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Der vorliegende Beitrag konzentriert sich nicht auf die interessanten, etwas späteren Vorbilder einer italienischen 'hybriden' Rezeption des Gotischen bzw. Phantastischen, die gleichzeitig einer neuen Sensibilität bzw. Ästhetik den Weg ebnete und die das Interesse der Forschung schon erweckte, sondern er verfolgt das Ziel, die weniger erforschten Wurzeln des Genres in Italien zu ergründen. Diese sind unerwartet in 'Fermo e Lucia', d.h. in jener unvollkommenen ersten bzw. 'Ur'-Fassung von Manzonis Prosameisterstück 'I promessi sposi' zu finden.
1896, kurz nach dem Tod Paul Verlaines, veröffentlicht der tschechische Künstler Karel Hlaváček seinen Gedichtband 'Pozdě k ránu' ('Spät, gegen Morgen'). Hlaváček wirkt im Kreis Arnošt Procházkas und Jiři Karásek ze Lvovices, Begründer und Herausgeber der Literaturzeitschrift 'Moderní Revue', die mit ihrer dezidiert europäischen Ausrichtung ein Gegengewicht zum nationalistisch-patriotischen Literaturbetrieb in Prag um 1900 bildet. Durch seine Verbindungen zum eher national konservativ orientierten Sokol ist das Verhältnis zu Arnošt Procházka zeitweilig angespannt, wenngleich die Missstimmung weniger konträren politischen Überzeugungen der beiden Männer als den divergierenden Attitüden von 'Moderní Revue' und Sokol geschuldet ist. Seit der Gründung der Zeitschrift 1894 entwirft der junge Hlaváček mehrere Cover für die 'Revue' und ist vorrangig an der Illustration des Blattes beteiligt. Das Oeuvre des mit 23 Jahren früh an Tuberkulose verstorbenen Tschechen ist überschaubar: neben Literaturkritiken und kürzeren Essays und den genannten Gedichtbänden sind 'Mstíva kantiléna' ('Die Rache der Kantilene') und die posthum veröffentlichen 'Žalmy' ('Psalme') seine einzigen Werke. In 'Pozdě k ránu' findet sich das Prosagedicht 'Subtilnost smutku', das nicht nur in einzigartiger Weise eine Auseinandersetzung der in Westeuropa beliebten Topoi und Schreibverfahren der Décadence darstellt, sondern darüber hinaus als kritischer Kommentar zum intellektuellen Milieu im Prag des ausgehenden 19. Jahrhunderts betrachtet werden kann. Der Wahnsinn fungiert in diesem Text im gleichen Maße als komplexe Metapher wie als strukturierendes Leitmotiv und stellt einen Knotenpunkt der verschiedenen Disziplinen, in denen der Begriff "Décadence" im Fin de siècle ungeheure Popularität erlangt, dar. Wenn der Kritiker Herben mit seiner polemischen Kritik versucht, Hlaváček als geisteskrank zu diskreditieren, so verfehlt er seine Absicht dergestalt, dass er nicht nur die Antihaltung des Künstlers befeuert, sondern er identifiziert darüberhinaus das Element, welches sich als Schlüssel zur Dechiffrierung der Stellung von 'Subtilnost smutku' in einem europäischen Rahmen erweisen soll.
