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Joppe, Mirko ; D'Imprima, Edoardo ; Salustros, Nina ; Paithankar, Karthik Shivaji ; Vonck, Janet ; Grininger, Martin ; Kühlbrandt, Werner
Single-particle electron cryo-microscopy (cryoEM) has undergone a `resolution revolution' that makes it possible to characterize megadalton (MDa) complexes at atomic resolution without crystals. To fully exploit the new opportunities in molecular microscopy, new procedures for the cloning, expression and purification of macromolecular complexes need to be explored. Macromolecular assemblies are often unstable, and invasive construct design or inadequate purification conditions and sample-preparation methods can result in disassembly or denaturation. The structure of the 2.6 MDa yeast fatty acid synthase (FAS) has been studied by electron microscopy since the 1960s. Here, a new, streamlined protocol for the rapid production of purified yeast FAS for structure determination by high-resolution cryoEM is reported. Together with a companion protocol for preparing cryoEM specimens on a hydrophilized graphene layer, the new protocol yielded a 3.1 Å resolution map of yeast FAS from 15 000 automatically picked particles within a day. The high map quality enabled a complete atomic model of an intact fungal FAS to be built.
Modular polyketide synthases (PKSs) produce complex, bioactive secondary metabolites in assembly line-like multistep reactions. Longstanding efforts to produce novel, biologically active compounds by recombining intact modules to new modular PKSs have mostly resulted in poorly active chimeras and decreased product yields. Recent findings demonstrate that the low efficiencies of modular chimeric PKSs also result from rate limitations in the transfer of the growing polyketide chain across the non-cognate module:module interface and further processing of the non-native polyketide substrate by the ketosynthase (KS) domain. In this study, we aim at disclosing and understanding the low efficiency of chimeric modular PKSs and at establishing guidelines for modular PKSs engineering. To do so, we work with a bimodular PKS testbed and systematically vary substrate specificity, substrate identity, and domain:domain interfaces of the KS involved reactions. We observe that KS domains employed in our chimeric bimodular PKSs are bottlenecks with regards to both substrate specificity as well as interaction with the ACP. Overall, our systematic study can explain in quantitative terms why early oversimplified engineering strategies based on the plain shuffling of modules mostly failed and why more recent approaches show improved success rates. We moreover identify two mutations of the KS domain that significantly increased turnover rates in chimeric systems and interpret this finding in mechanistic detail.
Inspired by the physiology of neuronal systems in the brain, artificial neural networks have become an invaluable tool for machine learning applications. However, their biological realism and theoretical tractability are limited, resulting in poorly understood parameters. We have recently shown that biological neuronal firing rates in response to distributed inputs are largely independent of size, meaning that neurons are typically responsive to the proportion, not the absolute number, of their inputs that are active. Here we introduce such a normalisation, where the strength of a neuron’s afferents is divided by their number, to various sparsely-connected artificial networks. The learning performance is dramatically increased, providing an improvement over other widely-used normalisations in sparse networks. The resulting machine learning tools are universally applicable and biologically inspired, rendering them better understood and more stable in our tests.
Achieving functional neuronal dendrite structure through sequential stochastic growth and retraction
(2020)
Castro, André Ferreira ; Baltruschat, Lothar Gunnar ; Stürner, Tomke ; Bahrami, Amirhoushang ; Jedlička, Peter ; Tavosanis, Gaia ; Cuntz, Hermann
Class I ventral posterior dendritic arborisation (c1vpda) proprioceptive sensory neurons respond to contractions in the Drosophila larval body wall during crawling. Their dendritic branches run along the direction of contraction, possibly a functional requirement to maximise membrane curvature during crawling contractions. Although the molecular machinery of dendritic patterning in c1vpda has been extensively studied, the process leading to the precise elaboration of their comb-like shapes remains elusive. Here, to link dendrite shape with its proprioceptive role, we performed long-term, non-invasive, in vivo time-lapse imaging of c1vpda embryonic and larval morphogenesis to reveal a sequence of differentiation stages. We combined computer models and dendritic branch dynamics tracking to propose that distinct sequential phases of stochastic growth and retraction achieve efficient dendritic trees both in terms of wire and function. Our study shows how dendrite growth balances structure–function requirements, shedding new light on general principles of self-organisation in functionally specialised dendrites.
Achieving functional neuronal dendrite structure through sequential stochastic growth and retraction
(2020)
Castro, André Ferreira ; Baltruschat, Lothar Gunnar ; Stürner, Tomke ; Bahrami, Amirhoushang ; Jedlička, Peter ; Tavosanis, Gaia ; Cuntz, Hermann
Class I ventral posterior dendritic arborisation (c1vpda) proprioceptive sensory neurons respond to contractions in the Drosophila larval body wall during crawling. Their dendritic branches run along the direction of contraction, possibly a functional requirement to maximise membrane curvature during crawling contractions. Although the molecular machinery of dendritic patterning in c1vpda has been extensively studied, the process leading to the precise elaboration of their comb-like shapes remains elusive. Here, to link dendrite shape with its proprioceptive role, we performed long-term, non-invasive, in vivo time-lapse imaging of c1vpda embryonic and larval morphogenesis to reveal a sequence of differentiation stages. We combined computer models and dendritic branch dynamics tracking to propose that distinct sequential phases of targeted growth and stochastic retraction achieve efficient dendritic trees both in terms of wire and function. Our study shows how dendrite growth balances structure–function requirements, shedding new light on general principles of self-organisation in functionally specialised dendrites.
Dendrites display a striking variety of neuronal type-specific morphologies, but the mechanisms and principles underlying such diversity remain elusive. A major player in defining the morphology of dendrites is the neuronal cytoskeleton, including evolutionarily conserved actin-modulatory proteins (AMPs). Still, we lack a clear understanding of how AMPs might support developmental phenomena such as neuron-type specific dendrite dynamics. To address precisely this level of in vivo specificity, we concentrated on a defined neuronal type, the class III dendritic arborisation (c3da) neuron of Drosophila larvae, displaying actin-enriched short terminal branchlets (STBs). Computational modelling reveals that the main branches of c3da neurons follow a general growth model based on optimal wiring, but the STBs do not. Instead, model STBs are defined by a short reach and a high affinity to grow towards the main branches. We thus concentrated on c3da STBs and developed new methods to quantitatively describe dendrite morphology and dynamics based on in vivo time-lapse imaging of mutants lacking individual AMPs. In this way, we extrapolated the role of these AMPs in defining STB properties. We propose that dendrite diversity is supported by the combination of a common step, refined by a neuron type-specific second level. For c3da neurons, we present a molecular model of how the combined action of multiple AMPs in vivo define the properties of these second level specialisations, the STBs.
The way in which dendrites spread within neural tissue determines the resulting circuit connectivity and computation. However, a general theory describing the dynamics of this growth process does not exist. Here we obtain the first time-lapse reconstructions of neurons in living fly larvae over the entirety of their developmental stages. We show that these neurons expand in a remarkably regular stretching process that conserves their shape. Newly available space is filled optimally, a direct consequence of constraining the total amount of dendritic cable. We derive a mathematical model that predicts one time point from the previous and use this model to predict dendrite morphology of other cell types and species. In summary, we formulate a novel theory of dendrite growth based on detailed developmental experimental data that optimises wiring and space filling and serves as a basis to better understand aspects of coverage and connectivity for neural circuit formation.
Disordered proteins and nucleic acids can condense into droplets that resemble the membraneless organelles observed in living cells. MD simulations offer a unique tool to characterize the molecular interactions governing the formation of these biomolecular condensates, their physico-chemical properties, and the factors controlling their composition and size. However, biopolymer condensation depends sensitively on the balance between different energetic and entropic contributions. Here, we develop a general strategy to fine-tune the potential energy function for molecular dynamics simulations of biopolymer phase separation. We rebalance protein-protein interactions against solvation and entropic contributions to match the excess free energy of transferring proteins between dilute solution and condensate. We illustrate this formalism by simulating liquid droplet formation of the FUS low complexity domain (LCD) with a rebalanced MARTINI model. By scaling the strength of the nonbonded interactions in the coarse-grained MARTINI potential energy function, we map out a phase diagram in the plane of protein concentration and interaction strength. Above a critical scaling factor of αc ≈ 0.6, FUS LCD condensation is observed, where α = 1 and 0 correspond to full and repulsive interactions in the MARTINI model, respectively. For a scaling factor α = 0.65, we recover the experimental densities of the dilute and dense phases, and thus the excess protein transfer free energy into the droplet and the saturation concentration where FUS LCD condenses. In the region of phase separation, we simulate FUS LCD droplets of four different sizes in stable equilibrium with the dilute phase and slabs of condensed FUS LCD for tens of microseconds, and over one millisecond in aggregate. We determine surface tensions in the range of 0.01 to 0.4mN/m from the fluctuations of the droplet shape and from the capillary-wave-like broadening of the interface between the two phases. From the dynamics of the protein end-to-end distance, we estimate shear viscosities from 0.001 to 0.02Pas for the FUS LCD droplets with scaling factors α in the range of 0.625 to 0.75, where we observe liquid droplets. Significant hydration of the interior of the droplets keeps the proteins mobile and the droplets fluid.
The protein Atg2 has been proposed to form a membrane tether that mediates lipid transfer from the ER to the phagophore in autophagy. However, recent kinetic measurements on the human homolog ATG2A indicated a transport rate of only about one lipid per minute, which would be far too slow to deliver the millions of lipids required to form a phagophore on a physiological time scale. Here, we revisit the analysis of the fluorescence quenching experiments. We develop a detailed kinetic model of the lipid transfer between two membranes bridged by a tether that forms a conduit for lipids. The model provides an excellent fit to the fluorescence experiments, with a lipid transfer rate of about 100 per second and protein. At this rate, Atg2-mediated transfer can supply a significant fraction of the lipids required in autophagosome biogenesis. Our kinetic model is generally applicable to lipid-transfer experiments, in particular to proteins forming organelle contact sites in cells.
Binding of the spike protein of SARS-CoV-2 to the human angiotensin converting enzyme 2 (ACE2) receptor triggers translocation of the virus into cells. Both the ACE2 receptor and the spike protein are heavily glycosylated, including at sites near their binding interface. We built fully glycosylated models of the ACE2 receptor bound to the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Using atomistic molecular dynamics (MD) simulations, we found that the glycosylation of the human ACE2 receptor contributes substantially to the binding of the virus. Interestingly, the glycans at two glycosylation sites, N90 and N322, have opposite effects on spike protein binding. The glycan at the N90 site partly covers the binding interface of the spike RBD. Therefore, this glycan can interfere with the binding of the spike protein and protect against docking of the virus to the cell. By contrast, the glycan at the N322 site interacts tightly with the RBD of the ACE2-bound spike protein and strengthens the complex. Remarkably, the N322 glycan binds into a conserved region of the spike protein identified previously as a cryptic epitope for a neutralizing antibody. By mapping the glycan binding sites, our MD simulations aid in the targeted development of neutralizing antibodies and SARS-CoV-2 fusion inhibitors.
Active efficient coding explains the development of binocular vision and its failure in amblyopia
(2020)
The development of vision during the first months of life is an active process that comprises the learning of appropriate neural representations and the learning of accurate eye movements. While it has long been suspected that the two learning processes are coupled, there is still no widely accepted theoretical framework describing this joint development. Here we propose a computational model of the development of active binocular vision to fill this gap. The model is based on a new formulation of the Active Efficient Coding theory, which proposes that eye movements, as well as stimulus encoding, are jointly adapted to maximize the overall coding efficiency. Under healthy conditions, the model self-calibrates to perform accurate vergence and accommodation eye movements. It exploits disparity cues to deduce the direction of defocus, which leads to co-ordinated vergence and accommodation responses. In a simulated anisometropic case, where the refraction power of the two eyes differs, an amblyopia-like state develops, in which the foveal region of one eye is suppressed due to inputs from the other eye. After correcting for refractive errors, the model can only reach healthy performance levels if receptive fields are still plastic, in line with findings on a critical period for binocular vision development. Overall, our model offers a unifying conceptual framework for understanding the development of binocular vision.
Klann, Kevin ; Bojkova, Denisa ; Tascher, Georg ; Ciesek, Sandra ; Münch, Christian ; Cinatl, Jindrich
SARS-CoV-2 infections are rapidly spreading around the globe. The rapid development of therapies is of major importance. However, our lack of understanding of the molecular processes and host cell signaling events underlying SARS-CoV-2 infection hinder therapy development. We employed a SARS-CoV-2 infection system in permissible human cells to study signaling changes by phospho-proteomics. We identified viral protein phosphorylation and defined phosphorylation-driven host cell signaling changes upon infection. Growth factor receptor (GFR) signaling and downstream pathways were activated. Drug-protein network analyses revealed GFR signaling as key pathway targetable by approved drugs. Inhibition of GFR downstream signaling by five compounds prevented SARS-CoV-2 replication in cells, assessed by cytopathic effect, viral dsRNA production, and viral RNA release into the supernatant. This study describes host cell signaling events upon SARS-CoV-2 infection and reveals GFR signaling as central pathway essential for SARS-CoV-2 replication. It provides with novel strategies for COVID-19 treatment.
Michaelis, Martin ; Voges, Yvonne ; Rothweiler, Florian ; Weipert, Fabian ; Zia-Ahmad, Amara ; Cinatl, Jaroslav ; Deimling, Andreas von ; Westermann, Frank ; Rödel, Franz ; Wass, Mark N. ; Cinatl, Jindrich
The survivin suppressant YM155 is a drug candidate for neuroblastoma. Here, we tested YM155 in 101 neuroblastoma cell lines (19 parental cell lines, 82 drug-adapted sublines). 77 cell lines displayed YM155 IC50s in the range of clinical YM155 concentrations. ABCB1 was an important determinant of YM155 resistance. The activity of the ABCB1 inhibitor zosuquidar ranged from being similar to that of the structurally different ABCB1 inhibitor verapamil to being 65-fold higher. ABCB1 sequence variations may be responsible for this, suggesting that the design of variant-specific ABCB1 inhibitors may be possible. Further, we showed that ABCC1 confers YM155 resistance. Previously, p53 depletion had resulted in decreased YM155 sensitivity. However, TP53-mutant cells were not generally less sensitive to YM155 than TP53 wild-type cells in this study. Finally, YM155 cross-resistance profiles differed between cells adapted to drugs as similar as cisplatin and carboplatin. In conclusion, the large cell line panel was necessary to reveal an unanticipated complexity of the YM155 response in neuroblastoma cell lines with acquired drug resistance. Novel findings include that ABCC1 mediates YM155 resistance and that YM155 cross-resistance profiles differ between cell lines adapted to drugs as similar as cisplatin and carboplatin.
Bojkova, Denisa ; McGreig, Jake E. ; McLaughlin, Katie-May ; Masterson, Stuart G. ; Widera, Marek ; Krähling, Verena ; Ciesek, Sandra ; Wass, Mark N. ; Michaelis, Martin ; Cinatl, Jindrich
SARS-CoV-2 is a novel coronavirus currently causing a pandemic. We show that the majority of amino acid positions, which differ between SARS-CoV-2 and the closely related SARS-CoV, are differentially conserved suggesting differences in biological behaviour. In agreement, novel cell culture models revealed differences between the tropism of SARS-CoV-2 and SARS-CoV. Moreover, cellular ACE2 (SARS-CoV-2 receptor) and TMPRSS2 (enables virus entry via S protein cleavage) levels did not reliably indicate cell susceptibility to SARS-CoV-2. SARS-CoV-2 and SARS-CoV further differed in their drug sensitivity profiles. Thus, only drug testing using SARS-CoV-2 reliably identifies therapy candidates. Therapeutic concentrations of the approved protease inhibitor aprotinin displayed anti-SARS-CoV-2 activity. The efficacy of aprotinin and of remdesivir (currently under clinical investigation against SARS-CoV-2) were further enhanced by therapeutic concentrations of the proton pump inhibitor omeprazole (aprotinin 2.7-fold, remdesivir 10-fold). Hence, our study has also identified anti-SARS-CoV-2 therapy candidates that can be readily tested in patients.
McLaughlin, Katie-May ; Bechtel, Marco ; Bojkova, Denisa ; Wass, Mark N. ; Michaelis, Martin ; Cinatl, Jindrich
SARS-CoV-2 is the causative agent of COVID-19. Severe COVID-19 disease has been associated with disseminated intravascular coagulation and thrombosis, but the mechanisms underlying COVID-19-related coagulopathy remain unknown. Since the risk of severe COVID-19 disease is higher in males than in females and increases with age, we combined proteomics data from SARS-CoV-2-infected cells with human gene expression data from the Genotype-Tissue Expression (GTEx) database to identify gene products involved in coagulation that change with age, differ in their levels between females and males, and are regulated in response to SARS-CoV-2 infection. This resulted in the identification of transferrin as a candidate coagulation promoter, whose levels increases with age and are higher in males than in females and that is increased upon SARS-CoV-2 infection. A systematic investigation of gene products associated with the GO term “blood coagulation” did not reveal further high confidence candidates, which are likely to contribute to COVID-19-related coagulopathy. In conclusion, the role of transferrin should be considered in the course of COVID-19 disease and further examined in ongoing clinic-pathological investigations.
