence of sea level, antecedent topography and subsidence of a volcanic island on late Quaternary reef development was evaluated based on six rotary core transects on the barrier and fringing reefs of Bora Bora. This study was designed to revalue the Darwinian model, the subsidence theory of reef development, which genetically connects fringing reef, barrier reef and atoll development by continuous subsidence of the volcanic basement. Postglacial sea-level rise, and to a minor degree subsidence, were identified as major factors controlling Holocene reef development in that they have created accommodation space and controlled reef architecture. Antecedent topography was also an important factor because the Holocene barrier reef is located on a Pleistocene barrier reef forming a topographic high. Pleistocene soil and basalt formed the pedestal of the fringing reef. Uranium-Thorium dating shows that barrier and fringing reefs developed contemporaneously during the Holocene.
In the barrier–reef lagoon of Bora Bora, the influence of environmental factors, such as sea level and climate, tsunamis and tropical cyclones controlling Holocene sediment dynamics was evaluated based on sedimentological, paleontological, geochronological and geochemical data. The lagoonal succession comprises mixed carbonate-siliciclastic sediments overlying peat and Pleistocene soil. The multi-proxy data set shows variations in grain-size, total organic carbon (proxy for primary productivity), Ca and Cl element intensities (proxies for carbonate availability and lagoonal salinity) during the mid-late Holocene. These patterns could result from event sedimentation during storms and correlate to event deposits found in nearby Tahaa, probably induced by elevated cyclone activity. Accordingly, elevated erosion and runoff from the volcanic island and lower lagoonal salinity would be a result of rainfall during repeated cyclone landfall. However, Ti/Ca and Fe/Ca ratios as proxies for terrigenous sediment delivery peaked out in the early Holocene and declined since the mid-Holocene. Benthic foraminifera assemblages do not indicate reef-to-lagoon transport. Alternatively, higher and sustained hydrodynamic energy is probably induced by stronger trade winds and a higher-than-present sea level during the mid-late Holocene. The increase in mid-late Holocene sediment dynamics within the back-reef lagoon is supposed to display sediment-load shedding of sand aprons due to the oversteepening of slopes at sand apron/lagoon edges during their progradation rather than an increase in tropical storm activity during that time.
The influence of sea-level and climate changes on sediment import, composition and distribution in the Bora Bora lagoon during the Holocene is validated. Lagoonal facies succession comprises siderite-rich marly wackestones, foraminifera-siderite wackestones, mollusk-foraminifera marly packstones and mollusk-rich wackestones during the early-mid Holocene, and mudstones since the mid-late Holocene. During the early Holocene, enhanced weathering and iron input from the volcanic island due to wetter climate conditions led to the formation of siderite within the lagoonal sediments. The geochemical composition of these siderites shows that precipitation was driven by microbial activity and iron reduction in the presence of dissolved bicarbonate. Chemical substitutions at grain margins illustrate changes in the oxidation state and probably reflect changes in pore water chemistry due to sea-level rise and climate change (rainfall). In the late Holocene, sediment transport into the lagoon is hampered by motus on the windward side of the lagoon, which led to early submarine lithification within the lagoon.
Gepulste dipolare EPR-Spektroskopie ist eine wertvolle Methode, um Abstände von 1.5 bis 10 nm zwischen zwei Spinmarkern zu messen. Diese Information kann für Strukturbestimmungen hilfreich sein, wo traditionelle Methoden wie Kristallstrukturanalyse und NMR nicht angewendet werden können. Zusätzlich ist es möglich, Änderungen in Konformation und Flexibilität zu verfolgen. Für diese Studien haben sich stabile Nitroxidradikale als Spinmarker etabliert. Diese werden spezifisch durch die site-directed spin labelling Methode (SDSL) kovalent an das zu untersuchende Biomolekül gebunden. In den letzten Jahren wurden weitere Spinmarker für Abstandsbestimmungen mittels EPR-Spektroskopie entwickelt. Besonders interessant sind Triarylmethylradikale (im Folgenden abgekürzt als Trityl) und paramagnetische Metallzentren.
