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Peripheral tolerance is an important mechanism by which the immune system can guarantee a second line of defense against autoreactive T and B cells. One autoimmune disease that is related to a break of peripheral tolerance is diabetes mellitus type 1. Using the RIP-GP mouse model, we analyzed the role of the spleen and lymph nodes (LNs) in priming CD8+ T cells and breaking peripheral tolerance. We found that diabetes developed in splenectomized mice infected with the lymphocytic choriomeningitis virus (LCMV), a finding showing that the spleen was not necessary in generating autoimmunity. By contrast, the absence of LNs prevented the priming of LCMV-specific CD8+ T cells, and diabetes did not develop in these mice. Additionally, we found that dendritic cells are responsible for the distribution of virus in secondary lymphoid organs, when LCMV was administered intravenously. Preventing this distribution with the sphingosine-1-phosphate receptor antagonist FTY720 inhibits the transport of antigen to peripheral LNs and consequently prevented the onset of diabetes. However, in case of subcutaneous infection, administration of FTY720 could not inhibit the onset of diabetes because the viral antigen is already presented in the peripheral LNs. These findings demonstrate the importance of preventing the presence of antigen in LNs for maintaining tolerance.
Background. Colorectal cancers (CRC) shed DNA into blood circulation. There is growing evidence that the analysis of circulating tumor DNA can be effectively used for monitoring of disease, to track tumor heterogeneity and to evaluate response to treatment. Case Presentation. Here, we describe two cases of patients with advanced CRC. The first case is about a patient with no available tissue for analysis of RAS mutation status. Liquid biopsy revealed RAS-wild-type and the therapy with anti-EGFR (epidermal growth factor receptor) monoclonal antibody cetuximab could be initiated. In the second case, the mutational profile of a patient with initial wild-type RAS-status was continually tracked during the course of treatment. An acquired KRAS exon 3 mutation was detected. The number of KRAS mutated fragments decreased continuously after the discontinuation of the therapy with EGFR-specific antibodies. Conclusion. Liquid biopsy provides a rapid genotype result, which accurately reproduces the current mutation status of tumor tissue. Furthermore, liquid biopsy enables close monitoring of the onset of secondary resistance to anti-EGFR therapy.
Die vorliegende Ergänzung baut auf der 'Johannes-Bobrowski-Bibliographie von 2002' auf. Sie folgt dieser in Herangehensweise und Gliederung. Neben einigen dort nicht aufgeführten älteren Titeln enthält sie vor allem solche wissenschaftlichen Arbeiten zu und über Johannes Bobrowski, die zwischen 2002 und 2016 publiziert worden sind. Nicht systematisch erfasst wurden Neuausgaben und Übersetzungen seines Werkes sowie Miszellen, Zeitungsartikel und künstlerische Resonanzen.
Die Bibliographie ist in vier Abteilungen untergliedert:
A Das Werk Johannes Bobrowskis
B Literatur zu Leben und Werk Johannes Bobrowskis
C Resonanzen auf Johannes Bobrowski in Musik, bildender Kunst, Film, Literatur und Hörfunk
D Bobrowski-Medaille, Johannes-Bobrowski-Gesellschaft
We study platform design in online markets in which buying involves a (nonmonetary) cost for consumers caused by privacy and security concerns. Firms decide whether to require registration at their website before consumers learn relevant product information. We derive conditions under which a monopoly seller benefits from ex ante registration requirements and demonstrate that the profitability of registration requirements is increased when taking into account the prospect of future purchases or an informational value of consumer registration to the firm. Moreover, we consider the effectiveness of discounts (store credit) as a means to influence the consumers’ registration decision. Finally, we confirm the profitability of ex ante registration requirements in the presence of price competition.
Mean age of stratospheric air can be derived from observations of sufficiently long lived trace gases with approximately linear trends in the troposphere. Mean age can serve as a tracer to investigate stratospheric transport and long term changes in the strength of the overturning Brewer-Dobson circulation of the stratosphere. For this purpose, a low-cost method is required in order to allow for regular observations up to altitudes of about 30 km. Despite the desired low costs, high precision and accuracy are required in order to allow determination of mean age. We present balloon borne AirCore observations from two mid latitude sites: Timmins in Ontario/Canada and Lindenberg in Germany. During the Timmins campaign five AirCores sampled air in parallel from a large stratospheric balloon and were analysed for CO2, CH4 and partly CO. We show that there is good agreement between the different AirCores (better than 0.1 %) especially when vertical gradients are small. The measurements from Lindenberg were performed using small low-cost balloons and yielded very comparable results. We have used the observations to extend our long term data set of mean age observations at Northern Hemi-sphere mid latitudes. The time series now covers more than 40 years and shows a small, statis-tically not significant positive trend of 0.15 ± 0.18 years/decade. This trend is slightly smaller than the previous estimate of 0.24 ± 0.22 years/decade which was based on observations up to the year 2006. These observations are still in contrast to strong negative trends of mean age as derived from some model calculations.
We study exchangeable coalescent trees and the evolving genealogical trees in models for neutral haploid populations.
We show that every exchangeable infinite coalescent tree can be obtained as the genealogical tree of iid samples from a random marked metric measure space when the marks are added to the metric distances. We apply this representation to generalize the tree-valued Fleming-Viot process to include the case with dust in which the genealogical trees have isolated leaves.
Using the Donnelly-Kurtz lookdown approach, we describe all individuals ever alive in the population model by a random complete and separable metric space, the lookdown space, which we endow with a family of sampling measures. This yields a pathwise construction of tree-valued Fleming-Viot processes. In the case of coming down from infinity, we also read off a process whose state space is endowed with the Gromov-Hausdorff-Prohorov topology. This process has additional jumps at the extinction times of parts of the population.
In the case with only binary reproduction events, we construct the lookdown space also from the Aldous continuum random tree by removing the root and the highest leaf, and by deforming the metric in a way that corresponds to the time change that relates the Fleming-Viot process with a Dawson-Watanabe process. The sampling measures on the lookdown space are then image measures of the normalized local time measures.
We also show invariance principles for Markov chains that describe the evolving genealogy in Cannings models. For such Markov chains with values in the space of distance matrix distributions, we show convergence to tree-valued Fleming-Viot processes under the conditions of Möhle and Sagitov for the convergence of the genealogy at a fixed time to a coalescent with simultaneous multiple mergers. For the convergence of Markov chains with values in the space of marked metric measure spaces, an additional assumption is needed in the case with dust.
