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Correlations in the hadron distributions produced in relativistic Au+Au collisions are studied in the discrete wavelet expansion method. The analysis is performed in the space of pseudorapidity (| eta | <= 1) and azimuth(full 2 pi ) in bins of transverse momentum (pt) from 0.14 <= pt <= 2.1GeV/c. In peripheral Au+Au collisions a correlation structure ascribed to minijet fragmentation is observed. It evolves with collision centrality and pt in a way not seen before, which suggests strong dissipation of minijet fragmentation in the longitudinally expanding medium.
Azimuthally sensitive Hanbury Brown-Twiss interferometry in Au+Au collisions at sqrt[sNN]=200 GeV
(2004)
We present the results of a systematic study of the shape of the pion distribution in coordinate space at freeze-out in Au+Au collisions at BNL RHIC using two-pion Hanbury Brown-Twiss (HBT) interferometry. Oscillations of the extracted HBT radii versus emission angle indicate sources elongated perpendicular to the reaction plane. The results indicate that the pressure and expansion time of the collision system are not sufficient to completely quench its initial shape.
The results from the STAR Collaboration on directed flow (v1), elliptic flow (v2), and the fourth harmonic (v4) in the anisotropic azimuthal distribution of particles from Au+Au collisions at sqrt[sNN]=200GeV are summarized and compared with results from other experiments and theoretical models. Results for identified particles are presented and fit with a blast-wave model. Different anisotropic flow analysis methods are compared and nonflow effects are extracted from the data. For v2, scaling with the number of constituent quarks and parton coalescence are discussed. For v4, scaling with v22 and quark coalescence are discussed.
We present a systematic analysis of two-pion interferometry in Au+Au collisions at sqrt[sNN]=200GeV using the STAR detector at Relativistic Heavy Ion Collider. We extract the Hanbury-Brown and Twiss radii and study their multiplicity, transverse momentum, and azimuthal angle dependence. The Gaussianness of the correlation function is studied. Estimates of the geometrical and dynamical structure of the freeze-out source are extracted by fits with blast-wave parametrizations. The expansion of the source and its relation with the initial energy density distribution is studied.
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.
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.
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.
The STAR Collaboration at the Relativistic Heavy Ion Collider presents measurements of 𝐽/𝜓→𝑒+𝑒− at midrapidity and high transverse momentum (𝑝𝑇>5 GeV/𝑐) in 𝑝+𝑝 and central Cu+Cu collisions at √𝑠𝑁𝑁=200 GeV. The inclusive 𝐽/𝜓 production cross section for Cu+Cu collisions is found to be consistent at high 𝑝𝑇 with the binary collision-scaled cross section for 𝑝+𝑝 collisions. At a confidence level of 97%, this is in contrast to a suppression of 𝐽/𝜓 production observed at lower 𝑝𝑇. Azimuthal correlations of 𝐽/𝜓 with charged hadrons in 𝑝+𝑝 collisions provide an estimate of the contribution of 𝐵-hadron decays to 𝐽/𝜓 production of 13%±5%.
We study the beam-energy and system-size dependence of \phi meson production (using the hadronic decay mode \phi -- K+K-) by comparing the new results from Cu+Cu collisions and previously reported Au+Au collisions at \sqrt{s_NN} = 62.4 and 200 GeV measured in the STAR experiment at RHIC. Data presented are from mid-rapidity (|y|<0.5) for 0.4 < pT < 5 GeV/c. At a given beam energy, the transverse momentum distributions for \phi mesons are observed to be similar in yield and shape for Cu+Cu and Au+Au colliding systems with similar average numbers of participating nucleons. The \phi meson yields in nucleus-nucleus collisions, normalised by the average number of participating nucleons, are found to be enhanced relative to those from p+p collisions with a different trend compared to strange baryons. The enhancement for \phi mesons is observed to be higher at \sqrt{s_NN} = 200 GeV compared to 62.4 GeV. These observations for the produced \phi(s\bar{s}) mesons clearly suggest that, at these collision energies, the source of enhancement of strange hadrons is related to the formation of a dense partonic medium in high energy nucleus-nucleus collisions and cannot be alone due to canonical suppression of their production in smaller systems.
National greenhouse gas inventories (GHGIs) are submitted annually to the United Nations Framework Convention on Climate Change (UNFCCC). They are estimated in compliance with Intergovernmental Panel on Climate Change (IPCC) methodological guidance using activity data, emission factors and facility-level measurements. For some sources, the outputs from these calculations are very uncertain. Inverse modelling techniques that use high-quality, long-term measurements of atmospheric gases have been developed to provide independent verification of national GHGIs. This is considered good practice by the IPCC as it helps national inventory compilers to verify reported emissions and to reduce emission uncertainty. Emission estimates from the InTEM (Inversion Technique for Emission Modelling) model are presented for the UK for the hydrofluorocarbons (HFCs) reported to the UNFCCC (HFC-125, HFC-134a, HFC-143a, HFC-152a, HFC-23, HFC-32, HFC-227ea, HFC-245fa, HFC-43-10mee and HFC-365mfc). These HFCs have high global warming potentials (GWPs), and the global background mole fractions of all but two are increasing, thus highlighting their relevance to the climate and a need for increasing the accuracy of emission estimation for regulatory purposes. This study presents evidence that the long-term annual increase in growth of HFC-134a has stopped and is now decreasing. For HFC-32 there is an early indication, its rapid global growth period has ended, and there is evidence that the annual increase in global growth for HFC-125 has slowed from 2018. The inverse modelling results indicate that the UK implementation of European Union regulation of HFC emissions has been successful in initiating a decline in UK emissions from 2018. Comparison of the total InTEM UK HFC emissions in 2020 with the average from 2009–2012 shows a drop of 35 %, indicating progress toward the target of a 79 % decrease in sales by 2030. The total InTEM HFC emission estimates (2008–2018) are on average 73 (62–83) % of, or 4.3 (2.7–5.9) Tg CO2-eq yr−1 lower than, the total HFC emission estimates from the UK GHGI. There are also significant discrepancies between the two estimates for the individual HFCs.
National Greenhouse Gas Inventories (GHGI) are submitted annually to the United Nations Framework Convention on Climate Change (UNFCCC). They are estimated in compliance with Intergovernmental Panel on Climate Change (IPCC) methodological guidance using activity data, emission factors and facility-level measurements. For some sources, the outputs from these calculations are very uncertain. Inverse modelling techniques that use high-quality, long-term measurements of atmospheric gases have been developed to provide independent verification of national GHGI. This is considered good practice by the IPCC as it helps national inventory compilers to verify reported emissions and to reduce emission uncertainty. Emission estimates from the InTEM (Inversion Technique for Emissions Modelling) model are presented for the UK for the hydrofluorocarbons (HFCs) reported to the UNFCCC (HFC-125, HFC-134a, HFC-143a, HFC-152a, HFC-23, HFC-32, HFC-227ea, HFC-245fa, HFC-43-10mee and HFC-365mfc). These HFCs have high Global Warming Potentials (GWPs) and the global background mole fractions of all but two are increasing, thus highlighting their relevance to the climate and a need for increasing the accuracy of emission estimation for regulatory purposes. This study presents evidence that the long-term annual increase in growth of HFC-134a has stopped and is now decreasing. For HFC-32 there is an early indication its rapid global growth period has ended, and there is evidence that the annual increase in global growth for HFC-125 has slowed from 2018. The inverse modelling results indicate that the UK implementation of European Union regulation of HFC emissions has been successful in initiating a decline in UK emissions in the since 2018. Comparison of the total InTEM UK HFC emissions in 2020 with the average from 2009–2012 shows a drop of 35%, indicating progress toward the target of a 79% decrease in sales by 2030. The total InTEM HFC emission estimates (2008–2018) are on average 73 (62–83)% of, or 4.3 (2.7–5.9) Tg CO2-eq yr−1 lower than, the total HFC emission estimates from the UK GHGI inventory. There are also significant discrepancies between the two estimates for the individual HFCs.
The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
Mapping cortical brain asymmetry in 17,141 healthy individuals worldwide via the ENIGMA Consortium
(2017)
RNA contains various chemical modifications that expand its otherwise limited repertoire to mediate complex processes like translation and gene regulation. 25S rRNA of the large subunit of ribosome contains eight base methylations. Except for the methylation of uridine residues, methyltransferases for all other known base methylations have been recently identified. Here we report the identification of BMT5 (YIL096C) and BMT6 (YLR063W), two previously uncharacterized genes, to be responsible for m3U2634 and m3U2843 methylation of the 25S rRNA, respectively. These genes were identified by RP-HPLC screening of all deletion mutants of putative RNA methyltransferases and were confirmed by gene complementation and phenotypic characterization. Both proteins belong to Rossmann-fold-like methyltransferases and the point mutations in the S-adenosyl-L-methionine binding pocket abolish the methylation reaction. Bmt5 localizes in the nucleolus, whereas Bmt6 is localized predominantly in the cytoplasm. Furthermore, we showed that 25S rRNA of yeast does not contain any m5U residues as previously predicted. With Bmt5 and Bmt6, all base methyltransferases of the 25S rRNA have been identified. This will facilitate the analyses of the significance of these modifications in ribosome function and cellular physiology.
Bei Damme, Gehrde und Rieste, 30 km nordöstlich von Osnabrück, kommt ein marin-sedimentäres, stratiformes Eisenerzlager vor, das aus Brauneisenerz-Geröllen und mergelig-glaukonitischer Matrix besteht und meist 2-7 m mächtig ist. Dieses Erzlager tritt in fünf unterschiedlich großen, linsenförmigen Zonen auf, die in 70-400 m Tiefe unter Gelände auf den flach einfallenden Flügeln einer 35 km langen und 10km breiten Oberkreide-Mulde liegen. Es gehört stratigraphisch dem Oberen Unter-Campan an und transgrediert auf tonige Gesteine der Unterkreide. In seinem Hangenden liegen Sedimentgesteine des Ober-Campan, Tertiär und Quartär. Das Erzlager entstand als marine Seife durch Abtragung, Umlagerung und Oxidation von Siderit-Konkretionen aus den tonigen Gesteinen der Unterkreide im Liegenden und in der Umgebung des Erzvorkommens. Von 1944-1967 ist das Erzlager in der jetzt auflässigen Grube Damme abgebaut worden. Dort erzeugte man aus Roherz mit 30-32 % Fe und 0,6-0,7% P durch naßmechanische Aufbereitung ein Konzentrat (versandfertiges Produkt) mit 46-47 % Fe und 0,8% P, das im Ruhrgebiet verhüttet wurde. Insgesamt wurden rund 9,2 Mio. t Roherz gefördert und 5,1 Mio. t Konzentrat erzeugt. Die Grube Damme ist aus wirtschaftlichen Gründen stillgelegt worden. Das Erz ist gegenwärtig nicht abbauwürdig. Deshalb sind die Erzvorräte noch nicht vollständig erkundet.
Under the Kigali Amendment to the Montreal Protocol, new controls are being implemented to reduce emissions of HFC-23 (CHF3), a by-product during the manufacture of HCFC-22 (CHClF2). Starting in 2015, China and India, who dominate global HCFC-22 production (75% in 2017), set out ambitious programs to reduce HFC-23 emissions. Here, we estimate that these measures should have seen global emissions drop by 87% between 2014 and 2017. Instead, atmospheric observations show that emissions have increased and in 2018 were higher than at any point in history (15.9 ± 0.9 Gg yr−1). Given the magnitude of the discrepancy between expected and observation-inferred emissions, it is likely that the reported reductions have not fully materialized or there may be substantial unreported production of HCFC-22, resulting in unaccounted-for HFC-23 by-product emissions. The difference between reported and observation-inferred estimates suggests that an additional ~309 Tg CO2-equivalent emissions were added to the atmosphere between 2015 and 2017.
Introduction: Acute stroke care delivered by interdisciplinary teams is time-sensitive. Simulation-based team training is a promising tool to improve team performance in medical operations. It has the potential to improve process times, team communication, patient safety, and staff satisfaction. We aim to assess whether a multi-level approach consisting of a stringent workflow revision based on peer-to-peer review and 2–3 one-day in situ simulation trainings can improve acute stroke care processing times in high volume neurocenters within a 6 months period.
Methods and Analysis: The trial is being carried out in a pre-test-post-test design at 7 tertiary care university hospital neurocenters in Germany. The intervention is directed at the interdisciplinary multiprofessional stroke teams. Before and after the intervention, process times of all direct-to-center stroke patients receiving IV thrombolysis (IVT) and/or endovascular therapy (EVT) will be recorded. The primary outcome measure will be the “door-to-needle” time of all consecutive stroke patients directly admitted to the neurocenters who receive IVT. Secondary outcome measures will be intervention-related process times of the fraction of patients undergoing EVT and effects on team communication, perceived patient safety, and staff satisfaction via a staff questionnaire.
