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Estimates of the recovery time of stratospheric ozone heavily rely on the exact knowledge of the processes that lead to the decomposition of the relevant halogenated source gases. Crucial parameters in this context are fractional release factors (FRFs) as well as stratospheric lifetimes and ozone depletion potentials (ODPs). We here present data from the analysis of air samples collected between 2009 and 2011 on board research aircraft flying in the mid- and high-latitude stratosphere and infer the above-mentioned parameters for ten major source gases: CFCl3 (CFC-11), CF2Cl2 (CFC-12), CF2ClCFCl2 (CFC-113), CCl4 (carbon tetrachloride), CH3CCl3 (methyl chloroform), CHF2Cl (HCFC-22), CH3CFCl2 (HCFC-141b), CH3CF2Cl (HCFC-142b), CF2ClBr (H-1211), and CF3Br (H-1301). The inferred correlations of their FRFs with mean ages of air reveal less decomposition as compared to previous studies for most compounds. When using the calculated set of FRFs to infer equivalent stratospheric chlorine, we find a reduction of more than 20% as compared to the values inferred in the most recent Scientific Assessment of Ozone Depletion by the World Meteorological Organisation (WMO, 2011). We also note that FRFs and their correlations with mean age are not generally time-independent as often assumed. The stratospheric lifetimes were calculated relative to that of CFC-11. Within our uncertainties the ratios between stratospheric lifetimes inferred here agree with the values in recent WMO reports except for CFC-11, CFC-12 and CH3CCl3. Finally, we calculate lower ODPs than recommended by WMO for six out of ten compounds, with changes most pronounced for the three HCFCs. Collectively these newly calculated values may have important implications for the severity and recovery time of stratospheric ozone loss.
Aboveground and belowground biomass compartments of vegetation fulfil different functions and they are coupled by complex interactions. These compartments exchange water, carbon and nutrients and the belowground biomass compartment has the capacity to buffer vegetation dynamics when aboveground biomass is removed by disturbances such as herbivory or fire. However, despite their importance, root-shoot interactions are often ignored in more heuristic vegetation models. Here, we present a simple two-compartment grassland model that couples aboveground and belowground biomass. In this model, the growth of belowground biomass is influenced by aboveground biomass and the growth of aboveground biomass is influenced by belowground biomass. We used the model to explore how the dynamics of a grassland ecosystem are influenced by fire and grazing. We show that the grassland system is most persistent at intermediate levels of aboveground-belowground coupling. In this situation, the system can sustain more extreme fire or grazing regimes than in the case of strong coupling. In contrast, the productivity of the system is maximised at high levels of coupling. Our analysis suggests that the yield of a grassland ecosystem is maximised when coupling is strong, however, the intensity of disturbance that can be sustained increases dramatically when coupling is intermediate. Hence, the model predicts that intermediate coupling should be selected for as it maximises the chances of persistence in disturbance driven ecosystems.
Accurate multidimensional localization of isolated fluorescent emitters is a time consuming process in single-molecule based super-resolution microscopy. We demonstrate a functional method for real-time reconstruction with automatic feedback control, without compromising the localization accuracy. Compatible with high frame rates of EM-CCD cameras, it relies on a wavelet segmentation algorithm, together with a mix of CPU/GPU implementation. A combination with Gaussian fitting allows direct access to 3D localization. Automatic feedback control ensures optimal molecule density throughout the acquisition process. With this method, we significantly improve the efficiency and feasibility of localization-based super-resolution microscopy.
Introduction: Vasospastic brain infarction is a devastating complication of aneurysmal subarachnoid hemorrhage (SAH). Using a probe for invasive monitoring of brain tissue oxygenation or blood flow is highly focal and may miss the site of cerebral vasospasm (CVS). Probe placement is based on the assumption that the spasm will occur either at the dependent vessel territory of the parent artery of the ruptured aneurysm or at the artery exposed to the focal thick blood clot. We investigated the likelihood of a focal monitoring sensor being placed in vasospasm or infarction territory on a hypothetical basis.
Methods: From our database we retrospectively selected consecutive SAH patients with angiographically proven (day 7–14) severe CVS (narrowing of vessel lumen >50%). Depending on the aneurysm location we applied a standard protocol of probe placement to detect the most probable site of severe CVS or infarction. We analyzed whether the placement was congruent with existing CVS/infarction.
Results: We analyzed 100 patients after SAH caused by aneurysms located in the following locations: MCA (n = 14), ICA (n = 30), A1CA (n = 4), AcoA or A2CA (n = 33), and VBA (n = 19). Sensor location corresponded with CVS territory in 93% of MCA, 87% of ICA, 76% of AcoA or A2CA, but only 50% of A1CA and 42% of VBA aneurysms. The focal probe was located inside the infarction territory in 95% of ICA, 89% of MCA, 78% of ACoA or A2CA, 50% of A1CA and 23% of VBA aneurysms.
Conclusion: The probability that a single focal probe will be situated in the territory of severe CVS and infarction varies. It seems to be reasonably accurate for MCA and ICA aneurysms, but not for ACA or VBA aneurysms.
Recent clinical data support the clinical use of oral lavender oil in patients suffering from subsyndromal anxiety. We identified the molecular mechanism of action that will alter the perception of lavender oil as a nonspecific ingredient of aromatherapy to a potent anxiolytic inhibiting voltage dependent calcium channels (VOCCs) as highly selective drug target. In contrast to previous publications where exorbitant high concentrations were used, the effects of lavender oil in behavioral, biochemical, and electrophysiological experiments were investigated in physiological concentrations in the nanomolar range, which correlate to a single dosage of 80 mg/d in humans that was used in clinical trials. We show for the first time that lavender oil bears some similarities with the established anxiolytic pregabalin. Lavender oil inhibits VOCCs in synaptosomes, primary hippocampal neurons and stably overexpressing cell lines in the same range such as pregabalin. Interestingly, Silexan does not primarily bind to P/Q type calcium channels such as pregabalin and does not interact with the binding site of pregabalin, the α2δ subunit of VOCCs. Lavender oil reduces non-selectively the calcium influx through several different types of VOCCs such as the N-type, P/Q-type and T-type VOCCs. In the hippocampus, one brain region important for anxiety disorders, we show that inhibition by lavender oil is mainly mediated via N-type and P/Q-type VOCCs. Taken together, we provide a pharmacological and molecular rationale for the clinical use of the oral application of lavender oil in patients suffering from anxiety.
Im Rahmen des Vortrags wird zunächst ein Überblick über die aktuell angewandten Linsensysteme in der (refraktiven) Kataraktchirurgie sowie im Rahmen des RLA gesprochen. Hierzu zählen die monofokalen sphärischen Standardlinsen, aber auch asphärische, torische und multifokale Implantate.
Speziell wird auf die Ergebnisse einer Studie zu einem neuen multifokalen-torischen Implantat eingegangen. Der Schwerpunkt des Vortrages liegt dann weiterhin auf den trifokalen Korrektionsmöglichkeiten. Zum einen wird die sog. binokulare Trifokalität, bei der zwei multifokale Intraokularlinsen unterschiedlicher Addition implantiert werden, besprochen. Durch die Anpassung jeweils eines Auges an den Intermediär- bzw. Nahbereich soll so bei verringerten optischen Phänomenen ein deutliches Sehen in drei Hauptdistanzen ermöglicht werden. Weiterhin befasst sich der Vortrag aber auch mit den neuen echten trifokalen Optiksystemen, welche ebenfalls deutliches Sehen in verschiedenen Entfernungen gewährleisten können.
Im dritten Teil des Vortrages werden aktuelle Langzeitergebnisse aus einer FDA Studie zur Evaluation einer kammerwinkelgestützten phaken Intraokularlinse, mit speziellem Augenmerk auf den cornealen Endothelzellverlust, sowie eine neuartige sulcusgestütze phake Intraokularlinse mit zentralem Loch zur Glaukomvermeidung vorgestellt.
Dual-processing altruism
(2013)
Altruism refers to an other-benefiting behavior that is costly but bears no direct profit to oneself. At least three different forms can be distinguished: help giving, altruistic punishment, and moral courage. We investigated the differential impact of two thinking modes, intuitive (System 1) and rational (System 2), on these three altruistic behaviors. Situational (state-related) thinking style was manipulated via experimental instructions and generally preferred thinking style (trait-related) was assessed via questionnaires. We found that of the subjectively preferred thinking styles (trait), faith in intuition (System 1) promoted sharing and altruistic punishment, whereas need for cognition (System 2) promoted volunteering in a situation that required moral courage. By contrast, we did not find a significant effect of situational thinking style (state) on any of the altruistic behaviors, although manipulation checks were positive. Results elucidate the affective-motivational underpinnings of different types of altruistic behaviors.
Years of endemic infections with highly pathogenic avian influenza (HPAI) A subtype H5N1 virus in poultry and high numbers of infections in humans provide ample opportunity in Egypt for H5N1-HPAIV to develop pandemic potential. In an effort to better understand the viral determinants that facilitate human infections of the Egyptian H5N1-HPAIVvirus, we developed a new phylogenetic algorithm based on a new distance measure derived from the informational spectrum method (ISM). This new approach, which describes functional aspects of the evolution of the hemagglutinin subunit 1 (HA1), revealed a growing group G2 of H5N1-HPAIV in Egypt after 2009 that acquired new informational spectrum (IS) properties suggestive of an increased human tropism and pandemic potential. While in 2006 all viruses in Egypt belonged to the G1 group, by 2011 these viruses were virtually replaced by G2 viruses. All of the G2 viruses displayed four characteristic mutations (D43N, S120(D,N), (S,L)129Δ and I151T), three of which were previously reported to increase binding to the human receptor. Already in 2006–2008 G2 viruses were significantly (p<0.02) more often found in humans than expected from their overall prevalence and this further increased in 2009–2011 (p<0.007). Our approach also identified viruses that acquired additional mutations that we predict to further enhance their human tropism. The extensive evolution of Egyptian H5N1-HPAIV towards a preferential human tropism underlines an urgent need to closely monitor these viruses with respect to molecular determinants of virulence.
Introduction: Gastropoda are guided by several sensory organs in the head region, referred to as cephalic sensory organs (CSOs). These CSOs are innervated by distinct nerves. This study proposes a unified terminology for the cerebral nerves and the categories of CSOs and then investigates the neuroanatomy and cellular innervation patterns of these cerebral nerves, in order to homologise them. The homologisation of the cerebral nerves in conjunction with other data, e.g. ontogenetic development or functional morphology, may then provide insights into the homology of the CSOs themselves.
Results: Nickel-lysine axonal tracing (“backfilling”) was used to stain the somata projecting into specific nerves in representatives of opisthobranch Gastropoda. Tracing patterns revealed the occurrence, size and relative position of somata and their axons and enabled these somata to be mapped to specific cell clusters. Assignment of cells to clusters followed a conservative approach based primarily on relative location of the cells. Each of the four investigated cerebral nerves could be uniquely identified due to a characteristic set of soma clusters projecting into the respective nerves via their axonal pathways.
Conclusions: As the described tracing patterns are highly conserved morphological characters, they can be used to homologise nerves within the investigated group of gastropods. The combination of adequate number of replicates and a comparative approach allows us to provide preliminary hypotheses on homologies for the cerebral nerves. Based on the hypotheses regarding cerebral nerve homology together with further data on ultrastructure and immunohistochemistry of CSOs published elsewhere, we can propose preliminary hypotheses regarding homology for the CSOs of the Opisthobranchia themselves.
Introduction: Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial.
Methods: HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in-situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro.
Results: Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, p<0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, p<0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (p=0.004), but not in HER2-positive/ESR1-negative tumors.
Conclusions: Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group.
Der "Beratungs-Wegweiser, Beratungsstellen und Adressverzeichnis" wird vom Studien-Service-Center (SSC) als ergänzendes Angebot zum „Wegweiser für Erstsemester“ sowie der Internetseite der Goethe-Universität herausgegeben und enthält studiengangbezogene Informationen und Kontaktdaten. Vertiefende Informationen zu diversitätsunterstützenden Angeboten der zentralen sowie fachübergreifenden Einrichtungen und der Fachbereiche können in der Broschüre "Diversity kompakt. Angebote für Studierende in unterschiedlichen Lebens und Studiensituationen" - herausgegeben von Di3 - nachgeschlagen werden.
