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The thermodynamics of Quantum Chromodynamics (QCD) in external (electro-)magnetic fields shows some unexpected features like inverse magnetic catalysis, which have been revealed mainly through lattice studies. Many effective descriptions, on the other hand, use Landau levels or approximate the system by just the lowest Landau level (LLL). Analyzing lattice configurations we ask whether such a picture is justified. We find the LLL to be separated from the rest by a spectral gap in the two-dimensional Dirac operator and analyze the corresponding LLL signature in four dimensions. We determine to what extent the quark condensate is LLL dominated at strong magnetic fields.
Die Einführung von Patient Blood Management (PBM) führt zu einem Paradigmenwechsel bezüglich Erkennen und Therapie der Anämie und zeigt Maßnahmen auf um die Entstehung einer Anämie zu verhindern. PBM unterstützt den Arzt im Entscheidungsdilemma zwischen positiver Wirkung und nachteiligen Nebenwirkungen von Bluttransfusionen. Mit PBM wird der Blutverbrauch deutlich reduziert und die Nebenwirkungen gesenkt. Nicht nur die therapeutischen Maßnahmen, sondern auch die diagnostischen PBM Maßnahmen im Labor führen zu einer relevanten Verringerung des Blutvolumens. PBM Studienergebnisse zeigen eine signifikant Reduktion der Morbidität und Mortalität und die Verbesserung des Patienten- Outcome. Ein weiterer positiver Nebeneffekt ist Schonung von Ressourcen in allen beteiligten Bereichen, welches zu einer relevanten Kostenreduktion und Steigerung der Wirtschaftlichkeit führt. Zusätzlich sensibilisiert das PBM bezüglich des Vorliegens, der Entwicklung und der Therapie einer anämischen Situation sowie den Umgang mit der kostbaren Ressource Blut. Die Bedeutung des PBM wird mittlerweile von der Industrie auch für das Labor unterstützt; für den Bereich POCT ist das PBM jedoch bisher noch nicht adäquat technisch realisiert.
Disturbed homeostasis as a result of tissue stress can provoke leukocyte responses enabling recovery. Since mild hypothermia displays specific clinically relevant tissue-protective properties and interleukin (IL)-22 promotes healing at host/environment interfaces, effects of lowered ambient temperature on IL-22 were studied. We demonstrate that a 5-h exposure of endotoxemic mice to 4°C reduces body temperature by 5.0° and enhances splenic and colonic il22 gene expression. In contrast, tumor necrosis factor-α and IL-17A were not increased. In vivo data on IL-22 were corroborated using murine splenocytes and human peripheral blood mononuclear cells (PBMC) cultured upon 33°C and polyclonal T cell activation. Upregulation by mild hypothermia of largely T-cell-derived IL-22 in PBMC required monocytes and associated with enhanced nuclear T-cell nuclear factor of activated T cells (NFAT)-c2. Notably, NFAT antagonism by cyclosporin A or FK506 impaired IL-22 upregulation at normothermia and entirely prevented its enhanced expression upon hypothermic culture conditions. Data suggest that intact NFAT signaling is required for efficient IL-22 induction upon normothermic and hypothermic conditions. Hypothermia furthermore boosted early signal transducer and activator of transcription 3 activation by IL-22 and shaped downstream gene expression in epithelial-like cells. Altogether, data indicate that hypothermia supports and fine-tunes IL-22 production/action, which may contribute to regulatory properties of low ambient temperature.
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.
The second and the third order anisotropic flow, V2 and V3, are mostly determined by the corresponding initial spatial anisotropy coefficients, ε2 and ε3, in the initial density distribution. In addition to their dependence on the same order initial anisotropy coefficient, higher order anisotropic flow, Vn (n > 3), can also have a significant contribution from lower order initial anisotropy coefficients, which leads to mode-coupling effects. In this Letter we investigate the linear and non-linear modes in higher order anisotropic flow Vn for n = 4, 5, 6 with the ALICE detector at the Large Hadron Collider. The measurements are done for particles in the pseudorapidity range |η| < 0.8 and the transverse momentum range 0.2 < pT < 5.0 GeV/c as a function of collision centrality. The results are compared with theoretical calculations and provide important constraints on the initial conditions, including initial spatial geometry and its fluctuations, as well as the ratio of the shear viscosity to entropy density of the produced system.
The KASCADE-Grande experiment has significantly contributed to the current knowledge about the energy spectrum and composition of cosmic rays for energies between the knee and the ankle. Meanwhile, post-LHC versions of the hadronic interaction models are available and used to interpret the entire data set of KASCADE-Grande. In addition, a new, combined analysis of both arrays, KASCADE and Grande, was developed significantly increasing the accuracy of the shower observables. First results of the new analysis with the entire data set of the KASCADE-Grande experiment will be the focus of this contribution.
New neutron cross section measurements of minor actinides have been performed recently in order to reduce the uncertainties in the evaluated data, which is important for the design of advanced nuclear reactors and, in particular, for determining their performance in the transmutation of nuclear waste. We have measured the 241Am(n,γ) cross section at the n_TOF facility between 0.2 eV and 10 keV with a BaF2 Total Absorption Calorimeter, and the analysis of the measurement has been recently concluded. Our results are in reasonable agreement below 20 eV with the ones published by C. Lampoudis et al. in 2013, who reported a 22% larger capture cross section up to 110 eV compared to experimental and evaluated data published before. Our results also indicate that the 241Am(n,γ) cross section is underestimated in the present evaluated libraries between 20 eV and 2 keV by 25%, on average, and up to 35% for certain evaluations and energy ranges.
The accuracy on neutron capture cross section of fissile isotopes must be improved for the design of future nuclear systems such as Gen-IV reactors and Accelerator Driven Systems. The High Priority Request List of the Nuclear Energy Agency, which lists the most important nuclear data requirements, includes also the neutron capture cross sections of fissile isotopes such as 233,235U and 239,241Pu. A specific experimental setup has been used at the CERN n_TOF facility for the measurement of the neutron capture cross section of 235U by a set of micromegas fission detectors placed inside a segmented BaF2 Total Absorption Calorimeter.
