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This article addresses concerns that the growth in global governance may be bringing with it a decline in the significance of democratic sources of political legitimacy. One approach in evaluating such concerns is to ask whether the respective patterns of legitimation for private and public authority differ or whether they refer to a similar set of normative standards. Private transnational governance regimes provide useful contexts in which to assess the presumed democratic erosion. They seem, almost of themselves, to make the case for such a decline: in them regulatory authority is exercised by non-state actors who, by their very nature, lack the kind of authorization afforded by the democratic procedures that legitimize state-based regulation; in addition, they are intrinsically linked to the notion of politics as a form of problem-solving rather than as the exercise of power. Given these characteristics, when governance arrangements of this kind are subjected to criticism, one would expect justificatory responses to relate primarily to performance, with normative criteria such as fundamental individual rights and the imperative for democratic procedure playing only a minor role. On the basis of a qualitative content analysis, the study tests three ideal-type patterns of legitimation for plausibility. The case selected for examination is the recent controversy surrounding the hybrid governance regime that operates to prevent the use of performance-enhancing drugs in sport. The debate offers the possibility of a ‘nutshell’ comparison of the respective patterns of legitimation used in criticizing and justifying state and non-state regulatory authority. This comparison yields two findings. The first is that the values used to appraise the state-based components of the sporting world’s hybrid regulatory regime do not differ systematically from those used to appraise the private elements: contestation and justification in both cases are founded on normative criteria relating to fundamental individual rights and democratic procedure and not just on performance-related considerations. The second finding is that justificatory grounds of the first type do not appear to be diminishing in importance vis-à-vis those of the second.
Corporatist regulation has a hybrid structure in that it covers state regulation, regulated self-regulation as well as private-public co-regulation. Notably diverging from the standard mode of state regulation, such arrangements required a higher degree of legitimation. Corporatist concepts flourished in the Weimar Republic. This paper deals with three legal scholars’ considerations regarding how to legitimize corporatist models, namely Edgar Tatarin-Tarnheyden, Heinrich Herrfahrdt, and Friedrich Glum. Their institutional touchstone was the Imperial Economic Council, as provided for by article 165 of the Weimar Constitution. This article envisioned a multi-level system of economic councils ranging from regional economic councils up to the Imperial Economic Council and involving representatives of all occupational groups in the performance of state tasks. However, only a Provisional Imperial Economic Council, with a restricted consultative remit, was ever actually established. Based on this model, Tatarin-Tarnheyden, Heinrich Herrfahrdt, and Friedrich Glum conceptualized organizational structures aiming at the comprehensive inclusion of non-state actors. They were legitimized primarily with reference to their output; that is, these organizational forms were supposed to enable a more appropriate and efficient realization of public interests. The input-based argument was basically a question of participation, which implies considerable proximity to typical topoi of democratic legitimation. This similarity is perhaps counter-intuitive, given that corporatist concepts are traditionally associated with anti-democratic ideologies due to their anti-parliamentarian slant. The numerous points of convergence between corporatist and democratic thought simultaneously reflect the heterogeneity of democratic reasoning in the Weimar period and the openness for ideas that were sceptical of—or even hostile to—parliamentary democracy and the party-based state.
This thematic issue brings together research from political science and legal history about legitimacy discourses covering different forms of public–private co-regulation and private self-regulation, domestic and transnational, past and present. These forms of governance highlight the important role of non-state actors in exercising public authority. There has been a growing debate about the legitimacy of non-state actors setting and enforcing norms and providing public goods and services. However, the focus of this thematic issue is not on developing abstract criteria of legitimacy. Rather, the authors analyze legitimacy discourses around different cases of privatized or partly privatized forms of governance from the early 20th century until today. Legitimacy is subject to empirical and not normative analysis. Legitimacy discourses are analyzed in order to shed light on the legitimacy conceptions that actors hold, what they consider as legitimate institutions, and based on what criteria. The particular focus of this thematic issue is to examine whether the significance of democratic legitimacy is decreasing as the importance of regulation exercised by private actors is increasing.
Die Reihe „Papers of Excellence 2.0: Ausgewählte Arbeiten aus den Fachdidaktiken und Bildungswissenschaften der Goethe-Universität Frankfurt a.M.“ ist eine neue, erweiterte und zusätzliche Auflage der bekannten Reihe „Papers of Excellence: Ausgewählte Arbeiten aus den Fachdidaktiken“, welche seit 2010 von Daniela Elsner und Anja Wildemann im Shaker-Verlag herausgegeben wird. In alter Tradition werden auch in der ab sofort zusätzlich zur Printausgabe erscheinenden Online Version dieser Buchreihe herausragende Examens- und Masterarbeiten, die sich durch eine ausgewiesene empirische, fachdidaktische Auseinandersetzung mit einem Thema auszeichnen, zusammenfassend vorgestellt. Neu ist, dass die Online Version nun auch Arbeiten mit einem bildungswissenschaftlichen Fokus aufnimmt und solche, die an der Schnittstelle zwischen Fachdidaktik und Bildungswissenschaften an-gelegt sind. Die Papers of Excellence 2.0, die derzeit nur Studien integriert, die an der Goethe Universität Frankfurt am Main angefertigt wurden, werden von Astrid Jurecka (Bildungswissenschaften) und Daniela Elsner (Fachdidaktik) herausgegeben und sind kostenfrei zugänglich.
The Gram-negative bacteria Photorhabdus and Xenorhabdus are known to produce a variety of different natural products (NP). These compounds play different roles since the bacteria live in symbiosis with nematodes and are pathogenic to insect larvae in the soil. Thus, a fine tuned regulatory system controlling NP biosynthesis is indispensable. Global regulators such as Hfq, Lrp, LeuO and HexA have been shown to influence NP production of Photorhabdus and Xenorhabdus. Additionally, photopyrones as quorum sensing (QS) signals were demonstrated to be involved in the regulation of NP production in Photorhabdus. In this study, we investigated the role of another possible QS signal, autoinducer-2 (AI-2), in regulation of NP production. The AI-2 synthase (LuxS) is widely distributed within the bacterial kingdom and has a dual role as a part of the activated methyl cycle pathway, as well as being responsible for AI-2 precursor production. We deleted luxS in three different entomopathogenic bacteria and compared NP levels in the mutant strains to the wild type (WT) but observed no difference to the WT strains. Furthermore, the absence of the small regulatory RNA micA, which is encoded directly upstream of luxS, did not influence NP levels. Phenotypic differences between the P. luminescens luxS deletion mutant and an earlier described luxS deficient strain of P. luminescens suggested that two phenotypically different strains have evolved in different laboratories.
Correlation of lumbar lateral recess stenosis in magnetic resonance imaging and clinical symptoms
(2017)
Aim: To assess the correlation of lateral recess stenosis (LRS) of lumbar segments L4/5 and L5/S1 and the Oswestry Disability Index (ODI).
Methods: Nine hundred and twenty-seven patients with history of low back pain were included in this uncontrolled study. On magnetic resonance images (MRI) the lateral recesses (LR) at lumbar levels L4/5 and L5/S1 were evaluated and each nerve root was classified into a 4-point grading scale (Grade 0-3) as normal, not deviated, deviated or compressed. Patient symptoms and disability were assessed using ODI. The Spearman’s rank correlation coefficient was used for statistical analysis (P < 0.05).
Results: Approximately half of the LR revealed stenosis (grade 1-3; 52% at level L4/5 and 42% at level L5/S1) with 2.2% and 1.9% respectively reveal a nerve root compression. The ODI score ranged from 0%-91.11% with an arithmetic mean of 34.06% ± 16.89%. We observed a very weak statistically significant positive correlation between ODI and LRS at lumbar levels L4/5 and L5/S1, each bilaterally (L4/5 left: rho < 0.105, P < 0.01; L4/5 right: rho < 0.111, P < 0.01; L5/S1 left: rho 0.128, P < 0.01; L5/S1 right: rho < 0.157, P < 0.001).
Conclusion: Although MRI is the standard imaging tool for diagnosing lumbar spinal stenosis, this study showed only a weak correlation of LRS on MRI and clinical findings. This can be attributed to a number of reasons outlined in this study, underlining that imaging findings alone are not sufficient to establish a reliable diagnosis for patients with LRS.
Microtubule-targeting agents (MTAs) are the most widely used chemotherapeutic drugs. Pretubulysin (PT), a biosynthetic precursor of the myxobacterial tubulysins, was recently identified as a novel MTA. Besides its strong anti-tumoral activities, PT attenuates tumor angiogenesis, exerts anti-vascular actions on tumor vessels and decreases cancer metastasis formation in vivo. The aim of the present study was to analyze the impact of PT on the interaction of endothelial and tumor cells in vitro to gain insights into the mechanism underlying its anti-metastatic effect. The influence of PT on tumor cell adhesion and transmigration onto/through the endothelium as well as its influence on cell adhesion molecules and the chemokine system CXCL12/CXCR4 was investigated. Treatment of human endothelial cells with PT increased the adhesion of breast cancer cells to the endothelial monolayer, whereas their transmigration through the endothelium was strongly reduced. Interestingly, the PT-induced upregulation of ICAM-1, VCAM-1 and CXCL12 were dispensable for the PT-evoked tumor cell adhesion. Tumor cells preferred to adhere to collagen exposed within PT-triggered endothelial gaps via β1-integrins on the tumor cell surface. Taken together, our study provides, at least in part, an explanation for the anti-metastatic potential of PT.
Background: Certain disadvantages of the standard hematopoietic stem and progenitor cell (HSPC) mobilizing agent G-CSF fuel the quest for alternatives. We herein report results of a Phase I dose escalation trial comparing mobilization with a peptidic CXCR4 antagonist POL6326 (balixafortide) vs. G-CSF.
Methods: Healthy male volunteer donors with a documented average mobilization response to G-CSF received, following ≥6 weeks wash-out, a 1–2 h infusion of 500–2500 µg/kg of balixafortide. Safety, tolerability, pharmacokinetics and pharmacodynamics were assessed.
Results: Balixafortide was well tolerated and rated favorably over G-CSF by subjects. At all doses tested balixafortide mobilized HSPC. In the dose range between 1500 and 2500 µg/kg mobilization was similar, reaching 38.2 ± 2.8 CD34 + cells/µL (mean ± SEM). Balixafortide caused mixed leukocytosis in the mid-20 K/µL range. B-lymphocytosis was more pronounced, whereas neutrophilia and monocytosis were markedly less accentuated with balixafortide compared to G-CSF. At the 24 h time point, leukocytes had largely normalized.
Conclusions: Balixafortide is safe, well tolerated, and induces efficient mobilization of HSPCs in healthy male volunteers. Based on experience with current apheresis technology, the observed mobilization at doses ≥1500 µg/kg of balixafortide is predicted to yield in a single apheresis a standard dose of 4× 10E6 CD34+ cells/kg from most individuals donating for an approximately weight-matched recipient. Exploration of alternative dosing regimens may provide even higher mobilization responses.
Trial Registration European Medicines Agency (EudraCT-Nr. 2011-003316-23) and clinicaltrials.gov (NCT01841476)
Most molecular cancer therapies act on protein targets but data on the proteome status of patients and cellular models for proteome‐guided pre‐clinical drug sensitivity studies are only beginning to emerge. Here, we profiled the proteomes of 65 colorectal cancer (CRC) cell lines to a depth of > 10,000 proteins using mass spectrometry. Integration with proteomes of 90 CRC patients and matched transcriptomics data defined integrated CRC subtypes, highlighting cell lines representative of each tumour subtype. Modelling the responses of 52 CRC cell lines to 577 drugs as a function of proteome profiles enabled predicting drug sensitivity for cell lines and patients. Among many novel associations, MERTK was identified as a predictive marker for resistance towards MEK1/2 inhibitors and immunohistochemistry of 1,074 CRC tumours confirmed MERTK as a prognostic survival marker. We provide the proteomic and pharmacological data as a resource to the community to, for example, facilitate the design of innovative prospective clinical trials.
Die vorliegende Dissertation befasst sich mit dem Umstieg von papierbasiertem (PBA) auf computerbasiertes Assessment (CBA), insbesondere in Large-Scale-Studien. In der Bildungsforschung war Papier lange Zeit das Medium für Assessments, im Zuge des digitalen Zeitalters erhält der Computer aber auch hier Einzug. So sind die großen Bildungsvergleichsstudien, wie PISA (Programme for International Student Assessment) oder PIAAC (Programme for the International Assessment of Adult Competencies), und nationalen Studien über Bildungsverläufe und -entwicklungen im Rahmen des NEPS (Nationales Bildungspanel) bereits umgestiegen oder befinden sich im Prozesses des Umstiegs von PBA auf CBA. Findet innerhalb dieser Studien ein Moduswechsel statt, dann muss die Vergleichbarkeit zwischen den Ergebnissen der unterschiedlichen Administrationsmodi gewährleistet werden. Unterschiede in den Eigenschaften der Modi, wie beispielsweise im Antwortformat, können sich dabei auf die psychometrischen Eigenschaften der Tests auswirken und zu sogenannten Modus Effekten führen. Diese Effekte wiederum können sich in Unterschieden zwischen den Testscores widerspiegeln, sodass diese nicht mehr direkt miteinander vergleichbar sind. Die zentrale Frage dabei ist, ob es durch den Moduswechsel zu einer Veränderung des gemessenen Konstruktes kommt. Ist dies der Fall, so können Testergebnisse aus unterschiedlichen Administrationsmodi nicht miteinander verglichen und die Ergebnisse aus dem computerbasierten Test nicht analog zu den Ergebnissen aus dem papierbasierten Test interpretiert werden. Auch Veränderungen, die aus Messungen zu verschiedenen Zeitpunkten und mit unterschiedlichen Modi resultieren, lassen sich dann nicht mehr beschreiben. Es kann jedoch auch Modus Effekte geben, die zwar nicht das gemessene Konstrukt betreffen, aber sich beispielsweise in der Schwierigkeit der Items niederschlagen. Solange aber das erfasste Konstrukt bei einem Moduswechsel unverändert bleibt, können diese Modus Effekte bei der Berechnung der Testscores berücksichtigt und die Vergleichbarkeit gewährleistet werden. Somit ist, nicht nur im Hinblick auf gültige Trendschätzungen, der Analyse von Modus-Effekten ein hoher Stellenwert beizumessen. Da die bisherige Befundlage in der Literatur zu Modus-Effekten sowohl hinsichtlich der Stärke der gefundenen Effekte, als auch in Bezug auf die verwendeten Methoden sehr heterogen ist, ist das Ziel des ersten Beitrags dieser publikationsbasierten Dissertation, eine Anleitung für eine systematische Durchführung einer Äquivalenzuntersuchung, speziell für Large-Scale Assessments, zu geben. Dabei wird die exemplarisch dargelegte Modus-Effekt-Analyse anhand von zuvor definierten und in ihrer Bedeutsamkeit belegten Kriterien auf der Test- und Item-Ebene illustriert. Zudem wird die Möglichkeit beschrieben, auftretende Effekte anhand von Eigenschaften des Administrationsmodus’, beispielsweise des Antwortformats oder der Navigationsmöglichkeiten innerhalb des Tests, zu erklären. Im zweiten und dritten Beitrag findet sich jeweils eine empirische Anwendung der im ersten Beitrag beschriebenen schematischen Modus-Effekt-Analyse mit unterschiedlicher Schwerpunktsetzung. Dazu wurden die Daten eines Leseverständnistests aus der Nationalen Begleitforschung von PISA 2012 sowie zweier Leseverständnistests im NEPS, die jeweils sowohl papier- als auch computerbasiert administriert wurden, analysiert. Das Kriterium der Konstrukt-Äquivalenz steht dabei als wichtigstes Äquivalenz-Kriterium im Fokus. Zusätzlich wurde Äquivalenz in Bezug auf die Reliabilität und die Item-Parameter (Schwierigkeit und Diskrimination) untersucht. Im zweiten Beitrag wurden darüber hinaus interindividuelle Unterschiede im Modus-Effekt in Bezug zu basalen Computerfähigkeiten und zum Geschlecht gesetzt. Der dritte Beitrag fokussiert die Item-Eigenschaften, die als mögliche Quellen von Modus-Effekten herangezogen werden können und bezieht diese zur Erklärung von Modusunterschieden in die Analyse mit ein. In beiden Studien wurde keine Evidenz gefunden, dass sich das Konstrukt bei einem Wechsel des Administrationsmodus ändert. Lediglich einzelne Items wiesen am Computer im Vergleich zum PBA eine erhöhte Schwierigkeit auf, wobei sich der größte Teil der Items als invariant zwischen den Modi erwies. Für zwei Item-Eigenschaften wurde ein Effekt auf die erhöhte Schwierigkeit der Items am Computer gefunden. Interindividuelle Unterschiede im Modus-Effekt konnten nicht durch basale Computerfähigkeiten oder das Geschlecht erklärt werden.