Die Wissenschaft steht unter Druck. In Zeiten, in denen es um nichts Geringeres geht als um die Transformation hin zu einer nachhaltigen Entwicklung, fordern Gesellschaft und Politik von ihr nicht nur gesichertes, sondern vor allem anwendbares Wissen. Um solches Wissen erzeugen zu können, muss die Wissenschaft ihre Strukturen und Arbeitsformen verändern. Ein erneuertes Verständnis von Kritik kann Orientierung in diesem von der Wissenschaft aktiv zu gestaltenden Veränderungsprozess bieten.
Background: Critical organ shortage results in the utilization of extended donor criteria (EDC) liver grafts. These marginal liver grafts are prone to increased ischemia reperfusion injury (IRI) which may contribute to deteriorated graft function and survival. Experimental data have shown that the calcineurin inhibitor tacrolimus exerts protective effects on hepatic IRI when applied intravenously or directly as a hepatic rinse. Therefore, the aim of the present study is to examine the effects of an ex vivo tacrolimus perfusion on IRI in transplantation of EDC liver grafts.
Methods/Design: The TOP-Study (tacrolimus organ perfusion) is a randomized multicenter trial comparing the ex vivo tacrolimus perfusion of marginal liver grafts with placebo. We hypothesize that a tacrolimus rinse reduces IRI, potentially improving organ survival following transplantation of EDC livers. The study includes livers with two or more EDC, according to Eurotransplant International Foundation’s definition of EDC livers. Prior to implantation, livers randomized to the treatment group are rinsed with tacrolimus at a concentration of 20 ng/ml in 1000 ml Custodiol solution and in the placebo group with Custodiol alone. The primary endpoint is the maximum serum alanine transamninase (ALT) level within the first 48 hours after surgery; however, the study design also includes a 1-year observation period following transplantation. The TOP-Study is an investigator-initiated trial sponsored by the University of Munich Hospital. Seven other German transplant centers are participating (Berlin, Frankfurt, Heidelberg, Mainz, Münster, Regensburg, Tübingen) and aim to include a total of 86 patients.
Discussion: Tacrolimus organ perfusion represents a promising strategy to reduce hepatic IRI following the transplantation of marginal liver grafts. This treatment may help to improve the function of EDC grafts and therefore safely expand the donor pool in light of critical organ shortage.
Trial register: EudraCT number: 2010-021333-31, ClinicalTrials.gov identifier: NCT01564095
Aufgrund von § 84 Abs. 3 Nr. 1 des Hessischen Hochschulgesetzes vom 14. Dezember 2009 (GVBl. I, S. 666), zuletzt geändert durch Gesetz vom 26. Juni 2012 (GVBl. I, S. 227), und von § 10 Abs. 6 der Ordnung der Aka-demie für Bildungsforschung und Lehrerbildung an der Johann Wolfgang Goethe-Universität vom 19. April 2011 (UniReport Satzungen und Ordnungen vom 19. April 2011) haben das Direktorium der Akademie für Bildungsforschung und Lehrerbildung am 7. Februar 2013 sowie der Fachbereichsrat des Fachbereichs 4 am 12. Februar 2013 nachstehenden Änderungen beschlossen: ...
Für das Studium des Studienanteils Bildungswissenschaften in den Studiengängen Lehramt an Grundschulen (L 1), Lehramt an Haupt- und Realschulen (L 2), Lehramt an Gymnasien (L 3) und Lehramt an Förderschulen (L 5) hat die Akademie für Bildungsforschung und Lehrerbildung (ABL) der Goethe-Universität im Benehmen mit den Fachbereichen Gesellschaftswissenschaften (03), Erziehungswissenschaften (04), sowie Psychologie und Sportwissenschaften (05) der Goethe-Universität auf der Grundlage von § 48 Abs. 2 Ziff. 1 HHG, §§ 10, 12 der Ordnung der ABL i.V. mit § 28 Abs. 2 SPoL folgende Regelungen (fachspezifischer Anhang zur SPoL gemäß § 2 Abs. 2 SPoL) erlassen: ...
Aufgrund des Beschlusses des Fachbereichsrats des Fachbereichs Sprach- und Kulturwissenschaften der Johann Wolfgang Goethe-Universität vom 21.12.2012 wird die Ordnung für den Bachelorstudiengang Islamische Studien vom 14.07.2010 in der Fassung vom 06.10.211 nachfolgend geändert beziehungsweise ergänzt: ...
Background: After induction of DNA double strand breaks (DSBs), the DNA damage response (DDR) is activated. One of the earliest events in DDR is the phosphorylation of serine 139 on the histone variant H2AX (gH2AX) catalyzed by phosphatidylinositol 3-kinases-related kinases. Despite being extensively studied, H2AX distribution[1] across the genome and gH2AX spreading around DSBs sites[2] in the context of different chromatin compaction states or transcription are yet to be fully elucidated.
Materials and methods: gH2AX was induced in human hepatocellular carcinoma cells (HepG2) by exposure to 10 Gy X-rays (250 kV, 16 mA). Samples were incubated 0.5, 3 or 24 hours post irradiation to investigate early, intermediate and late stages of DDR, respectively. Chromatin immunoprecipitation was performed to select H2AX, H3 and gH2AX-enriched chromatin fractions. Chromatin-associated DNA was then sequenced by Illumina ChIP-Seq platform. HepG2 gene expression and histone modification (H3K36me3, H3K9me3) ChIP-Seq profiles were retrieved from Gene Expression Omnibus (accession numbers GSE30240 and GSE26386, respectively).
Results: First, we combined G/C usage, gene content, gene expression or histone modification profiles (H3K36me3, H3K9me3) to define genomic compartments characterized by different chromatin compaction states or transcriptional activity. Next, we investigated H3, H2AX and gH2AX distributions in such defined compartments before and after exposure to ionizing radiation (IR) to study DNA repair kinetics during DDR. Our sequencing results indicate that H2AX distribution followed H3 occupancy and, thus, the nucleosome pattern. The highest H2AX and H3 enrichment was observed in transcriptionally active compartments (euchromatin) while the lowest was found in low G/C and gene-poor compartments (heterochromatin). Under physiological conditions, the body of highly and moderately transcribed genes was devoid of gH2AX, despite presenting high H2AX levels. gH2AX accumulation was observed in 5’ or 3’ flanking regions, instead. The same genes showed a prompt gH2AX accumulation during the early stage of DDR which then decreased over time as DDR proceeded.
Finally, during the late stage of DDR the residual gH2AX signal was entirely retained in heterochromatic compartments. At this stage, euchromatic compartments were completely devoid of gH2AX despite presenting high levels of non-phosphorylated H2AX.
Conclusions: We show that gH2AX distribution ultimately depends on H2AX occupancy, the latter following H3 occupancy and, thus, nucleosome pattern. Both H2AX and H3 levels were higher in actively transcribed compartments. However, gH2AX levels were remarkably low over the body of actively transcribed genes suggesting that transcription levels antagonize gH2AX spreading. Moreover, repair processes did not take place uniformly across the genome; rather, DNA repair was affected by genomic location and transcriptional activity. We propose that higher H2AX density in euchromaticcompartments results in high relative gH2AXconcentration soon after the activation of DDR, thus favoring the recruitment of the DNA repair machinery to those compartments. When the damage is repaired and gH2AX is removed, its residual fraction is retained in the heterochromatic compartments which are then targeted and repaired at later times.
Background: Castleman’s disease is a rare lymphoproliferative disorder. It typically presents as mediastinal masses and causes a wide range of clinical symptoms. Histologically, Castleman’s disease is classified as either a hyalinic vascular or plasma cell variant. The prognosis mainly depends on the histological type and broadly varies. We herein report our sonographic findings in a patient with Castleman’s disease, including gray-scale ultrasonography, color Doppler ultrasonography, and sonoelastography ultrasonography, which have not been previously reported in the literature. These findings allowed for a preoperative diagnosis and avoidance of overly aggressive therapy.
Case presentation: A 28-year-old European female patient with unicentric Castleman’s disease of hyalinic vascular type (HV) restricted to the axilla was referred to us because of a 4-month history of a painless, solitary mass located in the left axilla. The patient’s medical history was unremarkable.
Conclusion: Castleman’s disease is a pathologic entity of unknown etiology and pathogenesis. In this case report of unicentric HV-type CD, we demonstrate that typical sonographic findings can lead to a preoperative diagnosis of Castleman’s disease. Core needle biopsy usually allows for a final diagnosis and helps to avoid unnecessary operations and overtreatment.
Background: The introduction of fast-track treatment procedures following cardiac surgery has significantly shortened hospitalisation times in intensive care units (ICU). Readmission to intensive care units is generally considered a negative quality criterion. The aim of this retrospective study is to statistically analyse risk factors and predictors for re-admission to the ICU after a fast-track patient management program.
Methods: 229 operated patients (67 ± 11 years, 75% male, BMI 27 ± 3, 6/2010-5/2011) with use of extracorporeal circulation (70 ± 31 min aortic crossclamping, CABG 62%) were selected for a preoperative fast-track procedure (transfer on the day of surgery to an intermediate care (IMC) unit, stable circulatory conditions, extubated). A uni- and multivariate analysis were performed to identify independent predictors for re-admission to the ICU.
Results: Over the 11-month study period, 36% of all preoperatively declared fast-track patients could not be transferred to an IMC unit on the day of surgery (n = 77) or had to be readmitted to the ICU after the first postoperative day (n = 4). Readmission or ICU stay signifies a dramatic worsening of the patient outcome (mortality 0/10%, mean hospital stay 10.3 ± 2.5/16.5 ± 16.3, mean transfusion rate 1.4 ± 1,7/5.3 ± 9.1). Predicators for failure of the fast-track procedure are a preoperative ASA class > 3, NYHA class > III and an operation time >267 min ± 74. The significant risk factors for a major postoperative event (= low cardiac output and/or mortality and/or renal failure and/or re-thoracotomy and/or septic shock and/or wound healing disturbances and/or stroke) are a poor EF (OR 2.7 CI 95% 0.98-7.6) and the described ICU readmission (OR 0.14 CI95% 0.05-0.36).
Conclusion: Re-admission to the ICU or failure to transfer patients to the IMC is associated with a high loss of patient outcome. The ASA > 3, NYHA class > 3 and operation time >267 minutes are independent predictors of fast track protocol failure.
Aufgrund des Beschlusses des Fachbereichsrats des Fachbereichs Sprach- und Kulturwissenschaften der Johann Wolfgang Goethe-Universität vom 21.11.2012 wird die Ordnung für die Masterstudiengänge des Fachbereichs Sprach- und Kulturwissenschaften vom 21.05.2008, geändert am 11.05.2011, nachfolgend ergänzt: ...
Die folgende Grundordnung ist gemäß §§ 36 Abs. 2, 84 Abs. 2 S. 2 des Hessischen Hochschulgesetzes (HHG) vom 23. Dezember 2009 (GVBl. I 2009, S. 666), zuletzt geändert durch Artikel 1 des Gesetzes vom 26. Juni 2012 (GVBl. I S. 227), im Einvernehmen mit dem Präsidium vom Senat der Johann Wolfgang Goethe-Universität Frankfurt am Main in seiner Sitzung am 30. Januar 2013 beschlossen und vom Hochschulrat am 14. Februar 2013 genehmigt worden.
Over the last century, humans from industrialized societies have witnessed a radical increase in some dental diseases. A severe problem concerns the loss of dental materials (enamel and dentine) at the buccal cervical region of the tooth. This “modern-day” pathology, called non-carious cervical lesions (NCCLs), is ubiquitous and worldwide spread, but is very sporadic in modern humans from pre-industrialized societies. Scholars believe that several factors are involved, but the real dynamics behind this pathology are far from being understood. Here we use an engineering approach, finite element analysis (FEA), to suggest that the lack of dental wear, characteristic of industrialized societies, might be a major factor leading to NCCLs. Occlusal loads were applied to high resolution finite element models of lower second premolars (P2) to demonstrate that slightly worn P2s envisage high tensile stresses in the buccal cervical region, but when worn down artificially in the laboratory the pattern of stress distribution changes and the tensile stresses decrease, matching the results obtained in naturally worn P2s. In the modern industrialized world, individuals at advanced ages show very moderate dental wear when compared to past societies, and teeth are exposed to high tensile stresses at the buccal cervical region for decades longer. This is the most likely mechanism explaining enamel loss in the cervical region, and may favor the activity of other disruptive processes such as biocorrosion. Because of the lack of dental abrasion, our masticatory apparatus faces new challenges that can only be understood in an evolutionary perspective.
