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We report inclusive photon measurements about midrapidity ( |y| <0.5 ) from 197 Au + 197 Au collisions at sqrt[sNN ]=130 GeV at RHIC. Photon pair conversions were reconstructed from electron and positron tracks measured with the Time Projection Chamber (TPC) of the STAR experiment. With this method, an energy resolution of Delta E/E ~ 2% at 0.5 GeV has been achieved. Reconstructed photons have also been used to measure the transverse momentum ( pt ) spectra of pi 0 mesons about midrapidity ( |y| <1 ) via the pi 0 --> gamma gamma decay channel. The fractional contribution of the pi 0 --> gamma gamma decay to the inclusive photon spectrum decreases by 20%±5% between pt =1.65 GeV/c and pt =2.4 GeV/c in the most central events, indicating that relative to pi 0 --> gamma gamma decay the contribution of other photon sources is substantially increasing.
We report on the rapidity and centrality dependence of proton and antiproton transverse mass distributions from 197Au + 197Au collisions at sqrt[sNN ]=130 GeV as measured by the STAR experiment at the Relativistic Heavy Ion Collider (RHIC). Our results are from the rapidity and transverse momentum range of |y| <0.5 and 0.35< pt <1.00 GeV/c . For both protons and antiprotons, transverse mass distributions become more convex from peripheral to central collisions demonstrating characteristics of collective expansion. The measured rapidity distributions and the mean transverse momenta versus rapidity are flat within |y| <0.5 . Comparisons of our data with results from model calculations indicate that in order to obtain a consistent picture of the proton (antiproton) yields and transverse mass distributions the possibility of prehadronic collective expansion may have to be taken into account.
We present the first large-acceptance measurement of event-wise mean transverse momentum <pt> fluctuations for Au-Au collisions at nucleon-nucleon center-of-momentum collision energy sqrt[sNN] = 130 GeV. The observed nonstatistical <pt> fluctuations substantially exceed in magnitude fluctuations expected from the finite number of particles produced in a typical collision. The r.m.s. fractional width excess of the event-wise <pt> distribution is 13.7±0.1(stat) ±1.3(syst)% relative to a statistical reference, for the 15% most-central collisions and for charged hadrons within pseudorapidity range | eta |<1,2 pi azimuth, and 0.15 <= pt <= 2 GeV/c. The width excess varies smoothly but nonmonotonically with collision centrality and does not display rapid changes with centrality which might indicate the presence of critical fluctuations. The reported <pt> fluctuation excess is qualitatively larger than those observed at lower energies and differs markedly from theoretical expectations. Contributions to <pt> fluctuations from semihard parton scattering in the initial state and dissipation in the bulk colored medium are discussed.
We present STAR measurements of the azimuthal anisotropy parameter v2 and the binary-collision scaled centrality ratio RCP for kaons and lambdas ( Lambda + Lambda -bar) at midrapidity in Au+Au collisions at sqrt[sNN]=200 GeV. In combination, the v2 and RCP particle-type dependencies contradict expectations from partonic energy loss followed by standard fragmentation in vacuum. We establish pT ~ 5 GeV/c as the value where the centrality dependent baryon enhancement ends. The K0S and Lambda + Lambda -bar v2 values are consistent with expectations of constituent-quark-number scaling from models of hadron formation by parton coalescence or recombination.
Pion-kaon correlation functions are constructed from central Au+Au STAR data taken at sqrt[sNN]=130 GeV by the STAR detector at the Relativistic Heavy Ion Collider (RHIC). The results suggest that pions and kaons are not emitted at the same average space-time point. Space-momentum correlations, i.e., transverse flow, lead to a space-time emission asymmetry of pions and kaons that is consistent with the data. This result provides new independent evidence that the system created at RHIC undergoes a collective transverse expansion.
Data from the first physics run at the Relativistic Heavy-Ion Collider at Brookhaven National Laboratory, Au+Au collisions at sqrt[sNN]=130 GeV, have been analyzed by the STAR Collaboration using three-pion correlations with charged pions to study whether pions are emitted independently at freeze-out. We have made a high-statistics measurement of the three-pion correlation function and calculated the normalized three-particle correlator to obtain a quantitative measurement of the degree of chaoticity of the pion source. It is found that the degree of chaoticity seems to increase with increasing particle multiplicity.
We report high statistics measurements of inclusive charged hadron production in Au+Au and p+p collisions at sqrt[sNN]=200 GeV. A large, approximately constant hadron suppression is observed in central Au+Au collisions for 5<pT<12 GeV/c. The collision energy dependence of the yields and the centrality and pT dependence of the suppression provide stringent constraints on theoretical models of suppression. Models incorporating initial-state gluon saturation or partonic energy loss in dense matter are largely consistent with observations. We observe no evidence of pT-dependent suppression, which may be expected from models incorporating jet attenuation in cold nuclear matter or scattering of fragmentation hadrons.
The balance function is a new observable based on the principle that charge is locally conserved when particles are pair produced. Balance functions have been measured for charged particle pairs and identified charged pion pairs in Au+Au collisions at sqrt[sNN]=130 GeV at the Relativistic Heavy Ion Collider using STAR. Balance functions for peripheral collisions have widths consistent with model predictions based on a superposition of nucleon-nucleon scattering. Widths in central collisions are smaller, consistent with trends predicted by models incorporating late hadronization.
We present the results of charged particle fluctuations measurements in Au+Au collisions at sqrt[sNN ]=130 GeV using the STAR detector. Dynamical fluctuations measurements are presented for inclusive charged particle multiplicities as well as for identified charged pions, kaons, and protons. The net charge dynamical fluctuations are found to be large and negative providing clear evidence that positive and negative charged particle production is correlated within the pseudorapidity range investigated. Correlations are smaller than expected based on model-dependent predictions for a resonance gas or a quark-gluon gas which undergoes fast hadronization and freeze-out. Qualitative agreement is found with comparable scaled p+p measurements and a heavy ion jet interaction generation model calculation based on independent particle collisions, although a small deviation from the 1/N scaling dependence expected from this model is observed.
We report measurements of single-particle inclusive spectra and two-particle azimuthal distributions of charged hadrons at high transverse momentum (high pT) in minimum bias and central d+Au collisions at sqrt[sNN]=200 GeV. The inclusive yield is enhanced in d+Au collisions relative to binary-scaled p+p collisions, while the two-particle azimuthal distributions are very similar to those observed in p+p collisions. These results demonstrate that the strong suppression of the inclusive yield and back-to-back correlations at high pT previously observed in central Au+Au collisions are due to final-state interactions with the dense medium generated in such collisions.
Azimuthal anisotropy (v2) and two-particle angular correlations of high pT charged hadrons have been measured in Au+Au collisions at sqrt[sNN]=130 GeV for transverse momenta up to 6 GeV/c, where hard processes are expected to contribute significantly. The two-particle angular correlations exhibit elliptic flow and a structure suggestive of fragmentation of high pT partons. The monotonic rise of v2(pT) for pT<2 GeV/c is consistent with collective hydrodynamical flow calculations. At pT>3 GeV/c, a saturation of v2 is observed which persists up to pT=6 GeV/c.
Azimuthal anisotropy (v2) and two-particle angular correlations of high pT charged hadrons have been measured in Au+Au collisions at sqrt[sNN]=130 GeV for transverse momenta up to 6 GeV/c, where hard processes are expected to contribute significantly. The two-particle angular correlations exhibit elliptic flow and a structure suggestive of fragmentation of high pT partons. The monotonic rise of v2(pT) for pT<2 GeV/c is consistent with collective hydrodynamical flow calculations. At pT>3 GeV/c, a saturation of v2 is observed which persists up to pT=6 GeV/c.
Transverse mass and rapidity distributions for charged pions, charged kaons, protons, and antiprotons are reported for sqrt[sNN]=200 GeV pp and Au+Au collisions at Relativistic Heary Ion Collider (RHIC). Chemical and kinetic equilibrium model fits to our data reveal strong radial flow and long duration from chemical to kinetic freeze-out in central Au+Au collisions. The chemical freeze-out temperature appears to be independent of initial conditions at RHIC energies.
Measurements of the production of forward high-energy pi 0 mesons from transversely polarized proton collisions at sqrt[s]=200 GeV are reported. The cross section is generally consistent with next-to-leading order perturbative QCD calculations. The analyzing power is small at xF below about 0.3, and becomes positive and large at higher xF, similar to the trend in data at sqrt[s] <= 20 GeV. The analyzing power is in qualitative agreement with perturbative QCD model expectations. This is the first significant spin result seen for particles produced with pT>1 GeV/c at a polarized proton collider.
We report the first observations of the first harmonic (directed flow, v1) and the fourth harmonic (v4), in the azimuthal distribution of particles with respect to the reaction plane in Au+Au collisions at the BNL Relativistic Heavy Ion Collider (RHIC). Both measurements were done taking advantage of the large elliptic flow (v2) generated at RHIC. From the correlation of v2 with v1 it is determined that v2 is positive, or in-plane. The integrated v4 is about a factor of 10 smaller than v2. For the sixth (v6) and eighth (v8) harmonics upper limits on the magnitudes are reported.
Elliptic flow holds much promise for studying the early-time thermalization attained in ultrarelativistic nuclear collisions. Flow measurements also provide a means of distinguishing between hydrodynamic models and calculations which approach the low density (dilute gas) limit. Among the effects that can complicate the interpretation of elliptic flow measurements are azimuthal correlations that are unrelated to the reaction plane (nonflow correlations). Using data for Au + Au collisions at sqrt[sNN]=130 GeV from the STAR time projection chamber, it is found that four-particle correlation analyses can reliably separate flow and nonflow correlation signals. The latter account for on average about 15% of the observed second-harmonic azimuthal correlation, with the largest relative contribution for the most peripheral and the most central collisions. The results are also corrected for the effect of flow variations within centrality bins. This effect is negligible for all but the most central bin, where the correction to the elliptic flow is about a factor of 2. A simple new method for two-particle flow analysis based on scalar products is described. An analysis based on the distribution of the magnitude of the flow vector is also described.
We report the first observation of K*(892)0--> pi K in relativistic heavy ion collisions. The transverse momentum spectrum of (K*0+K*0)/2 from central Au+Au collisions at sqrt[sNN]=130 GeV is presented. The ratios of the K*0 yield derived from these data to the yields of negative hadrons, charged kaons, and phi mesons have been measured in central and minimum bias collisions and compared with model predictions and comparable e+e-, pp, and p-barp results. The data indicate no dramatic reduction of K*0 production in relativistic heavy ion collisions despite expected losses due to rescattering effects.
The STAR Collaboration reports the first observation of exclusive rho 0 photoproduction, AuAu-->AuAu rho 0, and rho 0 production accompanied by mutual nuclear Coulomb excitation, AuAu-->Au [star] Au [star] rho 0, in ultraperipheral heavy-ion collisions. The rho 0 have low transverse momenta, consistent with coherent coupling to both nuclei. The cross sections at sqrt[sNN]=130 GeV agree with theoretical predictions treating rho 0 production and Coulomb excitation as independent processes.
We report STAR results on the azimuthal anisotropy parameter v2 for strange particles K0S, Lambda , and Lambda -bar at midrapidity in Au+Au collisions at sqrt[sNN]=130 GeV at the Relativistic Heavy Ion Collider. The value of v2 as a function of transverse momentum, pt, of the produced particle and collision centrality is presented for both particles up to pt~3.0 GeV/c. A strong pt dependence in v2 is observed up to 2.0 GeV/c. The v2 measurement is compared with hydrodynamic model calculations. The physics implications of the pt integrated v2 magnitude as a function of particle mass are also discussed.
Inclusive transverse momentum distributions of charged hadrons within 0.2<pT<6.0 GeV/c have been measured over a broad range of centrality for Au+Au collisions at sqrt[sNN]=130 GeV. Hadron yields are suppressed at high pT in central collisions relative to peripheral collisions and to a nucleon-nucleon reference scaled for collision geometry. Peripheral collisions are not suppressed relative to the nucleon-nucleon reference. The suppression varies continuously at intermediate centralities. The results indicate significant nuclear medium effects on high-pT hadron production in heavy-ion collisions at high energy.
We report the first measurement of strange ( Lambda ) and antistrange ( Lambda -bar) baryon production from sqrt[sNN]=130 GeV Au+Au collisions at the Relativistic Heavy Ion Collider (RHIC). Rapidity density and transverse mass distributions at midrapidity are presented as a function of centrality. The yield of Lambda and Lambda -bar hyperons is found to be approximately proportional to the number of negative hadrons. The production of Lambda -bar hyperons relative to negative hadrons increases very rapidly with transverse momentum. The magnitude of the increase cannot be described by existing hadronic string fragmentation models alone.
Interleukin-7 (IL-7) is an important cytokine with pivotal pro-survival functions in the adaptive immune system. However, the role of IL-7 in innate immunity is not fully understood. In the present study, the impact of hepatic IL-7 on innate immune cells was assessed by functional experiments as well as in patients with different stages of liver cirrhosis or acute-on-chronic liver failure (ACLF). Human hepatocytes and liver sinusoidal endothelial cells secreted IL-7 in response to stimulation with interferons (IFNs) of type I and II, yet not type III. De novo translation of interferon-response factor-1 (IRF-1) restricted IL-7 production to stimulation with type I and II IFNs. LPS-primed human macrophages were identified as innate immune target cells responding to IL-7 signaling by inactivation of Glycogen synthase kinase-3 (GSK3). IL-7-mediated GSK3 inactivation augmented LPS-induced secretion of pro-inflammatory cytokines and blunted LPS tolerance of macrophages. The IFN-IRF-1-IL-7 axis was present in liver cirrhosis patients. However, liver cirrhosis patients with or without ACLF had significantly lower concentrations of IL-7 in serum compared to healthy controls, which might contribute to LPS-tolerance in these patients. In conclusion, we propose the presence of an inflammatory cascade where IFNs of type I/II induce hepatocellular IL-7 in an IRF-1-restriced way. Beyond its role in adaptive immune responses, IL-7 appears to augment the response of macrophages to LPS and to ameliorate LPS tolerance, which may improve innate immune responses against invading pathogens.
Two-pion correlation functions in Au+Au collisions at sqrt[sNN] = 130 GeV have been measured by the STAR (solenoidal tracker at RHIC) detector. The source size extracted by fitting the correlations grows with event multiplicity and decreases with transverse momentum. Anomalously large sizes or emission durations, which have been suggested as signals of quark-gluon plasma formation and rehadronization, are not observed. The Hanbury Brown-Twiss parameters display a weak energy dependence over a broad range in sqrt[sNN].