Einleitung: Begehen zwei Menschen infolge einer gemeinsamen Entscheidung Suizid, wird dies als Doppelsuizid oder gemeinschaftlicher Suizid definiert. Die rechtsmedizinische Begutachtung hängt von den Umständen des konkreten Einzelfalls ab und kann für die rechtliche Würdigung insbesondere bei Konstellationen, bei denen ein Beteiligter überlebt hat, wichtige Hinweise liefern.
Material und Methoden: Für einen 25-Jahres-Zeitraum von 1995 bis 2019 wurden retrospektiv alle Sektionsfälle mit vollendeten und versuchten Doppelsuiziden analysiert und, soweit erhältlich, mit den Ermittlungsakten abgeglichen.
Ergebnisse: Unter den erhobenen 23 Doppelsuizidfällen fanden sich 16 vollendete sowie 7 Fälle mit jeweils einem Überlebenden. In 83 % der Fälle handelte es sich um Ehepaare bzw. eingetragene Lebensgemeinschaften, in 13 % um Personen, die sich zuvor in einer psychiatrischen Einrichtung, und in 4 % um Personen, die sich in einem „Suizidforum“ im Internet kennengelernt hatten. Der Mittelwert des Sterbealters betrug bei den Männern 57,8 und bei den Frauen 63,4 Jahre. In etwa zwei Drittel der Fälle wurden Erkrankungen als vorherrschendes Suizidmotiv angegeben. Als häufigste Methode wurde eine Intoxikation gewählt. Am zweithäufigsten fanden Schusswaffen Anwendung, wobei ausnahmslos der Mann zuerst einen oder mehrere Kopfschüsse auf seine Frau abgab, bevor er sich suizidierte. Der häufigste Sterbe- und Auffindeort war das gemeinsame Bett der Suizidenten.
Diskussion: Im Gegensatz zu Suiziden i. Allg. wurden die Doppelsuizide am häufigsten mittels einer Intoxikation als sogenannte weiche Methode verübt. In Anlehnung an die rechtsmedizinische Literatur werden für einen Doppelsuizid typische Merkmale herausgearbeitet.
Schlussfolgerung: Doppelsuizide stellen seltene Fälle in der rechtsmedizinischen Praxis dar, wobei die Abgrenzung zu einem erweiterten Suizid (Homizid-Suizid) schwierig werden kann und zugleich unabdingbar ist. Hierfür ist eine ganzheitliche Berücksichtigung der Vorgeschichte, der rechtsmedizinisch erhobenen Befunde und der kriminalistischen Umstände erforderlich.
Bei Suizidformen mit mehreren Suizidenten und Opfern werden teilweise in Literatur und Rechtsprechung eine unterschiedliche Nomenklatur und Interpretation der Begrifflichkeiten vorgenommen. Der Beitrag analysiert die Begrifflichkeiten und befasst sich im Speziellen mit dem Phänomen des Doppelsuizids. Historische Fälle von Doppelsuiziden werden angeführt. Anhand von Fallkonstellationen werden rechtliche Bewertungen vorgenommen, die beim einseitig fehlgeschlagenen Doppelsuizid praxisrelevant werden können. Dabei werden die mitunter konträren Auffassungen in der einschlägigen Literatur und der Rechtsprechung dargestellt und Lösungsansätze aufgezeigt. Zudem verdeutlichen die Fallkonstellationen die Relevanz einer umfassenden Tatortarbeit und einer tatnahen Klärung der Motivationslage bei dem Überlebenden bzw. den Verstorbenen.
The 𝒮-cone provides a common framework for cones of polynomials or exponen- tial sums which establish non-negativity upon the arithmetic-geometric inequality, in particular for sums of non-negative circuit polynomials (SONC) or sums of arithmetic- geometric exponentials (SAGE). In this paper, we study the S-cone and its dual from the viewpoint of second-order representability. Extending results of Averkov and of Wang and Magron on the primal SONC cone, we provide explicit generalized second- order descriptions for rational S-cones and their duals.
Mia, Ibnul ; Le, Melanie Thanh Phuong ; Arendt, Christophe ; Brand, Diana ; Bremekamp, Sina ; D’Angelo, Tommaso ; Puntmann, Valentina O. ; Nagel, Eike
The aim of this study is to provide a systematic assessment of the influence of the position on the arterial input function (AIF) for perfusion quantification. In 39 patients with a wide range of left ventricular function the AIF was determined using a diluted contrast bolus of a cardiac magnetic resonance imaging in three left ventricular levels (basal, mid, apex) as well as aortic sinus (AoS). Time to peak signal intensities, baseline corrected peak signal intensity and upslopes were determined and compared to those obtained in the AoS. The error induced by sampling the AIF in a position different to the AoS was determined by Fermi deconvolution. The time to peak signal intensity was strongly correlated (r2 > 0.9) for all positions with a systematic earlier arrival in the basal (− 2153 ± 818 ms), the mid (− 1429 ± 928 ms) and the apical slice (− 450 ± 739 ms) relative to the AoS (all p < 0.001). Peak signal intensity as well as upslopes were strongly correlated (r2 > 0.9 for both) for all positions with a systematic overestimation in all positions relative to the AoS (all p < 0.001 and all p < 0.05). Differences between the positions were more pronounced for patients with reduced ejection fraction. The error of averaged MBF quantification was 8%, 13% and 27% for the base, mid and apex. The location of the AIF significantly influences core parameters for perfusion quantification with a systematic and ejection fraction dependent error. Full quantification should be based on obtaining the AIF as close as possible to the myocardium to minimize these errors.
We introduce a novel approach based on elas- tic and inelastic scattering rates to extract the hyper-surface of the chemical freeze-out from a hadronic transport model in the energy range from Elab = 1.23 AGeV to √sNN = 62.4 GeV. For this study, the Ultra-relativistic Quantum Molecular Dynamics (UrQMD) model combined with a coarse-graining method is employed. The chemical freeze- out distribution is reconstructed from the pions through sev- eral decay and re-formation chains involving resonances and taking into account inelastic, pseudo-elastic and string excita- tion reactions. The extracted average temperature and baryon chemical potential are then compared to statistical model analysis. Finally we investigate various freeze-out criteria suggested in the literature. We confirm within this micro- scopic dynamical simulation, that the chemical freeze-out at all energies coincides with ⟨E⟩/⟨N⟩ ≈ 1 GeV, while other criteria, like s/T 3 = 7 and nB +nB ̄ ≈ 0.12 fm−3 are limited to higher collision energies.
Der Tumormarker Sialinsäure
(2020)
Die vorliegende Übersicht zum Tumormarker Sialinsäure wird im Rahmen der Serie „Tumormarker“ des Zentralblatts für Arbeitsmedizin, Arbeitsschutz und Ergonomie publiziert, die sich mit dem immer häufigeren Gebrauch der Bestimmung von spezifischen Markern bei sog. Manager-Vorsorgen und Check-up-Untersuchungen beschäftigt. Sialinsäure eignet sich grundsätzlich nicht für solche Vorsorgen, sondern ist ein Marker zur Therapie‑, Verlaufs- und Rezidivkontrolle von Mundhöhlenkarzinomen. Hier zeigt dieser eine hohe Sensitivität und Spezifität, wobei der Marker aber auf keinen Fall als Screeningparameter zur Frühdiagnostik eingesetzt werden soll.
The production of light (anti-)nuclei and (anti-)hypernuclei in ultra-relativistic heavy-ion collisions, but also in more elementary collisions as proton–proton and proton–nucleus collisions, became recently a focus of interest. In particular, the fact that these objects are all loosely bound compared to the temperature and energies, e.g. the kinetic energies involved, is often stressed out to be special for their production. The binding energies of these (anti-)nuclei is between 130 keV (Λ separation energy in the hypertriton) and about 8 MeV per nucleon. Whereas the connected temperatures are of the order of 100 to 160 MeV. This lead to some difficulties in the interpretation of the usually discussed production models, i.e. coalescence and statistical-thermal models, as will be discussed here. In this brief review we discuss selected highlights of the production of light (anti-)nuclei, such as (anti-)deuteron, (anti-)helium and (anti-)alpha nuclei. In addition, we will discuss the current status of the highly debated lifetime of the (anti-)hypertriton and connected measurements and model results.
Köffer, Jasmin ; Scheiper-Welling, Stefanie ; Verhoff, Marcel A. ; Bajanowski, Thomas ; Kauferstein, Silke
The sudden infant death syndrome (SIDS) is one of the leading causes of postneonatal infant death. It has been shown that there exists a complex relationship between SIDS and inherited cardiac disease. Next-generation sequencing and surveillance of cardiac channelopathy and cardiomyopathy genes represent an important tool for investigating the cause of death in SIDS cases. In the present study, targeted sequencing of 80 genes associated with genetic heart diseases in a cohort of 31 SIDS cases was performed. To determine the spectrum and prevalence of genetic heart disease associated mutations as a potential monogenic basis for SIDS, a stringent variant classification was applied and the percentage of rare (minor allele frequency ≤ 0.2%) and ultra-rare variants (minor allele frequency ≤ 0.005%) in these genes was assessed. With a minor allele frequency of ≤ 0.005%, about 20% of the SIDS cases exhibited a variant of uncertain significance (VUS), but in only 6% of these cases, gene variants proved to be “potentially informative.” The present study shows the importance of careful variant interpretation. Applying stringent criteria misinterpretations are avoided, as the results of genetic analyses may have an important impact of the family members involved.
We investigate hadronic particle spectra and flow characteristics of heavy-ion reactions in the FAIR/NICA energy range of 1 AGeV ≤ Elab ≤ 10 AGeV within a relativistic ideal hydrodynamic one-fluid approach. The particlization is realized by sampling the Cooper-Frye distribution for a grand canonical hadron gas on a hypersurface of constant energy density. Results of the hydrodynamic calculations for different underlying equations of state are presented and compared with experimental data and microscopic transport simulations. The sensitivity of the approach to physical model inputs concerning the initial state and the particlization is studied.
Verboket, René ; Mühlenfeld, Nils ; Sterz, Jasmina ; Störmann, Philipp ; Marzi, Ingo ; Balcik, Yunus ; Rosenow, Felix ; Strzelczyk, Adam ; Willems, Laurent Maximilian
Hintergrund: Die Analyse krankheitsspezifischer Kosten gewinnt in einem zunehmend ökonomisch ausgerichteten Gesundheitssystem an Relevanz, wobei vor allem chronische Erkrankungen aufgrund der langen Krankheitsdauer sowie häufiger Hospitalisierung und Arztbesuche von besonderem Interesse sind. Epilepsien stellen eine häufige neurologische Erkrankung dar, welche mit paroxysmal auftretenden epileptischen Anfällen und häufig hiermit assoziierten Verletzungen einhergeht und alle Altersgruppen betrifft.
Ziel: Ziel der Arbeit ist die Aufarbeitung der stationären Behandlungskosten anfallsbedingter Verletzungen sowie die Analyse hinsichtlich relevanter kostenverursachender Faktoren. Mittels alternativer Kalkulation der Versorgungskosten soll zusätzlich der Frage nach potenziellen Vergütungsproblemen im aktuellen DRG-System („diagnosis related groups“) nachgegangen werden.
Methoden: Grundlage dieser monozentrischen, retrospektiven Analyse ist der tatsächliche Erlös der stationären Behandlung von 62 Patienten, die zwischen 01/2010 und 01/2018 im Universitätsklinikum Frankfurt aufgrund von Verletzungen im Rahmen epileptischer Anfälle erfolgte. Die Analyse potenzieller kostenverursachender Faktoren bezog sich auf relevante soziodemographische und klinische Aspekte, die alternative Kalkulation der Versorgungskosten wurde mit gängigen gesundheitsökonomischen Methoden durchgeführt.
Ergebnisse: Der mittlere DRG-Erlös betrug 7408 € (±8993 €, Median 5086 €, Spanne 563–44.519 €), die mittleren kalkulierten Kosten 9423 € (±11.113 €, 5626 €, Spanne 587–49.830 €). Als signifikant kostenverursachender Faktor konnte eine Liegedauer ≥7 Tage (p = 0,014) identifiziert werden. Aufgrund des signifikanten Unterschieds (p < 0,001) zwischen Erlös und kalkulierten Kosten erfolgte eine Analyse nach Faktoren für potenzielle Vergütungsprobleme, welche für eine Aufenthaltsdauer von ≥7 Tagen (p = 0,014) sowie für eine Behandlung auf Intensivstation (p = 0,019) signifikant verblieb.
Schlussfolgerung: Die stationären Versorgungskosten von Patienten mit Frakturen aufgrund epileptischer Anfälle sind hoch und daher gesundheitsökonomisch relevant. Generell scheint die auf Fallpauschalen basierende Vergütung nach G‑DRG die tatsächlichen Kosten zu decken, bei Patienten mit einer langen Liegedauer oder einen Aufenthalt auf Intensivstation können jedoch Vergütungsprobleme bestehen.
Purpose: The primary treatment goals for advanced-stage thumb carpometacarpal (CMC) joint osteoarthritis are complete pain relief and restoration of thumb strength. The purpose of the present study was to introduce a variation of the abductor pollicis longus (APL) suspension arthroplasty using a single looping of a radial slip from the APL tendon around the flexor carpi radialis (FCR) tendon combined with RegJoint™ interposition and to determine its efficacy in the treatment of thumb CMC joint osteoarthritis.
Methods: Between 2015 and 2017, 21 patients were included. The average age was 60.8 years (range 48–79). The mean follow-up was 27.7 months (range 8–50). Evaluation included pain, radial and palmar abduction, tip pinch and grip strength, and Disabilities of the Arm, Shoulder, and Hand (DASH) score.
Results: Pain averaged 0.3 (range 0–4) at rest and 1.4 (range 0–4) on exertion. The radial and palmar abduction were 97% and 99% compared to the contralateral side. The tip pinch and grip strength were 4.1 kg (range 3–6.5) and 22 kg (range 13.3–40), respectively. The DASH score accounted for 18.5 (range 0.8–41.7).
Conclusion: The modified APL suspension interposition arthroplasty was an efficient and simplified option for the treatment of thumb CMC joint osteoarthritis, with results comparable or better than other published procedures. The APL suspension technique was easy to perform avoiding difficult bone tunneling and incision of the FCR tendon. The RegJoint™ interposition as spacer prevented impingement of the first metacarpal base on the second metacarpal base or the trapezoid bone.
Developmental loss of ErbB4 in PV interneurons disrupts state-dependent cortical circuit dynamics
(2020)
GABAergic inhibition plays an important role in the establishment and maintenance of cortical circuits during development. Neuregulin 1 (Nrg1) and its interneuron-specific receptor ErbB4 are key elements of a signaling pathway critical for the maturation and proper synaptic connectivity of interneurons. Using conditional deletions of the ERBB4 gene in mice, we tested the role of this signaling pathway at two developmental timepoints in parvalbumin-expressing (PV) interneurons, the largest subpopulation of cortical GABAergic cells. Loss of ErbB4 in PV interneurons during embryonic, but not late postnatal, development leads to alterations in the activity of excitatory and inhibitory cortical neurons, along with severe disruption of cortical temporal organization. These impairments emerge by the end of the second postnatal week, prior to the complete maturation of the PV interneurons themselves. Early loss of ErbB4 in PV interneurons also results in profound dysregulation of excitatory pyramidal neuron dendritic architecture and a redistribution of spine density at the apical dendritic tuft. In association with these deficits, excitatory cortical neurons exhibit normal tuning for sensory inputs, but a loss of state-dependent modulation of the gain of sensory responses. Together these data support a key role for early developmental Nrg1/ErbB4 signaling in PV interneurons as powerful mechanism underlying the maturation of both the inhibitory and excitatory components of cortical circuits.
Von A bis Å. (Fast) alles über die Frankfurter Skandinavistik. Ausgabe 1 ; Wintersemester 2020/21
(2020)
Waard, Antonius A. de ; Verkerk, Tamara ; Jongsma, Marlieke L. M. ; Hoefakker, Kelly ; Sethumadhavan, Sunesh ; Gerke, Carolin ; Bliss, Sophie ; Janssen, George M. C. ; Ru, Arnoud H. de ; Claas, Frans H. J. ; Mulder, Arend ; Tampé, Robert ; Veelen, Peter A. van ; Halenius, Anne ; Spaapen, Robbert M.
With the emergence of immunotherapies, the understanding of functional HLA class I antigen presentation to T cells is more relevant than ever. Current knowledge on antigen presentation is based on decades of research in a wide variety of cell types with varying antigen presentation machinery (APM) expression patterns, proteomes and HLA haplotypes. This diversity complicates the establishment of individual APM contributions to antigen generation, selection and presentation. Therefore, we generated a novel Panel of APM Knockout Cell lines (PAKC) from the same genetic origin. After CRISPR/Cas9 genome-editing of ten individual APM components in a human cell line, we derived clonal cell lines and confirmed their knockout status and phenotype. We then show how PAKC will accelerate research on the functional interplay between APM components and their role in antigen generation and presentation. This will lead to improved understanding of peptide-specific T cell responses in infection, cancer and autoimmunity.
