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The Δ-isobar degrees of freedom are included in the covariant density functional (CDF) theory to study the equation of state (EoS) and composition of dense matter in compact stars. In addition to Δ's we include the full octet of baryons, which allows us to study the interplay between the onset of delta isobars and hyperonic degrees of freedom. Using both the Hartree and Hartree–Fock approximation we find that Δ's appear already at densities slightly above the saturation density of nuclear matter for a wide range of the meson–Δ coupling constants. This delays the appearance of hyperons and significantly affects the gross properties of compact stars. Specifically, Δ's soften the EoS at low densities but stiffen it at high densities. This softening reduces the radius of a canonical 1.4M⊙ star by up to 2 km for a reasonably attractive Δ potential in matter, while the stiffening results in larger maximum masses of compact stars. We conclude that the hypernuclear CDF parametrizations that satisfy the 2M⊙ maximum mass constraint remain valid when Δ isobars are included, with the important consequence that the resulting stellar radii are shifted toward lower values, which is in agreement with the analysis of neutron star radii.
Exposure to locusts, which belong to the arthropod phylum, is an underestimated health problem, especially among workers in research facilities exposed to laboratory animals. We describe a rare case of an occupational immediate-type reaction to locusts with a possible cross-reactivity between desert locust (Schistocerca gregaria) and migratory locust (Locusta migratoria).
Relevance of the natural HDAC inhibitor sulforaphane as a chemopreventive agent in urologic tumors
(2018)
Due to an increased understanding of molecular biology and the genomics of cancer, new and potent agents have been approved by the Food and Drug Administration (FDA) to fight this disease. However, all of these drugs cause severe side effects and resistance inevitably develops, re-activating tumor growth and dissemination. For this reason, patients turn to natural compounds as alternative or complementary treatment options, since it has been found that natural plant products may block, inhibit, or reverse cancer development. The present review focusses on the role of the natural compound sulforaphane (SFN) as an anti-tumor agent in urologic cancer. SFN is a natural compound found in cruciferous vegetables from the Brassicaceae family such as broccoli, cauliflower and cabbage. Several epidemiologic and clinical studies have documented chemopreventive properties of SFN, making it an interesting candidate for additive cancer treatment. SFN shows remarkable anti-tumor effects in vitro and in vivo without exerting toxicity. The review summarizes the current understanding of SFN and provides insights into its molecular mode of action with particular emphasis on epigenetic tumor control.
Cancer is the leading cause of death worldwide after cardiovascular diseases. This has been the case for the last few decades despite there being an increase in the number of cancer treatments. One reason for the apparent lack of drug effectiveness might be, at least in part, due to unspecificity for tumors; which often leads to substantial side effects. One way to improve the treatment of cancer is to increase the specificity of the treatment in accordance with the concept of individualized medicine. This will help to prevent further progression of an existing cancer or even to reduce the tumor burden. Alternatively it would be much more attractive and efficient to prevent the development of cancer in the first place. Therefore, it is important to understand the risk factors and the mechanisms of carcinogenesis in detail. One such risk factor, often associated with tumorigenesis and tumor progression, is an increased abundance of reactive oxygen species (ROS) arising from an imbalance of ROS-producing and -eliminating components. A surplus of ROS can induce oxidative damage of macromolecules including proteins, lipids and DNA. In contrast, ROS are essential for an adequate signal transduction and are known to regulate crucial cellular processes like cellular quiescence, differentiation and even apoptosis. Therefore, regulated ROS-formation at physiological levels can inhibit tumor formation and progression. With this review we provide an overview on the current knowledge of redox control in cancer development and progression.
Prenatal and postnatal experiences associated with epigenetic changes in the adult mouse brain
(2018)
To analyze the influences of early-life history on the brain epigenome, the offspring of mouse dams kept in an enriched or standard environment were exposed postnatally to enriched, standard, or adverse conditions. The methylation patterns of 7 candidate genes (9 loci) involved in developmental programming of stress vulnerability/resilience and psychiatric disease were analyzed in 6 brain regions of adult male and female mice. Exposure to an enriched prenatal environment was associated with widespread epigenetic changes (all of small effect size), affecting 29 of 324 (9%) gene/region-specific methylation patterns. The effects of either adverse or enriched postnatal conditions were tested separately in the two prenatal cohorts. Significant changes were observed in 2 of 324 (0.6%) loci in offspring of dams in a standard environment and 6 of 324 (1.9%) loci in animals that were exposed prenatally to an enriched environment. Prenatal life experiences appear to have a bigger effect on the adult brain epigenome than postnatal experiences. Positive prenatal life experiences may increase epigenetic plasticity of the brain later in life. All observed between-group differences were sex-specific, consistent with largely different developmental trajectories of the male and female brain. Multiple changes of small effect size are consistent with a multifactorial model of developmental programming of adult behavior and disease susceptibility.
Delayed-onset muscle soreness (DOMS) is a common symptom in people participating in exercise, sport, or recreational physical activities. Several remedies have been proposed to prevent and alleviate DOMS. In 2008 and 2015, two studies have been conducted to investigate the effects of acupuncture on symptoms and muscle function in eccentric exercise-induced DOMS of the biceps brachii muscle. In 2008 a prospective, randomized, controlled, observer and subject-blinded trial was undertaken with 22 healthy subjects (22–30 years; 12 females) being randomly assigned to three treatment groups: real acupuncture (deep needling at classic acupuncture points and tender points; n = 7), sham-acupuncture (superficial needling at non-acupuncture points; n = 8), and control (n = 7). In 2015, a five-arm randomized controlled study was conducted with 60 subjects (22 females, 23.6 ± 2.8 years). Participants were randomly allocated to needle, laser, sham needle, sham laser acupuncture, and no intervention.
In both cases treatment was applied immediately, 24 and 48 hours after DOMS induction.
The outcome measures included pain perception (visual analogue scale; VAS), mechanical pain threshold (MPT), maximum isometric voluntary force (MIVF) and pressure pain threshold (PPT).
Results: In 2008, following nonparametric testing, there were no significant differences between groups in outcome measures at baseline. After 72 hours, pain perception (VAS) was significantly lower in the acupuncture group compared to the sham acupuncture and control subjects. However, the mean MPT and MIVF scores were not significantly different between groups. This lead to the conclusion, that acupuncture seemed to have no effects on MPT and muscle function, but reduced perceived pain arising from exercise-induced DOMS.
The more recent results from 2015 indicated that neither verum nor sham interventions significantly improved outcomes within 72 hours when compared with the no treatment control (P > 0.05).
The enzyme acetyl-CoA carboxylase (ACC) plays a crucial role in fatty acid metabolism. In recent years, ACC has been recognized as a promising drug target for treating different diseases. However, the role of ACC in vascular endothelial cells (ECs) has been neglected so far. To characterize the role of ACC, we used the ACC inhibitor, soraphen A, as a chemical tool, and also a gene silencing approach. We found that ACC1 was the predominant isoform in human umbilical vein ECs as well as in human microvascular ECs and that soraphen A reduced the levels of malonyl-CoA. We revealed that ACC inhibition shifted the lipid composition of EC membranes. Accordingly, membrane fluidity, filopodia formation, and migratory capacity were reduced. The antimigratory action of soraphen A depended on an increase in the cellular proportion of PUFAs and, most importantly, on a decreased level of phosphatidylglycerol. Our study provides a causal link between ACC, membrane lipid composition, and cell migration in ECs. Soraphen A represents a useful chemical tool to investigate the role of fatty acid metabolism in ECs and ACC inhibition offers a new and valuable therapeutic perspective for the treatment of EC migration-related diseases.
Introduction: Ferroptosis has recently been identified as a form of programmed cell death caused by an accumulation of lipid reactive oxygen species (ROS). However, little is yet known about the role in hepatocellular carcinoma (HCC) and its signalling mechanism as well the modulation of ROS.
Material and methods: Human HCC cell lines were treated with different concentrations of ROS modulators (Auranofin, Erastin, BSO). Cell death was determined by analysis of PI-stained nuclei using flow cytometry. ROS production and lipid peroxidation were analysed at early time points before cell death starts. For mechanistic studies we performed Western Blot and a Proteome array. Different inhibitors of cell death target proteins, ROS-scavengers as well as lipoxygenase inhibitors were used. To investigate the functional relevance of NAPDH oxidases (NOX) 1 and 4 for ROS modulation and ferroptosis we genetically silenced its genes using three distinct siRNAs and we used the NOX1/4-inhibitor GKT137831.
Results and discussions: Compared to the single treatment, Auranofin/BSO-cotreatment as well as Erastin/BSO-cotreatment acted in concert to trigger cell death and to reduce cell viability of HCC cells in a dose- and time-dependent manner. Furthermore, both cotreatments induce ROS production, lipid peroxidation and ferroptotic cell death, which could be inhibited by the use of Ferrostatin-1 (inhibitor of lipid peroxidation) and Liproxstatin-1 (specific inhibitor of ferroptosis). The broad-range caspase inhibitor zVAD.fmk failed to rescue cells from Auranofin/BSO- or Erastin/BSO-cotreatment induced cell death. No activation of caspases-3 could be seen in the proteome profiler apoptosis assay. Importantly, the selective lipoxygenase (LOX) inhibitor Baicalain and the pan-LOX inhibitor NDGA protect HCC cells from Auranofin/BSO- and Erastin/BSO-cotreatment stimulated lipid peroxidation, ROS generation and cell death, indication that the induction of ferroptosis may bypass apoptosis resistance of HCC cells. Mechanistic studies showed that Auranofin/BSO-cotreatment decreased TrxR-activity, led to Nrf2 accumulation and promoted the activation of HO-1. In contrast, NOX 1 and 4 were involved in Erastin/BSO-mediated cell death and the use of the NOX1/4-inhibitor GKT137831 rescued HCC cells from the Erastin/BSO-induced cell death.
Conclusion: By providing new insights into the molecular regulation of ROS and ferroptosis, our study contributes to the development of novel treatment strategies to reactivate programmed cell death in HCC cells.
Der Beitrag beschäftigt sich mit der Typologie und Chronologie einer besonders vielfältigen und bisher schlecht fassbaren Gruppe unter den metallenen Wagenbeschlägen der Urnenfelder- und Hallstattzeit in Südost-, Mittel- und Westeuropa, den Tüllen und Kappen. Neben einem Gesamtüberblick über das entsprechende Fundmaterial werden einzelne Typen detailliert beschrieben, abgebildet und in ihren wechselseitigen Bezügen diskutiert. Deutlich lassen sich auch bei dieser Objektgruppe die engen typologischen Verbindungen zwischen den urnenfelder- und hallstattzeitlichen Wagenbeschlägen darstellen. Die quantitativ wie qualitativ sehr viel bessere Überlieferung der hallstattzeitlichen Wagen legt es nahe, die urnenfelderzeitliche Wagenentwicklung vor allem in der Rückschau zu betrachten. Insbesondere was den einstigen Anbringungsort der metallenen Beschläge am Wagen angeht, ist das Studium gut dokumentierter in situ-Befunde hallstattzeitlicher Wagengräber sehr hilfreich. Hinsichtlich der Tüllen und Kappen sind vielfältige Möglichkeiten der Anbringung festzustellen, die praktisch alle Teile des Wagens von den Achsen über die Zugvorrichtung und den Langbaum bis zum Wagenkasten betreffen. Eine interessante Möglichkeit ist zudem die Deutung einiger schmaler Tüllen als Griffenden von Treibstacheln, deren Existenz bereits in der Bronzezeit verschiedentlich belegbar ist...