Interventions: We are applying a multi-level intervention in cooperation with three “STREAM multipliers” from each center. First step is a central meeting of the multipliers at the sponsor's institution with the purposes of algorithm review in a peer-to-peer process that is recorded in a protocol and an introduction to the principles of simulation training and debriefing as well as crew resource management and team communication. Thereafter, the multipliers cooperate with the stroke team trainers from the sponsor's institution to plan and execute 2–3 one-day simulation courses in situ in the emergency department and CT room of the trial centers whereupon they receive teaching materials to perpetuate the trainings.
Clinical Trial Registration: STREAM is a registered trial at https://clinicaltrials.gov/ct2/show/NCT03228251.
Borrelia recurrentis, the etiologic agent of louse-borne relapsing fever in humans, has evolved strategies, including antigenic variation, to evade immune defence, thereby causing severe diseases with high mortality rates. Here we identify for the first time a multifunctional surface lipoprotein of B. recurrentis, termed HcpA, and demonstrate that it binds human complement regulators, Factor H, CFHR-1, and simultaneously, the host protease plasminogen. Cell surface bound factor H was found to retain its activity and to confer resistance to complement attack. Moreover, ectopic expression of HcpA in a B. burgdorferi B313 strain, deficient in Factor H binding proteins, protected the transformed spirochetes from complement-mediated killing. Furthermore, HcpA-bound plasminogen/plasmin endows B. recurrentis with the potential to resist opsonization and to degrade extracellular matrix components. Together, the present study underscores the high virulence potential of B. recurrentis. The elucidation of the molecular basis underlying the versatile strategies of B. recurrentis to escape innate immunity and to persist in human tissues, including the brain, may help to understand the pathological processes underlying louse-borne relapsing fever.
In this letter we report the first multi-differential measurement of correlated pion-proton pairs from 2 billion Au+Au collisions at sNN=2.42 GeV collected with HADES. In this energy regime the population of Δ(1232) resonances plays an important role in the way energy is distributed between intrinsic excitation energy and kinetic energy of the hadrons in the fireball. The triple differential d3N/dMπ±pdpTdy distributions of correlated π±p pairs have been determined by subtracting the πp combinatorial background using an iterative method. The invariant-mass distributions in the Δ(1232) mass region show strong deviations from a Breit-Wigner function with vacuum width and mass. The yield of correlated pion-proton pairs exhibits a complex isospin, rapidity and transverse-momentum dependence. In the invariant mass range 1.1<Minv(GeV/c2)<1.4, the yield is found to be similar for π+p and π−p pairs, and to follow a power law 〈Apart〉α, where 〈Apart〉 is the mean number of participating nucleons. The exponent α depends strongly on the pair transverse momentum (pT) while its pT-integrated and charge-averaged value is α=1.5±0.08st±0.2sy.
We present first data on sub-threshold production of Ks0 mesons and Λ hyperons in Au+Au collisions at sNN=2.4 GeV. We observe an universal 〈Apart〉 scaling of hadrons containing strangeness, independent of their corresponding production thresholds. Comparing the yields, their 〈Apart〉 scaling, and the shapes of the rapidity and the pt spectra to state-of-the-art transport model (UrQMD, HSD, IQMD) predictions, we find that none of them can simultaneously describe these observables with reasonable χ2 values.
We investigate identical pion HBT intensity interferometry in central Au+Au collisions at 1.23A GeV. High-statistics π−π− and π+π+ data are measured with HADES at SIS18/GSI. The radius parameters, derived from the correlation function depending on relative momenta in the longitudinally comoving system and parametrized as three-dimensional Gaussian distribution, are studied as function of transverse momentum. A substantial charge-sign difference of the source radii is found, particularly pronounced at low transverse momentum. The extracted source parameters agree well with a smooth extrapolation of the center-of-mass energy dependence established at higher energies, extending the corresponding excitation functions down towards a very low energy.
Background Anti-angiogenic treatment is believed to have at least cystostatic effects in highly vascularized tumours like pancreatic cancer. In this study, the treatment effects of the angiogenesis inhibitor Cilengitide and gemcitabine were compared with gemcitabine alone in patients with advanced unresectable pancreatic cancer. Methods A multi-national, open-label, controlled, randomized, parallel-group, phase II pilot study was conducted in 20 centers in 7 countries. Cilengitide was administered at 600 mg/m2 twice weekly for 4 weeks per cycle and gemcitabine at 1000 mg/m2 for 3 weeks followed by a week of rest per cycle. The planned treatment period was 6 four-week cycles. The primary endpoint of the study was overall survival and the secondary endpoints were progression-free survival (PFS), response rate, quality of life (QoL), effects on biological markers of disease (CA 19.9) and angiogenesis (vascular endothelial growth factor and basic fibroblast growth factor), and safety. An ancillary study investigated the pharmacokinetics of both drugs in a subset of patients. Results Eighty-nine patients were randomized. The median overall survival was 6.7 months for Cilengitide and gemcitabine and 7.7 months for gemcitabine alone. The median PFS times were 3.6 months and 3.8 months, respectively. The overall response rates were 17% and 14%, and the tumor growth control rates were 54% and 56%, respectively. Changes in the levels of CA 19.9 went in line with the clinical course of the disease, but no apparent relationships were seen with the biological markers of angiogenesis. QoL and safety evaluations were comparable between treatment groups. Pharmacokinetic studies showed no influence of gemcitabine on the pharmacokinetic parameters of Cilengitide and vice versa. Conclusion There were no clinically important differences observed regarding efficacy, safety and QoL between the groups. The observations lay in the range of other clinical studies in this setting. The combination regimen was well tolerated with no adverse effects on the safety, tolerability and pharmacokinetics of either agent.
Optogenetic manipulation of neuronal activity through excitatory and inhibitory opsins has become an indispensable experimental strategy in neuroscience research. For many applications bidirectional control of neuronal activity allowing both excitation and inhibition of the same neurons in a single experiment is desired. This requires low spectral overlap between the excitatory and inhibitory opsin, matched photocurrent amplitudes and a fixed expression ratio. Moreover, independent activation of two distinct neuronal populations with different optogenetic actuators is still challenging due to blue-light sensitivity of all opsins. Here we report BiPOLES, an optogenetic tool for potent neuronal excitation and inhibition with light of two different wavelengths. BiPOLES enables sensitive, reliable dual-color neuronal spiking and silencing with single- or two-photon excitation, optical tuning of the membrane voltage, and independent optogenetic control of two neuronal populations using a second, blue-light sensitive opsin. The utility of BiPOLES is demonstrated in worms, flies, mice and ferrets.
Linking epigenetic signature and metabolic phenotype in IDH mutant and IDH wildtype diffuse glioma
(2020)
Aims: Changes in metabolism are known to contribute to tumour phenotypes. If and how metabolic alterations in brain tumours contribute to patient outcome is still poorly understood. Epigenetics impact metabolism and mitochondrial function. The aim of this study is a characterisation of metabolic features in molecular subgroups of isocitrate dehydrogenase mutant (IDHmut) and isocitrate dehydrogenase wildtype (IDHwt) gliomas. Methods: We employed DNA methylation pattern analyses with a special focus on metabolic genes, large-scale metabolism panel immunohistochemistry (IHC), qPCR-based determination of mitochondrial DNA copy number and immune cell content using IHC and deconvolution of DNA methylation data. We analysed molecularly characterised gliomas (n = 57) for in depth DNA methylation, a cohort of primary and recurrent gliomas (n = 22) for mitochondrial copy number and validated these results in a large glioma cohort (n = 293). Finally, we investigated the potential of metabolic markers in Bevacizumab (Bev)-treated gliomas (n = 29). Results: DNA methylation patterns of metabolic genes successfully distinguished the molecular subtypes of IDHmut and IDHwt gliomas. Promoter methylation of lactate dehydrogenase A negatively correlated with protein expression and was associated with IDHmut gliomas. Mitochondrial DNA copy number was increased in IDHmut tumours and did not change in recurrent tumours. Hierarchical clustering based on metabolism panel IHC revealed distinct subclasses of IDHmut and IDHwt gliomas with an impact on patient outcome. Further quantification of these markers allowed for the prediction of survival under anti-angiogenic therapy. Conclusion: A mitochondrial signature was associated with increased survival in all analyses, which could indicate tumour subgroups with specific metabolic vulnerabilities.
Background: The objective of the STREAM Trial was to evaluate the effect of simulation training on process times in acute stroke care.
Methods: The multicenter prospective interventional STREAM Trial was conducted between 10/2017 and 04/2019 at seven tertiary care neurocenters in Germany with a pre- and post-interventional observation phase. We recorded patient characteristics, acute stroke care process times, stroke team composition and simulation experience for consecutive direct-to-center patients receiving intravenous thrombolysis (IVT) and/or endovascular therapy (EVT). The intervention consisted of a composite intervention centered around stroke-specific in situ simulation training. Primary outcome measure was the ‘door-to-needle’ time (DTN) for IVT. Secondary outcome measures included process times of EVT and measures taken to streamline the pre-existing treatment algorithm.
Results: The effect of the STREAM intervention on the process times of all acute stroke operations was neutral. However, secondary analyses showed a DTN reduction of 5 min from 38 min pre-intervention (interquartile range [IQR] 25–43 min) to 33 min (IQR 23–39 min, p = 0.03) post-intervention achieved by simulation-experienced stroke teams. Concerning EVT, we found significantly shorter door-to-groin times in patients who were treated by teams with simulation experience as compared to simulation-naive teams in the post-interventional phase (−21 min, simulation-naive: 95 min, IQR 69–111 vs. simulation-experienced: 74 min, IQR 51–92, p = 0.04).
Conclusion: An intervention combining workflow refinement and simulation-based stroke team training has the potential to improve process times in acute stroke care.
Using combined data from the Relativistic Heavy Ion and Large Hadron Colliders, we constrain the shear and bulk viscosities of quark-gluon plasma (QGP) at temperatures of ∼150–350 MeV. We use Bayesian inference to translate experimental and theoretical uncertainties into probabilistic constraints for the viscosities. With Bayesian model averaging we propagate an estimate of the model uncertainty generated by the transition from hydrodynamics to hadron transport in the plasma’s final evolution stage, providing the most reliable phenomenological constraints to date on the QGP viscosities.
Radiative transition of an excited baryon to a nucleon with emission of a virtual massive photon converting to dielectron pair (Dalitz decays) provides important information about baryon-photon coupling at low q2 in timelike region. A prominent enhancement in the respective electromagnetic transition Form Factors (etFF) at q2 near vector mesons ρ/ω poles has been predicted by various calculations reflecting strong baryon-vector meson couplings. The understanding of these couplings is also of primary importance for the interpretation of the emissivity of QCD matter studied in heavy ion collisions via dilepton emission. Dedicated measurements of baryon Dalitz decays in proton-proton and pion-proton scattering with HADES detector at GSI/FAIR are presented and discussed. The relevance of these studies for the interpretation of results obtained from heavy ion reactions is elucidated on the example of the HADES results.
In March 2019 the HADES experiment recorded 14 billion Ag+Ag collisions at √sNN = 2.55 GeV as a part of the FAIR phase-0 physics program. In this contribution, we present and investigate our capabilities to reconstruct and analyze weakly decaying strange hadrons and hypernuclei emerging from these collisions. The focus is put on measuring the mean lifetimes of these particles.
White matter abnormalities across different epilepsy syndromes in adults: an ENIGMA Epilepsy study
(2019)
The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analyzed from 1,069 non-epileptic controls and 1,249 patients: temporal lobe epilepsy with hippocampal sclerosis (N=599), temporal lobe epilepsy with normal MRI (N=275), genetic generalized epilepsy (N=182) and nonlesional extratemporal epilepsy (N=193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fiber tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at p<0.001). Across “all epilepsies” lower fractional anisotropy was observed in most fiber tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. Less robust effects were seen with mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippocampal sclerosis in the ipsilateral parahippocampal cingulum and external capsule, with smaller effects across most other tracts. Those with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippocampal sclerosis. Patients with generalized and extratemporal epilepsies had pronounced differences in fractional anisotropy in the corpus callosum, corona radiata and external capsule, and in mean diffusivity of the anterior corona radiata. Earlier age of seizure onset and longer disease duration were associated with a greater extent of microstructural abnormalities in patients with hippocampal sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibers in a large multicentre study of epilepsy. Overall, epilepsy patients showed white matter abnormalities in the corpus callosum, cingulum and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding new insights into pathological substrates that may be used to guide future therapeutic and genetic studies.