The first measurements of light antinucleus production in Au+Au collisions at the Relativistic Heavy-Ion Collider are reported. The observed production rates for d-bar and 3He-bar are much larger than in lower energy nucleus-nucleus collisions. A coalescence model analysis of the yields indicates that there is little or no increase in the antinucleon freeze-out volume compared to collisions at CERN SPS energy. These analyses also indicate that the 3He-bar freeze-out volume is smaller than the d-bar freeze-out volume.
We present the first measurement of midrapidity vector meson phi production in Au+Au collisions at RHIC (sqrt[sNN]=130 GeV) from the STAR detector. For the 11% highest multiplicity collisions, the slope parameter from an exponential fit to the transverse mass distribution is T=379±50(stat)±45(syst) MeV, the yield dN/dy=5.73±0.37(stat)±0.69(syst) per event, and the ratio N phi /Nh- is found to be 0.021±0.001(stat)±0.004(syst). The measured ratio N phi /Nh- and T for the phi meson at midrapidity do not change for the selected multiplicity bins.
Aim: Predicting future changes in species richness in response to climate change is one of the key challenges in biogeography and conservation ecology. Stacked species distribution models (S‐SDMs) are a commonly used tool to predict current and future species richness. Macroecological models (MEMs), regression models with species richness as response variable, are a less computationally intensive alternative to S‐SDMs. Here, we aim to compare the results of two model types (S‐SDMS and MEMs), for the first time for more than 14,000 species across multiple taxa globally, and to trace the uncertainty in future predictions back to the input data and modelling approach used.
Location: Global land, excluding Antarctica.
Taxon: Amphibians, birds and mammals.
Methods: We fitted S‐SDMs and MEMs using a consistent set of bioclimatic variables and model algorithms and conducted species richness predictions under current and future conditions. For the latter, we used four general circulation models (GCMs) under two representative concentration pathways (RCP2.6 and RCP6.0). Predicted species richness was compared between S‐SDMs and MEMs and for current conditions also to extent‐of‐occurrence (EOO) species richness patterns. For future predictions, we quantified the variance in predicted species richness patterns explained by the choice of model type, model algorithm and GCM using hierarchical cluster analysis and variance partitioning.
Results: Under current conditions, species richness predictions from MEMs and S‐SDMs were strongly correlated with EOO‐based species richness. However, both model types over‐predicted areas with low and under‐predicted areas with high species richness. Outputs from MEMs and S‐SDMs were also highly correlated among each other under current and future conditions. The variance between future predictions was mostly explained by model type.
Main conclusions: Both model types were able to reproduce EOO‐based patterns in global terrestrial vertebrate richness, but produce less collinear predictions of future species richness. Model type by far contributes to most of the variation in the different future species richness predictions, indicating that the two model types should not be used interchangeably. Nevertheless, both model types have their justification, as MEMs can also include species with a restricted range, whereas S‐SDMs are useful for looking at potential species‐specific responses.
Background: Isolated transient vertigo can be the only symptom of posterior circulation ischemia. Thus, it is important to differentiate isolated vertigo of a cerebrovascular origin from that of more benign origins, as patients with cerebral ischemia have a much higher risk for future stroke than do those with "peripheral" vertigo. The current study aims to identify risk factors for cerebrovascular origin of isolated transient vertigo, and for future cerebrovascular events.
Methods: From the files of 339 outpatients with isolated transient vertigo we extracted history, clinical and technical findings, diagnosis, and follow-up information on subsequent stroke or transient ischemic attack (TIA). Risk factors were analyzed using multivariate regression models (logistic or Cox) and reconfirmed in univariate analyses.
Results: On first presentation, 48 (14.2%) patients received the diagnosis "probable or definite cerebrovascular vertigo". During follow-up, 41 patients suffered stroke or TIA (event rate 7.9 per 100 person years, 95% confidence interval (CI) 5.5–10.4), 26 in the posterior circulation (event rate 4.8 per 100 person years, 95% CI 3.0–6.7). The diagnosis was not associated with follow-up cerebrovascular events. In multivariate models testing multiple potential determinants, only the presentation mode was consistently associated with the diagnosis and stroke risk: patients who presented because of vertigo (rather than reporting vertigo when they presented for other reasons) had a significantly higher risk for future stroke or TIA (p = 0.028, event rate 13.4 vs. 5.4 per 100 person years) and for future posterior circulation stroke or TIA (p = 0.044, event rate 7.8 vs. 3.5 per 100 person years).
Conclusions: We here report for the first time follow-up stroke rates in patients with transient isolated vertigo. In such patients, the identification of those with cerebrovascular origin remains difficult, and presentation mode was found to be the only consistent risk factor. Confirmation in an independent prospective sample is needed.
Background: In German breast cancer care, the S1-guidelines of the 1990s were substituted by national S3-guidelines in 2003. The application of guidelines became mandatory for certified breast cancer centers. The aim of the study was to assess guideline adherence according to time intervals and its impact on survival.
Methods: Women with primary breast cancer treated in three rural hospitals of one German geographical district were included. A cohort study design encompassed women from 1996–97 (N = 389) and from 2003–04 (N = 488). Quality indicators were defined along inpatient therapy sequences for each time interval and distinguished as guideline-adherent and guideline-divergent medical decisions. Based on all of the quality indicators, a binary overall adherence index was defined and served as a group indicator in multivariate Cox-regression models. A corrected group analysis estimated adjusted 5-year survival curves.
Results: From a total of 877 patients, 743 (85 %) and 504 (58 %) were included to assess 104 developed quality indicators and the resuming binary overall adherence index. The latter significantly increased from 13–15 % (1996–97) up to 33–35 % (2003–04). Within each time interval, no significant survival differences of guideline-adherent and -divergent treated patients were detected. Across time intervals and within the group of guideline-adherent treated patients only, survival increased but did not significantly differ between time intervals. Across time intervals and within the group of guideline-divergent treated patients only, survival increased and significantly differed between time intervals.
Conclusions: Infrastructural efforts contributed to the increase of process quality of the examined certified breast cancer center. Paradoxically, a systematic impact on 5-year survival has been observed for patients treated divergently from the guideline recommendations. This is an indicator for the appropriate application of guidelines. A maximization of guideline-based decisions instead of the ubiquitous demand of guideline adherence maximization is advocated.
Der nachfolgende Artikel stellt Regelungen zur Waldbehandlung dar, die nach den möglichen Auswirkungen bzw. Beeinträchtigungen des Lebensraumtypes durch forstliche Maßnahmen gegliedert sind. Die Auflistung für die einzelnen Lebenraumtypen ist jedoch nicht abschließend, sondern stellt nur eine Übersicht über die wesentlichen Maßnahmen einer Waldbehandlung dar.
LatticeQCD using OpenCL
(2011)
The Tarim River basin, located in Xinjiang, NW China, is the largest endorheic river basin in China and one of the largest in all of Central Asia. Due to the extremely arid climate, with an annual precipitation of less than 100 mm, the water supply along the Aksu and Tarim rivers solely depends on river water. This is linked to anthropogenic activities (e.g., agriculture) and natural and semi-natural ecosystems as both compete for water. The ongoing increase in water consumption by agriculture and other human activities in this region has been enhancing the competition for water between human needs and nature. Against this background, 11 German and 6 Chinese universities and research institutes have formed the consortium SuMaRiO (Sustainable Management of River Oases along the Tarim River; http://www.sumario.de), which aims to create a holistic picture of the availability of water resources in the Tarim River basin and the impacts on anthropogenic activities and natural ecosystems caused by the water distribution within the Tarim River basin. On the basis of the results from field studies and modeling approaches as well as from suggestions by the relevant regional stakeholders, a decision support tool (DST) will be implemented that will then assist stakeholders in balancing the competition for water, acknowledging the major external effects of water allocation to agriculture and to natural ecosystems. This consortium was formed in 2011 and is funded by the German Federal Ministry of Education and Research. As the data collection phase was finished this year, the paper presented here brings together the results from the fields from the disciplines of climate modeling, cryology, hydrology, agricultural sciences, ecology, geoinformatics, and social sciences in order to present a comprehensive picture of the effects of different water availability schemes on anthropogenic activities and natural ecosystems along the Tarim River. The second objective is to present the project structure of the whole consortium, the current status of work (i.e., major new results and findings), explain the foundation of the decision support tool as a key product of this project, and conclude with application recommendations for the region. The discharge of the Aksu River, which is the major tributary of the Tarim, has been increasing over the past 6 decades. From 1989 to 2011, agricultural area more than doubled: cotton became the major crop and there was a shift from small-scale to large-scale intensive farming. The ongoing increase in irrigated agricultural land leads to the increased threat of salinization and soil degradation caused by increased evapotranspiration. Aside from agricultural land, the major natural and semi-natural ecosystems are riparian (Tugai) forests, shrub vegetation, reed beds, and other grassland, as well as urban and peri-urban vegetation. Within the SuMaRiO cluster, focus has been set on the Tugai forests, with Populus euphratica as the dominant tree species, because these forests belong to the most productive and species-rich natural ecosystems of the Tarim River basin. At sites close to the groundwater, the annual stem diameter increments of Populus euphratica correlated with the river runoffs of the previous year. However, the natural river dynamics cease along the downstream course and thus hamper the recruitment of Populus euphratica. A study on the willingness to pay for the conservation of the natural ecosystems was conducted to estimate the concern of the people in the region and in China's capital. These household surveys revealed that there is a considerable willingness to pay for conservation of the natural ecosystems, with mitigation of dust and sandstorms considered the most important ecosystem service. Stakeholder dialogues contributed to creating a scientific basis for a sustainable management in the future.
It is long known that Kasugamycin inhibits translation of canonical transcripts containing a 5’-UTR with a Shine Dalgarno (SD) motif, but not that of leaderless transcripts. To gain a global overview of the influence of Kasugamycin on translation efficiencies, the changes of the translatome of Escherichia coli induced by a 10 minutes Kasugamycin treatment were quantified. The effect of Kasugamycin differed widely, 102 transcripts were at least twofold more sensitive to Kasugamycin than average, and 137 transcripts were at least twofold more resistant, and there was a more than 100-fold difference between the most resistant and the most sensitive transcript. The 5’-ends of 19 transcripts were determined from treated and untreated cultures, but Kasugamycin resistance did neither correlate with the presence or absence of a SD motif, nor with differences in 5’-UTR lengths or GC content. RNA Structure Logos were generated for the 102 Kasugamycin-sensitive and for the 137 resistant transcripts. For both groups a short Shine Dalgarno (SD) motif was retrieved, but no specific motifs associated with resistance or sensitivity could be found. Notably, this was also true for the region -3 to -1 upstream of the start codon and the presence of an extended SD motif, which had been proposed to result in Kasugamycin resistance. Comparison of the translatome results with the database RegulonDB showed that the transcript with the highest resistance was leaderless, but no further leaderless transcripts were among the resistant transcripts. Unexpectedly, it was found that translational coupling might be a novel feature that is associated with Kasugamycin resistance. Taken together, Kasugamycin has a profound effect on translational efficiencies of E. coli transcripts, but the mechanism of action is different than previously described.
In the context of Brexit, changes to the regulatory architecture of CCPs that empower the European securities markets regulator are under way to prevent the threat of a regulatory race to the bottom. However, this empowerment currently leaves the national supervision of common European rules within the EU intact. This policy letter argues that supervisory arbitrage is as much a threat within the EU as outside of it, wherefore a common supervision of CCP rules in the EU is called for. The paper traces the origins of the current set-up and criticizes the current regulatory proposal by the EU Commission as too cumbersome while discussing possible ways forward to achieve European supervision. In contrast to the current proposal of the Commission, we call for a unified supervision within ESMA, combined with a European fiscal backstop.
We report first results on elliptic flow of identified particles at midrapidity in Au+Au collisions at sqrt[sNN] = 130 GeV using the STAR TPC at RHIC. The elliptic flow as a function of transverse momentum and centrality differs significantly for particles of different masses. This dependence can be accounted for in hydrodynamic models, indicating that the system created shows a behavior consistent with collective hydrodynamical flow. The fit to the data with a simple model gives information on the temperature and flow velocities at freeze-out.
The minimum-bias multiplicity distribution and the transverse momentum and pseudorapidity distributions for central collisions have been measured for negative hadrons ( h-) in Au+Au interactions at sqrt[sNN] = 130 GeV. The multiplicity density at midrapidity for the 5% most central interactions is dNh-/d eta | eta = 0 = 280±1(stat)±20(syst), an increase per participant of 38% relative to pp-bar collisions at the same energy. The mean transverse momentum is 0.508±0.012 GeV/c and is larger than in central Pb+Pb collisions at lower energies. The scaling of the h- yield per participant is a strong function of pperp. The pseudorapidity distribution is almost constant within | eta |<1.
We report the first measurement of inclusive antiproton production at midrapidity in Au+Au collisions at sqrt[sNN] = 130 GeV by the STAR experiment at RHIC. The antiproton transverse mass distributions in the measured transverse momentum range of 0.25<pperp<0.95 GeV/c are found to fall less steeply for more central collisions. The extrapolated antiproton rapidity density is found to scale approximately with the negative hadron multiplicity density.
Microwave sensors in medical environments play a significant role due to the contact-less and non-invasive sensing mechanism to determine dielectric properties of tissue. In this work, a theranostic sensor based on Split Ring Resonators (SRRs) is presented that provides two operation modes to detect and treat tumor cells, exemplary in the liver. For the detection mode, resonance frequency changes due to abnormalities are evaluated, and in the treatment mode, microwave ablation is performed. The planar sensor structure can be integrated into a needle like a surgery tool that evokes challenges concerning size limitations and biocompatibility. To meet the size requirements and provide a reasonable operating frequency, properties of oval shaped SRRs are investigated. By elongating the radius of the SRR in one direction, the resonance frequency can be decreased significantly compared to circular SRR by a factor of two below 12 GHz. In order to validate the detection and treatment characteristics of the sensor, full wave simulations and measurements are examined. Clear resonance shifts are detected for loading the sensor structures with phantoms mimicking healthy and malignant tissue. For treatment mode evaluation, ex vivo beef liver tissue was ablated leading to a lesion zone 1.2 cm × 1 cm × 0.3 cm with a three minute exposure of maximum 2.1 W
An integrative correlation of myopathology, phenotype and genotype in late onset Pompe disease
(2019)
Aims: Pompe disease is caused by pathogenic mutations in the alpha 1,4‐glucosidase (GAA) gene and in patients with late onset Pome disease (LOPD), genotype–phenotype correlations are unpredictable. Skeletal muscle pathology includes glycogen accumulation and altered autophagy of various degrees. A correlation of the muscle morphology with clinical features and the genetic background in GAA may contribute to the understanding of the phenotypic variability.