Active efficient coding explains the development of binocular vision and its failure in amblyopia
(2020)
The development of vision during the first months of life is an active process that comprises the learning of appropriate neural representations and the learning of accurate eye movements. While it has long been suspected that the two learning processes are coupled, there is still no widely accepted theoretical framework describing this joint development. Here, we propose a computational model of the development of active binocular vision to fill this gap. The model is based on a formulation of the active efficient coding theory, which proposes that eye movements as well as stimulus encoding are jointly adapted to maximize the overall coding efficiency. Under healthy conditions, the model self-calibrates to perform accurate vergence and accommodation eye movements. It exploits disparity cues to deduce the direction of defocus, which leads to coordinated vergence and accommodation responses. In a simulated anisometropic case, where the refraction power of the two eyes differs, an amblyopia-like state develops in which the foveal region of one eye is suppressed due to inputs from the other eye. After correcting for refractive errors, the model can only reach healthy performance levels if receptive fields are still plastic, in line with findings on a critical period for binocular vision development. Overall, our model offers a unifying conceptual framework for understanding the development of binocular vision.
Salabura, Piotr ; Adamczewski-Musch, Jörn ; Arnoldi-Meadows, Benedict ; Belounnas, Amel ; Belyaev, Alexei V. ; Blanco, Alberto ; Blume, Christoph ; Böhmer, Michael ; Borisenko, S. ; Chlad, Lukáš ; Chudoba, Petr ; Ciepał, Izabela ; Dittert, Dominique ; Dreyer, Jörn ; Esmail, Waleed Ahmed Mohammed ; Dürr, Michael ; Fabbietti, Laura ; Fateev, Oleg ; Fonte, Paulo ; Friese, Jürgen ; Fröhlich, Ingo ; Förtsch, Jörg ; Galatyuk, Tetyana ; Gernhäuser, Roman ; Golosov, Oleg ; Golubeva, Marina ; Greifenhagen, Robert ; Guber, Fedor ; Gumberidze, Malgorzata ; Harabasz, Szymon ; Hensch, Roman ; Höhne, Claudia ; Holzmann, Romain ; Huck, Holger ; Ierusalimov, Alexander P. ; Ivashkin, Alexander ; Kämpfer, Burkhard ; Kampert, Karl-Heinz ; Kardan, Behruz ; Koenig, Ilse ; Koenig, Wolfgang ; Kornakov, Georgy ; Kornas, Frédéric Julian ; Kotte, Roland ; Kozela, Adam ; Kres, Ievgenii ; Kuboś, Joanna ; Kugler, Andrej ; Kulessa, Pawel ; Ladygin, Vladimir P. ; Lalik, Rafał Tomasz ; Lebedev, Alexei ; Lebedev, Semen ; Linev, Serguei ; Lopes, Luis Alberto Vieira ; Lorenz, Manuel ; Lykasov, Gennady ; Mahmoud, Tariq ; Malige, Akshay ; Markert, Jochen ; Matulewicz, Tomasz ; Maurus, Steffen ; Metag, Volker ; Michel, Jan ; Morozov, Sergey ; Müntz, Christian ; Naumann, Lothar ; Nowakowski, Krzysztof ; Otto, Jan-Hendrik ; Patel, Vivek ; Pauly, Christian ; Pechenov, Vladimir ; Pechenova, Olga ; Petukhov, Oleg ; Pfeifer, Dennis ; Piasecki, Krzysztof ; Pietraszko, Jerzy ; Prozorov, Alexandr ; Przygoda, Witold ; Pysz, Krzysztof ; Ramstein, Béatrice ; Rathod, Narendra ; Reshetin, Andrey ; Ritman, James Lambrecht ; Rodríguez Ramos, Pablo ; Rost, Adrian ; Salabura, Piotr ; Scozzi, Federico ; Seck, Florian ; Selyuzhenkov, Ilya ; Shabanov, I. ; Singh, Udai ; Smyrski, Jerzy ; Spies, Simon ; Ströbele, Herbert ; Stroth, Joachim ; Stumm, Julia ; Svoboda, Ondřej ; Szala, Melanie ; Tlustý, Pavel ; Traxler, Michael ; Ungethüm, Carina ; Vázquez Doce, Oton ; Wagner, Vladimir ; Weber, Adrian Amatus ; Wendisch, Christian ; Wiebusch, Michael ; Wintz, Peter ; Wirth, Joana ; Zhilin, Alexander ; Zumbruch, Peter W.
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.
Korn, Sophie ; Dhamotharan, Karthikeyan ; Fürtig, Boris ; Hengesbach, Martin ; Löhr, Frank ; Qureshi, Nusrat ; Richter, Christian ; Saxena, Krishna ; Schwalbe, Harald ; Tants, Jan-Niklas ; Weigand, Julia ; Wöhnert, Jens ; Schlundt, Andreas
The ongoing pandemic caused by the Betacoronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) demonstrates the urgent need of coordinated and rapid research towards inhibitors of the COVID-19 lung disease. The covid19-nmr consortium seeks to support drug development by providing publicly accessible NMR data on the viral RNA elements and proteins. The SARS-CoV-2 genome encodes for approximately 30 proteins, among them are the 16 so-called non-structural proteins (Nsps) of the replication/transcription complex. The 217-kDa large Nsp3 spans one polypeptide chain, but comprises multiple independent, yet functionally related domains including the viral papain-like protease. The Nsp3e sub-moiety contains a putative nucleic acid-binding domain (NAB) with so far unknown function and consensus target sequences, which are conceived to be both viral and host RNAs and DNAs, as well as protein-protein interactions. Its NMR-suitable size renders it an attractive object to study, both for understanding the SARS-CoV-2 architecture and drugability besides the classical virus’ proteases. We here report the near-complete NMR backbone chemical shifts of the putative Nsp3e NAB that reveal the secondary structure and compactness of the domain, and provide a basis for NMR-based investigations towards understanding and interfering with RNA- and small-molecule-binding by Nsp3e.
Piekarski, Florian ; Kaufmann, Jost ; Engelhardt, Thomas ; Raimann, Florian ; Lustenberger, Thomas ; Marzi, Ingo ; Lefering, Rolf ; Zacharowski, Kai ; Meybohm, Patrick
Purpose: Trauma is the leading cause of death in children. In adults, blood transfusion and fluid resuscitation protocols changed resulting in a decrease of morbidity and mortality over the past 2 decades. Here, transfusion and fluid resuscitation practices were analysed in severe injured children in Germany.
Methods: Severely injured children (maximum Abbreviated Injury Scale (AIS) ≥ 3) admitted to a certified trauma-centre (TraumaZentrum DGU®) between 2002 and 2017 and registered at the TraumaRegister DGU® were included and assessed regarding blood transfusion rates and fluid therapy.
Results: 5,118 children (aged 1–15 years) with a mean ISS 22 were analysed. Blood transfusion rates administered until ICU admission decreased from 18% (2002–2005) to 7% (2014–2017). Children who are transfused are increasingly seriously injured. ISS has increased for transfused children aged 1–15 years (2002–2005: mean 27.7–34.4 in 2014–2017). ISS in non-transfused children has decreased in children aged 1–15 years (2002–2005: mean 19.6 to mean 17.6 in 2014–2017). Mean prehospital fluid administration decreased from 980 to 549 ml without affecting hemodynamic instability.
Conclusion: Blood transfusion rates and amount of fluid resuscitation decreased in severe injured children over a 16-year period in Germany. Restrictive blood transfusion and fluid management has become common practice in severe injured children. A prehospital restrictive fluid management strategy in severely injured children is not associated with a worsened hemodynamic state, abnormal coagulation or base excess but leads to higher hemoglobin levels.
Peronospora aquilegiicola is a destructive pathogen of columbines and has wiped out most Aquilegia cultivars in several private and public gardens throughout Britain. The pathogen, which is native to East Asia was noticed in England and Wales in 2013 and quickly spread through the country, probably by infested plants or seeds. To our knowledge, the pathogen has so far not been reported from other parts of Europe. Here, we report the emergence of the pathogen in the northwest of Germany, based on morphological and phylogenetic evidence. As the pathogen was found in a garden in which no new columbines had been planted recently, we assume that the pathogen has already spread from its original point of introduction in Germany. This calls for an increased attention to the further spread of the pathogen and the eradication of infection spots to avoid the spread to naturally occurring columbines in Germany and to prevent another downy mildew from becoming a global threat, like Peronospora belbahrii and Plasmopara destructor, the downy mildews of basil and balsamines, respectively.
Oomycetes infecting diatoms are biotrophic parasitoids and live in both marine and freshwater environments. They are ubiquitous, but the taxonomic affinity of many species remains unclear and the majority of them have not been studied for their molecular phylogeny. Only recently, the phylogenetic and taxonomic placement of some diatom-infecting, early-diverging oomycetes was resolved, including the genera Ectrogella, Miracula, Olpidiopsis, and Pontisma. A group of holocarpic diatom parasitoids with zoospores swarming within the sporangium before release were found to be unrelated to the known genera with diatom-infecting species, and were re-classified to a new genus, Diatomophthora. However, about a dozen species of holocarpic diatom parasitoids with unclear affinity remained unsequenced, which includes a commonly occurring species so far identified as Ectrogella perforans. However, this assignment to Ectrogella is doubtful, as the species was not reported to feature a clear-cut diplanetism, a hallmark of Ectrogella s. str. and the whole class Saprolegniomycetes. It was the aim of the current study to clarify the phylogenetic affinities of the species and if the rather broad host range reported is correct or a reflection of cryptic species. By targeted screening, the parasitoid was rediscovered from Helgoland Roads, North Sea and Oslo Fjord, Southern Norway and investigated for its phylogenetic placement using small ribosomal subunit (18S) sequences. Stages of its life cycle on different marine diatoms were described and its phylogenetic placement in the genus Diatomophthora revealed. A stable host-parasite axenic culture from single spore strains of the parasitoid were established on several strains of Pleurosigma intermedium and Coscinodiscus concinnus. These have been continuously cultivated along with their hosts for more than 2 years, and cultural characteristics are reported. Cross-infection trials revealed the transferability of the strains between hosts under laboratory conditions, despite some genetic distance between the pathogen strains. Thus, we hypothesise that D. perforans might be in the process of active radiation to new host species.
Geoffrey Burnstock will be remembered as the scientist who set up an entirely new field of intercellular communication, signaling via nucleotides. The signaling cascades involved in purinergic signaling include intracellular storage of nucleotides, nucleotide release, extracellular hydrolysis, and the effect of the released compounds or their hydrolysis products on target tissues via specific receptor systems. In this context ectonucleotidases play several roles. They inactivate released and physiologically active nucleotides, produce physiologically active hydrolysis products, and facilitate nucleoside recycling. This review briefly highlights the development of our knowledge of two types of enzymes involved in extracellular nucleotide hydrolysis and thus purinergic signaling, the ectonucleoside triphosphate diphosphohydrolases, and ecto-5′-nucleotidase.
Wenzel, Mike ; Humke, Clara Julia ; Wicker, Sabine ; Mani, Jens ; Engl, Tobias A. ; Hintereder, Gudrun ; Vogl, Thomas J. ; Wild, Peter Johannes ; Köllermann, Jens ; Rödel, Claus ; Asgharie, S. ; Theißen, Lena Hermine ; Welte, Maria-Noemi ; Kluth, Luis ; Mandel, Philipp ; Chun, Felix ; Preißer, Felix Martin ; Becker, Andreas
hintergrund: Männer in Deutschland sterben früher als Frauen und nehmen weniger häufig Krebsvorsorgeuntersuchungen wahr.
Fragestellung: Ziel war die prospektive Evaluation einer „Movember-Gesundheitsinitiative“ am Universitätsklinikum Frankfurt (UKF) im November 2019.
Methoden: Im Rahmen der „Movember-Gesundheitsinitiative“ wurde allen männlichen Mitarbeitern des UKF ab dem 45. Lebensjahr und bei erstgradiger familiärer Vorbelastung eines Prostatakarzinoms ab dem 40. Lebensjahr im November 2019 gemäß S3-Leitlinien der Deutschen Gesellschaft für Urologie (DGU) eine Prostatakarzinom-Vorsorgeuntersuchung angeboten.
Ergebnisse: Insgesamt nahmen 14,4 % der Mitarbeiter teil. Eine familiäre Vorbelastung gaben insgesamt 14,0 % Teilnehmer an. Das mediane Alter betrug 54 Jahre. Der mediane PSA(prostataspezifisches Antigen)-Wert lag bei 0,9 ng/ml, der mediane PSA-Quotient bei 30 %. Bei 5 % (n = 6) zeigte sich ein suspekter Tastbefund in der DRU (digital-rektale Untersuchung). Nach Altersstratifizierung (≤ 50 vs. > 50 Lebensjahre) zeigten sich signifikante Unterschiede im medianen PSA-Wert (0,7 ng/ml vs. 1,0 ng/ml, p < 0,01) und der bereits zuvor durchgeführten urologischen Vorsorge (12,1 vs. 42,0 %, p < 0,01). Vier Teilnehmer (3,3 %) zeigten erhöhte Gesamt-PSA-Werte. Bei 32,2 % der Teilnehmer zeigte sich mindestens ein kontrollbedürftiger Befund. Insgesamt wurden 6 Prostatabiopsien durchgeführt. Hierbei zeigte sich in einem Fall ein intermediate-risk Prostatakarzinom (Gleason 3 + 4, pT3a, pPn1, pNx, R0).
Schlussfolgerungung: Im Rahmen der UKF-Movember-Gesundheitsinitiative 2019 konnten durch ein Vorsorgeangebot 121 Männer für eine Prostatakrebs-Vorsorge inklusive PSA-Testung gewonnen werden. Auffällige/kontrollbedürftige Befunde zeigten sich bei 32,2 %. Bei einem Mitarbeiter wurde ein therapiebedürftiges Prostatakarzinom entdeckt und therapiert.
La creación de audio-podcasts ofrece una excelente oportunidad para representar de forma oral los contenidos de matemáticas usando medios digitales tanto en la formación docente, como en la educación primaria. Sin embargo, en el proceso de creación de los audio- -podcasts hay fases gráficas-escritas y otras orales que están estrechamente vinculadas entre sí. Este artículo trata sobre la creación y utilización de podcast en la educación primaria (PriMaPodcast) y en la formación docente (MathePodcast) tanto para la enseñanza como para la investigación.Mathematics audio-podcasts: communication and representation with ICTLa creación de audio-podcasts ofrece una excelente oportunidad para representar de forma oral los contenidos de matemáticas usando medios digitales tanto en la formación docente, como en la educación primaria. Sin embargo, en el proceso de creación de los audio- -podcasts hay fases gráficas-escritas y otras orales que están estrechamente vinculadas entre sí. Este artículo trata sobre la creación y utilización de podcast en la educación primaria (PriMaPodcast) y en la formación docente (MathePodcast) tanto para la enseñanza como para la investigación.
Frankfurt, Leonid ; Strikman, Mark ; Larionov, Alexei ; Lehrach, Andreas ; Maier, Rudolf ; Hees, Hendrik van ; Spieles, Christian ; Vovchenko, Volodymyr ; Stöcker, Horst
Exciting new scientific opportunities are presented for the PANDA detector at the High Energy Storage Ring in the redefined p¯¯¯p(A) collider mode, HESR-C, at the Facility for Antiproton and Ion Research (FAIR) in Europe. The high luminosity, L∼1031 cm−2 s−1, and a wide range of intermediate and high energies, sNN−−−√ up to 30 GeV for p¯¯¯p(A) collisions will allow to explore a wide range of exciting topics in QCD, including the study of the production of excited open charm and bottom states, nuclear bound states containing heavy (anti)quarks, the interplay of hard and soft physics in the dilepton production, probing short-range correlations in nuclei, and the exploration of the early, complete p¯¯¯-p- annihilation phase, where an initially pure Yang–Mills gluon plasma is formed.
Harth, Simon ; Wagner, Jacqueline ; Sens, Tamina ; Choe, Jun-yong ; Benz, Philipp ; Weuster-Botz, Dirk ; Oreb, Igor-Mislav
D-Galacturonic acid (GalA) is the major constituent of pectin-rich biomass, an abundant and underutilized agricultural byproduct. By one reductive step catalyzed by GalA reductases, GalA is converted to the polyhydroxy acid l-galactonate (GalOA), the first intermediate of the fungal GalA catabolic pathway, which also has interesting properties for potential applications as an additive to nutrients and cosmetics. Previous attempts to establish the production of GalOA or the full GalA catabolic pathway in Saccharomyces cerevisiae proved challenging, presumably due to the inefficient supply of NADPH, the preferred cofactor of GalA reductases. Here, we tested this hypothesis by coupling the reduction of GalA to the oxidation of the sugar alcohol sorbitol that has a higher reduction state compared to glucose and thereby yields the necessary redox cofactors. By choosing a suitable sorbitol dehydrogenase, we designed yeast strains in which the sorbitol metabolism yields a “surplus” of either NADPH or NADH. By biotransformation experiments in controlled bioreactors, we demonstrate a nearly complete conversion of consumed GalA into GalOA and a highly efficient utilization of the co-substrate sorbitol in providing NADPH. Furthermore, we performed structure-guided mutagenesis of GalA reductases to change their cofactor preference from NADPH towards NADH and demonstrated their functionality by the production of GalOA in combination with the NADH-yielding sorbitol metabolism. Moreover, the engineered enzymes enabled a doubling of GalOA yields when glucose was used as a co-substrate. This significantly expands the possibilities for metabolic engineering of GalOA production and valorization of pectin-rich biomass in general.