Introduction: Metabolic acidosis during hemorrhagic shock is common and conventionally considered to be due to hyperlactatemia. There is increasing awareness, however, that other nonlactate, unmeasured anions contribute to this type of acidosis.
Methods: Eleven anesthetized dogs were hemorrhaged to a mean arterial pressure of 45 mm Hg and were kept at this level until a metabolic oxygen debt of 120 mLO2/kg body weight had evolved. Blood pH, partial pressure of carbon dioxide, and concentrations of sodium, potassium, magnesium, calcium, chloride, lactate, albumin, and phosphate were measured at baseline, in shock, and during 3 hours post-therapy. Strong ion difference and the amount of weak plasma acid were calculated. To detect the presence of unmeasured anions, anion gap and strong ion gap were determined. Capillary electrophoresis was used to identify potential contributors to unmeasured anions.
Results: During induction of shock, pH decreased significantly from 7.41 to 7.19. The transient increase in lactate concentration from 1.5 to 5.5 mEq/L during shock was not sufficient to explain the transient increases in anion gap (+11.0 mEq/L) and strong ion gap (+7.1 mEq/L), suggesting that substantial amounts of unmeasured anions must have been generated. Capillary electrophoresis revealed increases in serum concentration of acetate (2.2 mEq/L), citrate (2.2 mEq/L), alpha-ketoglutarate (35.3 microEq/L), fumarate (6.2 microEq/L), sulfate (0.1 mEq/L), and urate (55.9 microEq/L) after shock induction.
Conclusion: Large amounts of unmeasured anions were generated after hemorrhage in this highly standardized model of hemorrhagic shock. Capillary electrophoresis suggested that the hitherto unmeasured anions citrate and acetate, but not sulfate, contributed significantly to the changes in strong ion gap associated with induction of shock.
"Flechtenreiche Kiefernwälder" (FKW) waren früher in Bayern besonders im Nürnberger Reichswald und im Oberpfälzer/Bayerischen Wald großflächig vorhanden. Mittlerweile sind sie selten. Der Waldtyp gilt als akut gefährdet, ebenso seine Flechten. Wir haben folgende Fragen zu klären versucht: Wie bzw. wie stark hat sich die floristische Zusammensetzung dieser Wälder in den zurückliegenden Jahrzehnten verändert? In welchem Maße ist die Fläche dieser Wälder zurückgegangen? Welche Aussichten zum Erhalt dieses Waldtyps bestehen, und was muss dazu ggf. getan werden?
2.363 historische Kiefernwald-Aufnahmen aus Bayern wurden recherchiert, in eine Datenbank eingegeben und multivariat statistisch analysiert mit dem Ziel, einen Referenzdatensatz für FKW in Bayern zu erzeugen. Dabei ergaben sich 216 Aufnahmen, die den floristischen Zustand der FKW von Mitte bis Ende des zwanzigsten Jahrhunderts repräsentieren. Darin finden sich 30 terricole Flechtenarten, überwiegend der Gattung Cladonia. Die Gesamtdeckung der terricolen Flechten in den einzelnen Aufnahmen variiert zwischen 0,1 % und 81 %. In 50 % der Aufnahmen überschreiten die Flechten 18 % Gesamtdeckung, in 25 % der Fälle sogar 38 % Gesamtdeckung. Die Bezeichnung "flechtenreiche Kiefernwälder" war seinerzeit also qualitativ wie quantitativ gerechtfertigt.
Im Jahre 2014 wurden auf 85 historischen Aufnahmeflächen aus dem Zeitraum 1980 bis 1996 Neuerhebungen durchgeführt. Die gemeinsame multivariate Analyse von Erst- und Wiederholungsaufnahmen zeigt, dass in den vergangenen gut drei Jahrzehnten in den FKW in Bayern ein grundlegender floristischer Umbau stattgefunden hat. Während die Bodenvegetation dieser Bestände früher von zahlreichen Flechten sowie langsamwüchsigen, oft acrokarpen Moosen geprägt wurden, breitet sich heutzutage eine üppige Decke meist pleurokarper Moose aus, überstockt von einer dichten Zwergstrauchschicht und einer heranwachsenden Kiefern-Verjüngungsschicht. Diese Entwicklung findet sowohl in forstlich genutzten FKW als auch in Naturwaldreservaten (Totalreservat) statt. Als Ursachen sind vor allem der Wegfall des Nährstoffentzugs (Streurechen) sowie der Stickstoffeintrag durch die Luft anzunehmen. Der Vergleich einer Kartierung von FKW in Teilen des Nürnberger Reichswaldes von Anfang der 1980er Jahre mit einer Kartierung von 2012 weist einen Flächenverlust der FKW von 90 % aus.
Die FKW befinden sich auf einem dramatischen Rückzug. Ohne gezieltes Management werden die verbliebenen Bestände weitgehend und rasch verschwinden. Dies gilt auch in Schutzgebieten, die dem Schutz und Erhalt der flechtenreichen Kiefernwälder gewidmet sind. Selbst das Wiedereinführen des Streurechens wird heute kaum mehr ausreichen; vielmehr muss den wenigen verbliebenen Flechten mittels "Aussaat" von Thallus-Bruchstücken überhaupt die Möglichkeit gegeben werden, die neu angebotenen Flächen zu erreichen.
Simple Summary: The incidence of brain metastases from breast cancer is increasing and the treatment is still a major challenge. Several scores have been developed in order to estimate the prognosis of patients with brain metastases by objective criteria. Here, we validated all three published graded-prognostic-assessment (GPA)-scores in a subcohort of 882 breast cancer patients with brain metastases in the Brain Metastases in the German Breast Cancer (BMBC) registry. Although all three available GPA-scores were associated with OS, they all show limitations mainly in predicting short-term (below 3 months) survival but also in long-term (above 12 months) survival. We discuss the test performances of all scores in our work and provide evidence how physicians should use them as a tool to select patients for different treatment options.
Abstract: Several scores have been developed in order to estimate the prognosis of patients with brain metastases (BM) by objective criteria. The aim of this analysis was to validate all three published graded-prognostic-assessment (GPA)-scores in a subcohort of 882 breast cancer (BC) patients with BM in the Brain Metastases in the German Breast Cancer (BMBC) registry. The median age at diagnosis of BM was 57 years. All in all, 22.3% of patients (n = 197) had triple-negative, 33.4% (n = 295) luminal A like, 25.1% (n = 221) luminal B/HER2-enriched like and 19.2% (n = 169) HER2 positive like BC. Age ≥60 years, evidence of extracranial metastases (ECM), higher number of BM, triple-negative subtype and low Karnofsky-Performance-Status (KPS) were all associated with worse overall survival (OS) in univariate analysis (p < 0.001 each). All three GPA-scores were associated with OS. The breast-GPA showed the highest probability of classifying patients with survival above 12 months in the best prognostic group (specificity 68.7% compared with 48.1% for the updated breast-GPA and 21.8% for the original GPA). Sensitivities for predicting 3 months survival were very low for all scores. In this analysis, all GPA-scores showed only moderate diagnostic accuracy in predicting the OS of BC patients with BM.
Characteristics and clinical outcome of breast cancer patients with asymptomatic brain metastases
(2020)
Simple Summary: The prognosis for patients with breast cancer that has spread to the brain is poor, and survival for these women hasn’t improved over the last few decades. We do not currently test for asymptomatic brain metastases in breast cancer patients, although this does happen in some other types of cancer. In this study we wanted to find out more about breast cancer that has spread to the brain and in particular to see whether there might be any advantage to spotting brain metastases before the development of neurological symptoms. Overall, our results suggest that women could be better off if their brain metastases are diagnosed before they begin to cause symptoms. We now need to carry out a clinical trial to see what happens if we screen high-risk breast cancer patients for brain metastases. This will verify whether doing so could increase survival, symptom control or quality of life.
Abstract: Background: Brain metastases (BM) have become a major challenge in patients with metastatic breast cancer. Methods: The aim of this analysis was to characterize patients with asymptomatic BM (n = 580) in the overall cohort of 2589 patients with BM from our Brain Metastases in Breast Cancer Network Germany (BMBC) registry. Results: Compared to symptomatic patients, asymptomatic patients were slightly younger at diagnosis (median age: 55.5 vs. 57.0 years, p = 0.01), had a better performance status at diagnosis (Karnofsky index 80–100%: 68.4% vs. 57%, p < 0.001), a lower number of BM (>1 BM: 56% vs. 70%, p = 0.027), and a slightly smaller diameter of BM (median: 1.5 vs. 2.2 cm, p < 0.001). Asymptomatic patients were more likely to have extracranial metastases (86.7% vs. 81.5%, p = 0.003) but were less likely to have leptomeningeal metastasis (6.3% vs. 10.9%, p < 0.001). Asymptomatic patients underwent less intensive BM therapy but had a longer median overall survival (statistically significant for a cohort of HER2-positive patients) compared to symptomatic patients (10.4 vs. 6.9 months, p < 0.001). Conclusions: These analyses show a trend that asymptomatic patients have less severe metastatic brain disease and despite less intensive local BM therapy still have a better outcome (statistically significant for a cohort of HER2-positive patients) than patients who present with symptomatic BM, although a lead time bias of the earlier diagnosis cannot be ruled out. Our analysis is of clinical relevance in the context of potential trials examining the benefit of early detection and treatment of BM.
Background: Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it is unclear how the presence of hepatic and extrahepatic metastasis impacts the response and survival after ICB. Methods: A total of 178 patients with metastatic UM treated with ICB were included in this analysis. Patients were recruited from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of hepatic metastasis, two cohorts were compared: patients with liver metastasis only (cohort A, n = 55) versus those with both liver and extra-hepatic metastasis (cohort B, n = 123). Data were analyzed in both cohorts for response to treatment, progression-free survival (PFS), and overall survival (OS). The survival and progression probabilities were calculated with the Kaplan–Meier method. Log-rank tests, χ2 tests, and t-tests were performed to detect significant differences between both cohorts. Results: The median OS of the overall population was 16 months (95% CI 13.4–23.7) and the median PFS, 2.8 months (95% CI 2.5–3.0). The median OS was longer in cohort B than in cohort A (18.2 vs. 6.1 months; p = 0.071). The best objective response rate to dual ICB was 13.8% and to anti-PD-1 monotherapy 8.9% in the entire population. Patients with liver metastases only had a lower response to dual ICB, yet without significance (cohort A 8.7% vs. cohort B 16.7%; p = 0.45). Adverse events (AE) occurred in 41.6%. Severe AE were observed in 26.3% and evenly distributed between both cohorts. Conclusion: The survival of this large cohort of patients with advanced UM was more favorable than reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only.
Global water models (GWMs) simulate the terrestrial water cycle, on the global scale, and are used to assess the impacts of climate change on freshwater systems. GWMs are developed within different modeling frameworks and consider different underlying hydrological processes, leading to varied model structures. Furthermore, the equations used to describe various processes take different forms and are generally accessible only from within the individual model codes. These factors have hindered a holistic and detailed understanding of how different models operate, yet such an understanding is crucial for explaining the results of model evaluation studies, understanding inter-model differences in their simulations, and identifying areas for future model development. This study provides a comprehensive overview of how state-of-the-art GWMs are designed. We analyze water storage compartments, water flows, and human water use sectors included in 16 GWMs that provide simulations for the Inter-Sectoral Impact Model Intercomparison Project phase 2b (ISIMIP2b). We develop a standard writing style for the model equations to further enhance model improvement, intercomparison, and communication. In this study, WaterGAP2 used the highest number of water storage compartments, 11, and CWatM used 10 compartments. Seven models used six compartments, while three models (JULES-W1, Mac-PDM.20, and VIC) used the lowest number, three compartments. WaterGAP2 simulates five human water use sectors, while four models (CLM4.5, CLM5.0, LPJmL, and MPIHM) simulate only water used by humans for the irrigation sector. We conclude that even though hydrologic processes are often based on similar equations, in the end, these equations have been adjusted or have used different values for specific parameters or specific variables. Our results highlight that the predictive uncertainty of GWMs can be reduced through improvements of the existing hydrologic processes, implementation of new processes in the models, and high-quality input data.
