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Introduction: In the time of increasing resistance and paucity of new drug development there is a growing need for strategies to enhance rational use of antibiotics in German and Austrian hospitals. An evidence-based guideline on recommendations for implementation of antibiotic stewardship (ABS) programmes was developed by the German Society for Infectious Diseases in association with the following societies, associations and institutions: German Society of Hospital Pharmacists, German Society for Hygiene and Microbiology, Paul Ehrlich Society for Chemotherapy, The Austrian Association of Hospital Pharmacists, Austrian Society for Infectious Diseases and Tropical Medicine, Austrian Society for Antimicrobial Chemotherapy, Robert Koch Institute.
Materials and methods: A structured literature research was performed in the databases EMBASE, BIOSIS, MEDLINE and The Cochrane Library from January 2006 to November 2010 with an update to April 2012 (MEDLINE and The Cochrane Library). The grading of recommendations in relation to their evidence is according to the AWMF Guidance Manual and Rules for Guideline Development.
Conclusion: The guideline provides the grounds for rational use of antibiotics in hospital to counteract antimicrobial resistance and to improve the quality of care of patients with infections by maximising clinical outcomes while minimising toxicity. Requirements for a successful implementation of ABS programmes as well as core and supplemental ABS strategies are outlined. The German version of the guideline was published by the German Association of the Scientific Medical Societies (AWMF) in December 2013.
Background: Baker’s yeast, Saccharomyces cerevisiae, as one of the most often used workhorses in biotechnology has been developed into a huge family of application optimised strains in the last decades. Increasing numbers of strains render their characterisation highly challenging, even with the simple methods of growth-based analytics. Here we present a new sensor system for the automated, non-invasive and parallelisable monitoring of biomass in continuously shaken shake flask cultures, called CGQ (“cell growth quantifier”). The CGQ implements a dynamic approach of backscattered light measurement, allowing for efficient and accurate growth-based strain characterisation, as exemplarily demonstrated for the four most commonly used laboratory and industrial yeast strains, BY4741, W303-1A, CEN.PK2-1C and Ethanol Red.
Results: Growth experiments revealed distinct carbon source utilisation differences between the investigated S. cerevisiae strains. Phenomena such as diauxic shifts, morphological changes and oxygen limitations were clearly observable in the growth curves. A strictly monotonic non-linear correlation of OD600 and the CGQ’s backscattered light intensities was found, with strain-to-strain as well as growth-phase related differences. The CGQ measurements showed high resolution, sensitivity and smoothness even below an OD600 of 0.2 and were furthermore characterised by low background noise and signal drift in combination with high reproducibility.
Conclusions: With the CGQ, shake flask fermentations can be automatically monitored regarding biomass and growth rates with high resolution and parallelisation. This makes the CGQ a valuable tool for growth-based strain characterisation and development. The exceptionally high resolution allows for the identification of distinct metabolic differences and shifts as well as for morphologic changes. Applications that will benefit from that kind of automatized biomass monitoring include, amongst many others, the characterization of deregulated native or integrated heterologous pathways, the fast detection of co-fermentation as well as the realisation of rational and growth-data driven evolutionary engineering approaches.
Background: Histone lysine demethylases (KDMs) are of interest as drug targets due to their regulatory roles in chromatin organization and their tight associations with diseases including cancer and mental disorders. The first KDM inhibitors for KDM1 have entered clinical trials, and efforts are ongoing to develop potent, selective and cell-active ‘probe’ molecules for this target class. Robust cellular assays to assess the specific engagement of KDM inhibitors in cells as well as their cellular selectivity are a prerequisite for the development of high-quality inhibitors. Here we describe the use of a high-content cellular immunofluorescence assay as a method for demonstrating target engagement in cells.
Results: A panel of assays for the Jumonji C subfamily of KDMs was developed to encompass all major branches of the JmjC phylogenetic tree. These assays compare compound activity against wild-type KDM proteins to a catalytically inactive version of the KDM, in which residues involved in the active-site iron coordination are mutated to inactivate the enzyme activity. These mutants are critical for assessing the specific effect of KDM inhibitors and for revealing indirect effects on histone methylation status. The reported assays make use of ectopically expressed demethylases, and we demonstrate their use to profile several recently identified classes of KDM inhibitors and their structurally matched inactive controls. The generated data correlate well with assay results assessing endogenous KDM inhibition and confirm the selectivity observed in biochemical assays with isolated enzymes. We find that both cellular permeability and competition with 2-oxoglutarate affect the translation of biochemical activity to cellular inhibition.
Conclusions: High-content-based immunofluorescence assays have been established for eight KDM members of the 2-oxoglutarate-dependent oxygenases covering all major branches of the JmjC-KDM phylogenetic tree. The usage of both full-length, wild-type and catalytically inactive mutant ectopically expressed protein, as well as structure-matched inactive control compounds, allowed for detection of nonspecific effects causing changes in histone methylation as a result of compound toxicity. The developed assays offer a histone lysine demethylase family-wide tool for assessing KDM inhibitors for cell activity and on-target efficacy. In addition, the presented data may inform further studies to assess the cell-based activity of histone lysine methylation inhibitors.