Mühlenfeld, Nils ; Schindler, Cora ; Sterz, Jasmina ; Thönissen, Philipp Nikolaus ; Störmann, Philipp ; Marzi, Ingo ; Verboket, René
Zuraw, Bruce L. ; Lumry, William R. ; Johnston, Douglas T. ; Aygören-Pürsün, Emel ; Banerji, Aleena ; Bernstein, Jonathan A. ; Christiansen, Sandra C. ; Jacobs, Joshua S. ; Sitz, Karl V. ; Gower, Richard G. ; Gagnon, Remi ; Wedner, H. James ; Kinaciyan, Tamar ; Hakl, Roman ; Hanzlíková, Jana ; Anderson, John T. ; McNeil, Donald L. ; Fritz, Stephen B. ; Yang, William H. ; Tachdjian, Raffi ; Busse, Paula J. ; Craig, Timothy J. ; Li, H. Henry ; Farkas, Henriette ; Best, Jessica M. ; Clemons, Desiree ; Cornpropst, Melanie ; Dobo, Sylvia M. ; Iocca, Heather A. ; Kargl, Deborah ; Nagy, Eniko ; Murray, Sharon C. ; Collis, Phil ; Sheridan, William P. ; Maurer, Marcus ; Riedl, Marc A.
Background: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein in development for the prophylaxis of hereditary angioedema (HAE) attacks.
Objective: Our aim was to determine the efficacy, safety, and tolerability of berotralstat in patients with HAE over a 24-week treatment period (the phase 3 APeX-2 trial).
Methods: APeX-2 was a double-blind, parallel-group study that randomized patients at 40 sites in 11 countries 1:1:1 to receive once-daily berotralstat in a dose of 110 mg or 150 mg or placebo (Clinicaltrials.gov identifier NCT03485911). Patients aged 12 years or older with HAE due to C1 inhibitor deficiency and at least 2 investigator-confirmed HAE attacks in the first 56 days of a prospective run-in period were eligible. The primary efficacy end point was the rate of investigator-confirmed HAE attacks during the 24-week treatment period.
Results: A total of 121 patients were randomized; 120 of them received at least 1 dose of the study drug (n = 41, 40, and 39 in the 110-mg dose of berotralstat, 150-mg of dose berotralstat, and placebo groups, respectively). Berotralstat demonstrated a significant reduction in attack rate at both 110 mg (1.65 attacks per month; P = .024) and 150 mg (1.31 attacks per month; P < .001) relative to placebo (2.35 attacks per month). The most frequent treatment-emergent adverse events that occurred more with berotralstat than with placebo were abdominal pain, vomiting, diarrhea, and back pain. No drug-related serious treatment-emergent adverse events occurred.
Conclusion: Both the 110-mg and 150-mg doses of berotralstat reduced HAE attack rates compared with placebo and were safe and generally well tolerated. The most favorable benefit-to-risk profile was observed at a dose of 150 mg per day.
In welchen Situationen steht ein Tier unter Stress und wie beeinflusst Stress dessen Wohlbefinden? Dies sind die Kernfragen, mit denen Zoos konfrontiert sind, wenn es darum geht, den Bedürfnissen ihrer Tiere gerecht zu werden. Die Beantwortung dieser Fragen ist jedoch angesichts der großen individuellen Variabilität des Inputs, der Stress hervorrufen kann,und des Outputs, der das Wohlbefinden bestimmt, eine Herausforderung. Um diese Herausforderung zu meistern, brauchen Zoos Kenntnisse darüber, welche Haltungsbedingungen und Managementsituationen Verhaltens-, physiologische oder emotionale Veränderungen hervorrufen, sowohl positive als auch negative. Dies trifft insbesondere auf Arten zu, die aufgrund ihrer Biologie und des großen öffentlichen Interesses große Anforderungen an das Management in Menschenobhut stellen, wie den Afrikanischen Elefanten. Die vorliegende Arbeit hatte daher das Ziel, unter Berücksichtigung der individuellen Variation die Auswirkungen bestimmter Managementsituationen auf physiologischen Stress und das Wohlbefinden der Tiere zu evaluieren.
Für diese Arbeit wurden zehn Afrikanische Elefanten aus drei Zoos im Rahmen eines Experiments in 2016 und 2017 mehrmals untersucht. Dieses Experiment umfasste zum einen die Messung von physiologischem Stress auf der Basis der Konzentration des „Stresshormons“ Cortisol im Speichel der Elefanten. Zu diesem Zweck wurden an bestimmten Tagen und zu folgenden Zeitpunkten Speichelproben entnommen: morgens, nachmittags vor und mehrmals nach einer von zwei Managementsituationen (positives Verstärkungstraining [PRT] und neuartiges Enrichmentobjekt [NOV]). Zum anderen diente die Exposition gegenüber dem neuartigen Enrichmentobjekt als sogenannter Novel Object Test. Dieser Standardtest der Persönlichkeitsforschung bei Tieren deckte bei anderen Arten konsistente Verhaltensunterschiede zwischen Individuen auf. Um zu untersuchen, ob dies auch auf Afrikanische Elefanten zutrifft, wurden die individuellen Verhaltensreaktionen auf das neuartige Objekt aufgezeichnet. Darüber hinaus wurden unabhängig von dem Experiment vor und nach einem Transport jeweils morgens und nachmittags Speichelproben von dem transferierten Tier und von zwei Tieren im Bestimmungszoo gesammelt, um den Effekt dieses potenziellen Stressors auf die individuellen Cortisolspiegel zu untersuchen.
Publikation A zeigt, dass die Elefanten unter den Bedingungen des Routinemanagements (das heißt dem routinemäßigen Tagesablauf der Tierpflege) am Morgen signifikant höhere Cortisolwerte im Speichel aufwiesen als am Nachmittag. Diese diurnale Variation der Cortisolsekretion ist typisch für tagaktive Arten und wurde daher auch für die untersuchten Elefanten erwartet. Unter Stressbedingungen wurde weder ein signifikanter Unterschied zwischen den Cortisolspiegeln vor und nach dem Transport noch zwischen den Cortisolwerten am Morgen und am Nachmittag festgestellt. Der prozentuale Unterschied zwischen dem morgendlichen und nachmittäglichen Cortisolspiegel war jedoch beim transferierten Tier nach dem Transport wesentlich geringer als vor dem Transport, was möglicherweise auf eine Stressreaktion auf den Transport und die Eingewöhnung im neuen Zoo hindeutet. Darüber hinaus zeigten sich deutliche Cortisolanstiege unmittelbar nach der ersten Zusammenführung des transferierten Tiers mit dem Bullen im neuen Zoo. Dieses Ergebnis demonstriert zum einen, dass Cortisol physiologischen Stress widerspiegelt. Zum anderen zeigt es die Notwendigkeit, zeitnah nach einem Stressor Speichelproben zu entnehmen, was nach dem Transport nicht möglich war.
Die Studie in Manuskript B zeigt unterschiedliche durchschnittliche Zeitverläufe der Cortisolantworten im Speichel auf die Managementsituationen PRT und NOV. PRT könnte aufgrund des beobachteten cortisolsenkenden und damit potenziell stresspuffernden Effekts förderlich für das Wohlbefinden sein. NOV induzierte im Mittel eine moderate, kurzfristige Cortisolantwort. Dies deutet darauf hin, dass die Tiere geringem physiologischem Stress ausgesetzt waren, mit dem sie jedoch erfolgreich umgehen konnten. Außerdem bestand eine bemerkenswerte individuelle Variation in den Cortisolverläufen in derselben Situation. Die Unterschiede im Cortisolspiegel zwischen den Tieren hingen mit dem Alter (bei NOV) und dem Zoo (bei PRT) zusammen. Der Effekt des Geschlechts und des Haltungssystems auf den Cortisolspiegel war hingegen variabel. Die Ergebnisse der Studie zeigen, dass die individuelle Variation der Cortisolsekretion unbedingt berücksichtigt werden muss, um physiologischen Stress zuverlässig zu erkennen.
Die Studie in Manuskript C ergab, dass sich die untersuchten Tiere im Novel Object Test konsistent in ihrem Verhalten gegenüber einem neuartigen Objekt unterschieden. Dieses Ergebnis zeigt, dass der Novel Object Test auch bei Elefanten genutzt werden kann, um die Persönlichkeit der Tiere zu untersuchen...
Barbagallo, Massimo ; Aberle, Oliver ; Alcayne, Victor ; Amaducci, Simone ; Andrzejewski, Józef ; Audouin, Laurent ; Babiano Suarez, Victor ; Bacak, Michael ; Bennett, Samuel ; Berthoumieux, Eric ; Bosnar, Damir ; Brown, Adam S. ; Busso, Maurizio ; Caamaño, Manuel ; Caballero Ontanaya, Luis ; Calviani, Marco ; Calviño Tavares, Francisco ; Cano-Ott, Daniel ; Casanovas Hoste, Adrià ; Cerutti, Francesco ; Chiaveri, Enrico ; Colonna, Nicola ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Cosentino, Luigi ; Cristallo, Sergio ; Damone, Lucia Anna ; Davies, Paul John ; Diakaki, Maria ; Dietz, Mirco ; Domingo-Pardo, César ; Dressler, Rugard ; Ducasse, Quentin ; Dupont, Emmeric ; Durán, Ignacio ; Eleme, Zinovia ; Fernández Domínguez, Beatriz ; Ferrari, Alfredo ; Gonçalves, Isabel Maria Ferro ; Finocchiaro, Paolo ; Furman, Valter ; Garg, Ruchi ; Gawlik, Aleksandra ; Gilardoni, Simone ; Göbel, Kathrin ; González Romero, Enrique Miguel ; Guerrero Sánchez, Carlos ; Gunsing, Frank ; Heinitz, Stephan ; Heyse, Jan ; Jenkins, David ; Jericha, Erwin ; Jiri, U. ; Junghans, Arnd Rudolf ; Kadi, Yacine ; Käppeler, Franz ; Kimura, Atsushi ; Knapová, Ingrid ; Kokkoris, Michael ; Kopatch, Yuri N. ; Krtička, Milan ; Kurtulgil, Cem Deniz ; Ladarescu, Ion ; Lederer-Woods, Claudia ; Lerendegui-Marco, Jorge ; Lonsdale, Sarah-Jane ; Macina, Daniela ; Manna, Alice ; Martı́nez, Trinitario ; Masi, Alessandro ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Maugeri, Emilio Andrea ; Mazzone, Annamaria ; Mendoza Cembranos, Emilio ; Mengoni, Alberto ; Michalopoulou, Veatriki ; Milazzo, Paolo Maria ; Millán Callado, María de los Ángeles ; Mingrone, Federica ; Moreno-Soto, Javier ; Musumarra, Agatino ; Negret, Alexandru ; Ogállar Ruiz, Francisco ; Oprea, Andreea ; Patronis, Nikolas ; Pavlik, Andreas ; Perkowski, Jarosław ; Petrone, Cristina ; Piersanti, Luciano ; Pirovano, Elisa ; Porras Sánchez, José Ignacio ; Praena, Javier ; Quesada Molina, José Manuel ; Ramos Doval, Diego ; Reifarth, René ; Rochman, Dimitri ; Rubbia, Carlo ; Sabaté- Gilarte, M. ; Saxena, Alok ; Schillebeeckx, Peter ; Schumann, Dorothea ; Sekhar, Adhitya ; Smith, Alastair Gavin ; Sosnin, Nikolay V. ; Sprung, Peter ; Stamatopoulos, Athanasios ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tarifeño-Saldivia, Ariel ; Tassan-Got, Laurent ; Thomas, Benedikt ; Torres-Sánchez, Pablo ; Tsinganis, Andrea ; Urlaß, Sebastian ; Valenta, Stanislav ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Vescovi, Diego ; Vlachoudis, Vasilis ; Vlastou, Rosa ; Wallner, Anton ; Woods, Philip John ; Wright, Tobias J. ; Žugec, Petar
Although the 12C(n,p)12B and 12C(n,d)11B reactions are of interest in several fields of basic and applied Nuclear Physics the present knowledge of these two cross-sections is far from being accurate and reliable, with both evaluations and data showing sizable discrepancies. As part of the challenging n_TOF program on (n,cp) nuclear reactions study, the energy differential cross-sections of the 12C(n,p)12B and 12C(n,d)11 B reactions have been measured at CERN from the reaction thresholds up to 30 MeV neutron energy. Both measurements have been recently performed at the long flight-path (185 m) experimental area of the n_TOF facility at CERN using a pure (99.95%) rigid graphite target and two silicon telescopes. In this paper an overview of the experiment is presented together with a few preliminary results.
Babiano Suarez, Victor ; Lerendegui-Marco, Jorge ; Balibrea Correa, Javier ; Caballero Ontanaya, Luis ; Calvo, David ; Ladarescu, Ion ; Domingo-Pardo, César ; Calviño Tavares, Francisco ; Casanovas Hoste, Adrià ; Tarifeño-Saldivia, Ariel ; Alcayne, Victor ; Guerrero Sánchez, Carlos ; Millán Callado, María de los Ángeles ; Rodrı́guez-González, María Teresa ; Barbagallo, Massimo ; Aberle, Oliver ; Amaducci, Simone ; Andrzejewski, Józef ; Audouin, Laurent ; Bacak, Michael ; Bennett, Samuel ; Berthoumieux, Eric ; Billowes, Jonathan ; Bosnar, Damir ; Brown, Adam ; Busso, Maurizio ; Caamaño, Manuel ; Calviani, Marco ; Cano-Ott, Daniel ; Cerutti, Francesco ; Chiaveri, Enrico ; Colonna, Nicola ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Cosentino, Luigi ; Cristallo, Sergio ; Damone, Lucia Anna ; Davies, Paul John ; Diakaki, Maria ; Dietz, Mirco ; Dressler, Rugard ; Ducasse, Quentin ; Dupont, Emmeric ; Durán, Ignacio ; Eleme, Zinovia ; Fernández Domínguez, Beatriz ; Ferrari, Alfredo ; Finocchiaro, Paolo ; Furman, Valter ; Göbel, Kathrin ; Garg, Ruchi ; Gawlik, Aleksandra ; Gilardoni, Simone ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Gunsing, Frank ; Harada, Hideo ; Heinitz, Stephan ; Heyse, Jan ; Jenkins, David ; Junghans, Arnd Rudolf ; Käppeler, Franz ; Kadi, Yacine ; Kimura, Atsushi ; Knapova, Ingrid ; Kokkoris, Michael ; Kopatch, Yuri N. ; Krtička, Milan ; Kurtulgil, Cem Deniz ; Lederer-Woods, Claudia ; Leeb, Helmut ; Lonsdale, Sarah Jane ; Macina, Daniela ; Manna, Alice ; Martinez, Trinitario ; Masi, Alessandro ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Maugeri, Emilio Andrea ; Mazzone, Annamaria ; Mendoza Cembranos, Emilio ; Mengoni, Alberto ; Michalopoulou, Veatriki ; Milazzo, Paolo Maria ; Mingrone, Federica ; Moreno-Soto, Javier ; Musumarra, Agatino ; Negret, Alexandru ; Ogállar Ruiz, Francisco ; Oprea, Andreea ; Patronis, Nikolas ; Pavlik, Andreas ; Perkowski, Jarosław ; Piersanti, Luciano ; Petrone, Cristina ; Pirovano, Elisa ; Porras Sánchez, José Ignacio ; Praena, Javier ; Quesada Molina, José Manuel ; Ramos Doval, Diego ; Rauscher, Thomas ; Reifarth, René ; Rochman, Dimitri ; Rubbia, Carlo ; Sabaté-Gilarte, Marta ; Saxena, Alok ; Schillebeeckx, Peter ; Schumann, Dorothea ; Sekhar, Adhitya ; Smith, Alastair Gavin ; Sosnin, Nikolay V. ; Sprung, Peter ; Stamatopoulos, Athanasios ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tassan-Got, Laurent ; Thomas, Th. ; Torres-Sánchez, Pablo ; Tsinganis, Andrea ; Ulrich, Jiri ; Urlaß, Sebastian ; Valenta, Stanislav ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Vescovi, Diego ; Vlachoudis, Vasilis ; Vlastou, Rosa ; Wallner, Anton ; Woods, Philip John ; Wright, Tobias ; Žugec, Petar
i-TED is an innovative detection system which exploits Compton imaging techniques to achieve a superior signal-to-background ratio in (n,γ) cross-section measurements using time-of-flight technique. This work presents the first experimental validation of the i-TED apparatus for high-resolution time-of-flight experiments and demonstrates for the first time the concept proposed for background rejection. To this aim both 197Au(n,γ) and 56Fe(n,γ) reactions were measured at CERN n\_TOF using an i-TED demonstrator based on only three position-sensitive detectors. Two \cds detectors were also used to benchmark the performance of i-TED. The i-TED prototype built for this study shows a factor of ∼3 higher detection sensitivity than state-of-the-art \cds detectors in the ∼10~keV neutron energy range of astrophysical interest. This paper explores also the perspectives of further enhancement in performance attainable with the final i-TED array consisting of twenty position-sensitive detectors and new analysis methodologies based on Machine-Learning techniques.