We document that natural disasters significantly weaken the stability of banks with business activities in affected regions, as reflected in lower z-scores, higher probabilities of default, higher non-performing assets ratios, higher foreclosure ratios, lower returns on assets and lower bank equity ratios. The effects are economically relevant and suggest that insurance payments and public aid programs do not sufficiently protect bank borrowers against financial difficulties. We also find that the adverse effects on bank stability dissolve after some years if no further disasters occur in the meantime.
This paper applies the theory of structured finance to the regulation of asset backed securities. We find the current regulation in Europe (Article 405 of the CRR) and the US (Section D of Dodd-Frank Act) to be severely flawed with respect to its key intention: the imposition of a strict loss retention requirement. While nominal retention is always 5%, the true level of loss retention varies across available retention options between zero loss retention and full loss retention at the extreme ends. Based on a standard model of structured finance transactions, we propose a new risk retention metric RM measuring the level of an issuer’s skin-in-the-game. The new metric could help to achieve a better implementation of CRR/CRD-IV and DFA, by making disclosure of the RM-number compulsory for all ABS transactions. There are also implications for the operation of rating agencies. On a general level, the RM metric will be instrumental in achieving simplicity and transparency in securitizations (STS).
Die erste Phase des im Dezember 2016 in Kraft getretenen Friedensabkommens zwischen der kolumbianischen Regierung und den FARC-Rebellen ist mit der Ankunft von ca. 6300 Kämpfern in den vereinbarten 26 Konzentrationszonen abgeschlossen. Dort wird nun der Prozess der Entwaffnung beginnen und die Vorbereitung auf die Eingliederung in das zivile Leben, ein Schritt, der der kolumbianischen Gesellschaft noch große Opfer abverlangen wird – sei es bezogen auf die Prozesse der justiziellen Aufarbeitung der Vergangenheit, sei es hinsichtlich der notwendigen Versöhnungsprozesse oder sei es bei der Suche nach neuen Formen des friedlichen Zusammenlebens. Sich in das zivile Leben einzufinden, dürfte insbesondere den ca. 7000 geschätzten Kindersoldaten Kolumbiens schwer fallen, die teilweise bereits im Alter von 12 Jahren von den illegalen bewaffneten Akteuren des Landes an Waffen ausgebildet wurden und ihre Kindheit bzw. Jugend in Guerilla-Verbänden verbracht haben. Die umfassende Betreuung der Kindersoldaten ist einer der zentralen Indikatoren für einen erfolgreichen Verlauf des Friedensprozesses in Kolumbien, wenn der Teufelskreis aus Gewalt, Vertreibung und Rekrutierung Minderjähriger durchbrochen werden soll. Sonst droht eine Verlängerung von Gewaltbiographien, die die Geschichte des Landes bereits in der Vergangenheit maßgeblich geprägt haben.
Am Donnerstag, dem 26.01.17, beschloss der Deutsche Bundestag, wie schon im letzten Jahr, eine Ausweitung des Bundeswehreinsatzes im Rahmen der UN-Mission MINUSMA in Mali. Die maximale Anzahl der in und um Gao im Norden Malis eingesetzten Soldatinnen und Soldaten wird von bisher 650 auf 1000 erhöht, da Deutschland zukünftig auch die Bereitstellung von Kampf- und Rettungshubschraubern für MINUSMA übernimmt. Damit wird der Einsatz in Mali zum Größten der Bundeswehr. Der Befehlshaber des Einsatzführungskommandos hat das Gefährdungspotenzial schon im vergangenen Jahr mit der ISAF-Mission in Afghanistan verglichen und in keinem anderen UN-Einsatz sind im letzten Jahr mehr Soldaten getötet worden.
Die Entsendung weiterer Soldatinnen und Soldaten vom Deutschen Bundestag in einen Einsatz, in dem sie erheblichen Gefahren für Leib und Leben ausgesetzt sind, erfordert eine umfangreiche Begründung durch die politisch Verantwortlichen und eine kritische Würdigung durch die Zivilgesellschaft.
Ist es zum Lachen oder zum Weinen? Diese Frage stellt sich immer wieder bei der Beobachtung der Worte und Taten des neuen US-Präsidenten – zum Beispiel anläßlich seines ersten Fernsehinterviews mit dem Journalisten David Muir (ABC America, 27.1.2017). Trump benahm sich wie ein rechthaberisches, selbstbezogenes, liebesbedürftiges Kind. Er beharrte auf seiner Version der Amtseinführung, nach der noch nie so viele Menschen wie diesmal an der Zeremonie teilgenommen hätten. Er sprach nicht nur davon, er verwies auch auf Fotos, die er an Wänden im Weißen Haus hat aufhängen lassen. Trump wiederholte außerdem seine Behauptung, dass es viele illegale Stimmen gegeben hätte, und alle für Hillary Clinton. Natürlich würde man auch den einen oder anderen finden, der illegal für ihn abgestimmt habe. Diese Person würde man dann, sagte Trump, als Gegenbeweis vor die Kameras zerren. Aber die Wahrheit sei, dass Millionen von illegalen Stimmen fast ausnahmslos für Clinton abgegeben worden seien...
Despite an increasing demand for Burgundy truffles (Tuber aestivum), gaps remain in our understanding of the fungus’ overall lifecycle and ecology. Here, we compile evidence from three independent surveys in Hungary and Switzerland. First, we measured the weight and maturity of 2,656 T. aestivum fruit bodies from a three-day harvest in August 2014 in a highly productive orchard in Hungary. All specimens ranging between 2 and 755 g were almost evenly distributed through five maturation classes. Then, we measured the weight and maturity of another 4,795 T. aestivum fruit bodies harvested on four occasions between June and October 2015 in the same truffière. Again, different maturation stages occurred at varying fruit body size and during the entire fruiting season. Finally, the predominantly unrelated weight and maturity of 81 T. aestivum fruit bodies from four fruiting seasons between 2010 and 2013 in Switzerland confirmed the Hungarian results. The spatiotemporal coexistence of 7,532 small-ripe and large-unripe T. aestivum, which accumulate to ~182 kg, differs from species-specific associations between the size and ripeness that have been reported for other mushrooms. Although size-independent truffle maturation stages may possibly relate to the perpetual belowground environment, the role of mycelial connectivity, soil property, microclimatology, as well as other abiotic factors and a combination thereof, is still unclear. Despite its massive sample size and proof of concept, this study, together with existing literature, suggests consideration of a wider ecological and biogeographical range, as well as the complex symbiotic fungus-host interaction, to further illuminate the hidden development of belowground truffle fruit bodies.