Im alltäglichen Gespräch lässt sich beobachten, dass bei vielen in der Bundesrepublik aufgewachsenen Personen die Kinderbücher Astrid Lindgrens einen hohen Stellenwert und einen starken Einfluss auf Lebensvorstellungen und Werte des zwischenmenschlichen Miteinanders haben. Wenn die eigene Lebenswelt - wie etwa bestimmte Situationen, Lebensumstände, zwischenmenschliche Beziehungen, die äußere Umwelt, das Lebensgefühl - als besonders beglückend, ja geradezu als ideal empfunden werden, ziehen viele Menschen Parallelen zu den in den Texten Astrid Lindgrens modellierten Lebenswelten. Umgekehrt wird auch versucht, die eigene Lebenswelt nach dem Muster dieser Textwelten zu gestalten, um das Leben so schön, harmonisch und beglückend zu gestalten, wie es die Figuren in den Texten vorleben. Da Texte, die einen solch prägenden Eindruck auf uns ausüben und einen so hohen Stellenwert für die eigenen Lebensvorstellungen und die Lebensgestaltung haben, in der Regel auch an die Nachkommen weitergegeben werden, werden die in den Büchern modellierten Lebensvorstellungen und Werte häufig über mehrere Generationen hinweg tradiert und erhalten einen wichtigen identitätsstabilisierenden Platz im kollektiven Gedächtnis. So können bestimmte Welt-, Lebens- und Wertkonstrukte innerhalb einer Gesellschaft über einen längeren Zeitraum Bestand haben und ein fester Teil des gesellschaftlichen Diskurses werden. Ausgehend von diesen Beobachtungen und Hypothesen scheint es lohnend zu sein, folgende Fragen zu stellen: 1. Lässt sich die eingangs formulierte Alltagsbeobachtung von der Wichtigkeit der Bücher Astrid Lindgrens für die Lebensvorstellungen vieler Deutscher auch durch eine umfassende Untersuchung, also durch konkretes Zahlenmaterial, bestätigen? Oder allgemeiner gefragt: Gibt es Bücher, in denen viele Menschen eine ideale Lebenswelt wiederfinden? 2. Falls es wirklich eines oder mehrere solcher Bücher gibt: Wie genau sieht eine solche ideale Lebenswelt für uns aus? Um diese Fragen zu beantworten, wende ich eine Untersuchungsmethode an, die aus drei Schritten besteht: erstens einer quantitativen Befragung zur Ermittlung eines Textkorpus; zweitens einer literaturwissenschaftlichen Analyse der so ermittelten Texte zur Untersuchung der Rezeptionsangebote dieser Texte; drittens Leitfadeninterviews, um herauszuarbeiten, welche der Textangebote tatsächlich von den Rezipienten aktualisiert werden.
Decreased STARD10 expression is associated with defective insulin secretion in humans and mice
(2017)
Genetic variants near ARAP1 (CENTD2) and STARD10 influence type 2 diabetes (T2D) risk. The risk alleles impair glucose-induced insulin secretion and, paradoxically but characteristically, are associated with decreased proinsulin:insulin ratios, indicating improved proinsulin conversion. Neither the identity of the causal variants nor the gene(s) through which risk is conferred have been firmly established. Whereas ARAP1 encodes a GTPase activating protein, STARD10 is a member of the steroidogenic acute regulatory protein (StAR)-related lipid transfer protein family. By integrating genetic fine-mapping and epigenomic annotation data and performing promoter-reporter and chromatin conformational capture (3C) studies in β cell lines, we localize the causal variant(s) at this locus to a 5 kb region that overlaps a stretch-enhancer active in islets. This region contains several highly correlated T2D-risk variants, including the rs140130268 indel. Expression QTL analysis of islet transcriptomes from three independent subject groups demonstrated that T2D-risk allele carriers displayed reduced levels of STARD10 mRNA, with no concomitant change in ARAP1 mRNA levels. Correspondingly, β-cell-selective deletion of StarD10 in mice led to impaired glucose-stimulated Ca2+ dynamics and insulin secretion and recapitulated the pattern of improved proinsulin processing observed at the human GWAS signal. Conversely, overexpression of StarD10 in the adult β cell improved glucose tolerance in high fat-fed animals. In contrast, manipulation of Arap1 in β cells had no impact on insulin secretion or proinsulin conversion in mice. This convergence of human and murine data provides compelling evidence that the T2D risk associated with variation at this locus is mediated through reduction in STARD10 expression in the β cell.
Objective: ACPAs are associated with bone destruction in RA. The aim of this study was to evaluate the association between ACPA and bone destruction in patients with a distinct inflammatory disorder, PsA.
Methods: We used baseline data from a large observational study of PsA patients preparing to initiate treatment with adalimumab to analyse demographic and disease characteristics by ACPA status. To ensure a homogeneous PsA study population, only patients with active psoriatic skin manifestations who met Classification of Psoriatic Arthritis criteria for PsA were included in the analyses, thereby minimizing the risk of including misdiagnosed RA patients. Multiple logistic regression analyses were used to explore potential associations between ACPA seropositivity and bone destruction.