Malkomes, Patrizia ; Edmaier, Franziska ; Liese, Juliane ; Reinisch-Liese, Alexander ; Youzouri, Hanan el ; Schreckenbach, Teresa ; Bucher, Andreas M. ; Bechstein, Wolf Otto ; Schnitzbauer, Andreas
Purpose: The management of patients with suspected appendicitis remains a challenge in daily clinical practice, and the optimal management algorithm is still being debated. Negative appendectomy rates (NAR) continue to range between 10 and 15%. This prospective study evaluated the accuracy of a diagnostic pathway in acute appendicitis using clinical risk stratification (Alvarado score), routine ultrasonography, gynecology consult for females, and selected CT after clinical reassessment.
Methods: Patients presenting with suspected appendicitis between November 2015 and September 2017 from age 18 years and above were included. Decision-making followed a clear management pathway. Patients were followed up for 6 months after discharge. The hypothesis was that the algorithm can reduce the NAR to a value of under 10%.
Results: A total of 183 patients were included. In 65 of 69 appendectomies, acute appendicitis was confirmed by histopathology, corresponding to a NAR of 5.8%. Notably, all 4 NAR appendectomies had other pathologies of the appendix. The perforation rate was 24.6%. Only 36 patients (19.7%) received a CT scan. The follow-up rate after 30 days achieved 69%, including no patients with missed appendicitis. The sensitivity and specificity of the diagnostic pathway was 100% and 96.6%, respectively. The potential saving in costs can be as much as 19.8 million €/100,000 cases presenting with the suspicion of appendicitis.
Conclusion: The risk-stratified diagnostic algorithm yields a high diagnostic accuracy for patients with suspicion of appendicitis. Its implementation can safely reduce the NAR, simultaneously minimizing the use of CT scans and optimizing healthcare-related costs in the treatment of acute appendicitis.
We have designed and implemented an experimental module in the 2014 Health and Retirement Study to measure older persons' willingness to defer claiming of Social Security benefits. Under the current system’ status quo where delaying claiming boosts eventual benefits, we show that 46% of the respondents would delay claiming and work longer. If respondents were instead offered an actuarially fair lump sum payment instead of higher lifelong benefits, about 56% indicate they would delay claiming. Without a work requirement, the average amount needed to induce delayed claiming is only $60,400, while when part-time work is stipulated, the amount is slightly higher, $66,700. This small difference implies a low utility value of leisure foregone, of under 20% of average household income.
The modern tontine : an innovative instrument for longevity risk management in an aging society
(2020)
We investigate whether a historical pension concept, the tontine, yields enough innovative potential to extend and improve the prevailing privately funded pension solutions in a modern way. The tontine basically generates an age-increasing cash flow, which can help to match the increasing financing needs at old ages. In contrast to traditional pension products, however, the tontine generates volatile cash flows, which means that the insurance character of the tontine cannot be guaranteed in every situation. By employing Multi Cumulative Prospect Theory (MCPT) we answer the question to what extent tontines can be a complement to or a substitute for traditional annuities. We find that it is only optimal to invest in tontines for a certain range of initial wealth. In addition, we investigate in how far the tontine size, the volatility of individual liquidity needs and expected mortality rates contribute to the demand for tontines.
Seiler, Alexander ; Brandhofe, Annemarie ; Gracien, René-Maxime ; Pfeilschifter, Waltraud ; Hattingen, Elke ; Deichmann, Ralf ; Nöth, Ulrike ; Wagner, Marlies
Purpose: To investigate cortical thickness and cortical quantitative T2 values as imaging markers of microstructural tissue damage in patients with unilateral high-grade internal carotid artery occlusive disease (ICAOD).
Methods: A total of 22 patients with ≥70% stenosis (mean age 64.8 years) and 20 older healthy control subjects (mean age 70.8 years) underwent structural magnetic resonance imaging (MRI) and high-resolution quantitative (q)T2 mapping. Generalized linear mixed models (GLMM) controlling for age and white matter lesion volume were employed to investigate the effect of ICAOD on imaging parameters of cortical microstructural integrity in multivariate analyses.
Results: There was a significant main effect (p < 0.05) of the group (patients/controls) on both cortical thickness and cortical qT2 values with cortical thinning and increased cortical qT2 in patients compared to controls, irrespective of the hemisphere. The presence of upstream carotid stenosis had a significant main effect on cortical qT2 values (p = 0.01) leading to increased qT2 in the poststenotic hemisphere, which was not found for cortical thickness. The GLMM showed that in general cortical thickness was decreased and cortical qT2 values were increased with increasing age (p < 0.05).
Conclusion: Unilateral high-grade carotid occlusive disease is associated with widespread cortical thinning and prolongation of cortical qT2, presumably reflecting hypoperfusion-related microstructural cortical damage similar to accelerated aging of the cerebral cortex. Cortical thinning and increase of cortical qT2 seem to reflect different aspects and different pathophysiological states of cortical degeneration. Quantitative T2 mapping might be a sensitive imaging biomarker for early cortical microstructural damage.
Determination of the effective dose of bone marrow mononuclear cell therapy for bone healing in vivo
(2020)
Janko, Maren Carina ; Pöllinger, Sabrina ; Schaible, Alexander ; Bellen, Marlene ; Schröder, Katrin ; Heilani, Myriam Widad ; Fremdling, Charlotte ; Marzi, Ingo ; Nau, Christoph Heinrich Eugen ; Henrich, Dirk ; Verboket, René
Introduction: Cell-based therapy by bone marrow mononuclear cells (BMC) in a large-sized bone defect has already shown improved vascularization and new bone formation. First clinical trials are already being conducted. BMC were isolated from bone marrow aspirate and given back to patients in combination with a scaffold within some hours. However, the optimal concentration of BMC has not yet been determined for bone healing. With this study, we want to determine the optimal dosage of the BMC in the bone defect to support bone healing.
Material and methods: Scaffolds with increasing BMC concentrations were inserted into a 5 mm femoral defect, cell concentrations of 2 × 106 BMC/mL, 1 × 107 BMC/mL and 2 × 107 BMC/mL were used. Based on the initial cell number used to colonize the scaffolds, the groups are designated 1 × 106, 5 × 106 and 1 × 107 group. Bone healing was assessed biomechanically, radiologically (µCT), and histologically after 8 weeks healing time.
Results: Improved bone healing parameters were noted in the 1 × 106 and 5 × 106 BMC groups. A significantly higher BMD was observed in the 1 × 106 BMC group compared to the other groups. Histologically, a significantly increased bone growth in the defect area was observed in group 5 × 106 BMC. This finding could be supported radiologically.
Conclusion: It was shown that the effective dose of BMC for bone defect healing ranges from 2 × 106 BMC/mL to 1 × 107 BMC/mL. This concentration range seems to be the therapeutic window for BMC-supported therapy of large bone defects. However, further studies are necessary to clarify the exact BMC-dose dependent mechanisms of bone defect healing and to determine the therapeutically effective range more precisely.
The Brachybasidiaceae are a family of 22 known species of plant-parasitic microfungi belonging to Exobasidiales, Basidiomycota. Within this family, species of the largest genus Kordyana develop balls of basidia on top of stomatal openings. Basidial cells originate from fungal stroma filling substomatal chambers. Species of Kordyana typically infect species of Commelinaceae. During fieldwork in the neotropics, fungi morphologically similar to Kordyana spp. were found on Goeppertia spp. (syn. Calathea spp., Marantaceae), namely on G. panamensis in Panama and on G. propinqua in Bolivia. These specimens are proposed as representatives of a genus new to science, Marantokordyana, based on the distinct host family and molecular sequence data of ITS and LSU rDNA regions. The specimens on the two host species represent two species new to science, M. oberwinkleriana on G. panamensis and M. boliviana on G. propinqua. They differ by the size and shape of their basidia, molecular sequence data of ITS and LSU rDNA regions, and host plant species. In the past, the understanding of Brachybasidiaceae at order and family level was significantly improved by investigation realized by Franz Oberwinkler and his collaborators at the University of Tübingen, Germany. On species level, however, our knowledge is still very poor due to incomplete species descriptions of several existing names in literature, scarceness of specimens, as well as sequence data lacking for many taxa and for further barcode regions. Especially species of Kordyana and species of Dicellomyces are in need of revision.
Sreeramulu, Sridhar ; Richter, Christian ; Kühn, Till ; Azzaoui, Kamal ; Blommers, Marcel Jules José ; Del Conte, Rebecca ; Fragai, Marco ; Trieloff, Nils ; Schmieder, Peter ; Nazaré, Marc ; Specker, Edgar ; Ivanov, Vladimir ; Oschkinat, Hartmut ; Banci, Lucia ; Schwalbe, Harald
Fragment-based screening has evolved as a remarkable approach within the drug discovery process both in the industry and academia. Fragment screening has become a more structure-based approach to inhibitor development, but also towards development of pathway-specific clinical probes. However, it is often witnessed that the availability, immediate and long-term, of a high quality fragment-screening library is still beyond the reach of most academic laboratories. Within iNEXT (Infrastructure for NMR, EM and X-rays for Translational research), a EU-funded Horizon 2020 program, a collection of 782 fragments were assembled utilizing the concept of “poised fragments” with the aim to facilitate downstream synthesis of ligands with high affinity by fragment ligation. Herein, we describe the analytical procedure to assess the quality of this purchased and assembled fragment library by NMR spectroscopy. This quality assessment requires buffer solubility screening, comparison with LC/MS quality control and is supported by state-of-the-art software for high throughput data acquisition and on-the-fly data analysis. Results from the analysis of the library are presented as a prototype of fragment progression through the quality control process.
Schiweck, Carmen ; Claes, Stephan ; Oudenhove, Lukas van ; Lafit, Ginette ; Vaessen, Thomas ; Beeck, Gommaar op de ; Berghmans, Raf ; Wijkhuijs, Annemarie ; Müller, Norbert ; Arolt, Volker ; Drexhage, Hemmo ; Vrieze, Elske
Circulating monocytes contribute to inflammatory processes. We here validate abnormal expression of inflammation-related genes in monocytes of a large and well-characterised group of MDD patients, and relate the outcomes to pertinent clinical characteristics. Thirty-two genes of a previously established inflammation-related gene signature were assessed in 197 patients with MDD, and 151 controls collected during the EU-MOODINFLAME project. Monocyte gene- expression data were related to age, sex, BMI, depression severity, childhood adversity (CA) and suicide risk (SR). Three distinct gene profiles were identified within the MDD group (downregulated, mixed upregulated and strongly upregulated genes). Patients in the merged upregulated groups had a significantly higher prevalence of CA and high SR. Using hierarchical clustering of the genes, we found a cluster of mainly cytokine (production)-related genes; patients with SR had a significantly higher expression of this cluster than patients without SR (particularly for IL-6, IL1A and IL1B). Such difference did not emerge for patients with and without CA. A downregulated gene profile was found for patients not exposed to CA and without SR (particularly for glucocorticoid-signalling genes NR3C1a and HSPA1/B). No inflammatory changes were observed for healthy controls exposed to CA. Our data show that inflammatory activation in MDD is not uniform, and that immunologically discernible phenotypes of depression can be linked to CA and high SR. The absence of monocyte inflammatory activation in healthy controls exposed to CA suggests an inflammatory involvement in MDD-prone individuals exposed to early stressors, but not healthy controls.
Wölke, Sandra ; Donath, Helena ; Theis, Marius ; Kieslich, Matthias ; Auburger, Georg ; Schubert, Ralf ; Schrewe, Roland ; Zielen, Stefan ; Dücker, Ruth Pia
Ataxia telangiectasia (A-T) is a devastating multi-system disorder characterized by progressive cerebellar ataxia and immunodeficiency. The neurological decline may be caused by multiple factors of which ongoing inflammation and oxidative stress may play a dominant role. The objective of the present investigation was to determine cerebrospinal fluid (CSF) proteins and possible low-grade inflammation and its relation to age and neurological deterioration. In the present study, we investigated 15 patients with A-T from 2 to 16 years. Our investigation included blood and CSF tests, clinical neurological examination, A-T score, and MRI findings. The albumin ratio (AR) was analyzed to determine the blood–brain-barrier function. In addition, inflammatory cytokines (IL-1α, IL-6, IL-8, IL-12 p40, IL-17A, IFN-γ, TNF-α) were measured by the multiplex cytometric bead array. We compared the results with those from an age-matched control group. Three of the A-T patients were analyzed separately (one after resection of a cerebral meningioma, one after radiation and chemotherapy due to leukemia, one after stem cell transplantation). Patient had significantly more moderate and severe side effects due to CSF puncture (vomiting, headache, need for anti-emetic drugs) compared with healthy controls. Total protein, albumin, and the AR increased with age indicating a disturbed blood barrier function in older children. There were no differences for cytokines in serum and CSF with the exception of IL-2, which was significantly higher in controls in serum. The AR is significantly altered in A-T patients, but low-grade inflammation is not detectable in serum and CSF.
Batarfi, AbdulAziz ; Alenezi, Haitham ; Alshehri, Abdulrahman ; Balelah, Saud ; Kazim, Hameedullah ; Algthami, Mohammed ; Hussain, Mariam M. ; Alshehri, Nada ; Alsharif, Rahaf ; Ashour, Hadeel ; Althobaiti, Mutaz ; Alotaibi, Shomokh ; Steinmetz, Helmuth ; Förch, Christian
Fasting Ramadan is known to influence patients’ medication adherence. Data on patients’ behavior to oral anticoagulant (OAC) drug intake during Ramadan is missing. We aimed to determine patient-guided modifications of OAC medication regimen during Ramadan and to evaluate its consequences. A multicenter cross-sectional study conducted in Saudi Arabia. Data were collected shortly after Ramadan 2019. Participants were patients who fasted Ramadan and who were on long-term anticoagulation. Patient-guided medication changes during Ramadan in comparison to the regular intake schedule before Ramadan were recorded. Modification behavior was compared between twice daily (BID) and once daily (QD) treatment regimens. Rates of hospital admission during Ramadan were determined. We included 808 patients. During Ramadan, 53.1% modified their intake schedule (31.1% adjusted intake time, 13.2% skipped intakes, 2.2% took double dosing). A higher frequency of patient-guided modification was observed in patients on BID regimen compared to QD regimen. During Ramadan, 11.3% of patients were admitted to hospital. Patient-guided modification was a strong predictor for hospital admission. Patient-guided modification of OAC intake during Ramadan is common, particularly in patients on BID regimen. It increases the risk of hospital admission during Ramadan. Planning of OAC intake during Ramadan and patient education on the risk of low adherence are advisable.
Frey, Katharina ; Zöllner, Johann Philipp ; Knake, Susanne ; Oganian, Yulia ; Kay, Lara ; Mahr, Katharina Brigitte ; Keil, Fee ; Willems, Laurent Maximilian ; Menzler, Katja ; Bauer, Sebastian ; Schubert-Bast, Susanne ; Rosenow, Felix ; Strzelczyk, Adam
Objective: To evaluate the incidence and risk factors of generalized convulsive seizure (GCS)-related fractures and injuries during video-EEG monitoring.
Methods: We analyzed all GCSs in patients undergoing video-EEG-monitoring between 2007 and 2019 at epilepsy centers in Frankfurt and Marburg in relation to injuries, falls and accidents associated with GCSs. Data were gathered using video material, EEG material, and a standardized reporting form.
Results: A total of 626 GCSs from 411 patients (mean age: 33.6 years; range 3–74 years; 45.0% female) were analyzed. Severe adverse events (SAEs) such as fractures, joint luxation, corneal erosion, and teeth loosening were observed in 13 patients resulting in a risk of 2.1% per GCS (95% CI 1.2–3.4%) and 3.2% per patient (95% CI 1.8–5.2%). Except for a nasal fracture due to a fall onto the face, no SAEs were caused by falls, and all occurred in patients lying in bed without evidence of external trauma. In seven patients, vertebral body compression fractures were confirmed by imaging. This resulted in a risk of 1.1% per GCS (95% CI 0.5–2.2%) and 1.7% per patient (95% CI 0.8–3.3%). These fractures occurred within the tonic phase of a GCS and were accompanied by a characteristic cracking noise. All affected patients reported back pain spontaneously, and an increase in pain on percussion of the affected spine section.
Conclusions: GCSs are associated with a substantial risk of fractures and shoulder dislocations that are not associated with falls. GCSs accompanied by audible cracking, and resulting in back pain, should prompt clinical and imaging evaluations.
Sawicki, Olga Anastasia ; Müller, Angelina ; Glushan, Anastasiya ; Breitkreuz, Thorben ; Wicke, Felix Sebastin ; Karimova, Kateryna ; Gerlach, Ferdinand M. ; Wensing, Michel ; Smetak, Norbert ; Bosch, Ralph Frank ; Beyer, Martin
Since 2010, an intensified ambulatory cardiology care programme has been implemented in southern Germany. To improve patient management, the structure of cardiac disease management was improved, guideline-recommended care was supported, new ambulatory medical services and a morbidity-adapted reimbursement system were set up. Our aim was to determine the effects of this programme on the mortality and hospitalisation of enrolled patients with cardiac disorders. We conducted a comparative observational study in 2015 and 2016, based on insurance claims data. Overall, 13,404 enrolled patients with chronic heart failure (CHF) and 19,537 with coronary artery disease (CAD) were compared, respectively, to 8,776 and 16,696 patients that were receiving usual ambulatory cardiology care. Compared to the control group, patients enrolled in the programme had lower mortality (Hazard Ratio: 0.84; 95% CI: 0.77–0.91) and fewer all-cause hospitalisations (Rate Ratio: 0.94; 95% CI: 0.90–0.97). CHF-related hospitalisations in patients with CHF were also reduced (Rate Ratio: 0.76; 95% CI: 0.69–0.84). CAD patients showed a similar reduction in mortality rates (Hazard Ratio: 0.81; 95% CI: 0.76–0.88) and all-cause hospitalisation (Rate Ratio: 0.94; 95% CI: 0.91–0.97), but there was no effect on CAD-related hospitalisation. We conclude that intensified ambulatory care reduced mortality and hospitalisation in cardiology patients.