Ventriculoperitoneal shunts equipped with a reservoir and a valve to manually switch off the shunt function can be used for intraventricular injections of therapeutics in patients suffering from a communicating hydrocephalus caused by leptomeningeal metastases. These shunt devices avoid the risk of injecting therapeutics through the distal leg of the shunt system into the intraperitoneal space, which may cause toxicity. Furthermore, regular intraventricular injections of chemotherapeutics help to maintain sufficient concentrations in the ventricular space. Therefore, ventriculoperitoneal shunts equipped with an on-off valve are a useful tool to reliably inject chemotherapeutics into the ventricles. In order to systematically assess feasibility, safety, and efficacy of this procedure, we performed a retrospective analysis of all patients with leptomeningeal metastases who had received a shunt system at our institution. In total, six adult patients had a ventriculoperitoneal shunt equipped with an on-off valve implanted. Out of these six patients, two patients subsequently received intraventricular injections of chemotherapeutics. The configuration of the valve setting and the intraventricular injections were easily feasible in the setting of a neuro-oncology department. The complication of a shunt leakage occurred in one patient following the first intraventricular injection. No extra-central nervous system (CNS) toxicities were observed. In summary, ventriculoperitoneal shunts with on-off valves are useful tools for reliable intraventricular administration of therapeutics.
Purpose: Stereotactic radiosurgery (SRS) is an established primary treatment for newly diagnosed brain metastases with high local control rates. However, data about local re-irradiation in case of local failure after SRS (re-SRS) are rare. We evaluated the feasibility, efficacy and patient selection characteristics in treating locally recurrent metastases with a second course of SRS.
Methods: We retrospectively evaluated patients with brain metastases treated with re-SRS for local tumor progression between 2011 and 2017. Patient and treatment characteristics as well as rates of tumor control, survival and toxicity were analyzed.
Results: Overall, 32 locally recurrent brain metastases in 31 patients were irradiated with re-SRS. Median age at re-SRS was 64.9 years. The primary histology was breast cancer and non-small-cellular lung cancer (NSCLC) in respectively 10 cases (31.3%), in 5 cases malignant melanoma (15.6%). In the first SRS-course 19 metastases (59.4%) and in the re-SRS-course 29 metastases (90.6%) were treated with CyberKnife® and the others with Gamma Knife. Median planning target volume (PTV) for re-SRS was 2.5 cm3 (range, 0.1–37.5 cm3) and median dose prescribed to the PTV was 19 Gy (range, 12–28 Gy) in 1–5 fractions to the median 69% isodose (range, 53–80%). The 1-year overall survival rate was 61.7% and the 1-year local control rate was 79.5%. The overall rate of radiological radio-necrosis was 16.1% and four patients (12.9%) experienced grade ≥ 3 toxicities.
Conclusions: A second course of SRS for locally recurrent brain metastases after prior local SRS appears to be feasible with acceptable toxicity and can be considered as salvage treatment option for selected patients with high performance status. Furthermore, this is the first study utilizing robotic radiosurgery for this indication, as an additional option for frameless fractionated treatment.
Attention-deficit/hyperactivity disorder (ADHD) is highly heritable and the most common neurodevelopmental disorder in childhood. In recent decades, it has been appreciated that in a substantial number of cases the disorder does not remit in puberty, but persists into adulthood. Both in childhood and adulthood, ADHD is characterised by substantial comorbidity including substance use, depression, anxiety, and accidents. However, course and symptoms of the disorder and the comorbidities may fluctuate and change over time, and even age of onset in childhood has recently been questioned. Available evidence to date is poor and largely inconsistent with regard to the predictors of persistence versus remittance. Likewise, the development of comorbid disorders cannot be foreseen early on, hampering preventive measures. These facts call for a lifespan perspective on ADHD from childhood to old age. In this selective review, we summarise current knowledge of the long-term course of ADHD, with an emphasis on clinical symptom and cognitive trajectories, treatment effects over the lifespan, and the development of comorbidities. Also, we summarise current knowledge and important unresolved issues on biological factors underlying different ADHD trajectories. We conclude that a severe lack of knowledge on lifespan aspects in ADHD still exists for nearly every aspect reviewed. We encourage large-scale research efforts to overcome those knowledge gaps through appropriately granular longitudinal studies.
The mechanistic target of the rapamycin (mTOR) inhibitor, temsirolimus, has significantly improved the outcome of patients with renal cell carcinoma (RCC). However, development of temsirolimus-resistance limits its effect and metastatic progression subsequently recurs. Since integrin α7 (ITGA7) is speculated to promote metastasis, this investigation was designed to investigate whether temsirolimus-resistance is associated with altered ITGA7 expression in RCC cell lines and modified tumor cell adhesion and invasion. Caki-1, KTCTL-26, and A498 RCC cell lines were driven to temsirolimus-resistance by exposing them to temsirolimus over a period of 12 months. Subsequently, adhesion to human umbilical vein endothelial cells, to immobilized fibronectin, or collagen was investigated. Chemotaxis was evaluated with a modified Boyden chamber assay and ITGA7 expression by flow cytometry and western blotting. Chemotaxis significantly decreased in temsirolimus-sensitive cell lines upon exposure to low-dosed temsirolimus, but increased in temsirolimus-resistant tumor cells upon reexposure to the same temsirolimus dose. The increase in chemotaxis was accompanied by elevated ITGA7 at the cell surface membrane with simultaneous reduction of intracellular ITGA7. ITGA7 knock-down significantly diminished motility of temsirolimous-sensitive cells but elevated chemotactic activity of temsirolimus-resistant Caki-1 and KTCTL-26 cells. Therefore, ITGA7 appears closely linked to adhesion and migration regulation in RCC cells. It is postulated that temsirolimus-resistance is associated with translocation of ITGA7 from inside the cell to the outer surface. This switch forces RCC migration forward. Whether ITGA7 can serve as an important target in combatting RCC requires further investigation.
The debate on effects of globalization on welfare states is extensive. Often couched in terms of a battle between the compensation and the efficiency thesis, the scholarly literature has provided contradictory arguments and findings. This article contributes to the scholarly debate by exploring in greater detail the micro-level foundations of compensation theory. More specifically, we distinguish between individual policy preferences for compensatory social policies (unemployment insurance) and human capital-focused social investment policies (education) and expect globalization to mainly affect demand for educational investment. A multi-level analysis of ISSP survey data provides empirical support for this hypothesis. This finding provides an important revision and extension of the classical analytical perspective of compensation theory, because it shows that citizens value the social investment function of the welfare state above and beyond simple compensation via social transfers. This might be particularly relevant in today's skill-centered knowledge economies.
Species’ functional traits set the blueprint for pair-wise interactions in ecological networks. Yet, it is unknown to what extent the functional diversity of plant and animal communities controls network assembly along environmental gradients in real-world ecosystems. Here we address this question with a unique dataset of mutualistic bird–fruit, bird–flower and insect–flower interaction networks and associated functional traits of 200 plant and 282 animal species sampled along broad climate and land-use gradients on Mt. Kilimanjaro. We show that plant functional diversity is mainly limited by precipitation, while animal functional diversity is primarily limited by temperature. Furthermore, shifts in plant and animal functional diversity along the elevational gradient control the niche breadth and partitioning of the respective other trophic level. These findings reveal that climatic constraints on the functional diversity of either plants or animals determine the relative importance of bottom-up and top-down control in plant–animal interaction networks.
Knowledge about the biogeographic affinities of the world’s tropical forests helps to better understand regional differences in forest structure, diversity, composition, and dynamics. Such understanding will enable anticipation of region-specific responses to global environmental change. Modern phylogenies, in combination with broad coverage of species inventory data, now allow for global biogeographic analyses that take species evolutionary distance into account. Here we present a classification of the world’s tropical forests based on their phylogenetic similarity. We identify five principal floristic regions and their floristic relationships: (i) Indo-Pacific, (ii) Subtropical, (iii) African, (iv) American, and (v) Dry forests. Our results do not support the traditional neo- versus paleotropical forest division but instead separate the combined American and African forests from their Indo-Pacific counterparts. We also find indications for the existence of a global dry forest region, with representatives in America, Africa, Madagascar, and India. Additionally, a northern-hemisphere Subtropical forest region was identified with representatives in Asia and America, providing support for a link between Asian and American northern-hemisphere forests.
We report measurements of the inclusive J/ψ yield and average transverse momentum as a function of charged-particle pseudorapidity density dNch/dη in p–Pb collisions at √sNN = 5.02 TeV with ALICE at the LHC. The observables are normalised to their corresponding averages in non-single diffractive events. An increase of the normalised J/ψ yield with normalised dNch/dη, measured at mid-rapidity, is observed at mid-rapidity and backward rapidity. At forward rapidity, a saturation of the relative yield is observed for high charged-particle multiplicities. The normalised average transverse momentum at forward and backward rapidities increases with multiplicity at low multiplicities and saturates beyond moderate multiplicities. In addition, the forward-to-backward nuclear modification factor ratio is also reported, showing an increasing suppression of J/ψ production at forward rapidity with respect to backward rapidity for increasing charged-particle multiplicity.
First results on the longitudinal asymmetry and its effect on the pseudorapidity distributions in Pb–Pb collisions at √sNN = 2.76 TeV at the Large Hadron Collider are obtained with the ALICE detector. The longitudinal asymmetry arises because of an unequal number of participating nucleons from the two colliding nuclei, and is estimated for each event by measuring the energy in the forward neutron-ZeroDegree-Calorimeters (ZNs). The effect of the longitudinal asymmetry is measured on the pseudorapidity distributions of charged particles in the regions |η| < 0.9, 2.8 < η < 5.1 and −3.7 < η < −1.7 by taking the ratio of the pseudorapidity distributions from events corresponding to different regions of asymmetry. The coefficients of a polynomial fit to the ratio characterise the effect of the asymmetry. A Monte Carlo simulation using a Glauber model for the colliding nuclei is tuned to reproduce the spectrum in the ZNs and provides a relation between the measurable longitudinal asymmetry and the shift in the rapidity (y0) of the participant zone formed by the unequal number of participating nucleons. The dependence of the coefficient of the linear term in the polynomial expansion, c1, on the mean value of y0 is investigated.
The production of Σ0 baryons in the nuclear reaction p (3.5 GeV) + Nb (corresponding to sNN=3.18 GeV) is studied with the detector set-up HADES at GSI, Darmstadt. Σ0s were identified via the decay Σ0→Λγ with subsequent decays Λ→pπ− in coincidence with a e+e− pair from either external (γ→e+e−) or internal (Dalitz decay γ⁎→e+e−) gamma conversions. The differential Σ0 cross section integrated over the detector acceptance, i.e. the rapidity interval 0.5<y<1.1, has been extracted as ΔσΣ0=2.3±(0.2)stat±(−0.6+0.6)sys±(0.2)norm mb, yielding the inclusive production cross section in full phase space σΣ0total=5.8±(0.5)stat±(−1.4+1.4)sys±(0.6)norm±(1.7)extrapol mb by averaging over different extrapolation methods. The Λall/Σ0 ratio within the HADES acceptance is equal to 2.3±(0.2)stat±(−0.6+0.6)sys. The obtained rapidity and momentum distributions are compared to transport model calculations. The Σ0 yield agrees with the statistical model of particle production in nuclear reactions. Keywords: Hyperons, Strangeness, Proton, Nucleus.