Background: Running is a popular sport with high injury rates. Although risk factors have intensively been investigated, synthesized knowledge about the differences in injury rates of female and male runners is scarce. Objective: To systematically investigate the differences in injury rates and characteristics between female and male runners. Methods: Database searches (PubMed, Web of Science, PEDro, SPORTDiscus) were conducted according to PRISMA guidelines using the keywords “running AND injur*”. Prospective studies reporting running related injury rates for both sexes were included. A random-effects meta-analysis was used to pool the risk ratios (RR) for the occurrence of injuries in female vs. male runners. Potential moderators (effect modifiers) were analysed using meta-regression. Results: After removal of duplicates, 12,215 articles were screened. Thirty-eight studies were included and the OR of 31 could be pooled in the quantitative analysis. The overall injury rate was 20.8 (95% CI 19.9–21.7) injuries per 100 female runners and 20.4 (95% CI 19.7–21.1) injuries per 100 male runners. Meta-analysis revealed no differences between sexes for overall injuries reported per 100 runners (RR 0.99, 95% CI 0.90–1.10, n = 24) and per hours or athlete exposure (RR 0.94, 95% CI 0.69–1.27, n = 6). Female sex was associated with a more frequent occurrence of bone stress injury (RR (for males) 0.52, 95% CI 0.36–0.76, n = 5) while male runners had higher risk for Achilles tendinopathies (RR 1. 86, 95% CI 1.25–2.79, n = 2). Meta-regression showed an association between a higher injury risk and competition distances of 10 km and shorter in female runners (RR 1.08, 95% CI 1.00–1.69). Conclusion: Differences between female and male runners in specific injury diagnoses should be considered in the development of individualised and sex-specific prevention and rehabilitation strategies to manage running-related injuries.
Truffle fungi are well known for their enticing aromas partially emitted by microbes colonizing truffle fruiting bodies. The identity and diversity of these microbes remain poorly investigated, because few studies have determined truffle-associated bacterial communities while considering only a small number of fruiting bodies. Hence, the factors driving the assembly of truffle microbiomes are yet to be elucidated. Here we investigated the bacterial community structure of more than 50 fruiting bodies of the black truffle Tuber aestivum in one French and one Swiss orchard using 16S rRNA gene amplicon high-throughput sequencing. Bacterial communities from truffles collected in both orchards shared their main dominant taxa: while 60% of fruiting bodies were dominated by α-Proteobacteria, in some cases the β-Proteobacteria or the Sphingobacteriia classes were the most abundant, suggesting that specific factors (i.e., truffle maturation and soil properties) shape differently truffle-associated microbiomes. We further attempted to assess the influence in truffle microbiome variation of factors related to collection season, truffle mating type, degree of maturation, and location within the truffle orchards. These factors had differential effects between the two truffle orchards, with season being the strongest predictor of community variation in the French orchard, and spatial location in the Swiss one. Surprisingly, genotype and fruiting body maturation did not have a significant effect on microbial community composition. In summary, our results show, regardless of the geographical location considered, the existence of heterogeneous bacterial communities within T. aestivum fruiting bodies that are dominated by three bacterial classes. They also indicate that factors shaping microbial communities within truffle fruiting bodies differ across local conditions.
Global water models (GWMs) simulate the terrestrial water cycle on the global scale and are used to assess the impacts of climate change on freshwater systems. GWMs are developed within different modelling frameworks and consider different underlying hydrological processes, leading to varied model structures. Furthermore, the equations used to describe various processes take different forms and are generally accessible only from within the individual model codes. These factors have hindered a holistic and detailed understanding of how different models operate, yet such an understanding is crucial for explaining the results of model evaluation studies, understanding inter-model differences in their simulations, and identifying areas for future model development. This study provides a comprehensive overview of how 16 state-of-the-art GWMs are designed. We analyse water storage compartments, water flows, and human water use sectors included in models that provide simulations for the Inter-Sectoral Impact Model Intercomparison Project phase 2b (ISIMIP2b). We develop a standard writing style for the model equations to enhance model intercomparison, improvement, and communication. In this study, WaterGAP2 used the highest number of water storage compartments, 11, and CWatM used 10 compartments. Six models used six compartments, while four models (DBH, JULES-W1, Mac-PDM.20, and VIC) used the lowest number, three compartments. WaterGAP2 simulates five human water use sectors, while four models (CLM4.5, CLM5.0, LPJmL, and MPI-HM) simulate only water for the irrigation sector. We conclude that, even though hydrological processes are often based on similar equations for various processes, in the end these equations have been adjusted or models have used different values for specific parameters or specific variables. The similarities and differences found among the models analysed in this study are expected to enable us to reduce the uncertainty in multi-model ensembles, improve existing hydrological processes, and integrate new processes.
Despite an increasing demand for Burgundy truffles (Tuber aestivum), gaps remain in our understanding of the fungus’ overall lifecycle and ecology. Here, we compile evidence from three independent surveys in Hungary and Switzerland. First, we measured the weight and maturity of 2,656 T. aestivum fruit bodies from a three-day harvest in August 2014 in a highly productive orchard in Hungary. All specimens ranging between 2 and 755 g were almost evenly distributed through five maturation classes. Then, we measured the weight and maturity of another 4,795 T. aestivum fruit bodies harvested on four occasions between June and October 2015 in the same truffière. Again, different maturation stages occurred at varying fruit body size and during the entire fruiting season. Finally, the predominantly unrelated weight and maturity of 81 T. aestivum fruit bodies from four fruiting seasons between 2010 and 2013 in Switzerland confirmed the Hungarian results. The spatiotemporal coexistence of 7,532 small-ripe and large-unripe T. aestivum, which accumulate to ~182 kg, differs from species-specific associations between the size and ripeness that have been reported for other mushrooms. Although size-independent truffle maturation stages may possibly relate to the perpetual belowground environment, the role of mycelial connectivity, soil property, microclimatology, as well as other abiotic factors and a combination thereof, is still unclear. Despite its massive sample size and proof of concept, this study, together with existing literature, suggests consideration of a wider ecological and biogeographical range, as well as the complex symbiotic fungus-host interaction, to further illuminate the hidden development of belowground truffle fruit bodies.
Pathogens possess the ability to adapt and survive in some host species but not in others–an ecological trait known as host tropism. Transmitted through ticks and carried mainly by mammals and birds, the Lyme disease (LD) bacterium is a well-suited model to study such tropism. Three main causative agents of LD, Borrelia burgdorferi, B. afzelii, and B. garinii, vary in host ranges through mechanisms eluding characterization. By feeding ticks infected with different Borrelia species, utilizing feeding chambers and live mice and quail, we found species-level differences in bacterial transmission. These differences localize on the tick blood meal, and specifically complement, a defense in vertebrate blood, and a polymorphic bacterial protein, CspA, which inactivates complement by binding to a host complement inhibitor, Factor H (FH). CspA selectively confers bacterial transmission to vertebrates that produce FH capable of allele-specific recognition. CspA is the only member of the Pfam54 gene family to exhibit host-specific FH-binding. Phylogenetic analyses revealed convergent evolution as the driver of such uniqueness, and that FH-binding likely emerged during the last glacial maximum. Our results identify a determinant of host tropism in Lyme disease infection, thus defining an evolutionary mechanism that shapes host-pathogen associations.
Introduction: Deep brain stimulation (DBS) has become a well-established treatment modality for a variety of conditions over the last decades. Multiple surgeries are an essential part in the postoperative course of DBS patients if nonrechargeable implanted pulse generators (IPGs) are applied. So far, the rate of subclinical infections in this field is unknown. In this prospective cohort study, we used sonication to evaluate possible microbial colonization of IPGs from replacement surgery. Methods: All consecutive patients undergoing IPG replacement between May 1, 2019 and November 15, 2020 were evaluated. The removed hardware was investigated using sonication to detect biofilm-associated bacteria. Demographic and clinical data were analyzed. Results: A total of 71 patients with a mean (±SD) of 64.5 ± 15.3 years were evaluated. In 23 of these (i.e., 32.4%) patients, a positive sonication culture was found. In total, 25 microorganisms were detected. The most common isolated microorganisms were Cutibacterium acnes (formerly known as Propionibacterium acnes) (68%) and coagulase-negative Staphylococci (28%). Within the follow-up period (5.2 ± 4.3 months), none of the patients developed a clinical manifest infection. Discussions/Conclusions: Bacterial colonization of IPGs without clinical signs of infection is common but does not lead to manifest infection. Further larger studies are warranted to clarify the impact of low-virulent pathogens in clinically asymptomatic patients.
The forest, savanna, and grassland biomes, and the transitions between them, are expected to undergo major changes in the future due to global climate change. Dynamic global vegetation models (DGVMs) are very useful for understanding vegetation dynamics under the present climate, and for predicting its changes under future conditions. However, several DGVMs display high uncertainty in predicting vegetation in tropical areas. Here we perform a comparative analysis of three different DGVMs (JSBACH, LPJ-GUESS-SPITFIRE and aDGVM) with regard to their representation of the ecological mechanisms and feedbacks that determine the forest, savanna, and grassland biomes, in an attempt to bridge the knowledge gap between ecology and global modeling. The outcomes of the models, which include different mechanisms, are compared to observed tree cover along a mean annual precipitation gradient in Africa. By drawing on the large number of recent studies that have delivered new insights into the ecology of tropical ecosystems in general, and of savannas in particular, we identify two main mechanisms that need improved representation in the examined DGVMs. The first mechanism includes water limitation to tree growth, and tree–grass competition for water, which are key factors in determining savanna presence in arid and semi-arid areas. The second is a grass–fire feedback, which maintains both forest and savanna presence in mesic areas. Grasses constitute the majority of the fuel load, and at the same time benefit from the openness of the landscape after fires, since they recover faster than trees. Additionally, these two mechanisms are better represented when the models also include tree life stages (adults and seedlings), and distinguish between fire-prone and shade-tolerant forest trees, and fire-resistant and shade-intolerant savanna trees. Including these basic elements could improve the predictive ability of the DGVMs, not only under current climate conditions but also and especially under future scenarios.
The forest, savanna, and grassland biomes, and the transitions between them, are expected to undergo major changes in the future, due to global climate change. Dynamic Global Vegetation Models (DGVMs) are very useful to understand vegetation dynamics under present climate, and to predict its changes under future conditions. However, several DGVMs display high uncertainty in predicting vegetation in tropical areas. Here we perform a comparative analysis of three different DGVMs (JSBACH, LPJ-GUESS-SPITFIRE and aDGVM) with regard to their representation of the ecological mechanisms and feedbacks that determine the forest, savanna and grassland biomes, in an attempt to bridge the knowledge gap between ecology and global modelling. Model outcomes, obtained including different mechanisms, are compared to observed tree cover along a mean annual precipitation gradient in Africa. Through these comparisons, and by drawing on the large number of recent studies that have delivered new insights into the ecology of tropical ecosystems in general, and of savannas in particular, we identify two main mechanisms that need an improved representation in the DGVMs. The first mechanism includes water limitation to tree growth, and tree-grass competition for water, which are key factors in determining savanna presence in arid and semi-arid areas. The second is a grass-fire feedback, which maintains both forest and savanna occurrences in mesic areas. Grasses constitute the majority of the fuel load, and at the same time benefit from the openness of the landscape after fires, since they recover faster than trees. Additionally, these two mechanisms are better represented when the models also include tree life stages (adults and seedlings), and distinguish between fire-prone and shade-tolerant savanna trees, and fire-resistant and shade-intolerant forest trees. Including these basic elements could improve the predictive ability of the DGVMs, not only under current climate conditions but also and especially under future scenarios.
Comparing projections of future changes in runoff from hydrological and biome models in ISI-MIP
(2013)
Future changes in runoff can have important implications for water resources and flooding. In this study, runoff projections from ISI-MIP (Inter-sectoral Impact Model Intercomparison Project) simulations forced with HadGEM2-ES bias-corrected climate data under the Representative Concentration Pathway 8.5 have been analysed for differences between impact models. Projections of change from a baseline period (1981–2010) to the future (2070–2099) from 12 impacts models which contributed to the hydrological and biomes sectors of ISI-MIP were studied. The biome models differed from the hydrological models by the inclusion of CO2 impacts and most also included a dynamic vegetation distribution. The biome and hydrological models agreed on the sign of runoff change for most regions of the world. However, in West Africa, the hydrological models projected drying, and the biome models a moistening. The biome models tended to produce larger increases and smaller decreases in regionally averaged runoff than the hydrological models, although there is large inter-model spread. The timing of runoff change was similar, but there were differences in magnitude, particularly at peak runoff. The impact of vegetation distribution change was much smaller than the projected change over time, while elevated CO2 had an effect as large as the magnitude of change over time projected by some models in some regions. The effect of CO2 on runoff was not consistent across the models, with two models showing increases and two decreases. There was also more spread in projections from the runs with elevated CO2 than with constant CO2. The biome models which gave increased runoff from elevated CO2 were also those which differed most from the hydrological models. Spatially, regions with most difference between model types tended to be projected to have most effect from elevated CO2, and seasonal differences were also similar, so elevated CO2 can partly explain the differences between hydrological and biome model runoff change projections. Therefore, this shows that a range of impact models should be considered to give the full range of uncertainty in impacts studies.