Recent research on the dynamics between attentional and memory processes have outlined the idea that applying control in a conflicting situation directly leads to enhanced episodic memory of the processed information. However, in spite of a small subset of studies supporting this claim, the majority of the evidence in the field seems to support the opposite pattern. In this study, we used a face–word Stroop task to enforce different control modes either from trial to trial or in an item-specific manner. Both manipulations of congruency proved to be effective in making participants’ responses to conflicting stimuli more efficient over time by applying a trial-specific control mode. However, these manipulations had no impact on memory performance on a surprise recognition memory test. To our knowledge, this is the first attempt at measuring the memory consequences of the application of specific control modes at the trial level. The results reported here call for caution and possibly reconceptualization of the relationship between cognitive control and memory.
Deuker, Marina ; Rührup, Jessica ; Karakiewicz, Pierre I. ; Welte, Maria-Noemi ; Kluth, Luis ; Banek, Séverine ; Roos, Frederik ; Mandel, Philipp ; Chun, Felix ; Becker, Andreas
Purpose: We evaluated efficacy and safety profile of patients with anticoagulation therapy (AT) undergoing holmium laser enucleation of the prostate (HoLEP).
Methods: Within our prospective institutional database (11/2017 to 11/2019), we analyzed functional outcomes and 30-day complication rates of HoLEP patients according to Clavien–Dindo classification (CLD), stratified according to specific AT vs. no AT. Further analyses consisted of uni- and multivariate logistic regression models (LRM) predicting complications.
Results: Of 268 patients undergoing HoLEP, 104 (38.8%) received AT: 25.7% were treated with platelet aggregation inhibitors (PAI), 8.2% with new oral anticoagulants (NOAC) and 4.9% with AT-combinations or coumarins bridged with low molecular weight heparins (LMWH/combination). Patients receiving AT were significantly more comorbid (p < 0.01). Pre- and postoperative maximal flow rates, residual void urine and IPSS at 3 months after surgery were invariably improved after HoLEP for patients with/ without AT. Overall complication rate was 19.5% in patients with no AT vs. 26.1% vs. 27.3 vs. 46.2%, respectively, in patients with PAI, NOAC and LMWH/combination (p < 0.01). Major complications (CLD ≥ 3b) occurred in 6.1% of no AT patients vs. 4.3% vs. 4.5 vs. 0% in patients with PAI, NOAC and LMWH/combination, respectively (p < 0.01). In multivariate LRM, AT was not significantly associated with higher complication rates, whereas high ASA status (OR 2.2, p = 0.04), age (OR 1.04, p = 0.02) and bioptical or incidental prostate cancer (OR 2.5, p = 0.01) represented independent risk factors.
Conclusion: Despite higher overall complication rates in AT patients, major complications were not more frequent in AT patients. HoLEP is safe and effective in anticoagulated patients.
Oo, James A. ; Irmer, Barnabas ; Günther, Stefan ; Warwick, Timothy ; Pálfi, Katalin ; Izquierdo Ponce, Judit ; Teichmann, Tom ; Pflüger-Müller, Beatrice ; Gilsbach, Ralf ; Brandes, Ralf ; Leisegang, Matthias
Zinc finger proteins (ZNF) are a large group of transcription factors with diverse functions. We recently discovered that endothelial cells harbour a specific mechanism to limit the action of ZNF354C, whose function in endothelial cells is unknown. Given that ZNF354C has so far only been studied in bone and tumour, its function was determined in endothelial cells. ZNF354C is expressed in vascular cells and localises to the nucleus and cytoplasm. Overexpression of ZNF354C in human endothelial cells results in a marked inhibition of endothelial sprouting. RNA-sequencing of human microvascular endothelial cells with and without overexpression of ZNF354C revealed that the protein is a potent transcriptional repressor. ZNF354C contains an active KRAB domain which mediates this suppression as shown by mutagenesis analysis. ZNF354C interacts with dsDNA, TRIM28 and histones, as observed by proximity ligation and immunoprecipitation. Moreover, chromatin immunoprecipitation revealed that the ZNF binds to specific endothelial-relevant target-gene promoters. ZNF354C suppresses these genes as shown by CRISPR/Cas knockout and RNAi. Inhibition of endothelial sprouting by ZNF354C is dependent on the amino acids DV and MLE of the KRAB domain. These results demonstrate that ZNF354C is a repressive transcription factor which acts through a KRAB domain to inhibit endothelial angiogenic sprouting.
Eickholz, Peter ; Schröder, Mario Pascal ; Asendorf, Anne ; Schacher, Beate ; Oremek, Gerhard ; Kaiser, Frank ; Wohlfeil, Martin ; Nibali, Luigi
Aim: Assessment of the effect of nonsurgical periodontal therapy on haematological parameters in patients with grades B (BP) and C periodontitis (CP).
Methods: Eight BP and 46 CP patients received full-mouth periodontal debridement within 48 h, if positive for Aggregatibacter actinomycetemcomitans with adjunctive systemic antibiotics (4 BP, 17 CP). Clinical data were collected prior and 12 weeks after periodontal therapy. Blood was sampled prior to and 1 day as well as 6 and 12 weeks after the first SD visit. Erythrocyte count, haemoglobin value, haematocrit (HCT), mean erythrocyte volume (MCV), mean corpuscular haemoglobin (MCH), MCH concentration (MCHC), platelets (PLT) and heat shock protein 27 (Hsp27) were assessed.
Results: Both groups showed significant clinical improvement (p < 0.05). Using univariate analysis, MCV was noticeably lower in CP than BP at all examinations, HCT only at baseline. For CP, MCHC was noticeably higher 12 weeks after SD than at baseline and 1 day (p ≤ 0.005) and Hsp27 increased noticeably at 1 day (p < 0.05). Repeated measures analysis of variance revealed African origin to be associated with lower MCV and female sex with lower MCHC.
Conclusion: Based on multivariate analysis, periodontal diagnosis (BP/CP) was not associated with haematological parameters measured in this study or serum Hsp27. In CP, nonsurgical periodontal therapy improved MCHC 12 weeks after SD. Also in CP Hsp27 was increased 1 day after SD.
Blank, Martina ; Flug, Matthias ; Hussein, Jason ; Jovanović, Teodora ; Arfaoui, Rafik ; Bianco, Rosella ; Ortiz Cobo, Mónica ; Taccolini Pannagio, Annie ; Gonzalez Benson, Odessa ; Robinson, Daniel B. ; Robinson, Ingrid M. ; Currie, Vanessa ; Hall, Nathan
Acute kidney injury (AKI) is still associated with high morbidity and mortality incidence rates, and also bears an elevated risk of subsequent chronic kidney disease. Although the kidney has a remarkable capacity for regeneration after injury and may recover completely depending on the type of renal lesions, the options for clinical intervention are restricted to fluid management and extracorporeal kidney support. The development of novel therapies to prevent AKI, to improve renal regeneration capacity after AKI, and to preserve renal function is urgently needed. The Special Issue covers research articles that investigated the molecular mechanisms of inflammation and injury during different renal pathologies, renal regeneration, diagnostics using new biomarkers, and the effects of different stimuli like medication or bacterial components on isolated renal cells or in vivo models. The Special Issue contains important reviews that consider the current knowledge of cell death and regeneration, inflammation, and the molecular mechanisms of kidney diseases. In addition, the potential of cell-based therapy approaches that use mesenchymal stromal/stem cells or their derivates is summarized. This edition is complemented by reviews that deal with the current data situation on other specific topics like diabetes and diabetic nephropathy or new therapeutic targets.
Krüger, Britta ; Hettwer, Meike ; Zabicki, Adam ; Haas, Benjamin de ; Munzert, Jörn ; Zentgraf, Karen
Motor imagery is conceptualized as an internal simulation that uses motor-related parts of the brain as its substrate. Many studies have investigated this sharing of common neural resources between the two modalities of motor imagery and motor execution. They have shown overlapping but not identical activation patterns that thereby result in a modality-specific neural signature. However, it is not clear how far this neural signature depends on whether the imagined action has previously been practiced physically or only imagined. The present study aims to disentangle whether the neural imprint of an imagined manual pointing sequence within cortical and subcortical motor areas is determined by the nature of this prior practice modality. Each participant practiced two sequences physically, practiced two other sequences mentally, and did a behavioural pre-test without any further practice on a third pair of sequences. After a two-week practice intervention, participants underwent fMRI scans while imagining all six sequences. Behavioural data demonstrated practice-related effects as well as very good compliance with instructions. Functional MRI data confirmed the previously known motor imagery network. Crucially, we found that mental and physical practice left a modality-specific footprint during mental motor imagery. In particular, activation within the right posterior cerebellum was stronger when the imagined sequence had previously been practiced physically. We conclude that cerebellar activity is shaped specifically by the nature of the prior practice modality.
Electrical stimulation (EStim) has been shown to promote bone healing and regeneration both in animal experiments and clinical treatments. Therefore, incorporating EStim into promising new bone tissue engineering (BTE) therapies is a logical next step. The goal of current BTE research is to develop combinations of cells, scaffolds, and chemical and physical stimuli that optimize treatment outcomes. Recent studies demonstrating EStim’s positive osteogenic effects at the cellular and molecular level provide intriguing clues to the underlying mechanisms by which it promotes bone healing. In this review, we discuss results of recent in vitro and in vivo research focused on using EStim to promote bone healing and regeneration and consider possible strategies for its application to improve outcomes in BTE treatments. Technical aspects of exposing cells and tissues to EStim in in vitro and in vivo model systems are also discussed.
Die extrem hohen Interaktionsraten, die mit dem CBM Experiment verfügbar sein werden, erlauben die Messung von einigen der herausfordensten Observablen im Feld der Schwerionenphysik. Im besonderen die Messung von Dileptonen im mittleren Massenbereich ist nahezu unmöglich für eine Vielzahl anderer Experimente, da die extrem kleinen Wirkungsquerschnitte der Produktionskanäle das Auftreten eines messbaren Ereignisses so selten machen, so dass es nicht möglich ist eine ausreichende Anzahl dieser Ereignisse zu messen. Hinzu kommt, dass speziell im Energiebereich des CBM Experiments bisher absolut keine Messdaten verfügbar sind, obwohl es zahlreiche Hinweise von theoretischer Seite und von Messungen bei größeren Kollisionsenergien darauf gibt, dass wir im Energiebereich des CBM Experiments bedeutende Entdeckungen machen k¨onnten. Eine solche Messung dieser Observable könnte einen direkten Zugang zu Informationen bezüglich eines potentiellen Phasenubergangs von hadronischer Materie (bzw. im Hadronengas) in den Zustand eines Quark-Gluonen Plasmas liefern. Zusätzlich bieten Dileptonen noch die Möglichkeit Indikatoren für eine Wiederherstellung der chiralen Symmetrie zu messen...
In dieser Arbeit wurde die Messung des Flusses von Protonen in Silber-Silber-Kollisionen bei 1:58 AGeV beschrieben. Dabei wurden drei verschiedene Flow Koeffzienten betrachtet, der gerichtete, der elliptische sowie der dreieckige Fluss.
Nachdem die Protonen zunächst anhand ihrer Masse identifziert wurden, wurde die Reaktionsebene rekonstruiert. Nachfolgend wurde das Vorgehen zur Bestimmmung der ersten drei Flow-Koeffzienten v1, v2 und v3 beschrieben. Diese wurden anschließend in Abhäangigkeit des Transversalimpulses und der Rapidität für vier Zentralitätsklassen im Bereich von 0 - 40% Zentralität dargestellt.
Da die Daten ebenfalls Silber-Kohlenstoff Reaktionen enthalten, weisen die Spektren eine Abweichung vom erwarteten Verlauf auf. Daher wurden diese Reaktionen anhand des in Abschnitt 3.1 beschriebenen Energieverhältnisses ERAT abgeschätzt und mit Hilfe eines Cut-Off Werts ausgeschlossen. Die daraus resultierenden Spektren konnten dadurch verbessert werden.
Im Fall der Gold-Gold Strahlzeit aus dem Jahr 2012 konnten neben Daten der hier diskutierten Flow-Koeffzienten v1, v2 und v3 ebenfalls Koeffzienten höherer Ordnung, v4 und v5, sowie Hinweise auf ein Auftreten von v6 gefunden werden.
Ähnliche Analysen könnten im Fall der Daten der Silber-Silber Kollisionen durchgeführt werden. Hier tritt zwar ein quantitativ kleinerer Fluss auf, da es sich bei den kollidierenden Nuklei um ein kleineres System handelt, jedoch treten im Vergleich zu Gold-Gold Kollisionen etwa zweifach so hohe Event-Raten auf. Somit kann mit der in dieser Arbeit beschriebenen Herangehensweise unter Verwendung der Daten der gesamten Strahlzeit untersucht werden, ob Hinweise auf Flow-Koeffzienten höherer Ordnung zu finden sind.
Außerdem sollte bei den bestehenden Ergebnissen eine Korrektur des Effekts der Occupancy des Detektors durchgeführt werden, da dieser wie in Abschnitt 3.2.1 beschrieben zu Verfälschungen des gemessenen Flusses führt. Dieser Effekt wird insbesondere im Fall des gerichteten Flusses v1 deutlich.
Des Weiteren ist eine Abschätzung der systematischen Fehler der Messungen erforderlich.
Dafür kann untersucht werden, welche Auswahlkriterien und Parameter die Messung beeinflussen, beispielsweise die Spurrekonstruktion und -selektion oder die Teilchenidentifikation. Unter Betrachtung der Auswirkungen auf die Ergebnisse der Flow-Koeffzienten kann die Analyse daraufhin mit Variationen dieser Werte durchgeführt werden. Somit kann der Bereich der systematischen Fehler abgeschätzt werden.
In dieser Arbeit wurde der spezifische Energieverlust im TOF Detektor genutzt, um leichte Kerne zu identifizieren. Da die gemeinsame Betrachtung aller Szintillatorstäbe bei der aktuellen Kalibrierung des TOF Detektors keine eindeutige Zuordnung ermöglicht, wurde der Energieverlust der einzelnen Stäbe individuell parametrisiert. So konnten Helium und sogar Lithium Kerne selektiert werden. Die Impulskorrektur hat für zweifach geladene Kerne, abgesehen von sehr hohen Impulsen, eine erfolgreiche Korrektur der Masse ermöglicht. Bei Lithium hingegen wurde der Impuls überkorrigiert, sodass die Masse zu niedrig rekonstruiert wurde.
Durch Optimierung der Impulskorrektur könnte zusammen mit einer verbesserten Kalibrierung des TOF Detektors ein sehr hohes Auflösungsvermögen erreicht werden. Daher sollte die systematische Impulskorrektur für hohe Impulse durch weitere Simulationen verbessert und der Energieverlust vor dem Auftreffen auf den META Detektor genauer untersucht werden. Optimalerweise würde zur Kalibrierung des TOF Detektors die Abhängigkeit des Energieverlustes vom Winkel, in welchem die Teilchen auf den Detektor treffen, berücksichtigt werden. Ziel ist es, alle Stäbe pro zurückgelegter Wegstrecke zu kalibrieren, sodass weder ein Unterschied durch den Einfallwinkel der Teilchen noch durch die verschiedenen Stablängen aufkommt. Folglich wäre eine sehr spezifische Teilchenselektion möglich.
In dieser Arbeit wurde zunächst schrittweise das Vorgehen beim Bau der TRD Prototypkammern , sowie die Maßnahmen zur Verbesserung der Kammerstabilität erklärt, um sicherzustellen, dass die erhobenen Messdaten zuverlässig sind. Es ist an dieser Stelle nochmals hervorzuheben, dass bereits kleine Veränderungen in der Bauweise einen großen Einfluss auf die Kammerstabilität haben.
Es wurde mit der Kammer 3 der Anodenstrom, die deponierte Photonenenergie und die Clusterrate gemessen. Anschließend wurden diese Daten ausgewertet und aus den Ergebnissen die Gasverstärkung berechnet. Die Auswertung bestätigt, dass die Kammer im Proportionalbereich betrieben wurde. Nach dem Vergleich der Gasverstärkungsfaktoren der Messung mit den simulierten Werten, zeigt sich dass die Messungen stärker als erwartet von den simulierten Werten abweichen.
Für weitere, genauere Aussagen wäre es interessant die Ergebnisse dieser Arbeit durch modifizierte Messungen zu uberprüfen. Dabei könnte der Einfluss verschiedener Gasdrucke innerhalb und außerhalb der Kammer sowie die Variation der Raumtemperatur auf die Gasverstärkung explizit untersucht werden. Außerdem wäre es von großem Interesse, Messungen mit verschiedenen Ar und CO2 und Xe und CO2 Mischverhältnissen durchzuführen, da der TRD im CBM Experiment mit Xe und CO2 betrieben werden soll, und der Gasverstärkungsfaktor ausschlaggebend für die angelegte Anodenspannung im laufenden Betrieb sein wird.