Methods: Muscle biopsies taken before enzyme replacement therapy were analysed from 53 patients with LOPD. On resin sections, glycogen accumulation, fibrosis, autophagic vacuoles and the degree of muscle damage (morphology‐score) were analysed and the results were compared with clinical findings. Additional autophagy markers microtubule‐associated protein 1A/1B‐light chain 3, p62 and Bcl2‐associated athanogene 3 were analysed on cryosections from 22 LOPD biopsies.
Results: The myopathology showed a high variability with, in most patients, a moderate glycogen accumulation and a low morphology‐score. High morphology‐scores were associated with increased fibrosis and autophagy highlighting the role of autophagy in severe stages of skeletal muscle damage. The morphology‐score did not correlate with the patient's age at biopsy, disease duration, nor with the residual GAA enzyme activity or creatine‐kinase levels. In 37 patients with LOPD, genetic analysis identified the most frequent mutation, c.‐32‐13T>G, in 95%, most commonly in combination with c.525delT (19%). No significant correlation was found between the different GAA genotypes and muscle morphology type.
Conclusions: Muscle morphology in LOPD patients shows a high variability with, in most cases, moderate pathology. Increased pathology is associated with more fibrosis and autophagy.
Einleitung: Die konventionelle Galaktografie stellte jahrzehntelang das einzige bildgebende Verfahren zur Darstellung von Milchgängen in der Brust dar. Heute verfügen wir in der Diagnostik über ein multimodales Konzept aus hochauflösendem Ultraschall, der Magnetresonanz-(MR-)Mammografie und der Duktoskopie/Galaktoskopie mit Sensitivitäten und Spezifitäten bis zu 95%. Ziel unserer Untersuchung war es, erstmalig die Tomosynthesetechnik in der Galaktografie einzusetzen und die daraus generierten synthetischen digitalen 2-D-Vollfeld-Mammografien mit der etablierten Methode der duktusorientierten Sonografie zu vergleichen. Es sollen mit beiden Methoden invasive Mammakarzinome und deren Vorstufen wie duktale Carcinoma in situ (DCIS) sowie benigne Befunde erkannt werden. Material und Methoden: Wir führten bei 5 Patientinnen mit pathologischer Mamillensekretion sowohl eine duktusorientierte Sonografie, eine kontrastmittelunterstützte Galaktografie mithilfe der Tomosynthese in 3-D sowie auch den daraus generierten synthetischen digitalen 2-D-Vollfeld-Mammografien durch. Die Auswertung der unterschiedlichen Untersuchungsmodalitäten erfolgte durch 3 in der komplementären Mammadiagnostik erfahrene Untersucher (1, 5 und 15 Jahre) und wurde mit der endgültigen Histologie korreliert. Ergebnisse: Alle 3 Untersucher beurteilten unabhängig voneinander die Bilder des duktusorientierten Ultraschalls und der kontrastmittelunterstützten Galaktografie in Tomosynthesetechnik in 3-D und den daraus generierten, synthetischen digitalen 2-D-Vollfeld-Mammografien. Die Ergebnisse wurden mit den histopathologischen Befunden der Operationspräparate korreliert, wobei sich bei den 5 Patientinnen 1 invasives Mammakarzinom, 2-mal ein duktales Carcinoma in situ (DCIS) und 2 benigne Befunde ergaben. Alle drei Untersucher lagen bei der Verdachtsdiagnose in der Standardbildgebung der duktusorientierten Sonografie seltener richtig als bei der erstmalig durchgeführten, kontrastmittelunterstützten Galaktografie in Tomosynthesetechnik und den daraus generierten, synthetischen digitalen 2-D-Vollfeld-Mammografien. Schlussfolgerung: Erstmalig wurde die Brusttomosynthese in der Galaktografie (Galaktomosynthese) eingesetzt und ermöglichte eine digitale, 3-dimensionale Darstellung von suspekten Befunden. Zusammen mit den daraus synthetisierten, digitalen 2-D-Vollfeld-Mammografien könnte dies in Zukunft eine sinnvolle Ergänzung der komplementären Mammadiagnostik sein – und eine Renaissance dieser Methode. Im Vergleich mit dem duktusorientierten Ultraschall in Hochauflösung erzielten die Untersucher mit der kontrastmittelunterstützten Galaktografie in Tomosynthesetechnik und den daraus generierten, synthetischen digitalen 2-D-Vollfeld-Mammografien bessere Ergebnisse in Korrelation mit den histopathologischen Befunden.
Introduction: For decades, conventional galactography was the only imaging technique capable of showing the mammary ducts. Today, diagnosis is based on a multimodal concept which combines high-resolution ultrasound with magnetic resonance (MR) mammography and ductoscopy/galactoscopy and has a sensitivity and specificity of up to 95%. This study used tomosynthesis in galactography for the first time and compared the synthetic digital 2D full-field mammograms generated with this technique with the images created using the established method of ductal sonography. Both methods should be able to detect invasive breast cancers and their precursors such as ductal carcinoma in situ (DCIS) as well as being able to identify benign findings.
Material and Methods: Five patients with pathological nipple discharge were examined using ductal sonography, contrast-enhanced 3D galactography with tomosynthesis and the synthetic digital 2D full-field mammograms generated with the latter method. Evaluation of the images created with the different imaging modalities was done by three investigators with varying levels of experience with complementary breast diagnostics (1, 5 and 15 years), and their evaluations were compared with the histological findings.
Results: All 3 investigators independently evaluated the images created with ductal sonography, contrast-enhanced 3D galactography with tomosynthesis, and generated synthetic digital 2D full-field mammograms. Their evaluations were compared with the histopathological assessment of the surgical specimens resected from the 5 patients. There was 1 case of invasive breast cancer, 2 cases with ductal carcinoma in situ and 2 cases with benign findings. All 3 investigators made more mistakes when they used the standard imaging technique of ductal sonography to diagnose suspicious lesions than when they used contrast-enhanced galactography with tomosynthesis and the generated synthetic digital 2D full-field mammograms.
Conclusion: This is the first time breast tomosynthesis was used in galactography (galactomosynthesis) to create digital 3-dimensional images of suspicious findings. When used together with the generated synthetic digital 2D full-field mammograms, it could be a useful complementary procedure for the diagnosis of breast anomalies and could herald a renaissance of this method. Compared with high-resolution ductal ultrasound, the investigators achieved better results with contrast-enhanced galactography using tomosynthesis and the generated synthetic digital 2D full-field mammograms, as confirmed by histopathological findings.
We investigate the impact of reporting regulation on corporate innovation. Exploiting thresholds in Europe’s regulation and a major enforcement reform in Germany, we find that forcing firms to publicly disclose their financial statements discourages innovative activities. Our evidence suggests that reporting regulation has significant real effects by imposing proprietary costs on innovative firms, which in turn diminish their incentives to innovate. At the industry level, positive information spillovers (e.g., to competitors, suppliers, and customers) appear insufficient to compensate the negative direct effect on the prevalence of innovative activity. The spillovers instead appear to concentrate innovation among a few large firms in a given industry. Thus, financial reporting regulation has important aggregate and distributional effects on corporate innovation.
Although chest radiograph (CXR) is commonly used in diagnosing pediatric community acquired pneumonia (pCAP), limited data on interobserver agreement among radiologists exist. PedCAPNETZ is a prospective, observational, and multicenter study on pCAP. N = 233 CXR from patients with clinical diagnosis of pCAP were retrieved and n = 12 CXR without pathological findings were added. All CXR were interpreted by a radiologist at the site of recruitment and by two external, blinded pediatric radiologists. To evaluate interobserver agreement, the reporting of presence or absence of pCAP in CXR was analyzed, and prevalence and bias-adjusted kappa (PABAK) statistical testing was applied. Overall, n = 190 (82%) of CXR were confirmed as pCAP by two external pediatric radiologists. Compared with patients with pCAP negative CXR, patients with CXR-confirmed pCAP displayed higher C-reactive protein levels and a longer duration of symptoms before enrollment (p < .007). Further parameters, that is, age, respiratory rate, and oxygen saturation showed no significant difference. The interobserver agreement between the onsite radiologists and each of the two independent pediatric radiologists for the presence of pCAP was poor to fair (69%; PABAK = 0.39% and 76%; PABAK = 0.53, respectively). The concordance between the external radiologists was fair (81%; PABAK = 0.62). With regard to typical CXR findings for pCAP, chance corrected interrater agreement was highest for pleural effusions, infiltrates, and consolidations and lowest for interstitial patterns and peribronchial thickening. Our data show a poor interobserver agreement in the CXR-based diagnosis of pCAP and emphasized the need for harmonized interpretation standards.
Very-long-baseline interferometry (VLBI) observations of active galactic nuclei at millimetre wavelengths have the power to reveal the launching and initial collimation region of extragalactic radio jets, down to 10–100 gravitational radii (rg ≡ GM/c2) scales in nearby sources. Centaurus A is the closest radio-loud source to Earth. It bridges the gap in mass and accretion rate between the supermassive black holes (SMBHs) in Messier 87 and our Galactic Centre. A large southern declination of −43° has, however, prevented VLBI imaging of Centaurus A below a wavelength of 1 cm thus far. Here we show the millimetre VLBI image of the source, which we obtained with the Event Horizon Telescope at 228 GHz. Compared with previous observations, we image the jet of Centaurus A at a tenfold higher frequency and sixteen times sharper resolution and thereby probe sub-lightday structures. We reveal a highly collimated, asymmetrically edge-brightened jet as well as the fainter counterjet. We find that the source structure of Centaurus A resembles the jet in Messier 87 on ~500 rg scales remarkably well. Furthermore, we identify the location of Centaurus A’s SMBH with respect to its resolved jet core at a wavelength of 1.3 mm and conclude that the source’s event horizon shadow should be visible at terahertz frequencies. This location further supports the universal scale invariance of black holes over a wide range of masses.
Zoos attract millions of visitors every year, many of whom are schoolchildren. For this reason, zoos are important institutions for the environmental education of future generations. Empirical studies on the educational impact of environmental education programs in zoos are still rare. To address this issue, we conducted two studies: In study 1, we investigated students’ interests in different biological topics, including zoos (n = 1,587). Data analysis of individual topics revealed large differences of interest, with advanced students showing less interest in zoos. In study 2, we invited school classes of this age group to visit different guided tours at the zoo and tested connection to nature before and after each educational intervention (n = 608). The results showed that the guided tours are an effective tool to raise students’ connection to nature. Add-on components have the potential to further promote connection to nature. The education programs are most effective with students with a low initial nature connection.
Extensive black shale deposits formed in the Early Cretaceous South Atlantic, supporting the notion that this emerging ocean basin was a globally important site of organic carbon burial. The magnitude of organic carbon burial in marine basins is known to be controlled by various tectonic, oceanographic, hydrological, and climatic processes acting on different temporal and spatial scales, the nature and relative importance of which are poorly understood for the young South Atlantic. Here we present new bulk and molecular geochemical data from an Aptian–Albian sediment record recovered from the deep Cape Basin at Deep Sea Drilling Project (DSDP) Site 361, which we combine with general circulation model results to identify driving mechanisms of organic carbon burial. A multimillion-year decrease (i.e., Early Aptian–Albian) in organic carbon burial, reflected in a lithological succession of black shale, gray shale, and red beds, was caused by increasing bottom water oxygenation due to abating hydrographic restriction via South Atlantic–Southern Ocean gateways. These results emphasize basin evolution and ocean gateway development as a decisive primary control on enhanced organic carbon preservation in the Cape Basin at geological timescales (> 1 Myr). The Early Aptian black shale sequence comprises alternations of shales with high (> 6 %) and relatively low (∼ 3.5 %) organic carbon content of marine sources, the former being deposited during the global Oceanic Anoxic Event (OAE) 1a, as well as during repetitive intervals before and after OAE 1a. In all cases, these short-term intervals of enhanced organic carbon burial coincided with strong influxes of sediments derived from the proximal African continent, indicating closely coupled climate–land–ocean interactions. Supported by our model results, we show that fluctuations in weathering-derived nutrient input from the southern African continent, linked to changes in orbitally driven humidity and aridity, were the underlying drivers of repetitive episodes of enhanced organic carbon burial in the deep Cape Basin. These results suggest that deep marine environments of emerging ocean basins responded sensitively and directly to short-term fluctuations in riverine nutrient fluxes. We explain this relationship using the lack of wide and mature continental shelf seas that could have acted as a barrier or filter for nutrient transfer from the continent into the deep ocean.
Extensive black shale deposits formed in the Early Cretaceous South Atlantic, supporting the notion that this emerging ocean basin was a globally important site of organic carbon burial. The magnitude of organic carbon burial in marine basins is known to be controlled by various tectonic, oceanographic, hydrological, and climatic processes acting on different temporal and spatial scales, the nature and relative importance of which are poorly understood for the young South Atlantic. Here we present new bulk and molecular geochemical data from an Aptian–Albian sediment record recovered from the deep Cape Basin at Deep Sea Drilling Project (DSDP) Site 361, which we combine with general circulation model results to identify driving mechanisms of organic carbon burial. A multi-million year decrease (i.e. Early Aptian–Albian) in organic carbon burial, reflected in a lithological succession of black shale, gray shale, and red beds, was caused by increasing bottom water oxygenation due to abating tectonic restriction via South Atlantic-Southern Ocean gateways. These results emphasize basin evolution and ocean gateway development as a decisive primary control on enhanced organic carbon preservation in the Cape Basin at geological time scales (>1 Myr). The Early Aptian black shale sequence comprises alternations of shales with high (>5%) and relatively low (~3%) organic carbon content of marine sources, the former being deposited during the global Oceanic Anoxic Event (OAE) 1a, as well as during repetitive events before and after OAE 1a. In all cases, these short-term events of enhanced organic carbon burial coincided with strong influxes of sediments derived from the proximal African continent, indicating closely coupled climate–land–ocean interactions. Supported by our model results, we propose that fluctuations in weathering-derived nutrient input from the southern African continent, linked to fluctuations in pCO2 and/or orbitally driven humidity/aridity, were the underlying drivers of short-term organic carbon burial in the deep Cape Basin. These results suggest that deep marine environments of emerging ocean basins responded sensitively and directly to short term fluctuations in riverine nutrient fluxes. We explain this relationship by the lack of wide and mature continental shelf seas that could have acted as a barrier or filter for nutrient transfer from the continent into the deep ocean.