Projections of future changes in runoff can have important implications for water resources and flooding. In this study, runoff projections from ISI-MIP (Inter-sectoral Impact Model Intercomparison Project) simulations forced with HadGEM2-ES bias-corrected climate data under the Representative Concentration Pathway 8.5 have been analysed. Projections of change from the baseline period (1981–2010) to the future (2070–2099) from a number of different ecosystems and hydrological models were studied. The differences between projections from the two types of model were looked at globally and regionally. Typically, across different regions the ecosystem models tended to project larger increases and smaller decreases in runoff than the hydrological models. However, the differences varied both regionally and seasonally. Sensitivity experiments were also used to investigate the contributions of varying CO2 and allowing vegetation distribution to evolve on projected changes in runoff. In two out of four models which had data available from CO2 sensitivity experiments, allowing CO2 to vary was found to increase runoff more than keeping CO2 constant, while in two models runoff decreased. This suggests more uncertainty in runoff responses to elevated CO2 than previously considered. As CO2 effects on evapotranspiration via stomatal conductance and leaf-area index are more commonly included in ecosystems models than in hydrological models, this may partially explain some of the difference between model types. Keeping the vegetation distribution static in JULES runs had much less effect on runoff projections than varying CO2, but this may be more pronounced if looked at over a longer timescale as vegetation changes may take longer to reach a new state.
Simple Summary
Seizures are among the most common symptoms of meningioma patients even after surgery. This study sought to identify risk factors for early and late seizures in meningioma patients and to evaluate a modified version of a score to predict postoperative seizures on an independent cohort. The data underline that there are distinct factors identifying patients with a high risk of postoperative seizures following meningioma surgery which has been already shown before. We could further show that the high proportion of 43% of postoperative seizures occur as late seizures which are more dangerous because they may happen out of hospital. The modified STAMPE2 score could predict postoperative seizures when reaching very high scores but was not generally transferable to our independent cohort.
Abstract
Seizures are among the most common symptoms of meningioma. This retrospective study sought to identify risk factors for early and late seizures in meningioma patients and to evaluate a modified STAMPE2 score. In 556 patients who underwent meningioma surgery, we correlated different risk factors with the occurrence of postoperative seizures. A modified STAMPE2 score was applied. Risk factors for preoperative seizures were edema (p = 0.039) and temporal location (p = 0.038). For postoperative seizures preoperative tumor size (p < 0.001), sensomotory deficit (p = 0.004) and sphenoid wing location (p = 0.032) were independent risk factors. In terms of postoperative status epilepticus; sphenoid wing location (p = 0.022), tumor volume (p = 0.045) and preoperative seizures (p < 0.001) were independent risk factors. Postoperative seizures lead to a KPS deterioration and thus an impaired quality of life (p < 0.001). Late seizures occurred in 43% of patients with postoperative seizures. The small sub-cohort of patients (2.7%) with a STAMPE2 score of more than six points had a significantly increased risk for seizures (p < 0.001, total risk 70%). We concluded that besides distinct risk factors, high scores of the modified STAMPE2 score could estimate the risk of postoperative seizures. However, it seems not transferable to our cohort
Despite multidisciplinary local and systemic therapeutic approaches, the prognosis for most patients with brain metastases is still dismal. The role of adaptive and innate anti-tumor response including the Human Leukocyte Antigen (HLA) machinery of antigen presentation is still unclear. We present data on the HLA class II-chaperone molecule CD74 in brain metastases and its impact on the HLA peptidome complexity.
We analyzed CD74 and HLA class II expression on tumor cells in a subset of 236 human brain metastases, primary tumors and peripheral metastases of different entities in association with clinical data including overall survival. Additionally, we assessed whole DNA methylome profiles including CD74 promoter methylation and differential methylation in 21 brain metastases. We analyzed the effects of a siRNA mediated CD74 knockdown on HLA-expression and HLA peptidome composition in a brain metastatic melanoma cell line.
We observed that CD74 expression on tumor cells is a strong positive prognostic marker in brain metastasis patients and positively associated with tumor-infiltrating T-lymphocytes (TILs). Whole DNA methylome analysis suggested that CD74 tumor cell expression might be regulated epigenetically via CD74 promoter methylation. CD74high and TILhigh tumors displayed a differential DNA methylation pattern with highest enrichment scores for antigen processing and presentation. Furthermore, CD74 knockdown in vitro lead to a reduction of HLA class II peptidome complexity, while HLA class I peptidome remained unaffected.
In summary, our results demonstrate that a functional HLA class II processing machinery in brain metastatic tumor cells, reflected by a high expression of CD74 and a complex tumor cell HLA peptidome, seems to be crucial for better patient prognosis.
Objectives: A conometric concept was recently introduced in which conical implant abutments hold the matching crown copings by friction alone, eliminating the need for cement or screws. The aim of this in vitro study was to assess the presence of microgap formation and bacterial leakage at the Acuris conometric restorative interface of three different implant abutment systems. Material and methods: A total of 75 Acuris samples of three implant-abutment systems (Ankylos, Astra Tech EV, Xive) were subjected to microbiological (n = 60) and scanning electron microscopic (SEM) investigation (n = 15). Bacterial migration into and out of the conical coupling system were analyzed in an anaerobic workstation for 48, 96, 144, and 192 h. Bacterial DNA quantification using qrt-PCR was performed at each time point. The precision of the conometric coupling and internal fit of cemented CAD/CAM crowns on corresponding Acuris TiN copings were determined by means of SEM. Results: qrt-PCR results failed to demonstrate microbial leakage from or into the Acuris system. SEM analysis revealed minute punctate microgaps at the apical aspect of the conometric junction (2.04 to 2.64 µm), while mean cement gaps of 12 to 145 µm were observed at the crown-coping interface. Conclusions: The prosthetic morse taper connection of all systems examined does not allow bacterial passage. Marginal integrity and internal luting gap between the ceramic crown and the coping remained within the clinically acceptable limits. Clinical relevance: Conometrically seated single crowns provide sufficient sealing efficiency, relocating potential misfits from the crown-abutment interface to the crown-coping interface.
Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species’ threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project – and avert – future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups – including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems – www.predicts.org.uk). We make site-level summary data available alongside this article. The full database will be publicly available in 2015.
In Saccharomyces cerevisiae, the NDI1 gene encodes a mitochondrial NADH dehydrogenase, the catalytic side of which projects to the matrix side of the inner mitochondrial membrane. In addition to this NADH dehydrogenase, S. cerevisiae exhibits another mitochondrial NADH-dehydrogenase activity, which oxidizes NADH at the cytosolic side of the inner membrane. To investigate whether open reading frames YMR145c/NDE1 and YDL 085w/NDE2, which exhibit sequence similarity with NDI1, encode the latter enzyme, NADH-dependent mitochondrial respiration was assayed in wild-type S. cerevisiae and nde deletion mutants. Mitochondria were isolated from aerobic, glucose-limited chemostat cultures grown at a dilution rate (D) of 0. 10 h-1, in which reoxidation of cytosolic NADH by wild-type cells occurred exclusively by respiration. Compared with the wild type, rates of mitochondrial NADH oxidation were about 3-fold reduced in an nde1Delta mutant and unaffected in an nde2Delta mutant. NADH-dependent mitochondrial respiration was completely abolished in an nde1Delta nde2Delta double mutant. Mitochondrial respiration of substrates other than NADH was not affected in nde mutants. In shake flasks, an nde1Delta nde2Delta mutant exhibited reduced specific growth rates on ethanol and galactose but not on glucose. Glucose metabolism in aerobic, glucose-limited chemostat cultures (D = 0.10 h-1) of an nde1Delta nde2Delta mutant was essentially respiratory. Apparently, under these conditions alternative systems for reoxidation of cytosolic NADH could replace the role of Nde1p and Nde2p in S. cerevisiae.
A list of authors and their affiliations appears at the end of the paper New-particle formation is a major contributor to urban smog, but how it occurs in cities is often puzzling. If the growth rates of urban particles are similar to those found in cleaner environments (1–10 nanometres per hour), then existing understanding suggests that new urban particles should be rapidly scavenged by the high concentration of pre-existing particles. Here we show, through experiments performed under atmospheric conditions in the CLOUD chamber at CERN, that below about +5 degrees Celsius, nitric acid and ammonia vapours can condense onto freshly nucleated particles as small as a few nanometres in diameter. Moreover, when it is cold enough (below −15 degrees Celsius), nitric acid and ammonia can nucleate directly through an acid–base stabilization mechanism to form ammonium nitrate particles. Given that these vapours are often one thousand times more abundant than sulfuric acid, the resulting particle growth rates can be extremely high, reaching well above 100 nanometres per hour. However, these high growth rates require the gas-particle ammonium nitrate system to be out of equilibrium in order to sustain gas-phase supersaturations. In view of the strong temperature dependence that we measure for the gas-phase supersaturations, we expect such transient conditions to occur in inhomogeneous urban settings, especially in wintertime, driven by vertical mixing and by strong local sources such as traffic. Even though rapid growth from nitric acid and ammonia condensation may last for only a few minutes, it is nonetheless fast enough to shepherd freshly nucleated particles through the smallest size range where they are most vulnerable to scavenging loss, thus greatly increasing their survival probability. We also expect nitric acid and ammonia nucleation and rapid growth to be important in the relatively clean and cold upper free troposphere, where ammonia can be convected from the continental boundary layer and nitric acid is abundant from electrical storms.
A recent CLOUD (Cosmics Leaving OUtdoor Droplets) chamber study showed that sulfuric acid and dimethylamine produce new aerosols very efficiently and yield particle formation rates that are compatible with boundary layer observations. These previously published new particle formation (NPF) rates are reanalyzed in the present study with an advanced method. The results show that the NPF rates at 1.7 nm are more than a factor of 10 faster than previously published due to earlier approximations in correcting particle measurements made at a larger detection threshold. The revised NPF rates agree almost perfectly with calculated rates from a kinetic aerosol model at different sizes (1.7 and 4.3 nm mobility diameter). In addition, modeled and measured size distributions show good agreement over a wide range of sizes (up to ca. 30 nm). Furthermore, the aerosol model is modified such that evaporation rates for some clusters can be taken into account; these evaporation rates were previously published from a flow tube study. Using this model, the findings from the present study and the flow tube experiment can be brought into good agreement for the high base-to-acid ratios (∼ 100) relevant for this study. This confirms that nucleation proceeds at rates that are compatible with collision-controlled (a.k.a. kinetically controlled) NPF for the conditions during the CLOUD7 experiment (278 K, 38 % relative humidity, sulfuric acid concentration between 1 × 106 and 3 × 107 cm−3, and dimethylamine mixing ratio of ∼ 40 pptv, i.e., 1 × 109 cm−3).
A recent CLOUD (Cosmics Leaving OUtdoor Droplets) chamber study showed that sulfuric acid and dimethylamine produce new aerosols very efficiently, and yield particle formation rates that are compatible with boundary layer observations. These previously published new particle formation (NPF) rates are re-analyzed in the present study with an advanced method. The results show that the NPF rates at 1.7 nm are more than a factor of 10 faster than previously published due to earlier approximations in correcting particle measurements made at larger detection threshold. The revised NPF rates agree almost perfectly with calculated rates from a kinetic aerosol model at different sizes (1.7 nm and 4.3 nm mobility diameter). In addition, modeled and measured size distributions show good agreement over a wide range (up to ca. 30 nm). Furthermore, the aerosol model is modified such that evaporation rates for some clusters can be taken into account; these evaporation rates were previously published from a flow tube study. Using this model, the findings from the present study and the flow tube experiment can be brought into good agreement. This confirms that nucleation proceeds at rates that are compatible with collision-controlled (a.k.a. kinetically-controlled) new particle formation for the conditions during the CLOUD7 experiment (278 K, 38% RH, sulfuric acid concentration between 1×106 and 3×107 cm-3 and dimethylamine mixing ratio of ~40 pptv). Finally, the simulation of atmospheric new particle formation reveals that even tiny mixing ratios of dimethylamine (0.1 pptv) yield NPF rates that could explain significant boundary layer particle formation. This highlights the need for improved speciation and quantification techniques for atmospheric gas-phase amine measurements.
Although often depicted as rigid structures, proteins are highly dynamic systems, whose motions are essential to their functions. Despite this, it is difficult to investigate protein dynamics due to the rapid timescale at which they sample their conformational space, leading most NMR-determined structures to represent only an averaged snapshot of the dynamic picture. While NMR relaxation measurements can help to determine local dynamics, it is difficult to detect translational or concerted motion, and only recently have significant advances been made to make it possible to acquire a more holistic representation of the dynamics and structural landscapes of proteins. Here, we briefly revisit our most recent progress in the theory and use of exact nuclear Overhauser enhancements (eNOEs) for the calculation of structural ensembles that describe their conformational space. New developments are primarily targeted at increasing the number and improving the quality of extracted eNOE distance restraints, such that the multi-state structure calculation can be applied to proteins of higher molecular weights. We then review the implications of the exact NOE to the protein dynamics and function of cyclophilin A and the WW domain of Pin1, and finally discuss our current research and future directions.