Diese Dissertation leistet einen wesentlichen Beitrag zur Systematisierung von Äquivalenzuntersuchungen, insbesondere solchen in Large-Scale Assessments, indem sie die wesentlichen Kriterien für die Beurteilung von Äquivalenz herausstellt und diskutiert sowie deren Analyse methodisch aufbereitet. Die Relevanz von Modus-Effekt Studien wird dabei nicht zuletzt durch die Ergebnisse der beiden empirischen Beiträge hervorgehoben. Schließlich wird der Bedeutung des Einbezugs von Item-Eigenschaften hinsichtlich der Beurteilung der Äquivalenz Ausdruck verliehen.
In this study, we aimed to comparatively evaluate high-resolution 3D ultrasonography (hrUS), in-vivo micro-CT (μCT) and 9.4T MRI for the monitoring of tumor growth in an orthotopic renal cell carcinoma (RCC) xenograft model since there is a lack of validated, non-invasive imaging tools for this purpose. 1 × 106 Caki-2 RCC cells were implanted under the renal capsule of 16 immunodeficient mice. Local and systemic tumor growth were monitored by regular hrUS, μCT and MRI examinations. Cells engrafted in all mice and gave rise to exponentially growing, solid tumors. All imaging techniques allowed to detect orthotopic tumors and to precisely calculate their volumes. While tumors appeared homogenously radiolucent in μCT, hrUS and MRI allowed for a better visualization of intratumoral structures and surrounding soft tissue. Examination time was the shortest for hrUS, followed by μCT and MRI. Tumor volumes determined by hrUS, μCT and MRI showed a very good correlation with each other and with caliper measurements at autopsy. 10 animals developed pulmonary metastases being well detectable by μCT and MRI. In conclusion, each technique has specific strengths and weaknesses, so the one(s) best suitable for a specific experiment may be chosen individually.
The goal of heavy ion reactions at low beam energies is to explore the QCD phase diagram at high net baryon chemical potential. To relate experimental observations with a first order phase transition or a critical endpoint, dynamical approaches for the theoretical description have to be developed. In this summary of the corresponding plenary talk, the status of the dynamical modeling including the most recent advances is presented. The remaining challenges are highlighted and promising experimental measurements are pointed out.
We propose that resilience effectively helps people cope with stress, thus predominantly reducing the negative. However, we argue that individuals’ social identification has the potential to contribute to their well-being, thus fostering the positive. A two-wave survey study of 180 students shows that resilience is more strongly (negatively) associated with ill-health (i.e. stress and depression), whereas social identification is more strongly (positively) related to well-being (i.e. satisfaction and work engagement). We believe that it is necessary to see these two routes to improving people’s health as complementary, both in future research and for therapy and interventions.
Pediatric patients with recurrent, refractory or advanced soft tissue sarcoma (STS) who are simultaneously showing signs of cumulative treatment toxicity are in need of novel therapies. In this preclinical analysis, we identified ErbB2 as a targetable antigen on STS cells and used cytokine-induced killer (CIK) cells transduced with the lentiviral 2nd-generation chimeric antigen receptor (CAR) vector pS-5.28.z-IEW to target ErbB2-positive tumors. Solely CIK cell subsets with the CD3+ T cell phenotype showed up to 85% cell surface expression of the respective CAR. A comparison of wildtype (WT), mock-vector and ErbB2-CAR-CIK cells showed, that engineered cells exhibited diminished in vitro expansion, retained WT CIK cell phenotype with higher percentages of differentiated effector memory/effector cells. Activating natural killer (NK) cell receptor NKG2D-restricted target cell recognition and killing of WT and ErbB2-CAR-CIK cells was maintained against ErbB2-negative tumors, while ErbB2-CAR-CIK cells demonstrated significantly increased cytotoxicity against ErbB2-positive targets, including primary tumors. ErbB2-CAR- but not WT CIK cells proliferated, infiltrated and efficiently lysed tumor cell monolayers as well as 3D tumor spheroids.
Here, we demonstrate a potential cell therapeutic approach using ErbB2-CAR-CIK cells for the recognition and elimination of tumor cells expressing ErbB2, which we identified as a targetable antigen on high-risk STS cells.
Am Fachbereich Medizin und dem Klinikum der Johann Wolfgang-Goethe-Universität Frankfurt existierten bereits seit 2002 mehrere einzelne medizindidaktische Kurse. Diese Aktivitäten wurden 2011 strukturiert, ein umfassendes Kursangebot, das das breite Spektrum an Themen rund um die Lehre abdeckt, wurde aufgebaut und unter dem Dach der Frankfurter Arbeitsstelle für Medizindidaktik (FAM) am Fachbereich institutionalisiert. Folgende Faktoren waren für die erfolgreiche Umsetzung ausschlaggebend: vorhandene Programme in anderen Bundesländern (v.a. Baden-Württemberg, Nordrhein-Westfalen) mit entsprechenden Vorgaben, die Unterstützung der Studiendekane, die Verankerung der Teilnahme an medizindidaktischen Kursen in der Habilitationsordnung sowie eine kritische Masse von an der Lehre interessierten Mitarbeiterinnen und Mitarbeitern. Kernelemente des Angebots sind ein Basiskurs für alle neu eingestellten wissenschaftlichen Angestellten mit Lehrverpflichtung und ein modularer Aufbau des Programms, der individuellen Präferenzen bzw. Erfordernissen entgegen kommt. Gleichwohl die Teilnahme am Kursprogramm überwiegend verpflichtend erfolgt, zeigt sich eine hohe Zufriedenheit und ein nachhaltiger Wissenszuwachs bei den Kursteilnehmerinnen und Kursteilnehmern.
Sepsis is generally considered as a severe condition of inflammation that leads to lymphocyte apoptosis and multiple organ dysfunction. Hydroxysafflor yellow A (HSYA) exerts anti-inflammatory and anti-apoptotic effects in infectious diseases. However, the therapeutic effect of HSYA on polymicrobial sepsis remains unknown. This study was undertaken to investigate the therapeutic effects and the mechanisms of action of HSYA on immunosuppression in a murine model of sepsis induced by cecal ligation and puncture (CLP). NIH mice were randomly divided into four groups: control group, sham group, CLP group, and CLP+HSYA group. HSYA (120 mg/kg) was intravenously injected into experimental mice at 12 h before CLP, concurrent with CLP and 12 h after CLP. The levels of circulating inflammatory cytokines, the apoptosis of CD4+ and CD8+ T lymphocytes, and protein expression of cytochrome C (Cytc), Bax, Bcl-2, cleaved caspase-9, and cleaved caspase-3 were examined. Plasma levels of IL-6, IL-10 and TNF-alpha as well as the apoptosis of CD4+ T lymphocytes were increased compared with sham group. These changes were accompanied by increases of pro-apoptotic proteins including Cytc, Bax, cleaved caspase-9, and cleaved caspase-3 and decreases of anti-apoptotic protein Bcl-2 in CD4+ T lymphocytes from mice undergoing CLP. In contrast, we fail to observe significant effect of HSYA on the apoptosis of CD8+ T lymphocytes in CLP-treated group. Of note, HSYA treatment reversed all above changes observed in CD4+ T lymphocytes, and significantly increased the ratio of CD4+:CD8+ T lymphocytes in CLP-treated mice. In conclusion, HSYA was an effective therapeutic agent in ameliorating sepsis-induced apoptosis of CD4+ T lymphocytes probably through its anti-inflammatory and anti-apoptotic effects.
We present a method that enables the identification and analysis of conformational Markovian transition states from atomistic or coarse-grained molecular dynamics (MD) trajectories. Our algorithm is presented by using both analytical models and examples from MD simulations of the benchmark system helix-forming peptide Ala5, and of larger, biomedically important systems: the 15-lipoxygenase-2 enzyme (15-LOX-2), the epidermal growth factor receptor (EGFR) protein, and the Mga2 fungal transcription factor. The analysis of 15-LOX-2 uses data generated exclusively from biased umbrella sampling simulations carried out at the hybrid ab initio density functional theory (DFT) quantum mechanics/molecular mechanics (QM/MM) level of theory. In all cases, our method automatically identifies the corresponding transition states and metastable conformations in a variationally optimal way, with the input of a set of relevant coordinates, by accurately reproducing the intrinsic slowest relaxation rate of each system. Our approach offers a general yet easy-to-implement analysis method that provides unique insight into the molecular mechanism and the rare but crucial (i.e., rate-limiting) transition states occurring along conformational transition paths in complex dynamical systems such as molecular trajectories.
In 1905, the managing editor of the Jewish Encyclopedia, Isidore Singer (1859–1939), published an article in the journal Ost und West from a "bird’s eye perspective on the development of American Jewry in the last 250 years." In this historical overview, Singer eventually attested that Jewish scholarship in America had an "absolute dependency on the European motherland." This judgment was based on his disapproving view of the two American rabbinical seminaries that existed at that time. According to Singer, there were still no scholars at the Hebrew Union College (HUC) in Cincinnati of the "already American[-born] generation of Israel." In fact, Singer’s observation was appropriate because it applied to the Jewish Theological Seminary of America (JTSA) in New York as much as to the HUC.3 Despite the history of Jewish settlement in America, around 1900 there was still no native Jewish scholarship in America. The scene was dominated by scholars educated in Europe, who often came with broken English and a strict academic sense of mission. In 1903, Kaufmann Kohler (1843–1926), born in Bavaria and trained at German universities, was chosen as the president of HUC. And a year earlier, Solomon Schechter (1847–1915) had been called to the JTSA in New York as its new president. ...
We performed an intercomparison of river discharge regulated by dams under four meteorological forcings among five global hydrological models for a historical period by simulation. This is the first global multimodel intercomparison study on dam-regulated river flow. Although the simulations were conducted globally, the Missouri–Mississippi and Green–Colorado Rivers were chosen as case-study sites in this study. The hydrological models incorporate generic schemes of dam operation, not specific to a certain dam. We examined river discharge on a longitudinal section of river channels to investigate the effects of dams on simulated discharge, especially at the seasonal time scale. We found that the magnitude of dam regulation differed considerably among the hydrological models. The difference was attributable not only to dam operation schemes but also to the magnitude of simulated river discharge flowing into dams. That is, although a similar algorithm of dam operation schemes was incorporated in different hydrological models, the magnitude of dam regulation substantially differed among the models. Intermodel discrepancies tended to decrease toward the lower reaches of these river basins, which means model dependence is less significant toward lower reaches. These case-study results imply that, intermodel comparisons of river discharge should be made at different locations along the river's course to critically examine the performance of hydrological models because the performance can vary with the locations.
A dozen mRNAs are edited by multiple insertions and/or deletions of uridine residues in the mitochondrion of Trypanosoma brucei. Several protein complexes have been implicated in performing this type of RNA editing, including the mitochondrial RNA-binding complex 1 (MRB1). Two paralogous novel RNA-binding proteins, MRB8170 and MRB4160, are loosely associated with the core MRB1 complex. Their roles in RNA editing and effects on target mRNAs are so far not well understood. In this study, individual-nucleotide-resolution UV-cross-linking and affinity purification (iCLAP) revealed a preferential binding of both proteins to mitochondrial mRNAs, which was positively correlated with their extent of editing. Integrating additional in vivo and in vitro data, we propose that binding of MRB8170 and/or MRB4160 onto pre-mRNA marks it for the initiation of editing and that initial binding of both proteins may facilitate the recruitment of other components of the RNA editing/processing machinery to ensure efficient editing. Surprisingly, MRB8170 also binds never-edited mRNAs, suggesting that at least this paralog has an additional role outside RNA editing to shape the mitochondrial transcriptome.
The existence of individual variation in males' motivation to mate remains a conundrum as directional selection should favour high mating frequencies. Balancing selection resulting from (context-dependent) female mate choice could contribute to the maintenance of this behavioural polymorphism. In dichotomous choice tests, mosquitofish (Gambusia holbrooki) females preferred virtual males showing intermediate mating frequencies, reflecting females' tendencies to avoid harassment by highly sexually active males. When tested in the presence of a female shoal—which protects females from male harassment—focal females showed significantly stronger preferences for high sexual activity. A trade-off between (indirect) benefits and (direct) costs of mating with sexually active males probably explains context-dependent female mate choice, as costs depend on the social environment in which females choose their mates. No preference was observed when we tested virgin females, suggesting that the behavioural pattern described here is part of the learned behavioural repertoire of G. holbrooki females.
Empirical evidence suggests that investments in research and development (R&D) by older and larger firms are more spread out internationally than R&D investments by younger and smaller firms. In this paper, I explore the quantitative implications of this type of heterogeneity by assuming that incumbents, i.e. current monopolists engaging in incremental innovation, have a higher degree of internationalization in their R&D technologies than entrants, i.e. new firms engaging in radical innovation, in a two-country endogenous growth general equilibrium model. In particular, this assumption allows the model to break the perfect correlation between incumbents’ and entrants’ innovation probabilities and to match the empirical counterpart exactly.
Vor einem Monat haben sich mehr als zwei Millionen Katalanen für die Unabhängigkeit der Region von Spanien ausgesprochen. Auch wenn das Referendum für illegal erklärt wurde und weniger als die Hälfte der Katalanen teilnahmen, verraten uns die Ergebnisse einiges über die Stärke der Unabhängigkeitsbewegung. Dieser Beitrag untersucht, wie ein mögliches legales Referendum mit höherer Wahlbeteiligung ausgehen könnte. Auch wenn die rechtlichen Rahmenbedingungen ein solches Referendum nicht vorsehen, unterstützen laut aktueller Umfragen auch eine Mehrheit der Spanier diesen Weg der Konfliktlösung.
What processes transform (im)mobile individuals into ‘migrants’ and geographic movements across political-territorial borders into ‘migration’? To address this question, the article develops the doing migration approach, which combines perspectives from social constructivism, praxeology and the sociologies of knowledge and culture. ‘Doing migration’ starts with the processes of social attribution that differentiate between ‘migrants’ and ‘non-migrants’. Embedded in institutional, organizational and interactional routines these attributions generate unique social orders of migration. By illustrating these conceptual ideas, the article provides insights into the elements of the contemporary European order of ‘migration’. Its institutional routines contribute to the emergence of a European migration regime that involves narratives of economization, securitization and humanitarization. The organizational routines of the European migration order involve surveillance and diversity management, which have disciplining effects on those defined as ‘migrants’. The routines of everyday face-to-face interactions produce various micro-forms of doing ‘migration’ through stigmatization and othering, but they also provide opportunities to resist a social attribution as ‘migrant’.
This paper reviews social network analysis (SNA) as a method to be utilized in biographical research which is a novel contribution. We argue that applying SNA in the context of biography research through standardized data collection as well as visualization of networks can open up participants’ interpretations of relations throughout their lives, and allow a creative and innovative way of data collection that is responsive to participants’ own meanings and associations while allowing the researchers to conduct systematical data analysis. The paper discusses the analytical potential of SNA in biographical research, where the efficacy of this method is critically discussed, together with its limitations, and its potential within the context of biographical research.
Wassergefiltertes Infrarot A (wIRA) ist eine spezielle Form der Wärmestrahlung mit hohem Eindringvermögen in das Gewebe und geringer thermischer Belastung der Hautoberfläche.
wIRA steigert deutlich Temperatur, Sauerstoffpartialdruck und Durchblutung im Gewebe und wirkt auch über nicht-thermische zelluläre Effekte.
wIRA mindert indikationsübergreifend Schmerzen (mit relevant weniger Analgetikabedarf), Entzündung und vermehrte Sekretion und fördert Infektionsabwehr und Regeneration.