Pro-resolving lipid mediator Resolvin D1 serves as a marker of lung disease in cystic fibrosis
(2017)
Background: Cystic fibrosis (CF) is an autosomal recessive genetic disorder that affects multiple organs, including the lungs, pancreas, liver and intestine. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) locus lead to defective proteins and reduced Cl- secretion and Na+ hyperabsorption in the affected organs. In addition, patients suffering from CF display chronic inflammation that contributes to the pathogenesis of CF. Recent work suggests that CF patients have a reduced capacity to biosynthesize specialized pro-resolving lipid mediators (SPMs), which contributes to the development and duration of the unwanted inflammation. Alterations in the metabolism of arachidonic acid (AA) and docosahexaenoic acid (DHA) to specialized pro-resolving mediators (SPMs), like lipoxins (LXs), maresins (MaRs), protectins (PDs) and resolvins (Rvs), may play a major role on clinical impact of airway inflammation in CF.
Methods: In this study, our aims were to detect and quantitate Resolvin D1 (RvD1) in sputum and plasma from patients with CF and compare levels of RvD1 with biomarkers of inflammation and lung function. We studied 27 CF patients aged 6 to 55 years (median 16 years) in a prospective approach.
Results: DHA can be found in the plasma of our CF patients in the milligram range and is decreased in comparison to a healthy control group. The DHA-derived pro-resolving mediator Resolvin D1 (RvD1) was also present in the plasma (286.4 ± 50 pg/ mL, mean ± SEM) and sputum (30.0 ± 2.6 pg/ mL, mean ± SEM) samples from our patients with CF and showed a positive correlation with sputum inflammatory markers. The plasma concentrations of RvD1 were ten times higher than sputum concentrations. Interestingly, sputum RvD1/ IL-8 levels showed a positive correlation with FEV1 (rs = 0.3962, p< 0.05).
Conclusions: SPMs, like RvD1, are well known to down-regulate inflammatory pathways. Our study shows that the bioactive lipid mediator RvD1, derived from DHA, was present in sputum and plasma of CF patients and may serve as a representative peripheral biomarker of the lung resolution program for CF patients.
Objective: To investigate if plasma HIV-1 tropism testing could identify subjects at higher risk for clinical progression and death in routine clinical management.
Design: Nested case-control study within the EuroSIDA cohort.
Methods: Cases were subjects with AIDS or who died from any cause, with a plasma sample with HIV-1 RNA >1000 copies/mL available for tropism testing 3 to 12 months prior to the event. At least 1 control matched for age, HIV-1 RNA and HCV status at the time of sampling were selected per each case. Conditional logistic regression was used to investigate exposures associated with clinical progression to AIDS or death. A linear mixed model with random intercept was used to compare CD4+T-cell slopes by HIV tropism over the 12 months following the date of sampling.
Results: The study included 266 subjects, 100 cases and 166 controls; one quarter had X4 HIV; 26% were ART-naïve. Baseline factors independently associated with clinical progression or death were female gender (OR = 2.13 vs. male, 95CI = 1.04, 4.36), p = 0.038), CD4+T-cell count (OR = 0.90 (95CI = 0.80, 1.00) per 100 cells/mm3 higher, p = 0.058), being on ART (OR = 2.72 vs. being off-ART (95CI = 1.15, 6.41), p = 0.022) and calendar year of sample [OR = 0.84 (95CI = 0.77, 0.91) per more recent year, p<0.001). Baseline tropism was not associated with the risk of clinical progression or death. CD4+T-cell slopes did not differ within or between tropism groups.
Conclusions: The predictive role of plasma tropism determined using 454 sequencing in the context of people receiving cART with detectable VL is not helpful to identify subjects at higher risk for clinical progression to AIDS or death.
Cannabinoid antagonist SLV326 induces convulsive seizures and changes in the interictal EEG in rats
(2017)
Cannabinoid CB1 antagonists have been investigated for possible treatment of e.g. obesity-related disorders. However, clinical application was halted due to their symptoms of anxiety and depression. In addition to these adverse effects, we have shown earlier that chronic treatment with the CB1 antagonist rimonabant may induce EEG-confirmed convulsive seizures. In a regulatory repeat-dose toxicity study violent episodes of “muscle spasms” were observed in Wistar rats, daily dosed with the CB1 receptor antagonist SLV326 during 5 months. The aim of the present follow-up study was to investigate whether these violent movements were of an epileptic origin. In selected SLV326-treated and control animals, EEG and behavior were monitored for 24 hours. 25% of SLV326 treated animals showed 1 to 21 EEG-confirmed generalized convulsive seizures, whereas controls were seizure-free. The behavioral seizures were typical for a limbic origin. Moreover, interictal spikes were found in 38% of treated animals. The frequency spectrum of the interictal EEG of the treated rats showed a lower theta peak frequency, as well as lower gamma power compared to the controls. These frequency changes were state-dependent: they were only found during high locomotor activity. It is concluded that long term blockade of the endogenous cannabinoid system can provoke limbic seizures in otherwise healthy rats. Additionally, SLV326 alters the frequency spectrum of the EEG when rats are highly active, suggesting effects on complex behavior and cognition.
The formation of acquired drug resistance is a major reason for the failure of anti-cancer therapies after initial response. Here, we introduce a novel model of acquired oxaliplatin resistance, a sub-line of the non-MYCN-amplified neuroblastoma cell line SK-N-AS that was adapted to growth in the presence of 4000 ng/mL oxaliplatin (SK-N-ASrOXALI4000). SK-N-ASrOXALI4000 cells displayed enhanced chromosomal aberrations compared to SK-N-AS, as indicated by 24-chromosome fluorescence in situ hybridisation. Moreover, SK-N-ASrOXALI4000 cells were resistant not only to oxaliplatin but also to the two other commonly used anti-cancer platinum agents cisplatin and carboplatin. SK-N-ASrOXALI4000 cells exhibited a stable resistance phenotype that was not affected by culturing the cells for 10 weeks in the absence of oxaliplatin. Interestingly, SK-N-ASrOXALI4000 cells showed no cross resistance to gemcitabine and increased sensitivity to doxorubicin and UVC radiation, alternative treatments that like platinum drugs target DNA integrity. Notably, UVC-induced DNA damage is thought to be predominantly repaired by nucleotide excision repair and nucleotide excision repair has been described as the main oxaliplatin-induced DNA damage repair system. SK-N-ASrOXALI4000 cells were also more sensitive to lysis by influenza A virus, a candidate for oncolytic therapy, than SK-N-AS cells. In conclusion, we introduce a novel oxaliplatin resistance model. The oxaliplatin resistance mechanisms in SK-N-ASrOXALI4000 cells appear to be complex and not to directly depend on enhanced DNA repair capacity. Models of oxaliplatin resistance are of particular relevance since research on platinum drugs has so far predominantly focused on cisplatin and carboplatin.
