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We present a measurement of azimuthal correlations between inclusive J/ψ and charged hadrons in p–Pb collisions recorded with the ALICE detector at the CERN LHC. The J/ψ are reconstructed at forward (p-going, 2.03<y<3.53) and backward (Pb-going, −4.46<y<−2.96) rapidity via their μ+μ− decay channel, while the charged hadrons are reconstructed at mid-rapidity (|η|<1.8). The correlations are expressed in terms of associated charged-hadron yields per J/ψ trigger. A rapidity gap of at least 1.5 units is required between the trigger J/ψ and the associated charged hadrons. Possible correlations due to collective effects are assessed by subtracting the associated per-trigger yields in the low-multiplicity collisions from those in the high-multiplicity collisions. After the subtraction, we observe a strong indication of remaining symmetric structures at Δφ≈0 and Δφ≈π, similar to those previously found in two-particle correlations at middle and forward rapidity. The corresponding second-order Fourier coefficient (v2) in the transverse momentum interval between 3 and 6 GeV/c is found to be positive with a significance of about 5σ. The obtained results are similar to the J/ψ v2 coefficients measured in Pb–Pb collisions at sNN=5.02 TeV, suggesting a common mechanism at the origin of the J/ψ v2.
Macrophages in the tumor microenvironment respond to complex cytokine signals. How these responses shape the phenotype of tumor-associated macrophages (TAMs) is incompletely understood. Here we explored how cytokines of the tumor milieu, interleukin (IL)-6 and IL-4, interact to influence target gene expression in primary human monocyte-derived macrophages (hMDMs). We show that dual stimulation with IL-4 and IL-6 synergistically modified gene expression. Among the synergistically induced genes are several targets with known pro-tumorigenic properties, such as CC-chemokine ligand 18 (CCL18), transforming growth factor alpha (TGFA) or CD274 (programmed cell death 1 ligand 1 (PD-L1)). We found that transcription factors of the signal transducer and activator of transcription (STAT) family, STAT3 and STAT6 bind regulatory regions of synergistically induced genes in close vicinity. STAT3 and STAT6 co-binding further induces the basic leucine zipper ATF-like transcription factor (BATF), which participates in synergistic induction of target gene expression. Functional analyses revealed increased MCF-7 and MDA-MB 231 tumor cell motility in response to conditioned media from co-treated hMDMs compared to cells incubated with media from single cytokine-treated hMDMs. Flow cytometric analysis of T cell populations upon co-culture with hMDMs polarized by different cytokines indicated that dual stimulation promoted immunosuppressive properties of hMDMs in a PD-L1-dependent manner. Analysis of clinical data revealed increased expression of BATF together with TAM markers in tumor stroma of breast cancer patients as compared to normal breast tissue stroma. Collectively, our findings suggest that IL-4 and IL-6 cooperate to alter the human macrophage transcriptome, endowing hMDMs with pro-tumorigenic properties.
We investigate the properties of QCD at finite isospin chemical potential at zero and non-zero temperatures. This theory is not affected by the sign problem and can be simulated using Monte-Carlo techniques. With increasing isospin chemical potential and temperatures below the deconfinement transition the system changes into a phase where charged pions condense, accompanied by an accumulation of low modes of the Dirac operator. The simulations are enabled by the introduction of a pionic source into the action, acting as an infrared regulator for the theory, and physical results are obtained by removing the regulator via an extrapolation. We present an update of our study concerning the associated phase diagram using 2+1 flavours of staggered fermions with physical quark masses and the comparison to Taylor expansion. We also present first results for our determination of the equation of state at finite isospin chemical potential and give an example for a cosmological application. The results can also be used to gain information about QCD at small baryon chemical potentials using reweighting with respect to the pionic source parameter and the chemical potential and we present first steps in this direction.
We will discuss the issue of Landau levels of quarks in lattice QCD in an external magnetic field. We will show that in the two-dimensional case the lowest Landau level can be identified unambiguously even if the strong interactions are turned on. Starting from this observation, we will then show how one can define a “plowest Landau level” in the four-dimensional case, and discuss how much of the observed effects of a magnetic field can be explained in terms of it. Our results can be used to test the validity of low-energy models of QCD that make use of the lowest-Landau-level approximation.
Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families as well as 438 subjects from an independent, sporadic BD case-control cohort were analysed. Polygenic risk scores (PRS) for BD, schizophrenia, and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had significantly higher PRS for all three psychiatric disorders than the independent controls, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and sporadic BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses, therefore, demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. The PRS explained only part of the observed phenotypic variance and rare variants might have also contributed to disease development.
The authors argue, in line with recent research, that operationalizing gender ideology as a unidimensional construct ranging from traditional to egalitarian is problematic and propose an alternative framework that takes the multidimensionality of gender ideologies into account. Using latent class analysis, they operationalize their gender ideology framework based on data from the 2008 European Values Study, of which eight European countries reflecting the spectrum of current work–family policies were selected. The authors examine the form in which gender ideologies cluster in the various countries. Five ideology profiles were identified: egalitarian, egalitarian essentialism, intensive parenting, moderate traditional, and traditional. The five ideology profiles were found in all countries, but with pronounced variation in size. Ideologies mixing gender essentialist and egalitarian views appear to have replaced traditional ideologies, even in countries offering some institutional support for gendered separate spheres.
Inhibitory interneurons govern virtually all computations in neocortical circuits and are in turn controlled by neuromodulation. While a detailed understanding of the distinct marker expression, physiology, and neuromodulator responses of different interneuron types exists for rodents and recent studies have highlighted the role of specific interneurons in converting rapid neuromodulatory signals into altered sensory processing during locomotion, attention, and associative learning, it remains little understood whether similar mechanisms exist in human neocortex. Here, we use whole-cell recordings combined with agonist application, transgenic mouse lines, in situ hybridization, and unbiased clustering to directly determine these features in human layer 1 interneurons (L1-INs). Our results indicate pronounced nicotinic recruitment of all L1-INs, whereas only a small subset co-expresses the ionotropic HTR3 receptor. In addition to human specializations, we observe two comparable physiologically and genetically distinct L1-IN types in both species, together indicating conserved rapid neuromodulation of human neocortical circuits through layer 1.
Accurate spectroscopy of highly-charged high-Z ions in a storage ring is demonstrated to be feasible by the use of specially adapted crystal optics. The method has been applied for the measurement of the 1s Lamb shift in hydrogen-like gold (Au+78) in a storage ring through spectroscopy of the Lyman x-rays. This measurement represents the first result obtained for a high-Z element using high-resolution wavelength-dispersive spectroscopy in the hard x-ray regime, paving the way for sensitivity to higher- order QED effects.
The German Cancer Consortium ('Deutsches Konsortium für Translationale Krebsforschung', DKTK) is a long-term cancer consortium, bringing together the German Cancer Research Center (DKFZ), Germany's largest life science research center, and the leading University Medical Center-based Comprehensive Cancer Centers (CCCs) at seven sites across Germany. DKTK was founded in 2012 following international peer review and has positioned itself since then as the leading network for translational cancer research in Germany. DKTK is long term funded by the German Ministry of Research and Education and the federal states of each DKTK partner site. DKTK acts at the interface between basic and clinical cancer research, one major focus being to generate suitable multisite cooperation structures and provide the basis for including higher numbers of patients and facilitate effective collaborative forward and reverse translational cancer research. The consortium addresses areas of high scientific and medical relevance and develops critical infrastructures, for example, for omics technologies, clinical and research big data exchange and analysis, imaging, and clinical grade drug manufacturing. Moreover, DKTK provides a very attractive environment for interdisciplinary and interinstitutional training and career development for clinician and medical scientists.
Hepatitis C virus (HCV) infection is associated with alterations in host lipid and insulin signaling cascades, which are partially explained by a dependence of the HCV life cycle on key molecules in these metabolic pathways. Yet, little is known on the role in the HCV life cycle of glycogen synthase kinase 3 (GSK3), one of the most important kinases in cellular metabolism. Therefore, the impact of GSK3 on the HCV life cycle was assessed in human hepatoma cell lines harboring subgenomic genotype 1b and 2a replicons or producing cell culture-derived HCV genotype 2a by exposure to synthetic GSK3 inhibitors, GSK3 gene silencing, overexpression of GSK3 constructs and immunofluorescence analyses. In addition, the role of GSK3 in hepatitis E virus (HEV) replication was investigated to assess virus specificity of the observed findings. We found that both inhibition of GSK3 function by synthetic inhibitors as well as silencing of GSK3β gene expression resulted in a decrease of HCV replication and infectious particle production, whereas silencing of the GSK3α isoform had no relevant effect on the HCV life cycle. Conversely, overexpression of GSK3β resulted in enhanced HCV replication. In contrast, GSK3β had no effect on replication of subgenomic HEV replicon. The pro-viral effect of GSK3β on HCV replication was mediated by supporting expression of microRNA-122 (miR-122), a micro-RNA which is mandatory for wild-type HCV replication, as GSK3 inhibitors suppressed miR-122 levels and as inhibitors of GSK3 had no antiviral effect on a miR-122-independent HCV mutant. In conclusion, we have identified GSK3β is a novel host factor supporting HCV replication by maintaining high levels of hepatic miR-122 expression.