The experimental area 2 (EAR-2) at CERNs neutron time-of-flight facility (n_TOF), which is operational since 2014, is designed and built as a short-distance complement to the experimental area 1 (EAR-1). The Parallel Plate Avalanche Counter (PPAC) monitor experiment was performed to characterize the beam pro↓le and the shape of the neutron 'ux at EAR-2. The prompt γ-flash which is used for calibrating the time-of-flight at EAR-1 is not seen by PPAC at EAR-2, shedding light on the physical origin of this γ-flash.
Monte Carlo (MC) simulations are an essential tool to determine fundamental features of a neutron beam, such as the neutron flux or the γ-ray background, that sometimes can not be measured or at least not in every position or energy range. Until recently, the most widely used MC codes in this field had been MCNPX and FLUKA. However, the Geant4 toolkit has also become a competitive code for the transport of neutrons after the development of the native Geant4 format for neutron data libraries, G4NDL. In this context, we present the Geant4 simulations of the neutron spallation target of the n_TOF facility at CERN, done with version 10.1.1 of the toolkit. The first goal was the validation of the intra-nuclear cascade models implemented in the code using, as benchmark, the characteristics of the neutron beam measured at the first experimental area (EAR1), especially the neutron flux and energy distribution, and the time distribution of neutrons of equal kinetic energy, the so-called Resolution Function. The second goal was the development of a Monte Carlo tool aimed to provide useful calculations for both the analysis and planning of the upcoming measurements at the new experimental area (EAR2) of the facility.
Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine populations of European origin and 15 485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common and 5 rare). No findings reached genome-wide significance. Two notable common variants were identified: rs10791286, an intronic variant in OPCML (P=9.89 × 10−6), and rs7700147, an intergenic variant (P=2.93 × 10−5). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low-frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes.
Clustering of cardiovascular risk factors and carotid intima-media thickness : the USE-IMT study
(2017)
Background: The relation of a single risk factor with atherosclerosis is established. Clinically we know of risk factor clustering within individuals. Yet, studies into the magnitude of the relation of risk factor clusters with atherosclerosis are limited. Here, we assessed that relation.
Methods: Individual participant data from 14 cohorts, involving 59,025 individuals were used in this cross-sectional analysis. We made 15 clusters of four risk factors (current smoking, overweight, elevated blood pressure, elevated total cholesterol). Multilevel age and sex adjusted linear regression models were applied to estimate mean differences in common carotid intima-media thickness (CIMT) between clusters using those without any of the four risk factors as reference group.
Results: Compared to the reference, those with 1, 2, 3 or 4 risk factors had a significantly higher common CIMT: mean difference of 0.026 mm, 0.052 mm, 0.074 mm and 0.114 mm, respectively. These findings were the same in men and in women, and across ethnic groups. Within each risk factor cluster (1, 2, 3 risk factors), groups with elevated blood pressure had the largest CIMT and those with elevated cholesterol the lowest CIMT, a pattern similar for men and women.
Conclusion: Clusters of risk factors relate to increased common CIMT in a graded manner, similar in men, women and across race-ethnic groups. Some clusters seemed more atherogenic than others. Our findings support the notion that cardiovascular prevention should focus on sets of risk factors rather than individual levels alone, but may prioritize within clusters.
When binary systems of neutron stars merge, a very small fraction of their rest mass is ejected, either dynamically or secularly. This material is neutron-rich and its nucleosynthesis provides the astrophysical site for the production of heavy elements in the Universe, together with a kilonova signal confirming neutron-star mergers as the origin of short gamma-ray bursts. We perform full general-relativistic simulations of binary neutron-star mergers employing three different nuclear-physics equations of state (EOSs), considering both equal- and unequal-mass configurations, and adopting a leakage scheme to account for neutrino radiative losses. Using a combination of techniques, we carry out an extensive and systematic study of the hydrodynamical, thermodynamical, and geometrical properties of the matter ejected dynamically, employing the WinNet nuclear-reaction network to recover the relative abundances of heavy elements produced by each configurations. Among the results obtained, three are particularly important. First, we find that, within the sample considered here, both the properties of the dynamical ejecta and the nucleosynthesis yields are robust against variations of the EOS and masses. Second, using a conservative but robust criterion for unbound matter, we find that the amount of ejected mass is ≲10−3 M⊙, hence at least one order of magnitude smaller than what normally assumed in modelling kilonova signals. Finally, using a simplified and gray-opacity model we assess the observability of the infrared kilonova emission finding, that for all binaries the luminosity peaks around ∼1=2 day in the H-band, reaching a maximum magnitude of −13, and decreasing rapidly after one day.
We investigate the effect of large magnetic fields on the (2 + 1)-dimensional reduced-magnetohydrodynamical expansion of hot and dense nuclear matter produced in √sNN = 200 GeV Au+Au collisions. For the sake of simplicity,we consider the casewhere themagnetic field points in the direction perpendicular to the reaction plane. We also consider this field to be external, with energy density parametrized as a two-dimensional Gaussian. The width of the Gaussian along the directions orthogonal to the beam axis varies with the centrality of the collision. The dependence of the magnetic field on proper time (τ ) for the case of zero electrical conductivity of the QGP is parametrized following Deng et al. [Phys. Rev. C 85, 044907 (2012)], and for finite electrical conductivity following Tuchin [Phys. Rev. C 88, 024911 (2013)].We solve the equations of motion of ideal hydrodynamics for such an external magnetic field. For collisions with nonzero impact parameter we observe considerable changes in the evolution of the momentum eccentricities of the fireball when comparing the case when the magnetic field decays in a conducting QGP medium and when no magnetic field is present. The elliptic-flow coefficient v2 of π− is shown to increase in the presence of an external magnetic field and the increment in v2 is found to depend on the evolution and the initial magnitude of the magnetic field.
According to a proposal by 't Hooft, information loss introduced by constraints in certain classical dissipative systems may lead to quantization. This scheme can be realized within the Bateman model of two coupled oscillators, one damped and one accelerated. In this paper we analyze the links of this approach to effective Hamiltonians where the environmental degrees of freedom do not appear explicitly but their effect leads to the same friction force appearing in the Bateman model. In particular, it is shown that by imposing constraints, the Bateman Hamiltonian can be transformed into an effective one expressed in expanding coordinates. This one can be transformed via a canonical transformation into Caldirola and Kanai's effective Hamiltonian that can be linked to the conventional system-plus-reservoir approach, for example, in a form used by Caldeira and Leggett.