Ongoing liver inflammation in patients with chronic hepatitis C and sustained virological response
(2017)
Background: Novel direct-acting antiviral DAA combination therapies tremendously improved sustained virologic response (SVR) rates in patients with chronic HCV infection. SVR is typically accompanied by normalization of liver enzymes, however, hepatic inflammation, i.e. persistently elevated aminotransferase levels may persist despite HCV eradication. Aim: To investigate prevalence and risk factors for ongoing hepatic inflammation after SVR in two large patient cohorts.
Methods: This post-hoc analysis was based on prospectively collected demographic and clinical data from 834 patients with SVR after HCV treatment with either PegIFN- or DAA-based treatment regimens from the PRAMA trial (n = 341) or patients treated at our outpatient clinic (n = 493).
Results: We observed an unexpected high prevalence of post-SVR inflammation, including patients who received novel IFN-free DAA-based therapies. Up to 10% of patients had ongoing elevation of aminotransferase levels and another 25% showed aminotransferase activity above the so-called healthy range. Several baseline factors were independently associated with post-SVR aminotransferase elevation. Among those, particularly male gender, advanced liver disease and markers for liver steatosis were strongly predictive for persistent ALT elevation. The use of IFN-based antiviral treatment was independently correlated with post-SVR inflammation, further supporting the overall benefit of IFN-free combination regimens.
Conclusion: This is the first comprehensive study on a large patient cohort investigating the prevalence and risk factors for ongoing liver inflammation after eradication of HCV. Our data show a high proportion of patients with ongoing hepatic inflammation despite HCV eradication with potential implications for the management of approximately one third of all patients upon SVR.
The objective of this study was to characterize blaOXA-23 harbouring Acinetobacter indicus-like strains from cattle including genomic and phylogenetic analyses, antimicrobial susceptibility testing and evaluation of pathogenicity in vitro and in vivo. Nasal and rectal swabs (n = 45) from cattle in Germany were screened for carbapenem-non-susceptible Acinetobacter spp. Thereby, two carbapenem resistant Acinetobacter spp. from the nasal cavities of two calves could be isolated. MALDI-TOF mass spectrometry and 16S rDNA sequencing identified these isolates as A. indicus-like. A phylogenetic tree based on partial rpoB sequences indicated closest relation of the two bovine isolates to the A. indicus type strain A648T and human clinical A. indicus isolates, while whole genome comparison revealed considerable intraspecies diversity. High mimimum inhibitory concentrations were observed for carbapenems and other antibiotics including fluoroquinolones and gentamicin. Whole genome sequencing and PCR mapping revealed that both isolates harboured blaOXA-23 localized on the chromosome and surrounded by interrupted Tn2008 transposon structures. Since the pathogenic potential of A. indicus is unknown, pathogenicity was assessed employing the Galleria (G.) mellonella infection model and an in vitro cytotoxicity assay using A549 human lung epithelial cells. Pathogenicity in vivo (G. mellonella killing assay) and in vitro (cytotoxicity assay) of the two A. indicus-like isolates was lower compared to A. baumannii ATCC 17978 and similar to A. lwoffii ATCC 15309. The reduced pathogenicity of A. indicus compared to A. baumannii correlated with the absence of important virulence genes encoding like phospholipase C1+C2, acinetobactin outer membrane protein BauA, RND-type efflux system proteins AdeRS and AdeAB or the trimeric autotransporter adhesin Ata. The emergence of carbapenem-resistant A. indicus-like strains from cattle carrying blaOXA-23 on transposable elements and revealing genetic relatedness to isolates from human clinical sources requires further investigations regarding the pathogenic potential, genomic characteristics, zoonotic risk and putative additional sources of this new Acinetobacter species.
Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. BD shows substantial clinical and genetic overlap with other psychiatric disorders, in particular schizophrenia (SCZ). The genes underlying this etiological overlap remain largely unknown. A recent SCZ genome wide association study (GWAS) by the Psychiatric Genomics Consortium identified 128 independent genome-wide significant single nucleotide polymorphisms (SNPs). The present study investigated whether these SCZ-associated SNPs also contribute to BD development through the performance of association testing in a large BD GWAS dataset (9747 patients, 14278 controls). After re-imputation and correction for sample overlap, 22 of 107 investigated SCZ SNPs showed nominal association with BD. The number of shared SCZ-BD SNPs was significantly higher than expected (p = 1.46x10-8). This provides further evidence that SCZ-associated loci contribute to the development of BD. Two SNPs remained significant after Bonferroni correction. The most strongly associated SNP was located near TRANK1, which is a reported genome-wide significant risk gene for BD. Pathway analyses for all shared SCZ-BD SNPs revealed 25 nominally enriched gene-sets, which showed partial overlap in terms of the underlying genes. The enriched gene-sets included calcium- and glutamate signaling, neuropathic pain signaling in dorsal horn neurons, and calmodulin binding. The present data provide further insights into shared risk loci and disease-associated pathways for BD and SCZ. This may suggest new research directions for the treatment and prevention of these two major psychiatric disorders.