This letter presents the first measurement of jet mass in Pb–Pb and p–Pb collisions at sNN=2.76 TeV and sNN=5.02 TeV, respectively. Both the jet energy and the jet mass are expected to be sensitive to jet quenching in the hot Quantum Chromodynamics (QCD) matter created in nuclear collisions at collider energies. Jets are reconstructed from charged particles using the anti-kT jet algorithm and resolution parameter R=0.4. The jets are measured in the pseudorapidity range |ηjet|<0.5 and in three intervals of transverse momentum between 60 GeV/c and 120 GeV/c. The measurement of the jet mass in central Pb–Pb collisions is compared to the jet mass as measured in p–Pb reference collisions, to vacuum event generators, and to models including jet quenching. It is observed that the jet mass in central Pb–Pb collisions is consistent within uncertainties with p–Pb reference measurements. Furthermore, the measured jet mass in Pb–Pb collisions is not reproduced by the quenching models considered in this letter and is found to be consistent with PYTHIA expectations within systematic uncertainties.
We present data on charged kaons (K±) and ϕ mesons in Au(1.23A GeV)+Au collisions. It is the first simultaneous measurement of K− and ϕ mesons in central heavy-ion collisions below a kinetic beam energy of 10A GeV. The ϕ/K− multiplicity ratio is found to be surprisingly high with a value of 0.52±0.16 and shows no dependence on the centrality of the collision. Consequently, the different slopes of the K+ and K− transverse-mass spectra can be explained solely by feed-down, which substantially softens the spectra of K− mesons. Hence, in contrast to the commonly adapted argumentation in literature, the different slopes do not necessarily imply diverging freeze-out temperatures of K+ and K− mesons caused by different couplings to baryons.
The production of the charm-strange baryon Ξc0 is measured for the first time at the LHC via its semileptonic decay into eΞ−+νe in pp collisions at s=7 TeV with the ALICE detector. The transverse momentum (pT) differential cross section multiplied by the branching ratio is presented in the interval 1<pT<8 GeV/c at mid-rapidity, |y|<0.5. The transverse momentum dependence of the Ξc0 baryon production relative to the D0 meson production is compared to predictions of event generators with various tunes of the hadronisation mechanism, which are found to underestimate the measured cross-section ratio.
A necessary requirement for a pharmacological effect is that a drug molecule tightly interacts with its disease relevant target molecule in the patient. Kinases are regulatory, signal transmitting enzymes and are a large protein family that belongs to the most frequent targets of pharmaceutical industry, as deregulation of kinases has been associated with the development of a variety of diseases, including cancer. In drug discovery, equilibrium binding metrics such as the affinity (Ki, KD) or potency (IC50, EC50) are usually applied for the systematic profiling for potent and selective drug candidates. In recent years, dynamic binding parameters, the drugs association (kon) and dissociation (koff) rates for desired primary-targets and undesired off-targets, were discussed to be better predictors than steady-state affinity per se (KD = koff / kon) for the onset and duration of the drug-target complex in the open in vivo environment and thereby for the therapeutic effect and safety of the drug. It is yet unclear whether and when the binding kinetics parameters can influence drug action in the complex context of pharmacokinetics and pharmacodynamics and how the kinetic rate constants can be optimized rationally. One major obstacle for providing proof for the hypothesis that drug binding kinetics is of importance for drug action is the generation of large and comparable binding kinetic datasets.
The aim of this thesis was the comprehensive analysis of the binding kinetic and affinity parameters of a diverse spectrum of 270 small-molecule kinase inhibitors against a panel of pharmacologically relevant kinases to study the role played by binding kinetics for drug discovery: The generated dataset was utilized to assess the effect of chemical properties on drug binding kinetics, and to evaluate the impact of kinetic rate constants on the success of compounds in the drug discovery pipeline.
Large scale profiling was made possible by a recently developed “kinetic Probe Competition Assay” (kPCA), whose evaluation is based on Motulsky’s and Mahan’s “kinetics of competitive binding” theory. Monte Carlo analyses performed in this dissertation widened the theoretical knowledge of this theory, provided new insights into its limitations and allowed to derive recommendations about how to best design assays. It was demonstrated that kPCA is indeed high-throughput compatible and that it is comparable to other biochemical and biophysical assay formats in terms of precision and accuracy.
Multivariable linear regression for the description of the determined kinase inhibitors’ target binding characteristics (kon or koff or KD) using molecular properties and/or particular kinase-inhibitor interactions as descriptors supported the assumption that molecular properties of compounds might affect binding kinetics, generated new hypothesis about molecular determinants influencing binding kinetic parameters and provided a rational basis for following structure-kinetic relationship studies. Remarkably, the binding kinetic rate constants were better described by the established models than binding affinities.
Interestingly, the systematic, quantitative analysis of kinase inhibitors’ target binding kinetics indicated that a slow dissociation rate for the main target is a feature which is more frequently observed in inhibitors that reached approval or late stage clinical testing than in earlier phases of clinical development. In addition, it was demonstrated that binding kinetics of kinase inhibitors is a better predictor for the time course of target engagement in cells as compared to affinity per se. Furthermore, in some study cases simulations using a standard pharmacokinetics model and a modified model considering the inhibitors binding kinetics lead to different in vivo kinase occupancy time profiles. It was illustrated by simulations how the concept of kinetic selectivity can be applied to turn an unselective compound in equilibrium conditions into a more selective compound in the open in vivo situation, where the thermodynamic equilibrium of drug-target binding is not necessarily reached.
Thus the generated data and models provide evidence for the importance of binding kinetics in drug discovery and represent a valuable resource for future studies in this field.
Über die allmähliche Verfertigung des Romans beim Schreiben : zur Entstehungsgeschichte des "Butt"
(2018)
Nach dem Abschluss der später so genannten Danziger Trilogie war das Themenreservoir aus Nazi- und Kriegszeit, das Grass als Zeitgenosse und Augenzeuge zu 'anhaltender Schreibwut' angetrieben hatte, erschöpft. Um zu einem erneuten großen Wurf ausholen zu können, musste er sich dem Problem stellen, wie er einen neuen Stoff, der nicht aus der lebensgeschichtlichen Erfahrung stammt, aus der produktiven Einbildungskraft entwickeln könne – ein mühsamer Prozess der Ideenfindung, den die Untersuchung anhand der erhaltenen Vorarbeiten von den ersten Brainstormings an zu rekonstruieren versucht. Derartige assoziative Verfahren zur Erzeugung eines epischen flow mündeten allerdings in eine veritable Schreibkrise. Um die schweigende Muse zu reaktivieren, war eine Reihe von Impulsen vonnöten, wobei die Einflüsse 'exogenetischer', also psycho-sozio-kultureller Faktoren (die Schwangerschaft der Lebensgefährtin; der andauernd heftige Beziehungskrieg mit dieser; die Geburt der Tochter Helene) entscheidende Impulse erbrachten, die unmittelbar in Literatur umgesetzt wurden. Ein lange währendes 'warming up' – das Einschalten zahlreicher Gedichte und Graphiken – war aber immer noch vonnöten, um die autonome Motivation aufrechtzuerhalten, bis der wunderbare Fischfang gelang, der den Butt ans Tageslicht holte. Wie und unter welchen Umständen Grass dieser Ideenfund zufiel, einen sprechenden Plattfisch zur Zentralfigur seines Romans zu machen, bleibt im dunkeln verborgen: Es war ein echtes Serendipity-Erlebnis, das einen Kreativitätsschub zur Folge hatte, der allerdings weiterhin chaotisch, unstetig und sprunghaft verlief. Die amorphe Stoffmasse konnte erst bewältigt werden, nachdem mit der Disposition (dem Neunmonateschema der Schwangerschaft) und der diachronen Anlage vom Neolithikum bis in die Gegenwart des Autors das Organisationssystem erarbeitet war: Finderglück und selbstvergessenes Schreiben allein erzeugen noch kein episches Großwerk, sofern nicht 'die Fähigkeit zum Ausnutzen von Gelegenheiten' mitwirkt, die nach Luhmann Kreativität ausmacht.
Cryo-EM structures of KdpFABC suggest a K+ transport mechanism via two inter-subunit half-channels
(2018)
P-type ATPases ubiquitously pump cations across biological membranes to maintain vital ion gradients. Among those, the chimeric K+ uptake system KdpFABC is unique. While ATP hydrolysis is accomplished by the P-type ATPase subunit KdpB, K+ has been assumed to be transported by the channel-like subunit KdpA. A first crystal structure uncovered its overall topology, suggesting such a spatial separation of energizing and transporting units. Here, we report two cryo-EM structures of the 157 kDa, asymmetric KdpFABC complex at 3.7 Å and 4.0 Å resolution in an E1 and an E2 state, respectively. Unexpectedly, the structures suggest a translocation pathway through two half-channels along KdpA and KdpB, uniting the alternating-access mechanism of actively pumping P-type ATPases with the high affinity and selectivity of K+ channels. This way, KdpFABC would function as a true chimeric complex, synergizing the best features of otherwise separately evolved transport mechanisms.
The leptonic decay of the charged pion in the presence of background magnetic fields is investigated using quenched Wilson fermions. It is demonstrated that the magnetic field opens up a new channel for this decay. The magnetic field-dependence of the decay constants for both the ordinary and the new channel is determined. Using these inputs from QCD, we calculate the total decay rate perturbatively.
Background: Computed tomography (CT) allows estimation of coronary artery calcium (CAC) progression. We evaluated several progression algorithms in our unselected, population-based cohort for risk prediction of coronary and cardiovascular events.
Methods: In 3281 participants (45–74 years of age), free from cardiovascular disease until the second visit, risk factors, and CTs at baseline (b) and after a mean of 5.1 years (5y) were measured. Hard coronary and cardiovascular events, and total cardiovascular events including revascularization, as well, were recorded during a follow-up time of 7.8±2.2 years after the second CT. The added predictive value of 10 CAC progression algorithms on top of risk factors including baseline CAC was evaluated by using survival analysis, C-statistics, net reclassification improvement, and integrated discrimination index. A subgroup analysis of risk in CAC categories was performed.
Results: We observed 85 (2.6%) hard coronary, 161 (4.9%) hard cardiovascular, and 241 (7.3%) total cardiovascular events. Absolute CAC progression was higher with versus without subsequent coronary events (median, 115 [Q1–Q3, 23–360] versus 8 [0–83], P<0.0001; similar for hard/total cardiovascular events). Some progression algorithms added to the predictive value of baseline CT and risk assessment in terms of C-statistic or integrated discrimination index, especially for total cardiovascular events. However, CAC progression did not improve models including CAC5y and 5-year risk factors. An excellent prognosis was found for 921 participants with double-zero CACb=CAC5y=0 (10-year coronary and hard/total cardiovascular risk: 1.4%, 2.0%, and 2.8%), which was for participants with incident CAC 1.8%, 3.8%, and 6.6%, respectively. When CACb progressed from 1 to 399 to CAC5y≥400, coronary and total cardiovascular risk were nearly 2-fold in comparison with subjects who remained below CAC5y=400. Participants with CACb≥400 had high rates of hard coronary and hard/total cardiovascular events (10-year risk: 12.0%, 13.5%, and 30.9%, respectively).
Conclusions: CAC progression is associated with coronary and cardiovascular event rates, but adds only weakly to risk prediction. What counts is the most recent CAC value and risk factor assessment. Therefore, a repeat scan >5 years after the first scan may be of additional value, except when a double-zero CT scan is present or when the subjects are already at high risk.