Im Vergleich zu Nitroxidradikalen hat das Tritylradikal einige Vorteile: Eine höhere Stabilität in einer reduzierenden Umgebung wie im Inneren von Zellen, längere Elektronenspin-Relaxationszeiten bei Raumtemperatur und ein schmaleres EPR-Spektrum. Deswegen ist dieses organische Radikal ein alternativer Spinmarker, der besonders gut für die Forschung von Biomolekülen in einer nativen Umgebung unter physiologischen Bedingungen geeignet ist. Auch paramagnetische Metallzentren sind weniger reduktionsempfindlich als Nitroxidradikale. Zusätzlich sind diese Spinmarker interessant in biologischen Fragestellungen. Zum Beispiel besitzen zahlreiche Enzyme paramagnetische Manganzentren als Cofaktoren. Zudem kann Magnesium, ein wesentlicher Cofaktor in Enzymen, Nukleinsäuren und Nukleotid-Bindungsdomänen der G- und Membranproteine, oft durch das paramagnetische Mangan ersetzt werden. Um Abstandsmessungen an Biomolekülen, die nur ein Metallzentrum besitzen, durchzuführen, können zusätzliche Spinmarker in Form eines Nitroxid-, Tritylradikals oder eines anderen paramagnetischen Metallkomplexes mithilfe der SDSL-Methode kovalent gebunden werden.
Nitroxidradikale, Tritylradikale und Metallzentren haben deutlich unterschiedliche EPR-spektroskopische Eigenschaften, welche oft als orthogonale Spinmarker bezeichnet werden. Solche Spinmarker sind nützlich für die Untersuchung von verschiedenen Untereinheiten bei makromolekularen Komplexen. Somit können die intramolekularen Abstände innerhalb einer Untereinheit sowie intermolekularen Abstände zwischen den unterschiedlichen Untereinheiten mit nur einer einzigen Probe bestimmt werden. Zusätzlich können die orthogonalen Marker sehr effektiv genutzt werden, um Metallzentren in Biomolekülen mithilfe der Trilateration-Strategie genau zu lokalisieren.
Die hier vorliegende Doktorarbeit beschäftigt sich mit der Nutzung dieser neuen Spinmarker für Abstandsmessungen. Solche Spinmarker sind noch kaum erforscht, obwohl sie für biologische Anwendungen eine große Rolle spielen könnten.
Das erste Ziel dieser Doktorarbeit war eine Studie über Tritylradikale mithilfe der dipolaren EPR-Spektroskopie. Zu diesem Zweck wurden sowohl double quantum coherence (DQC) und single frequency technique for refocussing dipolar couplings (SIFTER) Experimente als auch Hochfrequenz pulsed electron electron double resonance (PELDOR) Experimente mit einem Trityl-Modellsystem durchgeführt. Dabei wurden die Besonderheiten der unterschiedlichen dipolaren Spektroskopiemethoden mit diesem Spinmarker untersucht, um die Empfindlichkeit und Robustheit für die Abstandsmessungen zu optimieren.
Das zweite Ziel war eine Studie über den Einfluss der Hochspin-Multiplizität des Mangans auf die Abstandsbestimmungen. Für diesen Zweck wurde zuerst ein Modellsystem mit einem orthogonalen Mn2+ Ion und Nitroxidradikal mithilfe der PELDOR-Spektroskopie untersucht. Anschließend wurde ein weiteres Modellsystem mit zwei Mn2+-Ionen untersucht, um PELDOR und relaxation-induced dipolar modulation enhancement (RIDME) Experimente bezüglich ihrer Empfindlichkeit und Robustheit sowie Genauigkeit der Datenanalyse zu optimieren.