Results: Of 1996 PsA patients who met the strict inclusion criteria, 105 (5.3%) were positive for ACPA. ACPA-positive patients had significantly higher swollen joint counts and 28-joint DAS values than ACPA-negative patients and significantly higher rates of erosive changes and dactylitis. Multiple logistic regression analysis confirmed the association of ACPA seropositivity with a 2.8-fold increase in the risk of erosive disease.
Conclusion: As has been previously shown for RA, ACPA is associated with bone destruction in PsA, suggesting that the osteocatabolic effect of ACPA is not confined to RA but is also detectable in the different pathogenetic context of a distinct disease entity.
Trial registration: ClinicalTrials.gov, NCT01111240.
Rationale: The AMP-activated protein kinase (AMPK) is stimulated by hypoxia, and although the AMPKα1 catalytic subunit has been implicated in angiogenesis, little is known about the role played by the AMPKα2 subunit in vascular repair.
Objective: To determine the role of the AMPKα2 subunit in vascular repair.
Methods and Results: Recovery of blood flow after femoral artery ligation was impaired (>80%) in AMPKα2-/- versus wild-type mice, a phenotype reproduced in mice lacking AMPKα2 in myeloid cells (AMPKα2ΔMC). Three days after ligation, neutrophil infiltration into ischemic limbs of AMPKα2ΔMC mice was lower than that in wild-type mice despite being higher after 24 hours. Neutrophil survival in ischemic tissue is required to attract monocytes that contribute to the angiogenic response. Indeed, apoptosis was increased in hypoxic neutrophils from AMPKα2ΔMC mice, fewer monocytes were recruited, and gene array analysis revealed attenuated expression of proangiogenic proteins in ischemic AMPKα2ΔMC hindlimbs. Many angiogenic growth factors are regulated by hypoxia-inducible factor, and hypoxia-inducible factor-1α induction was attenuated in AMPKα2-deficient cells and accompanied by its enhanced hydroxylation. Also, fewer proteins were regulated by hypoxia in neutrophils from AMPKα2ΔMC mice. Mechanistically, isocitrate dehydrogenase expression and the production of α-ketoglutarate, which negatively regulate hypoxia-inducible factor-1α stability, were attenuated in neutrophils from wild-type mice but remained elevated in cells from AMPKα2ΔMC mice.
Conclusions: AMPKα2 regulates α-ketoglutarate generation, hypoxia-inducible factor-1α stability, and neutrophil survival, which in turn determine further myeloid cell recruitment and repair potential. The activation of AMPKα2 in neutrophils is a decisive event in the initiation of vascular repair after ischemia.
MRI-detection rate and incidence of lumbar bleeding sources in 190 patients with non-aneurysmal SAH
(2017)
Background: Up to 15% of all spontaneous subarachnoid hemorrhages (SAH) have a non-aneurysmal SAH (NASAH). The evaluation of SAH patients with negative digital subtraction angiography (DSA) is sometimes a diagnostic challenge. Our goal in this study was to reassess the yield of standard MR-imaging of the complete spinal axis to rule out spinal bleeding sources in patients with NASAH.
Methods: We retrospectively analyzed the spinal MRI findings in 190 patients with spontaneous NASAH, containing perimesencephalic (PM) and non-perimesencephalic (NPM) SAH, diagnosed by computer tomography (CT) and/or lumbar puncture (LP), and negative 2nd DSA.
Results: 190 NASAH patients were included in the study, divided into PM-SAH (n = 87; 46%) and NPM-SAH (n = 103; 54%). Overall, 23 (22%) patients had a CT negative SAH, diagnosed by positive LP. MR-imaging of the spinal axis detected two patients with lumbar ependymoma (n = 2; 1,05%). Both patients complained of radicular sciatic pain. The detection rate raised up to 25%, if only patients with radicular sciatic pain received an MRI.
Conclusion: Routine radiological investigation of the complete spinal axis in NASAH patients is expensive and can not be recommended for standard procedure. However, patients with clinical signs of low-back/sciatic pain should be worked up for a spinal pathology.