Two-particle correlation functions of negative hadrons over wide phase space, and transverse mass spectra of negative hadrons and deuterons near mid-rapidity have been measured in central Pb+Pb collisions at 158 GeV per nucleon by the NA49 experiment at the CERN SPS. A novel Coulomb correction procedure for the negative two-particle correlations is employed making use of the measured oppositely charged particle correlation. Within an expanding source scenario these results are used to extract the dynamic characteristics of the hadronic source, resolving the ambiguities between the temperature and transverse expansion velocity of the source, that are unavoidable when single and two particle spectra are analysed separately. The source shape, the total duration of the source expansion, the duration of particle emission, the freeze-out temperature and the longitudinal and transverse expansion velocities are deduced.
We report measurements of Xi and Xi-bar hyperon absolute yields as a function of rapidity in 158 GeV/c Pb+Pb collisions. At midrapidity, dN/dy = 2.29 +/- 0.12 for Xi, and 0.52 +/- 0.05 for Xi-bar, leading to the ratio of Xi-bar/Xi = 0.23 +/- 0.03. Inverse slope parameters fitted to the measured transverse mass spectra are of the order of 300 MeV near mid-rapidity. The estimated total yield of Xi particles in Pb+Pb central interactions amounts to 7.4 +/- 1.0 per collision. Comparison to Xi production in properly scaled p+p reactions at the same energy reveals a dramatic enhancement (about one order of magnitude) of Xi production in Pb+Pb central collisions over elementary hadron interactions.
The directed and elliptic flow of protons and charged pions has been observed from the semi-central collisions of a 158 GeV/nucleon Pb beam with a Pb target. The rapidity and transverse momentum dependence of the flow has been measured. The directed flow of the pions is opposite to that of the protons but both exhibit negative flow at low pt. The elliptic flow of both is fairly independent of rapidity but rises with pt. PACS numbers: 25.75.-q, 25.75.Ld
Objective: Pancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognosis with an overall 5-year survival rate of 9%. Conventional combination chemotherapies are a clear advance in the treatment of PDAC; however, subtypes of the disease exist, which exhibit extensive resistance to such therapies. Genomic MYC amplifications represent a distinct subset of PDAC with an aggressive tumour biology. It is clear that hyperactivation of MYC generates dependencies that can be exploited therapeutically. The aim of the study was to find and to target MYC-associated dependencies.
Design: We analysed human PDAC gene expression datasets. Results were corroborated by the analysis of the small ubiquitin-like modifier (SUMO) pathway in a large PDAC cohort using immunohistochemistry. A SUMO inhibitor was used and characterised using human and murine two-dimensional, organoid and in vivo models of PDAC.
Results: We observed that MYC is connected to the SUMOylation machinery in PDAC. Components of the SUMO pathway characterise a PDAC subtype with a dismal prognosis and we provide evidence that hyperactivation of MYC is connected to an increased sensitivity to pharmacological SUMO inhibition.
Conclusion: SUMO inhibitor-based therapies should be further developed for an aggressive PDAC subtype.
Background: To evaluate clinical outcomes after either immediate or deferred initiation of antiretroviral therapy in HIV-1-infected patients, presenting late with pneumocystis pneumonia (PCP) or toxoplasma encephalitis (TE).
Methods: Phase IV, multicenter, prospective, randomized open-label clinical trial. Patients were randomized into an immediate therapy arm (starting antiretroviral therapy (ART) within 7 days after initiation of OI treatment) versus a deferred arm (starting ART after completing the OI-therapy). All patients were followed for 24 weeks. The rates of clinical progression (death, new or relapsing opportunistic infections (OI) and other grade 4 clinical endpoints) were compared, using a combined primary endpoint. Secondary endpoints were hospitalization rates after completion of OI treatment, incidence of immune reconstitution inflammatory syndrome (IRIS), virologic and immunological outcome, adherence to proteinase-inhibitor based antiretroviral therapy (ART) protocol and quality of life.
Results: 61 patients (11 patients suffering TE, 50 with PCP) were enrolled. No differences between the two therapy groups in all examined primary and secondary endpoints could be identified: immunological and virologic outcome was similar in both groups, there was no significant difference in the incidence of IRIS (11 and 10 cases), furthermore 9 events (combined endpoint of death, new/relapsing OI and grade 4 events) occurred in each group.
Conclusions: In summary, this study supports the notion that immediate initiation of ART with a ritonavir-boosted proteinase-inhibitor and two nucleoside reverse transcriptase inhibitors is safe and has no negative effects on incidence of disease progression or IRIS, nor on immunological and virologic outcomes or on quality of life.
Background: During the COVID-19 pandemic, decreased volumes of acute stroke admissions were reported. We aimed to examine whether subarachnoid hemorrhage (SAH) volumes demonstrated similar declines in our department. Furthermore, the impact of pandemic on disease progression should be analyzed.
Methods: We conducted a retrospective study in neurosurgical department of university hospital Frankfurt including patients with the diagnosis of aneurysmal SAH during the first year of COVID-pandemic. One year cumulative volume for SAH hospitalization procedures were compared to the one-year period before (03/2020–02/2021 versus 03/2019–02/2020) and the last 5 pre-COVID-pandemic years (2015-2020). All relevant patient characteristics concerning family history, disease history, clinical condition at admission, active/past COVID-infection, treatment management, complications and outcome were analyzed.
Results: There was a decline in SAH hospitalizations, with 84 admissions in the year immediately before and 56 admissions during the pandemic, without reaching a significance. No significant difference in analyzed patient characteristics including clinical condition at onset, treatment, complications and outcome, between 56 SAH patients admitted during COVID pandemic and treated patients in the last 5 years in pre-COVID period were found. Using a multivariable analysis, we detected young age (p<0.05;OR4,2) and no existence of early hydrocephalus (p<0.05;OR0,13) as important factors for a favorable outcome (mRS≤0-2) after aSAH during the COVID-pandemic. A past COVID-infection was detected in young patients suffering from aSAH (Age< 50years, p<0.05;OR10,5) with increased rate of cerebral vasospasm after SAH onset (p<0.05;OR26). Nevertheless, past COVID-infection did not reach a significance as a high risk factor for unfavorable outcome.
Conclusion: There was a relative decrease in the volume of SAH during the COVID-19 pandemic. Despite of extremely different conditions of hospitalization, there was no impairing significant effect on treatment and outcome of admitted SAH patients. A past COVID-infection seemed not to be a relevant limiting factor concerning favorable outcome.
Ongoing climate change is a major threat to biodiversity and impacts on species distributions and abundances are already evident. Heterogenous responses of species due to varying abiotic tolerances and dispersal abilities have the potential to further amplify or ameliorate these impacts through changes in species assemblages. Here we investigate the impacts of climate change on terrestrial bird distributions and, subsequently, on species richness as well as on different aspects of phylogenetic diversity of species assemblages across the globe. We go beyond previous work by disentangling the potential impacts on assemblage phylogenetic diversity of species gains vs. losses under climate change and compare the projected impacts to randomized assemblage changes.
We show that climate change might not only affect species numbers and composition of global species assemblages but could also have profound impacts on assemblage phylogenetic diversity, which, across extensive areas, differ significantly from random changes. Both the projected impacts on phylogenetic diversity and on phylogenetic structure vary greatly across the globe. Projected increases in the evolutionary history contained within species assemblages, associated with either increasing phylogenetic diversification or clustering, are most frequent at high northern latitudes. By contrast, projected declines in evolutionary history, associated with increasing phylogenetic over-dispersion or homogenisation, are projected across all continents.
The projected widespread changes in the phylogenetic structure of species assemblages show that changes in species richness do not fully reflect the potential threat from climate change to ecosystems. Our results indicate that the most severe changes to the phylogenetic diversity and structure of species assemblages are likely to be caused by species range shifts rather than range reductions and extinctions. Our findings highlight the importance of considering diverse measures in climate impact assessments and the value of integrating species-specific responses into assessments of entire community changes.
Background: Perioperative anaemia leads to impaired oxygen supply with a risk of vital organ ischaemia. In healthy and fit individuals, anaemia can be compensated by several mechanisms. Elderly patients, however, have less compensatory mechanisms because of multiple co-morbidities and age-related decline of functional reserves. The purpose of the study is to evaluate whether elderly surgical patients may benefit from a liberal red blood cell (RBC) transfusion strategy compared to a restrictive transfusion strategy.
Methods: The LIBERAL Trial is a prospective, randomized, multicentre, controlled clinical phase IV trial randomising 2470 elderly (≥ 70 years) patients undergoing intermediate- or high-risk non-cardiac surgery. Registered patients will be randomised only if Haemoglobin (Hb) reaches ≤9 g/dl during surgery or within 3 days after surgery either to the LIBERAL group (transfusion of a single RBC unit when Hb ≤ 9 g/dl with a target range for the post-transfusion Hb level of 9–10.5 g/dl) or the RESTRICTIVE group (transfusion of a single RBC unit when Hb ≤ 7.5 g/dl with a target range for the post-transfusion Hb level of 7.5–9 g/dl). The intervention per patient will be followed until hospital discharge or up to 30 days after surgery, whichever occurs first. The primary efficacy outcome is defined as a composite of all-cause mortality, acute myocardial infarction, acute ischaemic stroke, acute kidney injury (stage III), acute mesenteric ischaemia and acute peripheral vascular ischaemia within 90 days after surgery. Infections requiring iv antibiotics with re-hospitalisation are assessed as important secondary endpoint. The primary endpoint will be analysed by logistic regression adjusting for age, cancer surgery (y/n), type of surgery (intermediate- or high-risk), and incorporating centres as random effect.
Discussion: The LIBERAL-Trial will evaluate whether a liberal transfusion strategy reduces the occurrence of major adverse events after non-cardiac surgery in the geriatric population compared to a restrictive strategy within 90 days after surgery.
Trial registration: ClinicalTrials.gov (identifier: NCT03369210).
Rho-family GTPases like RhoA and Rac-1 are potent regulators of cellular signaling that control gene expression, migration and inflammation. Activation of Rho-GTPases has been linked to podocyte dysfunction, a feature of chronic kidney diseases (CKD). We investigated the effect of Rac-1 and Rho kinase (ROCK) inhibition on progressive renal failure in mice and studied the underlying mechanisms in podocytes. SV129 mice were subjected to 5/6-nephrectomy which resulted in arterial hypertension and albuminuria. Subgroups of animals were treated with the Rac-1 inhibitor EHT1846, the ROCK inhibitor SAR407899 and the ACE inhibitor Ramipril. Only Ramipril reduced hypertension. In contrast, all inhibitors markedly attenuated albumin excretion as well as glomerular and tubulo-interstitial damage. The combination of SAR407899 and Ramipril was more effective in preventing albuminuria than Ramipril alone. To study the involved mechanisms, podocytes were cultured from SV129 mice and exposed to static stretch in the Flexcell device. This activated RhoA and Rac-1 and led via TGFβ to apoptosis and a switch of the cells into a more mesenchymal phenotype, as evident from loss of WT-1 and nephrin and induction of α-SMA and fibronectin expression. Rac-1 and ROCK inhibition as well as blockade of TGFβ dramatically attenuated all these responses. This suggests that Rac-1 and RhoA are mediators of podocyte dysfunction in CKD. Inhibition of Rho-GTPases may be a novel approach for the treatment of CKD.
Endocannabinoids are important lipid-signaling mediators. Both protective and deleterious effects of endocannabinoids in the cardiovascular system have been reported but the mechanistic basis for these contradicting observations is unclear. We set out to identify anti-inflammatory mechanisms of endocannabinoids in the murine aorta and in human vascular smooth muscle cells (hVSMC). In response to combined stimulation with cytokines, IL-1β and TNFα, the murine aorta released several endocannabinoids, with anandamide (AEA) levels being the most significantly increased. AEA pretreatment had profound effects on cytokine-induced gene expression in hVSMC and murine aorta. As revealed by RNA-Seq analysis, the induction of a subset of 21 inflammatory target genes, including the important cytokine CCL2 was blocked by AEA. This effect was not mediated through AEA-dependent interference of the AP-1 or NF-κB pathways but rather through an epigenetic mechanism. In the presence of AEA, ATAC-Seq analysis and chromatin-immunoprecipitations revealed that CCL2 induction was blocked due to increased levels of H3K27me3 and a decrease of H3K27ac leading to compacted chromatin structure in the CCL2 promoter. These effects were mediated by recruitment of HDAC4 and the nuclear corepressor NCoR1 to the CCL2 promoter. This study therefore establishes a novel anti-inflammatory mechanism for the endogenous endocannabinoid AEA in vascular smooth muscle cells. Furthermore, this work provides a link between endogenous endocannabinoid signaling and epigenetic regulation.
Resonance assignments are challenging for membrane proteins due to the size of the lipid/detergent-protein complex and the presence of line-broadening from conformational exchange. As a consequence, many correlations are missing in the triple-resonance NMR experiments typically used for assignments. Herein, we present an approach in which correlations from these solution-state NMR experiments are supplemented by data from 13C unlabeling, single-amino acid type labeling, 4D NOESY data and proximity of moieties to lipids or water in combination with a structure of the protein. These additional data are used to edit the expected peaklists for the automated assignment protocol FLYA, a module of the program package CYANA. We demonstrate application of the protocol to the 262-residue proton pump from archaeal bacteriorhodopsin (bR) in lipid nanodiscs. The lipid-protein assembly is characterized by an overall correlation time of 44 ns. The protocol yielded assignments for 62% of all backbone (H, N, Cα, Cβ, C′) resonances of bR, corresponding to 74% of all observed backbone spin systems, and 60% of the Ala, Met, Ile (δ1), Leu and Val methyl groups, thus enabling to assign a large fraction of the protein without mutagenesis data. Most missing resonances stem from the extracellular half, likely due intermediate exchange line-broadening. Further analysis revealed that missing information of the amino acid type of the preceding residue is the largest problem, and that 4D NOESY experiments are particularly helpful to compensate for that information loss.