This paper presents an imaging radar system for structural health monitoring (SHM) of wind turbine blades. The imaging radar system developed here is based on two frequency modulated continuous wave (FMCW) radar sensors with a high output power of 30 dBm. They have been developed for the frequency bands of 24,05 GHz-24,25 GHz and 33.4 GHz-36.0 GHz, respectively. Following the successful proof of damage detection and localization in laboratory conditions, we present here the installation of the sensor system at the tower of a 2 MW wind energy plant at 95 m above ground. The realization of the SHM-system will be introduced including the sensor system, the data acquisition framework and the signal processing procedures. We have achieved an imaging of the rotor blades using inverse synthetic aperture radar techniques under changing environmental and operational condition. On top of that, it was demonstrated that the front wall and back wall radar echo can be extracted from the measured signals demonstrating the full penetration of wind turbine blades during operation.
Acetaminophen [paracetamol, N-acetyl-p-aminophenol (APAP)]-induced acute liver injury (ALI) not only remains a persistent clinical challenge but likewise stands out as well-characterized paradigmatic model of drug-induced liver damage. APAP intoxication associates with robust hepatic necroinflammation the role of which remains elusive with pathogenic but also pro-regenerative/-resolving functions being ascribed to leukocyte activation. Here, we shine a light on and put forward a unique role of the interleukin (IL)-1 family member IL-18 in experimental APAP-induced ALI. Indeed, amelioration of disease as previously observed in IL-18-deficient mice was further substantiated herein by application of the IL-18 opponent IL-18-binding protein (IL-18BPd:Fc) to wild-type mice. Data altogether emphasize crucial pathological action of this cytokine in APAP toxicity. Adding recombinant IL-22 to IL-18BPd:Fc further enhanced protection from liver injury. In contrast to IL-18, the role of prototypic pro-inflammatory IL-1 and tumor necrosis factor-α is controversially discussed with lack of effects or even protective action being repeatedly reported. A prominent detrimental function for IL-18 in APAP-induced ALI as proposed herein should relate to its pivotal role for hepatic expression of interferon-γ and Fas ligand, both of which aggravate APAP toxicity. As IL-18 serum levels increase in patients after APAP overdosing, targeting IL-18 may evolve as novel therapeutic option in those hard-to-treat patients where standard therapy with N-acetylcysteine is unsuccessful. Being a paradigmatic experimental model of ALI, current knowledge on ill-fated properties of IL-18 in APAP intoxication likewise emphasizes the potential of this cytokine to serve as therapeutic target in other entities of inflammatory liver diseases.
Um die Voraussetzungen für Heckers Wirken in Baden und das liberale Klima jener Zeit besser zu veranschaulichen, ist eine Betrachtung des Staats-Lexikons angebracht. Die Unterschiede zwischen den beiden ersten Auflagen, die im Deutschen Bund nicht veröffentlicht werden durften und der dritten Auflage sind geradezu umwälzend, sie veranschaulichen, warum das politische Klima des Vormärz nach der 1848er Revolution zum Erliegen kam. Das von Rotteck für die erste Auflage verfasste Vorwort (1834) sieht dessen Aufgabe darin, eine breite Menge der Bürger, Gelehrten und Gebildeten zu belehren und den gemeinen Menschenverstand zu schärfen.
IN THE CURRENT REGIME OF LOW INTEREST RATES, TAKING SOUND SAVINGS DECISIONS POSES A SIGNIFICANT CHALLENGE TO MOST INDIVIDUALS. FUND SAVINGS PLANS ALLOW TO ACCUMULATE PRIVATE SAVINGS VIA AUTOMATED RECURRING INVESTMENTS IN SELECTED FUNDS. LOW FEES AND SMALL MINIMUM INVESTMENT AMOUNTS MAKE THEM A SUITABLE SAVINGS VEHICLE ALSO FOR LOW NET-WORTH INDIVIDUALS. WHILE TRADITIONAL FINANCIAL ADVISORS ONLY RELUCTANTLY PROVIDE ADVICE ON SMALL-SCALE INVESTMENTS, THE RECENT SURGE OF ROBO-ADVISORS ENABLES ACCESS TO ADVICE ON SAVINGS PLAN CHOICES FOR INVESTORS FROM ALL WEALTH BANDS. IN THIS REPORT, WE PRESENT EMPIRICAL RESULTS ON THE IMPACT OF INTRODUCING AN AUTOMATED INVESTMENT TOOL AT A LARGE GERMAN ONLINE BANK ON PRIVATE INVESTORS’ SAVINGS DECISIONS.
Vorwort
(2018)
Das Reichsgesetz, betreffend die Grundrechte hat aus der Kritik an der französischen Menschenrechtserklärung gelernt, dass es Menschenrechte weder ohne System der Rechte und Pflichten des Bürgers noch ohne Verankerung in der einschlägigen Organisation der Staatsorgane geben kann, die gleichzeitig die Freiheit und die Einheit des Volkes sichern. Außerdem sieht die den Reichsgesetzen zugrunde liegende Auffassung keine Grundrechte ohne Verankerung im zu schützenden geistigen Leben des Volkes vor. Unter dem Einfluss der Rechts- und Staatsphilosophie J. G. Fichtes und Hegels wurden im Vormärz rechtsphilosophische Theorien entwickelt, die individuelle Menschenrechte nicht abstrakt, sondern nur in einem "System des Rechts" aufeinander bezogener Komponenten gelten lassen, das den Menschen grundsätzlich als gesellschaftliches Wesen betrachtet und dem eine organische und geistige Auffassung der Gesellschaft zugrunde liegt.
Cardiovascular disease remains a leading cause of morbidity and mortality globally. Changing natural history of the disease due to improved care of acute conditions and ageing population necessitates new strategies to tackle conditions which have more chronic and indolent course. These include an increased deployment of safe screening methods, life-long surveillance, and monitoring of both disease activity and tailored-treatment, by way of increasingly personalized medical care. Cardiovascular magnetic resonance (CMR) is a non-invasive, ionising radiation-free method, which can support a significant number of clinically relevant measurements and offers new opportunities to advance the state of art of diagnosis, prognosis and treatment. The objective of the SCMR Clinical Trial Taskforce was to summarizes the evidence to emphasize where currently CMR-guided clinical care can indeed translate into meaningful use and efficient deployment of resources results in meaningful and efficient use. The objective of the present initiative was to provide an appraisal of evidence on analytical validation, including the accuracy and precision, and clinical qualification of parameters in disease context, clarifying the strengths and weaknesses of the state of art, as well as the gaps in the current evidence This paper is complementary to the existing position papers on standardized acquisition and post-processing ensuring robustness and transferability for widespread use. Themed imaging-endpoint guidance on trial design to support drug-discovery or change in clinical practice (part II), will be presented in a follow-up paper in due course. As CMR continues to undergo rapid development, regular updates of the present recommendations are foreseen.
Aims: Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk.
Methods and results: From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies.
In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95–1.02) in group A, 0.98 (0.93–1.04) in group B, and 0.95 (0.89–1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07–1.23) in group A, 1.13 (1.05–1.22) in group B, and 1.12 (1.05–1.20) in group C.
Conclusions: We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals.
Using recent lattice data on the thermodynamics of QCD in the presence of a background magnetic field, we show that the ratio of transverse to longitudinal pressure exhibits, to good accuracy, a simple scaling behavior over a wide range of temperature and magnetic field, essentially depending only on the ratio T/B $$ T/\sqrt{B} $$. We compare this QCD response to the corresponding magnetoresponse in maximally supersymmetric Yang Mills theory. Given suitable calibrations defining the comparison, we find excellent agreement. This may be viewed as a further test of the applicability of holographic models for hot QCD.
We present a measurement of inclusive J /ψ production at mid-rapidity (|y| < 1) in p+p collisions at a center-of-mass energy of √s = 200 GeV with the STAR experiment at the Relativistic Heavy Ion Collider (RHIC). The differential production cross section for J /ψ as a function of transverse momentum (p T ) for 0 < p T < 14 GeV/c and the total cross section are reported and compared to calculations from the color evaporation model and the non-relativistic Quantum Chromodynamics model. The dependence of J /ψ relative yields in three p T intervals on charged-particle multiplicity at mid-rapidity is measured for the first time in p+p collisions at √s = 200 GeV and compared with that measured at √s = 7 TeV, PYTHIA8 and EPOS3 Monte Carlo generators, and the Percolation model prediction.
Azimuthally-differential femtoscopic measurements, being sensitive to spatio-temporal characteristics of the source as well as to the collective velocity fields at freeze out, provide very important information on the nature and dynamics of the system evolution. While the HBT radii oscillations relative to the second harmonic event plane measured recently reflect mostly the spatial geometry of the source, model studies have shown that the HBT radii oscillations relative to the third harmonic event plane are predominantly defined by the velocity fields. In this Letter, we present the first results on azimuthally-differential pion femtoscopy relative to the third harmonic event plane as a function of the pion pair transverse momentum kT for different collision centralities in Pb–Pb collisions at √sNN = 2.76 TeV. We find that the Rside and Rout radii, which characterize the pion source size in the directions perpendicular and parallel to the pion transverse momentum, oscillate in phase relative to the third harmonic event plane, similar to the results from 3+1D hydrodynamical calculations. The observed radii oscillations unambiguously signal a collective expansion and anisotropy in the velocity fields. A comparison of the measured radii scillations with the Blast-Wave model calculations indicate that the initial state triangularity is washedout at freeze out.
The first measurements of anisotropic flow coefficients vn for mid-rapidity charged particles in Xe–Xe collisions at √sNN = 5.44 TeV are presented. Comparing these measurements to those from Pb–Pb collisions at √sNN = 5.02 TeV, v2 is found to be suppressed for mid-central collisions at the same centrality, and enhanced for central collisions. The values of v3 are generally larger in Xe–Xe than in Pb–Pb at a given centrality. These observations are consistent with expectations from hydrodynamic predictions. When both v2 and v3 are divided by their corresponding eccentricities for a variety of initial state models, they generally scale with transverse density when comparing Xe–Xe and Pb–Pb, with some deviations observed in central Xe–Xe and Pb–Pb collisions. These results assist in placing strong constraints on both the initial state geometry and medium response for relativistic heavy-ion collisions.
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.
The access to information on the dynamic behaviour of large proteins is usually hindered as spectroscopic methods require the site-specific attachment of biophysical probes. A powerful emerging tool to tackle this issue is amber codon suppression. Till date, its application on large and complex multidomain proteins of MDa size has not been reported. Herein, we systematically investigate the feasibility to introduce different non-canonical amino acids into a 540 kDa homodimeric fatty acid synthase type I by genetic code expansion with subsequent fluorescent labelling. Our approach relies on a microplate-based reporter assay of low complexity using a GFP fusion protein to quickly screen for sufficient suppression conditions. Once identified, these findings were successfully utilized to upscale both the expression scale and the protein size to full-length constructs. These fluorescently labelled samples of fatty acid synthase were subjected to initial biophysical experiments, including HPLC analysis, activity assays and fluorescence spectroscopy. Successful introduction of such probes into a molecular machine such as fatty acid synthases may pave the way to understand the conformational variability, which is a primary intrinsic property required for efficient interplay of all catalytic functionalities, and to engineer them.