Regulation of protein turnover allows cells to react to their environment and maintain homeostasis. Proteins can show different turnover rates in different tissue, but little is known about protein turnover in different brain cell types. We used dynamic SILAC to determine half-lives of over 5100 proteins in rat primary hippocampal cultures as well as in neuron-enriched and glia-enriched cultures ranging from <1 to >20 days. In contrast to synaptic proteins, membrane proteins were relatively shorter-lived and mitochondrial proteins were longer-lived compared to the population. Half-lives also correlate with protein functions and the dynamics of the complexes they are incorporated in. Proteins in glia possessed shorter half-lives than the same proteins in neurons. The presence of glia sped up or slowed down the turnover of neuronal proteins. Our results demonstrate that both the cell-type of origin as well as the nature of the extracellular environment have potent influences on protein turnover.
Nein, Langeweile kommt bei Franck Collard nicht auf, ist er doch Historiker des Gifts und der Leidenschaft. Seit seinem Werk "Le crime de poison au Moyen Âge" greift er immer wieder das Problem des Einsatzes von Gift in der Welt des Spätmittelalters, vor allem im 15. Jahrhundert, auf; einem Saeculum, in dessen erster Hälfte – zumal in einem im Innern zerrissenen und vom Hundertjährigen Krieg heimgesuchten Frankreich – ebenso das Thema der "passions" eine zentrale Rolle spielt, dem er bereits 2015 die Studie "Politique des passions et anthropologie des pulsions à la cour de Charles VII" widmete . Eine Annäherung an Jeanne d’Arc unter solches Vorzeichen zu stellen lag nahe, einmal aufgrund besagter "passions au sens de déchirements" im Königreich, sodann angesichts von Johannas "passion au sens d’exaltation affective et d’amour extrême" wie auch – mit Blick auf ihren Prozess und Tod in Rouen – wegen ihrer "passion … au sens de souffrance sacrificielle" (S. 11). ...
Background: Concomitant radiation with BRAF inhibitor (BRAFi) therapy may increase radiation-induced side effects but also potentially improve tumour control in melanoma patients.
Methods: A total of 155 patients with BRAF-mutated melanoma from 17 European skin cancer centres were retrospectively analysed. Out of these, 87 patients received concomitant radiotherapy and BRAFi (59 vemurafenib, 28 dabrafenib), while in 68 patients BRAFi therapy was interrupted during radiation (51 vemurafenib, 17 dabrafenib). Overall survival was calculated from the first radiation (OSRT) and from start of BRAFi therapy (OSBRAFi).
Results: The median duration of BRAFi treatment interruption prior to radiotherapy was 4 days and lasted for 17 days. Median OSRT and OSBRAFi in the entire cohort were 9.8 and 12.6 months in the interrupted group and 7.3 and 11.5 months in the concomitant group (P=0.075/P=0.217), respectively. Interrupted vemurafenib treatment with a median OSRT and OSBRAFi of 10.1 and 13.1 months, respectively, was superior to concomitant vemurafenib treatment with a median OSRT and OSBRAFi of 6.6 and 10.9 months (P=0.004/P=0.067). Interrupted dabrafenib treatment with a median OSRT and OSBRAFi of 7.7 and 9.8 months, respectively, did not differ from concomitant dabrafenib treatment with a median OSRT and OSBRAFi of 9.9 and 11.6 months (P=0.132/P=0.404). Median local control of the irradiated area did not differ in the interrupted and concomitant BRAFi treatment groups (P=0.619). Skin toxicity of grade ≥2 (CTCAE) was significantly increased in patients with concomitant vemurafenib compared to the group with treatment interruption (P=0.002).
Conclusions: Interruption of vemurafenib treatment during radiation was associated with better survival and less toxicity compared to concomitant treatment. Due to lower number of patients, the relevance of treatment interruption in dabrafenib treated patients should be further investigated. The results of this analysis indicate that treatment with the BRAFi vemurafenib should be interrupted during radiotherapy. Prospective studies are desperately needed.