The establishment and maintenance of protected areas (PAs) is viewed as a key action in delivering post-2020 biodiversity targets. PAs often need to meet multiple objectives, ranging from biodiversity protection to ecosystem service provision and climate change mitigation, but available land and conservation funding is limited. Therefore, optimizing resources by selecting the most beneficial PAs is vital. Here, we advocate for a flexible and transparent approach to selecting protected areas based on multiple objectives, and illustrate this with a decision support tool on a global scale. The tool allows weighting and prioritization of different conservation objectives according to user-specified preferences, as well as real-time comparison of the selected areas that result from such different priorities. We apply the tool across 1347 terrestrial PAs and highlight frequent trade-offs among different objectives, e.g., between species protection and ecosystem integrity. Outputs indicate that decision makers frequently face trade-offs among conflicting objectives. Nevertheless, we show that transparent decision-support tools can reveal synergies and trade-offs associated with PA selection, thereby helping to illuminate and resolve land-use conflicts embedded in divergent societal and political demands and values.
Background: About 2000 children and adolescents under the age of 18 are diagnosed with cancer each year in Germany. Because of current medical treatment methods, a high survival rate can be reached for many types of the disease. Nevertheless, patients face a number of long-term effects related to the treatment. As a result, physical and psychological consequences have increasingly become the focus of research in recent years. Social dimensions of health have received little attention in health services research in oncology so far. Yet, there are no robust results that allow an estimation of whether and to what extent the disease and treatment impair the participation of children and adolescents and which factors mediate this effect. Social participation is of great importance especially because interactions with peers and experiences in different areas of life are essential for the development of children and adolescents.
Methods: Data are collected in a longitudinal, prospective, observational multicenter study. For this purpose, all patients and their parents who are being treated for cancer in one of the participating clinics throughout Germany will be interviewed within the first month after diagnosis (t1), after completion of intensive treatment (t2) and half a year after the end of intensive treatment (t3) using standardized questionnaires. Analysis will be done by descriptive and multivariate methods.
Discussion: The results can be used to identify children and adolescents in high-risk situations at an early stage in order to be able to initiate interventions tailored to the needs. Such tailored interventions will finally reduce the risk of impairments in the participation of children and adolescents and increase quality of life.
Trial registration: ClinicalTrials.gov: NCT04101123.
Apheresis therapies for NMOSD attacks : a retrospective study of 207 therapeutic interventions
(2018)
Objective: To analyze whether 1 of the 2 apheresis techniques, therapeutic plasma exchange (PE) or immunoadsorption (IA), is superior in treating neuromyelitis optica spectrum disorder (NMOSD) attacks and to identify predictive factors for complete remission (CR).
Methods: This retrospective cohort study was based on the registry of the German Neuromyelitis Optica Study Group, a nationwide network established in 2008. It recruited patients with neuromyelitis optica diagnosed according to the 2006 Wingerchuk criteria or with aquaporin-4 (AQP4-ab)-antibody–seropositive NMOSD treated at 6 regional hospitals and 16 tertiary referral centers until March 2013. Besides descriptive data analysis of patient and attack characteristics, generalized estimation equation (GEE) analyses were applied to compare the effectiveness of the 2 apheresis techniques. A GEE model was generated to assess predictors of outcome.
Results: Two hundred and seven attacks in 105 patients (87% AQP4-ab-antibody seropositive) were treated with at least 1 apheresis therapy. Neither PE nor IA was proven superior in the therapy of NMOSD attacks. CR was only achieved with early apheresis therapy. Strong predictors for CR were the use of apheresis therapy as first-line therapy (OR 12.27, 95% CI: 1.04–144.91, p = 0.047), time from onset of attack to start of therapy in days (OR 0.94, 95% CI: 0.89–0.99, p = 0.014), the presence of AQP4-ab-antibodies (OR 33.34, 95% CI: 1.76–631.17, p = 0.019), and monofocal attack manifestation (OR 4.71, 95% CI: 1.03–21.62, p = 0.046).
Conclusions: Our findings suggest early use of an apheresis therapy in NMOSD attacks, particularly in AQP4-ab-seropositive patients. No superiority was shown for one of the 2 apheresis techniques.
Classification of evidence: This study provides Class IV evidence that for patients with NMOSD, neither PE nor IA is superior in the treatment of attacks.
This summary provides an overview of how new therapies or new aspects of established therapies relate to the latest findings. Neoadjuvant therapy, local therapy, new aspects of systemic therapy, and prognostic and predictive factors are presented. In the neoadjuvant setting, the association between pathological complete response (pCR) and prognosis is still of interest as is the identification of new molecular predictors for new therapies such as CDK4/6 inhibitors. As regards surgical treatment, the target is still to reduce the aggressiveness of surgery. To achieve this, a better understanding particularly of ductal carcinoma in situ is required. With regard to systemic therapy, more data on the best combinations and therapy sequences for existing therapies is available. Finally, the use of prognostic and predictive factors may help to avoid overtreatment and ensure that patients only receive therapies which have been shown to be effective for their specific condition and have fewer side effects.
Update Mammakarzinom 2018 (Teil 2) – fortgeschrittenes Mammakarzinom, Lebensqualität und Prävention
(2018)
Die Behandlung des metastasierten Mammakarzinoms hat bei immer neu zu testenden Therapien deutlich an Komplexität zugenommen. Therapien werden nunmehr nur noch für spezielle klinische oder molekulare Subgruppen entwickelt. Hierbei spielen die intrinsischen, molekularen Subtypen zwar immer noch die größte Rolle, jedoch gibt es zunehmend auch Therapien, die subgruppen- oder sogar histologieübergreifend entwickelt werden, wie z. B. der PARP-Inhibitor bei BRCA-mutierten Patientinnen (Mamma- und Ovarialkarzinom). Aber auch Supportivtherapien entwickeln sich weiter, sodass Probleme wie die Alopezie besser behandelt werden können und neue Therapiearten von Übelkeit und Erbrechen etabliert werden. In einem engen Zusammenhang mit den Supportivtherapien stehen die Nebenwirkungen, welche bei Patientinnen mit einem metastasierten Mammakarzinom einen direkten Einfluss auf die Prognose haben. Hier könnten digitale Werkzeuge helfen, um ein besseres Patientinnenmanagement zu etablieren. Diese Übersichtsarbeit soll diese Aspekte vor dem Hintergrund neuer, aktuell publizierter Studien beleuchten und einen Einblick geben, wie sich diese Studien zu etablierten Routinetherapien verhalten. Zusätzlich werden aktuelle Aspekte der Mammakarzinomprävention beleuchtet.
The treatment of metastatic breast cancer has become more complicated due to increasing numbers of new therapies which need to be tested. Therapies are now being developed to treat special clinical or molecular subgroups. Even though intrinsic molecular subtypes play a major role, more and more new therapies for subgroups and histological subtypes are being developed, such as the use of PARP inhibitors to treat patients with BRCA mutations (breast and ovarian cancer). Supportive therapies are also evolving, allowing problems such as alopecia or nausea and vomiting to be treated more effectively. Treatment-related side effects have a direct impact on the prognosis of patients with metastatic breast cancer, and supportive therapy can improve compliance. Digital tools could be useful to establish better patient management systems. This overview provides an insight into recent trials and how the findings could affect routine treatment. Current aspects of breast cancer prevention are also presented.
In dieser Übersichtsarbeit wird dargestellt, wie neue Therapien oder neue Aspekte etablierter Therapien in Zusammenhang mit neuesten, aktuellen Erkenntnissen stehen. Neoadjuvanz, Lokaltherapie, neue Aspekte der Systemtherapie und Prognose- sowie Prädiktivfaktoren werden beleuchtet. In der Neoadjuvanz ist nach wie vor der Zusammenhang zwischen pCR und Prognose von Interesse, ebenso wie neue molekulare Prädiktoren für neue Therapien wie CDK4/6-Inhibitoren zu identifizieren. Bei der operativen Behandlung wird weiter nach einer Reduktion der Aggressivität gestrebt. Insbesondere das duktale Carcinoma in situ muss dafür noch besser verstanden werden. Bei den Systemtherapien wächst die Datenlage zum Verständnis der besten Kombinationen und Therapieabläufe für bestehende Therapieverfahren. Letztendlich muss mithilfe von Prognose- und Prädiktivfaktoren vermieden werden, dass Übertherapien stattfinden und nur die Patientin spezifische Therapien erhält, welche bei dieser individuellen Patientin eine nachgewiesene Wirksamkeit mit wenig Nebenwirkungen haben.
Background: We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC).
Patients and methods: ALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders.
Results: Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients [PFS 3.9 months (95% CI: 2.4–5.6) versus 10.3 months (95% CI: 8.6–12.0), P < 0.001; OS 15.0 months (95% CI: 5.0–24.9) versus 50.0 months (95% CI: 22.9–77.1), P = 0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only [PFS first-line chemotherapy 2.6 months (95% CI: 1.3–4.1) versus 6.2 months (95% CI: 1.8–10.5), P = 0.021; OS 2.0 months (95% CI: 0.0–4.6) versus 9.0 months (95% CI: 6.1–11.9), P = 0.035], crizotinib plus chemotherapy [PFS crizotinib 5.0 months (95% CI: 2.9–7.2) versus 14.0 months (95% CI: 8.0–20.1), P < 0.001; OS 17.0 months (95% CI: 6.7–27.3) versus not reached, P = 0.049] and crizotinib followed by next-generation ALK-inhibitor [PFS next-generation inhibitor 5.4 months (95% CI: 0.1–10.7) versus 9.9 months (95% CI: 6.4–13.5), P = 0.039; OS 7.0 months versus 50.0 months (95% CI: not reached), P = 0.001).
Conclusions: In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.
The nuclear factor kappa beta (NFκB) signaling pathway plays an important role in liver homeostasis and cancer development. Tax1-binding protein 1 (Tax1BP1) is a regulator of the NFκB signaling pathway, but its role in the liver and hepatocellular carcinoma (HCC) is presently unknown. Here we investigated the role of Tax1BP1 in liver cells and murine models of HCC and liver fibrosis. We applied the diethylnitrosamine (DEN) model of experimental hepatocarcinogenesis in Tax1BP1+/+ and Tax1BP1−/− mice. The amount and subsets of non-parenchymal liver cells in in Tax1BP1+/+ and Tax1BP1−/− mice were determined and activation of NFκB and stress induced signaling pathways were assessed. Differential expression of mRNA and miRNA was determined. Tax1BP1−/− mice showed increased numbers of inflammatory cells in the liver. Furthermore, a sustained activation of the NFκB signaling pathway was found in hepatocytes as well as increased transcription of proinflammatory cytokines in isolated Kupffer cells from Tax1BP1−/− mice. Several differentially expressed mRNAs and miRNAs in livers of Tax1BP1−/− mice were found, which are regulators of inflammation or are involved in cancer development or progression. Furthermore, Tax1BP1−/− mice developed more HCCs than their Tax1BP1+/+ littermates. We conclude that Tax1BP1 protects from liver cancer development by limiting proinflammatory signaling.
The Tarim River Basin, located in Xinjiang, NW China, is the largest endorheic river basin of China and one of the largest in whole Central Asia. Due to the extremely arid climate with an annual precipitation of less than 100 mm, the water supply along the Aksu and Tarim River solely depends on river water. This applies for anthropogenic activities (e.g. agriculture) as well as for the natural ecosystems so that both compete for water. The on-going increase of water consumption by agriculture and other human activities in this region has been enhancing the competition for water between human needs and nature. Against this background, 11 German and 6 Chinese universities and research institutes formed the consortium SuMaRiO (www.sumario.de), which aims at gaining a holistic picture of the availability of water resources in the Tarim River Basin and the impacts on anthropogenic activities and natural ecosystems caused by the water distribution within the Tarim River Basin. The discharge of the Aksu River, which is the major tributary to the Tarim, has been increasing over the past 6 decades due to enhanced glacier melt. Alone from 1989 to 2011, the area under agriculture more than doubled. Thereby, cotton became the major crop and there was a shift from small-scale farming to large-scale intensive farming. The major natural ecosystems along the Aksu and Tarim River are riparian ecosystems: Riparian (Tugai) forests, shrub vegetation, reed beds, and other grassland. Within the SuMaRiO Cluster the focus was laid on the Tugai forests, with Populus euphratica as dominant tree, because the most productive and species-rich natural ecosystems can be found among those forests. On sites with groundwater distance of less than 7.5 m the annual increments correlated with river runoffs of the previous year. But, the further downstream along the Tarim River, the more the natural river dynamics ceased, which impacts on the recruitment of Populus euphratica. Household surveys revealed that there is a considerable willingness to pay for conservation of those riparian forests with the mitigation of dust and sandstorms considered as the most important ecosystem service. This interdisciplinary project will result in a decision support tool (DST), build on the participation of regional stakeholders and models based on results and field experiments. This DST finally shall assist stakeholders in balancing the water competition acknowledging the major external effects of any water allocation.
We investigate the impact of reporting regulation on corporate innovation. Exploiting thresholds in Europe’s regulation and a major enforcement reform in Germany, we find that forcing firms to publicly disclose their financial statements discourages innovative activities. Our evidence suggests that reporting regulation has significant real effects by imposing proprietary costs on innovative firms, which in turn diminish their incentives to innovate. At the industry level, positive information spillovers (e.g., to competitors, suppliers, and customers) appear insufficient to compensate the negative direct effect on the prevalence of innovative activity. The spillovers instead appear to concentrate innovation among a few large firms in a given industry. Thus, financial reporting regulation has important aggregate and distributional effects on corporate innovation.
General intelligence is a psychological construct that captures in a single metric the overall level of behavioural and cognitive performance in an individual. While previous research has attempted to localise intelligence in circumscribed brain regions, more recent work focuses on functional interactions between regions. However, even though brain networks are characterised by substantial modularity, it is unclear whether and how the brain’s modular organisation is associated with general intelligence. Modelling subject-specific brain network graphs from functional MRI resting-state data (N = 309), we found that intelligence was not associated with global modularity features (e.g., number or size of modules) or the whole-brain proportions of different node types (e.g., connector hubs or provincial hubs). In contrast, we observed characteristic associations between intelligence and node-specific measures of within- and between-module connectivity, particularly in frontal and parietal brain regions that have previously been linked to intelligence. We propose that the connectivity profile of these regions may shape intelligence-relevant aspects of information processing. Our data demonstrate that not only region-specific differences in brain structure and function, but also the network-topological embedding of fronto-parietal as well as other cortical and subcortical brain regions is related to individual differences in higher cognitive abilities, i.e., intelligence.