The 124Xe(p,γ) reaction has been measured for the first time at energies around the Gamow window by using stored ions at the ESR facility. The desired beam energies below 10 MeV/u introduce new experimental challenges like windowless ions detection under UHV conditions, extremely short beam lifetimes and efficient beam deceleration and cooling, all of which have been successfully met.
Background: Kyrgyzstan, where HIV is concentrated in prisons and driven by injection drug use, provides a prison-based methadone maintenance therapy program as well as abstinence-oriented therapeutic community based on the 12-step model called the “Clean Zone.” We aimed to qualitatively assess how prisoners navigate between these treatment options to understand the persistence of the Clean Zone despite a lack of evidence to support its effectiveness in treating opioid use disorders.
Methods: We conducted an analysis of policy documents and over 60 h of participant observation in February 2016, which included focus groups with a convenience sample of 20 therapeutic community staff members, 110 prisoners across three male and one female prisons, and qualitative interviews with two former Clean Zone participants. Field notes containing verbatim quotes from participants were analyzed through iterative reading and discussion to understand how participants generally perceive the program, barriers to entry and retention, and implications for future treatment within prisons.
Results: Our analyses discerned three themes: pride in the mission of the Clean Zone, idealism regarding addiction treatment outcomes against all odds, and the demonization of methadone.
Conclusion: Despite low enrollment and lack of an evidence base, the therapeutic community is buttressed by the strong support of the prison administration and its clients as an “ordered” alternative to what is seen as chaotic life outside of the Clean Zone. The lack of services for Clean Zone patients after release likely contributes to high rates of relapse to drug use. The Clean Zone would benefit from integration of stabilized methadone patients combined with a post-release program.
The electron transferring flavoprotein/butyryl-CoA dehydrogenase (EtfAB/Bcd) catalyzes the reduction of one crotonyl-CoA and two ferredoxins by two NADH within a flavin-based electron-bifurcating process. Here we report on the X-ray structure of the Clostridium difficile (EtfAB/Bcd)4 complex in the dehydrogenase-conducting D-state, α-FAD (bound to domain II of EtfA) and δ-FAD (bound to Bcd) being 8 Å apart. Superimposing Acidaminococcus fermentans EtfAB onto C. difficile EtfAB/Bcd reveals a rotation of domain II of nearly 80°. Further rotation by 10° brings EtfAB into the bifurcating B-state, α-FAD and β-FAD (bound to EtfB) being 14 Å apart. This dual binding mode of domain II, substantiated by mutational studies, resembles findings in non-bifurcating EtfAB/acyl-CoA dehydrogenase complexes. In our proposed mechanism, NADH reduces β-FAD, which bifurcates. One electron goes to ferredoxin and one to α-FAD, which swings over to reduce δ-FAD to the semiquinone. Repetition affords a second reduced ferredoxin and δ-FADH−, which reduces crotonyl-CoA.
SDF-1/CXCR4 expression in head and neck cancer and outcome after postoperative radiochemotherapy
(2017)
Introduction: Outcome after postoperative radiochemotherapy (RT-CT) for patients with advanced head and neck squamous cell carcinomas (HNSCC) remains unsatisfactory, especially among those with HPV negative tumours. Therefore, new biomarkers are needed to further define subgroups for individualised therapeutic approaches. Preclinical and first clinical observations showed that the chemokine receptor CXCR4 and its ligand SDF-1 (CXCL12) play an important role in tumour cell proliferation, survival, cancer progression, metastasis and treatment resistance. However, the data on the prognostic value of SDF-1/CXCR4 expression for HNSCC are conflicting. The aim of our hypothesis-generating study was to retrospectively explore the prognostic potential of SDF-1/CXCR4 in a well-defined cohort of HNSCC patients collected within the multicenter biomarker study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG).
Material and methods: Patients with stage III and IVA HNSCC of the oral cavity, oropharynx and hypopharynx were treated with resection and adjuvant radiotherapy (RT) with ≥60 Gy and concurrent cisplatin-based chemotherapy (CT). Tissue micro-arrays (TMAs) from a total of 221 patients were generated from surgical specimens, 201 evaluated for the SDF-1 and CXCR4 expression by immunofluorescence and correlated with clinico-pathological and outcome data.
Results: In univariate and multivariate analyses intracellular SDF-1 expression was associated with lower loco-regional control (LRC) in the entire patient group as well as in the HPV16 DNA negative subgroup. CXCR4 expression showed a trend for lower LRC in the univariate analysis which was not confirmed in the multivariate analysis. Neither for SDF-1 nor CXCR4 expression associations with distant metastasis free or overall survival were found.
Conclusions: Our exploratory data support the hypothesis that overexpression of intracellular SDF-1 is an independent negative prognostic biomarker for LRC after postoperative RT-CT in high-risk HNSCC. Prospective validation is warranted and further exploration of SDF-1/CXCR4 as a potential therapeutic target to overcome treatment resistance in HNSCC appears promising.
Nach Lektüre dieses Werks ist man zunächst geneigt, von einer Rezension im Wortsinn abzusehen, um die Autoren stattdessen einfach zu einer rundum Respekt und Bewunderung verdienenden Leistung zu beglückwünschen, haben sie doch auf nicht weniger als 1100 Seiten ihr Thema von der ausgehenden Karolingerzeit bis an die Schwelle des 16.Jahrhunderts mit hoher Kompetenz unter allen nur denkbaren Aspekten abgehandelt und diese durchgängig mit einer schier überbordenden Fülle von Belegen und Beispielen illustriert. Der durchmessene Raum reicht von Norwegen bis Byzanz und von Polen bis zur Iberischen Halbinsel; einen gewissen Schwerpunkt bilden dabei das römisch-deutsche Reich und Frankreich. Solch in einem französischen Handbuch nicht unbedingt zu erwartender Doppelakzent verdankt sich Jean-Marie Moeglin, der bereits 2010/2011 mit seiner "Deutsch-Französischen Geschichte im Spätmittelalter" ein ähnlich gelehrtes Monument vorgelegt hat. Wie sehr er in den Kulturen beider Länder heimisch ist – in München, dem für Mediävisten deutschen Bibliotheksmekka, hat er inzwischen ein zweites Zuhause –, zeigt sich bis in die Anmerkungen und in eine (mit Unternummern) weit über 3000 Titel umfassende Bibliografie, die für europäische und insbesondere eben deutsche und französische Benutzerinnen und Benutzer künftig eine unverzichtbare Referenz sein dürfte. Gerade in einem Organ vom Profil der Francia-Recensio sei darauf mit Nachdruck empfehlend hingewiesen. ...