Das CBM-Experiment konzentriert sich auf die Untersuchung der Eigenschaften des Quark-Gluon-Plasmas bei hohen Netto-Baryonendichten und moderaten Temperaturen. An der zukünftigen Beschleunigeranlage FAIR an der GSI findet das Experiment, neben vielen anderen Experimenten, ihren Platz. Der TRD ist, neben dem RICH, STS und TOF, einer der zentralen Detektoren im CBM-Experiment. Der TRD nutzt dabei den physikalischen Effekt der Übergangsstrahlung, die durch ein geladenes Teilchen beim Durchqueren einer Grenze zweier Medien mit unterschiedlichen Dielektrizitätskonstanten mit einer gewissen Wahrscheinlichkeit entsteht, um Elektronen von Pionen trennen zu können. Im Jahr 2017 wurde an der DESY 4 TRD-Prototypen in einer Teststrahlzeit getestet. Dabei handelt es sich um große TRD-Module mit den Maßen 95 · 95 cm2 , was dem finalen Design sehr nahe kommt. Die Untersuchung der DESY-Daten in Kapitel 5 brachte große Problematiken in den Daten zum Vorschein. Die Hauptprobleme der DESY-Daten sind: 1) Bug des SPADIC-Chips 2.0, bei der FN-Trigger zeitlich verschoben wurden; 2) schwache und suboptimale Trigger-Bedingung, wodurch sehr viel Rauschen aufgenommen wurde. Die Daten müssen für weitere Auswertung aufbereitet werden, wobei sehr viel Information und Statistik verloren geht, da einige Daten durch diverse Probleme nicht mehr rekonstruierbar sind. Kapitel 6 beschäftigt sich mit der Simulation der Detektorantwort und geht genauer auf die einzelnen Schritte, die zur Simulation des vom SPADIC erzeugten Pulses benötigt werden, ein. Am Ende werden Ergebnisse aus beiden Datensätzen miteinander verglichen. Um einen optimalen Vergleich zu gewähren, wird die Simulation bestmöglich an die Einstellungen in der Teststrahlzeit angepasst. Hauptsächlich geht es um die Erhöhung des Gasgains und der Verschiebung der Peaking-Zeit des Pulses. Im Allgemeinen können wir in der Simulation einige Effekte, die auch in den DESY-Daten vorkommen, nachsimulieren. Wir erhalten zum Teil sehr unterschiedliche Ergebnisse in der Simulation, deren Richtigkeit nicht verifiziert werden kann, da die Daten aufgrund der Probleme unzuverlässig werden. Durch die Analyse der DESY-Daten konnten wir die Problematik in den Daten besser verstehen. Eine sinnvolle Anpassung der Simulation wird durch die Unzuverlässigkeit der DESY-Daten unmöglich. Für die Optimierung der Simulation müsste man einen Vergleich mit neueren, zuverlässigeren Daten aus zukünftigen Teststrahlzeiten nehmen.
Varga, László ; Davinson, Thomas ; Glorius, Jan ; Jurado Apruzzese, Beatriz ; Langer, Christoph ; Lederer-Woods, Claudia ; Litvinov, Yuri A. ; Reifarth, René ; Slavkovská, Zuzana ; Stöhlker, Thomas ; Woods, Philip John ; Xing, Yuan Ming
Stored and cooled, highly-charged ions offer unprecedented capabilities for precision studies in the realm of atomic, nuclear structure and astrophysics[1]. After the successful investigation of the 96Ru(p,7)97Rh reaction cross section in 2009[2], the first measurement of the 124Xe(p,7)125Cs reaction cross section has been performed with decelerated, fully-ionized 124Xe ions in 2016 at the Experimental Storage Ring (ESR) of GSI[3]. Using a Double Sided Silicon Strip Detector, introduced directly into the ultra-high vacuum environment of a storage ring, the 125Cs proton-capture products have been successfully detected. The cross section has been measured at 5 different energies between 5.5AMeV and 8AMeV, on the high energy tail of the Gamow-window for hot, explosive scenarios such as supernovae and X-ray binaries. The elastic scattering on the H2 gas jet target is the major source of background to count the (p,7) events. Monte Carlo simulations show that an additional slit system in the ESR in combination with the energy information of the Si detector will enable background free measurements of the proton-capture products. The corresponding hardware is being prepared and will increase the sensitivity of the method tremendously.
Varga, László ; Blaum, Klaus ; Davinson, Thomas ; Glorius, Jan ; Jurado Apruzzese, Beatriz ; Langer, Christoph ; Lederer-Woods, Claudia ; Litvinov, Yuri A. ; Reifarth, René ; Slavkovská, Zuzana ; Stöhlker, Thomas ; Woods, Philip John ; Xing, Yuan Ming
Stored and cooled highly-charged ions offer unprecedented capabilities for precision studies in realm of atomic-, nuclear-structure and astrophysics. In context of the latter, after the successful investigation of the cross section of 96Ru(p,γ) in 2009, in 2016 the first measurement of the 124Xe(p,γ)125Cs reaction was performed at the Experimental Storage Ring (ESR) at GSI.
Impact parameter sensitive study of inner-shell atomic processes in Xe54+, Xe52+ → Xe collisions
(2020)
Gumberidze, Alexandre ; Kozhuharov, Christophor ; Zhang, Ruitian ; Trotsenko, Sergiy ; Kozhedub, Yury S. ; DuBois, Robert D. ; Beyer, Heinrich F. ; Blumenhagen, Karl-Heinz ; Brandau, Carsten ; Bräuning-Demian, Angela ; Chen, Weidong ; Forstner, Oliver ; Gao, Bingshui ; Gaßner, Tobias ; Grisenti, Robert Evaristo ; Hagmann, Siegbert ; Hillenbrand, Pierre-Michel ; Indelicato, Paul ; Kumar, Ajay ; Lestinsky, Michael ; Litvinov, Yuri A. ; Petridis, Nikolaos ; Schury, Daniel ; Spillmann, Uwe ; Trageser, Christian ; Trassinelli, Martino ; Tu, Xiaolin ; Stöhlker, Thomas
In this work, we present a pilot experiment in the experimental storage ring (ESR) at GSI devoted to impact parameter sensitive studies of inner shell atomic processes for bare and He-like xenon ions (Xe54+, Xe52+) colliding with neutral xenon gas atoms. The projectile and target x-rays have been measured at different observation angles for all impact parameters as well as for the impact parameter range of ∼35 - 70 fm.
Göbel, Kathrin ; Heil, Michael ; Bott, Lukas ; Brandenburg, Leonard ; Caesar, Christoph ; Deuter, Isabell ; Grein, Alexander ; Keliç-Heil, Aleksandra ; Körper, Daniel ; Löher, Bastian ; Reifarth, René ; Savran, Deniz ; Schulte, Hendrik ; Simon, Haik ; Törnqvist, Hans Toshihide ; Almusidi, Tahani ; Álvarez-Pol, Héctor ; Atkins, Liam ; Aumann, Thomas ; Bemmerer, Daniel ; Benlliure Anaya, Jose Fernando ; Boretzky, Konstanze ; Brückner, Benjamin ; Cabanelas Eiras, Pablo ; Casarejos Ruiz, Enrique ; Cederkäll, Joakim ; Chulkov, Leonid V. ; Cortina Gil, Dolores ; Danilov, Andrey ; Erbacher, Philipp ; Escribano Rodriguez, Sonia ; Fülöp, Zsolt ; Falduto, Ashton ; Fiebiger, Stefan ; Gašparić, Igor ; Garcia Borge, Maria José ; Gernhäuser, Roman ; Glorius, Jan ; Gonzales Caamaño, David ; Hartig, Anna-Lena ; Heftrich, Tanja ; Heggen, Henning ; Heine, Marcel ; Heinz, Andreas ; Hensel, Thomas ; Holl, Matthias ; Johansson, Håkan T. ; Jonson, Björn ; Kalantar-Nayestanaki, Nasser ; Kamenyero, Armel ; Khasawneh, Kafa al- ; Kiselev, Oleg A. ; Klenze, Philipp ; Kohls, Marvin ; Kröll, Thorsten ; Kresan, Dmytro ; Kurtulgil, Cem Deniz ; Kurz, Nikolaus ; Langer, Christoph ; Lehr, Christopher ; Litvinov, Yuri A. ; Lorenz, Enis ; Murillo Morales, Silvia ; Nácher González, Enrique ; Nilsson, Thomas ; Park, Joochun ; Paschalis, Stefanos ; Perea Martinez, Angel ; Petri, Marina ; Plag, Ralf ; Ponnath, Lukas ; Popočovski, Romana ; Reich, Markus ; Rhee, Han-Bum ; Rodriguez Sanchez, Jose Luis ; Rossi, Dominic M. ; Scheit, Heiko ; Schmidt, Konrad ; Slavkovská, Zuzana ; Starostin, Viktor ; Storck, Sonja ; Sürder, Christian ; Tanaka, Junki ; Tengblad, Olof ; Thomas, Benedikt ; Typel, Stefan ; Varga, László ; Volk, Klaus ; Volknandt, Meiko ; Wagner, Vadim ; Wamers, Felix ; Weigand, Mario ; Zanetti, Lorenzo
We measured the Coulomb dissociation of 16O into 4He and 12C at the R3B setup in a first campaign within FAIR Phase 0 at GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt. The goal was to improve the accuracy of the experimental data for the 12C(α,γ)16O fusion reaction and to reach lower center-ofmass energies than measured so far.
The experiment required beam intensities of 109 16O ions per second at an energy of 500 MeV/nucleon. The rare case of Coulomb breakup into 12C and 4He posed another challenge: The magnetic rigidities of the particles are so close because of the same mass-to-charge-number ratio A/Z = 2 for 16O, 12C and 4He. Hence, radical changes of the R3B setup were necessary. All detectors had slits to allow the passage of the unreacted 16O ions, while 4He and 12C would hit the detectors' active areas depending on the scattering angle and their relative energies. We developed and built detectors based on organic scintillators to track and identify the reaction products with sufficient precision.
Otomo, Kanako ; Perkins, Jessica ; Kulkarni, Anand ; Stojanovic, Strahinja ; Roeper, Jochen ; Paladini, Carlos A.
The in vivo firing patterns of ventral midbrain dopamine neurons are controlled by afferent and intrinsic activity to generate sensory cue and prediction error signals that are essential for reward-based learning. Given the absence of in vivo intracellular recordings during the last three decades, the subthreshold membrane potential events that cause changes in dopamine neuron firing patterns remain unknown. To address this, we established in vivo whole-cell recordings and obtained over 100 spontaneously active, immunocytochemically-defined midbrain dopamine neurons in isoflurane-anaesthetized adult mice. We identified a repertoire of subthreshold membrane potential signatures associated with distinct in vivo firing patterns. Dopamine neuron activity in vivo deviated from single-spike pacemaking by phasic increases in firing rate via two qualitatively distinct biophysical mechanisms: 1) a prolonged hyperpolarization preceding rebound bursts, accompanied by a hyperpolarizing shift in action potential threshold; and 2) a transient depolarization leading to high-frequency plateau bursts, associated with a depolarizing shift in action potential threshold. Our findings define a mechanistic framework for the biophysical implementation of dopamine neuron firing patterns in the intact brain.
Kröger, Felix Martin ; Weber, Günter ; Herdrich, Marc Oliver ; Glorius, Jan ; Langer, Christoph ; Slavkovská, Zuzana ; Bott, Lukas ; Brandau, Carsten ; Brückner, Benjamin ; Blaum, Klaus ; Chen, Xin ; Dababneh, Saed ; Davinson, Thomas ; Erbacher, Philipp ; Fiebiger, Stefan ; Gaßner, Tobias ; Göbel, Kathrin ; Groothuis, Mathias ; Gumberidze, Alexandre ; Gyürky, György ; Hagmann, Siegbert ; Hahn, Christoph ; Heil, Michael ; Heß, Regina ; Hensch, Roman ; Hillmann, Paula ; Hillenbrand, Pierre-Michel ; Hinrichs, Ole Djürko ; Jurado Apruzzese, Beatriz ; Kausch, Tanja ; Khodaparast, Anahita ; Kisselbach, Timo ; Klapper, Nadine ; Kozhuharov, Christopher ; Kurtulgil, Cem Deniz ; Lane, Gregory J. ; Lederer-Woods, Claudia ; Lestinsky, Michael ; Litvinov, Sergey A. ; Litvinov, Yuri A. ; Löher, Bastian ; Nolden, Fritz ; Petridis, Nikolaos ; Popp, Ulrich ; Reed, Matthew ; Reifarth, René ; Sanjari, Mohammad Shahab ; Simon, Haik ; Spillmann, Uwe ; Steck, Markus ; Stumm, Julia ; Szücs, Tamas ; Nguyen, Thien Tam ; Taremi Zadeh, Ashkan ; Thomas, Benedikt ; Torilov, Sergey Yu. ; Törnqvist, Hans Toshihide ; Trageser, Christian ; Trotsenko, Sergiy ; Volknandt, Meiko ; Weigand, Mario ; Wolf, Clemens ; Woods, Philip John ; Ševelʹko, Vjačeslav P. ; Stöhlker, Thomas
The electron-capture process was studied for Xe54+ colliding with H2 molecules at the internal gas target of the Experimental Storage Ring (ESR) at GSI, Darmstadt. Cross-section values for electron capture into excited projectile states were deduced from the observed emission cross section of Lyman radiation, being emitted by the hydrogenlike ions subsequent to the capture of a target electron. The ion beam energy range was varied between 5.5 and 30.9 MeV/u by applying the deceleration mode of the ESR. Thus, electron-capture data were recorded at the intermediate and, in particular, the low-collision-energy regime, well below the beam energy necessary to produce bare xenon ions. The obtained data are found to be in reasonable qualitative agreement with theoretical approaches, while a commonly applied empirical formula significantly overestimates the experimental findings.
Purpose of Review: To review the latest developments and the current role of the cardiac magnetic resonance (CMR) in pericardial diseases and their complications.
Recent Findings: Cardiac Magnetic Resonance (CMR) has the ability to incorporate anatomy, physiology, and “virtual histology” strategies to achieve the most accurate diagnosis for even the most demanding, pericardial diseases.
Summary: Acute, chronic, recurrent, and constrictive pericarditis as well as pericarditis related complications, pericardial masses and congenital pericardial defects are commonly encountered in clinical practice with relatively significant morbidity and mortality. Owing to the challenging diagnosis, CMR imaging is often employed in confirming the diagnosis and elucidating the underling pathophysiology. In this review we outline the common CMR techniques and their expected diagnostic outcomes.
Die Bestimmung von ACE im Serum oder Heparinplasma stellt einen wesentlichen Bestandteil der Diagnostik, Verlaufskontrolle und Therapieüberwachung von benignen Lungenerkrankungen dar. ACE ist ein Marker, der bei Sarkoidose wertvolle Aussagen zur Diagnosefindung ermöglicht. Hier zeichnet er sich durch hohe Sensitivität und Spezifität aus.
Hilger, Kirsten ; Winter, Nils R. ; Leenings, Ramona ; Sassenhagen, Jona ; Hahn, Tim ; Basten, Ulrike ; Fiebach, Christian
A positive association between brain size and intelligence is firmly established, but whether region-specific anatomical differences contribute to general intelligence remains an open question. Results from voxel-based morphometry (VBM) - one of the most widely used morphometric methods - have remained inconclusive so far. Here, we applied cross-validated machine learning-based predictive modeling to test whether out-of-sample prediction of individual intelligence scores is possible on the basis of voxel-wise gray matter volume. Features were derived from structural magnetic resonance imaging data (N = 308) using (a) a purely data-driven method (principal component analysis) and (b) a domain knowledge-based approach (atlas parcellation). When using relative gray matter (corrected for total brain size), only the atlas-based approach provided significant prediction, while absolute gray matter (uncorrected) allowed for above-chance prediction with both approaches. Importantly, in all significant predictions, the absolute error was relatively high, i.e., greater than ten IQ points, and in the atlas-based models, the predicted IQ scores varied closely around the sample mean. This renders the practical value even of statistically significant prediction results questionable. Analyses based on the gray matter of functional brain networks yielded significant predictions for the fronto-parietal network and the cerebellum. However, the mean absolute errors were not reduced in contrast to the global models, suggesting that general intelligence may be related more to global than region-specific differences in gray matter volume. More generally, our study highlights the importance of predictive statistical analysis approaches for clarifying the neurobiological bases of intelligence and provides important suggestions for future research using predictive modeling.