Fragestellung: Es existiert eine Vielzahl von Begriffen für Verhaltenssüchte, die Mängel in Operationalisierung, Bezug zum Verhalten, Kompatibilität mit internationalen Klassifikationen sowie nicht stigmatisierender Nutzung aufweisen. Daher werden einheitliche Begriffe für Verhaltenssüchte benötigt. Methode: Im Rahmen einer Leitlinie zur Diagnostik und Behandlung Internetbezogener Störungen wurden Lösungen in Form eines Expertenkonsens entwickelt. Ergebnisse: Als Grundlage wurde die Einteilung von Verhaltenssüchten in der 11. Revision der International Classification of Diseases (ICD-11) genutzt. Es wurden die Begriffe Computerspielstörung (CSS) und Glücksspielstörung (GSS) für die beiden in ICD-11 enthaltenen Verhaltenssüchte gewählt sowie drei weitere spezifizierte Verhaltenssüchte vorgeschlagen: Soziale-Netzwerke-Nutzungsstörung (SNS), Shoppingstörung (ShS) und Pornografie-Nutzungsstörung (PNS). Für CSS, GSS und ShS wird weiterhin zwischen vorwiegend online oder vorwiegend offline unterschieden. Als Oberbegriff wird Störungen aufgrund von Verhaltenssüchten vorgeschlagen. Für Störungen aufgrund von Verhaltenssüchten, die sich vorwiegend auf online ausgeübte Verhaltensweisen beziehen, kann alternativ der Oberbegriff Internetnutzungsstörungen verwendet werden. Schlussfolgerung: Die vorgeschlagenen Termini weisen Verbesserungen im Vergleich zu uneindeutigen oder aus anderen Gründen ungünstigen Begriffen dar. Gleichzeitig konnte eine Kompatibilität mit der ICD-11 ermöglicht werden.
We aimed to prospectively assess changes in chronic stress among young adults transitioning from high school to university or working life. A population-based cohort in Munich and Dresden (Germany) was followed from age 16–18 (2002–2003) to age 20–23 (2007–2009) (n = 1688). Using the Trier Inventory for the Assessment of Chronic Stress, two dimensions of stress at university or work were assessed: work overload and work discontent. In the multiple ordinal generalized estimating equations, socio-demographics, stress outside the workplace, and job history were additionally considered. At follow-up, 52% of the population were university students. Work overload increased statistically significantly from first to second follow-up, while work discontent remained constant at the population level. Students, compared to employees, reported a larger increase in work overload (adjusted odds ratio (OR): 1.33; 95% confidence interval (95% CI): 1.07, 1.67), while work discontent did not differ between the groups. In conclusion, work overload increases when young adults transition from school to university/job life, with university students experiencing the largest increase.
Background: Pediatric community acquired pneumonia (pedCAP) is one of the leading causes for childhood morbidity accounting for up to 20% of pediatric hospital admissions in high income countries. In spite of its high morbidity, updated epidemiological and pathogen data after introduction of preventive vaccination and novel pathogen screening strategies are limited. Moreover, there is a need for validated recommendations on diagnostic and treatment regimens in pedCAP. Through collection of patient data and analysis of pathogen and host factors in a large sample of unselected pedCAP patients in Germany, we aim to address and substantially improve this situation.
Methods: pedCAPNETZ is an observational, multi-center study on pedCAP. Thus far, nine study centers in hospitals, outpatient clinics and practices have been initiated and more than 400 patients with radiologically confirmed pneumonia have been enrolled, aiming at a total of 1000 study participants. Employing an online data base, information on disease course, treatment as well as demographical and socioeconomical data is recorded. Patients are followed up until day 90 after enrollment; Comprehensive biosample collection and a central pedCAPNETZ biobank allow for in-depth analyses of pathogen and host factors. Standardized workflows to assure sample logistics and data management in more than fifteen future study centers have been established.
Discussion: Through comprehensive epidemiological, clinical and biological analyses, pedCAPNETZ fills an important gap in pediatric and infection research. To secure dissemination of the registry, we will raise clinical and scientific awareness at all levels. We aim at participating in decision making processes for guidelines and prevention strategies. Ultimately, we hope the results of the pedCAPNETZ registry will help to improve care and quality of life in pedCAP patients in the future.
Eine erfolgreiche Implementierung medizindidaktischer Qualifizierungsmaßnahmen setzt zwingend voraus, dass die Fakultäten nicht nur für entsprechende Angebote, sondern mittelfristig auch für lehrförderliche Rahmenbedingungen sorgen. Dabei müssen sowohl institutionelle Aspekte, die sich aus der Struktur und Funktion der Fakultät als Organisation ergeben als auch individuelle Aspekte der Zielgruppe der Lehrenden berücksichtigt werden. Von institutioneller Seitemuss vor allem Dermatologie und Deutschland die für alle sichtbare Unterstützung des Programms sichergestellt werden. Ebenfalls von zentraler Bedeutung ist die Bereitschaft, die medizindidaktische Qualifikation als einen wesentlichen Baustein der akademischen Laufbahn zu bewerten. Im Hinblick auf die Lehrenden geht es vor allem darum, das Angebot bekannt zu machen und seinen Nutzen herauszustellen, was mit Hilfe karrierebezogener Anreize naturgemäß leichter ist.
With an increased understanding of the tumor biology of squamous cell carcinoma of the head and neck (SCCHN), targeted therapies have found their way into the clinical treatment routines against this entity. Nevertheless, to date platinum-based cytostatic agents remain the first line choice and targeting the epidermal growth factor-receptor (EGFR) with combined cetuximab and radiation therapy remains the only targeted therapy approved in the curative setting. Investigation of immune checkpoint inhibitors (ICI), such as antibodies targeting programmed cell death protein 1 (PD-1) and its ligand PD-L1, resulted in a change of paradigms in oncology and in the first approval of new drugs for treating SCCHN. Nivolumab and pembrolizumab, two anti-PD-1 antibodies, were the first agents shown to improve overall survival for patients with metastatic/recurrent tumors in recent years. Currently, several clinical trials investigate the role of ICI in different therapeutic settings. A robust set of biomarkers will be an inevitable tool for future individualized treatment approaches including radiation dose de-escalation and escalation strategies. This review aims to summarize achieved goals, the current status and future perspectives regarding targeted therapies and ICI in the management of SCCHN.
Background: Conditions during blood product storage and transportation should maintain quality. The aim of this in vitro study was to investigate the effect of interruption of agitation, temporary cooling (TC), and pneumatic tube system transportation (PTST) on the aggregation ability (AA) and mitochondrial function (MF) of platelet concentrates (PC).
Study Design and Methods: A PC was divided equally into four subunits and then allocated to four test groups. The control group (I) was stored as recommended (continuous agitation, 22 ± 2°C) for 4 days. The test groups were stored without agitation (II), stored as recommended, albeit 4°C for 60 minutes on day (d)2 (III) and PTST (IV). Aggregometry was measured using Multiplate (RocheAG; ADPtest, ASPItest, TRAPtest, COLtest) and MF using Oxygraph‐2k (Oroboros Instruments). The basal and maximum mitochondrial respiratory rate (MMRR) were determined. AA and MF were measured daily in I and II and AA in III and IV on d2 after TC/PTST. Statistical analysis was performed using tests for matched observations.
Results: Eleven PCs were used. TRAP‐6 induced AA was significantly lower in II when compared to I on d4 (P = 0.015*). In III the ASPItest was significantly lower (P = 0.032*). IV showed no significant differences. The basal and MMRR were significantly reduced over 4 days in I and II (for both rates in both groups: P = <0.0001*). No significant differences occurred on d4 (P = 0.495).
Conclusion: Our results indicate that ex vivo AA and MF of PCs are unaffected, even in no‐ideal storage and transport circumstances with respect to agitation, temperature, and force.
Background: In many species males face a higher predation risk than females because males display elaborate traits that evolved under sexual selection, which may attract not only females but also predators. Females are, therefore, predicted to avoid such conspicuous males under predation risk. The present study was designed to investigate predator-induced changes of female mating preferences in Atlantic mollies (Poecilia mexicana). Males of this species show a pronounced polymorphism in body size and coloration, and females prefer large, colorful males in the absence of predators. Results: In dichotomous choice tests predator-naïve (lab-reared) females altered their initial preference for larger males in the presence of the cichlid Cichlasoma salvini, a natural predator of P. mexicana, and preferred small males instead. This effect was considerably weaker when females were confronted visually with the non-piscivorous cichlid Vieja bifasciata or the introduced non-piscivorous Nile tilapia (Oreochromis niloticus). In contrast, predator experienced (wild-caught) females did not respond to the same extent to the presence of a predator, most likely due to a learned ability to evaluate their predators' motivation to prey. Conclusions: Our study highlights that (a) predatory fish can have a profound influence on the expression of mating preferences of their prey (thus potentially affecting the strength of sexual selection), and females may alter their mate choice behavior strategically to reduce their own exposure to predators. (b) Prey species can evolve visual predator recognition mechanisms and alter their mate choice only when a natural predator is present. (c) Finally, experiential effects can play an important role, and prey species may learn to evaluate the motivational state of their predators. Keywords: Sexual selection; female choice; non-independent mate choice; predator recognition; Poecilia mexicana
Highlights
• A big dataset reveals age-related alterations in EEG biomarkers and cognition.
• Prominent decline of individual alpha peak frequency primarily in temporal lobes.
• A positive association between individual alpha peak frequency and working memory.
• Absence of age-related alpha power decline when controlling for 1/f decay of the PSD.
• Alpha power is negatively associated with the speed of processing in elderly sample.
Abstract
While many structural and biochemical changes in the brain have previously been associated with older age, findings concerning functional properties of neuronal networks, as reflected in their electrophysiological signatures, remain rather controversial. These discrepancies might arise due to several reasons, including diverse factors determining general spectral slowing in the alpha frequency range as well as amplitude mixing between the rhythmic and non-rhythmic parameters. We used a large dataset (N = 1703, mean age 70) to comprehensively investigate age-related alterations in multiple EEG biomarkers taking into account rhythmic and non-rhythmic activity and their individual contributions to cognitive performance. While we found strong evidence for an individual alpha peak frequency (IAF) decline in older age, we did not observe a significant relationship between theta power and age while controlling for IAF. Not only did IAF decline with age, but it was also positively associated with interference resolution in a working memory task primarily in the right and left temporal lobes suggesting its functional role in information sampling. Critically, we did not detect a significant relationship between alpha power and age when controlling for the 1/f spectral slope, while the latter one showed age-related alterations. These findings thus suggest that the entanglement of IAF slowing and power in the theta frequency range, as well as 1/f slope and alpha power measures, might explain inconsistencies reported previously in the literature. Finally, despite the absence of age-related alterations, alpha power was negatively associated with the speed of processing in the right frontal lobe while 1/f slope showed no consistent relationship to cognitive performance. Our results thus demonstrate that multiple electrophysiological features, as well as their interplay, should be considered for the comprehensive assessment of association between age, neuronal activity, and cognitive performance.
Objectives: To investigate the prevalence of depressive symptoms in rheumatoid arthritis (RA) patients using two previously validated questionnaires in a large patient sample, and to evaluate depressive symptoms in the context of clinical characteristics (e.g. remission of disease) and patient-reported impact of disease.
Methods: In this cross-sectional study, the previously validated Patient Health Questionnaire (PHQ-9) and Beck-Depression Inventory II (BDI-II) were used to assess the extent of depressive symptoms in RA patients. Demographic background, RA disease activity score (DAS28), RA impact of disease (RAID) score, comorbidities, anti-rheumatic therapy and antidepressive treatment, were recorded. Cut-off values for depressive symptomatology were PHQ-9 ≥5 or BDI-II ≥14 for mild depressive symptoms or worse and PHQ-9 ≥ 10 or BDI-II ≥ 20 for moderate depressive symptoms or worse. Prevalence of depressive symptomatology was derived by frequency analysis while factors independently associated with depressive symptomatology were investigated by using multiple logistic regression analyses. Ethics committee approval was obtained, and all patients provided written informed consent before participation.
Results: In 1004 RA-patients (75.1% female, mean±SD age: 61.0±12.9 years, mean disease duration: 12.2±9.9 years, DAS28 (ESR): 2.5±1.2), the prevalence of depressive symptoms was 55.4% (mild or worse) and 22.8% (moderate or worse). Characteristics independently associated with depressive symptomatology were: age <60 years (OR = 1.78), RAID score >2 (OR = 10.54) and presence of chronic pain (OR = 3.25). Of patients classified as having depressive symptoms, only 11.7% were receiving anti-depressive therapy.
Conclusions: Mild and moderate depressive symptoms were common in RA patients according to validated tools. In routine clinical practice, screening for depression with corresponding follow-up procedures is as relevant as incorporating these results with patient-reported outcomes (e.g. symptom state), because the mere assessment of clinical disease activity does not sufficiently reflect the prevalence of depressive symptoms.
Clinical trial registration number: This study is registered in the Deutsches Register Klinischer Studien (DRKS00003231) and ClinicalTrials.gov (NCT02485483).
Epigenetic marks critically control gene expression and thus the cellular activity state. The functions of many epigenetic modifiers in the vascular system have not yet been studied. We screened for histone modifiers in endothelial cells and observed a fairly high expression of the histone plant homeodomain finger protein 8 (PHF8). Given its high expression, we hypothesize that this histone demethylase is important for endothelial cell function. Overexpression of PHF8 catalyzed the removal of methyl-groups from histone 3 lysine 9 (H3K9) and H4K20, whereas knockdown of the enzyme increased H3K9 methylation. Knockdown of PHF8 by RNAi also attenuated endothelial proliferation and survival. As a functional readout endothelial migration and tube formation was studied. PHF8 siRNA attenuated the capacity for migration and developing of capillary-like structures. Given the impact of PHF8 on cell cycle genes, endothelial E2F transcription factors were screened, which led to the identification of the gene repressor E2F4 to be controlled by PHF8. Importantly, PHF8 maintains E2F4 but not E2F1 expression in endothelial cells. Consistently, chromatin immunoprecipitation revealed that PHF8 reduces the H3K9me2 level at the E2F4 transcriptional start site, demonstrating a direct function of PHF8 in endothelial E2F4 gene regulation. Conclusion: PHF8 by controlling E2F4 expression maintains endothelial function.