The bile acid activated transcription factor farnesoid X receptor (FXR) regulates numerous metabolic processes and is a rising target for the treatment of hepatic and metabolic disorders. FXR agonists have revealed efficacy in treating non-alcoholic steatohepatitis (NASH), diabetes and dyslipidemia. Here we characterize imatinib as first-in-class allosteric FXR modulator and report the development of an optimized descendant that markedly promotes agonist induced FXR activation in a reporter gene assay and FXR target gene expression in HepG2 cells. Differential effects of imatinib on agonist-induced bile salt export protein and small heterodimer partner expression suggest that allosteric FXR modulation could open a new avenue to gene-selective FXR modulators.
Ausgangspunkt der Studie ist die These, dass sprachlich und kulturell heterogene Lerngruppen, an denen Studierende mit und ohne spanischsprachigen Familienhintergrund gemeinsam teilnehmen, als eine günstige Lernsituation betrachtet werden können. Voraussetzung dafür ist, dass die unterschiedlichen sprachlichen und kulturellen Gegebenheiten als Ressourcen für den Unterricht verstanden werden.
Mit dem Fokus auf Sprachveranstaltungen in Spanisch, die von Studierenden an der Johann Wolfgang Goethe-Universität Frankfurt am Main besucht werden, und die im Rahmen ihres Lehramtsstudiums im Fach Spanisch stattfinden, wurden in dieser Studie folgende Forschungsfragen verfolgt:
1. Wie entstehen und entwickeln sich Sprachlernprozesse in sprachlich und kulturell vielfältigen Lernkontexten?
2. Wie zeichnet sich das Lernen in sprachlich und kulturell vielfältigen Lernkontexten aus?
3. Welche sprachlichen und kulturellen Ressourcen können für die sprachliche und kulturelle Förderung genutzt und bewusst eingesetzt werden?
Wichtigste Forschungsergebnisse:
Es wurde festgestellt, dass Sprachlernprozesse bei Studierenden mit und ohne spanischsprachigen Familienhintergrund sowohl im kognitiven als auch im emotionalen Bereich qualitativ unterschiedlich verlaufen und, dass in sprachlich und kulturell vielfältigen Lernkontexten individuelle und überindividuelle Sprachlern-prozesse stattfinden, die einander bedingen.
Was das gemeinsame Lernen angeht, konnte festgestellt werden, dass Studierende ohne spanischsprachigen Familienhintergrund widersprüchliche Erwartungen an die Studierenden mit spanischsprachigem Familienhintergrund haben: Einerseits schätzen sie die Präsenz ihrer Kommilitonen und sehen sie als Mittler zwischen dem Unterricht und der Realität außerhalb des Unterrichts, weil sie die „echte“ Sprache und Kultur in den Klassenraum bringen. Anderseits fühlen sie sich durch ihre Anwesenheit im Unterricht verunsichert, was ihre sprachliche Entwicklung zum Teil hemmt. Bei den Studierenden mit spanischsprachigem Familienhintergrund konnten unterschiedliche Phasen in ihrem Sprachlernprozess beobachtet werden, die ihre Lernattitüde und ihre Haltung zu den Kommilitoninnen und Kommilitonen konditionieren.
Entscheidend für die Konstruktion gemeinsamer Sprachlernprozessen ist, dass die Studierenden ihre Positionierung als peer ihrer Kommilitoninnen und Kommilitonen bewusst wahrnehmen, was nicht immer der Fall ist. Auch die Bewusstwerdung der eigenen Funktion als Mittler zwischen Sprachen und Kulturen insbesondere (aber nicht nur) bei Studierenden mit spanischsprachigem Familienhintergrund soll im Unterricht durch die Reflexion über die eigene sprachliche und kulturelle Identität gefördert werden.
Im Umgang mit solchen Lerngruppen haben Dozentinnen und Dozenten unterschiedliche Erwartungen. In der Regel werden aber Lerninhalte vermittelt, die die sprachliche und kulturelle Vielfalt im Unterricht nicht berücksichtigen. Für die Leistungsbewertung beider Studierendengruppen werden oft unterschiedliche Kriterien angewendet, woraus Konflikte zwischen den Veranstaltungsteilnehmerinnen und -teilnehmern entstehen.
Die Rolle der Dozentinnen und Dozenten selbst ist in der Gestaltung gemeinsamer Lernkontexte, in denen die Interaktion der Studierenden gefördert werden, grundlegend. Damit dies gelingt, sollen sie einerseits für Mehrsprachigkeit als Phänomen der Gesellschaft, das den Sprachunterricht im besonderen Maße betrifft, sensibilisiert sein. Andererseits soll ihnen bewusst werden, dass das Sprachenlernen aus einer kognitiven und einer emotionalen Seite besteht, die in engem Zusammenhang mit mehrsprachigen und mehrkulturellen Identitätskonstruktionen stehen. Beide Seiten sollen im Unterricht gefördert werden.
Objective: To evaluate the efficacy and tolerability of brivaracetam (BRV) in a severely drug refractory cohort of patients with epileptic encephalopathies (EE).
Method: A multicenter, retrospective cohort study recruiting all patients treated with EE who began treatment with BRV in an enrolling epilepsy center between 2016 and 2017.
Results: Forty-four patients (27 male [61%], mean age 29 years, range 6 to 62) were treated with BRV. The retention rate was 65% at 3 months, 52% at 6 months and 41% at 12 months. A mean retention time of 5 months resulted in a cumulative exposure to BRV of 310 months. Three patients were seizure free during the baseline. At 3 months, 20 (45%, 20/44 as per intention-to-treat analysis considering all patients that started BRV including three who were seizure free during baseline) were either seizure free (n = 4; 9%, three of them already seizure-free at baseline) or reported at least 25% (n = 4; 9%) or 50% (n = 12; 27%) reduction in seizures. An increase in seizure frequency was reported in two (5%) patients, while there was no change in the seizure frequency of the other patients. A 50% long-term responder rate was apparent in 19 patients (43%), with two (5%) free from seizures for more than six months and in nine patients (20%, with one [2 %] free from seizures) for more than 12 months. Treatment-emergent adverse events were predominantly of psychobehavioural nature and were observed in 16%.
Significance: In this retrospective analysis the rate of patients with a 50% seizure reduction under BRV proofed to be similar to those seen in regulatory trials for focal epilepsies. BRV appears to be safe and relatively well tolerated in EE and might be considered in patients with psychobehavioral adverse events while on levetiracetam.
In the current contribution we present a comprehensive study on the heteronuclear carbonyl complex H2FeRu3(CO)13 covering its low energy electron induced fragmentation in the gas phase through dissociative electron attachment (DEA) and dissociative ionization (DI), its decomposition when adsorbed on a surface under controlled ultrahigh vacuum (UHV) conditions and exposed to irradiation with 500 eV electrons, and its performance in focused electron beam induced deposition (FEBID) at room temperature under HV conditions. The performance of this precursor in FEBID is poor, resulting in maximum metal content of 26 atom % under optimized conditions. Furthermore, the Ru/Fe ratio in the FEBID deposit (≈3.5) is higher than the 3:1 ratio predicted. This is somewhat surprising as in recent FEBID studies on a structurally similar bimetallic precursor, HFeCo3(CO)12, metal contents of about 80 atom % is achievable on a routine basis and the deposits are found to maintain the initial Co/Fe ratio. Low temperature (≈213 K) surface science studies on thin films of H2FeRu3(CO)13 demonstrate that electron stimulated decomposition leads to significant CO desorption (average of 8–9 CO groups per molecule) to form partially decarbonylated intermediates. However, once formed these intermediates are largely unaffected by either further electron irradiation or annealing to room temperature, with a predicted metal content similar to what is observed in FEBID. Furthermore, gas phase experiments indicate formation of Fe(CO)4 from H2FeRu3(CO)13 upon low energy electron interaction. This fragment could desorb at room temperature under high vacuum conditions, which may explain the slight increase in the Ru/Fe ratio of deposits in FEBID. With the combination of gas phase experiments, surface science studies and actual FEBID experiments, we can offer new insights into the low energy electron induced decomposition of this precursor and how this is reflected in the relatively poor performance of H2FeRu3(CO)13 as compared to the structurally similar HFeCo3(CO)12.
Hydrogenation of CO₂ at ambient pressure catalyzed by a highly active thermostable biocatalyst
(2018)
Background: Replacing fossil fuels as energy carrier requires alternatives that combine sustainable production, high volumetric energy density, easy and fast refueling for mobile applications, and preferably low risk of hazard. Molecular hydrogen (H2) has been considered as promising alternative; however, practical application is struggling because of the low volumetric energy density and the explosion hazard when stored in large amounts. One way to overcome these limitations is the transient conversion of H2 into other chemicals with increased volumetric energy density and lower risk hazard, for example so-called liquid organic hydrogen carriers such as formic acid/formate that is obtained by hydrogenation of CO2. Many homogenous and heterogenous chemical catalysts have been described in the past years, however, often requiring high pressures and temperatures. Recently, the first biocatalyst for this reaction has been described opening the route to a biotechnological alternative for this conversion.
Results: The hydrogen-dependent CO2 reductase (HDCR) is a highly active biocatalyst for storing H2 in the form of formic acid/formate by reversibly catalyzing the hydrogenation of CO2. We report the identification, isolation, and characterization of the first thermostable HDCR operating at temperatures up to 70 °C. The enzyme was isolated from the thermophilic acetogenic bacterium Thermoanaerobacter kivui and displays exceptionally high activities in both reaction directions, substantially exceeding known chemical catalysts. CO2 hydrogenation is catalyzed at mild conditions with a turnover frequency of 9,556,000 h−1 (specific activity of 900 µmol formate min−1 mg−1) and the reverse reaction, H2 + CO2 release from formate, is catalyzed with a turnover frequency of 9,892,000 h−1 (930 µmol H2 min−1 mg−1). The HDCR of T. kivui consists of a [FeFe] hydrogenase subunit putatively coupled to a tungsten-dependent CO2 reductase/formate dehydrogenase subunit by an array of iron–sulfur clusters.
Conclusions: The discovery of the first thermostable HDCR provides a promising biological alternative for a chemically challenging reaction and might serve as model for the better understanding of catalysts able to efficiently reduce CO2. The catalytic activity for reversible CO2 hydrogenation of this enzyme is the highest activity known for bio- and chemical catalysts and requiring only ambient temperatures and pressures. The thermostability provides more flexibility regarding the process parameters for a biotechnological application.
Challenges of FAIR phase 0
(2018)
After two-year's shutdown, the GSI accelerators plus the latest addition of storage ring CRYRING, will be back into operation in 2018 as the FAIR phase 0 with the goal to fulfill the needs of scientific community and the FAIR accelerators and detector development. Even though GSI has been well known for its operation of a variety of ion beams ranging from proton up to uranium for multi research areas such as nuclear physics, astrophysics, biophysics, material science, the upcoming beam time faces a number of challenges in re-commissioning its existing circular accelerators with brand new control system and upgrade of beam instrumentations, as well as in rising failures of dated components and systems. The cycling synchrotron SIS18 has been undergoing a set of upgrade measures for fulfilling future FAIR operation, among which many measures will also be commissioned during the upcoming beam time. This paper presents the highlights of the challenges such as re-establishing the high intensity heavy ion operation as well as parallel operation mode for serving multi users. The status of preparation including commissioning results will also be reported.