Blood levels of Glial Fibrillary Acidic Protein (GFAP) in patients with neurological diseases
(2013)
Background and Purpose: The brain-specific astroglial protein GFAP is a blood biomarker candidate indicative of intracerebral hemorrhage in patients with symptoms suspicious of acute stroke. Comparably little, however, is known about GFAP release in other neurological disorders. In order to identify potential “specificity gaps” of a future GFAP test used to diagnose intracerebral hemorrhage, we measured GFAP in the blood of a large and rather unselected collective of patients with neurological diseases.
Methods: Within a one-year period, we randomly selected in-patients of our university hospital for study inclusion. Patients with ischemic stroke, transient ischemic attack and intracerebral hemorrhage were excluded. Primary endpoint was the ICD-10 coded diagnosis reached at discharge. During hospital stay, blood was collected, and GFAP plasma levels were determined using an advanced prototype immunoassay at Roche Diagnostics.
Results: A total of 331 patients were included, covering a broad spectrum of neurological diseases. GFAP levels were low in the vast majority of patients, with 98.5% of cases lying below the cut-off that was previously defined for the differentiation of intracerebral hemorrhage and ischemic stroke. No diagnosis or group of diagnoses was identified that showed consistently increased GFAP values. No association with age and sex was found.
Conclusion: Most acute and chronic neurological diseases, including typical stroke mimics, are not associated with detectable GFAP levels in the bloodstream. Our findings underline the hypothesis that rapid astroglial destruction as in acute intracerebral hemorrhage is mandatory for GFAP increase. A future GFAP blood test applied to identify patients with intracerebral hemorrhage is likely to have a high specificity.
Background: Protein translocation across membranes is a central process in all cells. In the past decades the molecular composition of the translocation systems in the membranes of the endoplasmic reticulum, peroxisomes, mitochondria and chloroplasts have been established based on the analysis of model organisms. Today, these results have to be transferred to other plant species. We bioinformatically determined the inventory of putative translocation factors in tomato (Solanum lycopersicum) by orthologue search and domain architecture analyses. In addition, we investigated the diversity of such systems by comparing our findings to the model organisms Saccharomyces cerevisiae, Arabidopsis thaliana and 12 other plant species.
Results: The literature search end up in a total of 130 translocation components in yeast and A. thaliana, which are either experimentally confirmed or homologous to experimentally confirmed factors. From our bioinformatic analysis (PGAP and OrthoMCL), we identified (co-)orthologues in plants, which in combination yielded 148 and 143 orthologues in A. thaliana and S. lycopersicum, respectively. Interestingly, we traced 82% overlap in findings from both approaches though we did not find any orthologues for 27% of the factors by either procedure. In turn, 29% of the factors displayed the presence of more than one (co-)orthologue in tomato. Moreover, our analysis revealed that the genomic composition of the translocation machineries in the bryophyte Physcomitrella patens resemble more to higher plants than to single celled green algae. The monocots (Z. mays and O. sativa) follow more or less a similar conservation pattern for encoding the translocon components. In contrast, a diverse pattern was observed in different eudicots.
Conclusions: The orthologue search shows in most cases a clear conservation of components of the translocation pathways/machineries. Only the Get-dependent integration of tail-anchored proteins seems to be distinct. Further, the complexity of the translocation pathway in terms of existing orthologues seems to vary among plant species. This might be the consequence of palaeoploidisation during evolution in plants; lineage specific whole genome duplications in Arabidopsis thaliana and triplications in Solanum lycopersicum.
Background: In a previous analysis (Int J Radiat Oncol Biol Phys 70:828-835,2010), we assessed whether an adjuvant supplementation with selenium (Se) improves Se status and reduces the radiation-induced side-effects of patients treated by adjuvant radiotherapy (RT) for cervical and uterine cancer. Now, a potential relation between the planning target volume (PTV) of the RT and the Se effect concerning radiation induced diarrhoea was evaluated in detail.
Methods: Whole blood Se concentrations had been measured in patients with cervical (n=11) and uterine cancer (n=70) after surgical treatment, during, and at the end of RT. Patients with initial Se concentrations of less than 84 μg/l were categorized as Se-deficient and randomized before RT to receive Se (as sodium selenite) per os on the days of RT, or to receive no supplement during RT. Diarrhoea was graded according to the Common Toxicity Criteria system (CTC, Version 2a). The evaluation of the PTV of the RT was ascertained with the help of a specialised computer-assisted treatment planning software used for radiation planning procedure.
Results: A total of 81 patients had been randomized for the initial supplementation study, 39 of which received Se [selenium group, SeG] and 42 serving as controls [control group, CG]. Mean Se levels did not differ between SeG and CG upon study initiation, but were significantly higher in the SeG compared to the CG at the end of RT. The actuarial incidence of at least CTC 2 radiation induced diarrhoea in the SeG was 20.5% compared to 44.5% in the CG (p=0.04). The median PTV in both groups was 1302 ml (916–4608). With a PTV of <= 1302 ml (n=41) the actuarial incidence of at least CTC 2 diarrhoea in the SeG was 22.3% (4 of 18 patients) compared to 34.8% (8 of 23 patients) in the CG (p=0.50). In patients with a PTV of > 1302 ml (n=40) the actuarial incidence of at least CTC 2 diarrhoea in the SeG was 19.1% (4 of 21 patients) versus 52.6% (10 of 19 patients) in the CG (p=0.046).
Conclusions: Se supplementation during RT was effective to improve blood Se status in Se-deficient cervical and uterine cancer patients, and reduces episodes and severity of RT-induced diarrhoea. This effect was most pronounced and significant in patients with large PTV (> 1302 ml).
Der Gemeinsame Vertreter kann in das Fadenkreuz der Anleihegläubiger geraten und in das des Emittenten. Er hat daher das rechte Maß zu finden zwischen Engagement, Sorgfalt und Konfliktbewältigung bei der Erfüllung seiner Aufgaben. Das gilt insbesondere dann, wenn der Schuldner in die Krise geraten ist und im Kreis der Anleihegläubiger der Ruf nach einem „aktiven“ und engagierten Vertreter laut wird.
Um einen „Hilferuf“ handelt es sich dabei nicht immer. Vielmehr haben sich einzelne Investoren darauf spezialisiert, Anleihebedingungen zu durchforsten, um etwaige – und sei es auch nur „technische“ - Verstöße gegen dort enthaltene rechtliche Vorgaben zu entdecken. Sind sie fündig geworden, aber durch „no-action“-Klauseln daran gehindert, selbst tätig zu werden, schauen sie auf den Gemeinsamen Vertreter und erwarten von ihm die aggressive Wahrnehmung ihrer Rechte. Dazu kann gehören, aktiv die Fälligstellung zu fordern und so Drohpotential gegen den Emittenten aufzubauen;2 freilich, das muss nicht jedem Gläubiger recht sein, z.B. solchen, die bei zunächst eintretenden Kursverfall aus anlagerechtlichen Gründen gehalten ist, sich kostspielig vom Engagement zu trennen.
Konflikte innerhalb derselben Anleihegläubigerklasse sind damit programmiert. Und sie übertragen und bündeln sich dann in der Person des Gemeinsamen Vertreters – jedenfalls dann, wenn er exklusiv damit betraut ist, über die Ausübung von Gläubigerrechten zu befinden. Der gemeinsame Vertreter steht dann vor der Frage, ob er den Erwartungen aggressiver Obligationäre nachgeben soll oder nicht.3 Er muss deshalb wissen, was seine Rolle ist. Dazu ist die Reichweite seiner Interventionsmöglichkeiten und –pflichten im Spannungsfeld zwischen gesetzlicher und rechtsgeschäftlicher Aufgabenzuweisung, business judgment rule, Haftungsbeschränkung und der Beschlusskontrolle näher zu bestimmen; ansonsten wird es nicht zur gewünschten Koordinierung des Gläubigerverhaltens durch den Gemeinsamen Vertreter kommen.
Im Folgenden soll eine Diskussion über die dabei entstehenden Rückkoppelungseffekte angestoßen werden, welche sich mit dem gesetzgeberischen Idealbild nicht so recht zu vertragen scheinen.
Seit Erlass des Schuldverschreibungsgesetzes von 2009 (SchVG) zeichnet sich ab, dass die Emissionspraxis der deutschen Staatsanleihen im Hinblick auf kollektive Gläubigermechanismen („Collective Action Clauses“ – CACs), wie sie das SchVG erstmals rechtssicher ermöglicht, substantiellen Änderungen unterliegen wird. Während die Haltung inländischer öffentliche Emittenten noch bei Verabschiedung des SchVG reserviert war, hat sich die Situation seit Mai 2010 grundlegend geändert: Verschiedene Mitgliedstaaten der Eurozone sind mit Verbindlichkeiten in ihrer Währung in Schwierigkeiten geraten und mussten um internationale Hilfe nachsuchen. Vor dem Hintergrund der politischen Forderung nach einer Beteiligung der bestehenden Gläubigerschaft („private sector involvement“, „PSI“) musste schließlich Griechenland im Frühjahr 2012 eine Umschuldung (mithilfe entsprechender Klauseln) bemühen. Politische und rechtliche Festlegungen der Eurogruppe über die künftige Dokumentation der (verbrieften) Staatenschuld im Hinblick auf eine potentiell erforderlich werdende Umschuldung folgten. Bei den nationalen Umsetzungsarbeiten sind auch gewisse „Unzulänglichkeiten“ des durch das SchVG geschaffenen gesetzlichen Gestaltungsrahmens aufgegriffen worden.
Die nachfolgende Abhandlung zeichnet im Einzelnen die verschiedenen Entwicklungslinien nach, beginnend (i) mit dem SchVG und der darin zum Ausdruck gekommenen traditionellen Haltung der öffentlichen Hand zu CACs, leitet über (ii) zur GriechenlandUmschuldung („PSI“) und deren rechtlichen Besonderheiten und Ergebnisse unter dem (neuen) Blickwinkel einer Beteiligung privater Gläubiger, soll (iii) die von der Eurogruppe gezogenen Konsequenzen in Gestalt der Empfehlungen des Wirtschafts- und Finanzausschusses für „Umschuldungsklauseln“ der Mitgliedsstaaten der Eurozone im Hinblick auf Art. 12 Abs. 3 des ESM-Vertrags erläutern und schließlich (iv) einen Überblick über die gesetzgeberischen Schritte in Deutschland zur Umsetzung der Empfehlungen liefern.
Thesen
1. Um die Anerkennung einer Beschlussnichtigkeit in extremen Situationen wird man kaum umhin kommen. Der Gesetzgeber sollte die Nichtigkeitsgründe und ihre Geltendmachung wie im Aktienrecht klarstellend einschränken.
2. Gläubigerbeschlüsse unterliegen einer (begrenzten) materiellen Beschlusskontrolle anhand des Maßstabs der „gemeinsamen Interessen“ der Gläubigergesamtheit. Ohne ein derartiges materielles Kriterium wird man nicht auskommen. Wie es letztendlich benannt wird, ist dann nichts weiter als eine Frage der Begrifflichkeit. Eine gesetzliche Klarstellung erscheint nicht zwingend. Inhaltlich muss sich die materielle Beschlusskontrolle beschränken auf den Ausschluss sachfremder Erwägungen als Grundlage eines Eingriffs der Mehrheit in Rechte und Ansprüche der Minderheit.
3. Die Gestaltungswirkung des der Anfechtungsklage stattgebenden Urteils folgt bereits aus der kollektiven Bindung des § 4 SchVG. Eine – wenngleich nicht zwingende – gesetzliche Klarstellung könnte in Gestalt eines Hinweises in § 20 SchVG erfolgen, dass ein der Anfechtungs- (und Nichtigkeits-) Klage stattgebendes Urteil der kollektiven Bindung des § 4 SchVG unterliegt.
Der gesetzlichen Korrektur und Präzisierung bedürfen, nicht zuletzt im Interesse der Beschleunigung, Vollzugssperre und Freigabeverfahren.
Die vorstehenden Überlegungen führen zu folgenden Ergebnissen:
1. Das SchVG erlaubt den Gläubigern sämtlicher vor Inkrafttreten des Gesetzes begebenen Anleihen, einschließlich solcher die nicht dem SchVG 1899 unterliegen, einen Beschluss über die Anwendbarkeit des SchVG zu fassen (Opt-in).
2. Der Anwendbarkeit des SchVG und damit insbesondere auch der Opt-in-Regelung steht eine Teilrechtswahl ausländischen Rechts in den Anleihebedingungen nicht entgegen, solange die Substanz der verbrieften Forderung deutschem Recht unterliegt.