In Germany, orthopedic workforce planning relies on population-to-provider-ratios represented by the "official degree of care provision". However, with geographic information systems (GIS), more sophisticated measurements are available. By utilizing GIS-based technologies we analyzed the current state of demand and supply of the orthopedic workforce in Germany (orthopedic accessibility) with the integrated Floating Catchment Area method. The analysis of n = 153,352,220 distances revealed significant geographical variations on national scale: 5,617,595 people (6.9% of total population) lived in an area with significant low orthopedic accessibility (average z-score = -4.0), whereas 31,748,161 people (39.0% of total population) lived in an area with significant high orthopedic accessibility (average z-score = 8.0). Accessibility was positively correlated with the degree of urbanization (r = 0.49; p<0.001) and the official degree of care provision (r = 0.33; p<0.001) and negatively correlated with regional social deprivation (r = -0.47; p<0.001). Despite advantages of simpler measures regarding implementation and acceptance in health policy, more sophisticated measures of accessibility have the potential to reduce costs as well as improve health care. With this study, significant geographical variations were revealed that show the need to reduce oversupply in less deprived urban areas in order to enable adequate care in more deprived rural areas.
Background: Previous magnetic resonance imaging (MRI) research suggests that, prior to the onset of psychosis, high risk youths already exhibit brain abnormalities similar to those present in patients with schizophrenia.
Objectives: The goal of the present study was to describe the functional organization of endogenous activation in young adolescents who report auditory verbal hallucinations (AVH) in view of the “distributed network” hypothesis of psychosis. We recruited 20 young people aged 13–16 years who reported AVHs and 20 healthy controls matched for age, gender and handedness from local schools.
Methods: Each participant underwent a semi-structured clinical interview and a resting state (RS) neuroimaging protocol. We explored functional connectivity (FC) involving three different networks: 1) default mode network (DMN) 2) salience network (SN) and 3) central executive network (CEN). In line with previous findings on the role of the auditory cortex in AVHs as reported by young adolescents, we also investigated FC anomalies involving both the primary and secondary auditory cortices (A1 and A2, respectively).
Further, we explored between-group inter-hemispheric FC differences (laterality) for both A1 and A2. Compared to the healthy control group, the AVH group exhibited FC differences in all three networks investigated. Moreover, FC anomalies were found in a neural network including both A1 and A2. The laterality analysis revealed no between-group, inter-hemispheric differences.
Conclusions: The present study suggests that young adolescents with subclinical psychotic symptoms exhibit functional connectivity anomalies directly and indirectly involving the DMN, SN, CEN and also a neural network including both primary and secondary auditory cortical regions.
Biogenesis of mitochondrial cytochrome c oxidase (COX) is a complex process involving the coordinate expression and assembly of numerous subunits (SU) of dual genetic origin. Moreover, several auxiliary factors are required to recruit and insert the redox-active metal compounds, which in most cases are buried in their protein scaffold deep inside the membrane. Here we used a combination of gel electrophoresis and pull-down assay techniques in conjunction with immunostaining as well as complexome profiling to identify and analyze the composition of assembly intermediates in solubilized membranes of the bacterium Paracoccus denitrificans. Our results show that the central SUI passes through at least three intermediate complexes with distinct subunit and cofactor composition before formation of the holoenzyme and its subsequent integration into supercomplexes. We propose a model for COX biogenesis in which maturation of newly translated COX SUI is initially assisted by CtaG, a chaperone implicated in CuB site metallation, followed by the interaction with the heme chaperone Surf1c to populate the redox-active metal-heme centers in SUI. Only then the remaining smaller subunits are recruited to form the mature enzyme which ultimately associates with respiratory complexes I and III into supercomplexes.
According to the Bank Recovery and Resolution Directive (BRRD), introduced as a lesson from the recent financial crisis, the losses a failing bank incurred should generally be borne by its investors. Before a minimum bail-in has occurred, government money can only be injected in emergency cas-es to remedy a serious disturbance in the economy and to preserve financial stability. This policy letter argues that in case of the Italian Bank Monte dei Paschi di Siena (MPS), which the Italian gov-ernment currently plans to bail out, a resolution would most likely not cause such a systemic event. A bailout contrary to the existing rules will lead to a mispricing of bank capital and retard the re-structuring of the European banking sector, the authors write. They appeal to the European Central Bank, the Systemic Risk Board and the EU Commission to follow the rules as the test-case MPS will have a direct impact on the credibility of the new BRRD regime and the responsible institutions.
The Capital Markets Union-project of the European Commission aims for an increase of marketbased debt financing of small and medium-sized enterprises (SMEs), complementing bank lending. In this essay we argue that rather than focussing on pure non-bank lending, a reasonable mix of bankand market-based financing should be considered. Banks are said to have a comparative advantage in critical lending functions such as credit screening, debtor monitoring and debt renegotiation. All forms of lending require a persistent skin-in-the-game of critical players in order to be effective. The regulator should insist on full disclosure of skin-in-the-game, thereby improving capital allocation and reducing systemic risks.
The impact of network connectivity on factor exposures, asset pricing and portfolio diversification
(2017)
This paper extends the classic factor-based asset pricing model by including network linkages in linear factor models. We assume that the network linkages are exogenously provided. This extension of the model allows a better understanding of the causes of systematic risk and shows that (i) network exposures act as an inflating factor for systematic exposure to common factors and (ii) the power of diversification is reduced by the presence of network connections. Moreover, we show that in the presence of network links a misspecified traditional linear factor model presents residuals that are correlated and heteroskedastic. We support our claims with an extensive simulation experiment.
Causality is a widely-used concept in theoretical and empirical economics. The recent financial economics literature has used Granger causality to detect the presence of contemporaneous links between financial institutions and, in turn, to obtain a network structure. Subsequent studies combined the estimated networks with traditional pricing or risk measurement models to improve their fit to empirical data. In this paper, we provide two contributions: we show how to use a linear factor model as a device for estimating a combination of several networks that monitor the links across variables from different viewpoints; and we demonstrate that Granger causality should be combined with quantile-based causality when the focus is on risk propagation. The empirical evidence supports the latter claim.
Der Beitrag arbeitet die moralische Subjektivierungsform ökonomischer Verschuldung heraus. In Auseinandersetzung mit Friedrich Nietzsche, Max Weber und Pierre Bourdieu wird argumentiert, dass die Form der Verschuldung durch eine spezifische Zeitlichkeit geprägt ist. Die zentrale These lautet, dass sich das Zeitregime von Schuld und Schulden als paradox erweist: Einerseits ermöglicht die moderne "Entzauberung der Welt" (Max Weber) eine Öffnung auf gesellschaftliche Zukünfte hin und diese temporale Öffnung bildet auch eine notwendige Bedingung kapitalistischer Investitionstätigkeiten. Andererseits verstellt das gegenwärtige rigide Zeitregime der Schuld(en) jedoch die Möglichkeit subjektiver und politischer neuer Anfänge in der Zeit, da die Verschuldung eine Dynamik der ökonomischen Determinierung gegenwärtiger Handlungsoptionen durch den Zwang zur Rückzahlung ins Werk setzt.