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.
Background: Peritonitis is responsible for thousands of deaths annually in Germany alone. Even source control (SC) and antibiotic treatment often fail to prevent severe sepsis or septic shock, and this situation has hardly improved in the past two decades. Most experimental immunomodulatory therapeutics for sepsis have been aimed at blocking or dampening a specific pro-inflammatory immunological mediator. However, the patient collective is large and heterogeneous. There are therefore grounds for investigating the possibility of developing personalized therapies by classifying patients into groups according to biomarkers. This study aims to combine an assessment of the efficacy of treatment with a preparation of human immunoglobulins G, A, and M (IgGAM) with individual status of various biomarkers (immunoglobulin level, procalcitonin, interleukin 6, antigen D-related human leucocyte antigen (HLA-DR), transcription factor NF-κB1, adrenomedullin, and pathogen spectrum).
Methods/design: A total of 200 patients with sepsis or septic shock will receive standard-of-care treatment (SoC). Of these, 133 patients (selected by 1:2 randomization) will in addition receive infusions of IgGAM for 5 days. All patients will be followed for approximately 90 days and assessed by the multiple-organ failure (MOF) score, by the EQ QLQ 5D quality-of-life scale, and by measurement of vital signs, biomarkers (as above), and survival.
Discussion: This study is intended to provide further information on the efficacy and safety of treatment with IgGAM and to offer the possibility of correlating these with the biomarkers to be studied. Specifically, it will test (at a descriptive level) the hypothesis that patients receiving IgGAM who have higher inflammation status (IL-6) and poorer immune status (low HLA-DR, low immunoglobulin levels) have a better outcome than patients who do not receive IgGAM. It is expected to provide information that will help to close the knowledge gap concerning the association between the effect of IgGAM and the presence of various biomarkers, thus possibly opening the way to a personalized medicine.
Trial registration: EudraCT, 2016–001788-34; ClinicalTrials.gov, NCT03334006. Registered on 17 Nov 2017.
Trial sponsor: RWTH Aachen University, represented by the Center for Translational & Clinical Research Aachen (contact Dr. S. Isfort).
Introduction: Deep brain stimulation (DBS) has become a well-established treatment modality for a variety of conditions over the last decades. Multiple surgeries are an essential part in the postoperative course of DBS patients if nonrechargeable implanted pulse generators (IPGs) are applied. So far, the rate of subclinical infections in this field is unknown. In this prospective cohort study, we used sonication to evaluate possible microbial colonization of IPGs from replacement surgery. Methods: All consecutive patients undergoing IPG replacement between May 1, 2019 and November 15, 2020 were evaluated. The removed hardware was investigated using sonication to detect biofilm-associated bacteria. Demographic and clinical data were analyzed. Results: A total of 71 patients with a mean (±SD) of 64.5 ± 15.3 years were evaluated. In 23 of these (i.e., 32.4%) patients, a positive sonication culture was found. In total, 25 microorganisms were detected. The most common isolated microorganisms were Cutibacterium acnes (formerly known as Propionibacterium acnes) (68%) and coagulase-negative Staphylococci (28%). Within the follow-up period (5.2 ± 4.3 months), none of the patients developed a clinical manifest infection. Discussions/Conclusions: Bacterial colonization of IPGs without clinical signs of infection is common but does not lead to manifest infection. Further larger studies are warranted to clarify the impact of low-virulent pathogens in clinically asymptomatic patients.
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.
Inflammatory diseases including psoriasis are associated with metabolic and cardiovascular comorbidities, including obesity and metabolic syndrome. Obesity is associated with greater psoriasis disease severity and reduced response to treatment. Therefore, targeting metabolic comorbidities could improve patients’ health status and psoriasis-specific outcomes. METABOLyx is a randomized controlled trial evaluating the combination of a lifestyle intervention program with secukinumab treatment in psoriasis. Here, the rationale, methodology and baseline patient characteristics of METABOLyx are presented. A total of 768 patients with concomitant moderate to severe plaque psoriasis and metabolic syndrome were randomized to secukinumab 300 mg, or secukinumab 300 mg plus a tailored lifestyle intervention program, over 24 weeks. A substudy of immunologic and metabolic biomarkers is ongoing. The primary endpoint of METABOLyx is PASI90 response at week 24. Other endpoints include patient-reported outcomes and safety. METABOLyx represents the first large scale clinical trial of an immunomodulatory biologic in combination with a standardized lifestyle intervention.
Development of fragmented low-Z ion beams for the NA61 fixed-target experiment at the CERN SPS
(2011)
The NA61 experiment, aims to study the properties of the onset of deconfinement at low SPS energies and to find signatures of the critical point of strongly interacting matter. A broad range in T-μB phase diagram will be covered by performing an energy (13A-158A GeV/c) and system size (p+p, Be+Be, Ar+Ca, Xe+La) scan. In a first phase, fragmented ion beams of 7Be or 11C produced as secondaries with the same momentum per nucleon when the incident primary Pb-ion beam hits a thin Be target will be used. The H2 beam line that transports the beam to the experiment acts as a double spectrometer which combined with a new thin target (degrader) where fragments loose energy proportional to the square of their charge allows the separation of the wanted A/Z fragments. Thin scintillators and TOF measurement for the low energy points are used as particle identification devices. In this paper results from the first test of the fragmented ion beam done in 2010 will be presented showing that a pure Be beam can be obtained satisfying the needs of the experiment.
Archaeological evidence indicates that pig domestication had begun by ∼10,500 y before the present (BP) in the Near East, and mitochondrial DNA (mtDNA) suggests that pigs arrived in Europe alongside farmers ∼8,500 y BP. A few thousand years after the introduction of Near Eastern pigs into Europe, however, their characteristic mtDNA signature disappeared and was replaced by haplotypes associated with European wild boars. This turnover could be accounted for by substantial gene flow from local European wild boars, although it is also possible that European wild boars were domesticated independently without any genetic contribution from the Near East. To test these hypotheses, we obtained mtDNA sequences from 2,099 modern and ancient pig samples and 63 nuclear ancient genomes from Near Eastern and European pigs. Our analyses revealed that European domestic pigs dating from 7,100 to 6,000 y BP possessed both Near Eastern and European nuclear ancestry, while later pigs possessed no more than 4% Near Eastern ancestry, indicating that gene flow from European wild boars resulted in a near-complete disappearance of Near East ancestry. In addition, we demonstrate that a variant at a locus encoding black coat color likely originated in the Near East and persisted in European pigs. Altogether, our results indicate that while pigs were not independently domesticated in Europe, the vast majority of human-mediated selection over the past 5,000 y focused on the genomic fraction derived from the European wild boars, and not on the fraction that was selected by early Neolithic farmers over the first 2,500 y of the domestication process.
The widespread application of fertilizers has greatly influenced many processes and properties of agroecosystems, and agricultural fertilization is expected to increase even further in the future. To date, most research on fertilizer impacts has used short-term studies, which may be unrepresentative of long-term responses, thus hindering our capacity to predict long-term impacts. Here, we examined the effects of long-term fertilizer addition on key ecosystem properties in a long-term grassland experiment (Palace Leas Hay Meadow) in which farmyard manure (FYM) and inorganic fertilizer treatments have been applied consistently for 120 years in order to characterize the experimental site more fully and compare ecosystem responses with those observed at other long-term and short-term experiments. FYM inputs increased soil organic carbon (SOC) stocks, hay yield, nutrient availability and acted as a buffer against soil acidification (>pH 5). In contrast, N-containing inorganic fertilizers strongly acidified the soil (<pH 4.5) and increased surface SOC stocks by increasing the C stored in the coarse (2.8 mm-200 μm) and fine (200–50 μm) fractions. Application of N fertilizers also reduced plant species richness and the abundance of forbs and legumes. Overall, our results were broadly consistent with those observed in other very long-term studies (the Park Grass and Steinach Grassland experiments) in that fertilization effects on plant and soil properties appeared to be driven by differences in both nutrient input and changes to soil pH. We also established that the direction of long-term fertilization effects tended to be comparable with short-term experiments, but that their magnitude differed considerably, particularly where ammonium sulphate-induced acidification had occurred. We therefore conclude that short-term studies are unlikely to possess the required timeframe to accurately predict long-term responses, thus necessitating the use of long-term study sites. Such experiments should be strategically established in regions where future fertilizer use is expected to increase rapidly.
Background: Identification of families at risk for ovarian cancer offers the opportunity to consider prophylactic surgery thus reducing ovarian cancer mortality. So far, identification of potentially affected families in Germany was solely performed via family history and numbers of affected family members with breast or ovarian cancer. However, neither the prevalence of deleterious variants in BRCA1/2 in ovarian cancer in Germany nor the reliability of family history as trigger for genetic counselling has ever been evaluated.
Methods: Prospective counseling and germline testing of consecutive patients with primary diagnosis or with platinum-sensitive relapse of an invasive epithelial ovarian cancer. Testing included 25 candidate and established risk genes. Among these 25 genes, 16 genes (ATM, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, NBN, PMS2, PTEN, PALB2, RAD51C, RAD51D, STK11, TP53) were defined as established cancer risk genes. A positive family history was defined as at least one relative with breast cancer or ovarian cancer or breast cancer in personal history.
Results: In total, we analyzed 523 patients: 281 patients with primary diagnosis of ovarian cancer and 242 patients with relapsed disease. Median age at primary diagnosis was 58 years (range 16–93) and 406 patients (77.6%) had a high-grade serous ovarian cancer. In total, 27.9% of the patients showed at least one deleterious variant in all 25 investigated genes and 26.4% in the defined 16 risk genes. Deleterious variants were most prevalent in the BRCA1 (15.5%), BRCA2 (5.5%), RAD51C (2.5%) and PALB2 (1.1%) genes. The prevalence of deleterious variants did not differ significantly between patients at primary diagnosis and relapse. The prevalence of deleterious variants in BRCA1/2 (and in all 16 risk genes) in patients <60 years was 30.2% (33.2%) versus 10.6% (18.9%) in patients ≥60 years. Family history was positive in 43% of all patients. Patients with a positive family history had a prevalence of deleterious variants of 31.6% (36.0%) versus 11.4% (17.6%) and histologic subtype of high grade serous ovarian cancer versus other showed a prevalence of deleterious variants of 23.2% (29.1%) and 10.2% (14.8%), respectively. Testing only for BRCA1/2 would miss in our series more than 5% of the patients with a deleterious variant in established risk genes.
Conclusions: 26.4% of all patients harbor at least one deleterious variant in established risk genes. The threshold of 10% mutation rate which is accepted for reimbursement by health care providers in Germany was observed in all subgroups analyzed and neither age at primary diagnosis nor histo-type or family history sufficiently enough could identify a subgroup not eligible for genetic counselling and testing. Genetic testing should therefore be offered to every patient with invasive epithelial ovarian cancer and limiting testing to BRCA1/2 seems to be not sufficient.
Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.
Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
Background: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. Methods: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun’s electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). Results: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p < 0.01. Conclusion: A large change in solar insolation, both between winter and summer and between the minimum and maximum monthly values, may increase the risk of suicide attempts in bipolar I disorder. With frequent circadian rhythm dysfunction and suicidal behavior in bipolar disorder, greater understanding of the optimal roles of daylight and electric lighting in circadian entrainment is needed.
Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
Aim: The cytokine receptor tumor necrosis factor receptor superfamily member 9 (TNFRSF9) is mainly considered to be a co-stimulatory activation marker in hematopoietic cells. Several preclinical models have shown a dramatic beneficial effect of treatment approaches targeting TNFRSF9 with agonistic antibodies. However, preliminary clinical phase I/II studies were stopped after the occurrence of several severe deleterious side effects. In a previous study, it was demonstrated that TNFRSF9 was strongly expressed by reactive astrocytes in primary central nervous system (CNS) tumors, but was largely absent from tumor or inflammatory cells. The aim of the present study was to address the cellular source of TNFRSF9 expression in the setting of human melanoma brain metastasis, a highly immunogenic tumor with a prominent tropism to the CNS.
Methods: Melanoma brain metastasis was analyzed in a cohort of 78 patients by immunohistochemistry for TNFRSF9 and its expression was correlated with clinicopathological parameters including sex, age, survival, tumor size, number of tumor spots, and BRAF V600E expression status.