Entsprechend breit sind die klinischen Anwendungsmöglichkeiten von wIRA.
wIRA ist ein kontaktfreies, verbrauchsmaterialfreies, leicht anzuwendendes, (selbst bei Wunden) als angenehm empfundenes Verfahren mit guter Tiefenwirkung und anhaltendem Wärmedepot.
wIRA ist u.a. einsetzbar zur Verbesserung der Heilung akuter und chronischer Wunden (wobei selbst eine ungestört "normal" ablaufende Wundheilung noch verbessert werden kann: schneller, schmerzärmer), bei Hauterkrankungen (wie vulgären Warzen, Herpes labialis, Herpes Zoster, Sklerodermie, Akne papulopustulosa; aktinischen Keratosen im Rahmen einer Photodynamischen Therapie), zur Resorptionsverbesserung topisch applizierter Substanzen, bei muskuloskeletalen Erkrankungen (wie Arthrosen, Arthritiden, Lumbago, ankylosierender Spondyloarthritis), zur Regeneration nach Sport, beim komplexen regionalen Schmerzsyndrom (CRPS), bei Polyneuropathien und in Kombination mit Strahlentherapie oder Chemotherapie in der Onkologie.
Case description: A patient with a Barrett oesophageal carcinoma and a resection of the oesophagus with gastric pull-up developed swallowing disorders 6 years and 2 months after the operation. Within 1 year and 7 months two recurrences of the tumor at the anastomosis were found and treated with combined chemoradiotherapy or chemotherapy respectively. 7 years and 9 months after the operation local tumor masses and destruction were present with no ability to orally drink or eat (full feeding by jejunal PEG tube): quality of life was poor, as saliva and mucus were very viscous (pulling filaments) and could not be swallowed and had to be spat out throughout the day and night resulting in short periods of sleep (awaking from the necessity to spit out). In total the situation was interpreted more as a problem related to a feeling of choking (with food or fluid) in the sense of a functional dysphagia rather than as a swallowing disorder from a structural stenosis.
At that time acetylcysteine (2 times 200 mg per day, given via the PEG tube) and irradiation with water-filtered infrared-A (wIRA), a special form of heat radiation, of the ventral part of the neck and the thorax were added to the therapy. Within 1 day with acetylcysteine saliva and mucus became less viscous. Within 2 days with wIRA (one day with 4 to 5 hours with irradiation with wIRA at home) salivation decreased markedly and quality of life clearly improved: For the first time the patient slept without interruption and without the need for sleep-inducing medication. After 5 days with wIRA the patient could eat his first soft dumpling although drinking of fluids was still not possible. After 2½ weeks with wIRA the patient could eat his first minced schnitzel (escalope).
Following the commencement of wIRA (with typically approximately 90–150 minutes irradiation with wIRA per day) the patient had 8 months with good quality of life with only small amounts of liquid saliva and mucus and without the necessity to spit out. During this period the patient was able to sleep during the night.
Discussion: The main physiological effects of water-filtered infrared-A (wIRA) are: wIRA increases tissue temperature, tissue oxygen partial pressure and tissue perfusion markedly.
The five main clinical effects of wIRA are: wIRA decreases pain, inflammation and exudation/hypersecretion, and promotes infection defense and regeneration, all in a cross-indication manner. Therefore there is a wide range of indications for wIRA.
The effects of wIRA are based on both its thermal effects (relying on transfer of heat energy) and thermic effects (temperature-dependent effects, occurring together with temperature changes) as well as on non-thermal and temperature-independent effects like direct effects on cells, cell structures or cell substances.
Conclusion: Besides in a variety of other indications for wIRA, in cases of swallowing disorders (functional dysphagia) and hypersalivation or hypersecretion of mucus the use of wIRA should be considered as part of the treatment regime for improving a patient’s quality of life.
Diese kulturanthropologische Studie beschäftigt sich mit gegenwärtigen Veränderungen des Nachkriegsphänomens Städtepartnerschaften. Ausgangspunkt ist die Beobachtung, dass, obwohl einstige Gründungsmotive wegfallen, Städtepartnerschaften derzeit nicht etwa abgeschafft oder ersetzt, sondern neu ausgerichtet werden. Im Zentrum der Arbeit steht daher die Frage nach den Charakteristiken des gegenwärtigen Wandels und der kulturellen Spezifik von Städtepartnerschaften sowie möglichen Folgen. Dem wird am Beispiel von deutsch-polnischen und deutsch-türkischen Städtepartnerschaften des Ruhrgebiets mit Methoden einer transnational ausgerichteten empirisch-ethnografischen Feldforschung und einer akteurszentrierten und praxisorientierten Anwendung des Assemblage-Konzepts nachgegangen. Die Ergebnisse, die sich schwerpunktmäßig auf einen Zeitraum zwischen 2007 und 2012 beziehen, machen nicht zuletzt durch ihren länderbezogenen Kontrast deutlich: In Städtepartnerschaften trifft derzeit eine Vielzahl von aktuellen Entwicklungen, Prozessen und Akteuren aufeinander. Städtepartnerschaften werden derzeit staatsgrenzenübergreifend von verschiedenen Akteuren aus Politik, Zivilgesellschaft und Bürgerschaft mit je eigenen derzeitigen Herausforderungen wie Integrationsfragen und Wirtschaftsförderung, urbanem Standortwettbewerb sowie biografischen Bestrebungen und Mobilitätsinteressen verbunden. Dabei führen insbesondere auf deutscher Seite normative Ansprüche dazu, dass einstige Prinzipien und Aktivitäten von Städtepartnerschaften beibehalten und abgewandelt werden, weshalb von einem Format und einem Formatwandel gesprochen werden kann, was nicht jede beliebige Veränderung zulässt. In den neueren Varianten von Städtepartnerschaften zeigen sich aber auch nicht zwangsläufig intendierte, doch sehr wirkungsvolle Formen von Europäisierung und Governance durch Kommunen und ihre Bürgerinnen und Bürger.
Walter Greiner: in memoriam
(2017)
Walter Greiner (29 October 1935 - 6 October 2016) was a German theoretical physicist. His scientific research interests include the thematic areas of atomic physics, heavy ion physics, nuclear physics, elementary particle physics (particularly quantum electrodynamics and quantum chromodynamics). He is most known in Germany for his series of books in theoretical physics, but he is also well known around the world. Greiner was born on October 29, 1935, in Neuenbau, Sonnenberg, Germany. He studied physics at the University of Frankfurt (Goethe University in Frankfurt Am Main), receiving in this institution a BSci in physics and a Master’s degree in 1960 with a thesis on plasma-reactors, and a PhD in 1961 at the University of Freiburg under Hans Marshal, with a thesis on the nuclear polarization in μμ-mesic atoms. During the period of 1962 to 1964 he was assistant professor at the University of Maryland, followed by a position as research associate at the University of Freiburg, in 1964. Starting in 1965, he became a full professor at the Institute for Theoretical Physics at Goethe University until 2003. Greiner has been a visiting professor to many universities and laboratories, including Florida State University, the University of Virginia, the University of California, the University of Melbourne, Vanderbilt University, Yale University, Oak Ridge National Laboratory and Los Alamos National Laboratory. In 2003, with Wolf Singer, he was the founding Director of the Frankfurt Institute for Advanced Studies (FIAS), and gave lectures and seminars in elementary particle physics. He died on October 6, 2016 at the age of 80.
Walter Greiner was an excellent teacher, researcher, friend. And he was a great supporter of the series of events known by the acronyms IWARA - International Workshop on Astronomy and Relativistic Astrophysics, STARS - Caribbean Symposium on Cosmology, Gravitation, Nuclear and Astroparticle Physics, and SMFNS - International Symposium on Strong Electromagnetic Fields and Neutron Stars. Walter Greiner left us. But his memory will remain always alive among us who have had the privilege of knowing him and enjoy his wisdom and joy of living.
Land surface and hydrologic models (LSM/HM) are used at diverse spatial resolutions ranging from 1-10 km in catchment-scale applications to over 50 km in global-scale applications. Application of the same model structure at different spatial scales requires that the model estimates similar fluxes independent of the model resolution and fulfills a flux-matching condition across scales. An analysis of state-of-the-art LSMs and HMs reveals that most do not have consistent and realistic parameter fields for land surface geophysical properties. Multiple experiments with the mHM, Noah-MP, PCR-GLOBWB and WaterGAP models are conducted to demonstrate the pitfalls of poor parameterization practices currently used in most operational models, which are insufficient to satisfy the flux-matching condition. These examples demonstrate that J. Dooge’s 1982 statement on the unsolved problem of parameterization in these models remains true. We provide a short review of existing parameter regionalization techniques and discuss a method for obtaining seamless hydrological predictions of water fluxes and states across multiple spatial resolutions. The multiscale parameter regionalization (MPR) technique is a practical and robust method that provides consistent (seamless) parameter and flux fields across scales. A general model protocol is presented to describe how MPR can be applied to a specific model, with an example of this application using the PCR-GLOBWB model. Applying MPR to PCR-GLOBWB substantially improves the flux-matching condition. Estimation of evapotranspiration without MPR at 5 arcmin and 30 arcmin spatial resolutions for the Rhine river basin results in a difference of approximately 29%. Applying MPR reduce this difference to 9%. For total soil water, the differences without and with MPR are 25% and 7%, respectively.
Land surface and hydrologic models (LSMs/HMs) are used at diverse spatial resolutions ranging from catchment-scale (1–10 km) to global-scale (over 50 km) applications. Applying the same model structure at different spatial scales requires that the model estimates similar fluxes independent of the chosen resolution, i.e., fulfills a flux-matching condition across scales. An analysis of state-of-the-art LSMs and HMs reveals that most do not have consistent hydrologic parameter fields. Multiple experiments with the mHM, Noah-MP, PCR-GLOBWB, and WaterGAP models demonstrate the pitfalls of deficient parameterization practices currently used in most operational models, which are insufficient to satisfy the flux-matching condition. These examples demonstrate that J. Dooge's 1982 statement on the unsolved problem of parameterization in these models remains true. Based on a review of existing parameter regionalization techniques, we postulate that the multiscale parameter regionalization (MPR) technique offers a practical and robust method that provides consistent (seamless) parameter and flux fields across scales. Herein, we develop a general model protocol to describe how MPR can be applied to a particular model and present an example application using the PCR-GLOBWB model. Finally, we discuss potential advantages and limitations of MPR in obtaining the seamless prediction of hydrological fluxes and states across spatial scales.
A randomised, double-blind, placebo-controlled trial of trichuris suis ova in active crohn's disease
(2017)
BACKGROUND AND AIMS To investigate the efficacy and safety of three different dosages of embryonated, viable eggs of Trichuris suis [TSO] versus placebo for induction of remission in mildly-to-moderately active ileocolonic, uncomplicated Crohn's disease [CD].
METHODS Adults with active CD [n = 252] randomly received six fortnightly doses of 250, 2500, or 7500 TSO/15 ml suspension/day [TSO 250, TSO 2500, TSO 7500], or 15 ml placebo solution/day, in a double-blind fashion, with 4 weeks' follow-up. Primary endpoint was the rate of clinical remission [Crohn's Disease Activity Index [CDAI] < 150] at end of treatment, ie at Week 12 or withdrawal. Secondary endpoints included the course of clinical remission, rate of clinical response, change in CDAI, change in markers of inflammation, mucosal healing, and Physician's Global Assessment.
RESULTS Clinical remission at Week 12 occurred in 38.5%, 35.2%, and 47.2% of TSO 250, TSO 2500, and TSO 7500 patients, respectively, and in 42.9% of placebo recipients. TSO induced a dose-dependent immunological response. There was no response regarding laboratory markers of inflammation. Other secondary efficacy variables also showed no advantage of TSO over placebo for treatment of active CD. Administration of TSO did not result in any serious adverse drug reaction. Review of non-serious suspected adverse drug reactions following TSO did not reveal any safety concerns.
CONCLUSIONS Administration of 250-7500 TSO fortnightly over 12 weeks was safe and showed a dose-dependent immunological response, but no TSO dose showed a clinically relevant effect over placebo for induction of clinical remission or response in mildly-to-moderately active, ileocolonic CD.
Kinematic analysis of work-related musculoskeletal loading of trunk among dentists in Germany
(2017)
BACKGROUND: In Germany, about 86.7 % of the dentists have stated to suffer from pain in the neck and shoulder region. These findings are predominantly based on surveys. Therefore the objective of this study is to conduct a kinematic analysis of occupational posture in dentistry.
METHODS: Twenty one dentists (11 f/10 m; age: 40.1 ± 10.4 years) have participated in this examination. The CUELA-System was used to collect kinematic data of the activities on an average dental workday. A detailed, computer-based task analysis took place parallel to the kinematic examination. Through the synchronization of data collected from both measurements, patterns of posture were arranged chronologically and in conjunction with the tasks performed: (I) "treatment" (II) "office" and (III) "other activities". For the data analysis, characteristic data of joint angular distributions (percentiles P05, P25, P50, P75 and P95) of head, neck and torso at pre-defined tasks were examined and assessed corresponding to ergonomic standards.
RESULTS: Forty one percent of tasks executed on an average dental workday can be categorized as the treatment of patients. These tasked are most frequently performed in "straight back" positions (78.7 %), whereas 20.1 % were carried out in a "twisted or inclined" torso posture, 1.1 % "bowed" and only 0.1 % "bowed and twisted/inclined to the side" upper body position. In particular, it can be observed that in the area of the cervical and thoracic spine the 75th and 95th percentile show worse angular values during treatment than during non-dental tasks. For the period of treatment (at a standardized dental chair construction), a seated position with a strong inclination of the thoracic spine to the right while the lumbar spine is inclined towards the left is adopted.
CONCLUSION: The kinematic analysis of dentists illustrates typical patterns of postures during tasks that are essential to the dental treatment of patients. The postures in the area of the cervical and thoracic spine have higher angular values during treatment compared to other dental tasks. Consistently, appropriate ergonomic design measures to optimize the dental chair and equipment as well as integrated training in ergonomics as part of the study of dentistry to prevent musculoskeletal are recommended.
A precise definition of a brain state has proven elusive. Here, we introduce the novel local-global concept of intrinsic ignition characterizing the dynamical complexity of different brain states. Naturally occurring intrinsic ignition events reflect the capability of a given brain area to propagate neuronal activity to other regions, giving rise to different levels of integration. The ignitory capability of brain regions is computed by the elicited level of integration for each intrinsic ignition event in each brain region, averaged over all events. This intrinsic ignition method is shown to clearly distinguish human neuroimaging data of two fundamental brain states (wakefulness and deep sleep). Importantly, whole-brain computational modelling of this data shows that at the optimal working point is found where there is maximal variability of the intrinsic ignition across brain regions. Thus, combining whole brain models with intrinsic ignition can provide novel insights into underlying mechanisms of brain states.
The signal transducer and activator of transcription 5 (STAT5) regulates differentiation, survival, proliferation and transformation of hematopoietic cells. Upon cytokine stimulation, STAT5 tyrosine phosphorylation (pYSTAT5) is transient, while in diverse neoplastic cells persistent overexpression and enhanced pYSTAT5 are frequently found. Post-translational modifications might contribute to enhanced STAT5 activation in the context of transformation, but the strength and duration of pYSTAT5 are incompletely understood. We found that O-GlcNAcylation and tyrosine phosphorylation act together to trigger pYSTAT5 levels and oncogenic transcription in neoplastic cells. The expression of a mutated hyperactive gain-of-function (GOF) STAT5 without O-GlcNAcylation resulted in decreased tyrosine phosphorylation, oligomerization and transactivation potential and complete loss of oncogenic transformation capacity. The lack of O-GlcNAcylation diminished phospho-ERK and phospho-AKT levels. Our data show that O-GlcNAcylation of STAT5 is an important process that contributes to oncogenic transcription through enhanced STAT5 tyrosine phosphorylation and oligomerization driving myeloid transformation. O-GlcNAcylation of STAT5 could be required for nutrient sensing and metabolism of cancer cells.
In 2006, the Task Force of the European Society of Cardiology published its consensus document on the use of autologous cell therapy for repair of the heart. Since then, there have been numerous clinical trials and analyses performed to establish the role of autologous cell therapy in the treatment of both acute and chronic cardiac disease. The majority of these studies have been Phase II clinical trials. Phase III clinical trials of autologous cell therapy have been launched (e.g. BAMI), which marks the successful progression of clinical investigation of autologous cell therapy in heart disease. The Task Force has reviewed its 2006 recommendations and the developments in this area of research and proposes updated recommendations for the future of autologous cell therapy in the heart. This article does not duplicate the many reviews on stem cells and the heart but gives considered recommendations based on the experience from the last 10 years.