Jargon
(2018)
Jargon ist nicht nur ein Wort aus der Fremde, sondern auch seiner Bedeutung nach mit dem Andersartigen und zugleich Vertrauten, dem Nicht-Identischen, teils Unübersetzbaren und nur Halbbekannten von Sprache(n) verbündet. Anders als Fremdwörter, deren Verständnis Bildung voraussetzt, wurden Jargons über lange Zeit hinweg marginalisierten gesellschaftlichen Gruppen, sogenannten 'Gaunern' und 'Vagabunden', zugeschrieben, wobei sie sich häufig auf Gegenstände des alltäglichen Lebens bezogen.
Der Beitrag liest die Marsyas-Episode aus Ovids "Metamorphosen" als Erzählung über die Bedeutung von Erinnerungsmaterial für das Verhältnis von historischer und gegenwärtiger Erfahrung und knüpft daran Analysen zum Umgang mit der Marsyas-Motivik in Heiner Müllers Stück "Macbeth, nach Shakespeare" (1972) und Rainer Werner Fassbinders Film "In einem Jahr mit 13 Monden" (1978). Müller setzt Ovids Marsyas-Erzählung als Kommentar auf das endlose Ende der Geschichte und den Horror einer Auflösung von Unterschieden ein. Die Ovid-Bezüge lassen die dargestellte Grausamkeit zwischen Buchstäblichkeit und Bildlichkeit, historischem Kommentar und anthropologischer Reflexion oszillieren und weisen darüber hinaus auf politisches Reflexionsmaterial in den "Metamorphosen" zurück. Auch bei Fassbinder markiert die Häutung ein individuelles Leiden als politisches. "In einem Jahr mit 13 Monden" überführt die bis zur Verwandlungsbereitschaft reichende Liebe der Hauptfigur in der Schlachthausszene, die Material aus Ovids Marsyas-Erzählung, aus Tizians Gemälde "Die Schindung des Marsyas" und aus Goethes "Torquato Tasso" enthält, in ein darstellerisches Extrem. Fassbinder spaltet die in den Kunstwerken enthaltenen Motive und Formelemente auf, ordnet sie in neuer, anders verdichteter Konstellation an und erreicht so eine den filmischen Realismus mythologisch aufladende Wirkung.
Buchstäblich auf der Flucht rutschte Kurt Goldstein sein Hauptwerk aus der Feder. Im Frühjahr 1934, während eines Zwischenaufenthalts in Amsterdam, schrieb er binnen weniger Monate "Der Aufbau des Organismus: Einführung in die Biologie unter besonderer Berücksichtigung der Erfahrungen am kranken Menschen". In diesem Buch entfaltete Goldstein seine auf der Basis von klinischen Erfahrungen gewonnenen physiologischen Anschauungen zu einer allgemeinen Theorie des Organismus. Zentraler Gedanke dieser Theorie war die These, dass sich die Leistungsvielfalt eines Organismus nicht als Summe möglichst exakt zu zergliedernder Einzelreaktionen beschreiben, sondern nur aus dem Gefüge ihres Zusammenwirkens erfassen lasse.
We examined alterations in E/I-balance in schizophrenia (ScZ) through measurements of resting-state gamma-band activity in participants meeting clinical high-risk (CHR) criteria (n = 88), 21 first episode (FEP) patients and 34 chronic ScZ-patients. Furthermore, MRS-data were obtained in CHR-participants and matched controls. Magnetoencephalographic (MEG) resting-state activity was examined at source level and MEG-data were correlated with neuropsychological scores and clinical symptoms. CHR-participants were characterized by increased 64–90 Hz power. In contrast, FEP- and ScZ-patients showed aberrant spectral power at both low- and high gamma-band frequencies. MRS-data showed a shift in E/I-balance toward increased excitation in CHR-participants, which correlated with increased occipital gamma-band power. Finally, neuropsychological deficits and clinical symptoms in FEP and ScZ-patients were correlated with reduced gamma band-activity, while elevated psychotic symptoms in the CHR group showed the opposite relationship. The current study suggests that resting-state gamma-band power and altered Glx/GABA ratio indicate changes in E/I-balance parameters across illness stages in ScZ.
Hypofunction of the N-methyl-D-aspartate receptor (NMDAR) has been implicated as a possible mechanism underlying cognitive deficits and aberrant neuronal dynamics in schizophrenia. To test this hypothesis, we first administered a sub-anaesthetic dose of S-ketamine (0.006 mg/kg/min) or saline in a single-blind crossover design in 14 participants while magnetoencephalographic data were recorded during a visual task. In addition, magnetoencephalographic data were obtained in a sample of unmedicated first-episode psychosis patients (n = 10) and in patients with chronic schizophrenia (n = 16) to allow for comparisons of neuronal dynamics in clinical populations versus NMDAR hypofunctioning. Magnetoencephalographic data were analysed at source-level in the 1–90 Hz frequency range in occipital and thalamic regions of interest. In addition, directed functional connectivity analysis was performed using Granger causality and feedback and feedforward activity was investigated using a directed asymmetry index. Psychopathology was assessed with the Positive and Negative Syndrome Scale. Acute ketamine administration in healthy volunteers led to similar effects on cognition and psychopathology as observed in first-episode and chronic schizophrenia patients. However, the effects of ketamine on high-frequency oscillations and their connectivity profile were not consistent with these observations. Ketamine increased amplitude and frequency of gamma-power (63–80 Hz) in occipital regions and upregulated low frequency (5–28 Hz) activity. Moreover, ketamine disrupted feedforward and feedback signalling at high and low frequencies leading to hypo- and hyper-connectivity in thalamo-cortical networks. In contrast, first-episode and chronic schizophrenia patients showed a different pattern of magnetoencephalographic activity, characterized by decreased task-induced high-gamma band oscillations and predominantly increased feedforward/feedback-mediated Granger causality connectivity. Accordingly, the current data have implications for theories of cognitive dysfunctions and circuit impairments in the disorder, suggesting that acute NMDAR hypofunction does not recreate alterations in neural oscillations during visual processing observed in schizophrenia.
Background: Protective effects of vitamin D have been reported in autoimmune and malignant thyroid diseases, though little is known about the underlying mechanism. Sirtuin 1 histon deacethylase (SIRT1) links the vitamin D pathway with regulation of transcription factor FOXO3a, a key player in cell cycle regulation and apoptosis. Aim of the present study was to investigate common single nucleotide polymorphisms (SNP's) in FOXO3a gene in respect to thyroid diseases, as well as to evaluate the hypothesis of Sirtuin1-FOXO3a interaction being a mediator of anti-proliferative vitamin D effects.
Methods: The SNP's FOXO3a rs4946936/rs4945816/rs9400239 were genotyped in 257 patients with differentiated thyroid carcinoma (DTC), 139 patients with Hashimoto thyroiditis (HT) and 463 healthy controls (HC). Moreover, T-helper cells of HC and papillary thyroid cancer cell line BCPAP were incubated with 1,25(OH)2D3 and/or SIRT1 inhibitor Ex-527 in order to elucidate SIRT1- dependent vitamin D effects on cell proliferation and FOXO3a gene expression in vitro.
Results: Patients with DTC tended to carry more often allele C in FOXO3a rs4946936 in comparison to HC (pcorrected = pc = 0.08). FOXO3a rs9400239T and rs4945816C was more frequent in HT in comparison to HC (pc = 0.02 and pc = 0.01, respectively). In both DTC and HT, we could not find a correlation of FOXO3a SNP's with vitamin D status. However, on in vitro level, 1,25(OH)2D3 showed an anti-proliferative effect in both T-helper cells and BCPAP, that was blocked by SIRT1 inhibition (T-helper cells: p = 0.0059, BCPAP: p = 0.04) and accompanied by elevated FOXO3a gene expression in T-helper cells (p = 0.05).
Conclusions: FOXO3a rs9400239T and rs4945816C may constitute risk factors for HT, independent of the vitamin D status.This indicates the implication of FOXO3a in pathogenesis of autoimmune thyroid diseases. The dependency of anti-proliferative vitamin D effects on SIRT1 activity further suggests a key role of vitamin D-SIRT1-FOXO3a axis for protective vitamin D effects.
Lizards of Paraguay: an integrative approach to solve taxonomic problems in central South America
(2018)
Paraguay is located in the center of South America with drier and warmer climatic conditions in the western part of the country, and more temperate and humid in the eastern region. Biogeographically, Paraguay is a key spot in South America, where several ecoregions converge. In my study, I sampled most of the ecoregions of Paraguay. The main objective of my work is to solve taxonomic problems, identified through genetic barcoding analyses, in the central region of South America. To achieve this objective, I used selected taxa of the Paraguayan Squamata as models taking into consideration the crucial geographic position of the country, plus the scarce available genetic data of Paraguayan reptiles.
The collecting activities were performed in the framework of a barcoding inventory project of the Paraguayan herpetofauna and carried out mostly in rural areas searching for animals in different types of habitats using active search as the sampling technique.
For genetics, the extraction of DNA was performed with DNeasy® Blood & Tissue Kit of Qiagen® for sets of few samples, and the fiber glass plate protocol for sets of 96 samples. I assessed the quality of sequences after amplification in agarose gel electrophoresis. The first marker sequenced was 16S mtDNA, used for barcoding analysis. A DNA barcode is a genetic identifier for a species. Once a taxonomic problem was detected, I generate more gene sequences to target the issue.
All the analyses to test phylogenetic hypotheses (based on single genes or concatenated datasets) were performed under Maximum Likelihood and Bayesian approaches. To root the phylogenetic trees, I chose the available taxon (or taxa) most closely related to the respective studied group as outgroups. For the general tree of Paraguayan Squamata, based on barcodes of 16S, I chose Sphenodon punctatus.
I generated a total of 142 sequences of 64 species of Squamata from Paraguay (Appendix I). The final alignment of 615 bp comprised 249 samples. The best substitution model for the Barcoding dataset based on the gene 16S was GTR+G, according to the BIC.
To complement molecular evidence generated with the ML grouping of 16S barcodes, I took a morphological approach based on voucher specimens collected during fieldwork (usually the same specimens that I used for genetic analysis), supplemented by the revision of museum collections.
Summarizing my results, samples of Colobosaura exhibit large genetic distances, and accordingly I revalidated Colobosaura kraepelini (Appendix II). Tropidurus of the spinulosus group show two clades and among them there is little genetic and morphological variation, I synonymized T. tarara and T. teyumirim with T. lagunablanca, and T. guarani with T. spinulosus (Appendix III). I detected the presence of candidate species of Homonota, and I restricted the name H. horrida for Argentina, and described two new species of Homonota (Appendices IV and V), and a new species of Phyllopezus also in the Family Phyllodactylidae (Appendix VI).
In this work I present the most comprehensive analysis of genetic samples of Squamata from Paraguay. The results obtained here will be useful to help to clarify further taxonomic issues regarding the squamate fauna from the central region of South America. Moreover, the data generated for this study will have a positive impact in a larger geographic context, beyond Paraguayan borders.
Regarding the conservation of the Paraguayan reptiles, and considering the taxonomic changes accomplished here, it is important to note that many species lack legal protection. In Paraguay, the major problem for conservation is habitat loss due to extensive crop farming. Thus, currently, the protected areas are the best strategy for conservation of biodiversity in the country. However, many such areas face legal problems (e.g., lack of official measurements, management plans, forest guards, infrastructure, etc.) so that the maintenance of their biodiversity over time is not guaranteed.