Human beings are assumed to possess an approximate number system (ANS) dedicated to extracting and representing approximate numerical magnitude information. The ANS is assumed to be fundamental to arithmetic learning and has been shown to be associated with arithmetic performance. It is, however, still a matter of debate whether better arithmetic skills are reflected in the ANS. To address this issue, Chinese and German adults were compared regarding their performance in simple arithmetic tasks and in a non-symbolic numerical magnitude comparison task. Chinese participants showed a better performance in solving simple arithmetic tasks and faster reaction times in the non-symbolic numerical magnitude comparison task without making more errors than their German peers. These differences in performance could not be ascribed to differences in general cognitive abilities. Better arithmetic skills were thus found to be accompanied by a higher speed of retrieving non-symbolic numerical magnitude knowledge but not by a higher precision of non-symbolic numerical magnitude representations. The group difference in the speed of retrieving non-symbolic numerical magnitude knowledge was fully mediated by the performance in arithmetic tasks, suggesting that arithmetic skills shape non-symbolic numerical magnitude processing skills.
The acidification of the oceans could potentially alter marine plankton communities with consequences for ecosystem functioning. While several studies have investigated effects of ocean acidification on communities using traditional methods, few have used genetic analyses. Here, we use community barcoding to assess the impact of ocean acidification on the composition of a coastal plankton community in a large scale, in situ, long-term mesocosm experiment. High-throughput sequencing resulted in the identification of a wide range of planktonic taxa (Alveolata, Cryptophyta, Haptophyceae, Fungi, Metazoa, Hydrozoa, Rhizaria, Straminipila, Chlorophyta). Analyses based on predicted operational taxonomical units as well as taxonomical compositions revealed no differences between communities in high CO2 mesocosms (~ 760 μatm) and those exposed to present-day CO2 conditions. Observed shifts in the planktonic community composition were mainly related to seasonal changes in temperature and nutrients. Furthermore, based on our investigations, the elevated CO2 did not affect the intraspecific diversity of the most common mesozooplankter, the calanoid copepod Pseudocalanus acuspes. Nevertheless, accompanying studies found temporary effects attributed to a raise in CO2. Differences in taxa composition between the CO2 treatments could, however, only be observed in a specific period of the experiment. Based on our genetic investigations, no compositional long-term shifts of the plankton communities exposed to elevated CO2 conditions were observed. Thus, we conclude that the compositions of planktonic communities, especially those in coastal areas, remain rather unaffected by increased CO2.
Background: Legionella pneumophila (L. pneumophila) is a causative agent of severe pneumonia. It is highly adapted to intracellular replication and manipulates host cell functions like vesicle trafficking and mRNA translation to its own advantage. However, it is still unknown to what extent microRNAs (miRNAs) are involved in the Legionella-host cell interaction.
Methods: WT and MyD88-/- murine bone marrow-derived macrophages (BMM) were infected with L. pneumophila, the transcriptome was analyzed by high throughput qPCR array (microRNAs) and conventional qPCR (mRNAs), and mRNA-miRNA interaction was validated by luciferase assays with 3´-UTR mutations and western blot.
Results: L. pneumophila infection caused a pro-inflammatory reaction and significant miRNA changes in murine macrophages. In MyD88-/- cells, induction of inflammatory markers, such as Ccxl1/Kc, Il6 and miR-146a-5p was reduced. Induction of miR-125a-3p was completely abrogated in MyD88-/- cells. Target prediction analyses revealed N-terminal asparagine amidase 1 (NTAN1), a factor from the n-end rule pathway, to be a putative target of miR-125a-3p. This interaction could be confirmed by luciferase assay and western blot.
Conclusion: Taken together, we characterized the miRNA regulation in L. pneumophila infection with regard to MyD88 signaling and identified NTAN1 as a target of miR-125a-3p. This finding unravels a yet unknown feature of Legionella-host cell interaction, potentially relevant for new treatment options.
Introduction: Preclinical CT-guided radiotherapy platforms are increasingly used but the CT images are characterized by poor soft tissue contrast. The aim of this study was to develop a robust and accurate method of MRI-guided radiotherapy (MR-IGRT) delivery to abdominal targets in the mouse.
Methods: A multimodality cradle was developed for providing subject immobilisation and its performance was evaluated. Whilst CT was still used for dose calculations, target identification was based on MRI. Each step of the radiotherapy planning procedure was validated initially in vitro using BANG gel dosimeters. Subsequently, MR-IGRT of normal adrenal glands with a size-matched collimated beam was performed. Additionally, the SK-N-SH neuroblastoma xenograft model and the transgenic KPC model of pancreatic ductal adenocarcinoma were used to demonstrate the applicability of our methods for the accurate delivery of radiation to CT-invisible abdominal tumours.