Dies ergibt sich bereits aus dem gültigen Gesetz. Aufgrund entgegenstehender instanzgerichtlicher Rechtsprechung besteht allerdings Klarstellungsbedarf. Dies insbesondere auch deshalb, weil hiermit Fragen angesprochen sind, welche die Funktionsfähigkeit und Marktakzeptanz des neuen Gesetzes in wesentlichen Anwendungsbereichen berühren. Im Rahmen der Reform des Schuldverschreibungsrechts hat die Bundesregierung angekündigt, laufend zu prüfen, ob beabsichtigten Wirkungen dieses Gesetzes erreicht worden sind, und, soweit erforderlich, rechtzeitig die hieraus resultierenden erforderlichen Maßnahmen zu ergreifen.48 Nachdem unlängst bereits die Straffung des Freigabeverfahrens erfolgte49 ist zu hoffen, dass auch der hier identifizierte gesetzliche Klarstellungsbedarf zügig in Angriff genommen wird.
Ribosome biogenesis is best understood in the yeast Saccharomyces cerevisiae. In human or mammalian ribosome biogenesis, it has been shown that basic principles are conserved to yeast, but additional features have been reported. Our understanding about the interplay between proteins and RNA in human ribosome biogenesis is far from complete.
The present study focused on the analysis of the human ribosome biogenesis co-factors PWP2, EMG1 and Exportin 5 (XPO5) to understand the degree of conservation of ribosome biogenesis. The proteins were characterized in respect to their localization and interaction partners. For the early 90S co-factor, PWP2, it was possible to pull down and identify the human UTP-B complex with MALDI mass spectrometry. Besides the orthologues of the members of this complex known in yeast (TBL3, WDR3, WDR36, UTP6, UTP18), the human UTP-B complex is not only conserved from yeast to humans, but contains also additional components, like the DEAD-box RNA helicase DDX21, which lacks a yeast orthologue. DDX21 was localized to the nucleus, assembled to the native UTP-B complex and co-precipitated also with other UTP-B complex members, presumably extending the functions of this complex in ribosome biogenesis.
This phenomenon was also observed for the 90S co-factor EMG1, an RNA methyltransferase, whose mutant form causes the Bowen-Conradi syndrome, if aspartic acid is mutated to glycine at position 86. This study revealed that the mutant, EMG1-D86G, clearly lost its nucleolar localization and co-precipitated to histones for unknown reasons.
A participation of the nuclear export receptor XPO5 in human ribosome biogenesis was shown in this study. Pulldown analysis, sucrose density gradients and UV crosslinking and analysis of cDNAs of XPO5 revealed the involvement of XPO5 in pre-60S subunit maturation. Moreover, besides the known pre-miRNAs and tRNAs as substrates for nuclear export, XPO5 crosslinked to snoRNAs. XPO5 was further demonstrated to interact with the miRNA Let-7a, which has an important regulatory function for MYC, a transcription factor required for ribosome biogenesis.
All results support a role of these proteins in human ribosome biogenesis and therefore it seems that the biogenesis of ribosomes in human cells requires additional components, like DDX21 and XPO5.
Are books different? : Die Auswirkungen des Falls der Buchpreisbindung in Großbritannien 1995 - 2006
(2013)
Sicherlich gibt es im Buchhandel wie in jeder anderen Branche Zeiten der Krise und des Umsatzrückgangs, aber grundsätzlich legen die Zahlen nicht nah, dass das Ende bevorsteht. Es stellt sich also die Frage, ob zutrifft, was Richter Buckley in seinem zum geflügelten Wort gewordenen Urteil feststellte: Sind Bücher wirklich anders, oder anders gefragt, braucht der Buchhandel den Schutz des Staates, um seine Funktion erfüllen zu können?
Um eine Antwort auf diese Fragen zu finden, soll in dieser Arbeit das Hauptaugenmerk auf die Entwicklung des britischen Buchhandels im Zeitraum von 1995 (dem Jahr der faktischen Abschaffung des Net Book Agreement bis 2006 gelegt werden. Nach dem beinahe hundertjährigen Bestehen der Buchpreisbindung waren diese Jahre richtungweisend für die Neuorientierung des britischen Buchhandels auf die Bedingungen eines freien Marktes, und es soll untersucht werden, welche Umwälzungen sich daraus für die Branche ergeben haben.
Current theories of the pathophysiology of schizophrenia have focused on abnormal temporal coordination of neural activity. Oscillations in the gamma-band range (>25 Hz) are of particular interest as they establish synchronization with great precision in local cortical networks. However, the contribution of high gamma (>60 Hz) oscillations toward the pathophysiology is less established. To address this issue, we recorded magnetoencephalographic (MEG) data from 16 medicated patients with chronic schizophrenia and 16 controls during the perception of Mooney faces. MEG data were analysed in the 25–150 Hz frequency range. Patients showed elevated reaction times and reduced detection rates during the perception of upright Mooney faces while responses to inverted stimuli were intact. Impaired processing of Mooney faces in schizophrenia patients was accompanied by a pronounced reduction in spectral power between 60–120 Hz (effect size: d = 1.26) which was correlated with disorganized symptoms (r = −0.72). Our findings demonstrate that deficits in high gamma-band oscillations as measured by MEG are a sensitive marker for aberrant cortical functioning in schizophrenia, suggesting an important aspect of the pathophysiology of the disorder.
As inhibitor of apoptosis (IAP) proteins can regulate additional signaling pathways beyond apoptosis, we investigated the effect of the second mitochondrial activator of caspases (Smac) mimetic BV6, which antagonizes IAP proteins, on non-apoptotic functions in glioblastoma (GBM). Here, we identify non-canonical nuclear factor-κB (NF-κB) signaling and a tumor necrosis factor-α (TNFα)/TNF receptor 1 (TNFR1) autocrine/paracrine loop as critical mediators of BV6-stimulated migration and invasion of GBM cells. In addition to GBM cell lines, BV6 triggers cell elongation, migration and invasion in primary, patient-derived GBM cells at non-toxic concentrations, which do not affect cell viability or proliferation, and also increases infiltrative tumor growth in vivo underscoring the relevance of these findings. Molecular studies reveal that BV6 causes rapid degradation of cellular IAP proteins, accumulation of NIK, processing of p100 to p52, translocation of p52 into the nucleus, increased NF-κB DNA binding and enhanced NF-κB transcriptional activity. Electrophoretic mobility shift assay supershift shows that the NF-κB DNA-binding subunits consist of p50, p52 and RelB further confirming the activation of the non-canonical NF-κB pathway. BV6-stimulated NF-κB activation leads to elevated mRNA levels of TNFα and additional NF-κB target genes involved in migration (i.e., interleukin 8, monocyte chemoattractant protein 1, CXC chemokine receptor 4) and invasion (i.e., matrix metalloproteinase-9). Importantly, inhibition of NF-κB by overexpression of dominant-negative IκBα superrepressor prevents the BV6-stimulated cell elongation, migration and invasion. Similarly, specific inhibition of non-canonical NF-κB signaling by RNA interference-mediated silencing of NIK suppresses the BV6-induced cell elongation, migration and invasion as well as upregulation of NF-κB target genes. Intriguingly, pharmacological or genetic inhibition of the BV6-stimulated TNFα autocrine/paracrine loop by the TNFα-blocking antibody Enbrel or by knockdown of TNFR1 abrogates BV6-induced cell elongation, migration and invasion. By demonstrating that the Smac mimetic BV6 at non-toxic concentrations promotes migration and invasion of GBM cells via non-canonical NF-κB signaling, our findings have important implications for the use of Smac mimetics as cancer therapeutics.
The efficacy of monetary authority actions depends primarily on the ability of the monetary authority to affect inflation expectations, which ultimately depend on agents' trust. We propose a model embedding trust cycles, as emerging from sequential coordination games between atomistic agents and the policy maker, in a monetary model. Trust affects agents' stochastic discount factor, namely the price of future risk, and their expectation formation process: these effects in turn interact with the monetary transmission mechanism. Using data from the Eurobarometer survey we analyze the link between trust on the one side and the transmission mechanism of shocks and of the policy rate on the other: data show that the two interact significantly and in a way comparable to the obtained in our model.
This paper investigates risk-taking in the liquid portfolios held by a large panel of Swedish twins. We document that the portfolio share invested in risky assets is an increasing and concave function of financial wealth, leading to different risk sensitivities across investors. Human capital, which we estimate directly from individual labor income, also drives risk-taking positively, while internal habit and expenditure commitments tend to reduce it. Our micro findings lend strong support to decreasing relative risk aversion and habit formation preferences. Furthermore, heterogeneous risk sensitivities across investors help reconcile individual preferences with representative-agent models.
We develop a dynamic network model whose links are governed by banks' optmizing decisions and by an endogenous tâtonnement market adjustment. Banks in our model can default and engage in firesales: risk is transmitted through direct and cascading counterparty defaults as well as through indirect pecuniary externalities triggered by firesales. We use the model to assess the evolution of the network configuration under various prudential policy regimes, to measure banks' contribution to systemic risk (through Shapley values) in response to shocks and to analyze the effects of systemic risk charges. We complement the analysis by introducing the possibility of central bank liquidity provision.
This paper analyzes the equilibrium pricing implications of contagion risk in a Lucas-tree economy with recursive preferences and jumps. We introduce a new economic channel allowing for the possibility that endowment shocks simultaneously trigger a regime shift to a bad economic state. We document that these contagious jumps have far-reaching asset pricing implications. The risk premium for such shocks is superadditive, i.e. it is 2.5\% larger than the sum of the risk premia for pure endowment shocks and regime switches. Moreover, contagion risk reduces the risk-free rate by around 0.5\%. We also derive semiclosed-form solutions for the wealth-consumption ratio and the price-dividend ratios in an economy with two Lucas trees and analyze cross-sectional effects of contagion risk qualitatively. We find that heterogeneity among the assets with respect to contagion risk can increase risk premia disproportionately. In particular, big assets with a large exposure to contagious shocks carry significantly higher risk premia.
Seit über 30 Jahren steht der Blaue Engel für besonders umweltfreundliche Produkte und Dienstleistungen. Damit ist er das älteste Umweltschutzzeichen in Deutschland. In den vergangenen Jahren wurden das Produktportfolio des Blauen Engel neu ausgerichtet und die Darstellung des Zeichens modernisiert. Seit 2008 ist der Blaue Engel auch das offizielle Klimaschutzzeichen der Bundesregierung. Regelmäßige empirische Umfragen zeigen, dass der Blaue Engel eine hohe Bekanntheit in der Bevölkerung besitzt. Über ein Drittel der Konsumentinnen und Konsumenten nutzen das Umweltzeichen als Orientierung beim Einkauf. Anders als vor 30 Jahren, muss sich der Blaue Engel heute in der öffentlichen Wahrnehmung in einer Flut von Umwelt- und Nachhaltigkeitszeichen behaupten.
Dieser Studientext präsentiert die Ergebnisse einer empirischen Befragung von Verbraucherinnen und Verbrauchern zu Wahrnehmung und Akzeptanz des Blauen Engel, die das ISOE für das Umweltbundesamt durchgeführt hat. In einer bundesweiten Online-Erhebung wurden 2.034 Personen befragt. Ergänzend erfolgte eine vertiefende qualitative Befragung mit Hilfe von Fokusgruppen. Die Befunde liefern wichtige Erkenntnisse darüber, wofür der Blaue Engel in den Augen der KonsumentInnen steht und wie er im Kontext anderer Label wahrgenommen wird. Darüberhinaus wird deutlich, welche Erwartungen aus Verbrauchersicht mit diesem Zeichen verbunden sind und welche Produkte und Produktgruppen mit ihm assoziiert werden.
Arzneimittelrückstände im Wasser – Lösungen liegen bei den Verursachern +++ Der Blaue Engel – ein Klassiker mit Potenzial +++ ISOE ist Partner von „Hessen schafft Wissen“ +++ Wie gelingt eine erfolgreiche Umsetzung von Forschungsergebnissen in die Praxis? +++ Wasser für das südliche Afrika – Neues Forschungsprojekt des ISOE im Rahmen der internationalen Initiative SASSCAL +++ Kooperation mit der Goethe-Universität Frankfurt am Main – Neue Lehrveranstaltungen zur Sozialen Ökologie im Sommersemester 2013 +++ Weltwassertag – Frankfurt-Premiere des Dokumentarfilms WaterChanges +++ Aus dem ISOE +++ Aktuelle Termine +++ Publikationen
This paper presents a theory that explains why it is beneficial for banks to engage in circular lending activities on the interbank market. Using a simple network structure, it shows that if there is a non-zero bailout probability, banks can significantly increase the expected repayment of uninsured creditors by entering into cyclical liabilities on the interbank market before investing in loan portfolios. Therefore, banks are better able to attract funds from uninsured creditors. Our results show that implicit government guarantees incentivize banks to have large interbank exposures, to be highly interconnected, and to invest in highly correlated, risky portfolios. This can serve as an explanation for the observed high interconnectedness between banks and their investment behavior in the run-up to the subprime mortgage crisis.