Background: Recognizing patients at risk for pulmonary complications (PC) is of high clinical relevance. Migration of polymorphonuclear leukocytes (PMN) to inflammatory sites plays an important role in PC, and is tightly regulated by specific chemokines including interleukin (IL)−8 and other mediators such as leukotriene (LT)B4. Previously, we have reported that LTB4 indicated early patients at risk for PC after trauma. Here, the relevance of LTB4 to indicating lung integrity in a newly established long-term porcine severe trauma model (polytrauma, PT) was explored.
Methods: mTwelve pigs (3 months old, 30 ± 5 kg) underwent PT including standardized femur fracture, lung contusion, liver laceration, hemorrhagic shock, subsequent resuscitation and surgical fracture fixation. Six animals served as controls (sham). After 72 h lung damage and inflammatory changes were assessed. LTB4 was determined in plasma before the experiment, immediately after trauma, and after 2, 4, 24 or 72 h. Bronchoalveolar lavage (BAL)-fluid was collected prior and after the experiment.
Results: Lung injury, local gene expression of IL-8, IL-1β, IL-10, IL-18 and PMN-infiltration into lungs increased significantly in PT compared with sham. Systemic LTB4 increased markedly in both groups 4 h after trauma. Compared with declined plasma LTB4 levels in sham, LTB4 increased further in PT after 72 h. Similar increase was observed in BAL-fluid after PT.
Conclusions: In a severe trauma model, sustained changes in terms of lung injury and inflammation are determined at day 3 post-trauma. Specifically, increased LTB4 in this porcine long-term model indicated a rapid inflammatory alteration both locally and systemically. The results support the concept of LTB4 as a biomarker for PC after severe trauma and lung contusion.
The KER for electron capture of vibrational cooled HeH+ and H3 + ions at 20 keV from residual gas atoms has been measured in the Frankfurt Low Energy Storage Ring (FLSR). At a vacuum in the order of few 10-11 mbar, this residual gas consists to 99% of H2 molecules. For the identification of the recoil products of this reaction, a recoil spectrometer (with an MCP-detector with position and time sensitive read out) was installed at one of the focus points (IP) in the FLSR. The planned extension of this set up by a gas target to a full COLTRIMS reaction microscope will be discussed.
Background: Taxonomy offers precise species identification and delimitation and thus provides basic information for biological research, e.g. through assessment of species richness. The importance of molecular taxonomy, i.e., the identification and delimitation of taxa based on molecular markers, has increased in the past decade. Recently developed exploratory tools now allow estimating species-level diversity in multi-locus molecular datasets.
Results: Here we use molecular species delimitation tools that either quantify differences in intra- and interspecific variability of loci, or divergence times within and between species, or perform coalescent species tree inference to estimate species-level entities in molecular genetic datasets. We benchmark results from these methods against 14 morphologically readily differentiable species of a well-defined subgroup of the diverse Drusinae subfamily (Trichoptera, Limnephilidae). Using a 3798 bp (6 loci) molecular data set we aim to corroborate a geographically isolated new species by integrating comparative morphological studies and molecular taxonomy.
Conclusions: Our results indicate that only multi-locus species delimitation provides taxonomically relevant information. The data further corroborate the new species Drusus zivici sp. nov. We provide differential diagnostic characters and describe the male, female and larva of this new species and discuss diversity patterns of Drusinae in the Balkans. We further discuss potential and significance of molecular species delimitation. Finally we argue that enhancing collaborative integrative taxonomy will accelerate assessment of global diversity and completion of reference libraries for applied fields, e.g., conservation and biomonitoring.
Neuroblastoma is a biologically and clinically heterogeneous pediatric malignancy that includes a high-risk subset for which new therapeutic agents are urgently required. As well as MYCN amplification, activating point mutations of ALK and NRAS are associated with high-risk and relapsing neuroblastoma. As both ALK and RAS signal through the MEK/ERK pathway, we sought to evaluate two previously reported inhibitors of ETS-related transcription factors, which are transcriptional mediators of the Ras-MEK/ERK pathway in other cancers. Here we show that YK-4-279 suppressed growth and triggered apoptosis in nine neuroblastoma cell lines, while BRD32048, another ETV1 inhibitor, was ineffective. These results suggest that YK-4-279 acts independently of ETS-related transcription factors. Further analysis reveals that YK-4-279 induces mitotic arrest in prometaphase, resulting in subsequent cell death. Mechanistically, we show that YK-4-279 inhibits the formation of kinetochore microtubules, with treated cells showing a broad range of abnormalities including multipolar, fragmented and unseparated spindles, together leading to disrupted progression through mitosis. Notably, YK-4-279 does not affect microtubule acetylation, unlike the conventional mitotic poisons paclitaxel and vincristine. Consistent with this, we demonstrate that YK-4-279 overcomes vincristine-induced resistance in two neuroblastoma cell-line models. Furthermore, combinations of YK-4-279 with vincristine, paclitaxel or the Aurora kinase A inhibitor MLN8237/Alisertib show strong synergy, particularly at low doses. Thus, YK-4-279 could potentially be used as a single-agent or in combination therapies for the treatment of high-risk and relapsing neuroblastoma, as well as other cancers.
Background: In the area of education research, it is well-known that studies of a defi ned question are seldom replicated. Furthermore, e-learning resources with evidence-based content in dentistry have received relatively little attention from researchers.
The Context and Purpose of the Study: The aim of this clinical study was to evaluate how dentistry students from two consecutive cohorts in their fi rst clinical semester rate a long-standing evidencebased dentistry (EbD) resource in an e-learning environment using a questionnaire of 43 specifi c items on 1) general questions regarding user-friendliness and acceptability, as well as 2) specifi c questions on content and functional range (A), handling and technical aspects (B), and didactics and educational value (C) based on a Likert scale from 0 = ‘strongly disagree’ to 3 = ‘strongly agree’, and how this compares to a primary study in which the resource was addressed as a novelty. The data were analyzed statistically using a one-way ANOVA followed by a Kruskal-Wallis multiple-comparison Z-test.
Results: A response rate of 100% was achieved. The majority of the users thought the topic of EbD to be important. The e-learning resource was rated with a score of 2.40 ± 0.66 (on a Likert scale from 1-6 where 1 = "very good" and 6 = "insuffi cient"). 86.15% of the students stated that they consider the resource benefi cial for their study in clinical simulation and in patient treatment courses. The results averaged for A: 1.92 (±0.57; median: 1.928), B: 1.48 (±0.60), and C: 2.27 (±0.67). The obtained results in the replication study showed no statistical signifi cant differences to the primary study.
Conclusions: The e-learning resource with dentistry vignettes cases and learning components on evidence-based principles was consistently rated positively by the students. Owing to their agreement with the data of the primary study, the results of the present study point to the remarkable validity of the method of evaluation. This should be addressed in future studies with larger cohorts.
Background: Self-myofascial release (SMR) aims to mimic the effects of manual therapy and tackle dysfunctions of the skeletal muscle and connective tissue. It has been shown to induce improvements in flexibility, but the underlying mechanisms are still poorly understood. In addition to neuronal mechanisms, improved flexibility may be driven by acute morphological adaptations, such as a reduction in passive tissue stiffness or improved movement between fascial layers. The aim of the intended study is to evaluate the acute effects of SMR on the passive tissue stiffness of the anterior thigh muscles and the sliding properties of the associated fasciae.
Methods: In a crossover study de sign, 16 participants will receive all of the following interventions in a permutated random order: (1) one session of 2 × 60 s of SMR at the anterior thigh, (2) one session of 2 × 60 s of passive static stretching of the anterior thigh and (3) no intervention. Passive tissue stiffness, connective tissue sliding, angle of first stretch sensation, as well as maximal active and passive knee flexion angle, will be evaluated before and directly after each intervention.
Discussion: The results of the intended study will allow a better understanding of, and provide further evidence on, the local effects of SMR techniques and the underlying mechanisms for flexibility improvements.
Human immunodeficiency virus type 1 (HIV-1) infection of dividing and nondividing cells involves regulatory interactions with the nuclear pore complex (NPC), followed by translocation to the nucleus and preferential integration into genomic areas in proximity to the inner nuclear membrane (INM). To identify host proteins that may contribute to these processes, we performed an overexpression screen of known membrane-associated NE proteins. We found that the integral transmembrane proteins SUN1/UNC84A and SUN2/UNC84B are potent or modest inhibitors of HIV-1 infection, respectively, and that suppression corresponds to defects in the accumulation of viral cDNA in the nucleus. While laboratory strains (HIV-1NL4.3 and HIV-1IIIB) are sensitive to SUN1-mediated inhibition, the transmitted founder viruses RHPA and ZM247 are largely resistant. Using chimeric viruses, we identified the HIV-1 capsid (CA) protein as a major determinant of sensitivity to SUN1, and in vitro-assembled capsid-nucleocapsid (CANC) nanotubes captured SUN1 and SUN2 from cell lysates. Finally, we generated SUN1−/− and SUN2−/− cells by using CRISPR/Cas9 and found that the loss of SUN1 had no effect on HIV-1 infectivity, whereas the loss of SUN2 had a modest suppressive effect. Taken together, these observations suggest that SUN1 and SUN2 may function redundantly to modulate postentry, nuclear-associated steps of HIV-1 infection.
IMPORTANCE HIV-1 causes more than 1 million deaths per year. The life cycle of HIV-1 has been studied extensively, yet important steps that occur between viral capsid release into the cytoplasm and the expression of viral genes remain elusive. We propose here that the INM components SUN1 and SUN2, two members of the linker of nucleoskeleton and cytoskeleton (LINC) complex, may interact with incoming HIV-1 replication complexes and affect key steps of infection. While overexpression of these proteins reduces HIV-1 infection, disruption of the individual SUN2 and SUN1 genes leads to a mild reduction or no effect on infectivity, respectively. We speculate that SUN1/SUN2 may function redundantly in early HIV-1 infection steps and therefore influence HIV-1 replication and pathogenesis.
Although often depicted as rigid structures, proteins are highly dynamic systems, whose motions are essential to their functions. Despite this, it is difficult to investigate protein dynamics due to the rapid timescale at which they sample their conformational space, leading most NMR-determined structures to represent only an averaged snapshot of the dynamic picture. While NMR relaxation measurements can help to determine local dynamics, it is difficult to detect translational or concerted motion, and only recently have significant advances been made to make it possible to acquire a more holistic representation of the dynamics and structural landscapes of proteins. Here, we briefly revisit our most recent progress in the theory and use of exact nuclear Overhauser enhancements (eNOEs) for the calculation of structural ensembles that describe their conformational space. New developments are primarily targeted at increasing the number and improving the quality of extracted eNOE distance restraints, such that the multi-state structure calculation can be applied to proteins of higher molecular weights. We then review the implications of the exact NOE to the protein dynamics and function of cyclophilin A and the WW domain of Pin1, and finally discuss our current research and future directions.
Background and aims: Liver steatosis has shown to be associated with coronary artery disease (CAD). The aim of our study was to evaluate the association between the presence and severity of CAD and Non-alcoholic fatty liver disease (NAFLD) assessed by transient elastography (TE) and controlled attenuation parameter (CAP).
Methods: 576 Patients undergoing coronary angiography were enrolled in this prospective study, receiving at least 10 TE and CAP measurements using the FibroScan® M-probe. Clinically relevant CAD (CAD 3) was defined as stenosis with ≥75% reduction of the luminal diameter. NAFLD was determined by CAP ≥234 dB/m. NAFLD with advanced fibrosiswas determined by TE-values ≥7.9kPa in the presence of NAFLD and absence of congestive or right-sided heart failure. Rates and 95% confidence intervals are shown.
Results: 505 patients were available for analysis of NAFLD. However, only 392 patients were available for analysis of NAFLD with advanced fibrosis, since 24 patients had to be excluded due to non valid TE-measurements and 89 patients due to congestive or right-sided heart failure or suspected concomitant liver disease, respectively. 70.5% (66.3%-74.4%) of patients had CAD 3, 71.5% (67.3%-75.4%) were diagnosed with NAFLD, and 11.2% (8.3%-14.8%) with NAFLD with advanced fibrosis. Patients with CAD 3 had higher median CAP-values (273±61 vs. 260±66 dB/m; p = 0.038) and higher degrees of steatosis as compared to patients without CAD 3. While NAFLD was significantly more often diagnosed in patients with CAD 3 (75.0% vs. 63.1%, p = 0.0068), no significant difference was found for NAFLD with advanced fibrosis (10.7% vs. 12.5%, p = 0.60).
Conclusions: Clinically relevant CAD is frequently associated with the presence of NAFLD, but not NAFLD with advanced fibrosis.
The process of urbanization is one of the major causes of the global loss of biodiversity; however, cities nowadays also have the potential to serve as new habitats for wildlife. The European rabbit (Oryctolagus cuniculus, L. 1758) is a typical example of a wildlife species that reaches stable population densities in cities. Due to intense plant and soil damages, German city authorities aim to control high rabbit densities through the application of a yearly hunting regime (e. g., in Munich, Berlin or Frankfurt am Main). In contrast, population densities of O. cuniculus are on decline in German rural areas, i. e., numbers of yearly hunting bags decreased. The aim of my doctoral thesis was to answer the following research questions: Do population densities of the European rabbit correlate with the intensity of urbanization in and around Frankfurt am Main and if so, which factors play a role in varying densities? How are burrow construction behaviors and group sizes, daytime activity patterns and anti-predator behaviors as well as communication behaviors of this mammal affected by urbanization?
In my first study, I focused on population dynamics across 17 different study sites in and around Frankfurt. As one of yet few studies, I invented an approach that quantified the intensity of urbanization (degree of urbanity) of each study site base on four variables: (1) intensity of anthropogenic disturbance per min and ha, (2) number of residents within a radius of 500 m, (3) proportion of artificial ground cover and (4) numbers of anthropogenic objects per ha. Spearman rank correlations confirmed that with increasing degree of urbanity also rabbit and burrow densities increased. The access to dense shrubs, bushes etc. as suitable sites for burrow construction is the most determining factor for rabbit abundances, and therefore I presumed different densities along the rural-to-urban gradient to be driven by shifts in the availability of thick vegetation.
In the second study, I calculated two indices that in both cases classified burrows to be either accumulated, evenly or randomly distributed within study sites. Additionally, in cooperation with local hunters the number of burrow entrances and animals that occupy the same burrow had been determined during the hunting season. With increasing degree of urbanity burrow distribution patterns shifted from accumulated in rural areas towards more evenly distributed within the city center of Frankfurt. This is a clear sign for an increasing access to sites suitable for burrow construction along the rural to-urban gradient. Additional Spearman rank correlations revealed that the external dimensions of burrows decreased (shorter distances between entrances) and that burrows became less complex (fewer entrances) along the rural-to-urban gradient. In accordance, the number of rabbits that commonly shared the same burrow system was highest within rural areas, whereas I found mainly pairs and single individuals within highly urbanized study sites.
In the last study I compared activity patterns, burrow use and percentages of anti-predator behaviors from one hour before sunrise until one hour after sunset of rural, suburban and urban rabbit groups. A linear mixed model (LMM) and Spearman rank correlations confirmed that rabbits located at urban and suburban sites spent more time outside their protective burrows compared to their rural conspecifics. At suburban sites, individuals invested the least amount of time in anti-predator behavior. Results of this third study gave evidence that suburban rabbit populations on one hand benefit from less predation pressure by natural predators in comparison to rural sites, whereas on the other hand are exposed to less intense disturbance by humans compared to urban study sites.
The last study focused on the effects that urbanization had on the latrine-based communication behavior of rabbits. As many other mammals, O. cuniculus exchange information via the deposition of excreta in latrines, and depending on the intended receiver(s), latrines are either formed in central areas for within-group communication or at territorial boundaries, e. g., for between-group communication. The relative importance of within- vs. between-group communication depends on, amongst other factors, population densities and group sizes which I proved both to shift along the considered rural-to-urban gradient. I determined latrine sizes, latrine densities and latrine utilization frequencies relative to their distance to the nearest burrow at 15 different study sites. Latrine densities and utilization frequencies increased with increasing distance from the burrow in suburban and urban populations whereas at rural sites, largest latrines and those containing the most fecal pellets were close to the burrow, suggesting that within-group communication prevailed.