Aims: Patients with aortic stenosis (AS) may have concomitant heart failure (HF) that determines prognosis despite successful transcatheter aortic valve implantation (TAVI). We compared outcomes of TAVI patients with low stroke volume index (SVI) ≤35 ml/m2 body surface area in different HF classes.
Methods and results: Patients treated by transfemoral TAVI at our center (n = 1822) were classified as 1) ‘HF with preserved ejection fraction (EF)’ (HFpEF, EF ≥50%), 2) ‘HF with mid-range EF’ (HFmrEF, EF 40–49%), or 3) ‘HF with reduced EF’ (HFrEF, EF <40%). Patients with SVI >35 ml/m2 served as controls. The prevalence of cardiovascular disease and symptoms increased stepwise from controls (n = 968) to patients with HFpEF (n = 591), HFmrEF (n = 97), and HFrEF (n = 166). Mortality tended to be highest in HFrEF patients 30 days post-procedure, and it became significant after one year: 10.2% (controls), 13.5% (HFpEF), 13.4% (HFmrEF), and 23.5% (HFrEF). However, symptomatic improvement in survivors of all groups was achieved in the majority of patients without differences among groups.
Conclusions: Patients with AS and HF benefit from TAVI with respect to symptom alleviation. TAVI in patients with HFpEF and HFmrEF led to an identical, favorable post-procedural prognosis that was significantly better than that of patients with HFrEF, which remains a high-risk population.
Objectives: There is sparse information on the safety of early primary discharge from the emergency department (ED) after rule-out of myocardial infarction in suspected acute coronary syndrome (ACS). This prospective registry aimed to confirm randomised study results in patients at low-to-intermediate risk, with a broader spectrum of symptoms, across different institutional standards and with a range of local troponin assays including high-sensitivity cTn (hs-cTn), cardiac troponin (cTn) and point-of-care troponin (POC Tn).
Design: Prospective, multicentre European registry.
Setting: 18 emergency departments in nine European countries (Germany, Austria, Switzerland, France, Spain, UK, Turkey, Lithuania and Hungary)
Participants: The final study cohort consisted of 2294 patients (57.2% males, median age 57 years) with suspected ACS.
Interventions: Using the new dual markers strategy, 1477 patients were eligible for direct discharge, which was realised in 974 (42.5%) of patients.
Main outcome measures: The primary endpoint was all-cause mortality at 30 days.
Results: Compared with conventional workup after dual marker measurement, the median length of ED stay was 60 min shorter (228 min, 95% CI: 219 to 239 min vs 288 min, 95% CI: 279 to 300 min) in the primary dual marker strategy (DMS) discharge group. All-cause mortality was 0.1% (95% CI: 0% to 0.6%) in the primary DMS discharge group versus 1.1% (95% CI: 0.6% to 1.8%) in the conventional workup group after dual marker measurement. Conventional workup instead of discharge despite negative DMS biomarkers was observed in 503 patients (21.9%) and associated with higher prevalence of ACS (17.1% vs 0.9%, p<0.001), cardiac diagnoses (55.2% vs 23.5%, p<0.001) and risk factors (p<0.01), but with a similar all-cause mortality of 0.2% (95% CI: 0% to 1.1%) versus primary DMS discharge (p=0.64).
Conclusions: Copeptin on top of cardiac troponin supports safe discharge in patients with chest pain or other symptoms suggestive of ACS under routine conditions with the use of a broad spectrum of local standard POC, conventional and high-sensitivity troponin assays.
Trial registration number NCT02490969.
Background: Leukocyte progenitors derived from clonal hematopoiesis of undetermined potential (CHIP) are associated with increased cardiovascular events. However, the prevalence and functional relevance of CHIP in coronary artery disease (CAD) are unclear, and cells affected by CHIP have not been detected in human atherosclerotic plaques.
Methods: CHIP mutations in blood and tissues were identified by targeted deep-DNA-sequencing (DNAseq: coverage >3,000) and whole-genome-sequencing (WGS: coverage >35). CHIP-mutated leukocytes were visualized in human atherosclerotic plaques by mutaFISHTM. Functional relevance of CHIP mutations was studied by RNAseq.
Results: DNAseq of whole blood from 540 deceased CAD patients of the Munich cardIovaScular StudIes biObaNk (MISSION) identified 253 (46.9%) CHIP mutation carriers (mean age 78.3 years). DNAseq on myocardium, atherosclerotic coronary and carotid arteries detected identical CHIP mutations in 18 out of 25 mutation carriers in tissue DNA. MutaFISHTM visualized individual macrophages carrying DNMT3A CHIP mutations in human atherosclerotic plaques. Studying monocyte-derived macrophages from Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task (STARNET; n=941) by WGS revealed CHIP mutations in 14.2% (mean age 67.1 years). RNAseq of these macrophages revealed that expression patterns in CHIP mutation carriers differed substantially from those of non-carriers. Moreover, patterns were different depending on the underlying mutations, e.g. those carrying TET2 mutations predominantly displayed upregulated inflammatory signaling whereas ASXL1 mutations showed stronger effects on metabolic pathways.
Conclusions: Deep-DNA-sequencing reveals a high prevalence of CHIP mutations in whole blood of CAD patients. CHIP-affected leukocytes invade plaques in human coronary arteries. RNAseq data obtained from macrophages of CHIP-affected patients suggest that pro-atherosclerotic signaling differs depending on the underlying mutations. Further studies are necessary to understand whether specific pathways affected by CHIP mutations may be targeted for personalized treatment.
DGK and DZHK position paper on genome editing: basic science applications and future perspective
(2021)
For a long time, gene editing had been a scientific concept, which was limited to a few applications. With recent developments, following the discovery of TALEN zinc-finger endonucleases and in particular the CRISPR/Cas system, gene editing has become a technique applicable in most laboratories. The current gain- and loss-of function models in basic science are revolutionary as they allow unbiased screens of unprecedented depth and complexity and rapid development of transgenic animals. Modifications of CRISPR/Cas have been developed to precisely interrogate epigenetic regulation or to visualize DNA complexes. Moreover, gene editing as a clinical treatment option is rapidly developing with first trials on the way. This article reviews the most recent progress in the field, covering expert opinions gathered during joint conferences on genome editing of the German Cardiac Society (DGK) and the German Center for Cardiovascular Research (DZHK). Particularly focusing on the translational aspect and the combination of cellular and animal applications, the authors aim to provide direction for the development of the field and the most frequent applications with their problems.
Downstream effects of plectin mutations in epidermolysis bullosa simplex with muscular dystrophy
(2016)
Mutations of the human plectin gene (PLEC) on chromosome 8q24 cause autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). In the present study we analyzed the downstream effects of PLEC mutations on plectin protein expression and localization, the structure of the extrasarcomeric desmin cytoskeleton, protein aggregate formation and mitochondrial distribution in skeletal muscle tissue from three EBS-MD patients.
PLEC gene analysis in a not previously reported 35-year-old EBS-MD patient with additional disease features of cardiomyopathy and malignant arrhythmias revealed novel compound heterozygous (p.(Phe755del) and p.(Lys1040Argfs*139)) mutations resulting in complete abolition of plectin protein expression. In contrast, the other two patients with different homozygous PLEC mutations showed preserved plectin protein expression with one only expressing rodless plectin variants, and the other markedly reduced protein levels. Analysis of skeletal muscle tissue from all three patients revealed severe disruption of the extrasarcomeric intermediate filament cytoskeleton, protein aggregates positive for desmin, syncoilin, and synemin, degenerative myofibrillar changes, and mitochondrial abnormalities comprising respiratory chain dysfunction and an altered organelle distribution and amount.
Our study demonstrates that EBS-MD causing PLEC mutations universally result in a desmin protein aggregate myopathy phenotype despite marked differences in individual plectin protein expression patterns. Since plectin is the key cytolinker protein that regulates the structural and functional organization of desmin filaments, the defective anchorage and spacing of assembled desmin filaments is the key pathogenetic event that triggers the formation of desmin protein aggregates as well as secondary mitochondrial pathology.
How much data do we need? Lower bounds of brain activation states to predict human cognitive ability
(2022)
Human functional brain connectivity can be temporally decomposed into states of high and low cofluctuation, defined as coactivation of brain regions over time. Despite their low frequency of occurrence, states of particularly high cofluctuation have been shown to reflect fundamentals of intrinsic functional network architecture (derived from resting-state fMRI) and to be highly subject-specific. However, it is currently unclear whether such network-defining states of high cofluctuation also contribute to individual variations in cognitive abilities – which strongly rely on the interactions among distributed brain regions. By introducing CMEP, an eigenvector-based prediction framework, we show that functional connectivity estimates from as few as 20 temporally separated time frames (< 3% of a 10 min resting-state fMRI scan) are significantly predictive of individual differences in intelligence (N = 281, p < .001). In contrast and against previous expectations, individual’s network-defining time frames of particularly high cofluctuation do not achieve significant prediction of intelligence. Multiple functional brain networks contribute to the prediction, and all results replicate in an independent sample (N = 831). Our results suggest that although fundamentals of person-specific functional connectomes can be derived from few time frames of highest brain connectivity, temporally distributed information is necessary to extract information about cognitive abilities from functional connectivity time series. This information, however, is not restricted to specific connectivity states, like network-defining high-cofluctuation states, but rather reflected across the entire length of the brain connectivity time series.
The proton drip-line nucleus 17Ne is investigated experimentally in order to determine its two-proton halo character. A fully exclusive measurement of the 17Ne(p, 2p)16F∗ →15O+p quasi-free one-proton knockout reaction has been performed at GSI at around 500 MeV/nucleon beam energy. All particles resulting from the scattering process have been detected. The relevant reconstructed quantities are the angles of the two protons scattered in quasi-elastic kinematics, the decay of 16F into 15O (including γ decays from excited states) and a proton, as well as the 15O+p relative-energy spectrum and the 16F momentum distributions. The latter two quantities allow an independent and consistent determination of the fractions of l = 0 and l = 2 motion of the valence protons in 17Ne. With a resulting relatively small l = 0 component of only around 35(3)%, it is concluded that 17Ne exhibits a rather modest halo character only. The quantitative agreement of the two values deduced from the energy spectrum and the momentum distributions supports the theoretical treatment of the calculation of momentum distributions after quasi-free knockout reactions at high energies by taking into account distortions based on the Glauber theory. Moreover, the experimental data allow the separation of valence-proton knockout and knockout from the 15O core. The latter process contributes with 11.8(3.1) mb around 40% to the total proton-knockout cross section of 30.3(2.3) mb, which explains previously reported contradicting conclusions derived from inclusive cross sections.
We measured the Coulomb dissociation of 16O into 4He and 12C at the R3B setup in a first campaign within FAIR Phase 0 at GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt. The goal was to improve the accuracy of the experimental data for the 12C(α,γ)16O fusion reaction and to reach lower center-ofmass energies than measured so far.
The experiment required beam intensities of 109 16O ions per second at an energy of 500 MeV/nucleon. The rare case of Coulomb breakup into 12C and 4He posed another challenge: The magnetic rigidities of the particles are so close because of the same mass-to-charge-number ratio A/Z = 2 for 16O, 12C and 4He. Hence, radical changes of the R3B setup were necessary. All detectors had slits to allow the passage of the unreacted 16O ions, while 4He and 12C would hit the detectors' active areas depending on the scattering angle and their relative energies. We developed and built detectors based on organic scintillators to track and identify the reaction products with sufficient precision.
Background: The angiogenic function of endothelial cells is regulated by numerous mechanisms, but the impact of long noncoding RNAs (lncRNAs) has hardly been studied. We set out to identify novel and functionally important endothelial lncRNAs.
Methods: Epigenetically controlled lncRNAs in human umbilical vein endothelial cells were searched by exon-array analysis after knockdown of the histone demethylase JARID1B. Molecular mechanisms were investigated by RNA pulldown and immunoprecipitation, mass spectrometry, microarray, several knockdown approaches, CRISPR-Cas9, assay for transposase-accessible chromatin sequencing, and chromatin immunoprecipitation in human umbilical vein endothelial cells. Patient samples from lung and tumors were studied for MANTIS expression.
Results: A search for epigenetically controlled endothelial lncRNAs yielded lncRNA n342419, here termed MANTIS, as the most strongly regulated lncRNA. Controlled by the histone demethylase JARID1B, MANTIS was downregulated in patients with idiopathic pulmonary arterial hypertension and in rats treated with monocrotaline, whereas it was upregulated in carotid arteries of Macaca fascicularis subjected to atherosclerosis regression diet, and in endothelial cells isolated from human glioblastoma patients. CRISPR/Cas9-mediated deletion or silencing of MANTIS with small interfering RNAs or GapmeRs inhibited angiogenic sprouting and alignment of endothelial cells in response to shear stress. Mechanistically, the nuclear-localized MANTIS lncRNA interacted with BRG1, the catalytic subunit of the switch/sucrose nonfermentable chromatin-remodeling complex. This interaction was required for nucleosome remodeling by keeping the ATPase function of BRG1 active. Thereby, the transcription of key endothelial genes such as SOX18, SMAD6, and COUP-TFII was regulated by ensuring efficient RNA polymerase II machinery binding.
Conclusion: MANTIS is a differentially regulated novel lncRNA facilitating endothelial angiogenic function.
Oxidized phospholipids (oxPAPC) induce endothelial dysfunction and atherosclerosis. Here we show that oxPAPC induce a gene network regulating serine-glycine metabolism with the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) as a causal regulator using integrative network modeling and Bayesian network analysis in human aortic endothelial cells. The cluster is activated in human plaque material and by atherogenic lipoproteins isolated from plasma of patients with coronary artery disease (CAD). Single nucleotide polymorphisms (SNPs) within the MTHFD2-controlled cluster associate with CAD. The MTHFD2-controlled cluster redirects metabolism to glycine synthesis to replenish purine nucleotides. Since endothelial cells secrete purines in response to oxPAPC, the MTHFD2-controlled response maintains endothelial ATP. Accordingly, MTHFD2-dependent glycine synthesis is a prerequisite for angiogenesis. Thus, we propose that endothelial cells undergo MTHFD2-mediated reprogramming toward serine-glycine and mitochondrial one-carbon metabolism to compensate for the loss of ATP in response to oxPAPC during atherosclerosis.