In conclusion, in this study I present contributions on the taxonomy of mostly lizards from Paraguay. Due to lack of samples, I was not able to deal with a deep taxonomic revision of the country's snakes. Based on my results, I can argue that analyses of Xenodontini and Pseudoboini are currently a pressing research issue. This barcoding project may continue since some colleagues in Paraguay are interested in collaboration. Given that the sequenced specimens are yet a small portion of the actual diversity of Paraguay, it will be of utmost importance to continue and expand these studies that will further improve our taxonomic knowledge. Furthermore, it is desirable to have Paraguayan scientists not only involved, but to see them taking the lead of high quality taxonomic research.
Objectives: The aim of this multicenter retrospective study was to investigate safety and efficacy of direct acting antiviral (DAA) treatment in the rare subgroup of patients with HCV/HIV-coinfection and advanced liver cirrhosis on the liver transplant waiting list or after liver transplantation, respectively.
Methods: When contacting 54 German liver centers (including all 23 German liver transplant centers), 12 HCV/HIV-coinfected patients on antiretroviral combination therapy were reported having received additional DAA therapy while being on the waiting list for liver transplantation (patient characteristics: Child-Pugh A (n = 6), B (n = 5), C (n = 1); MELD range 7–21; HCC (n = 2); HCV genotype 1a (n = 8), 1b (n = 2), 4 (n = 2)). Furthermore, 2 HCV/HIV-coinfected patients were denoted having received DAA therapy after liver transplantation (characteristics: HCV genotype 1a (n = 1), 4 (n = 1)).
Results: Applied DAA regimens were SOF/DAC (n = 7), SOF/LDV/RBV (n = 3), SOF/RBV (n = 3), PTV/r/OBV/DSV (n = 1), or PTV/r/OBV/DSV/RBV (n = 1), respectively. All patients achieved SVR 12, in the end. In one patient, HCV relapse occurred after 24 weeks of SOF/DAC therapy; subsequent treatment with 12 weeks PTV/r/OBV/DSV achieved SVR 12. One patient underwent liver transplantation while on DAA treatment. Analysis of liver function revealed either stable parameters or even significant improvement during DAA therapy and in follow-up. MELD scores were found to improve in 9/13 therapies in patients on the waiting list for liver transplantation; in only 2 patients a moderate increase of MELD scores persisted at the end of follow-up.
Conclusion: DAA treatment was safe and highly effective in this nation-wide cohort of patients with HCV/HIV-coinfection awaiting liver transplantation or being transplanted.
Background & Aims: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are increasingly a cause of cirrhosis and hepatocellular carcinoma globally. This burden is expected to increase as epidemics of obesity, diabetes and metabolic syndrome continue to grow. The goal of this analysis was to use a Markov model to forecast NAFLD disease burden using currently available data.
Methods: A model was used to estimate NAFLD and NASH disease progression in eight countries based on data for adult prevalence of obesity and type 2 diabetes mellitus (DM). Published estimates and expert consensus were used to build and validate the model projections.
Results: If obesity and DM level off in the future, we project a modest growth in total NAFLD cases (0–30%), between 2016–2030, with the highest growth in China as a result of urbanization and the lowest growth in Japan as a result of a shrinking population. However, at the same time, NASH prevalence will increase 15–56%, while liver mortality and advanced liver disease will more than double as a result of an aging/increasing population.
Conclusions: NAFLD and NASH represent a large and growing public health problem and efforts to understand this epidemic and to mitigate the disease burden are needed. If obesity and DM continue to increase at current and historical rates, both NAFLD and NASH prevalence are expected to increase. Since both are reversible, public health campaigns to increase awareness and diagnosis, and to promote diet and exercise can help manage the growth in future disease burden.
Lay summary: Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis can lead to advanced liver disease. Both conditions are becoming increasingly prevalent as the epidemics of obesity and diabetes continue to increase. A mathematical model was built to understand how the disease burden associated with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis will change over time. Results suggest increasing cases of advanced liver disease and liver-related mortality in the coming years.
Purpose: Collaborative care is effective in improving symptoms of patients with depression. The aims of this study were to characterize symptom trajectories in patients with major depression during one year of collaborative care and to explore associations between baseline characteristics and symptom trajectories.
Methods: We conducted a cluster-randomized controlled trial in primary care. The collaborative care intervention comprised case management and behavioral activation. We used the Patient Health Questionnaire-9 (PHQ-9) to assess symptom severity as the primary outcome. Statistical analyses comprised latent growth mixture modeling and a hierarchical binary logistic regression model.
Results: We included 74 practices and 626 patients (310 intervention and 316 control recipients) at baseline. Based on a minimum of 12 measurement points for each intervention recipient, we identified two latent trajectories, which we labeled "fast improvers" (60.5%) and "slow improvers" (39.5%). At all measurements after baseline, "fast improvers" presented higher PHQ mean values than "slow improvers". At baseline, "fast improvers" presented fewer physical conditions, higher health-related quality of life, and had made fewer suicide attempts in their history.
Conclusions: A notable proportion of 39.5% of patients improved only "slowly" and probably needed more intense treatment. The third follow-up in month two could well be a sensible time to adjust treatment to support "slow improvers".
Cervical spine injuries are frequent and often caused by a blunt trauma mechanism. They can have severe consequences, with a high mortality rate and a high rate of neurological lesions.Diagnosis is a three-step process: 1) risk assessment according to the history and clinical features, guided by a clinical decision rule such as the Canadian C-Spine rule; 2) imaging if needed; 3) classification of the injury according to different classification systems in the different regions of the cervical spine.The urgency of treatment is dependent on the presence of a neurological lesion and/or instability. The treatment strategy depends on the morphological criteria as defined by the classification.
We summarize previous work on b̅b̅ud four-quark systems in the Born-Oppenheimer approximation and discuss first steps towards an extension to the theoretically more challenging bb̅ud̅ system. Strategies to identify a possibly existing bb̅ud̅ bound state are discussed and first numerical results are presented.
We study tetraquark resonances with lattice QCD potentials computed for two static quarks and two dynamical quarks, the Born-Oppenheimer approximation and the emergent wave method of scattering theory. As a proof of concept we focus on systems with isospin I = 0, but consider different relative angular momenta l of the heavy b quarks. We compute the phase shifts and search for S and T matrix poles in the second Riemann sheet. We predict a new tetraquark resonance for l = 1, decaying into two B mesons, with quantum numbers I(JP) = 0(1−), mass MeV and decay width MeV.
Роботу «Філософія і вчитель» Теодор Адорно вперше прочитав як доповідь у Будинку студентів міста Франкфурта-на-Майні в листопаді 1961 року. У цій доповіді Адорно продовжив тему критики тих чинників тодішньої освіти Західної Німеччини, які унеможливлюють особисту боротьбу інтелектуала з культурними залишками тоталітарного суспільства. Адорно зауважив такий важливий елемент освітнього процесу, яким є іспит із філософії. Цей іспит мають складати майбутні вчителі, кандидати на посаду викладача ґімназії. Також Адорно звернув свою увагу на тенденцію формалістичного дотримання Правил складання іспитів деякими майбутніми вчителями, які не здатні зрозуміти гуманістичну, емансипаційно-духовну суть філософії, а отже й не розуміють мету проведення названого іспиту. Ушанувавши давню традицію академічної свободи німецького Університету, Адорно зауважив постать німецького філософа, охарактеризувавши його тією людиною, інтелектуальна діяльність якої вплинула на гуманізацію освіти в німецькому Університеті, що безпосередньо далося взнаки відповідним социокультурним перетворенням. Однак, на думку Адорно, в повоєнних університетах ФРН переважає тенденція дотримання засад саме наукового пізнання. Ця тенденція поєднана зі ставленням деяких майбутніх учителів до знання як до привласненого у споживацький спосіб, що зумовлено браком особистої любові до власного фаху й до своїх студентів. Адорно був переконаний у тому, що такі вчителі байдужі до свого фаху й не мають до нього покликання. Ознакою відсутності покликання в цих людях Адорно назвав інтелектуальну недбалість, провінційність мовлення і провінційну нездатність зрозуміти свободу людини як духовну цінність. Подібні вчителі неспроможні пропонувати нове знання своїм студентам як за допомогою добірного усного мовлення, так і за допомогою досконалого письмового викладу. Цілком іншою Адорно запропонував убачати людину, яка здатна засвоювати знання, що потрібні для розуміння свого професійного обов’язку. Використовуючи саморозуміння та саморефлексію, вона зможе самостійно збагнути сенс своєї педагогічної роботи. Ця людина сумлінно і терпляче виконуватиме свою роботу задля практичного впровадження в суспільство гуманістичних ідеалів попереднього філософського знання.
Using a data sample of e+e− collision data corresponding to an integrated luminosity of 2.93 fb−1 collected with the BESIII detector at a center-of-mass energy of s=3.773GeV, we search for the singly Cabibbo-suppressed decays D0→π0π0π0, π0π0η, π0ηη and ηηη using the double tag method. The absolute branching fractions are measured to be B(D0→π0π0π0)=(2.0±0.4±0.3)×10−4, B(D0→π0π0η)=(3.8±1.1±0.7)×10−4 and B(D0→π0ηη)=(7.3±1.6±1.5)×10−4 with the statistical significances of 4.8σ, 3.8σ and 5.5σ, respectively, where the first uncertainties are statistical and the second ones systematic. No significant signal of D0→ηηη is found, and the upper limit on its decay branching fraction is set to be B(D0→ηηη)<1.3×10−4 at the 90% confidence level.
Що означає «опрацювання минулого» : (переклад з німецької, анотація і післямова Віталія Брижніка)
(2018)
Роботу «Що означає «опрацювання Минулого» Адорно вперше прочитав як доповідь 6 листопада 1959 року перед Координаційною радою з питань християнсько-єврейської співпраці. У цій доповіді Адорно розглянув суть соціальної ідеології, панівної в повоєнній Німеччині, яка зумовлювала стратегії суспільного примирення з політичними злочинами колишньої націонал-соціалістичної влади. На думку філософа, соціальна ідеологія суспільства споживання використовує чималу кількість відповідних засобів, аби стабілізувати свій панівний статус у суспільстві. Й передусім вона намагається ліквідувати колективну історичну пам’ять людей про жахи воєнного періоду, прагнучи витиснути їх із колективної свідомості, зокрема й завдяки спогадам людей про «кращі часи» життя під «опікою» попередньої, тоталітарної влади. Філософ назвав суроґатною ідентичність цих людей, соціально інтеґрованих лише завдяки авторитету владної особистості. Вони не ототожнюють себе з жертвами тоталітарного режиму через уплив на їхню свідомість культурних елементів цієї соціальної ідеології. Іншим наслідком даного впливу також стає відчуження цих людей від ідеї демократії як чинника належних соціокультурних перетворень. Дієвим засобом подолання цього впливу Адорно визначив нову, «демократичну педагогіку» і просвіту як «другу освіту», що практично здійснюють у суспільстві освічені люди, які володіють знанням про минулі злочини тоталітарного режиму. Тим самим вони зумовлюють у межах освітнього процесу дієве «опрацювання Минулого» через формування особистого розуміння окремої людини соціальних причин і жахливих наслідків панування тоталітарного режиму. Це ліквідує її «політичне неповноліття» й тим самим унеможливлює історичне повторення в Європі злочинів авторитарної влади.