Results: Tumor necrosis factor receptor superfamily member 9 was frequently expressed independently on both melanoma and endothelial cells. In addition, TNFRSF9 was also present on smooth muscle cells of larger vessels and on a subset of lymphomonocytic tumor infiltrates. No association between TNFRSF9 expression and patient survival or other clinicopathological parameters was seen. Of note, several cases showed a gradual increase in TNFRSF9 expression on tumor cells with increasing distance from blood vessels, an observation that might be linked to hypoxia-driven TNFRSF9 expression in tumor cells.
Conclusion: The findings indicate that the cellular source of TNFRSF9 in melanoma brain metastasis largely exceeds the lymphomonocytic pool, and therefore further careful (re-) assessment of potential TNFRSF9 functions in cell types other than hematopoietic cells is needed. Furthermore, the hypothesis of hypoxia-driven TNFRSF9 expression in brain metastasis melanoma cells requires further functional testing.
All-optical closed-loop voltage clamp for precise control of muscles and neurons in live animals
(2023)
Excitable cells can be stimulated or inhibited by optogenetics. Since optogenetic actuation regimes are often static, neurons and circuits can quickly adapt, allowing perturbation, but not true control. Hence, we established an optogenetic voltage-clamp (OVC). The voltage-indicator QuasAr2 provides information for fast, closed-loop optical feedback to the bidirectional optogenetic actuator BiPOLES. Voltage-dependent fluorescence is held within tight margins, thus clamping the cell to distinct potentials. We established the OVC in muscles and neurons of Caenorhabditis elegans, and transferred it to rat hippocampal neurons in slice culture. Fluorescence signals were calibrated to electrically measured potentials, and wavelengths to currents, enabling to determine optical I/V-relationships. The OVC reports on homeostatically altered cellular physiology in mutants and on Ca2+-channel properties, and can dynamically clamp spiking in C. elegans. Combining non-invasive imaging with control capabilities of electrophysiology, the OVC facilitates high-throughput, contact-less electrophysiology in individual cells and paves the way for true optogenetic control in behaving animals.
Under certain conditions, secondary organic aerosol (SOA) particles can exist in the atmosphere in an amorphous solid or semi-solid state. To determine their relevance to processes such as ice nucleation or chemistry occurring within particles requires knowledge of the temperature and relative humidity (RH) range for SOA to exist in these states. In the CLOUD experiment at CERN, we deployed a new in-situ optical method to detect the viscosity of α-pinene SOA particles and measured their transition from the amorphous viscous to liquid state. The method is based on the depolarising properties of laboratory-produced non-spherical SOA particles and their transformation to non-depolarising spherical liquid particles during deliquescence. We found that particles formed and grown in the chamber developed an asymmetric shape through coagulation. A transition to spherical shape was observed as the RH was increased to between 35 % at −10 ◦C and 80 % at −38 ◦C, confirming previous calculations of the viscosity transition conditions. Consequently, α-pinene SOA particles exist in a viscous state over a wide range of ambient conditions, including the cirrus region of the free troposphere. This has implications for the physical, chemical and ice-nucleation properties of SOA and SOA-coated particles in the atmosphere.
Simple cells in primary visual cortex were famously found to respond to low-level image components such as edges. Sparse coding and independent component analysis (ICA) emerged as the standard computational models for simple cell coding because they linked their receptive fields to the statistics of visual stimuli. However, a salient feature of image statistics, occlusions of image components, is not considered by these models. Here we ask if occlusions have an effect on the predicted shapes of simple cell receptive fields. We use a comparative approach to answer this question and investigate two models for simple cells: a standard linear model and an occlusive model. For both models we simultaneously estimate optimal receptive fields, sparsity and stimulus noise. The two models are identical except for their component superposition assumption. We find the image encoding and receptive fields predicted by the models to differ significantly. While both models predict many Gabor-like fields, the occlusive model predicts a much sparser encoding and high percentages of ‘globular’ receptive fields. This relatively new center-surround type of simple cell response is observed since reverse correlation is used in experimental studies. While high percentages of ‘globular’ fields can be obtained using specific choices of sparsity and overcompleteness in linear sparse coding, no or only low proportions are reported in the vast majority of studies on linear models (including all ICA models). Likewise, for the here investigated linear model and optimal sparsity, only low proportions of ‘globular’ fields are observed. In comparison, the occlusive model robustly infers high proportions and can match the experimentally observed high proportions of ‘globular’ fields well. Our computational study, therefore, suggests that ‘globular’ fields may be evidence for an optimal encoding of visual occlusions in primary visual cortex.
We present measurements of exclusive ensuremathπ+,0 and η production in pp reactions at 1.25GeV and 2.2GeV beam kinetic energy in hadron and dielectron channels. In the case of π+ and π0 , high-statistics invariant-mass and angular distributions are obtained within the HADES acceptance as well as acceptance-corrected distributions, which are compared to a resonance model. The sensitivity of the data to the yield and production angular distribution of Δ (1232) and higher-lying baryon resonances is shown, and an improved parameterization is proposed. The extracted cross-sections are of special interest in the case of pp → pp η , since controversial data exist at 2.0GeV; we find \ensuremathσ=0.142±0.022 mb. Using the dielectron channels, the π0 and η Dalitz decay signals are reconstructed with yields fully consistent with the hadronic channels. The electron invariant masses and acceptance-corrected helicity angle distributions are found in good agreement with model predictions.
Droughts are anticipated to intensify in many parts of the world due to climate change. However, the issue of drought definition, namely the diversity of drought indices, makes it difficult to compare drought assessments. This issue is widely known, but its relative importance has never been quantitatively evaluated in comparison to other sources of uncertainty. Here, encompassing three drought categories (meteorological, agricultural, and hydrological droughts) with four temporal scales of interest, we evaluated changes in the drought frequency using multi-model and multi-scenario simulations to identify areas where the definition issue could result in pronounced uncertainties and to what extent. We investigated the disagreement in the signs of changes between drought definitions and decomposed the variance into four main factors: drought definitions, greenhouse gas concentration scenarios, global climate models, and global water models, as well as their interactions. The results show that models were the primary sources of variance over 82% of the global land area. On the other hand, the drought definition was the dominant source of variance in the remaining 17%, especially in parts of northern high-latitudes. Our results highlight specific regions where differences in drought definitions result in a large spread among projections, including areas showing opposite signs of significant changes. At a global scale, 7% of the variance resulted independently from the definition issue, and that value increased to 44% when 1st and 2nd order interactions were considered. The quantitative results suggest that by clarifying hydrological processes or sectors of interest, one could avoid these uncertainties in drought assessments to obtain a clearer picture of future drought change.
Emissions of the potent greenhouse gas perfluorocyclobutane (c-C4F8, PFC-318, octafluorocyclobutane) into the global atmosphere inferred from atmospheric measurements have been increasing sharply since the early 2000s. We find that these inferred emissions are highly correlated with the production of hydrochlorofluorocarbon-22 (HCFC-22, CHClF2) for feedstock (FS) uses, because almost all HCFC-22 FS is pyrolyzed to produce (poly)tetrafluoroethylene ((P)TFE) and hexafluoropropylene (HFP), a process in which c-C4F8 is a known by-product, causing a significant fraction of global c-C4F8 emissions. We find a global emission factor of ∼0.003 kg c-C4F8 per kilogram of HCFC-22 FS pyrolyzed. Mitigation of these c-C4F8 emissions, e.g., through process optimization, abatement, or different manufacturing processes, such as refined methods of electrochemical fluorination and waste recycling, could reduce the climate impact of this industry. While it has been shown that c-C4F8 emissions from developing countries dominate global emissions, more atmospheric measurements and/or detailed process statistics are needed to quantify c-C4F8 emissions at country to facility levels.
Background: The nonmotor symptom spectrum of Parkinson’s disease (PD) includes progressive cognitive decline mainly in late stages of the disease. The aim of this study was to map the patterns of altered structural connectivity of patients with PD with different cognitive profiles ranging from cognitively unimpaired to PD-associated dementia.
Methods: Diffusion tensor imaging and neuropsychological data from the observational multicentre LANDSCAPE study were analyzed. A total of 134 patients with PD with normal cognitive function (56 PD-N), mild cognitive impairment (67 PD-MCI), and dementia (11 PD-D) as well as 72 healthy controls were subjected to whole-brain-based fractional anisotropy mapping and covariance analysis with cognitive performance measures.
Results: Structural data indicated subtle changes in the corpus callosum and thalamic radiation in PD-N, whereas severe white matter impairment was observed in both PD-MCI and PD-D patients including anterior and inferior fronto-occipital, uncinate, insular cortices, superior longitudinal fasciculi, corona radiata, and the body of the corpus callosum. These regional alterations were demonstrated for PD-MCI and were more pronounced in PD-D. The pattern of involved regions was significantly correlated with the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) total score.
Conclusions: The findings in PD-N suggest impaired cross-hemispherical white matter connectivity that can apparently be compensated for. More pronounced involvement of the corpus callosum as demonstrated for PD-MCI together with affection of fronto-parieto-temporal structural connectivity seems to lead to gradual disruption of cognition-related cortico-cortical networks and to be associated with the onset of overt cognitive deficits. The increase of regional white matter damage appears to be associated with the development of PD-associated dementia.
No association between Parkinson disease and autoantibodies against NMDA-type glutamate receptors
(2019)
Background: IgG-class autoantibodies to N-Methyl-D-Aspartate (NMDA)-type glutamate receptors define a novel entity of autoimmune encephalitis. Studies examining the prevalence of NMDA IgA/IgM antibodies in patients with Parkinson disease with/without dementia produced conflicting results. We measured NMDA antibodies in a large, well phenotyped sample of Parkinson patients without and with cognitive impairment (n = 296) and controls (n = 295) free of neuropsychiatric disease. Detailed phenotyping and large numbers allowed statistically meaningful correlation of antibody status with diagnostic subgroups as well as quantitative indicators of disease severity and cognitive impairment.
Methods: NMDA antibodies were analysed in the serum of patients and controls using well established validated assays. We used anti-NMDA antibody positivity as the main independent variable and correlated it with disease status and phenotypic characteristics.
Results: The frequency of NMDA IgA/IgM antibodies was lower in Parkinson patients (13%) than in controls (22%) and higher than in previous studies in both groups. NMDA IgA/IgM antibodies were neither significantly associated with diagnostic subclasses of Parkinson disease according to cognitive impairment, nor with quantitative indicators of disease severity and cognitive impairment. A positive NMDA antibody status was positively correlated with age in controls but not in Parkinson patients.
Conclusion: It is unlikely albeit not impossible that NMDA antibodies play a significant role in the pathogenesis or progression of Parkinson disease e.g. to Parkinson disease with dementia, while NMDA IgG antibodies define a separate disease of its own.
Under certain conditions, secondary organic aerosol (SOA) particles can exist in the atmosphere in an amorphous solid or semi-solid state. To determine their relevance to processes such as ice nucleation or chemistry occurring within particles requires knowledge of the temperature and relative humidity (RH) range for SOA to exist in these states. In the Cosmics Leaving Outdoor Droplets (CLOUD) experiment at The European Organisation for Nuclear Research (CERN), we deployed a new in situ optical method to detect the viscous state of α-pinene SOA particles and measured their transition from the amorphous highly viscous state to states of lower viscosity. The method is based on the depolarising properties of laboratory-produced non-spherical SOA particles and their transformation to non-depolarising spherical particles at relative humidities near the deliquescence point. We found that particles formed and grown in the chamber developed an asymmetric shape through coagulation. A transition to a spherical shape was observed as the RH was increased to between 35 % at −10 °C and 80 % at −38 °C, confirming previous calculations of the viscosity-transition conditions. Consequently, α-pinene SOA particles exist in a viscous state over a wide range of ambient conditions, including the cirrus region of the free troposphere. This has implications for the physical, chemical, and ice-nucleation properties of SOA and SOA-coated particles in the atmosphere.
We present the first measurements of charge-dependent correlations on angular difference variables η1 − η2 (pseudorapidity) and φ1 − φ2 (azimuth) for primary charged hadrons with transverse momentum 0.15 <= pt <= 2 GeV/c and |η| <= 1.3 from Au–Au collisions at √sNN = 130 GeV. We observe correlation structures not predicted by theory but consistent with evolution of hadron emission geometry with increasing centrality from one-dimensional fragmentation of color strings along the beam direction to an at least two-dimensional hadronization geometry along the beam and azimuth directions of a hadron-opaque bulk medium.