To sum up, for the first time, I was able to relate shifts in the ecology and behavior of the European rabbit as adaptations to a gradual anthropogenic habitat alteration that are typical for “urban exploiters”. Especially the suburban habitat provides high landscape heterogeneity (“edge habitat“) which is essential for high and stable rabbit populations. Moreover, here, comparably low human disturbance and predation pressure are given in contrast to the agriculturally transformed, open landscapes which are nowadays typical for most rural areas in central Europe. I argue that this mainly leads to the observed behavioral changes along the rural-to-urban gradient. Future plans for rural land management actions should aim to increase refuge availability by generating networks of ecotones. This would also benefit species that depend on similar ecosystem structures as the European rabbit and are on decline in Germany.
The chemopreventive and anticancer effects of resveratrol (RSV) are widely reported in the literature. Specifically, mechanisms involving epigenetic regulation are promising targets to regulate tumor development. Bromodomains act as epigenetic readers by recognizing lysine acetylation on histone tails and boosting gene expression in order to regulate tissue-specific transcription. In this work, we showed that RSV is a pan-BET inhibitor. Using Differential Scanning Fluorimetry (DSF), we showed that RSV at 100 µM increased the melting temperature (∆Tm) of BET bromodomains by around 2.0 °C. The micromolar dissociation constant (Kd) range was characterized using Isothermal Titration Calorimetry (ITC). The RSV Kd value accounted to 6.6 µM in case of BRD4(1). Molecular docking proposed the binding mode of RSV against BRD4(1) mimicking the acetyl-lysine interactions. All these results suggest that RSV can also recognize epigenetic readers domains by interacting with BET bromodomains.
Sexuelle Dysfunktionen bei Frauen mit Posttraumatischer
Belastungsstörung – ein Übersichtsartikel
(2017)
Sexual dysfunctions, clinical as well as subclinical, and other sexual complaints that accompany aversive emotions, cognitions, and sexual risk behavior are very common among women after experiences of sexual violence and are underestimated as a problem. Anyway, among victims of other kinds of traumatic experiences, a high prevalence of sexual distress is found as well. Explanatory approaches concentrate on learning theory as well as the phenomenology of Posttraumatic Stress Disorder (PTSD) itself. Sexuality is an important source of vitality, and the maintenance of sexual dysfunctions can be accompanied by a risk of impairments in quality of life and self-esteem as well as relationship problems. Aside clinical practice, there is also a lack of knowledge in clinical science regarding the association between sexual dysfunctions and traumatic experiences, especially sexual ones. In this article, the phenomenology and diagnostic instruments of female sexual dysfunctions are presented, and consequences of sexual violence on sexuality, also in the context of PTSD, are further explained. Suggestions are being made on how to include suitable interventions into therapy.
Die Psoriasis vulgaris (PsV) ist eine immunvermittelte entzündliche Erkrankung der Haut mit einer Prävalenzrate von 2-3 %, sodass etwa zwei Millionen Menschen in Deutschland an dieser erkrankt sind. Charakteristisch für die PsV sind veränderte Hautareale (Plaques), die im Rahmen der der entzündungsbedingten Durchblutungssteigerung gerötet erscheinen und eine silbrig-weiße Schuppung als Resultat einer vermehrten Abschilferung abgestorbener Keratinozyten aus der hyperproliferativen Epidermis aufweisen.
In dieser Arbeit wurde die Bedeutung des proinflammatorischen Zytokins granulocyte-macrophage colony-stimulating factor (GM-CSF) in der Pathogenese einer modellhaften Experimentalerkrankung der PsV untersucht. GM-CSF wird unter anderem von Interleukin (IL-) 17 produzierenden T-Helferzellen (Th17-Zellen) sezerniert, deren pathogenetische Bedeutung für die PsV gut etabliert ist. Die pathogene Wirkung von GM-CSF als Effektorzytokin konnte bereits in Tiermodellen anderer Th17-vermittelter Autoimmunerkrankungen wie der multiplen Sklerose und der rheumatoiden Arthritis (RA) gezeigt und die therapeutische Wirkung von GM-CSF-neutralisierenden Antikörpern in klinischen Studien an RA-Patienten demonstriert werden.
Das in dieser Arbeit angewendete murine Krankheitsmodell der Imiquimod (IMQ-) induzierten psoriasiformen Dermatitis wird durch die topische Anwendung des Medikaments Aldara®, dessen Wirkstoff IMQ ist, ausgelöst und führt zu einer Entzündung der Haut, die in vielen Aspekten dem humanen Krankheitsbild einer PsV ähnelt. Die pathogenetische Bedeutung von GM-CSF für die IMQ-induzierte psoriasiforme Dermatitis wurde über zwei unterschiedliche experimentelle Ansätze untersucht. So wurde GM-CSF in C57Bl/6J Mäusen mittels eines spezifischen, rekombinanten murinen Antikörpers in der Induktionsphase des Krankheitsmodells neutralisiert und zeitgleich der modifizierte Psoriasis Area Severity Index (PASI-)Score als Parameter des Schweregrades der klinischen Manifestationen ermittelt. Des Weiteren wurde am Versuchsende die Infiltration von Immunzellen in das entzündete Gewebeareal untersucht. Diese Ergebnisse wurden mit den Daten einer Behandlungsgruppe, nach Applikation eines IgG-Isotyp identischen Kontrollantikörpers verglichen. Dabei zeigte die Neutralisierung des Zytokins einen therapeutischen Effekt, der in einem signifikant niedrigeren PASI-Score, einer verringerten Tnfa mRNA Expression und einer reduzierten Infiltration mit neutrophilen Granulozyten resultierte.
Parallel zu diesen Versuchen wurde die Modellerkrankung auch in einer GM-CSF-defizienten C57Bl/6J Mauslinien (GM-CSF-/-) studiert. Die funktionelle Inaktivität des GM-CSF-kodierenden Csf2 Gens wurde 1994 durch gezielte genetische Manipulation etabliert. Unter den experimentellen Bedingungen war der Schweregrad der IMQ-induzierten psoriasiformen Dermatitis in GM-CSF-/- Mäusen nicht signifikant different von dem der wildtypischen (Wt) Mäuse und zeigte somit im Gegensatz zu den Ergebnissen aus den Versuchsreihen der Antikörper vermittelten Zytokinneutralisierung keinen offensichtlichen Hinweis auf eine GM-CSF-Abhängigkeit. In den GM-CSF-defizienten Tieren war jedoch nach IMQ-Induktion eine signifikant höhere Il6 und Il22 mRNA Expression am Entzündungsort im Vergleich zu den Wt Mäusen auffällig. Aufgrund dieser Ergebnisse wurde der Phänotyp der GM-CSF-defizienten Mäuse genauer untersucht und eine vermehrte Anzahl plasmazytoider dendritischen Zellen (pDCs) in Milz und Lymphknoten nachgewiesen. Diese Zellen werden im Rahmen ihrer Differenzierung aus Vorläuferzellen durch GM-CSF suppressiv reguliert und sind sowohl in die Entwicklung der PsV im Menschen als auch die Pathogenese der IMQ-induzierten psoriasiformen Dermatitis involviert. Aufgrund des in den sekundären lymphatischen Organen GM-CSF-defizienter Mäuse expandierten pDC-Kompartiments wurde die Beteiligung dieser Zellen in der Initiationsphase des Modells analysiert. Im Vergleich mit GM-CSF-suffizienten C57Bl/6J Mäusen weisen die Tiere der GM-CSF-defizienten Mauslinie zu diesen Zeitpunkten eine verstärkte Infiltration von pDCs in die Haut auf. Für pDCs ist bekannt, dass sie über die Produktion von IL-6 und TNF die Effektorzelldifferenzierung aktivierter, naiver T-Lymphozyten in Richtung Th22-Zellen polarisieren können. Dieser Mechanismus liefert ein hypothetisches Konzept, das die Ergebnisse zur gesteigerten IL-6-Produktion und Differenzierung IL-22-produzierender T-Zellen in IMQ-behandelten GM-CSF-/- Mäusen im Kontext der nachweisbaren Expansion von pDCs, erklären könnte. Dieser in den GM-CSF-/- Mäusen nachweisbare alternative Pathogenesemechanismus, ist offenbar geeignet die proinflammatorische Wirkung des genetisch fehlenden Zytokins zu kompensieren, aber hinsichtlich seiner Etablierung über ein verändertes pDC-Kompartiment von Dauer und Ausmaß der GM-CSF-Defizienz abhängig. So erklärt sich, warum die zeitlich limitierte Antikörper vermittelte GM-CSF-Neutralisierung in GM-CSF-suffizienten-Mäusen zu keiner pDC-Expansion und Steigerung von IL-6 und IL-22 Expression nach IMQ-Induktion führt.
Die GM-CSF-Neutralisierung durch einen rekombinanten murinen Antikörper reduziert deutlich die Krankheitsschwere der IMQ-induzierten psoriasiformen Dermatitis und belegt damit das therapeutische Potenzial dieses Therapieansatzes für die Humanerkrankung der PsV. Die unter angeborener GM-CSF-Defizienz in den Studien darüber hinaus aufgedeckten Veränderungen des pDC-Kompartiments sind von potenzieller Relevanz für zukünftige therapeutische Anwendungen dieses Prinzips, da unter einer dauerhaften GM-CSF-Neutralisierung mit therapeutischen Antikörpern ein Monitoring dieser Zellpopulation empfehlenswert erscheint z.B. über veränderte Interferonsignaturen durch pDCs, um mögliche Wirkverluste, aber auch unerwünschte Effekte zu erkennen.
Reticulate evolution is considered to be among the main mechanisms of plant evolution, often leading to the establishment of new species. However, complex evolutionary scenarios result in a challenging definition of evolutionary and taxonomic units. In this study, we aimed to examine the evolutionary origin and revise the species status of Campanula baumgartenii, a rare endemic species from the polyploid complex Campanula section Heterophylla. Morphometry, flow cytometric ploidy estimation, amplified fragment length polymorphisms (AFLPs), as well as chloroplast and nuclear DNA sequence markers were used to assess the morphological and genetic differentiation among C. baumgartenii, Campanula rotundifolia and other closely related taxa. Tetra- and hexaploid C. baumgartenii is morphologically and molecularly (AFLP) differentiated from sympatric C. rotundifolia. Contrasting signals from nuclear (ITS) and chloroplast (trnL-rpl32) markers suggest a hybrid origin of C. baumgartenii with C. rotundifolia and a taxon related to the alpine Campanula scheuchzeri as ancestors. Additionally, hexaploid C. baumgartenii currently hybridizes with co-occurring tetraploid C. rotundifolia resulting in pentaploid hybrids, for which C. baumgartenii serves as both seed and pollen donor. Based on the molecular and morphological differentiation, we propose to keep C. baumgartenii as a separate species. This study exemplifies that detailed population genetic studies can provide a solid basis for taxonomic delimitation within Campanula section Heterophylla as well as for sound identification of conservation targets.
According to a proposal by 't Hooft, information loss introduced by constraints in certain classical dissipative systems may lead to quantization. This scheme can be realized within the Bateman model of two coupled oscillators, one damped and one accelerated. In this paper we analyze the links of this approach to effective Hamiltonians where the environmental degrees of freedom do not appear explicitly but their effect leads to the same friction force appearing in the Bateman model. In particular, it is shown that by imposing constraints, the Bateman Hamiltonian can be transformed into an effective one expressed in expanding coordinates. This one can be transformed via a canonical transformation into Caldirola and Kanai's effective Hamiltonian that can be linked to the conventional system-plus-reservoir approach, for example, in a form used by Caldeira and Leggett.
Rechtspopulistische Bewegungen machen sich zur Zeit in vielen westlichen Staaten zum Sprachrohr angeblich bisher unterdrückter Bevölkerungsgruppen und Meinungen. Die identitäre Bewegung entwickelt diesen Ansatz weiter zu einem Projekt der autoritären Staatlichkeit gegen Multikulturalismus, Islam und Einwanderung. Dabei verbindet sie ihre Kampagne für einen ethnisch geschlossen Nationalstaat mit der Kritik an der kapitalistischen Globalisierung. Mit einem Sprachduktus, der Politik emotionalisiert, wird durch «geistige Verschärfung» das Programm eines defensiven Ethnonationalismus entfaltet. Dieser beruft sich auf Traditionsbestandteile eines völkischen Antimodernismus und eine von dem russischen Philosophen Alexander Dugin entworfene eurasische Geopolitik.
Ein europäischer Keynesianismus als Grundlage für ein gesamteuropäisches Wirtschaftskonzept würde als offensive Gegenstrategie die Idee einer sozialstaatlichen Erneuerung propagieren können. Zudem sind Akteure aus der Zivilgesellschaft aufgefordert, gegen Fremdenfeindlichkeit und Orientierungsverlust aufklärerisch zu wirken.
Background: Modulation of cortical excitability by transcranial magnetic stimulation (TMS) is used for investigating human brain functions. A common observation is the high variability of long-term depression (LTD)-like changes in human (motor) cortex excitability. This study aimed at analyzing the response subgroup distribution after paired continuous theta burst stimulation (cTBS) as a basis for subject selection.
Methods: The effects of paired cTBS using 80% active motor threshold (AMT) in 31 healthy volunteers were assessed at the primary motor cortex (M1) corresponding to the representation of the first dorsal interosseous (FDI) muscle of the left hand, before and up to 50 min after plasticity induction. The changes in motor evoked potentials (MEPs) were analyzed using machine-learning derived methods implemented as Gaussian mixture modeling (GMM) and computed ABC analysis.
Results: The probability density distribution of the MEP changes from baseline was tri-modal, showing a clear separation at 80.9%. Subjects displaying at least this degree of LTD-like changes were n = 6 responders. By contrast, n = 7 subjects displayed a paradox response with increase in MEP. Reassessment using ABC analysis as alternative approach led to the same n = 6 subjects as a distinct category.
Conclusion: Depressive effects of paired cTBS using 80% AMT endure at least 50 min, however, only in a small subgroup of healthy subjects. Hence, plasticity induction by paired cTBS might not reflect a general mechanism in human motor cortex excitability. A mathematically supported criterion is proposed to select responders for enrolment in assessments of human brain functional networks using virtual brain lesions.
In this work we present, for the first time, the non-perturbative renormalization for the unpolarized, helicity and transversity quasi-PDFs, in an RI′ scheme. The proposed prescription addresses simultaneously all aspects of renormalization: logarithmic divergences, finite renormalization as well as the linear divergence which is present in the matrix elements of fermion operators with Wilson lines. Furthermore, for the case of the unpolarized quasi-PDF, we describe how to eliminate the unwanted mixing with the twist-3 scalar operator.
We utilize perturbation theory for the one-loop conversion factor that brings the renormalization functions to the MS-scheme at a scale of 2 GeV. We also explain how to improve the estimates on the renormalization functions by eliminating lattice artifacts. The latter can be computed in one-loop perturbation theory and to all orders in the lattice spacing.
We apply the methodology for the renormalization to an ensemble of twisted mass fermions with Nf = 2 + 1 + 1 dynamical quarks, and a pion mass of around 375 MeV.
Motivated by recent experimental suggestions of charge-order-driven ferroelectricity in organic charge-transfer salts, such as κ-(BEDT-TTF)2Cu[N(CN)2]Cl, we investigate magnetic and charge-ordered phases that emerge in an extended two-orbital Hubbard model on the anisotropic triangular lattice at 3/4 filling. This model takes into account the presence of two organic BEDT-TTF molecules, which form a dimer on each site of the lattice, and includes short-range intramolecular and intermolecular interactions and hoppings. By using variational wave functions and quantum Monte Carlo techniques, we find two polar states with charge disproportionation inside the dimer, hinting to ferroelectricity. These charge-ordered insulating phases are stabilized in the strongly correlated limit and their actual charge pattern is determined by the relative strength of intradimer to interdimer couplings. Our results suggest that ferroelectricity is not driven by magnetism, since these polar phases can be stabilized also without antiferromagnetic order and provide a possible microscopic explanation of the experimental observations. In addition, a conventional dimer-Mott state (with uniform density and antiferromagnetic order) and a nonpolar charge-ordered state (with charge-rich and charge-poor dimers forming a checkerboard pattern) can be stabilized in the strong-coupling regime. Finally, when electron–electron interactions are weak, metallic states appear, with either uniform charge distribution or a peculiar 12-site periodicity that generates honeycomb-like charge order.