Basel III and CEO compensation in banks: pay structures as a regulatory signal : [March 6, 2013]
(2013)
This paper proposes a new regulatory approach that implements capital requirements contingent on managerial compensation. We argue that excessive risk taking in the financial sector originates from the shareholder moral hazard created by government guarantees rather than from corporate governance failures within banks. The idea of the proposed regulation is to utilize the compensation scheme to drive a wedge between the interests of top management and shareholders to counteract shareholder risk-shifting incentives. The decisive advantage of this approach compared to existing regulation is that the regulator does not need to be able to properly measure the bank investment risk, which has been shown to be a difficult task during the 2008-2009 financial crisis.
We assess the effects of monetary policy on bank risk to verify the existence of a risk-taking channel - monetary expansions inducing banks to assume more risk. We first present VAR evidence confirming that this channel exists and tends to concentrate on the bank funding side. Then, to rationalize this evidence we build a macro model where banks subject to runs endogenously choose their funding structure (deposits vs. capital) and risk level. A monetary expansion increases bank leverage and risk. In turn, higher bank risk in steady state increases asset price volatility and reduces equilibrium output.
Euro area data show a positive connection between sovereign and bank risk, which increases with banks’ and sovereign long run fragility. We build a macro model with banks subject to incentive problems and liquidity risk (in the form of liquidity based banks’ runs) which provides a link between endogenous bank capital and macro and policy risk. Our banks also invest in risky government bonds used as capital buffer to self-insure against liquidity risk. The model can replicate the positive connection between sovereign and bank risk observed in the data. Central bank liquidity policy, through full allotment policy, is successful in stabilizing the spiraling feedback loops between bank and sovereign risk.
This paper studies the relation between firm value and a firm's growth options. We find strong empirical evidence that (average) Tobin's Q increases with firm-level volatility. However, the significance mainly comes from R&D firms, which have more growth options than non-R&D firms. By decomposing firm-level volatility into its systematic and unsystematic part, we also document that only idiosyncratic volatility (ivol) has a significant effect on valuation. Second, we analyze the relation of stock returns to realized contemporaneous idiosyncratic volatility and R&D expenses. Single sorting according to the size of idiosyncratic volatility, we only find a significant ivol anomaly for non-R&D portfolios, whereas in a four-factor model the portfolio alphas of R&D portfolios are all positive. Double sorting on idiosyncratic volatility and R&D expenses also reveals these differences between R&D and non-R&D firms. To simultaneously control for several explanatory variables, we also run panel regressions of portfolio alphas which confirm the relative importance of idiosyncratic volatility that is amplified by R&D expenses.
We study whether prices of traded options contain information about future extreme market events. Our option-implied conditional expectation of market loss due to tail events, or tail loss measure, predicts future market returns, magnitude, and probability of the market crashes, beyond and above other option-implied variables. Stock-specific tail loss measure predicts individual expected returns and magnitude of realized stock-specific crashes in the cross-section of stocks. An investor that cares about the left tail of her wealth distribution benefits from using the tail loss measure as an information variable to construct managed portfolios of a risk-free asset and market index.
Recently, we evaluated a fiscal consolidation strategy for the United States that would bring the government budget into balance by gradually reducing government spending relative to GDP to the ratio that prevailed prior to the crisis (Cogan et al, JEDC 2013). Specifically, we published an analysis of the macroeconomic consequences of the 2013 Budget Resolution that was passed by the U.S. House of Representatives in March 2012. In this note, we provide an update of our research that evaluates this year’s budget reform proposal that is to be discussed and voted on in the House of Representative in March 2013. Contrary to the views voiced by critics of fiscal consolidation, we show that such a reduction in government purchases and transfer payments can increase GDP immediately and permanently relative to a policy without spending restraint. Our research makes use of a modern structural model of the economy that incorporates the long-standing essential features of economics: opportunity costs, efficiency, foresight and incentives. GDP rises because households take into account that spending restraint helps avoid future increases in tax rates. Lower taxes imply less distorted incentives for work, investment and production relative to a scenario without fiscal consolidation and lead to higher growth.
Whereas fossil evidence indicates extensive treeless vegetation and diverse grazing megafauna in Europe and northern Asia during the last glacial, experiments combining vegetation models and climate models have to-date simulated widespread persistence of trees. Resolving this conflict is key to understanding both last glacial ecosystems and extinction of most of the mega-herbivores. Using a dynamic vegetation model (DVM) we explored the implications of the differing climatic conditions generated by a general circulation model (GCM) in “normal” and “hosing” experiments. Whilst the former approximate interstadial conditions, the latter, designed to mimic Heinrich Events, approximate stadial conditions. The “hosing” experiments gave simulated European vegetation much closer in composition to that inferred from fossil evidence than did the “normal” experiments. Given the short duration of interstadials, and the rate at which forest cover expanded during the late-glacial and early Holocene, our results demonstrate the importance of millennial variability in determining the character of last glacial ecosystems.
We use unique data from financial advisers’ professional exam scores and combine it with other variables to create an index of financial sophistication. Using this index to explain long-term stock return expectations, we find that more sophisticated financial advisers tend to have lower return expectations. A one standard deviation increase in the sophistication index reduces expected returns by 1.1 percentage points. The effect is stronger for emerging market stocks (2.3 percentage points). The sophistication effect contributes 60% to the model fit, while employer fixed effects combined contribute less than 30%. These results help understand the formation of potentially excessively optimistic expectations.
Den Menschen als vernunftbegabtes Wesen, als animal rationale, zu begreifen heißt, ihn als rechtfertigendes Wesen anzusehen. Die Vernunft ist die Fähigkeit, sich anhand rechtfertigender Gründe in der Welt zu orientieren. Denn „ratio, raison, reason bedeutet“, wie Tugendhat hervorhebt, „ebenso sehr ‚Grund‘ wie ‚Vernunft‘. Das Vermögen der Vernunft ist die Fähigkeit, für seine Meinungen und für seine Handlungen Rede und Antwort stehen zu können; lat. rationem reddere, griech. logon didonai.“ Dieses Rede-und-Antwort-Stehen ist eine soziale Praxis kulturell und historisch situierter Wesen, die einerseits frei sind, ihre Gründe zu wählen und zu prüfen, andererseits aber daran gebunden, welche Gründe ihnen zur Verfügung stehen und welche als gut oder rechtfertigend gelten. Der Raum der Gründe ist ein Raum der Rechtfertigungen, die nicht nur Einzelhandlungen, sondern auch komplexe Handlungsordnungen, also soziale Verhältnisse und politische Institutionen, legitimieren.
Menschen sind aber auch erzählende Wesen. Der Raum der Gründe, in dem sie sich orientieren, ist kein nackter Raum einzelner Sätze oder gar Normen, sondern bevölkert von Narrativen.
A natural experiment in which customer-owned mutual companies converted to publicly listed firms created a plausibly exogenous shock to the stock market participation status of tens of thousands of people. We find the shock changed the way people vote in the affected areas, with a 10% increase in share-ownership rate being followed by a 1.3%–3.1% increase in right-of-center vote share. The institutional details and additional tests suggest that wealth, liquidity, and tax-related incentives cannot fully explain the results. A plausible explanation is that the associated increase in the salience of stock ownership causes a shift in voters’ attention.
The European Commission recently put forward a proposal for a regulation to amend and strengthen the 2009 version of the EU's rules on the regulation of credit rating agencies ("CRA3"). Among other things, Art. 35a of the draft proposal introduces strict liability for rating agencies. This liability proposal is at odds with the aim to strengthen competition in the rating sector and could have a chilling effect on capital markets. The paper analyses existing rules on civil liability of rating agencies under different legal systems. Subsequently, the provision under Art. 35a of the Draft Proposal is examinded more closely. Suggestions on possible improvemts of the proposal are made.
SAFE Newsletter : 2013, Q1
(2013)
Debt-induced crises, including the subprime, are usually attributed exclusively to supply-side factors. We uncover an additional factor contributing to debt culture, namely social influences emanating from the perceived average income of peers. Using unique information from a representative household survey of the Dutch population that circumvents the need to define the social circle, we consider collateralized, consumer, and informal loans. We find robust social effects on borrowing – especially among those who consider themselves poorer than their peers – and on indebtedness, suggesting a link to financial distress. We check the robustness of our results using several approaches to rule out spurious associations and handle correlated effects.
Planar cell polarity (PCP)–the coordinated polarisation of a whole field of cells within the plane of a tissue–relies on the interaction of three modules: a global module that couples individual cellular polarity to the tissue axis, a local module that aligns the axis of polarisation of neighbouring cells, and a readout module that directs the correct outgrowth of PCP-regulated structures such as hairs and bristles. While much is known about the molecular components that are required for PCP, the functional details of–and interactions between–the modules remain unclear. In this work, we perform a mathematical and computational analysis of two previously proposed computational models of the local module (Amonlirdviman et al., Science, 307, 2005; Le Garrec et al., Dev. Dyn., 235, 2006). Both models can reproduce wild-type and mutant phenotypes of PCP observed in the Drosophila wing under the assumption that a tissue-wide polarity cue from the global module persists throughout the development of PCP. We demonstrate that both models can also generate tissue-level PCP when provided with only a transient initial polarity cue. However, in these models such transient cues are not sufficient to ensure robustness of the resulting cellular polarisation.
Since the 1980s, advances in wastewater treatment technology have led to considerably improved surface water quality in the urban areas of many high income countries. However, trace concentrations of organic wastewater-associated contaminants may still pose a key environmental hazard impairing the ecological quality of surface waters. To identify key impact factors, we analyzed the effects of a wide range of anthropogenic and environmental variables on the aquatic macroinvertebrate community. We assessed ecological water quality at 26 sampling sites in four urban German lowland river systems with a 0–100% load of state-of-the-art biological activated sludge treated wastewater. The chemical analysis suite comprised 12 organic contaminants (five phosphor organic flame retardants, two musk fragrances, bisphenol A, nonylphenol, octylphenol, diethyltoluamide, terbutryn), 16 polycyclic aromatic hydrocarbons, and 12 heavy metals. Non-metric multidimensional scaling identified organic contaminants that are mainly wastewater-associated (i.e., phosphor organic flame retardants, musk fragrances, and diethyltoluamide) as a major impact variable on macroinvertebrate species composition. The structural degradation of streams was also identified as a significant factor. Multiple linear regression models revealed a significant impact of organic contaminants on invertebrate populations, in particular on Ephemeroptera, Plecoptera, and Trichoptera species. Spearman rank correlation analyses confirmed wastewater-associated organic contaminants as the most significant variable negatively impacting the biodiversity of sensitive macroinvertebrate species. In addition to increased aquatic pollution with organic contaminants, a greater wastewater fraction was accompanied by a slight decrease in oxygen concentration and an increase in salinity. This study highlights the importance of reducing the wastewater-associated impact on surface waters. For aquatic ecosystems in urban areas this would lead to: (i) improvement of the ecological integrity, (ii) reduction of biodiversity loss, and (iii) faster achievement of objectives of legislative requirements, e.g., the European Water Framework Directive.
This study indicates that embryonic stem cells [ESCs] cultured with retinoic acid and activin A significantly upregulate the miRNA let-7e. This specific miRNA modulates the Wnt pathway and the expression of early nephrogenic markers under these differentiation conditions. The differentiation markers WT1, Pax2 and Wnt4 were downregulated when miRNA let-7e was silenced, thus indicating the role of miRNA let-7e in the differentiation process. PKCβ, GSK3β phosphorylation (GSK3βP) and β-catenin expression was reduced in differentiated cells and reversed by miRNA let-7e silencing. Addition of a PKCβ inhibitor to the miRNA let-7e silenced cells abolished let-7e-derived effects in differentiation markers, and reversed the increase in GSK3βP and β-catenin, thus indicating that miRNA let-7e is involved in differentiation via the modulation of GSK3β phosphorylation and β-catenin production.