Der Titel lässt eine Behandlung von Streitschriften und anderen Zeugnissen aus der Zeit des großen abendländischen Schismas erwarten, mit denen sich Vertreter der zwei bzw. drei Obödienzen positionierten und einander bekämpften. Doch vor die Quellen hat die Verfasserin die Theorie gesetzt: Ohne Habermas, Bourdieu und Foucault kein Jean Gerson, Simon de Cramaud oder Nicolas Eymerich. Man wähnt sich anfangs weniger in der Welt der Pariser Universität und der avignonesischen Kurie um 1400 als im soziologischen und literaturtheoretischen Oberseminar (die klassische Ideengeschichte wird kurzerhand als "très périmée" beiseite geschoben [S. 13]) und fürchtet, zumindest als nicht eben theorieversessener Historiker, schon den anstehenden Marsch durch entsprechende Textwüsten, zumal die Autorin expressis verbis einen anderen Ansatz als Hélène Millet vertritt, die sich mit ihren – am Dictum Lucien Febvres "Et l’homme dans tout cela?" orientierten – biografischen und prosopografischen Arbeiten um die Erforschung des Schismas bekanntlich sehr verdient gemacht hat: "Hélène Millet aime cerner les hommes du temps, quand j’aime scruter les textes" (S. 16). ...
Selten dürfte es einem Gelehrten vergönnt sein, die Summe seiner über 50 Jahre währenden Tätigkeit in zwei Alterswerken ziehen zu können, wie es bei Philippe Contamine der Fall ist mit dem wesentlich von ihm gestalteten "Dictionnaire de Jeanne d’Arc" und der nunmehr vorliegenden Biografie Karls VII. Diese beiden Persönlichkeiten markieren Schwerpunkte in einem staunenswerte Kontinuität, Intensität und Konsequenz zeigenden Œuvre, in dem nicht nur, so doch immer wieder die Geschichte Frankreichs im 14. und vor allem 15.Jahrhundert im Zentrum steht. Der Verfasser pflegt eine politisch akzentuierte Geschichtsschreibung, die sich abseits aller Moden und Theoriedebatten grundsätzlich der Quellenerschließung und -interpretation verpflichtet weiß. Geschrieben wurde auch der hier anzuzeigende Band stets entlang den oft in Auszügen zitierten und im Fall von Traktaten eines Alain Chartier oder Jean Juvénal des Ursins gar eigene Unterkapitel ausfüllenden Quellen, darin einmal mehr eingeschlossen handschriftliches Material. Unspektakulär geht der Autor diesen seinen Weg; dabei erfolgt auch, bis auf eine kurze lobende Erwähnung der monumentalen Monografie von Du Fresne de Beaucourt (1881/1891, vgl. S. 16), keine Auseinandersetzung mit früheren Biografien Karls VII., selbst nicht mit der – trotz fragwürdiger Grundthese lohnenswerten – von M.G. A. Vale oder der jüngsten, übrigens ebenfalls bei Perrin erschienenen – und m. E. weniger lohnenden – von Georges Minois; von dem noch 2001 wieder aufgelegten und recht eigenwilligen, da Karls VII. Schwiegermutter Yolande von Aragón als dessen mystère in den Mittelpunkt stellenden Buch eines Philippe Erlanger ganz zu schweigen. ...
Background: Malaria remains one of the most serious infections for travellers to tropical countries. Due to the lack of harmonized guidelines a large variety of treatment regimens is used in Europe to treat severe malaria.
Methods: The European Network for Tropical Medicine and Travel Health (TropNet) conducted an 8-year, multicentre, observational study to analyse epidemiology, treatment practices and outcomes of severe malaria in its member sites across Europe. Physicians at participating TropNet centres were asked to report pseudonymized retrospective data from all patients treated at their centre for microscopically confirmed severe Plasmodium falciparum malaria according to the 2006 WHO criteria.
Results: From 2006 to 2014 a total of 185 patients with severe malaria treated in 12 European countries were included. Three patients died, resulting in a 28-day survival rate of 98.4%. The majority of infections were acquired in West Africa (109/185, 59%). The proportion of patients treated with intravenous artesunate increased from 27% in 2006 to 60% in 2013. Altogether, 56 different combinations of intravenous and oral drugs were used across 28 study centres. The risk of acute renal failure (36 vs 17% p = 0.04) or cerebral malaria (54 vs 20%, p = 0.001) was significantly higher in patients ≥60 years than in younger patients. Respiratory distress with the need for mechanical ventilation was significantly associated with the risk of death in the study population (13 vs 0%, p = 0.001). Post-artemisinin delayed haemolysis was reported in 19/70 (27%) patients treated with intravenous artesunate.
Conclusion: The majority of patients with severe malaria in this study were tourists or migrants acquiring the infection in West Africa. Intravenous artesunate is increasingly used for treatment of severe malaria in many European treatment centres and can be given safely to European patients with severe malaria. Patients treated with intravenous artesunate should be followed up to detect and manage late haemolytic events.
Cytokine regulation of high-output nitric oxide (NO) derived from inducible NO synthase (iNOS) is critically involved in inflammation biology and host defense. Herein, we set out to characterize the role of type I interferon (IFN) as potential regulator of hepatic iNOS in vitro and in vivo. In this regard, we identified in murine Hepa1-6 hepatoma cells a potent synergism between pro-inflammatory interleukin-β/tumor necrosis factor-α and immunoregulatory IFNβ as detected by analysis of iNOS expression and nitrite release. Upregulation of iNOS by IFNβ coincided with enhanced binding of signal transducer and activator of transcription-1 to a regulatory region at the murine iNOS promoter known to support target gene expression in response to this signaling pathway. Synergistic iNOS induction under the influence of IFNβ was confirmed in alternate murine Hepa56.1D hepatoma cells and primary hepatocytes. To assess iNOS regulation by type I IFN in vivo, murine acetaminophen (APAP)-induced sterile liver inflammation was investigated. In this model of acute liver injury, excessive necroinflammation drives iNOS expression in diverse liver cell types, among others hepatocytes. Herein, we demonstrate impaired iNOS expression in type I IFN receptor-deficient mice which associated with diminished APAP-induced liver damage. Data presented indicate a vital role of type I IFN within the inflamed liver for fine-tuning pathological processes such as overt iNOS expression.