Ultrasonic guided waves have been used successfully in structural health monitoring systems to detect damage in isotropic and composite materials with simple and complex geometry. A limitation of current research is given by a lack of freely available benchmark measurements to comparatively evaluate existing methods. This article introduces the extendable online platform Open Guided Waves (http://www.open-guided-waves.de) where high-quality and well-documented datasets for guided wave-based inspections are provided. In this article, we describe quasi-isotropic carbon-fiber-reinforced polymer plates with embedded piezoelectric transducers as a first benchmark structure. Intentionally, this is a structure of medium complexity to enable many researchers to apply their methods. In a first step, ultrasound and X-ray measurements were acquired to verify pristine conditions. Next, mechanical testing was done to determine the stiffness tensor and sample density based on standard test procedures. Guided wave measurements were divided into two parts: first, acoustic wave fields were acquired for a broad range of frequencies by three-dimensional scanning laser Doppler vibrometry. Second, structural health monitoring measurements in the carbon-fiber-reinforced polymer plate were collected at constant temperature using a distributed transducer network and a surface-mounted reversible defect model. Initial results serving as validation are presented and discussed.
Carbon-fiber-reinforced plastics are widely used in lightweight marine structures due to their high strength and superior fatigue behavior. In this article, we will present an innovative methodology for simultaneous load and structural monitoring of a carbon-fiber-reinforced plastic rudder stock as part of a big commercial vessel. Experimental results are presented here from a quasi-static tensile test in which the load monitoring is performed using embedded strain sensors. Structural monitoring is based on high-frequency electromechanical impedance spectroscopy combined with dedicated signal processing and surface-mounted piezoelectric transducers. We have achieved the following results: (1) the demonstration of a hybrid monitoring system including load and structural monitoring, (2) successful embedding of strain gauges during composite manufacturing of the carbon-fiber-reinforced plastic rudder stock, (3) development of instrumentation hardware for multichannel electromechanical impedance measurements, and (4) successful damage detection by means of electromechanical impedance spectroscopy in thick carbon-fiber-reinforced plastic rudder stock samples exploiting strain data.
Hemispherical and cylindrical antenna arrays are widely used in radar-based and tomography-based microwave breast imaging systems. Based on the dielectric contrast between healthy and malignant tissue, a three-dimensional image could be formed to locate the tumor. However, conventional X-ray mammography as the golden standard in breast cancer screening produces two-dimensional breast images so that a comparison between the 3D microwave image and the 2D mammogram could be difficult. In this paper, we present the design and realisation of a UWB breast imaging prototype for the frequency band from 1 to 9 GHz. We present a refined system design in light of the clinical usage by means of a planar scanning and compare microwave images with those obtained by X-ray mammography. Microwave transmission measurements were processed to create a two-dimensional image of the breast that can be compared directly with a two-dimensional mammogram. Preliminary results from a patient study are presented and discussed showing the ability of the proposed system to locate the tumor.
Der Beitrag erkundet die besondere Zeitlichkeit der Psychoanalyse ausgehend von Muße und Müßiggang, Konzepten, die in Nietzsches "Fröhlicher Wissenschaft" eine wichtige Rolle spielen, in Freuds Werk, in dem bekanntlich zahlreiche Arbeitsbegriffe dominieren, jedoch kaum vorkommen. Dennoch lässt sich im Briefwechsel zwischen Freud und Arnold Zweig eine wichtige Spur des Müßiggangs für Freuds eigenes Schreiben aufzeigen. Freud spricht in einer signifikanten Passage, in der es um die existenzielle Bedrohung durch den Nationalsozialismus geht, von einem "Überschuss an Muße". Aus dieser Suspension heraus entsteht sein letztes großes Schreibprojekt: "Der Mann Moses". Muße erweist sich zunehmend als ein Begriff, in dem sich eine andere Zeitlichkeit eröffnet, die etwas mit der Arbeit des Unbewussten in der Psychoanalyse zu tun hat. Der Beitrag schließt, indem die Autorin ihre persönliche Erfahrung dieser anderen Zeitlichkeit schildert. Dabei gerät der Warteraum des Psychoanalytikers als Schwellenraum zwischen der alltäglichen Arbeit und der Arbeit in der Psychoanalyse in den Blick.