Transition path sampling is a powerful tool in the study of rare events. Shooting trial trajectories from configurations along existing transition paths proved particularly efficient in the sampling of reactive trajectories. However, most shooting attempts tend not to result in transition paths, in particular in cases where the transition dynamics has diffusive character. To overcome the resulting efficiency problem, we developed an algorithm for “shooting from the top.” We first define a shooting range through which all paths have to pass and then shoot off trial trajectories only from within this range. For a well chosen shooting range, nearly every shot is successful, resulting in an accepted transition path. To deal with multiple mechanisms, weighted shooting ranges can be used. To cope with the problem of unsuitably placed shooting ranges, we developed an algorithm that iteratively improves the location of the shooting range. The transition path sampling procedure is illustrated for models of diffusive and Langevin dynamics. The method should be particularly useful in cases where the transition paths are long so that only relatively few shots are possible, yet reasonable order parameters are known.
A booming middle class, new attractive study destinations and a resulting shift in student mobility trends have recently established a new dynamic in international higher education. To stay competitive, countries apply marketing strategies to promote and "sell" their higher education to international students-cum-customers. With the growing use of the Internet to research study destinations, the role of online channels in higher education promotion is becoming increasingly important. The current study investigates the case of Malaysian higher education branding in cyberspace. By applying content analysis to the two major higher education online platforms, this study identifies the core brand values of Malaysian higher education and evaluates their coherence. The research findings demonstrate that both platforms combine nation and higher education branding efforts to create a harmonised image of the national higher education system. Additionally, several suggestions are made concerning the optimisation of the architecture and information presentation of the websites to enhance their attractiveness for users. Finally, the necessity of further investigation into higher education branding for the successful implementation of internationalisation policies in Malaysia is emphasised.
Binding free energy calculations that make use of alchemical pathways are becoming increasingly feasible thanks to advances in hardware and algorithms. Although relative binding free energy (RBFE) calculations are starting to find widespread use, absolute binding free energy (ABFE) calculations are still being explored mainly in academic settings due to the high computational requirements and still uncertain predictive value. However, in some drug design scenarios, RBFE calculations are not applicable and ABFE calculations could provide an alternative. Computationally cheaper end-point calculations in implicit solvent, such as molecular mechanics Poisson–Boltzmann surface area (MMPBSA) calculations, could too be used if one is primarily interested in a relative ranking of affinities. Here, we compare MMPBSA calculations to previously performed absolute alchemical free energy calculations in their ability to correlate with experimental binding free energies for three sets of bromodomain–inhibitor pairs. Different MMPBSA approaches have been considered, including a standard single-trajectory protocol, a protocol that includes a binding entropy estimate, and protocols that take into account the ligand hydration shell. Despite the improvements observed with the latter two MMPBSA approaches, ABFE calculations were found to be overall superior in obtaining correlation with experimental affinities for the test cases considered. A difference in weighted average Pearson () and Spearman () correlations of 0.25 and 0.31 was observed when using a standard single-trajectory MMPBSA setup ( = 0.64 and = 0.66 for ABFE; = 0.39 and = 0.35 for MMPBSA). The best performing MMPBSA protocols returned weighted average Pearson and Spearman correlations that were about 0.1 inferior to ABFE calculations: = 0.55 and = 0.56 when including an entropy estimate, and = 0.53 and = 0.55 when including explicit water molecules. Overall, the study suggests that ABFE calculations are indeed the more accurate approach, yet there is also value in MMPBSA calculations considering the lower compute requirements, and if agreement to experimental affinities in absolute terms is not of interest. Moreover, for the specific protein–ligand systems considered in this study, we find that including an explicit ligand hydration shell or a binding entropy estimate in the MMPBSA calculations resulted in significant performance improvements at a negligible computational cost.
Random graph models, originally conceived to study the structure of networks and the emergence of their properties, have become an indispensable tool for experimental algorithmics. Amongst them, hyperbolic random graphs form a well-accepted family, yielding realistic complex networks while being both mathematically and algorithmically tractable. We introduce two generators MemGen and HyperGen for the G_{alpha,C}(n) model, which distributes n random points within a hyperbolic plane and produces m=n*d/2 undirected edges for all point pairs close by; the expected average degree d and exponent 2*alpha+1 of the power-law degree distribution are controlled by alpha>1/2 and C. Both algorithms emit a stream of edges which they do not have to store. MemGen keeps O(n) items in internal memory and has a time complexity of O(n*log(log n) + m), which is optimal for networks with an average degree of d=Omega(log(log n)). For realistic values of d=o(n / log^{1/alpha}(n)), HyperGen reduces the memory footprint to O([n^{1-alpha}*d^alpha + log(n)]*log(n)). In an experimental evaluation, we compare HyperGen with four generators among which it is consistently the fastest. For small d=10 we measure a speed-up of 4.0 compared to the fastest publicly available generator increasing to 29.6 for d=1000. On commodity hardware, HyperGen produces 3.7e8 edges per second for graphs with 1e6 < m < 1e12 and alpha=1, utilising less than 600MB of RAM. We demonstrate nearly linear scalability on an Intel Xeon Phi.
We have developed and characterized the novel PTR3, a proton transfer reaction-time-of-flight mass spectrometer (PTR-TOF) using a new gas inlet and an innovative reaction chamber design. The reaction chamber consists of a tripole operated with rf voltages generating an electric field only in the radial direction. An elevated electrical field is necessary to reduce clustering of primary hydronium (H3O+) and product ions with water molecules present in the sample gas. The axial movement of the ions is achieved by the sample gas flow only. Therefore, the new design allows a 30-fold longer reaction time and a 40-fold increase in pressure compared to standard PTR-TOF-MS. First calibration tests show sensitivities of up to 18000 counts per second/parts per billion and volume (cps/ppbv) at a mass resolution of >8000 m/Δm (fwhm). The new inlet using center-sampling through a critical orifice reduces wall losses of low volatility compounds. Therefore, the new PTR3 instrument is sensitive to VOC typically present in the ppbv range as well as to semivolatile organic compounds (SVOC) and even highly oxidized organic molecules (HOMs) present in the parts per quadrillion per volume (ppqv) range in the atmosphere.
We present a calculation of the global polarization of Λ hyperons in relativistic Au–Au collisions at RHIC Beam Energy Scan range sNN−−−√=7.7−200 GeV with a 3+1-dimensional cascade+viscous hydro model, UrQMD+vHLLE. Within this model, the mean polarization of Λ in the out-of-plane direction is predicted to decrease rapidly with collision energy from a top value of about 2% at the lowest energy examined. We explore the connection between the polarization signal and thermal vorticity and estimate the feed-down contribution to Λ polarization due to the decay of higher mass hyperons.
We are pleased to introduce the sixth Journal Club. This edition is focused on several relevant studies published in the last years in the field of Strength and Conditioning, chosen by our Editorial Board members and their colleagues. We hope to stimulate your curiosity in this field and to share with you the passion for sport and exercise seen from a scientific point of view. The Editorial Board members wish you an inspiring read.
Within the last year, expressions of second-hand embarrassment on Twitter significantly increased. We show how this relates to the current situation in U.S. politics under Trump and provide two explanations for why people feel this way in response to his actions. First, compared to former politicians, Trump’s norm violations seem intentional. Second, intentional norm violations specifically threaten the social integrity of in-group members—in this case, U.S citizens. We theorize that these strong, frequent and widespread feelings of second-hand embarrassment motivate political actions to prevent further harm to individuals’ self-concept and protect their social integrity.
Objectives The following study analyses the influence of risk factors among the occupational group of truck drivers on postural control and body mass index (BMI).
Design Observational study.
Setting One motorway station close to several highways in Germany.
Participants 180 truck drivers (177 male/3 female), aged 21–65 years old, took part in this study.
Outcome measures Postural control was examined using a pressure plate. In order to examine the influence of body weight (BMI) and working years on postural control, subjects were divided into samples of five and three groups, respectively. Furthermore, it was evaluated whether the subjects suffered from back pain. For data analysis, the Kruskal-Wallis test was used as the data were not normally distributed. Once the p value of the Kruskal-Wallis test was p≤0.05, the Conover-Iman comparison and afterwards the Bonferroni-Holm correction were used. The significance level was set at α ≤0.05.
Results Regarding the number of working years, a significant increase of frontal (p≤0.04) and sagittal (p≤0.001) sway were observed. The correlation of the five BMI groups with the number of working years demonstrates that an increase of the working years leads to an increase of BMI (p≤0.03). Furthermore, the majority of truck drivers participating in this study suffered from back pain (61.7%).
Conclusions BMI and musculoskeletal impairment are indicators of health risk factors. In this study, it is shown that an increasing number of working years and an increasing BMI lead to a decrease in frontal and sagittal postural sway. In addition, the number of working years correlates with body weight and back pain.
SAFE Newsletter : 2017, Q4
(2017)
People know surprisingly little about their own visual behavior, which can be problematic when learning or executing complex visual tasks such as search of medical images. We investigated whether providing observers with online information about their eye position during search would help them recall their own fixations immediately afterwards. Seventeen observers searched for various objects in “Where's Waldo” images for 3 s. On two-thirds of trials, observers made target present/absent responses. On the other third (critical trials), they were asked to click twelve locations in the scene where they thought they had just fixated. On half of the trials, a gaze-contingent window showed observers their current eye position as a 7.5° diameter “spotlight.” The spotlight “illuminated” everything fixated, while the rest of the display was still visible but dimmer. Performance was quantified as the overlap of circles centered on the actual fixations and centered on the reported fixations. Replicating prior work, this overlap was quite low (26%), far from ceiling (66%) and quite close to chance performance (21%). Performance was only slightly better in the spotlight condition (28%, p = 0.03). Giving observers information about their fixation locations by dimming the periphery improved memory for those fixations modestly, at best.
Gene trap mutagenesis is a powerful tool to create loss-of-function mutations in mice and other model organisms. Modifications of traditional gene trap cassettes, including addition of conditional features in the form of Flip-excision (FlEx) arrays to enable directional gene trap cassette inversions by Cre and Flpe site-specific recombinases, greatly enhanced their experimental potential. By taking advantage of these conditional gene trap cassettes, we developed a generic strategy for generating conditional mutations and validated this strategy in mice carrying a multipurpose allele of the Prdm16 transcription factor gene. We demonstrate that the gene trap insertion creates a null mutation replicating the Pierre Robin sequence-type cleft palate phenotype of other Prdm16 mutant mice. Consecutive breeding to Flpe and Emx1IREScre deleter mice spatially restricted Prdm16 loss to regions of the forebrain expressing the homeobox gene Emx1, demonstrating the utility of the technology for the analysis of tissue-specific gene functions.
The measurement of psychopathic personality traits via self-report has become an important tool in legal psychology. One prominent instrument is the Psychopathic Personality Inventory (PPI; Lilienfeld and Andrews, 1996), a well-validated questionnaire that is widely applied in many countries. In Germany, it is the only questionnaire assessing psychopathic traits that is available from a publisher with a manual edited for easy administration. Nevertheless, the PPI shows certain shortcomings: the high number of 154 items makes it less economic, it was developed on a non-representative undergraduate sample, and studies revealed an inconsistent factor structure. To overcome these points, a new questionnaire, the Questionnaire of Psychopathic Personality Traits [German: Fragebogen Psychopathischer Persönlichkeitseigenschaften (FPP)] was developed. The sample consists of n = 132 civilians (56% female) and n = 173 inmates of German correctional facilities (30% female). The FPP comprises 30 items, whose wording was short and adequate for inmates. It shows satisfying psychometric properties regarding factorial structure, item properties, and reliability. Partial invariance regarding both subsamples allows for interpretation of latent means. Results supported validity such as associations with self-reported crime, and inmates’ misconduct. The factorial structure was cross-validated on a second sample of N = 517 participants (71% female) from an online study. The FPP is useful in large-scale research studies as well as for clinical settings, e.g., for treatment planning in correctional facilities.
Public employees in many developing economies earn much higher wages than similar privatesector workers. These wage premia may reflect an efficient return to effort or unobserved skills, or an inefficient rent causing labor misallocation. To distinguish these explanations, we exploit the Kenyan government’s algorithm for hiring eighteen-thousand new teachers in 2010 in a regression discontinuity design. Fuzzy regression discontinuity estimates yield a civil-service wage premium of over 100 percent (not attributable to observed or unobserved skills), but no effect on motivation, suggesting rent-sharing as the most plausible explanation for the wage premium.
This article reports the results of a replication of Bobbitt-Zeher’s 2007 article "The Gender Income Gap and the Role of Education". Models that emulate the original specifications (by and large) reproduce the original results. However, models that adhere to Bobbitt-Zeher’s theory concerning the gendered effect of family formation call into question her finding that "values appear to matter only modestly, while family formation has virtually no effect on the income gap".
Der negative Einfluss auf die Abstoßungsrate, die Transplantatfunktion und das Transplantatüberleben bei Nierentransplantationen von Antikörpern, die im Serum von Transplantatempfängern nachgewiesen werden, ist unumstritten. Die Entwicklung immer sensitiverer Methoden zur Antikörperdetektion wie beispielsweise die Luminex-Technologie wirft jedoch neue Fragen auf: Sind die hier nachgewiesenen, zum Teil sehr niedrigtitrigen Antikörper immer noch relevant für das Outcome von Transplantationen? Oder bergen die hier zusätzlich aufgedeckten Antikörper nur die Gefahr in sich, die Organallokation zu erschweren und mögliche komplikationslose Transplantationen zu verhindern? Zur Beantwortung dieser Fragen erfolgte die Durchführung dieser retrospektiven Studie.
In die Studie wurden Seren von 197 Nierentransplantatempfängern eingeschlossen. Diese Seren wurden vor der Transplantation auf Antikörper im Luminex untersucht und anschließend deren Transplantatfunktion und das Transplantatüberleben in Abhängigkeit vom Antikörperstatus ermittelt. Zusätzlich erfolgte eine Gegenüberstellung mit den Ergebnissen aus den im Rahmen der aktuellen Richtlinien zur Transplantationskompatibilität durchgeführten Testmethoden LCT und ELISA.
Bei einem Vergleich der drei unterschiedlichen Techniken zum HLA-Antikörpernachweis zeigte sich, dass der Luminex eine deutlich größere Sensitivität als der ELISA und insbesondere als der LCT besitzt. Außerdem war nachweisbar, dass die mittels Luminex Technology nachgewiesenen HLA-Antikörper ein schlechteres Transplantatüberleben bewirken (Graphik 4). Dies zeigte sich insbesondere, wenn HLA-Klasse I oder gleichzeitig HLA-Klasse I und HLA-Klasse II Antikörper bei Patienten vorhanden sind (Graphik 5). Im Gegensatz dazu fanden sich bei der Betrachtung der Patienten mit im LCT oder im ELISA nachgewiesen HLA-Antikörpern deutlich geringere, klinisch prognostische Hinweise auf das Transplantatüberleben (Graphik 10 und 13).
Das Transplantatüberleben war signifikant besser bei nicht-immunisierten Patienten als bei der Kohorte, die mittels einer der Nachweismethoden HLA-spezifische Antikörper aufwies. Eine Analyse der Transplantatfunktion, die mithilfe der Proteinurie und des Serum-Kreatinins bestimmt wurde, ergab, dass nicht immunisierte Patienten ein besser funktionierendes Transplantat besitzen als antikörperpositive Empfänger. Ein besonders negativer Einfluss donorspezifischer Antikörper konnte hier jedoch nicht nachgewiesen werden.
Im Hinblick auf die klinische Relevanz der nachgewiesenen HLA-Antikörper erfolgte die Auswertung mit unterschiedlichen MFI Kategorien (MFI 1000, 2000, 3000 und 4000). Anhand dieser Arbeit wurde ein MFI-Grenzwert zur Bestimmung des Antikörperstatus im Luminex von größer oder gleich 1000 im Luminex festgelegt, der am besten mit dem Transplantatoutcome korrelierte. Ein negativer Einfluss donorspezifischer Antikörper konnte jedoch nicht nachgewiesen werden. Es zeigte sich dennoch bei MFI Werten über 2000 ein tendenziell schlechteres Transplantatüberleben, wenn donorspezifische Antikörper vorliegen (Graphik 7).