Background: Caloric restriction is associated with broad therapeutic potential in various diseases and an increase in health and life span. In this study, we assessed the impact of caloric restriction on acute and inflammatory nociception in mice, which were either fed ad libitum or subjected to caloric restriction with 80% of the daily average for two weeks.
Results: The behavioral tests revealed that inflammatory nociception in the formalin test and in zymosan-induced mechanical hypersensitivity were significantly decreased when mice underwent caloric restriction. As potential mediators of the diet-induced antinociception, we assessed genes typically induced by inflammatory stimuli, AMP-activated kinase, and the endocannabinoid system which have all already been associated with nociceptive responses. Zymosan-induced inflammatory markers such as COX-2, TNFα, IL-1β, and c-fos in the spinal cord were not altered by caloric restriction. In contrast, AMPKα2 knock-out mice showed significant differences in comparison to C57BL/6 mice and their respective wild type littermates by missing the antinociceptive effects after caloric restriction. Endocannabinoid levels of anandamide and 2-arachidonyl glyceroldetermined in serum by LC-MS/MS were not affected by either caloric restriction alone or in combination with zymosan treatment. However, cannabinoid receptor type 1 expression in the spinal cord, which was not altered by caloric restriction in control mice, was significantly increased after caloric restriction in zymosan-induced paw inflammation. Since increased cannabinoid receptor type 1 signaling might influence AMP-activated kinase activity, we analyzed effects of anandamide on AMP-activated kinase in cell culture and observed a significant activation of AMP-activated kinase. Thus, endocannabionoid-induced AMP-activated kinase activation might be involved in antinociceptive effects after caloric restriction.
Conclusion: Our data suggest that caloric restriction has an impact on inflammatory nociception which might involve AMP-activated kinase activation and an increased activity of the endogenous endocannabinoid system by caloric restriction-induced cannabinoid receptor type 1 upregulation.
"Ihr sollt euch nicht zu den Götzen wenden, und gegossene Götter sollt ihr euch nicht machen [...](Lev 19,4) [...] sollen wir nicht meinen, daß das Göttliche dem Gold und Silber oder Stein, einem Gebilde der Kunst und der Erfindung des Menschen gleich sei. (Acta 17,29) Pfui über euch und über das, was ihr an Gottes Statt verehrt! [...] (Q 21,67)"
Diese drei Sätze stammen nacheinander aus der hebräischen Bibel, dem Neuen Testament und dem Koran. Man kann sie beinahe wie einen Text lesen, an dem sich die These des Ägyptologen Jan Assmann belegen ließe, dass mit der Herausbildung monotheistischer Religionen wie Judentum, Christentum und Islam im Allgemeinen und dem Bilderverbot im Besonderen die Unterscheidung zwischen wahr und falsch in die Götterwelt gekommen sei (Assmann 1998, S. 17). ...
Tortonian teleost otoliths from northern Italy: taxonomic synthesis and stratigraphic significance
(2017)
The Tortonian fish otoliths of northern Italy have been studied for more than a century and represent one of the best known otolith-based teleost faunas in the Miocene of the Mediterranean Basin. Yet with the growing knowledge on Recent otoliths, an updated taxonomic overview of this fauna is needed. Moreover, new material from hemipelagic Tortonian marls sampled at nine localities is described herein, revealing 109 taxa of which 88 are recognised at species level. Four of these are new: Coryphaenoides biobtusus sp. nov., “Merluccius” rattazzii sp. nov., Neobythites auriculatus sp. nov. and Lesueurigobius stironensis sp. nov. The compilation of previously studied and newly acquired material revealed a total of 118 nominal Tortonian species. At generic level, the fauna is characterised by many modern forms; more than 90% can be assigned to present day genera. At species level, however, more than half of the represented taxa are extinct. Based on the fossil otolith record, the Tortonian fauna of the Mediterranean is most similar to that of the Langhian (Badenian) of the Central Paratethys by sharing many extinct Miocene species, but it is also very close to that of the Pliocene Mediterranean, by sharing many modern Atlantic-Mediterranean forms. The Tortonian fauna is further characterised by many species that are apparently confined to the upper Miocene, resulting in a unique combination of its taxonomic composition.
Recently, Aumüller and Dietzfelbinger proposed a version of a dual-pivot Quicksort, called "Count", which is optimal among dual-pivot versions with respect to the average number of key comparisons required. In this master's thesis we provide further probabilistic analysis of "Count". We derive an exact formula for the average number of swaps needed by "Count" as well as an asymptotic formula for the variance of the number of swaps and a limit law. Also for the number of key comparisons the asymptotic variance and a limit law are identified. We also consider both complexity measures jointly and find their asymptotic correlation.
Binding free energy calculations that make use of alchemical pathways are becoming increasingly feasible thanks to advances in hardware and algorithms. Although relative binding free energy (RBFE) calculations are starting to find widespread use, absolute binding free energy (ABFE) calculations are still being explored mainly in academic settings due to the high computational requirements and still uncertain predictive value. However, in some drug design scenarios, RBFE calculations are not applicable and ABFE calculations could provide an alternative. Computationally cheaper end-point calculations in implicit solvent, such as molecular mechanics Poisson–Boltzmann surface area (MMPBSA) calculations, could too be used if one is primarily interested in a relative ranking of affinities. Here, we compare MMPBSA calculations to previously performed absolute alchemical free energy calculations in their ability to correlate with experimental binding free energies for three sets of bromodomain–inhibitor pairs. Different MMPBSA approaches have been considered, including a standard single-trajectory protocol, a protocol that includes a binding entropy estimate, and protocols that take into account the ligand hydration shell. Despite the improvements observed with the latter two MMPBSA approaches, ABFE calculations were found to be overall superior in obtaining correlation with experimental affinities for the test cases considered. A difference in weighted average Pearson () and Spearman () correlations of 0.25 and 0.31 was observed when using a standard single-trajectory MMPBSA setup ( = 0.64 and = 0.66 for ABFE; = 0.39 and = 0.35 for MMPBSA). The best performing MMPBSA protocols returned weighted average Pearson and Spearman correlations that were about 0.1 inferior to ABFE calculations: = 0.55 and = 0.56 when including an entropy estimate, and = 0.53 and = 0.55 when including explicit water molecules. Overall, the study suggests that ABFE calculations are indeed the more accurate approach, yet there is also value in MMPBSA calculations considering the lower compute requirements, and if agreement to experimental affinities in absolute terms is not of interest. Moreover, for the specific protein–ligand systems considered in this study, we find that including an explicit ligand hydration shell or a binding entropy estimate in the MMPBSA calculations resulted in significant performance improvements at a negligible computational cost.