Software evolves. Developers and programmers manifest the needs that arise due to evolving software by making changes to the source code. While developers make such changes, reusing old code and rewriting existing code are inevitable. There are many challenges that a developer faces when manually reusing old code or rewriting existing code. Software tools and program transformation systems aid such reuse or rewriting of program source code. But there are significantly occuring development tasks that are hard to accomplish manually, where the current state-of-the-art tools are still not able to adequately automate these tasks. In this thesis, we discuss some of these unexplored challenges that a developer faces while reusing and rewriting program source code, the significance of such challenges, the existing automation support for these challenges and how we can improve upon them.
Modern software development relies on code reuse, which software developers
typically realize through hand-written abstractions, such as functions,
methods, or classes. However, such abstractions can be challenging to
develop and maintain. An alternative form of reuse is \emph{copy-paste-modify}, in which developers explicitly duplicate source code to adapt the duplicate for a new purpose. Copy-pasted code results in code clones, i.e., groups of code fragments that are similar to each other. Past research strongly suggests that copy-paste-modify is a popular technique among software developers. In this paper, we perform a small user study that shows that copy-paste-modify can be substantially faster to use than manual abstraction.
One might propose that software developers should forego hand-written abstractions in favour of copying and pasting. However, empirical evidence also shows that copy-paste-modify complicates software maintenance and increases the frequency of bugs. Furthermore, the developers in an informal poll we conducted strongly preferred to read code written using abstractions. To address the concern around copy-paste-modify, we propose a tool that merges similar pieces of code and automatically creates suitable abstractions. Our tool allows developers to get the best of both worlds: easy reuse together with custom abstractions. Because different kinds of abstractions may be beneficial in different contexts, our tool provides multiple abstraction mechanisms, which we selected based on a study of popular open-source repositories.
To demonstrate the feasibility of our approach, we have designed and implemented a prototype merging tool for C++ and evaluated our tool on a number of clones exhibiting some variation, i.e near clones, in popular Open Source packages. We observed that maintainers find our algorithmically created abstractions to be largely preferable to existing duplicated code. Rewriting existing code can be considered as a form of program transformation, where a program in one form is transformed into a program in another form. One significant form of program transformation is data representation migration that involves changing the type of a particular data structure, and then updating all of the operations that has a control or data dependence on that data structure according to the new type. Changing the data representation can provide benefits such as improving efficiency and improving the quality of the computed results. Performing such a transformation is challenging, because it requires applying data-type specific changes to code fragments that may be widely scattered throughout the source code connected by dataflow dependencies. Refactoring systems are typically sensitive to dataflow dependencies, but are not programmable with respect to the features of particular data types. Existing program transformation languages provide the needed flexibility, but do not concisely support reasoning about dataflow dependencies.
To address the needs of data representation migration, we propose a new approach to program transformation that relies on a notion of semantic dependency: every transformation step propagates the transformation process onward to code that somehow depends on the transformed code. Our approach provides a declarative transformation specification language, for expressing type-specific transformation rules. We further provide scoped rules, a mechanism for guiding rule application, and tags, a device for simple program analysis within our framework, to enable more powerful program transformations.
We have implemented a prototype transformation system based on these ideas for C and C++ code and evaluate it against three example specifications, including vectorization, transformation of integers to big integers, and transformation of array-of-structs data types to struct-of-arrays format. Our evaluation shows that our approach can improve program performance and the precision of the computed results, and that it scales to programs of at least 3700 lines.
This dissertation provides a comprehensive account of the grammar of relative clause extraposition in English. Based on a systematic review and evaluation of the empirical generalizations and theoretical approaches provided in the literature on generative grammar, it is shown that none of the previous theories is able to account for all the relevant facts. Among the most problematic data are the Principle C and scope effects of relative clause extraposition, cases with obligatory relative clauses, and relative clauses with elliptical NPs as antecedents.
I propose a new analysis of relative clause extraposition within the constraint-based, monostratal grammatical framework of Head-driven Phrase Structure Grammar (HPSG), enhanced with the semantic theory of Lexical Resource Semantics (LRS). Crucially, it is a general analysis of relative clause attachment, since both canonical and extraposed relative clauses are licensed by the same syntactic and semantic constraints. The basic assumption is that a relative clause can be adjoined to any phrase that contains a suitable antecedent of the relative pronoun. The semantic information that licenses the relative clause is introduced by the determiner of the antecedent NP. The techniques of underspecified semantics and the standard semantic representation language used by LRS make it possible to formulate constraints which yield the correct intersective interpretation of the relative clause (arbitrarily distant from its antecedent NP) and at the same time link the scope of the antecedent NP to the adjunction site of the relative clause.
In combination with the revised HPSG binding theory developed in this dissertation, the proposed analysis is able to capture the major properties of relative clause attachment within a unified and internally consistent monostratal constraint-based grammatical framework.
People who delay claiming Social Security receive higher lifelong benefits upon retirement. We survey individuals on their willingness to delay claiming later, if they could receive a lump sum in lieu of a higher annuity payment. Using a moment-matching approach, we calibrate a lifecycle model tracking observed claiming patterns under current rules and predict optimal claiming outcomes under the lump sum approach. Our model correctly predicts that early claimers under current rules would delay claiming most when offered actuarially fair lump sums, and for lump sums worth 87% as much, claiming ages would still be higher than at present.
The international diffusion of technology plays a key role in stimulating global growth and explaining co-movements of international equity returns. Existing empirical evidence suggests that countries are heterogeneous in their attitude toward innovation: Some countries rely more on technology adoption while other countries rely more on internal technology production. European countries that rely more on adoption are also typically characterized by lower fiscal policy exibility and higher labor market rigidity. We develop a two-country model – where both countries rely on R&D and adoption – to study the short-run and long-run effects of aggregate technology and adoption probability shocks on economic growth in the presence of the aforementioned asymmetries. Our framework suggests that an increase in the ability to adopt technology from abroad stimulates economic growth in the country that benefits from higher adoption rates but the beneficial effects also spread to the foreign country. Moreover, it helps explaining the differences in macro quantities and equity returns observed in the international data.