Based on an 𝑒+𝑒− collision data sample corresponding to an integrated luminosity of 567 pb−1 taken at the center-of-mass energy of √𝑠=4.6 GeV with the BESIII detector, we measure the absolute branching fraction of the inclusive decay Λ+𝑐→Λ+𝑋 to be ℬ(Λ+𝑐→Λ+𝑋)=(38.2+2.8−2.2±0.9)% using the double-tag method, where 𝑋 refers to any possible final state particles. In addition, we search for direct 𝐶𝑃 violation in the charge asymmetry of this inclusive decay for the first time, and obtain 𝒜𝐶𝑃≡[ℬ(Λ+𝑐→Λ+𝑋)−ℬ(¯Λ−𝑐 → ¯Λ+𝑋)]/[ℬ(Λ+𝑐→Λ+𝑋)+ℬ(¯Λ−𝑐 → ¯Λ+𝑋)]=(2.1+7.0−6.6±1.6)%, a statistically limited result with no evidence of 𝐶𝑃 violation.
Using an 𝑒+𝑒− collision data sample of 2.93 fb−1 collected at a center-of-mass energy of 3.773 GeV by the BESIII detector at BEPCII, we report the observation of 𝐷0→𝑎0(980)−𝑒+𝜈𝑒 and evidence for 𝐷+→𝑎0(980)0𝑒+𝜈𝑒 with significances of 6.4𝜎 and 2.9𝜎, respectively. The absolute branching fractions are determined to be ℬ(𝐷0→𝑎0(980)−𝑒+𝜈𝑒)×ℬ(𝑎0(980)−→𝜂𝜋−) = [1.33+0.33−0.29(stat)±0.09(syst)]×10−4 and ℬ(𝐷+→𝑎0(980)0𝑒+𝜈𝑒)×ℬ(𝑎0(980)0→𝜂𝜋0)=[1.66+0.81
−0.66(stat)±0.11(syst)]×10−4. This is the first time the 𝑎0(980) meson has been measured in a 𝐷0 semileptonic decay, which would open one more interesting page in the investigation of the nature of the puzzling 𝑎0(980) states.
Using a data sample of 448.1×106 𝜓(3686) events collected with the BESIII detector operating at the BEPCII, we perform search for the hadronic transition ℎ𝑐→𝜋+𝜋−𝐽/𝜓 via 𝜓(3686)→𝜋0ℎ𝑐. No signals of the transition are observed, and the upper limit on the product branching fraction ℬ(𝜓(3686)→𝜋0ℎ𝑐)ℬ(ℎ𝑐→𝜋+𝜋−𝐽/𝜓) at the 90% confidence level (C.L.) is determined to be 2.0×10−6. This is the most stringent upper limit to date.
The decay 𝐽/𝜓→𝛾𝛾𝜙 is studied using a sample of 1.31×109 𝐽/𝜓 events collected with the BESIII detector. Two structures around 1475 MeV/𝑐2 and 1835 MeV/𝑐2 are observed in the 𝛾𝜙 invariant mass spectrum for the first time. With a fit on the 𝛾𝜙 invariant mass, which takes into account the interference between the two structures, and a simple analysis of the angular distribution, the structure around 1475 MeV/𝑐2 is found to favor an assignment as the 𝜂(1475) and the mass and width for the structure around 1835 MeV/𝑐2 are consistent with the 𝑋(1835). The statistical significances of the two structures are 13.5𝜎 and 6.3𝜎, respectively. The results indicate that both 𝜂(1475) and 𝑋(1835) contain a sizeable 𝑠¯𝑠 component.
Using a low background data sample of 9.7×105 𝐽/𝜓→𝛾𝜂′, 𝜂′→𝛾𝜋+𝜋− events, which are 2 orders of magnitude larger than those from the previous experiments, recorded with the BESIII detector at BEPCII, the decay dynamics of 𝜂′→𝛾𝜋+𝜋− are studied with both model-dependent and model-independent approaches. The contributions of 𝜔 and the 𝜌(770)−𝜔 interference are observed for the first time in the decays 𝜂′→𝛾𝜋+𝜋− in both approaches. Additionally, a contribution from the box anomaly or the 𝜌(1450) resonance is required in the model-dependent approach, while the process specific part of the decay amplitude is determined in the model-independent approach.
Using a data sample of 448.1 × 106 ψ(3686) events collected with the BESIII detector at the BEPCII collider, we report the first observation of the electromagnetic Dalitz decay ψ(3686) → η e+e−, with significances of 7.0σ and 6.3σ when reconstructing the η meson via its decay modes η → γπ+π− and η → π+π−η (η → γγ ), respectively. The weighted average branching fraction is determined to be B(ψ(3686) → η e+e−) = (1.90 ± 0.25 ± 0.11) × 10−6, where the first uncertainty is statistical and the second systematic.
The transversity distribution, which describes transversely polarized quarks in transversely polarized nucleons, is a fundamental component of the spin structure of the nucleon, and is only loosely constrained by global fits to existing semi-inclusive deep inelastic scattering (SIDIS) data. In transversely polarized p↑+p collisions it can be accessed using transverse polarization dependent fragmentation functions which give rise to azimuthal correlations between the polarization of the struck parton and the final state scalar mesons.This letter reports on spin dependent di-hadron correlations measured by the STAR experiment. The new dataset corresponds to 25 pb−1 integrated luminosity of p↑+p collisions at s=500 GeV, an increase of more than a factor of ten compared to our previous measurement at s=200 GeV. Non-zero asymmetries sensitive to transversity are observed at a Q2 of several hundred GeV and are found to be consistent with the former measurement and a model calculation. We expect that these data will enable an extraction of transversity with comparable precision to current SIDIS datasets but at much higher momentum transfers where subleading effects are suppressed.
Fluctuations of conserved quantities such as baryon number, charge, and strangeness are sensitive to the correlation length of the hot and dense matter created in relativistic heavy-ion collisions and can be used to search for the QCD critical point. We report the first measurements of the moments of net-kaon multiplicity distributions in Au+Au collisions at √sNN = 7.7, 11.5, 14.5, 19.6, 27, 39, 62.4, and 200 GeV. The collision centrality and energy dependence of the mean (M), variance (σ 2), skewness (S), and kurtosis (κ) for net-kaon multiplicity distributions as well as the ratio σ 2/M and the products Sσ and κσ 2 are presented. Comparisons are made with Poisson and negative binomial baseline calculations as well as with UrQMD, a transport model (UrQMD) that does not include effects from the QCD critical point. Within current uncertainties, the net-kaon cumulant ratios appear to be monotonic as a function of collision energy.
New measurements of directed flow for charged hadrons, characterized by the Fourier coefficient v1, are presented for transverse momenta pT, and centrality intervals in Au+Au collisions recorded by the STAR experiment for the center-of-mass energy range √sN N = 7.7–200 GeV. The measurements underscore the importance of momentum conservation, and the characteristic dependencies on √sN N , centrality and pT are consistent with the expectations of geometric fluctuations generated in the initial stages of the collision, acting in concert with a hydrodynamic-like expansion. The centrality and pT dependencies of veven 1 , as well as an observed similarity between its excitation function and that for v3, could serve as constraints for initial-state models. The veven 1 excitation function could also provide an important supplement to the flow measurements employed for precision extraction of the temperature dependence of the specific shear viscosity.
We report new measurements of the cross sections for the production of Dbar D final states at the ψ(3770) resonance. Our data sample consists of an integrated luminosity of 2.93 fb−1 of e+e− annihilation data produced by the BEPCII collider and collected and analyzed with the BESIII detector. We exclusively reconstruct three D0 and six D+ hadronic decay modes and use the ratio of the yield of fully reconstructed Dbar D events ("double tags") to the yield of all reconstructed D or bar D mesons ("single tags") to determine the number of D0bar D0 and D+D− events, benefiting from the cancellation of many systematic uncertainties. Combining these yields with an independent determination of the integrated luminosity of the data sample, we find the cross sections to be σ(e+e− → D0bar D0) nb and σ(e+e− → D+D−) = (2.830 ± 0.011 ± 0.026) nb, where the uncertainties are statistical and systematic, respectively.
Using a data sample of 𝑒+𝑒− collisions corresponding to an integrated luminosity of 567 pb−1 collected at a center-of-mass energy of √𝑠=4.6 GeV with the BESIII detector, we measure the absolute branching fraction of the inclusive semileptonic Λ+𝑐 decay with a double-tag method. We obtain ℬ(Λ+𝑐→𝑋𝑒+𝜈𝑒)=(3.95±0.34±0.09)%, where the first uncertainty is statistical and the second systematic. Using the known Λ+𝑐 lifetime and the charge-averaged semileptonic decay width of nonstrange charmed mesons (𝐷0 and 𝐷+), we obtain the ratio of the inclusive semileptonic decay widths Γ(Λ+𝑐→𝑋𝑒+𝜈𝑒)/¯Γ(𝐷→𝑋𝑒+𝜈𝑒)=1.26±0.12.
b̄b̄ud tetraquark resonances in the Born-Oppenheimer approximation using lattice QCD potentials
(2018)
We study tetraquark resonances using lattice QCD potentials for a pair of static antiquarks b¯b¯ in the presence of two light quarks ud. The system is treated in the Born-Oppenheimer approximation and we use the emergent wave method. We focus on the isospin I=0 channel, but consider different orbital angular momenta l of the heavy antiquarks b¯b¯. We extract the phase shifts and search for S and T matrix poles on the second Riemann sheet. For orbital angular momentum l=1 we find a tetraquark resonance with quantum numbers I(JP)=0(1−), resonance mass m=10576+4−4MeV and decay width Γ=112+90−103MeV, which can decay into two B mesons.
Chamomile, parsley, and celery represent major botanical sources of apigenin, a well-known flavone with chemopreventive properties. The aim of this study was to assess the phytochemical composition, antioxidant, and anti-inflammatory potential of methanol extracts obtained from chamomile, parsley, and celery collected from Romania, as well as the biological activity against A375 human melanoma and human dendritic cells. Results have shown that all three extracts are rich in polyphenolic compounds and flavonoids, and they generate a radical scavenger capacity, iron chelation potential, as well as lipoxygenase inhibition capacity. Chamomile and celery extracts present weak antiproliferative and pro-apoptotic properties in the set experimental conditions, while parsley extract draws out significant pro-apoptotic potential against A375 human melanoma cells. Parsley and chamomile extracts affected the fibroblast-like morphology of the screened tumor cell line. On the other hand, chamomile and celery extracts abrogated the expansion of LPS-activated dendritic cells, while the metabolic activity was attenuated by stimulation with celery extract; chamomile and parsley extracts had no effect upon this parameter. Chamomile and parsley extracts incubation with naive dendritic cells did not trigger cytokine secretion (TNF-alpha, IL-6, IL-10), but celery extract stimulation significantly reduced the anti-inflammatory, cytokine IL-10.
Using a sample of 4.48×108 ψ(3686) events collected with the BESIII detector at the BEPCII collider, we study the two-photon decays of the pseudoscalar mesons π0, η, η′, η(1405), η(1475), η(1760), and X(1835) in J/ψ radiative decays using ψ(3686)→π+π−J/ψ events. The π0, η and η′ mesons are clearly observed in the two-photon mass spectra, and the branching fractions are determined to be B(J/ψ→γπ0→3γ)=(3.57±0.12±0.16)×10−5, B(J/ψ→γη→3γ)=(4.42±0.04±0.18)×10−4, and B(J/ψ→γη′→3γ)=(1.26±0.02±0.05)×10−4, where the first errors are statistical and the second systematic. No clear signal for η(1405), η(1475), η(1760) or X(1835) is observed in the two-photon mass spectra, and upper limits at the 90% confidence level on the product branching fractions are obtained.