Bei der Betrachtung des Antikörperstatus im LCT und im ELISA war kein Unterschied hinsichtlich des Transplantatüberlebens in Abhängigkeit vom Antikörperstatus sichtbar. Jedoch wurden die Patientenseren mit diesen beiden Methoden vor der Durchführung der Transplantation auf präformierte Antikörper untersucht und bei positiver Befundung eine intensivierte Immunsuppression veranlasst, was zu einer Beeinflussung des Transplantatoutcomes führt. Eine Unterteilung der nicht immunisierten Patienten im LCT und im ELISA anhand des Luminex-Ergebnisses zeigt, dass Patienten, die sowohl im LCT bzw. ELISA als auch im Luminex keine Antikörper aufweisen ein signifikant besseres Transplantatüberleben besitzen als Empfänger, die nur im Luminex immunisiert sind, jedoch nicht im LCT bzw. im ELISA. Dies lässt darauf schließen, dass die Beachtung von Antikörpern, die ausschließlich im Luminex nachgewiesen werden können, zu einem besseren Transplantatoutcome führt. Somit ist eine Durchführung des Luminex in Kombination mit anderen Antikörpernachweisverfahren von Vorteil.
Zur genauen Beantwortung der anfangs aufgeworfenen Fragen bedarf es sicherlich trotz einiger bereits vorhandener Arbeiten – mit zum Teil jedoch sehr unterschiedlichen Ergebnissen – noch zusätzlicher Studien. Auch sollte die Rolle der Denaturierung der HLA-Antigene auf den Beads, die zu falsch positiven und negativen Resultaten führen können, weiter analysiert werden. Außerdem muss der Einfluss komplementaktivierender Antikörper, wie mit der C1q- und C4d-Technik im Luminex nachweisbar, und der Einfluss nicht HLA-spezifischer Antikörper noch genauer erläutert werden.
Autophagy is a membrane-trafficking process that directs degradation of cytoplasmic material in lysosomes. The process promotes cellular fidelity, and while the core machinery of autophagy is known, the mechanisms that promote and sustain autophagy are less well defined. Here we report that the epigenetic reader BRD4 and the methyltransferase G9a repress a TFEB/TFE3/MITF-independent transcriptional program that promotes autophagy and lysosome biogenesis. We show that BRD4 knockdown induces autophagy in vitro and in vivo in response to some, but not all, situations. In the case of starvation, a signaling cascade involving AMPK and histone deacetylase SIRT1 displaces chromatin-bound BRD4, instigating autophagy gene activation and cell survival. Importantly, this program is directed independently and also reciprocally to the growth-promoting properties of BRD4 and is potently repressed by BRD4-NUT, a driver of NUT midline carcinoma. These findings therefore identify a distinct and selective mechanism of autophagy regulation.
Eiskeime (INP) sind Aerosolpartikel, die das Entstehen von Eiskristallen in der Atmosphäre zwischen 0 und -37°C ermöglichen, indem sie die zur Ausbildung der Eisphase nötige Energie gegenüber einem reinen Wassersystem stark herabsetzen. Dabei sind aktive Stellen auf der Oberfläche dieser Partikel für die erste Nukleation von Eis verantwortlich. In der Folge können die Eiskristalle zulasten von verdunstenden Wasserdampfmolekülen und Wassertröpfchen weiter anwachsen. Über Eismultiplikationsprozesse zersplittern und vervielfältigen sich die Eiskristalle und wachsen über Bereifung schließlich zu einer kritischen Größe heran, wodurch sie als Niederschlag zu Boden fallen können. Auch wenn der Anteil der zur heterogenen Eisnukleation fähigen Aerosole vergleichsweise gering ist, spielen INP eine entscheidende Rolle für die Entwicklung von Niederschlag und nehmen Einfluss auf Strahlungsprozesse, indem sie auf die Phase der Wolken und damit auf deren Strahlungseigenschaften einwirken. Viele Fragen im Forschungsgebiet der heterogenen Eisnukleation sind jedoch weiterhin nicht hinreichend genau geklärt. Ohne eine verbesserte Kenntnis von Konzentrationen, geographischer und vertikaler Verteilung, sowie zeitlicher Variation, Quellen und Natur von INP, sind noch vorhandene Wissenslücken im Strahlungsantrieb durch Wechselwirkungen von Aerosolen und Wolken nur zu einem gewissem Grad zu reduzieren. Dies ist nötig, um aktuelle Beobachtungsdaten der sich erwärmenden Atmosphäre besser verstehen und die zukünftigen Änderungen des Klimas sicherer vorhersagen zu können. In dieser Arbeit wird die Vakuumdiffusionskammer FRIDGE verwendet, um atmosphärische INP-Konzentrationen zu bestimmen. Aerosolpartikel werden dabei in einem ersten Schritt auf einem Silicium-Probenträger elektrostatisch niedergeschlagen. Die Effizienz des Sammelprozesses, also der Anteil der Partikel die tatsächlich auf dem Si-Substrat abgeschieden werden, wurde mittels zweier unabhängiger Methoden auf etwa 60% bestimmt. In einem zweiten Mess-Schritt werden die Proben in FRIDGE typischen Bedingungen von Mischphasenwolken ausgesetzt, wodurch Eiskristalle an den INP aktiviert werden und im Verlauf einer Messung anwachsen. Eine Kamera beobachtet die durch das Eiswachstum entstehenden Helligkeitsänderungen auf dem dunklen Probensubstrat. Die Kriterien, wann ein Objekt als Eiskristall identifiziert und gezählt wird, mussten im Rahmen dieser Arbeit neu entwickelt werden. In der zu Beginn der Arbeit vorgefundenen Einstellung hatte bereits eine sehr geringe Helligkeitsänderung, wie sie durch das hygroskopische Wachstum von Aerosolpartikeln hervorgerufen wird, zu Signalen geführt, die fälschlicherweise als Eiskristalle gezählt wurden. Das reevaluierte Messverfahren von FRIDGE wurde im Zuge der FIN-02 Kampagne in einem groß angelegten Laborexperiment an der AIDA Wolkenkammer mit zahlreichen anderen INP-Zählern aus der ganzen Welt verglichen. Für den Großteil der Messungen der untersuchten Modell-Aerosoltypen konnte eine zufriedenstellende Übereinstimmung mit den anderen Instrumenten erzielt werden. In einer einmonatigen Feldmesskampagne im östlichen Mittelmeerraum konnten die ersten INP-Messungen an Bord eines unbemannten Flugzeugs durchgeführt werden. Während der Kampagne auf Zypern wurden mehrere Fälle von transportiertem Saharastaub beprobt, in denen die INP-Konzentration maßgeblich erhöht war. Lidar-Beobachtungen und ein Staubtransportmodell zeigten, dass sich das Maximum der Staubschichten zumeist in etwa 2-4 Kilometern Höhe befand. In der Höhe wurden INP-Konzentrationen gefunden, die im Mittel um einen Faktor 10 größer waren als auf Bodenniveau. Es wird gefolgert, dass INP-Messungen am Boden möglicherweise nur begrenzte Aussagekraft über die Situation nahe der Wolkenbildung besitzen. Im Rahmen BACCHUS-Projekts wurden zwischen August 2014 und Januar 2017 (mit Unterbrechungen) alle 1-2 Tage Proben an drei Reinluftstationen gesammelt (insgesamt über 900). Das INP-Messnetz mit einer geographischen Ausdehnung von der Arktis zum Äquator bestand aus Stationen in Spitzbergen, Martinique und im Amazonas. Die Station im brasilianischen Regenwald ist durch wechselnde Bedingungen von sauberer Regen- und verunreinigter Trockenzeit charakterisiert. In der Trockenzeit steigen die Partikelkonzentrationen durch starke Belastung aus Biomassenverbrennung um eine Größenordnung an; eine gleichzeitige Zunahme der INP-Konzentrationen konnte nicht beobachtet werden. Daraus kann vermutet werden, dass Partikel aus Feueremissionen keine ausgezeichneten Fähigkeiten zur Eisnukleation aufweisen. Die INP-Konzentrationen in der Karibik konnten mit dem Jahresgang von transportieren Saharastaub in Verbindung gebracht werden. In der Arktis wurden die niedrigsten INP-Konzentrationen der drei Stationen beobachtet. Zum Zeitpunkt des Erstellens dieser Arbeit können die determinierenden Einflussfaktoren, sowie der anthropogene Einfluss zur Zeit des arktischen Dunstes noch nicht abschließend geklärt werden.
Schiller and Goethe have very different conceptions of tragedy. In his play Don Carlos, Schiller, especially in the character of Philip II, shows us the conflict between blood and positive law. In Goethe´s novel Elective Affinities, the individual will is ignorant of fate and helpless against it. So to speak, Schiller applies the "Antigone´s Model" and Goethe applies the "Oedipus Model". In his dramatic vision of the conflict, Schiller is inspired by Shakespeare´s plays. However, Goethe´s point of view is based on his reflections on Natural Philosophy.
This is a brief in the bEUcitizen policy brief series. The bEUcitizen project - funded by the European Union - set out to identify, investigate, discuss, and ameliorate the barriers to the active use of rights (and knowledge of duties, the concomitant to rights, in so far as there are any) by European citizens. The project aimed to provide a comparative overview and classification of the various barriers to the exercise of the rights and obligations of European Union citizens in the member states. Simultaneously, the project analysed whether and how such barriers can be overcome and the future opportunities and challenges the European Union and its member states face to further develop the idea and reality of European Union citizenship.
Drawing on research conducted during the project, this policy brief discusses the problems preventing European Union citizens from becoming active political citizens. European citizenship as active political citizenship has been underdeveloped from the start and is currently under strong pressure. Over time, European Union citizens seem to have lost enthusiasm for the European political process: Voter turnout in European Parliament elections decreased from 61,99% in 1979 to 42,61% in 2014. Attempts to transform elections for the European Parliament into a meaningful decision about the policies and the personnel of European institutions have been ineffective so far in two ways: On the one hand, they did not raise more interest in European affairs; on the other hand, and even more problematically, the "Spitzenkandidaten"-experiment was overshadowed by the power struggle between national leaders and the European Parliament.
Although similar tendencies towards decreasing voter turnout can be observed in national elections, the trend of fading popular support is particularly alarming at the European Union level. It threatens to undermine the legitimacy and functionality of the European Union, thus jeopardizing the entire integration process. Institutions without support cannot last. The European Union provokes a rather negative political reaction among its citizens and populist activism is challenging its policies and the integration process more broadly. The Brexit decision expresses this problem in an ideal-typical form: Europe-friendly citizens do not use their right to vote while anti-European activism brings citizens to the ballot box. Concerned with this passivity as well as with the activism mobilised by anti-European populism, Europe-friendly observers and actors see a major opportunity for the European Union to strengthen the European Parliament as the core institution of a European representative democracy.
In dieser Dissertation wurde die Rolle des Proteins Carboxypeptidase E (CPE) im Glioblastom (GBM) untersucht. Ursprünglich wurde CPE in der neuroendokrinen Regulation beschrieben, wo es die Reifung der meisten Neuropeptide und Hormone reguliert und somit Einfluss auf Stoffwechsel und humorale Effekte hat (Fricker et al., 1982; Fricker & Snyder, 1982 and 1983; Davidson & Hutton, 1987; Shen & Loh, 1997; Lou et al., 2005). Ab 1989 wurde CPE in unterschiedlichen Tumorentitäten nachgewiesen (Grimwood et al., 1989; Manser et al., 1991), jedoch ohne Hinweise, welche Bedeutung das Protein dort haben könnte. Erst im letzten Jahrzehnt konnten sowohl pro- als auch anti-tumorigene Wirkungen von CPE gezeigt werden. Die beschriebenen Wirkungen von CPE sind jedoch von dessen Isoform abhängig. Das ∂(delta)N-trunkierte CPE zeigte sich mit erhöhtem Tumorwachstum und schlechter Überlebensprognose in verschiedenen Krebsentitäten assoziiert (Murthy et al., 2010; Lee et al., 2011; Zhou et al., 2013). Im Gegensatz dazu verringerte sezerniertes CPE (sCPE) im Fibrosarkom und Glioblastom die Zellmigration, was einen anti-tumorigenen Effekt suggeriert (Höring et al., 2012; Murthy et al., 2013a). Die Molekularmechanismen, die für die Regulation der Migration zuständig sind, sind jedoch kaum untersucht. Die meisten Untersuchungen von sCPE in Normal- und Tumorgewebe beschränken sich hauptsächlich auf Apoptose und Zellüberleben (Skalka et al., 2013; Murthy et al., 2013b; Cheng et al., 2013; Selvaraj et al., 2015; Cheng et al., 2015). Die vorliegende Arbeit ist demzufolge die erste Studie, die sich dem Mechanismus der Migrationsregulation durch sCPE im Glioblastom widmet.
Humane Gliome stellen die größte und bösartigste Gruppe hirneigener Tumore dar. Bösartige Gliome sind höchst resistent gegen alle zurzeit verfügbaren Behandlungsmethoden. Einer der Hauptgründe dafür ist, dass die Tumorzellen durch diffuse Infiltration in das Gehirn einwandern können. Ferner sind Gliomzellen metabolisch sehr aktiv und können sich dadurch an schnell verändertes Milieu anpassen (Fack et al., 2015; Demeure et al., 2016). Über die grundlegenden Mechanismen für diese Art des infiltrierenden Tumorwachstums ist bisher noch nicht viel bekannt. Zurzeit sind nur wenige Schlüsselfaktoren beschrieben, die den sogenannten Mechanismus der Migration oder Proliferation ("go or grow") in bösartigen Tumoren beeinflussen: wenige Transkriptionsfaktoren, miRNAs sowie metabolische Faktoren. Interessanterweise, sind miRNAs zum Teil mit der Regulation des Metabolismus in Tumorzellen assoziiert. Eine vorangehende Studie aus unserem Labor hat sCPE aufgrund seines Potentials, Zellwanderung zu verringern, als einen weiteren Schlüsselfaktor identifiziert. Wir konnten zeigen, dass sCPE in der Gliomzelllinie LNT-229 zur einer differentiellen Regulation von Migration und Proliferation führt (Höring et al., 2012). Die vorliegende Arbeit widmet sich nun der Frage nach den genauen zugrundeliegenden Mechanismen, wie sCPE seine Effekte auf molekularer Ebene vermittelt. Darüber hinaus soll geklärt werden, ob sCPE auch in der metabolischen Adaptation eine Rolle spielt und dadurch ebenfalls die Gliomzellmigration beeinflußen kann.
Carboxypeptidase E (CPE) has recently been described as a multifunctional protein that regulates proliferation, migration and survival in several tumor entities. In glioblastoma (GBM), the most malignant primary brain tumor, secreted CPE (sCPE) was shown to modulate tumor cell migration. In our current study, we aimed at clarifying the underlying molecular mechanisms regulating anti-migratory as well as novel metabolic effects of sCPE in GBM. Here we show that sCPE activates mTORC1 signaling in glioma cells detectable by phosphorylation of its downstream target RPS6. Additionally, sCPE diminishes glioma cell migration associated with a negative regulation of Rac1 signaling via RPS6, since both inhibition of mTOR and stimulation of Rac1 results in a reversed effect of sCPE on migration. Knockdown of CPE leads to a decrease of active RPS6 associated with increased GBM cell motility. Apart from this, we show that sCPE enhances glucose flux into the tricarboxylic acid cycle at the expense of lactate production, thereby decreasing aerobic glycolysis, which might as well contribute to a less invasive behavior of tumor cells. Our data contributes to a better understanding of the complexity of GBM cell migration and sheds new light on how tumor cell invasion and metabolic plasticity are interconnected.
WiWi news ; Nr. 1 [2017]
(2017)
Wie verhalten sich Freiheit und Geld zueinander? In der liberalen Tradition der Philosophie und der Ökonomik wird Geld meist als bloßes Mittel gefasst, dessen Einführung den Austausch von Waren erleichtert, darüber hinaus jedoch keine tiefergreifenden sozialen Folgen zeitigt. Im Gegensatz hierzu wird in diesem Working Paper der Zusammenhang von Geld und (Un-)Freiheit herausgearbeitet. Im Anschluss an die Tradition kritischer Sozialphilosophie und in Auseinandersetzung mit Marx, Simmel und der neueren Geldsoziologie wird dabei in einem ersten Schritt der paradoxe Charakter dieser gesellschaftlich eröffneten Freiheit dargelegt: Zum einen kultiviert Geld in kapitalistischen Ökonomien eine individuelle Form von Wahlfreiheit. Zum anderen wird über Geld der Zugang zum gesellschaftlichen Reichtum auf ungleiche und disziplinierende Weise strukturiert: Je nach individueller Verfügung über finanzielle Mittel ist man auf unterschiedliche Weise zum Verkauf der eigenen Arbeitskraft angehalten, um den Zugriff auf Güter und die eigene Reproduktion zu sichern. Diese paradoxe Form von Freiheit wird in einem zweiten Schritt hinsichtlich ihrer Entfremdungstendenz befragt: Insofern die über die Institution des Geldes eröffnete Freiheit ihren gesellschaftlichen Ermöglichungsgrund verdeckt, kann sie als eine fetischisierte Form von Freiheit begriffen werden.