Poster Einleitung Im Rahmen effizienzsteigernder Maßnahmen sind klinische Behandlungspfade unter DRG- Bedingungen und im Rahmen der Qualitätssicherung wichtige Instrumente. Material und Methoden Aus der Analyse zweier erfahrungsbasierter klinischer Behandlungspfade in Frankfurt/D und Newcastle/GB wurde ein halbstandardisierter clinical pathway Carotisstenose entwickelt, der der heterogenen Befundkonstellation bei Aufnahme, den unterschiedlichen klinischen Stadien der Erkrankung und den individuellen Patientenbedürfnissen Rechnung trägt. Es wurden dazu zwei Gruppen mit je 25 konsekutiv in Frankfurt/D ( Gruppe FrankfurtI) und New Castle/GB ( Gruppe New Castle )operierten Patienten retrospektiv analysiert.Aus den retrospektiv erhobenen Daten wurde ein stadienbezogener und der Zuweisersituation gerecht werdender klinischer Behandlungspfad erstellt, der anhand von 20 konsekutiv operierten Patienten, davon 60 % im Stadium IV der Erkrankung, ( Gruppe FrankfurtII ) analysiert wurde. Ergebnisse In Frankfurt 1 wurde 21 mal eine Eversions-TEA und 4 mal eine TEA/ Patchplastik angewendet, 62 % der Patienten befanden sich im Stadium 1 der Erkrankung, ,65 % erhielten präoperativ eine i.a.DSA der supraaortalen Äste ,100% eine Duplexsonografie und eine CCT; postoperativ fielen insgesamt 12 Intensiv- Pflegetage an sowie eine Revision aufgrund einer Nachblutung. In der Gruppe New Castle befanden sich 68% der Patienten in einem klinischen Stadium 2,es wurde 25 mal offen thrombendarteriektomiert, davon 21 mal mit Direktnaht verschlossen und 4 mal mit Patchplastik, alle Patienten erhielten präoperativ eine CT- Angiografie und eine Duplexsonografie; postoperativ fiel 1 Intensivpflegetag an und eine Revision wegen Nachblutung. Die Morbiditäts-/ Mortalitätsrate betrug in beiden Gruppen 0%. Betriebswirtschaftlich wurden bei einer Liegedauer von durchschnittlich 10 Tagen in Frankfurt 1 tatsächliche Kosten von 2768.96€ pro Patient ermittelt, in New Castle,bei einer Liegedauer von durchschnittlich 5 Tagen und einer differenten Kostenstruktur von 2510.56 €. In der Gruppe Frankfurt 2 wurde 11mal eine TEA mit Patchplastik und 9 mal eine Eversions-TEA durchgeführt, alle Patienten erhielten präoperativ eine Duplexsonografie und eine CCT , postoperativ fielen insgesamt 6 Intensivtage an, es wurde nicht revidiert, die Morbiditäts-/Mortalitätsrate lag ebenfalls bei 0%. Durch Einführung eines klinischen Behandlungspfades wurde also die Liegedauer in Frankfurt um 40 % reduziert sowie die tatsächlichen Kosten auf 2384.41€ pro Fall und damit im Mittel um 14 % gemindert. Schlussfolgerung Unter DRG-Bedingungen trägt daher die Anwendung eines klinischen Behandlungspfades in der Carotischirurgie zu einer Verbesserung der Erlössituation ohne Qualitätseinbuße bei.
Background The detection of the new Coranavirus (CoV) causing agent of the severe acute respiratory syndrome (SARS) for diagnostic purposes is still a critical step in prevention of secondary hospital infections. In this respect the PCR for SARS diagnostic is the fastest and most sensitive method and was published very early after the description of the new pathogen by different groups. To evaluate the quality and sensitivity of the SARS PCR performed in diagnostic laboratories all over the world an external quality assurance (EQA) for SARS PCR was initiated by the WHO, the European Network for Diagnostics of "Imported" Viral Diseases (ENIVD) and the Robert Koch-Institut. Methods Therefore 10 samples of inactivated SARS CoV strains isolated in Frankfurt and Hong Kong in different dilutions and negative controls were prepared. The freeze dried samples were send by mail to 62 different laboratories, in 37 countries in Europe and Israel (35), Asia (11), The Americas (11), Australia and New Zealand (4) and Africa (1). The results were returned by email or fax 1 week (13), 2 weeks (14), 3 weeks (6) and later (29) after receiving the material which does not mimic at all the possible speed of this fast method. But this was not considered in the evaluation of these first SARS EQA. Results 44 laboratories showed good or excellent results (26 = 100%, 18 = 90%) and even the 14 laboratories which archived only 80% (10) or 70% (4) correct results are mostly lacking sensitivity. The results of the other 4 laboratories show basic problems in regard to sensitivity, specificity and consistency of results and must be overcome as soon as possible. 4 laboratories seem to have problems with the specificity finding a positive signal in negative samples. The different methods used for preparation of the SARS CoV genome and diagnostic PCR test procedure used by the participating laboratories will be discussed in more detail in the presentation. Conclusion However, in contrast to previous EQAs for Ebola, Lassa and Orthopoxviruses the quality of PCR results was rather good which might be caused by the early publication and distribution of well developed PCR methods. An EQA for evaluation of SARS specific serology is still ongoing, first results will be available beginning of April 2004.
Maßgeblich unter dem wachsenden externen Druck hat die didaktische Qualifizierung in den medizinischen Fakultäten an Bedeutung gewonnen. Im Rahmen der Professionalisierung der medizinischen Aus-, Fort- und Weiterbildung ist eine pädagogisch-didaktische Ausbildung der Lehrenden unumgänglich. Um Orientierung und Argumentationshilfe zu geben, werden in einer dreiteiligen Artikelfolge Stellenwert der Medizindidaktik, Anforderungsprofil der Angebote und Konzepte zur Implementierung und zur Erfolgsmessung für den deutschsprachigen Raum beleuchtet. In Teil II beleuchten wir den Ausbildungsbedarf und erstellen ein Anforderungsprofil für ein strukturiertes systematisches Qualifizierungsangebot. Der Hauptbedarf besteht in der Qualifizierung der Lehrenden, die den täglichen Unterricht durchführen. Insbesondere sie brauchen das Handwerkszeug, das ihnen erlaubt, ihre verschiedenen Lehraufgaben effizienter zu bewältigen. Seitens der Fakultät und der Studierenden bestehen Ansprüche an qualifizierte Lehrende; ebenso bestehen Forderungen seitens der Lehrenden an adäquat qualifizierende Kurse. Zur Umsetzung dieser berechtigten Ansprüche sind modular aufgebaute Programme nötig, die eine zumindest national qualitativ und quantitativ vergleichbare Ausbildung gewährleisten. Anforderungen an derartige Kurse sind bereits definiert und lokal zum Beispiel in Baden-Württemberg und zum Teil auch in Nordrhein-Westfalen umgesetzt. Es gilt nun, diese auf breiter Basis in die Praxis umzusetzen.
Maßgeblich unter dem wachsenden externen Druck hat die didaktische Qualifizierung in den medizinischen Fakultäten an Bedeutung gewonnen. Im Rahmen der Professionalisierung der medizinischen Aus-, Fort- und Weiterbildung ist eine pädagogisch-didaktische Ausbildung der Lehrenden unumgänglich. Um Orientierung und Argumentationshilfe zu geben, werden in einer dreiteiligen Artikelfolge Stellenwert der Medizindidaktik, Anforderungsprofil der Angebote und Konzepte zur Implementierung und zur Erfolgsmessung für den deutschsprachigen Raum beleuchtet. In Teil I geben wir eine Bestandsaufnahme zur Medizindidaktik. Aktuell gibt es bundesweit ein breit gefächertes Qualifizierungsangebot. Es reicht von einfachen unstrukturierten Kurzfortbildungen wie zum Beispiel Vorträgen und Seminaren, die inhaltlich, formal und qualitativ eine große Beliebigkeit zeigen, bis hin zu umfassenden mehrjährigen (Aufbau-)Studiengängen mit "Master-Degree". Im internationalen Vergleich fehlt in Deutschland ein allgemein verbindliches "Basis-Programm", das die täglich Lehrenden systematisch auf ihre Ausbildungsaufgaben vorbereitet. Dies ist bisher nur lokal umgesetzt wie zum Beispiel in Baden-Württemberg mit dem ministeriell zertifizierten Programm der Medizindidaktischen Qualifikation I und II. Vergleichbares ist in Nordrhein-Westfalen und Bayern im Aufbau.
Epigenetic control of microsomal prostaglandin E synthase-1 by HDAC-mediated recruitment of p300
(2017)
Nonsteroidal anti-inflammatory drugs are the most widely used medicine to treat pain and inflammation, and to inhibit platelet function. Understanding the expression regulation of enzymes of the prostanoid pathway is of great medical relevance. Histone acetylation crucially controls gene expression. We set out to identify the impact of histone deacetylases (HDACs) on the generation of prostanoids and examine the consequences on vascular function. HDAC inhibition (HDACi) with the pan-HDAC inhibitor, vorinostat, attenuated prostaglandin (PG)E2 generation in the murine vasculature and in human vascular smooth muscle cells. In line with this, the expression of the key enzyme for PGE2 synthesis, microsomal PGE synthase-1 (PTGES1), was reduced by HDACi. Accordingly, the relaxation to arachidonic acid was decreased after ex vivo incubation of murine vessels with HDACi. To identify the underlying mechanism, chromatin immunoprecipitation (ChIP) and ChIP-sequencing analysis were performed. These results suggest that HDACs are involved in the recruitment of the transcriptional activator p300 to the PTGES1 gene and that HDACi prevented this effect. In line with the acetyltransferase activity of p300, H3K27 acetylation was reduced after HDACi and resulted in the formation of heterochromatin in the PTGES1 gene. In conclusion, HDAC activity maintains PTGES1 expression by recruiting p300 to its gene.
Purpose: Scientific and clinical achievements in radiation, medical, and surgical oncology are changing the landscape of interdisciplinary oncology. The German Society for Radiation Oncology (DEGRO) working group of young clinicians and scientists (yDEGRO) and the DEGRO representation of associate and full professors (AKRO) are aware of the essential role of radiation oncology in multidisciplinary treatment approaches. Together, yDEGRO and AKRO endorsed developing a German radiotherapy & radiation oncology vision 2030 to address future challenges in patient care, research, and education. The vision 2030 aims to identify priorities and goals for the next decade in the field of radiation oncology. Methods: The vision development comprised three phases. During the first phase, areas of interest, objectives, and the process of vision development were defined jointly by the yDEGRO, AKRO, and the DEGRO board. In the second phase, a one-day strategy retreat was held to develop AKRO and yDEGRO representatives’ final vision from medicine, biology, and physics. The third phase was dedicated to vision interpretation and program development by yDEGRO representatives. Results: The strategy retreat’s development process resulted in conception of the final vision “Innovative radiation oncology Together – Precise, Personalized, Human.” The first term “Innovative radiation oncology” comprises the promotion of preclinical research and clinical trials and highlights the development of a national committee for strategic development in radiation oncology research. The term “together” underpins collaborations within radiation oncology departments as well as with other partners in the clinical and scientific setting. “Precise” mainly covers technological precision in radiotherapy as well as targeted oncologic therapeutics. “Personalized” emphasizes biology-directed individualization of radiation treatment. Finally, “Human” underlines the patient-centered approach and points towards the need for individual longer-term career curricula for clinicians and researchers in the field. Conclusion: The vision 2030 balances the ambition of physical, technological, and biological innovation as well as a comprehensive, patient-centered, and collaborative approach towards radiotherapy & radiation oncology in Germany.
Glioblastoma multiforme (GBM) is treated by surgical resection followed by radiochemotherapy. Bevacizumab is commonly deployed for anti‐angiogenic therapy of recurrent GBM; however, innate immune cells have been identified as instigators of resistance to bevacizumab treatment. We identified angiopoietin‐2 (Ang‐2) as a potential target in both naive and bevacizumab‐treated glioblastoma. Ang‐2 expression was absent in normal human brain endothelium, while the highest Ang‐2 levels were observed in bevacizumab‐treated GBM. In a murine GBM model, VEGF blockade resulted in endothelial upregulation of Ang‐2, whereas the combined inhibition of VEGF and Ang‐2 leads to extended survival, decreased vascular permeability, depletion of tumor‐associated macrophages, improved pericyte coverage, and increased numbers of intratumoral T lymphocytes. CD206+ (M2‐like) macrophages were identified as potential novel targets following anti‐angiogenic therapy. Our findings imply a novel role for endothelial cells in therapy resistance and identify endothelial cell/myeloid cell crosstalk mediated by Ang‐2 as a potential resistance mechanism. Therefore, combining VEGF blockade with inhibition of Ang‐2 may potentially overcome resistance to bevacizumab therapy.
Um eine gezielte Prophylaxe und Therapie der Urolithiasis zu ermöglichen und um die Rezidivrate zu senken, ist die genaue Kenntnis der Steinzusammensetzung erforderlich. Wegen des hohen Beschaffungspreises sind Röntgendiffraktion und Infrarotspektroskopie nur wenigen Laboratorien vorbehalten, andererseits sollten unspezifisch-chemische Steinanalysenmethoden wegen deren geringeren Sensitivität und Spezifität heute nicht mehr angewendet werden.
In dieser Arbeit wird eine unter dem Mikroskop durchführbare Harnsteinkomponentenanalysenmethode (Harzalith) beschrieben. Es handelt sich um eine mikroskopisch-mikrochemische Harnsteinanalysenmethode. Sie basiert auf der Auswertung mikroskopisch typischer, leicht einprägsamer Farbmuster, die sich je nach Steinzusammensetzung in charakteristischer Weise nach Zugabe des Steinmaterials zum Reagenz innerhalb von Sekunden entwickeln.
Eine Bewertung der mikroskopisch-mikrochemischen Harnsteinkomponentenanalyse gegenüber Röntgendiffraktion, Infrarotspektroskopie und unspezifisch-chemischen Methoden erfolgt anhand von Ergebnissen aus über 10jähriger eigener Anwendungserfahrung.
Folgende Vorteile werden kurz dargestellt:
1. Es werden Steinkomponenten und nicht nur Ionen erfaßt.
2. Es können geringste Steinprobenmengen analysiert werden.
3. Die Ergebnisse der Methode hinsichtlich Richtigkeit, Sensitivität und Spezifität sind in gleicher Größenordnung wie die von Infrarotspektroskopie und Röntgendiffraktion.
4. Die Methode ist einfach zu erlernen, schnell, genau und von leichter Handhabung. Sie ist damit eine echte Alternative gegenüber den anderen apparativ-aufwendigen Harnsteinanalysenverfahren.