Die Dissertation stellt das Machtgeflecht in der Islamischen Stadt Marawi City (Mindanao, Philippinen) dar, in die die dortigen Gender-Debatten involviert sind. In einer Umgebung, die als Konsequenz des Mindanao Konfliktes als “no war, no peace”-Umgebung definiert werden kann, gibt es drei Hauptdarsteller: die nationale Regierung des mehrheitlich christlichen Staates der Philippinen (GRP), die Autonome Regierung im Muslimischen Mindanao (ARMM), zu der auch Marawi City zählt, und die islamische Rebellengruppe Moro Islamic Liberation Front (MILF), die einen islamischen (unter-)Staat fordert. Die GRP unterstützt Re-Islamisierungs- und Re-Traditionalisierungsbewegungen in der ARMM, um die Opposition zur MILF zu stärken. Die Konsequenz ist jedoch keine Kollaboration zwischen der GRP und der ARMM. Stattdessen nutzen Politiker ihre Privilegien aus, um ihren eigenen Absichten zu folgen. Sei dies, um politische Gegner auszuspielen oder das traditionelle Sultanatssystem zu fördern. Für Gender-Debatten gibt es in diesem Kontext der ungelösten nationalen Frage kaum Spielraum außerhalb einer Islamischen Narrative; dies bedeutet jedoch nicht, dass Gender nicht debattiert wird, sondern, dass die Debatten inner-Islamisch sind, hauptsächlich zwischen Repräsentanten des traditionell synkretistischen Islam und Vertretern Islamischer Revitalisierungsbewegungen. Speziell erstere erscheinen sehr einflussreich bezüglich Gender Strategien in der Region. Dies ist nur teilweise auf die Unterstützung der nationalen Regierung zurückzuführen, sondern ist vor allem eine Frage von Identität. Diese wiederum wird nicht vorranging über Religion, sondern nach ethnischen Maßstäben und im Speziellen im Rahmen von Clanstrukturen definiert.
Orthotopic bladder cancer xenografts are essential for testing novel therapies and molecular manipulations of cell lines in vivo. Current xenografts rely on tumor cell inoculation by intravesical instillation or direct injection into the bladder wall. Instillation is limited by the lack of cell lines that are tumorigenic when delivered in this manner. The invasive model inflicts morbidity on the mice by the need for laparotomy and mobilization of the bladder. Furthermore this procedure is complex and time-consuming. Three bladder cancer cell lines (UM-UC1, UM-UC3, UM-UC13) were inoculated into 50 athymic nude mice by percutaneous injection under ultrasound guidance. PBS was first injected between the muscle wall and the mucosa to separate these layers, and tumor cells were subsequently injected into this space. Bioluminescence and ultrasound were used to monitor tumor growth. Contrast-enhanced ultrasound was used to study changes in tumor perfusion after systemic gemcitabine/cisplatin treatment. To demonstrate proof of principle that therapeutic agents can be injected into established xenografts under ultrasound guidance, oncolytic virus (VSV) was injected into UM-UC3 tumors. Xenograft tissue was harvested for immunohistochemistry after 23–37 days. Percutaneous injection of tumor cells into the bladder wall was performed efficiently (mean time: 5.7 min) and without complications in all 50 animals. Ultrasound and bioluminescence confirmed presence of tumor in the anterior bladder wall in all animals 3 days later. The average tumor volumes increased steadily over the study period. UM-UC13 tumors showed a marked decrease in volume and perfusion after chemotherapy. Immunohistochemical staining for VSV-G demonstrated virus uptake in all UM-UC3 tumors after intratumoral injection. We have developed a novel method for creating orthotopic bladder cancer xenograft in a minimally invasive fashion. In our hands this has replaced the traditional model requiring laparotomy, because this model is more time efficient, more precise and associated with less morbidity for the mice.
Natural killer (NK) cells are highly specialized effectors of the innate immune system that hold promise for adoptive cancer immunotherapy. Their cell killing activity is primarily mediated by the pro-apoptotic serine protease granzyme B (GrB), which enters targets cells with the help of the pore-forming protein perforin. We investigated expression of a chimeric GrB fusion protein in NK cells as a means to augment their antitumoral activity. For selective targeting to tumor cells, we fused the epidermal growth factor receptor (EGFR) peptide ligand transforming growth factor α (TGFα) to human pre-pro-GrB. Established human NKL natural killer cells transduced with a lentiviral vector expressed this GrB-TGFα (GrB-T) molecule in amounts comparable to endogenous wildtype GrB. Activation of the genetically modified NK cells by cognate target cells resulted in the release of GrB-T together with endogenous granzymes and perforin, which augmented the effector cells' natural cytotoxicity against NK-sensitive tumor cells. Likewise, GrB-T was released into the extracellular space upon induction of degranulation with PMA and ionomycin. Secreted GrB-T fusion protein displayed specific binding to EGFR-overexpressing tumor cells, enzymatic activity, and selective target cell killing in the presence of an endosomolytic activity. Our data demonstrate that ectopic expression of a targeted GrB fusion protein in NK cells is feasible and can enhance antitumoral activity of the effector cells.
Despite numerous large-scale phylogenomic studies, certain parts of the mammalian tree are extraordinarily difficult to resolve. We used the coding regions from 19 completely sequenced genomes to study the relationships within the super-clade Euarchontoglires (Primates, Rodentia, Lagomorpha, Dermoptera and Scandentia) because the placement of Scandentia within this clade is controversial. The difficulty in resolving this issue is due to the short time spans between the early divergences of Euarchontoglires, which may cause incongruent gene trees. The conflict in the data can be depicted by network analyses and the contentious relationships are best reconstructed by coalescent-based analyses. This method is expected to be superior to analyses of concatenated data in reconstructing a species tree from numerous gene trees. The total concatenated dataset used to study the relationships in this group comprises 5,875 protein-coding genes (9,799,170 nucleotides) from all orders except Dermoptera (flying lemurs). Reconstruction of the species tree from 1,006 gene trees using coalescent models placed Scandentia as sister group to the primates, which is in agreement with maximum likelihood analyses of concatenated nucleotide sequence data. Additionally, both analytical approaches favoured the Tarsier to be sister taxon to Anthropoidea, thus belonging to the Haplorrhine clade. When divergence times are short such as in radiations over periods of a few million years, even genome scale analyses struggle to resolve phylogenetic relationships. On these short branches processes such as incomplete lineage sorting and possibly hybridization occur and make it preferable to base phylogenomic analyses on coalescent methods.
Neuronal activity differs between wakefulness and sleep states. In contrast, an attractor state, called self-organized critical (SOC), was proposed to govern brain dynamics because it allows for optimal information coding. But is the human brain SOC for each vigilance state despite the variations in neuronal dynamics? We characterized neuronal avalanches – spatiotemporal waves of enhanced activity - from dense intracranial depth recordings in humans. We showed that avalanche distributions closely follow a power law – the hallmark feature of SOC - for each vigilance state. However, avalanches clearly differ with vigilance states: slow wave sleep (SWS) shows large avalanches, wakefulness intermediate, and rapid eye movement (REM) sleep small ones. Our SOC model, together with the data, suggested first that the differences are mediated by global but tiny changes in synaptic strength, and second, that the changes with vigilance states reflect small deviations from criticality to the subcritical regime, implying that the human brain does not operate at criticality proper but close to SOC. Independent of criticality, the analysis confirms that SWS shows increased correlations between cortical areas, and reveals that REM sleep shows more fragmented cortical dynamics.
Bücher und Zeitschriften, aber auch weitere Materialien wie Zeitungen, Notendrucke, Autographen und anderes gehören seit Jahrhunderten zum Bestand wissenschaftlicher Bibliotheken und sind gleichzeitig Objekte für Lehre und Forschung. Sie zu sammeln, zu erschließen und den Interessierten zugänglich zu machen, war und ist die Aufgabe von Bibliotheken. Nun befinden wir uns heute jedoch in einer Zeit des fundamentalen Wandels. Von Vielen wird er als Paradigma beschrieben, welches dadurch gekennzeichnet ist, dass die Welt der gedruckten Texte und Bilder (Gutenberg-Galaxis) abgelöst wird von einer digitalen Welt (Turing-Galaxis), in der Information nicht mehr an einen und schon gar nicht analogen Träger gebunden ist. In der Folge der Entwicklung des Internets sind in den letzten zwei Jahrzehnten mit Suchmaschinen und "Discovery Systemen", mit elektronischen Zeitschriften und ebensolchen Büchern, mit Hypertexten und dem "Semantic Web" Strukturen entstanden, denen eines gemeinsam ist. Ihre informationellen Inhalte sind nicht mehr an ein physisches Objekt gebunden, sie sind nicht mehr lokalisierbar und von daher im Prinzip von überall her und zu jeder Zeit nutzbar. ...
Paging is one of the prominent problems in the field of on-line algorithms. While in the deterministic setting there exist simple and efficient strongly competitive algorithms, in the randomized setting a tradeoff between competitiveness and memory is still not settled. Bein et al. [4] conjectured that there exist strongly competitive randomized paging algorithms, using o(k) bookmarks, i.e. pages not in cache that the algorithm keeps track of. Also in [4] the first algorithm using O(k) bookmarks (2k more precisely), Equitable2, was introduced, proving in the affirmative a conjecture in [7].
We prove tighter bounds for Equitable2, showing that it requires less than k bookmarks, more precisely ≈ 0.62k. We then give a lower bound for Equitable2 showing that it cannot both be strongly competitive and use o(k) bookmarks. Nonetheless, we show that it can trade competitiveness for space. More precisely, if its competitive ratio is allowed to be (Hk + t), then it requires k/(1 + t) bookmarks.
Our main result proves the conjecture that there exist strongly competitive paging algorithms using o(k) bookmarks. We propose an algorithm, denoted Partition2, which is a variant of the Partition algorithm byMcGeoch and Sleator [13]. While classical Partition is unbounded in its space requirements, Partition2 uses θ(k/ log k) bookmarks. Furthermore, we show that this result is asymptotically tight when the forgiveness steps are deterministic.
Recht und die Vorstellung von dem, was Recht ist, sind nicht allein an Territorien oder Herrschaften gebunden, sondern wandern mit den Menschen mit. Treffen mehrere möglicherweise anwendbare Rechte aufeinander, steht für heutige Gerichte ein Kollisionsrecht wie das Internationale Privatrecht bereit, dass über den Umgang mit diesem Konflikt entscheidet , indem es den Fall einer bestimmten nationalstaatlichen Regelung unterstellt. Andere Lösungen sind jedoch ebenfalls denkbar und wurden in der Vergangenheit auch praktiziert, was heute schwer nachzuvollziehen ist. Um die Denkstruktur und Grenzen der modernen Herangehensweise deutlich werden zu lassen, sollen in diesem Beitrag die Schwierigkeiten erläutert werden, das Konzept des Internationalen Privatrechts auf das Neben- und Miteinander verschiedener rechtlicher Traditionen im hellenistischen Ägypten zu übertragen. Ziel ist es, auch Nichtjuristen damit einen Einstieg und eine Übersicht über die Diskussion innerhalb der antiken Rechtsgeschichte zu ermöglichen.
This thesis presents various algorithms which have been developed for on-line event reconstruction in the CBM experiment at GSI, Darmstadt and the ALICE experiment at CERN, Geneve. Despite the fact that the experiments are different — CBM is a fixed target experiment with forward geometry, while ALICE has a typical collider geometry — they share common aspects when reconstruction is concerned.
The thesis describes:
— general modifications to the Kalman filter method, which allows one to accelerate, to improve, and to simplify existing fit algorithms;
— developed algorithms for track fit in CBM and ALICE experiment, including a new method for track extrapolation in non-homogeneous magnetic field.
— developed algorithms for primary and secondary vertex fit in the both experiments. In particular, a new method of reconstruction of decayed particles is presented.
— developed parallel algorithm for the on-line tracking in the CBM experiment.
— developed parallel algorithm for the on-line tracking in High Level Trigger of the ALICE experiment.
— the realisation of the track finders on modern hardware, such as SIMD CPU registers and GPU accelerators.
All the presented methods have been developed by or with the direct participation of the author.
The way we perceive the visual world depends crucially on the state of the observer. In the present study we show that what we are holding in working memory (WM) can bias the way we perceive ambiguous structure from motion stimuli. Holding in memory the percept of an unambiguously rotating sphere influenced the perceived direction of motion of an ambiguously rotating sphere presented shortly thereafter. In particular, we found a systematic difference between congruent dominance periods where the perceived direction of the ambiguous stimulus corresponded to the direction of the unambiguous one and incongruent dominance periods. Congruent dominance periods were more frequent when participants memorized the speed of the unambiguous sphere for delayed discrimination than when they performed an immediate judgment on a change in its speed. The analysis of dominance time-course showed that a sustained tendency to perceive the same direction of motion as the prior stimulus emerged only in the WM condition, whereas in the attention condition perceptual dominance dropped to chance levels at the end of the trial. The results are explained in terms of a direct involvement of early visual areas in the active representation of visual motion in WM.