The Global Irrigation Model (GIM) is used within the framework of the global hydrological model WaterGAP to calculate monthly irrigation crop water use. Results on a 0.5 degrees grid include, consumption (ICU) and, via division by irrigation efficiencies, water withdrawal (IWU). The model distinguishes up to two cropping periods of rice and non-rice crops, each grown for 150 days, using a grid of area equipped for irrigation (AEI). Historical development of AEI and fraction of area actually irrigated (AAI) was previously considered via scaling of cell-specific results with country-specific factors for each year. In this study, GIM was adapted to use the new Historical Irrigation Data set (HID) with cell-specific AEI for 14 time slices between 1900 and 2005. AEI grids were temporally interpolated, and using the optional grid of AAI/AEI, results for years 1901-2014 were generated (runs "HID-ACT"). Thus, new installation or abandonment of irrigation infrastructure in new grid cells can be represented in a spatially explicit manner. For evaluated years 1910, 1960, 1995, and 2005, ICU from HID-ACT was superior to country-specific scaled results (run "HID-ACTHIST") in representing historical development of the spatial pattern. Compared to US state-level reference data, spatial patterns were better, while country totals were not always better. For calculating the cropping periods, 30-years climate means are needed, the choice of which is relevant. Four chosen periods before 1981-2010 all resulted in considerable, pertaining changes of ICU spatial pattern, and various percent changes in country totals. This might be because of already present climate change.
There is a consensus that transnational soft governance has unleashed the forces of change in higher education. However, individual national HE systems are still anchored in country-specific regulatory regimes, which reflect national-historical, institutional, and cultural developments. Against this background, three crucial questions guide our study: How does the state react to transnational pressures for change? How is transnationally inspired policy change ‘digested’ by the preexisting country-specific governance structures? And to what extent have national HE systems converged on a common governance model? To address these questions, we conduct a multilevel comparative analysis of developments in Germany, France, and Italy. We first break down the concept of higher education governance into sub-dimensions and derive concrete policy indicators for three historically embedded governance ideal types. Drawing on historical institutionalism and institutional isomorphism, we explore how historical legacies and transnational communication have impacted policy pathways over the past 30 years. We graphically illustrate the policy trajectories using our ‘governance triangles’, which encompass the balance of power between multiple actors, including the state and universities, university management and the academic profession, and external stakeholders.
his articles discusses and contextualises tripleC's republication of Franz L. Neumann's essay Anxiety and Politics. It provides some background information on Neumann's life and works. The essay ascertains that in the age of new nationalisms, rising right-wing authoritarianism and authoritarian capitalism, Franz L Neumann's works can help us to critically understand contemporary society.
Sustainable Development Goals (SDGs) comprise of 17 goals and 169 targets. All SDGs are interlinked to produce synergetic eff ects and emphasize health in all policies. Among the 17 Goals, Goal 3 has a central focus on health, which is underpinned by 13 targets. Th e other 16 goals are also directly or indirectly related to health and will contribute to achieving the associated targets for Goal 3. Th e ambitious SDG agenda and their progress can be tracked by measuring numerous goals, targets, and indicators. The main objective of this paper is to provide an overview about how health- related SDGs and their targets and indicators are being tracked in the national context of Nepal. Adequate investment in research for knowledge generation, capacity building and innovation, and continous research communication among policy makers, researchers and external development partners will contribute to tracking the progress of SDGs in Nepal.
Glaucoma quality of life
(2017)
Background: Delayed-onset muscle soreness (DOMS) refers to dull pain and discomfort in people after participating in exercise, sport or recreational physical activities. The aim of this study was to detect underlying mechanical thresholds in an experimental model of DOMS.
Methods: Randomised study to detect mechanical pain thresholds in a randomised order following experimentally induced DOMS of the non-dominant arm in healthy participants. Main outcome was the detection of the pressure pain threshold (PPT), secondary thresholds included mechanical detection (MDT) and pain thresholds (MPT), pain intensity, pain perceptions and the maximum isometric voluntary force (MIVF).
Results: Twenty volunteers (9 female and 11 male, age 25.2 ± 3.2 years, weight 70.5 ± 10.8 kg, height 177.4 ± 9.4 cm) participated in the study. DOMS reduced the PPT (at baseline 5.9 ± 0.4 kg/cm2) by a maximum of 1.5 ± 1.4 kg/cm2 (-24%) at 48 hours (p < 0.001). This correlated with the decrease in MIVF (r = -0.48, p = 0.033). Whereas subjective pain was an indicator of the early 48 hours, the PPT was still present after 72 hours (r = 0.48, p = 0.036). Other mechanical thresholds altered significantly due to DOMS, but did show no clinically or physiologically remarkable changes.
Conclusions: Functional impairment following DOMS seems related to the increased excitability of high-threshold mechanosensitive nociceptors. The PPT was the most valid mechanical threshold to quantify the extent of dysfunction. Thus PPT rather than pain intensity should be considered a possible marker indicating the athletes’ potential risk of injury.
Die chemischen und physikalischen Eigenschaften eines Festkörpers sind vom inneren Aufbau des Festkörpers abhängig. Die Methode der Wahl zur Bestimmung von Kristallstrukturen sind Beugungsexperimente. Fehlordnungen in den Kristallstrukturen werden mit Beugungsexperimenten häufig nur unzureichend ausgewertet oder ignoriert. In dieser Arbeit wurden die (möglichen) Stapelfehlordnungen der Aminosäuren DL-Norleucin und DL-Methionin, sowie von Chloro (phthalocyaninato)aluminium(III) untersucht. Dazu wurden Gitterenergieminimierungen mit Kraftfeld- und quantenchemischen Methoden an einem Satz geordneter Modellstrukturen durchgeführt.
In den Kristallstrukturen der α- und β-Phasen von DL-Norleucin ordnen sich die Moleküle in Doppelschichten an und bilden jeweils eine Schichtstruktur mit unterschiedlicher Stapelsequenz. Röntgenbeugungsexperimente an Kristallen dieser Verbindung zeigen charakteristische diffuse Streuung. Die durchgeführten Gitterenergieminimierungen reproduzieren die experimentelle Stabilitätenreihenfolge der beiden Polymorphe von DL-Norleucin. Die berechneten Gitterenergien zeigen, dass es für DL-Norleucin bevorzugte Stapelsequenzen gibt. Die Gitterenergien und Molekülstrukturen einer einzelnen Doppelschicht sind dabei von der Anordnung benachbarter Doppelschichten abhängig. Zudem wurden Strukturmodelle mit Stapelsequenzen aufgebaut, die aus kristallographischer Sicht möglich sind, jedoch experimentell nicht beobachtet wurden, und deren Gitterenergie berechnet. Diese Stapelsequenzen liefern im Vergleich zu den energetisch günstigsten Stapelsequenzen einen signifikanten Energieverlust und treten daher selten auf. Ausgehend von den Ergebnissen der Gitterenergieminimierungen mit DFT-D-Methoden wurden Stapelwahrscheinlichkeiten mit Hilfe der Boltzmann-Statistik berechnet. Es wurde ein großes geordnetes Modell mit einer Stapelsequenz gemäß der Stapelwahrscheinlichkeiten aufgebaut. Dieses Modell wurde verwendet, um Beugungsexperimente zu simulieren und mit experimentellen Daten zu vergleichen. Die theoretischen und experimentellen Beugungsdaten waren in guter Übereinstimmung.
Die Moleküle in den Kristallstrukturen der α- und β-Phasen von DL-Methionin bilden Doppelschichten. Die beiden Phasen unterscheiden sich in der Stapelung der Doppelschichten und der Molekülkonformation. Es wurden Gitterenergieminimierungen sowohl mit Kraftfeld-Methoden als auch mit DFT-DMethoden an geordneten Modellen mit unterschiedlichen Stapelsequenzendurchgeführt. Die experimentell bestimmte Stabilitätenreihenfolge der Polymorphe von DL-Methionin bei tiefen Temperaturen wurde durch die Ergebnisse der kraftfeldbasierten Rechnungen reproduziert. Die Modellstrukturen wurden während den Rechnungen moderat verzerrt. Die Bandbreite der relativen Energien aller Modelle ist relativ gering, sodass eine Stapelfehlordnung aus thermodynamischer Sicht nicht ausgeschlossen werden kann. In der Regel liefern Gitterenergieminimierungen mit DFT-D Methoden genauere Ergebnisse. Die Modellstrukturen wurden während den Rechnungen nur leicht verzerrt. Allerdings unterscheidet sich das Energieranking zwischen den Kraftfeld- und DFT-D-Methoden deutlich. Die experimentell bestimmte Stabilitätenreihenfolge der Polymorphe von DL-Methionin wurde mit DFT-D-Methoden nicht reproduziert. Die Energieunterschiede zwischen den beiden Polymorphen (ΔE = 1,60 kJ∙mol−1 (DFT-D2) bzw. ΔE = 0,83 kJ∙mol−1 (DFT-D3)) sind relativ gering und liegen im Fehlerbereich der Methode. Die Bandbreite der relativen Energien aller Strukturmodelle beträgt nur etwa 1,8 kJ∙mol−1. Auf dieser Grundlage ist eine Stapelfehlordnung in den Kristallstrukturen von DL-Methionin möglich, jedoch nicht experimentell beobachtet. Nicht nur die Kraftfeld-,sondern auch die DFT-D-Methoden scheinen für die Berechnung der Gitterenergien für das System DL-Methionin nicht genügend genau zu sein. Die erhaltenen relativen Energien sollten daher mit Vorsicht betrachtet werden.
Chloro(phthalocyaninato)aluminium(III) (AlPcCl) bildet eine Schichtstruktur, in der sich die Moleküle zu Doppelschichten zusammenlagern. Die 1984 durchgeführte Kristallstrukturbestimmung [98] lieferte auf Grund der schlechten Datenqualität nur eine ungenaue Kristallstruktur. Die asymmetrische Einheit enthält zwei Moleküle, von denen das eine Molekül geordnet, das andere fehlgeordnet ist. Die Kristallstruktur von AlPcCl ist fehlgeordnet, weil eine einzelne Doppelschicht von Molekülen eine tetragonale P4/n-Symmetrie aufweist, die vier symmetrieäquivalente Möglichkeiten bietet, eine zweite Doppelschicht auf einer ersten Doppelschicht zu platzieren. Mit Hilfe der OD-Theorie wurde ein Satz geordneter Modelle mit verschiedenen Stapelsequenzen aufgestellt und die Gitterenergie zunächst mit Kraftfeld-Methoden und anschließend mit DFT-DMethoden berechnet. Auf Grund unzureichender Parametrisierung, musste das Kraftfeld an das System AlPcCl angepasst werden. Die Modellstrukturen werden während den Kraftfeld-Rechnungen nur leicht verzerrt. Die berechneten Gitterenergien hängen allerdings stark von der verwendeten Parametrisierung und den Atomladungen ab und sollten daher mit Vorsicht betrachtet werden. Genauere Ergebnisse erzielten Gitterenergieminimierungen mit DFT-D-Methoden. Die verschiedenen Stapelsequenzen haben eine ähnliche Energie, was die Stapelfehlordnung in der Kristallstruktur von AlPcCl erklärt. Die Überlagerung der vier energetisch günstigsten geordneten Stapelsequenzen führt zu einer gemittelten Struktur, die sehr gut die fehlgeordnete experimentelle Kristallstruktur von AlPcCl erklärt.
Background: The angiogenic function of endothelial cells is regulated by numerous mechanisms, but the impact of long noncoding RNAs (lncRNAs) has hardly been studied. We set out to identify novel and functionally important endothelial lncRNAs.
Methods: Epigenetically controlled lncRNAs in human umbilical vein endothelial cells were searched by exon-array analysis after knockdown of the histone demethylase JARID1B. Molecular mechanisms were investigated by RNA pulldown and immunoprecipitation, mass spectrometry, microarray, several knockdown approaches, CRISPR-Cas9, assay for transposase-accessible chromatin sequencing, and chromatin immunoprecipitation in human umbilical vein endothelial cells. Patient samples from lung and tumors were studied for MANTIS expression.
Results: A search for epigenetically controlled endothelial lncRNAs yielded lncRNA n342419, here termed MANTIS, as the most strongly regulated lncRNA. Controlled by the histone demethylase JARID1B, MANTIS was downregulated in patients with idiopathic pulmonary arterial hypertension and in rats treated with monocrotaline, whereas it was upregulated in carotid arteries of Macaca fascicularis subjected to atherosclerosis regression diet, and in endothelial cells isolated from human glioblastoma patients. CRISPR/Cas9-mediated deletion or silencing of MANTIS with small interfering RNAs or GapmeRs inhibited angiogenic sprouting and alignment of endothelial cells in response to shear stress. Mechanistically, the nuclear-localized MANTIS lncRNA interacted with BRG1, the catalytic subunit of the switch/sucrose nonfermentable chromatin-remodeling complex. This interaction was required for nucleosome remodeling by keeping the ATPase function of BRG1 active. Thereby, the transcription of key endothelial genes such as SOX18, SMAD6, and COUP-TFII was regulated by ensuring efficient RNA polymerase II machinery binding.
Conclusion: MANTIS is a differentially regulated novel lncRNA facilitating endothelial angiogenic function.
In bacteria, the regulation of gene expression by cis-acting transcriptional riboswitches located in the 5'-untranslated regions of messenger RNA requires the temporal synchronization of RNA synthesis and ligand binding-dependent conformational refolding. Ligand binding to the aptamer domain of the riboswitch induces premature termination of the mRNA synthesis of ligand-associated genes due to the coupled formation of 3'-structural elements acting as terminators. To date, there has been no high resolution structural description of the concerted process of synthesis and ligand-induced restructuring of the regulatory RNA element. Here, we show that for the guanine-sensing xpt-pbuX riboswitch from Bacillus subtilis, the conformation of the full-length transcripts is static: it exclusively populates the functional off-state but cannot switch to the on-state, regardless of the presence or absence of ligand. We show that only the combined matching of transcription rates and ligand binding enables transcription intermediates to undergo ligand-dependent conformational refolding.
The outset of Joyce’s A Portrait of the Artist as a Young Man presents a stage of life and language that is commonly evoked and, at the same time, systematically avoided in autobiographies as well as theoretical approaches to language: infancy. This textual strategy refers back to Augustine’s Confessiones, one of the most canonical autobiographies, reading it as a mainstay for an unconventional hypothesis: Rather that understanding infancy as an early stage of, or even before, language, Joyce expounds that the condition called infancy – the openness for receiving language while being unable to master it – accompanies all speech, be it childlike or eloquent. The article analyses Joyce’s text as one instance of a general paradox of autobiographical writing: initial aphasia. Setting out with birth or infancy, autobiographical texts precede articulate discourse. In Joyce, this paradox appears as starting point for a poetical – rather than theoretical – thinking about language, and language acquisition.
While for centuries Greek tragedies were performed only intermittently (Flashar 1991; Foley 1999; Macintosh et al. 2005; Hall and Macintosh 2005), the 1960s saw an enormous growth internationally in the staging of ancient dramas, and between 1960 and today, more Greek tragedies have been performed than in the entire period from antiquity to 1960.1 The new interest in ancient tragedy corresponded with a fundamental crisis in Western culture, issuing from the Shoah and gradually forcing its way into consciousness. After World War II, and especially since the 1960s, the question of history needed to be reconsidered. With the increasing dissolution of tradition, the interval between antiquity and the present became an unresolved problem. At the same time, a teleological understanding, which sees history as something that can be planned and calculated, had to be considered as failed, since fascism and communism "in the name of history" had erected totalitarian systems. What then appeared in this historical void?