Das Trityl-Modellsystem wurde in der Arbeitsgruppe von Prof. Sigurdsson synthetisiert. Die EPR Messungen wurden bei zwei verschiedenen Mikrowellenfrequenzen (34 und 180 GHz) durchgeführt. Es wurde gezeigt, dass die Auswahl der optimalen Methode von den EPR-spektroskopischen Eigenschaften des Systems bei den jeweiligen Mikrowellenfrequenzen abhängig ist. Das EPR-Spektrum des Trityls ist bei 34 GHz so schmal, dass das ganze Spektrum von einem üblichen Mikrowellenpuls angeregt werden kann. In diesem Fall sind die DQC und SIFTER Experimente am besten geeignet. Der mit diesen Methoden bestimmte Abstand von 4.9 nm ist in guter Übereinstimmung mit Werten aus der Literatur. Es wurde festgestellt, dass die SIFTER Messung eine höhere Empfindlichkeit als DQC besitzt, da das Signal-zu-Rausch Verhältnis um den Faktor vier größer ist. Außerdem ist die SIFTER-Methode experimentell weniger anspruchsvoll, da ein deutlich kürzerer Phasenzyklus für die Mikrowellenpulse benötigt wird. ...
In the dentate gyrus (DG) of the mammalian hippocampus, neurogenesis continues to take place throughout an organism’s life. Adult neurogenesis includes proliferation and differentiation of neural stem cells into dentate granule cells (GCs) that mature and integrate into the existing cellular network. This thesis work presents a novel approach that enables longitudinal examination of living postnatally generated GCs in their endogenous niche by using retroviral (RV) labeling in organotypic entorhino-hippocampal slice cultures (OTCs). Older GCs were fluorescence-labeled with an adeno-associated virus controlled by the synapsin 1 promoter (AAV-Syn). The combination of time-lapse imaging and 3-D reconstruction of newborn developing GCs and older, more mature GCs enabled comparative analyses of dendritic growth and cellular dynamics as well as investigations of spine formation and the establishment of synaptic contacts.
Postnatal neurogenesis was studied in the mouse and rat DG in vivo by analysis of the distribution of chemical neuronal maturation markers doublecortin (DCX) and calbindin in combination with the GC marker Prox1 between P7 and P42. The marker expression patterns at different time points indicated that the number of mature GCs increased gradually over time and that young, immature GCs were added to the inner layers of the granule cell layer (GCL), as is the case in the adult brain. The most substantial shift in GC maturation took place between P7 and P14, though GCs in the rat DG matured faster (i.e. by ~5 days) than GCs in the mouse. Immunocytochemical in vitro analysis in OTCs at DIV 7, 14, and 28 exhibited a distribution of marker expression over time that was comparable to in vivo, though the number of DCX-expressing GCs was low at DIV 28, indicating a considerable decrease in neurogenesis rate over time in the OTC. Nevertheless, RV-labeling of newborn GCs at DIV 0 yielded successful visualization and enabled time-lapse imaging of complete developing GCs up to 4 weeks after mitosis. During the second week of development, newborn GCs exhibited a high level of structural dynamics, including extension and retraction of dendritic segments. In the third week, newborn GCs displayed high dendritic complexity which was followed by pronounced dendritic pruning. Finally, a phase of structural stabilization and local refinement could be observed during the fourth week. Older AAV-Syn-labeled GCs did not exhibit such dynamic structural remodeling. Anterograde tracing of entorhinal projection fibers using the biotinylated dextran amine Mini Ruby showed innervation of the outer molecular layer (OML) by entorhinal axons at early time points, i.e. DIV 8 when newborn GCs started to extend dendrites into the ML, as well as at DIV 20 when RV-labeled GCs exhibited elaborate dendritic trees with processes in the OML intermingling with entorhinal fibers. This shows that newborn GCs in the OTC grow into an area of existing entorhinal axon terminals, which is highly similar to the situation in the adult brain. Hence, the results show that postnatal neurogenesis can be studied effectively in the OTC system as a model of adult neurogenesis. The first appearance of spine-like protrusions in newborn GCs was observed two weeks post RV injection. Ultrastructural electron-microscopic images revealed that spines established synaptic contacts with axonal boutons. These findings suggest that newborn GCs are successfully integrated into the existing cellular circuitry in the OTC system. The high level of structural flexibility found in this study might be a necessary requisite of new neurons for successful dendritic maturation and functional integration into a neuronal network. Thus, live imaging of postnatally born GCs in the OTC appears as a useful novel approach to elucidate the mechanisms that affect cellular dynamics of neurogenesis.