Results: The BANG gel phantoms demonstrated a targeting efficiency error of 0.56 ± 0.18 mm. The in vivo stability tests of body motion during MR-IGRT and the associated cradle transfer showed that the residual body movements are within this MR-IGRT targeting error. Accurate MR-IGRT of the normal adrenal glands with a size-matched collimated beam was confirmed by γH2AX staining. Regression in tumour volume was observed almost immediately post MR-IGRT in the neuroblastoma model, further demonstrating accuracy of x-ray delivery. Finally, MR-IGRT in the KPC model facilitated precise contouring and comparison of different treatment plans and radiotherapy dose distributions not only to the intra-abdominal tumour but also to the organs at risk.
Conclusion: This is, to our knowledge, the first study to demonstrate preclinical MR-IGRT in intra-abdominal organs. The proposed MR-IGRT method presents a state-of-the-art solution to enabling robust, accurate and efficient targeting of extracranial organs in the mouse and can operate with a sufficiently high throughput to allow fractionated treatments to be given.
Glial cell line-derived neurotrophic factor (GDNF) is a ligand that activates, through co-receptor GDNF family receptor alpha-1 (GFRα1) and receptor tyrosine kinase “RET”, several signaling pathways crucial in the development and sustainment of multiple neuronal populations. We decided to study whether non-mammalian orthologs of these three proteins have conserved their function: can they activate the human counterparts? Using the baculovirus expression system, we expressed and purified Danio rerio RET, and its binding partners GFRα1 and GDNF, and Drosophila melanogaster RET and two isoforms of co-receptor GDNF receptor-like. Our results report high-level insect cell expression of post-translationally modified and dimerized zebrafish RET and its binding partners. We also found that zebrafish GFRα1 and GDNF are comparably active as mammalian cell-produced ones. We also report the first measurements of the affinity of the complex to RET in solution: at least for zebrafish, the Kd for GFRα1-GDNF binding RET is 5.9 μM. Surprisingly, we also found that zebrafish GDNF as well as zebrafish GFRα1 robustly activated human RET signaling and promoted the survival of cultured mouse dopaminergic neurons with comparable efficiency to mammalian GDNF, unlike E. coli-produced human proteins. These results contradict previous studies suggesting that mammalian GFRα1 and GDNF cannot bind and activate non-mammalian RET and vice versa.
Cixidia fusca and Synecdoche impunctata (Hemiptera: Achilidae) are reported from Missouri for the first time, new state records. Ecological and trapping information is also provided.
The eight species in the genus Tomarus Erichson (Coleoptera: Scarabaeidae) in Argentina, Chile, and Uruguay are reviewed. Tomarus roigjunenti new species and Tomarus spinipenis new species are described from Argentina. We include a key to species, representative habitus illustrations for all species, character illustrations, and distribution maps for each, as well as commentary about the natural history and distributions for each species. Diagnostic characters are discussed for each species, and species relationships are hypothesized based on the analysis of internal and external morphological characters. The male of T. bidentulus (Fairmaire) is described for fi rst time. The following taxonomic changes are made: Tomarus guianucai Dechambre and Lumaret, 1985 is a new junior synonym of Tomarus rubripes (Boheman, 1858), which was formerly and incorrectly cited as occurring in Argentina.
Descriptions and illustrations of the triungulin, 5th instar, and prepupal larval forms for Nematodes penetrans (LeConte, 1852) (Coleoptera: Eucnemidae: Macraulacinae: Nematodini) are given. The descriptions are based on triungulins collected in a plastic vial as well as 5th instars and prepupal larval stages collected from hard sections of sugar maple (Acer saccharum Marshall; Aceraceae) logs and limbs. Adults were reared from those pieces placed in plastic bags. Biological information is provided, based on literature search and personal observations.
Comparative studies between larvae of N. penetrans and the European species, Nematodes fi lum (Fabricius, 1801) along with other Nearctic larval forms are briefl y discussed. This discovery represents the fi rst larval description for the genus in the Nearctic region.