Asymmetric social norms
(2017)
Studies of cooperation in infinitely repeated matching games focus on homogeneous economies, where full cooperation is efficient and any defection is collectively sanctioned. Here we study heterogeneous economies where occasional defections are part of efficient play, and show how to support those outcomes through contagious punishments.
This paper sets the background for the Special Issue of the Journal of Empirical Finance on the European Sovereign Debt Crisis. It identifies the channel through which risks in the financial industry leaked into the public sector. It discusses the role of the bank rescues in igniting the sovereign debt crisis and reviews approaches to detect early warning signals to anticipate the buildup of crises. It concludes with a discussion of potential implications of sovereign distress for financial markets.
Low probability events are overweighted in the pricing of out-of the-money index puts and single stock calls. We find that this behavioral bias is strongly time-varying, linked to equity market sentiment, and higher moments of the risk-neutral density. An implied volatility (IV) sentiment measure that is jointly derived from index and single stock options explains investors' overweight of tail events the best. Our findings also suggest that IV-sentiment predicts equity markets reversals better than overweight of small probabilities itself. When employed in a trading strategy, IV-sentiment delivers economically significant results, which are more consistent than the ones produced by the market sentiment factor. The joint use of information from the single stock and index option markets seems to explain the forecasting power of IV-sentiment. Out-of-sample tests on reversal prediction show that our IV-sentiment measure adds value over and above traditional factors in the equity risk premium literature, especially as an equity-buying signal. This reversals prediction seems to improve time-series and cross-sectional momentum strategies.
BACKGROUND: The analysis of microarray time series promises a deeper insight into the dynamics of the cellular response following stimulation. A common observation in this type of data is that some genes respond with quick, transient dynamics, while other genes change their expression slowly over time. The existing methods for detecting significant expression dynamics often fail when the expression dynamics show a large heterogeneity. Moreover, these methods often cannot cope with irregular and sparse measurements.
RESULTS: The method proposed here is specifically designed for the analysis of perturbation responses. It combines different scores to capture fast and transient dynamics as well as slow expression changes, and performs well in the presence of low replicate numbers and irregular sampling times. The results are given in the form of tables including links to figures showing the expression dynamics of the respective transcript. These allow to quickly recognise the relevance of detection, to identify possible false positives and to discriminate early and late changes in gene expression. An extension of the method allows the analysis of the expression dynamics of functional groups of genes, providing a quick overview of the cellular response. The performance of this package was tested on microarray data derived from lung cancer cells stimulated with epidermal growth factor (EGF).
CONCLUSION: Here we describe a new, efficient method for the analysis of sparse and heterogeneous time course data with high detection sensitivity and transparency. It is implemented as R package TTCA (transcript time course analysis) and can be installed from the Comprehensive R Archive Network, CRAN. The source code is provided with the Additional file 1.
Donald Trump’s foreign policy agenda has been characterized as unpredictable, unprecedented and – after a telling neologism of the president himself – unpresidented. In this blog post I will argue that the constituent parts of Trump’s foreign policy are all but new. What is new is their combination. Moreover, while Trump’s Jeffersonianism-Jacksonianism stands in stark contrast to the Wilsonianism-Hamiltonianism that Hillary Clinton embraced during her election campaign, it is only a partial departure from Barack Obama’s Jeffersonianism-Hamiltonianism.
Das Yin und Yang des Terrors
(2017)
Man stelle sich folgendes Szenario vor: Björn Höcke und Abū Bakr al-Baġdādī diskutieren bei Sandra Maischberger darüber, welche Konsequenzen Deutschland aus dem islamistischen Terrorismus ziehen sollte – und sie sind sich dabei einig.
Die Fiktion mag hanebüchen klingen. Nicht nur, weil der Möchtegern-Kalif des „Islamischen Staats“ (IS) unter keinen Umständen als Gast einer deutschen Talkshow in Erscheinung treten könnte – oder auch nur wollte. Sondern auch, weil der Möchtegern-Goebbels aus Thüringen sich stets als ritterlicher Gegner der Islamisten präsentiert, deren Denken und Handeln völlig unvereinbar sei mit dem Willen des hiesigen Volkes, den die Rechtspopulisten zu repräsentieren meinen. Gleicht man allerdings die (migrations-)politischen Willensbekundungen, die AFD und Co. als Antwort auf den islamistischen Terror bieten, ab mit den politischen Reaktionen, die sich der IS von Anschlägen in Europa erhofft, fällt es schwer, hier einen Widerspruch zu sehen. Vielmehr lässt ein solcher Abgleich die deutschen – und auch europäischen – Rechtspopulisten, für die Höcke hier stellvertretend steht, fast schon als heimliche Partner des IS erscheinen, deren Absichten sich bestens mit den Vorstellungen der IS-Strategen ergänzen.
Damit ist ein dialektisches Problem angesprochen, das dem Umgang mit dem Terrorismus stets inhärent ist. Immerhin gehört es zu den Binsenweisheiten der Konfliktforschung, dass terroristische Akteure Reaktionen provozieren wollen, die ihnen neue Handlungsmöglichkeiten eröffnen. Und dies wiederum verweist darauf, dass Politiker und Sicherheitsbehörden, aber auch die Medien dabei (ungewollt) zu Erfüllungsgehilfen werden können, wenn deren Reflexe dem terroristischen Kalkül entsprechen. Die Dynamik des Terrors speist sich eben nicht nur aus den Aktionen der Terroristen, sondern auch aus dem Verhalten ihrer Antagonisten und der Öffentlichkeit. Um jene Dynamik zu verstehen, reicht daher der Blick auf terroristische Strategien keineswegs aus. Vielmehr ist deren Effekt von den Reaktionen relationaler Akteure abhängig. Wer also dem Terrorismus das Wasser abgraben will, der muss – so paradox das klingt – auch Vorsicht gegenüber denen walten lassen, die Anstoß an ihm nehmen.