The chemopreventive and anticancer effects of resveratrol (RSV) are widely reported in the literature. Specifically, mechanisms involving epigenetic regulation are promising targets to regulate tumor development. Bromodomains act as epigenetic readers by recognizing lysine acetylation on histone tails and boosting gene expression in order to regulate tissue-specific transcription. In this work, we showed that RSV is a pan-BET inhibitor. Using Differential Scanning Fluorimetry (DSF), we showed that RSV at 100 µM increased the melting temperature (∆Tm) of BET bromodomains by around 2.0 °C. The micromolar dissociation constant (Kd) range was characterized using Isothermal Titration Calorimetry (ITC). The RSV Kd value accounted to 6.6 µM in case of BRD4(1). Molecular docking proposed the binding mode of RSV against BRD4(1) mimicking the acetyl-lysine interactions. All these results suggest that RSV can also recognize epigenetic readers domains by interacting with BET bromodomains.
Die Reihe „Papers of Excellence 2.0: Ausgewählte Arbeiten aus den Fachdidaktiken und Bildungswissenschaften der Goethe-Universität Frankfurt a.M.“ ist eine neue, erweiterte und zusätzliche Auflage der bekannten Reihe „Papers of Excellence: Ausgewählte Arbeiten aus den Fachdidaktiken“, welche seit 2010 von Daniela Elsner und Anja Wildemann im Shaker-Verlag herausgegeben wird. In alter Tradition werden auch in der ab sofort zusätzlich zur Printausgabe erscheinenden Online Version dieser Buchreihe herausragende Examens- und Masterarbeiten, die sich durch eine ausgewiesene empirische, fachdidaktische Auseinandersetzung mit einem Thema auszeichnen, zusammenfassend vorgestellt. Neu ist, dass die Online Version nun auch Arbeiten mit einem bildungswissenschaftlichen Fokus aufnimmt und solche, die an der Schnittstelle zwischen Fachdidaktik und Bildungswissenschaften an-gelegt sind. Die Papers of Excellence 2.0, die derzeit nur Studien integriert, die an der Goethe Universität Frankfurt am Main angefertigt wurden, werden von Astrid Jurecka (Bildungswissenschaften) und Daniela Elsner (Fachdidaktik) herausgegeben und sind kostenfrei zugänglich.
BRAF V600E mutations occur frequently in malignant melanoma, but are rare in most malignant glioma subtypes. Besides, more benign brain tumors such as ganglioglioma, dysembryoblastic neuroepithelial tumours and supratentorial pilocytic astrocytomas, only pleomorphic xanthoastrocytomas (50-78%) and epitheloid glioblastoma (50%) regularly exhibit BRAF mutations. In the present study, we report on three patients with recurrent malignant gliomas harbouring a BRAF V600E mutation. All patients presented with markedly disseminated leptomeningeal disease at recurrence and had progressed after radiotherapy and alkylating chemotherapy. Therefore, estimated life expectancy at recurrence was a few weeks. All three patients received dabrafenib as a single agent and all showed a complete or nearly complete response. Treatment is ongoing and patients are stable for 27 months, 7 months and 3 months, respectively. One patient showed a dramatic radiologic and clinical response after one week of treatment. We were able to generate an ex vivo tumor cell culture from CSF in one patient. Treatment of this cell culture with dabrafenib resulted in reduced cell density and inhibition of ERK phosphorylation in vitro. To date, this is the first series on adult patients with BRAF-mutated malignant glioma and leptomeningeal dissemination treated with dabrafenib monotherapy. All patients showed a dramatic response with one patient showing an ongoing response for more than two years.
We explored the characteristics and motivations of people who, having obtained their genetic or genomic data from Direct-To-Consumer genetic testing (DTC-GT) companies, voluntarily decide to share them on the publicly accessible web platform openSNP. The study is the first attempt to describe open data sharing activities undertaken by individuals without institutional oversight. In the paper we provide a detailed overview of the distribution of the demographic characteristics and motivations of people engaged in genetic or genomic open data sharing. The geographical distribution of the respondents showed the USA as dominant. There was no significant gender divide, the age distribution was broad, educational background varied and respondents with and without children were equally represented. Health, even though prominent, was not the respondents’ primary or only motivation to be tested. As to their motivations to openly share their data, 86.05% indicated wanting to learn about themselves as relevant, followed by contributing to the advancement of medical research (80.30%), improving the predictability of genetic testing (76.02%) and considering it fun to explore genotype and phenotype data (75.51%). Whereas most respondents were well aware of the privacy risks of their involvement in open genetic data sharing and considered the possibility of direct, personal repercussions troubling, they estimated the risk of this happening to be negligible. Our findings highlight the diversity of DTC-GT consumers who decide to openly share their data. Instead of focusing exclusively on health-related aspects of genetic testing and data sharing, our study emphasizes the importance of taking into account benefits and risks that stretch beyond the health spectrum. Our results thus lend further support to the call for a broader and multi-faceted conceptualization of genomic utility.
Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of dendritic spines in the brains of patients with major mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for major mood disorders involved in synaptic function and related intermediate phenotypes.
El libro Serve the Power(s), Serve the State, editado por los historiadores Juan Carlos Garavaglia, Michael Braddick y Christian Lamouroux en el año 2016, es una apuesta por estudiar sistemáticamente la historia del Estado y de aproximarse a nuevas y diversas lecturas historiográficas al tema, el cual ha ocupado un lugar importante en las reflexiones académicas de las últimas décadas. Esta preocupación por el Estado y su proceso de formación, no sólo ha sido objeto de reflexión desde la Historia, sino además, desde otras disciplinas como la Ciencia Política, la Sociología y la Antropología, entre otras. Así, esta publicación en la que participan quince diferentes autores, con diferentes trayectorias e intereses, surge de la Conferencia Internacional llevada a cabo en el 2011 en la Universidad Pompeu Fabra en Barcelona, la cual estuvo fundada en la reflexión sobre el Estado como problema y objeto de estudio desde una perspectiva histórica. ...