Die Rezeption von Kosellecks Konzeption der Begriffsgeschichte in Polen begann Anfang der 1990er Jahre auf Umwegen und als Resultat von Zufällen. Die Tatsache, dass der polnische Philosoph Krzysztof Michalski (1948–2013), der Direktor des Wiener 'Instituts für die Wissenschaften vom Menschen', die Ergebnisse der vom ihm organisierten Castelgandolfo-Gespräche nicht nur im deutschen Original, sondern ab 1990 auch in Polen herausgab, führte dazu, dass auch drei Vorträge Kosellecks in polnischer Übersetzung erschienen. Da Koselleck in zweien seiner Vorträge mit 'Krise' und 'Emanzipation' die Geschichte von Begriffen behandelte, die er auch in den 'Geschichtlichen Grundbegriffen' (GG) erörtert hatte, gelangten auf dem Umweg der Castelgandolfo-Sammelbände erstmals Texte Kosellecks zur Begriffsgeschichte in den akademischen Diskurs in Polen. Auch in seinem dritten Castelgandolfo-Vortrag, in dem es um die Möglichkeit eines auf der historischen Semantik basierenden Vergleichs bürgerlicher Gesellschaften ging, hatte Koselleck weiterreichende Konsequenzen der Begriffsgeschichte behandelt. In den 1990er Jahren selbst erfuhren die genannten Texte in Polen allerdings noch kaum Beachtung. Dies sollte sich erst 2001 ändern, als der Germanist Hubert Orłowski in der von ihm verantworteten 'Posener Deutschen Bibliothek' (Poznańska Biblioteka Niemiecka) einen Sammelband mit vom ihm ausgewählten Aufsätzen Kosellecks zur historischen Semantik herausgab, der im Wesentlichen auf dessen Band 'Vergangene Zukunft. Zur Semantik geschichtlicher Zeiten' (1979) basierte, allerdings um die Einleitung zu den GG und weitere Texte ergänzt worden war.
Die offensichtlichen Ähnlichkeiten zwischen Neurasthenie und Burnout dürfen den wissenschaftlichen Blick jedoch nicht dazu verleiten, vorschnell von einer substantiellen Identität auszugehen. Es ist keineswegs gleichgültig, unter welchem Namen ein Leiden amtiert. Vielmehr gehe ich davon aus, dass die Etablierung eines neuen Begriffs ein Ereignis ist, das genauer in den Blick genommen zu werden verdient, weil es auf eine veränderte Problemlage hinweist. Die Frage lautet also, wie genau sich das Verhältnis zwischen Neurasthenie und Burnout darstellt, was diese beiden Begriffe trennt und verbindet, welche semantischen Bedeutungsebenen sich in ihnen jeweils abgelagert haben und welche Rückschlüsse sich aus der Untersuchung dieser Bedeutungsschichten für das Verständnis unserer Gegenwart möglicherweise ziehen lassen. Der erste Schritt einer solchen Fragestellung muss immer darin bestehen, die Phänomene gegeneinander zu legen und sie auf ihre Gemeinsamkeiten und Unterschiede hin zu untersuchen, um auf dieser Grundlage eine schärfere Kontur ihrer Besonderheiten zu erlangen - was im Folgenden geschehen soll.
Das Thema der Entstehung der modernen Welt steht im Zentrum des Interesses Reinhart Kosellecks, sowohl in Bezug auf die historische Semantik der politischen Begriffe, als auch bezüglich der sozialen Veränderungen der gesellschaftlichen Strukturen. Kosellecks Begriffsgeschichte geht es darum, den "Umwandlungsprozess zur Moderne" zu zeigen, wie er sich in der Verwendung der politischen Sprache ereignet. Mit der Theorie historischer Zeiten entwickelt Koselleck eine eigene Theorie der Entstehung der Neuzeit, die die Absicht hat, die spezifischen und charakteristischen Merkmale der modernen Welt und ihrer Zeitlichkeit durch die Darstellung der Beziehung zwischen den Erfahrungsräumen und den Erwartungen zu beschreiben. In seiner Doktorarbeit hat Koselleck die Diagnose über den Beginn der modernen Welt auf die Beziehung zwischen aufklärerischer Kritik und politischer Krise zurückgeführt; 1959 wurde die Doktorarbeit verbessert und veröffentlicht. Nun wird die Genese der modernen Welt zur "Pathogenese der bürgerlichen Welt", also vor allem im Sinne einer Krankheit verstanden: die Krise der Moderne entspricht also einer Pathologie. Der Horizont des strukturellen Verhältnisses zwischen der Neuzeit und der Krise bleibt auch in den folgenden Schriften das Thema Kosellecks, wenn er sich mit der historischen Zeitlichkeit beschäftigt. Das Ziel dieses Aufsatzes besteht darin, diese Beziehung zu rekonstruieren, und zwar darzustellen, wie Koselleck den auf den semantischen Raum der Krankheit und der Pathologie verweisenden Krisenbegriff als diagnostische und prognostische Kategorie verwendet, um die spezifische Natur der historischen Wandlung zur modernen Welt festzulegen.