Diese Prämisse eröffnet eine kritische Perspektive auf Formen des Anti-Terrorismus. Denn demnach können Versuche, dem Terror die Stirn zu bieten, unbeabsichtigte (Neben-)Folgen mit sich bringen, welche die Dynamik des Terrors verstärken. Derartige backfire mechanisms sind es, die in diesem Beitrag problematisiert werden. Jedoch widmet er sich nicht der staatlichen Antiterrorpolitik, sondern erörtert, inwiefern das Zusammenspiel von Medien und Rechtspopulismus zur aktuellen Dynamik des islamistischen Terrorismus beiträgt. Diese Frage stellt sich vor dem Hintergrund, dass die jüngsten Anschläge in Europa eine virtuelle Form des Terrorismus darstellen, wo häufig Einzelpersonen im Namen des IS agieren, aber kaum bis gar nicht im Kontakt mit der Organisation standen. Es scheint daher die Vermutung nicht abwegig, dass co-konstitutive Faktoren – wie die Berichterstattung über den Terror und anti-muslimische Diskurse – eine nicht unbedeutende Rolle bei deren Radikalisierung und Aktivierung spielen.
We investigate the effect of overreaction in the fine art market. Using a unique sample of auction prices of modern prints, we define an overvalued (undervalued) print as a print that was bought for a price above (below) its high (low) auction pricing estimate. Based on the overreaction hypothesis, we predict that overvalued (undervalued) prints generate a negative (positive) excess return at a subsequent sale. Our empirical findings confirm our expectations. We report that prints that were bought for a price 10 percent above (below) its high (low) pricing estimate generate a positive (negative) excess return of 12 percent (17 percent) after controlling for the general price movement on the prints market. The price correction for overvalued (undervalued) prints is more pronounced during recessions (expansions).
In situ single particle analysis of ice particle residuals (IPRs) and out-of-cloud aerosol particles was conducted by means of laser ablation mass spectrometry during the intensive INUIT-JFJ/CLACE campaign at the high alpine research station Jungfraujoch (3580 m a.s.l.) in January–February 2013. During the 4-week campaign more than 70 000 out-of-cloud aerosol particles and 595 IPRs were analyzed covering a particle size diameter range from 100 nm to 3 µm. The IPRs were sampled during 273 h while the station was covered by mixed-phase clouds at ambient temperatures between −27 and −6 °C. The identification of particle types is based on laboratory studies of different types of biological, mineral and anthropogenic aerosol particles. The outcome of these laboratory studies was characteristic marker peaks for each investigated particle type. These marker peaks were applied to the field data. In the sampled IPRs we identified a larger number fraction of primary aerosol particles, like soil dust (13 ± 5 %) and minerals (11 ± 5 %), in comparison to out-of-cloud aerosol particles (2.4 ± 0.4 and 0.4 ± 0.1 %, respectively). Additionally, anthropogenic aerosol particles, such as particles from industrial emissions and lead-containing particles, were found to be more abundant in the IPRs than in the out-of-cloud aerosol. In the out-of-cloud aerosol we identified a large fraction of aged particles (31 ± 5 %), including organic material and secondary inorganics, whereas this particle type was much less abundant (2.7 ± 1.3 %) in the IPRs. In a selected subset of the data where a direct comparison between out-of-cloud aerosol particles and IPRs in air masses with similar origin was possible, a pronounced enhancement of biological particles was found in the IPRs.
BACKGROUND: Despite its impact on female health worldwide, no efforts have been made to depict the global architecture of ovarian cancer research and to understand the trends in the related literature. Hence, it was the objective of this study to assess the global scientific performance chronologically, geographically and in regards to economic benchmarks using bibliometric tools and density equalizing map projections.
METHODS: The NewQIS platform was employed to identify all ovarian cancer related articles published in the Web of Science since 1900. The items were analyzed regarding quantitative aspects (e.g. publication date, country of origin) and parameters describing the recognition of the work by the scientific community (e.g. citation rates).
RESULTS: 23,378 articles on ovarian cancer were analyzed. The USA had the highest activity of ovarian cancer research with a total of n = 9312 ovarian cancer-specific publications, followed by the UK (n = 1900), China (n = 1813), Germany (n = 1717) and Japan (n = 1673). Ovarian cancer-specific country h-index also showed a leading position of the USA with an h-index (HI) of 207, followed by the UK (HI = 122), Canada (HI = 99), Italy (HI = 97), Germany (HI = 84), and Japan (HI = 81). In the socio-economic analysis, the USA were ranked first with an average of 175.6 ovarian cancer-related publications per GDP per capita in 1000 US-$, followed by Italy with an index level of 46.85, the UK with 45.48, and Japan with 43.3. Overall, the USA and Western European nations, China and Japan constituted the scientific power players publishing the majority of highly cited ovarian cancer-related articles and dominated international collaborative efforts. African, Asian and South American countries played almost no visible role in the scientific community.
CONCLUSIONS: The quantity and scientific recognition of publications related to ovarian cancer are continuously increasing. The research endeavors in the field are concentrated in high-income countries with no involvement of lower-resource nations. Hence, worldwide collaborative efforts with the aim to exchange epidemiologic data, resources and knowledge have to be strengthened in the future to successfully alleviate the global burden related to ovarian cancer.
It is long known that Kasugamycin inhibits translation of canonical transcripts containing a 5’-UTR with a Shine Dalgarno (SD) motif, but not that of leaderless transcripts. To gain a global overview of the influence of Kasugamycin on translation efficiencies, the changes of the translatome of Escherichia coli induced by a 10 minutes Kasugamycin treatment were quantified. The effect of Kasugamycin differed widely, 102 transcripts were at least twofold more sensitive to Kasugamycin than average, and 137 transcripts were at least twofold more resistant, and there was a more than 100-fold difference between the most resistant and the most sensitive transcript. The 5’-ends of 19 transcripts were determined from treated and untreated cultures, but Kasugamycin resistance did neither correlate with the presence or absence of a SD motif, nor with differences in 5’-UTR lengths or GC content. RNA Structure Logos were generated for the 102 Kasugamycin-sensitive and for the 137 resistant transcripts. For both groups a short Shine Dalgarno (SD) motif was retrieved, but no specific motifs associated with resistance or sensitivity could be found. Notably, this was also true for the region -3 to -1 upstream of the start codon and the presence of an extended SD motif, which had been proposed to result in Kasugamycin resistance. Comparison of the translatome results with the database RegulonDB showed that the transcript with the highest resistance was leaderless, but no further leaderless transcripts were among the resistant transcripts. Unexpectedly, it was found that translational coupling might be a novel feature that is associated with Kasugamycin resistance. Taken together, Kasugamycin has a profound effect on translational efficiencies of E. coli transcripts, but the mechanism of action is different than previously described.