Zeitgenossen und Nachfolger Wagners griffen die von ihm selbst akzeptierte Inszenierungsstrategie als nationaler Kulturheros auf. Wagners "außerordentliche Verflechtung mit der deutschen Geschichte" war von ihm selbst beabsichtigt und vom Ehrgeiz bestimmt, "mit seinem Werk an der Nationwerdung der Deutschen im 19. Jahrhundert mitzuwirken. Dies ist ihm in einem Ausmaß gelungen, wie es bei keiner anderen Gestalt der deutschen Kulturgeschichte seit Luther festzustellen ist." Das Wagnersche Werk wie seine Selbstinszenierungen wurzeln sowohl in der europäischen Moderne als auch im spezifisch deutschen kulturell-politischen Kontext des 19. und frühen 20. Jahrhunderts. Beide Bereiche verraten allerdings eine gewisse interne Brüchigkeit, wie sie schon Adorno als Wagners Grundmerkmal diagnostiziert hatte. Er konstatierte eine den Wagnerschen künstlerisch-theatralischen und politisch-selbstrepräsentativen Gesten inhärente Tendenz zur Selbstde(kon)struktion. Nachfolgend wird diese Brüchigkeit analysiert, die sich in die Produktionsbedingungen seiner als heroische Kulturtaten konstruierten Werke eingeschrieben hat.
Obwohl mit dem "Personenkult" um Josef Stalin (1878−1953) vor allem die Inszenierungen seiner Macht und sein Führungsstil bezeichnet werden, ging der Kult um seine Person über den Rahmen des Politischen hinaus: Stalin wurde mit der Zeit zunehmend zu einer kulturstiftenden Figur, ja gar zu einem kulturellen Symbol stilisiert, das eine ganze Epoche prägte. Wenn überhaupt von einem "Gesamtkunstwerk Stalin" (Boris Groys) die Rede sein kann, dann bezeichnet dieser Begriff gleichermaßen die Epoche Stalins wie ihren Hauptprotagonisten, dessen Selbstinszenierungen als ein Kulturphänomen, ein 'Kunstwerk' der Zeit betrachtet werden können. In diesem "Gesamtkunstwerk" erscheint er sowohl als ein demiurgischer Herrscher als auch als ein prometheischer Heros - als Befreier und Kulturstifter. Der "Führer", der die sowjetischen Völker zum Siege führt, ist zugleich der "Lehrer", der lehrt was richtig und was falsch ist. [...] Er ist eine Figur der Revolution, berufen, sein Land aus dem Chaos zu führen und eine neue Ordnung herzustellen. Diese neue Ordnung reicht über das Machtpolitische hinaus ins Kulturelle: Der revolutionäre Heros ist ein Kulturstifter, dessen Mission eine prometheische Tat, und zwar die Erschaffung eines neuen Menschen ist. Die Herrscher, die als Kulturheroen inszeniert werden, sind vor allem nationale Heroen und werden mit einer Nation identifiziert, die sie vertreten. Im Falle Stalins ist dieses Modell komplizierter, denn er steht an der Spitze des Vielvölkerstaates, der sich als eine "Völkerfamilie" darstellt. Daher muss er als Heros für alle Völker der UdSSR gleichermaßen gelten. Zugleich ist er aber ein Georgier und diese Tatsache beschert seinem Geburtsland eine symbolische Sonderstellung, sie verleiht Stalin als kulturheroischer Figur gewissermaßen zwei Gesichter: das allgemeinsowjetische und das national-georgische.
Exposure to community violence through witnessing or being directly victimized has been associated with conduct problems in a range of studies. However, the relationship between community violence exposure (CVE) and conduct problems has never been studied separately in healthy individuals and individuals with conduct disorder (CD). Therefore, it is not clear whether the association between CVE and conduct problems is due to confounding factors, because those with high conduct problems also tend to live in more violent neighborhoods, i.e., an ecological fallacy. Hence, the aim of the present study was: (1) to investigate whether the association between recent CVE and current conduct problems holds true for healthy controls as well as adolescents with a diagnosis of CD; (2) to examine whether the association is stable in both groups when including effects of aggression subtypes (proactive/reactive aggression), age, gender, site and socioeconomic status (SES); and (3) to test whether proactive or reactive aggression mediate the link between CVE and conduct problems. Data from 1178 children and adolescents (62% female; 44% CD) aged between 9 years and 18 years from seven European countries were analyzed. Conduct problems were assessed using the Kiddie-Schedule of Affective Disorders and Schizophrenia diagnostic interview. Information about CVE and aggression subtypes was obtained using self-report questionnaires (Social and Health Assessment and Reactive-Proactive aggression Questionnaire (RPQ), respectively). The association between witnessing community violence and conduct problems was significant in both groups (adolescents with CD and healthy controls). The association was also stable after examining the mediating effects of aggression subtypes while including moderating effects of age, gender and SES and controlling for effects of site in both groups. There were no clear differences between the groups in the strength of the association between witnessing violence and conduct problems. However, we found evidence for a ceiling effect, i.e., individuals with very high levels of conduct problems could not show a further increase if exposed to CVE and vice versa. Results indicate that there was no evidence for an ecological fallacy being the primary cause of the association, i.e., CVE must be considered a valid risk factor in the etiology of CD.
Callous-unemotional traits are characterized by a lack of empathy, a disregard for others' feelings and shallow or deficient affect, such as a lack of remorse or guilt. Neuroanatomical correlates of callous-unemotional traits have been demonstrated in clinical samples (i.e., adolescents with disruptive behavior disorders). However, it is unknown whether callous-unemotional traits are associated with neuroanatomical correlates within normative populations without clinical levels of aggression or antisocial behavior. Here we investigated the relationship between callous-unemotional traits and gray matter volume using voxel-based morphometry in a large sample of typically-developing boys and girls (N = 189). Whole-brain multiple regression analyses controlling for site, total intracranial volume, and age were conducted in the whole sample and in boys and girls individually. Results revealed that sex and callous-unemotional traits interacted to predict gray matter volume when considering the whole sample. This interaction was driven by a significant positive correlation between callous-unemotional traits and bilateral anterior insula volume in boys, but not girls. Insula gray matter volume explained 19% of the variance in callous-unemotional traits for boys. Our results demonstrate that callous-unemotional traits are related to variations in brain structure beyond psychiatric samples. This association was observed for boys only, underlining the importance of considering sex as a factor in future research designs. Future longitudinal studies should determine whether these findings hold over childhood and adolescence, and whether the neuroanatomical correlates of callous-unemotional traits are predictive of future psychiatric vulnerability.