Folding of G-protein coupled receptors (GPCRs) according to the two-stage model (Popot, J. L., and Engelman, D. M. (1990) Biochemistry 29, 4031–4037) is postulated to proceed in 2 steps: partitioning of the polypeptide into the membrane followed by diffusion until native contacts are formed. Herein we investigate conformational preferences of fragments of the yeast Ste2p receptor using NMR. Constructs comprising the first, the first two, and the first three transmembrane (TM) segments, as well as a construct comprising TM1–TM2 covalently linked to TM7 were examined. We observed that the isolated TM1 does not form a stable helix nor does it integrate well into the micelle. TM1 is significantly stabilized upon interaction with TM2, forming a helical hairpin reported previously (Neumoin, A., Cohen, L. S., Arshava, B., Tantry, S., Becker, J. M., Zerbe, O., and Naider, F. (2009) Biophys. J. 96, 3187–3196), and in this case the protein integrates into the hydrophobic interior of the micelle. TM123 displays a strong tendency to oligomerize, but hydrogen exchange data reveal that the center of TM3 is solvent exposed. In all GPCRs so-far structurally characterized TM7 forms many contacts with TM1 and TM2. In our study TM127 integrates well into the hydrophobic environment, but TM7 does not stably pack against the remaining helices. Topology mapping in microsomal membranes also indicates that TM1 does not integrate in a membrane-spanning fashion, but that TM12, TM123, and TM127 adopt predominantly native-like topologies. The data from our study would be consistent with the retention of individual helices of incompletely synthesized GPCRs in the vicinity of the translocon until the complete receptor is released into the membrane interior.
Background: Prostate cancer is a major health concern in aging men. Paralleling an aging society, prostate cancer prevalence increases emphasizing the need for efcient diagnostic algorithms.
Methods: Retrospectively, 106 prostate tissue samples from 48 patients (mean age,
66 ± 6.6 years) were included in the study. Patients sufered from prostate cancer (n = 38) or benign prostatic hyperplasia (n = 10) and were treated with radical prostatectomy or Holmium laser enucleation of the prostate, respectively. We constructed tissue microarrays (TMAs) comprising representative malignant (n = 38) and benign (n = 68) tissue cores. TMAs were processed to histological slides, stained, digitized and assessed for the applicability of machine learning strategies and open–source tools in diagnosis of prostate cancer. We applied the software QuPath to extract features for shape, stain intensity, and texture of TMA cores for three stainings, H&E, ERG, and PIN-4. Three machine learning algorithms, neural network (NN), support vector machines (SVM), and random forest (RF), were trained and cross-validated with 100 Monte Carlo random splits into 70% training set and 30% test set. We determined AUC values for single color channels, with and without optimization of hyperparameters by exhaustive grid search. We applied recursive feature elimination to feature sets of multiple color transforms.
Results: Mean AUC was above 0.80. PIN-4 stainings yielded higher AUC than H&E and
ERG. For PIN-4 with the color transform saturation, NN, RF, and SVM revealed AUC of 0.93 ± 0.04, 0.91 ± 0.06, and 0.92 ± 0.05, respectively. Optimization of hyperparameters improved the AUC only slightly by 0.01. For H&E, feature selection resulted in no increase of AUC but to an increase of 0.02–0.06 for ERG and PIN-4.
Conclusions: Automated pipelines may be able to discriminate with high accuracy between malignant and benign tissue. We found PIN-4 staining best suited for classifcation. Further bioinformatic analysis of larger data sets would be crucial to evaluate the reliability of automated classifcation methods for clinical practice and to evaluate potential discrimination of aggressiveness of cancer to pave the way to automatic precision medicine.
Higher grade meningiomas tend to recur. We aimed to evaluate protein levels of vascular endothelial growth factor (VEGF)-A with the VEGF-receptors 1-3 and the co-receptors Neuropilin (NRP)-1 and -2 in WHO grade II and III meningiomas to elucidate the rationale for targeted treatments. We investigated 232 specimens of 147 patients suffering from cranial meningioma, including recurrent tumors. Immunohistochemistry for VEGF-A, VEGFR-1-3, and NRP-1/-2 was performed on tissue micro arrays. We applied a semiquantitative score (staining intensity x frequency). VEGF-A, VEGFR-1-3, and NRP-1 were heterogeneously expressed. NRP-2 was mainly absent. We demonstrated a significant increase of VEGF-A levels on tumor cells in WHO grade III meningiomas (p = 0.0098). We found a positive correlation between expression levels of VEGF-A and VEGFR-1 on tumor cells and vessels (p < 0.0001). In addition, there was a positive correlation of VEGF-A and VEGFR-3 expression on tumor vessels (p = 0.0034). VEGFR-2 expression was positively associated with progression-free survival (p = 0.0340). VEGF-A on tumor cells was negatively correlated with overall survival (p = 0.0084). The VEGF-A-driven system of tumor angiogenesis might still present a suitable target for adjuvant therapy in malignant meningioma disease. However, its role in malignant tumor progression may not be as crucial as expected. The value of comprehensive testing of the ligand and all receptors prior to administration of anti-angiogenic therapy needs to be evaluated in clinical trials.
We compiled an NMR data set consisting of exact nuclear Overhauser enhancement (eNOE) distance limits, residual dipolar couplings (RDCs) and scalar (J) couplings for GB3, which forms one of the largest and most diverse data set for structural characterization of a protein to date. All data have small experimental errors, which are carefully estimated. We use the data in the research article Vogeli et al., 2015, Complementarity and congruence between exact NOEs and traditional NMR probes for spatial decoding of protein dynamics, J. Struct. Biol., 191, 3, 306–317, doi:10.1016/j.jsb.2015.07.008 [1] for cross-validation in multiple-state structural ensemble calculation. We advocate this set to be an ideal test case for molecular dynamics simulations and structure calculations.
TRIANNI mice carry an entire set of human immunoglobulin V region gene segments and are a powerful tool to rapidly isolate human monoclonal antibodies. After immunizing these mice with DNA encoding the spike protein of SARS-CoV-2 and boosting with spike protein, we identified 29 hybridoma antibodies that reacted with the SARS-CoV-2 spike protein. Nine antibodies neutralize SARS-CoV-2 infection at IC50 values in the subnanomolar range. ELISA-binding studies and DNA sequence analyses revealed one cluster of three clonally related neutralizing antibodies that target the receptor-binding domain and compete with the cellular receptor hACE2. A second cluster of six clonally related neutralizing antibodies bind to the N-terminal domain of the spike protein without competing with the binding of hACE2 or cluster 1 antibodies. SARS-CoV-2 mutants selected for resistance to an antibody from one cluster are still neutralized by an antibody from the other cluster. Antibodies from both clusters markedly reduced viral spread in mice transgenic for human ACE2 and protected the animals from SARS-CoV-2-induced weight loss. The two clusters of potent noncompeting SARS-CoV-2 neutralizing antibodies provide potential candidates for therapy and prophylaxis of COVID-19. The study further supports transgenic animals with a human immunoglobulin gene repertoire as a powerful platform in pandemic preparedness initiatives.
Objectives: To analyze the performance of radiological assessment categories and quantitative computational analysis of apparent diffusion coefficient (ADC) maps using variant machine learning algorithms to differentiate clinically significant versus insignificant prostate cancer (PCa). Methods: Retrospectively, 73 patients were included in the study. The patients (mean age, 66.3 ± 7.6 years) were examined with multiparametric MRI (mpMRI) prior to radical prostatectomy (n = 33) or targeted biopsy (n = 40). The index lesion was annotated in MRI ADC and the equivalent histologic slides according to the highest Gleason Grade Group (GrG). Volumes of interest (VOIs) were determined for each lesion and normal-appearing peripheral zone. VOIs were processed by radiomic analysis. For the classification of lesions according to their clinical significance (GrG ≥ 3), principal component (PC) analysis, univariate analysis (UA) with consecutive support vector machines, neural networks, and random forest analysis were performed. Results: PC analysis discriminated between benign and malignant prostate tissue. PC evaluation yielded no stratification of PCa lesions according to their clinical significance, but UA revealed differences in clinical assessment categories and radiomic features. We trained three classification models with fifteen feature subsets. We identified a subset of shape features which improved the diagnostic accuracy of the clinical assessment categories (maximum increase in diagnostic accuracy ΔAUC = + 0.05, p < 0.001) while also identifying combinations of features and models which reduced overall accuracy. Conclusions: The impact of radiomic features to differentiate PCa lesions according to their clinical significance remains controversial. It depends on feature selection and the employed machine learning algorithms. It can result in improvement or reduction of diagnostic performance.
Our purpose was to analyze the robustness and reproducibility of magnetic resonance imaging (MRI) radiomic features. We constructed a multi-object fruit phantom to perform MRI acquisition as scan-rescan using a 3 Tesla MRI scanner. We applied T2-weighted (T2w) half-Fourier acquisition single-shot turbo spin-echo (HASTE), T2w turbo spin-echo (TSE), T2w fluid-attenuated inversion recovery (FLAIR), T2 map and T1-weighted (T1w) TSE. Images were resampled to isotropic voxels. Fruits were segmented. The workflow was repeated by a second reader and the first reader after a pause of one month. We applied PyRadiomics to extract 107 radiomic features per fruit and sequence from seven feature classes. We calculated concordance correlation coefficients (CCC) and dynamic range (DR) to obtain measurements of feature robustness. Intraclass correlation coefficient (ICC) was calculated to assess intra- and inter-observer reproducibility. We calculated Gini scores to test the pairwise discriminative power specific for the features and MRI sequences. We depict Bland Altmann plots of features with top discriminative power (Mann–Whitney U test). Shape features were the most robust feature class. T2 map was the most robust imaging technique (robust features (rf), n = 84). HASTE sequence led to the least amount of rf (n = 20). Intra-observer ICC was excellent (≥ 0.75) for nearly all features (max–min; 99.1–97.2%). Deterioration of ICC values was seen in the inter-observer analyses (max–min; 88.7–81.1%). Complete robustness across all sequences was found for 8 features. Shape features and T2 map yielded the highest pairwise discriminative performance. Radiomics validity depends on the MRI sequence and feature class. T2 map seems to be the most promising imaging technique with the highest feature robustness, high intra-/inter-observer reproducibility and most promising discriminative power.
Abrasion-ablation models and the empirical EPAX parametrization of projectile fragmentation are described. Their cross section predictions are compared to recent data of the fragmentation of secondary beams of neutron-rich, unstable 19,20,21O isotopes at beam energies near 600 MeV/nucleon as well as data for stable 17,18O beams.
Aims: Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk.
Methods and results: From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies.
In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95–1.02) in group A, 0.98 (0.93–1.04) in group B, and 0.95 (0.89–1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07–1.23) in group A, 1.13 (1.05–1.22) in group B, and 1.12 (1.05–1.20) in group C.
Conclusions: We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals.
Aims: Averaged measurements, but not the progression based on multiple assessments of carotid intima-media thickness, (cIMT) are predictive of cardiovascular disease (CVD) events in individuals. Whether this is true for conventional risk factors is unclear.
Methods and results: An individual participant meta-analysis was used to associate the annualised progression of systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with future cardiovascular disease risk in 13 prospective cohort studies of the PROG-IMT collaboration (n = 34,072). Follow-up data included information on a combined cardiovascular disease endpoint of myocardial infarction, stroke, or vascular death. In secondary analyses, annualised progression was replaced with average. Log hazard ratios per standard deviation difference were pooled across studies by a random effects meta-analysis. In primary analysis, the annualised progression of total cholesterol was marginally related to a higher cardiovascular disease risk (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00 to 1.07). The annualised progression of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol was not associated with future cardiovascular disease risk. In secondary analysis, average systolic blood pressure (HR 1.20 95% CI 1.11 to 1.29) and low-density lipoprotein cholesterol (HR 1.09, 95% CI 1.02 to 1.16) were related to a greater, while high-density lipoprotein cholesterol (HR 0.92, 95% CI 0.88 to 0.97) was related to a lower risk of future cardiovascular disease events.
Conclusion: Averaged measurements of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol displayed significant linear relationships with the risk of future cardiovascular disease events. However, there was no clear association between the annualised progression of these conventional risk factors in individuals with the risk of future clinical endpoints.
The Coulomb Dissociation (CD) cross sections of the stable isotopes 92,94,100Mo and of the unstable isotope 93Mo were measured at the LAND/R3B setup at GSI Helmholtzzentrum für Schwerionenforschung in Darmstadt, Germany. Experimental data on these isotopes may help to explain the problem of the underproduction of 92,94Mo and 96,98Ru in the models of p-process nucleosynthesis. The CD cross sections obtained for the stable Mo isotopes are in good agreement with experiments performed with real photons, thus validating the method of Coulomb Dissociation. The result for the reaction 93Mo(γ,n) is especially important since the corresponding cross section has not been measured before. A preliminary integral Coulomb Dissociation cross section of the 94Mo(γ,n) reaction is presented. Further analysis will complete the experimental database for the (γ,n) production chain of the p-isotopes of molybdenum.