Language and transnationalism : language discourse in transnational Salsa communities of practice
(2013)
Language ideologies in contemporary Western societies are characterised by a strong influence of the idea that one language ‘pertains’ to one culture. Yet, cultural developments of globalisation, such as migration, the construction of transnational networks or global mass media, question national frameworks of culture and language.
In this thesis, after reviewing the field of language ideology and discussing historical examples of the development of national language discourse, language ideologies in a transnational context are examined. Using ethnographic research methods and a discursive approach to interview data, concepts and ideas revolving around language of transnational Communities of Practice constituted through Salsa dancing are analysed. Due to its connections to the Latin American cultural space, the practice of Salsa dancing in non-Latin contexts intrinsically constructs transnational ties. Different Salsa Communities of Practice are studied in Sydney, Australia, and Frankfurt, Germany. Interestingly, different local communities show very different ideologies concerning the role of language, multilingualism, concepts of authenticity or influences of capitalist discourse. The cross-national approach allows studying the influence of different national discourses on the formation of local ideologies in transnational contexts.
Thus, next to scrutinising the traditional concept of a ‘language’ and its relevance in a transnational age, the theoretical aim of this study is to analyse the interaction of discourses from different realms – local, regional, national, transnational – in the formation of contemporary discourses on language. These construct new symbolic meanings of language that co-exist next to the national concept of the relationship of language and culture, so that a multiplication of language boundaries can be considered to be a characteristic trait of contemporary language discourse.
Bibliotheken sind im Erwerbungsalltag mit einer Vielzahl unterschiedlichster Lizenzverträge für die Beschaffung von elektronischen Medien konfrontiert. Dabei nimmt die Komplexität durch das Anwachsen der Zahl der Marktteilnehmer aus Buchhandel und Agenturen, Verlagen und auch der verschiedenen Konsortien sowohl auf nationaler als auch auf internationaler Ebene wie durch die immer größer werdende Vielzahl der Produkte und Lizenzmodelle ständig zu. Die Transaktionskosten bei der Lizenzierung neuer Produkte, aber auch die Aktivitäten zur Verlängerung bestehender Lizenzverträge, steigen proportional mit der Zunahme der Bedeutung und Gewichtung, die elektronische Medienangebote einnehmen. Geschäftsgangmodelle, die ein Verfahren ohne Reibungsverluste garantieren, sind nicht vorhanden - wenn denn ein entsprechendes Problembewusstsein für die Bedeutung und den Wirkungsgrad bestimmter Lizenzvertragsklauseln existiert. Aufgrund der prinzipiell vorhandenen Vertragsfreiheit steht es den Partnern im Grunde frei, einen Vertrag entsprechend den Wünschen und Vorstellungen auszuhandeln. Dies wird in bestimmten Fällen von Vorteil sein, wenn es sich z.B. um Verträge von Konsortien mit Produkteanbietern handelt. Wie aber verhält es sich mit individuell abzuschließenden Lizenzverträgen einzelner Institutionen, z.B. beim Nachkauf von E-Books oder Ergänzungen von weiteren Datenbankprodukten des gleichen Anbieters. In vielen Fällen ist jedesmal ein Lizenzvertrag neu abzuschließen, wobei die minutiöse Lektüre aller Klauseln dringend angeraten sei. Hier würde sich anbieten, den Geschäftsverkehr der Vertragspartner zu vereinfachen, wenn nur schon die Vertragstexte soweit standardisiert wären, dass einheitliche Definitionen und Formulierungen für die einzelnen Regelungspunkte Verwendung fänden und lediglich Sonderabsprachen oder -vereinbarungen als Addenda beizufügen wären.
Vascular endothelial growth factors (VEGFs), initially thought to act specifically on the vascular system, exert trophic effects on neural cells during development and adulthood. Therefore, the VEGF system serves as a promising therapeutic target for brain pathologies, but its simultaneous action on vascular cells paves the way for harmful side effects. To circumvent these deleterious effects, many studies have aimed to clarify whether VEGFs directly affect neural cells or if the effects are mediated secondarily via other cell types, like vascular cells. A great number of reports have shown the expression and function of VEGF receptors (VEGFRs), mainly VEGFR-1 and -2, in neural cells, where VEGFR-2 has been described as the major mediator of VEGF-A signals. This review aims to summarize and compare the divergent roles of VEGFR-1 and -2 during CNS development and homeostasis.
"PULS." – a blog-based online-magazine for students of medicine of the Goethe University Frankfurt
(2013)
In the context of nationwide protests 2009 also students of the faculty of medicine/dentistry at Goethe-University in Frankfurt demanded more transparency and communication. To satisfy these demands, a web 2.0-tool offered an innovative solution: A blog-based online-magazine for students and other faculty-members. The online-magazine "PULS." is realized with the share-ware blog-software (wordpress version 3.1.3) and is conceived and written by an online-journalist. "PULS." is available from https://newsmagazin.puls.med.uni-frankfurt.de/wp/. The articles are generated from own investigations and from ideas of different groups of the faculty– deanship, students and lecturers. A user-analysis is conducted with the open-source software Piwik and considers the data security. Additionally, every year an anonymous online-user-survey (Survey Monkey) is conducted. "PULS." is continuously online since 14.02.2010 and has published 806 articles (state: 27.11.2012) and has about 2400 readers monthly. The content focuses on the needs of Frankfurt medical students. The close cooperation with different groups of the faculty - deanship, students and lecturers - furthermore guarantees themes relevant to the academic faculty. "PULS." flanks complex projects and decisions with background-information and communicates them understandable. The user-evaluation shows a growing number of readers and a high acceptance for the online-magazine, its themes and its style. The web 2.0-tool "Blog" and the web-specific language comply with media habits of the main target group, the students of the faculty medicine/dentistry. Thus, "PULS." has proven as a suitable and strategic instrument. It pushes towards a higher transparency, more communication and a stronger identification of the students with their faculty.
"PULS." - Ein Blog als Online-Magazin für Medizinstudierende der Goethe-Universität Frankfurt
(2013)
Im Herbst 2009 forderten Studierende im Rahmen landesweiter Proteste auch am Fachbereich Medizin/Zahnmedizin der Goethe-Universität Frankfurt mehr Transparenz und Kommunikation zu Angelegenheiten ihres Studiums. Einen innovativen Lösungsansatz, um diesen Forderungen nachzukommen, bietet eines der Web 2.0 Werkzeuge: ein auf einer Blog-Software basierendes Online-Magazin für Studierende und andere Mitglieder des Fachbereichs.
Das öffentlich zugängliche Online-Magazin "PULS." (https://newsmagazin.puls.med.uni-frankfurt.de/wp/) wird mit einer freien Blog-Software (wordpress Version 3.1.3.) realisiert und von einer Online-Redakteurin konzipiert und geschrieben. Die Beiträge entstehen nach eigenen Recherchen sowie aus Anregungen und Gesprächen mit verschiedenen Personengruppen des Fachbereichs. Die datenschutzkonforme Auswertung der Zugriffe erfolgt über eine open-source Webanalyse-Software (Piwik). Zusätzlich werden jährlich mit dem Online-Umfrage-Tool Survey Monkey die Nutzer anonym befragt.
"PULS." ist seit dem 14.02.2010 ununterbrochen online und hat seitdem 806 Beiträge (Stand: 27.11.2012) publiziert und wird von ca. 2400 Besuchern monatlich gelesen. Das Themenspektrum ist zentriert auf die Anliegen der Frankfurter Medizin- und Zahnmedizinstudierenden. Die enge Zusammenarbeit mit verschiedenen Gruppierungen des Fachbereichs – Dekanat, Studierende und Lehrende – garantiert darüber hinaus ein fachbereichs-relevantes Themenspektrum. Das Online-Magazin begleitet komplexe Projekte und Entscheidungen mit Hintergrundinformationen und kommuniziert sie verständlich. Eine jährliche Nutzer-Evaluierung zeigt eine wachsende Leserzahl und eine sehr hohe Zustimmung für das Online-Magazin, seine Inhalte und seinen Stil. Das Web 2.0-Medium "Blog" und seine web-typische Sprache entsprechen dem Medienverhalten der Zielgruppe, d.h. den Studierenden des Fachbereichs Medizin.
"PULS." hat sich als ein geeignetes und strategisches Instrument erwiesen, um größere Transparenz, mehr Kommunikation und letztendlich eine stärkere Identifikation der Studierenden mit ihrem Fachbereich voranzutreiben.
he Influence of trehalose-based glycolipids in the virulence of Mycobacterium tuberculosis (Mtb) is recognised; however, the actual role of these cell-wall glycolipids in latent infection is unknown. As an initial approach, we determined by two-dimensional thin-layer chromatography the sulfolipid (SL) and diacyltrehalose/polyacyltrehalose (DAT/PAT) profile of the cell wall of hypoxic Mtb. Then, qRT-PCR was extensively conducted to determine the transcription profile of genes involved in the biosynthesis of these glycolipids in non-replicating persistent 1 (NRP1) and anaerobiosis (NRP2) models of hypoxia (Wayne model), and murine models of chronic and progressive pulmonary tuberculosis. A diminished content of SL and increased amounts of glycolipids with chromatographic profile similar to DAT were detected in Mtb grown in the NRP2 stage. A striking decrease in the transcription of mmpL8 and mmpL10 transporter genes and increased transcription of the pks (polyketidesynthase) genes involved in SL and DAT biosynthesis were detected in both the NRP2 stage and the murine model of chronic infection. All genes were found to be up-regulated in the progressive disease. These results suggest that SL production is diminished during latent infection and the DAT/PAT precursors can be accumulated inside tubercle bacilli and are possibly used in reactivation processes.
Few sequence alignment methods have been designed specifically for integral membrane proteins, even though these important proteins have distinct evolutionary and structural properties that might affect their alignments. Existing approaches typically consider membrane-related information either by using membrane-specific substitution matrices or by assigning distinct penalties for gap creation in transmembrane and non-transmembrane regions. Here, we ask whether favoring matching of predicted transmembrane segments within a standard dynamic programming algorithm can improve the accuracy of pairwise membrane protein sequence alignments. We tested various strategies using a specifically designed program called AlignMe. An updated set of homologous membrane protein structures, called HOMEP2, was used as a reference for optimizing the gap penalties. The best of the membrane-protein optimized approaches were then tested on an independent reference set of membrane protein sequence alignments from the BAliBASE collection. When secondary structure (S) matching was combined with evolutionary information (using a position-specific substitution matrix (P)), in an approach we called AlignMePS, the resultant pairwise alignments were typically among the most accurate over a broad range of sequence similarities when compared to available methods. Matching transmembrane predictions (T), in addition to evolutionary information, and secondary-structure predictions, in an approach called AlignMePST, generally reduces the accuracy of the alignments of closely-related proteins in the BAliBASE set relative to AlignMePS, but may be useful in cases of extremely distantly related proteins for which sequence information is less informative. The open source AlignMe code is available at https://sourceforge.net/projects/alignme/, and at http://www.forrestlab.org, along with an online server and the HOMEP2 data set.
Purpose: Metabolic changes upon antiangiogenic therapy of recurrent glioblastomas (rGBMs) may provide new biomarkers for treatment efficacy. Since in vitro models showed that phospholipid membrane metabolism provides specific information on tumor growth we employed in-vivo MR-spectroscopic imaging (MRSI) of human rGBMs before and under bevacizumab (BVZ) to measure concentrations of phosphocholine (PCho), phosphoethanolamine (PEth), glycerophosphocholine (GPC), and glyceroethanolamine (GPE).
Methods: 1H and 31P MRSI was prospectively performed in 32 patients with rGBMs before and under BVZ therapy at 8 weeks intervals until tumor progression. Patients were dichotomized into subjects with long overall survival (OS) (>median OS) and short OS (<median OS) survival time from BVZ-onset. Metabolite concentrations from tumor tissue and their ratios were compared to contralateral normal-appearing tissue (control).