The release of RNA-containing extracellular vesicles (EV) into the extracellular milieu has been demonstrated in a multitude of different in vitro cell systems and in a variety of body fluids. RNA-containing EV are in the limelight for their capacity to communicate genetically encoded messages to other cells, their suitability as candidate biomarkers for diseases, and their use as therapeutic agents. Although EV-RNA has attracted enormous interest from basic researchers, clinicians, and industry, we currently have limited knowledge on which mechanisms drive and regulate RNA incorporation into EV and on how RNA-encoded messages affect signalling processes in EV-targeted cells. Moreover, EV-RNA research faces various technical challenges, such as standardisation of EV isolation methods, optimisation of methodologies to isolate and characterise minute quantities of RNA found in EV, and development of approaches to demonstrate functional transfer of EV-RNA in vivo. These topics were discussed at the 2015 EV-RNA workshop of the International Society for Extracellular Vesicles. This position paper was written by the participants of the workshop not only to give an overview of the current state of knowledge in the field, but also to clarify that our incomplete knowledge – of the nature of EV(-RNA)s and of how to effectively and reliably study them – currently prohibits the implementation of gold standards in EV-RNA research. In addition, this paper creates awareness of possibilities and limitations of currently used strategies to investigate EV-RNA and calls for caution in interpretation of the obtained data.
Androgen receptor deregulation drives bromodomain-mediated chromatin alterations in prostate cancer
(2017)
Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10) for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in selected patients in which BRD-mediated TF binding is enhanced or modified as cancer progresses.
Serine/arginine-protein kinase 1 (SRPK1) regulates alternative splicing of VEGF-A to pro-angiogenic isoforms and SRPK1 inhibition can restore the balance of pro/antiangiogenic isoforms to normal physiological levels. The lack of potency and selectivity of available compounds has limited development of SRPK1 inhibitors, with the control of alternative splicing by splicing factor-specific kinases yet to be translated. We present here compounds that occupy a binding pocket created by the unique helical insert of SRPK1, and trigger a backbone flip in the hinge region, that results in potent (<10 nM) and selective inhibition of SRPK1 kinase activity. Treatment with these inhibitors inhibited SRPK1 activity and phosphorylation of serine/arginine splicing factor 1 (SRSF1), resulting in alternative splicing of VEGF-A from pro-angiogenic to antiangiogenic isoforms. This property resulted in potent inhibition of blood vessel growth in models of choroidal angiogenesis in vivo. This work identifies tool compounds for splice isoform selective targeting of pro-angiogenic VEGF, which may lead to new therapeutic strategies for a diversity of diseases where dysfunctional splicing drives disease development.
NEK family kinases are serine/threonine kinases that have been functionally implicated in the regulation of the disjunction of the centrosome, the assembly of the mitotic spindle, the function of the primary cilium and the DNA damage response. NEK1 shows pleiotropic functions and has been found to be mutated in cancer cells, ciliopathies such as the polycystic kidney disease, as well as in the genetic diseases short-rib thoracic dysplasia, Mohr-syndrome and amyotrophic lateral sclerosis. NEK1 is essential for the ionizing radiation DNA damage response and priming of the ATR kinase and of Rad54 through phosphorylation. Here we report on the structure of the kinase domain of human NEK1 in its apo- and ATP-mimetic inhibitor bound forms. The inhibitor bound structure may allow the design of NEK specific chemo-sensitizing agents to act in conjunction with chemo- or radiation therapy of cancer cells. Furthermore, we characterized the dynamic protein interactome of NEK1 after DNA damage challenge with cisplatin. Our data suggest that NEK1 and its interaction partners trigger the DNA damage pathways responsible for correcting DNA crosslinks.
Two missense mutations of the DYRK1B gene have recently been found to co-segregate with a rare autosomal-dominant form of metabolic syndrome. This gene encodes a member of the DYRK family of protein kinases, which depend on tyrosine autophosphorylation to acquire the catalytically active conformation. The mutations (H90P and R102C) affect a structural element named DYRK homology (DH) box and did not directly interfere with the conformation of the catalytic domain in a structural model of DYRK1B. Cellular assays showed that the mutations did not alter the specific activity of mature kinase molecules. However, a significant part of the mutant DYRK1B protein accumulated in detergent-insoluble cytoplasmic aggregates and was underphosphorylated on tyrosine. The mutant DYRK1B variants were more vulnerable to the HSP90 inhibitor ganetespib and showed enhanced binding to the co-chaperone CDC37 as compared to wild type DYRK1B. These results support the hypothesis that the mutations in the DH box interfere with the maturation of DYRK1B by tyrosine autophosphorylation and compromise the conformational stability of the catalytic domain, which renders the kinase susceptible to misfolding.
Most molecular cancer therapies act on protein targets but data on the proteome status of patients and cellular models for proteome‐guided pre‐clinical drug sensitivity studies are only beginning to emerge. Here, we profiled the proteomes of 65 colorectal cancer (CRC) cell lines to a depth of > 10,000 proteins using mass spectrometry. Integration with proteomes of 90 CRC patients and matched transcriptomics data defined integrated CRC subtypes, highlighting cell lines representative of each tumour subtype. Modelling the responses of 52 CRC cell lines to 577 drugs as a function of proteome profiles enabled predicting drug sensitivity for cell lines and patients. Among many novel associations, MERTK was identified as a predictive marker for resistance towards MEK1/2 inhibitors and immunohistochemistry of 1,074 CRC tumours confirmed MERTK as a prognostic survival marker. We provide the proteomic and pharmacological data as a resource to the community to, for example, facilitate the design of innovative prospective clinical trials.
In search for new natural products, which may lead to the development of new drugs for all kind of applications, novel methods are needed. Here we describe the identification of electrophilic natural products in crude extracts via their reactivity against azide as a nucleophile followed by their subsequent enrichment using a cleavable azide-reactive resin (CARR). Using this approach, natural products carrying epoxides and α,β-unsaturated enones as well as several unknown compounds were identified in crude extracts from entomopathogenic Photorhabdus bacteria.