The amyloid precursor protein (APP) was discovered in the 1980s as the precursor protein of the amyloid A4 peptide. The amyloid A4 peptide, also known as A-beta (Aβ), is the main constituent of senile plaques implicated in Alzheimer’s disease (AD). In association with the amyloid deposits, increasing impairments in learning and memory as well as the degeneration of neurons especially in the hippocampus formation are hallmarks of the pathogenesis of AD. Within the last decades much effort has been expended into understanding the pathogenesis of AD. However, little is known about the physiological role of APP within the central nervous system (CNS). Allocating APP to the proteome of the highly dynamic presynaptic active zone (PAZ) identified APP as a novel player within this neuronal communication and signaling network. The analysis of the hippocampal PAZ proteome derived from APP-mutant mice demonstrates that APP is tightly embedded in the underlying protein network. Strikingly, APP deletion accounts for major dysregulation within the PAZ proteome network. Ca2+-homeostasis, neurotransmitter release and mitochondrial function are affected and resemble the outcome during the pathogenesis of AD. The observed changes in protein abundance that occur in the absence of APP as well as in AD suggest that APP is a structural and functional regulator within the hippocampal PAZ proteome. Within this review article, we intend to introduce APP as an important player within the hippocampal PAZ proteome and to outline the impact of APP deletion on individual PAZ proteome subcommunities.
Background: Infection is a main cause of morbidity and mortality after heart surgery, with multi-resistant pathogens increasingly representing a challenge. Daptomycin provides bactericidal activity against gram-positive organisms that are resistant to standard treatment including vancomycin.
Methods: A cohort of cardiac surgical patients, treated with daptomycin for major infection at two tertiary care centers, were retrospectively studied with a particular focus on the type of infection, causative pathogens and co-infections, daptomycin dosage, adverse events and outcome in order to provide evidence for the efficiency and safety of daptomycin in a distinct high-risk patient population.
Results: Sixty-five patients (87.7 % males, 60.4 ± 13.5 years) who had undergone aortic surgery (20.0 %), ventricular assist device (VAD) implantation (21.5 %), combined procedures (21.5 %), coronary artery bypass grafting (12.3 %), isolated valve surgery (15.4 %) and heart transplantation (7.7 %) were diagnosed with catheter-related infection (26.1 %), valve endocarditis (18.8 %), sternal wound (13.0 %), VAD-associated (11.6 %), cardiac implantable electrophysiological device (CIED)-associated (4.1 %), respiratory tract (4.3 %), bloodstream (4.3 %) and other infection (4.3 %). In 13.0 %, no focus of infection was identified though symptoms of severe infection were present. The most frequent pathogens were Staphylococcus epidermidis (30.4 %), Staphylococcus aureus (23.1 %) and Enterococcus species (10.1 %). Daptomycin doses ranging from 3 mg/kg every 48 h to 10 mg/kg every 24 h were administered for 15.4 ± 11.8 days. 87.0 % of the cases were classified as success, 7.2 % as treatment failure and 5.8 as non-evaluable. Adverse events were limited to one case of mild and one case of moderate neutropenia with recovery upon termination of treatment.
Conclusion: Daptomycin proved safe and effective in major infection in high-risk cardiac surgical patients.
A small collection of Odonata from Nuku Hiva Island, Marquesas Islands is presented. It adds Anax guttatus as a new species to this oceanic group. Hemicordulia sp. nov. is reported, but not described because the same species has been sampled before and is pending a formal description. A short taxonomic discussion on observed morphological similarity of male anal appendages in taxa presently assigned to Amorphostigma, Hivaagrion and Ischnura east of New Caledonia is provided. Important considerations for biogeography of the Pacific Odonata are discussed too.
New data on Odonata of the Guadalcanal Island, Solomon Islands are provided following a recently completed Rapid Biodiversity Assessment of the Tetena Haiaja ridge. Two new species, Lieftinckia ulunorum and Procordulia valevahalo are described.
The first is a new member of the Solomon Islands endemic genus while the second is a new genus for the country and the second validated species from the Corduliidae family known from this Pacific archipelago. As L. ulunorum is found to be very closely related to formerly known L. lairdi Lieftinck, 1963, which was also collected during the field trip, both are described in detail based on mature adults and teneral specimens. Comparison with L. salomonis Kimmins, 1957 (investigated only from figures published in the original species description) and Salomoncnemis gerdae Lieftinck, 1987 (also sampled during this study) were provided as well.
Additional morphological data is given on the following species: Teinobasis bradleyi Kimmins, 1957, female is illustrated here for the first time; Anax sp. cf. gibbosulus, second record of the genus for the country and Gynacantha amphora Marinov & Theischinger, 2012, originally described by a single male, here the description of the female is provided.
All other species collected during the field trip will be published separately in the final expedition report.