Results: Before BVZ, 1H-detectable choline signals (total GPC and PCho) in rGBMs were elevated but significance failed after dichotomizing. For metabolite ratios obtained by 31P MRSI, the short-OS group showed higher PCho/GPC (p = 0.004) in rGBMs compared to control tissue before BVZ while PEth/GPE was elevated in rGBMs of both groups (long-OS p = 0.04; short-OS p = 0.003). Under BVZ, PCho/GPC and PEth/GPE in the tumor initially decreased (p = 0.04) but only PCho/GPC re-increased upon tumor progression (p = 0.02). Intriguingly, in normal-appearing tissue an initial PEth/GPE decrease (p = 0.047) was followed by an increase at the time of tumor progression (p = 0.031).
Conclusion: An elevated PCho/GPC ratio in the short-OS group suggests that it is a negative predictive marker for BVZ efficacy. These gliomas may represent a malignant phenotype even growing under anti-VEGF treatment. Elevated PEth/GPE may represent an in-vivo biomarker more sensitive to GBM infiltration than MRI.
In complex networks such as gene networks, traffic systems or brain circuits it is important to understand how long it takes for the different parts of the network to effectively influence one another. In the brain, for example, axonal delays between brain areas can amount to several tens of milliseconds, adding an intrinsic component to any timing-based processing of information. Inferring neural interaction delays is thus needed to interpret the information transfer revealed by any analysis of directed interactions across brain structures. However, a robust estimation of interaction delays from neural activity faces several challenges if modeling assumptions on interaction mechanisms are wrong or cannot be made. Here, we propose a robust estimator for neuronal interaction delays rooted in an information-theoretic framework, which allows a model-free exploration of interactions. In particular, we extend transfer entropy to account for delayed source-target interactions, while crucially retaining the conditioning on the embedded target state at the immediately previous time step. We prove that this particular extension is indeed guaranteed to identify interaction delays between two coupled systems and is the only relevant option in keeping with Wiener’s principle of causality. We demonstrate the performance of our approach in detecting interaction delays on finite data by numerical simulations of stochastic and deterministic processes, as well as on local field potential recordings. We also show the ability of the extended transfer entropy to detect the presence of multiple delays, as well as feedback loops. While evaluated on neuroscience data, we expect the estimator to be useful in other fields dealing with network dynamics.
The Behavioral Inhibition System (BIS) as defined within the Reinforcement Sensitivity Theory (RST) modulates reactions to stimuli indicating aversive events. Gray’s trait Anxiety determines the extent to which stimuli activate the BIS. While studies have identified the amygdala-septo-hippocampal circuit as the key-neural substrate of this system in recent years and measures of resting-state dynamics such as randomness and local synchronization of spontaneous BOLD fluctuations have recently been linked to personality traits, the relation between resting-state dynamics and the BIS remains unexplored. In the present study, we thus examined the local synchronization of spontaneous fMRI BOLD fluctuations as measured by Regional Homogeneity (ReHo) in the hippocampus and the amygdala in twenty-seven healthy subjects. Correlation analyses showed that Gray’s trait Anxiety was significantly associated with mean ReHo in both the amygdala and the hippocampus. Specifically, Gray’s trait Anxiety explained 23% and 17% of resting-state ReHo variance in the left amygdala and the left hippocampus, respectively. In summary, we found individual differences in Gray’s trait Anxiety to be associated with ReHo in areas previously associated with BIS functioning. Specifically, higher ReHo in resting-state neural dynamics corresponded to lower sensitivity to punishment scores both in the amygdala and the hippocampus. These findings corroborate and extend recent findings relating resting-state dynamics and personality while providing first evidence linking properties of resting-state fluctuations to Gray’s BIS.
Background: To compare the effect of aprotinin with the effect of lysine analogues (tranexamic acid and ε-aminocaproic acid) on early mortality in three subgroups of patients: low, intermediate and high risk of cardiac surgery.
Methods and Findings: We performed a meta-analysis of randomised controlled trials and observational with the following data sources: Medline, Cochrane Library, and reference lists of identified articles. The primary outcome measure was early (in-hospital/30-day) mortality. The secondary outcome measures were any transfusion of packed red blood cells within 24 hours after surgery, any re-operation for bleeding or massive bleeding, and acute renal dysfunction or failure within the selected cited publications, respectively.
Out of 328 search results, 31 studies (15 trials and 16 observational studies) included 33,501 patients. Early mortality was significantly increased after aprotinin vs. lysine analogues with a pooled risk ratio (95% CI) of 1.58 (1.13–2.21), p<0.001 in the low (n = 14,297) and in the intermediate risk subgroup (1.42 (1.09–1.84), p<0.001; n = 14,427), respectively. Contrarily, in the subgroup of high risk patients (n = 4,777), the risk for mortality did not differ significantly between aprotinin and lysine analogues (1.03 (0.67–1.58), p = 0.90).
Conclusion: Aprotinin may be associated with an increased risk of mortality in low and intermediate risk cardiac surgery, but presumably may has no effect on early mortality in a subgroup of high risk cardiac surgery compared to lysine analogues. Thus, decisions to re-license aprotinin in lower risk patients should critically be debated. In contrast, aprotinin might probably be beneficial in high risk cardiac surgery as it reduces risk of transfusion and bleeding complications.
The FK506-binding protein 51 (FKBP51) is an Hsp90-associated co-chaperone which regulates steroid receptors and kinases. In pancreatic cancer cell lines, FKBP51 was shown to recruit the phosphatase PHLPP to facilitate dephosphorylation of the kinase Akt, which was associated with reduced chemoresistance. Here we show that in addition to FKBP51 several other members of the FKBP family bind directly to Akt. FKBP51 can also form complexes with other AGC kinases and mapping studies revealed that FKBP51 interacts with Akt via multiple domains independent of their activation or phosphorylation status. The FKBP51-Akt1 interaction was not affected by FK506 analogs or Akt active site inhibitors, but was abolished by the allosteric Akt inhibitor VIII. None of the FKBP51 inhibitors affected AktS473 phosphorylation or downstream targets of Akt. In summary, we show that FKBP51 binds to Akt directly as well as via Hsp90. The FKBP51-Akt interaction is sensitive to the conformation of Akt1, but does not depend on the FK506-binding pocket of FKBP51. Therefore, FKBP inhibitors are unlikely to inhibit the Akt-FKBP-PHLPP network.
The membrane proximal external region (MPER) of the HIV-1 glycoprotein gp41 is targeted by the broadly neutralizing antibodies 2F5 and 4E10. To date, no immunization regimen in animals or humans has produced HIV-1 neutralizing MPER-specific antibodies. We immunized llamas with gp41-MPER proteoliposomes and selected a MPER-specific single chain antibody (VHH), 2H10, whose epitope overlaps with that of mAb 2F5. Bi-2H10, a bivalent form of 2H10, which displayed an approximately 20-fold increased affinity compared to the monovalent 2H10, neutralized various sensitive and resistant HIV-1 strains, as well as SHIV strains in TZM-bl cells. X-ray and NMR analyses combined with mutagenesis and modeling revealed that 2H10 recognizes its gp41 epitope in a helical conformation. Notably, tryptophan 100 at the tip of the long CDR3 is not required for gp41 interaction but essential for neutralization. Thus bi-2H10 is an anti-MPER antibody generated by immunization that requires hydrophobic CDR3 determinants in addition to epitope recognition for neutralization similar to the mode of neutralization employed by mAbs 2F5 and 4E10.
The inner structural Gag proteins and the envelope (Env) glycoproteins of human immunodeficiency virus (HIV-1) traffic independently to the plasma membrane, where they assemble the nascent virion. HIV-1 carries a relatively low number of glycoproteins in its membrane, and the mechanism of Env recruitment and virus incorporation is incompletely understood. We employed dual-color super-resolution microscopy visualizing Gag assembly sites and HIV-1 Env proteins in virus-producing and in Env expressing cells. Distinctive HIV-1 Gag assembly sites were readily detected and were associated with Env clusters that always extended beyond the actual Gag assembly site and often showed enrichment at the periphery and surrounding the assembly site. Formation of these Env clusters depended on the presence of other HIV-1 proteins and on the long cytoplasmic tail (CT) of Env. CT deletion, a matrix mutation affecting Env incorporation or Env expression in the absence of other HIV-1 proteins led to much smaller Env clusters, which were not enriched at viral assembly sites. These results show that Env is recruited to HIV-1 assembly sites in a CT-dependent manner, while Env(ΔCT) appears to be randomly incorporated. The observed Env accumulation surrounding Gag assemblies, with a lower density on the actual bud, could facilitate viral spread . Keeping Env molecules on the nascent virus low may be important for escape from the humoral immune response, while cell-cell contacts mediated by surrounding Env molecules could promote HIV-1 transmission through the virological synapse.
Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is a rare inherited childhood neurodegenerative disease that is caused by a mutation in the gene CLN3. The function of the protein produced by the gene has remained elusive, and therefore the disease mechanism of JNCL is as of yet unknown. The disease is fatal, and no cure is currently available. We believe that simvastatin shows promise as a possible treatment. Simvastatin is well tolerated in children, and as currently no other viable, less invasive treatment for JNCL exists, at least pilot-scale clinical trials for this new off-label use of simvastatin are warranted.
The protein CLN3 has been indicated to have several different subcellular localizations and functions, but conclusive evidence about its role in cellular metabolism is lacking. It is also unclear why the mutation causes the distinct phenotype of the JNCL disease. In order to bring lucidity to the issue, we set out to identify metabolic pathways related to the phenotype of JNCL by using Multi-Epitope Ligand Cartography (MELC) and the related field of toponomics. Toponomic methods are required to process the massive amount of data generated by the MELC runs in order to extract information from them.
Our disease model of choice was the CLN3Δex7/8 knock-in mouse. To separate cause from effect, we compared embryonal wild type and mutant mouse brains to their adult counterparts. The first analyses revealed progressively abnormal Combinatorial Molecular Patterns (CMPs, an unit of toponomic data) related to cholera toxin/ganglioside 1 (Ctx/GM1), which is a membrane microdomain marker.
Cholesterol is an essential part of microdomains, so we utilized filipin staining to see if there were actual changes in cholesterol concentration and localization between healthy and diseased animals. After the disturbance in cholesterol metabolism was verified, we investigated the metabolic pathway that synthesizes cholesterol, the mevalonate pathway. Simvastatin is a drug that specifically down-regulates the mevalonate pathway. Fish oil affects lipid homeostasis and has some effects similar to those of simvastatin, and both of these drugs have previously been studied for their effects on neurodegenerative diseases. After treatment of mice with these drugs, highperformance liquid chromatography (HPLC) measurements on the brain homogenate showed a decrease in levels of farnesyl pyrophosphate (FPP) and geranyl-geranyl pyrophosphate (GGPP), products of the mevalonate pathway, confirming the effect of these drugs on the brains of the animals. Analyses of motor function of the mice further supported the notion that simvastatin had a positive effect on the condition of the diseased animals.
CMP analyses from the simvastatin treated mice showed a rescue of the Ctx/GM1 CMPs, suggesting at least a partial restoration of membrane microdomain homeostasis. Filipin staining revealed reversion of the apparent cholesterol depletion in the adult mutant mouse hippocampus by simvastatin. Interestingly, an additional effect of the treatment was found: simvastatin also affected glutamate receptor homeostasis, especially as regarding to N-methyl-D-aspartate (NMDA) and alphaamino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors. This finding suggested that excitotoxicity could be a part of the disease process, and pointed towards glutamate receptors as possible therapy targets. This is in line with previous studies that have shown that attenuation of AMPA receptors and L voltage-dependent channels improve the phenotype of a JNCL mouse and cell model, respectively.
Simvastatin mediates many of its effects via downregulation of the mevalonate pathway products, such as isoprenoids and cholesterol. However, simvastatin also has multiple pleiotropic effects that include suppression of excitotoxicity and granting neuroprotection. It is apparent that simvastatin treatment has a positive effect on JNCL mice, but if its effects are mediated via cholesterol (and membrane microdomains), isoprenoids (and isoprenylated proteins) or via a fully cholesterol independent mechanism remains to be solved.
In this study we have shown that with the MELC method and toponomics it is possible to approach rare diseases with confounded disease mechanisms with a hypothesis-free approach, to identify possible drug targets, and to monitor the effects of the drugs on treated individuals. This should open up a new avenue in the research of the many diseases that so far have avoided all attempts at discerning their nature.
Introduction: Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI.
Methods: We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection.
Results: Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2].[IGFBP7] was significantly superior to all previously described markers of AKI (P <0.002), none of which achieved an AUC >0.72. Furthermore, [TIMP-2].[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2].[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method.
Conclusions: Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI. Trial registration: ClinicalTrials.gov number NCT01209169.