Carl von Clausewitz’ Denken über den Krieg steht paradigmatisch für ein instrumentelles Verständnis von Gewalt in der Politik. Gewalt ist für Clausewitz ein Mittel, das im Krieg verwendet wird, um politische Zwecke zu erreichen. Seit dem Ende des Ost-West-Konflikts ist jedoch die Ansicht weit verbreitet, dass Clausewitz’ Überlegungen keine Gültigkeit mehr besitzen. Gegenwärtige Formen des Krieges seien zwar gewaltsam, aber nicht mehr politisch, weil sie nicht allein von Staaten oder aus einer eng verstandenen Staatsräson heraus geführt werden. Der Einwand missversteht jedoch Clausewitz’ Begriff der Politik. Dieser soll im vorliegenden Aufsatz systematisch rekonstruiert werden. Dem zu entwickelnden Interpretationsvorschlag zufolge bezeichnet „Politik“ in Clausewitz’ theoretischem System zunächst einmal nur ganz allgemein eine Interaktion von zwei oder mehr Akteuren, die jeweils ihren Willen realisieren wollen, deren Willen sich jedoch nicht vollständig vereinen lassen. Krieg ist für Clausewitz dann solche Politik, die mit gewaltsamen Mitteln betrieben wird. Vor diesem Hintergrund wird argumentiert, dass Clausewitz’ Theorie des Krieges einen fruchtbaren Analyserahmen bietet, mit dem sich die Transformationen der politischen Gewalt von den Kabinettskriegen des 18. Jahrhunderts bis zu den „neuen Kriegen“ unserer Zeit nachvollziehen lassen.
Purpose: In this study, we examined distress levels and quality of life (QoL) of patients with hematologic malignancies under treatment in an acute setting. We used external- and self-assessment instruments for distress. Additionally, we investigated the relation between distress and QoL as well as whether highly distressed patients differed from less distressed patients concerning their QoL.
Methods: A cross-sectional study with patients of the Medical Clinic II of the University Hospital Frankfurt was conducted. One hundred and nine patients were assessed with an expert rating scale and completed self-report questionnaires. Data were exploratively analyzed and group comparisons between patients who scored above the cut-off of the respective screening instruments and those who did not were conducted.
Results: Patients with hematologic malignancies experience high levels of distress and low QoL. Especially, role and social functioning are affected. Patients suffer most from fatigue, appetite loss, and insomnia. Using established cut-offs, all screening instruments were able to differentiate between patients regarding distress and QoL. Patients scoring above the cut-off were significantly more distressed and had a lower QoL. There was a medium-to-strong correlation between distress and QoL indicators.
Conclusion: Cancer-specific screening instruments seem to be able to identify treatment needs more specifically. They also allowed a better differentiation concerning QoL. The close link between distress and QoL needs to be recognized to enable a holistic approach to treatment and thereby optimize the quality of treatment.
Bauer, Jan ; Brüggmann, Dörthe ; Klingelhöfer, Doris ; Maier, Werner Albert ; Schwettmann, Lars ; Maier, Werner Albert ; Schwettmann, Lars ; Weiss, Daniel J. ; Groneberg, Jan David Alexander
Purpose: The coronavirus disease 2019 (COVID-19) poses major challenges to health-care systems worldwide. This pandemic demonstrates the importance of timely access to intensive care and, therefore, this study aims to explore the accessibility of intensive care beds in 14 European countries and its impact on the COVID-19 case fatality ratio (CFR).
Methods: We examined access to intensive care beds by deriving (1) a regional ratio of intensive care beds to 100,000 population capita (accessibility index, AI) and (2) the distance to the closest intensive care unit. The cross-sectional analysis was performed at a 5-by-5 km spatial resolution and results were summarized nationally for 14 European countries. The relationship between AI and CFR was analyzed at the regional level.
Results: We found national-level differences in the levels of access to intensive care beds. The AI was highest in Germany (AI = 35.3), followed by Estonia (AI = 33.5) and Austria (AI = 26.4), and lowest in Sweden (AI = 5) and Denmark (AI = 6.4). The average travel distance to the closest hospital was highest in Croatia (25.3 min by car) and lowest in Luxembourg (9.1 min). Subnational results illustrate that capacity was associated with population density and national-level inventories. The correlation analysis revealed a negative correlation of ICU accessibility and COVID-19 CFR (r = − 0.57; p < 0.001).
Conclusion: Geographical access to intensive care beds varies significantly across European countries and low ICU accessibility was associated with a higher proportion of COVID-19 deaths to cases (CFR). Important differences in access are due to the sizes of national resource inventories and the distribution of health-care facilities relative to the human population. Our findings provide a resource for officials planning public health responses beyond the current COVID-19 pandemic, such as identifying potential locations suitable for temporary facilities or establishing logistical plans for moving severely ill patients to facilities with available beds.
Bauer, Jan ; Klingelhöfer, Doris ; Maier, Werner Albert ; Schwettmann, Lars ; Groneberg, Jan David Alexander
Improving spatial accessibility to hospitals is a major task for health care systems which can be facilitated using recent methodological improvements of spatial accessibility measures. We used the integrated floating catchment area (iFCA) method to analyze spatial accessibility of general inpatient care (internal medicine, surgery and neurology) on national level in Germany determining an accessibility index (AI) by integrating distances, hospital beds and morbidity data. The analysis of 358 million distances between hospitals and population locations revealed clusters of lower accessibility indices in areas in north east Germany. There was a correlation of urbanity and accessibility up to r = 0.31 (p < 0.001). Furthermore, 10% of the population lived in areas with significant clusters of low spatial accessibility for internal medicine and surgery (neurology: 20%). The analysis revealed the highest accessibility for heart failure (AI = 7.33) and the lowest accessibility for stroke (AI = 0.69). The method applied proofed to reveal important aspects of spatial accessibility i.e. geographic variations that need to be addressed. However, for the majority of the German population, accessibility of general inpatient care was either high or at least not significantly low, which suggests rather adequate allocation of hospital resources for most parts of Germany.
Existing social stressor concepts disregard the variety of task-related situations at work that require skillful social behavior to maintain good social relationships while achieving certain task goals. In this article, we challenge the view that social stressors at work are solely dysfunctional aspects evoking employee ill health. Drawing from the challenge-hindrance stressor framework, we introduce the concept of social challenge stressors as a job characteristic and examine their relationships with individual well-and ill-being. In study 1, we developed a new scale for the measurement of social challenge stressors and tested the validity of the scale. Results from two independent samples indicated support for a single-factor structure and showed that social challenge stressors are distinct from related stressor concepts. Using two samples, one of which was already used to test the factor structure, we analyzed the unique contribution of social challenge stressors in predicting employee well- and ill-being. As expected, social challenge stressors were simultaneously related to psychological strain and well-being. Using time-lagged data, study 2 investigated mechanisms that may explain how social challenge stressors are linked to well-being and strain. In line with the stress-as-offense-to-self approach, we expected indirect relationships via self-esteem. Additionally, social support was expected to moderate the relationships between social stressors and self-esteem. Whereas the indirect relationships were mostly confirmed, we found no support for the buffering role of social support in the social hindrance stressors-self-esteem link. Although we found a moderation effect for social challenge stressors, results indicated a compensation model that conflicted with expectations.
Solute carrier (SLC) are related to various diseases in human and promising pharmaceutical targets but more structural and functional information on SLCs is required to expand their use for drug design and therapy. The 7-transmembrane segment inverted (7-TMIR) fold was identified for the SLC families 4, 23 and 26 in the last decade thus detailed analysis of the structure function relationship of one of these families might also yield insights for the other two. SVCT1 and SVCT2 from the SLC23 family are sodium dependent ascorbic acid transporters in human but structural analysis of the SLC23 family is exclusively based on two homologs – UraA from E. coli and UapA from A. nidulans – yielding two inward-facing and one occluded conformation. In combination with outward-facing conformations from SLC4 transporters, and additional information from the SLC26 family, an elevator transport mechanism for all 7-TMIR proteins was identified but detailed mechanistic features of the transport remain elusive due to the lack of multiple conformations from individual transporters.
To increase the understanding of 7-TMIR protein structure and function in this study, the transport mechanism of SLC23 transporters was analyzed by two strategies including selection of alpaca derived nanobodies and synthetic nanobodies against UraA as prokaryotic model protein of the SLC23 family. The second strategy involved mutagenesis of UraA at functional relevant positions regarding the conformational change during transport. Therefore, available structures of 7-TMIR proteins and less related elevator transporters were analyzed and a common motif identified – the alpha helical inter-domain linkers. The proposed rigid body movement for transport in combination with the characteristic alpha helical secondary structure of the linkers connecting both rigid bodies led to the hypothesis of functional relevance of the linkers and a conformational hinge being located in close proximity to the linkers. These positions were identified and used to modulate the biophysical properties of the transporter. Mutagenesis at three relevant positions led to loss of transport functionality and these UraA variants could be recombinantly produced and purified to further examine the underlying mechanistic effects. The variants UraAG320P and UraAP330G from the periplasmic inter-domain linker showed increased dimerization and thermal stability as well as substrate binding in solution. The substrate affinity of UraAG320P was identified to be 5-fold higher compared to the wildtype. The solvent accessibility of the substrate binding site in UraAG320P and UraAP330G revealed reduced open probability that indicated an altered conformational space compared to UraAWT. This phenomenon was analyzed in more detail by differential hydrogen-deuterium exchange mass spectrometry and the results supported the hypothesis of a reduced open probability and gave further insights into the impact of the two mutations in the periplasmic inter-domain linker in UraA.
This thesis further presents strategies for phage display selection of nanobodies with epitope bias and a post selection analysis pipeline to identify nanobodies with desired binding characteristics. Thereby, whole cell transport inhibition highlighted periplasmic epitope binders and conformational selectivity. A cytoplasmic epitope could be identified by pulldown with inside-out membrane vesicles for one cytoplasmic side binder. Thermal stabilization analysis of the target protein in differential scanning fluorometry was performed in presence of two different nanobodies to identify simultaneous binding by additional thermal stabilization respectively competition by intermediate melting temperatures. Combination of epitope information with simultaneous DSF could be used to identify the stabilization of different UraA conformations by a set of binders and presents a general nanobody selection strategy for other SLCs. Synthetic nanobodies (sybodies) were also included in the analysis pipeline and Sy45 identified as promising candidate for co-crystallization that gave rise to UraAWT crystals in several conditions in presence or absence of uracil. Similar crystals could be obtained in combination with UraAG320P that were further optimized to gain structural information on this mutant. The structure was solved by molecular replacement and the model refined at 3.1 Å resolution confirming the cytoplasmic epitope of Sy45 as predicted by the selection pipeline. The stabilized conformation was inward-facing similar to the reported UapA structure but significantly different to the previously reported inward-facing structure of UraA. The structure further confirmed the structural integrity of the UraA mutant G320P. Despite the monomeric state of UraA in the structure, the gate domain aligned reasonably well with the gate domain of the previously published dimeric UraA structure in the occluded conformation and allowed detailed analysis of the conformational transition in UraA from inward-facing to occluded by a single rigid body movement. Thereby little movement in the gate domain of UraA was observed in contrast to a previously reported transport mechanism. Core domain rotation around a rotation axis parallel to the substrate barrier was found to explain the major part of conformational transition from inward-facing to occluded and experimentally supported the hypothesized mechanism by Chang et al. (2017). Additionally, the conformational hinge around position G320 in UraA could be identified as well as the impact of the backbone rigidity introduced by the highly conserved proline residue at position 330 in UraA on the conformational transition. This position was found to serve as anchoring point the inter-domain linker and determines the coordinated movement of inter-domain linker and core domain. The functional analysis further highlighted the requirement of alpha helical secondary structure within the inter-domain linker that serves as amphipathic structural entity that can adjust to changed core-gate domain distances and angles during transport by extension/compression or bending while preserving the rigid linkage.
The applied strategies to modulate the conformational space of UraA by mutagenesis at the hinge positions in the inter-domain linkers is transferrable to other transporters and might facilitate their structural and functional characterization.
Further, this study discusses the conformational thermostabilization of UraA that is based on increased melting temperatures upon restriction of its conformational freedom. The term ‘conformational thermostabilization’ introduced by Serrano-Vega et al. (2007) could be experimentally supported and the direct correlation between the conformational freedom and thermostabilization was qualitatively analyzed for UraA. The concept of conformational thermostabilization might help in characterization of other dynamic transport systems as well.
We derive a simple criterion that ensures uniqueness, Lipschitz stability and global convergence of Newton’s method for the finite dimensional zero-finding problem of a continuously differentiable, pointwise convex and monotonic function. Our criterion merely requires to evaluate the directional derivative of the forward function at finitely many evaluation points and for finitely many directions. We then demonstrate that this result can be used to prove uniqueness, stability and global convergence for an inverse coefficient problem with finitely many measurements. We consider the problem of determining an unknown inverse Robin transmission coefficient in an elliptic PDE. Using a relation to monotonicity and localized potentials techniques, we show that a piecewise-constant coefficient on an a-priori known partition with a-priori known bounds is uniquely determined by finitely many boundary measurements and that it can be uniquely and stably reconstructed by a globally convergent Newton iteration. We derive a constructive method to identify these boundary measurements, calculate the stability constant and give a numerical example.
Steidl, Eike ; Langen, Karl-Josef ; Abu Hmeidan, Sarah ; Polomac, Nenad ; Filß, Christian ; Galldiks, Norbert ; Lohmann, Philipp ; Keil, Fee ; Filipski, Katharina Johanna ; Mottaghy, Felix ; Shah, N. Jon ; Steinbach, Joachim Peter ; Hattingen, Elke ; Maurer, Gabriele D.
Purpose: Perfusion-weighted MRI (PWI) and O-(2-[18F]fluoroethyl-)-l-tyrosine ([18F]FET) PET are both applied to discriminate tumor progression (TP) from treatment-related changes (TRC) in patients with suspected recurrent glioma. While the combination of both methods has been reported to improve the diagnostic accuracy, the performance of a sequential implementation has not been further investigated. Therefore, we retrospectively analyzed the diagnostic value of consecutive PWI and [18F]FET PET.
Methods: We evaluated 104 patients with WHO grade II–IV glioma and suspected TP on conventional MRI using PWI and dynamic [18F]FET PET. Leakage corrected maximum relative cerebral blood volumes (rCBVmax) were obtained from dynamic susceptibility contrast PWI. Furthermore, we calculated static (i.e., maximum tumor to brain ratios; TBRmax) and dynamic [18F]FET PET parameters (i.e., Slope). Definitive diagnoses were based on histopathology (n = 42) or clinico-radiological follow-up (n = 62). The diagnostic performance of PWI and [18F]FET PET parameters to differentiate TP from TRC was evaluated by analyzing receiver operating characteristic and area under the curve (AUC).
Results: Across all patients, the differentiation of TP from TRC using rCBVmax or [18F]FET PET parameters was moderate (AUC = 0.69–0.75; p < 0.01). A rCBVmax cutoff > 2.85 had a positive predictive value for TP of 100%, enabling a correct TP diagnosis in 44 patients. In the remaining 60 patients, combined static and dynamic [18F]FET PET parameters (TBRmax, Slope) correctly discriminated TP and TRC in a significant 78% of patients, increasing the overall accuracy to 87%. A subgroup analysis of isocitrate dehydrogenase (IDH) mutant tumors indicated a superior performance of PWI to [18F]FET PET (AUC = 0.8/< 0.62, p < 0.01/≥ 0.3).
Conclusion: While marked hyperperfusion on PWI indicated TP, [18F]FET PET proved beneficial to discriminate TP from TRC when PWI remained inconclusive. Thus, our results highlight the clinical value of sequential use of PWI and [18F]FET PET, allowing an economical use of diagnostic methods. The impact of an IDH mutation needs further investigation.
This paper contributes to the clarification of the concept of “typicality” discussed in contemporary philosophy of physics by conceiving the nomological status of a typical behaviour such as that expressed in the Second Law of Thermodynamics as a “minutis rectis law”. A brief sketch of the discovery of “typicality” shows that there were ideas of typical behaviour not only in physics but also in sociology. On this basis and in analogy to the Second Law of Thermodynamics, it is shown that the nomological status of sociological laws such as Gresham’s Law can also be conceived as “minutis rectis laws”.
Self-compassion has been theorized to have three components, each with a positive pole and a negative pole: self-kindness versus self-judgment, common humanity versus isolation, and mindfulness versus over-identification. Neff (Self Identity 2:85–101, 2003a) proposes that they mutually influence each other, however, this proposition has not been tested yet. We conducted a pilot study to see if improvements from training one component spilled over to the other two—and whether these trainings had an impact on well-being. 80 participants completed 8 weeks of self-compassionate writing exercises to enhance either self-kindness, common humanity, or mindfulness. Trait self-compassion was assessed using the six-factor model of the self-compassion scale. To address issues of alpha-error-inflation, the false discovery rate was fixed at 5%, and critical p values were adjusted accordingly. Participants in the mindfulness condition reported increased total self-compassion (p = .009), which was accompanied by increased self-kindness (p = .027) and lower isolation (p = .045). Participants in the common humanity condition reported improved total self-compassion (p = .018), lower over-identification (p = .045), and higher life-satisfaction (p = .049). The training in self-kindness failed to improve self-kindness or any other factor. These findings provide initial evidence that the components of self-compassion mutually enhance each other. They also emphasize the importance of mindfulness within the conceptualization of self-compassion.
The hot and dense QCD matter produced in nuclear collisions at ultrarelativistic energy is characterized by very intense electromagnetic fields which attain their maximal strength in the early pre-equilibrium stage and interplay with the strong vorticity induced in the plasma by the large angular momentum of the colliding system. A promising observable keeping trace of these phenomena is the directed flow of light hadrons and heavy mesons produced in symmetric and asymmetric heavy-ion collisions as well as in proton-induced reactions. In particular, the splitting of the directed flow between particles with the same mass but opposite electric charge as a function of rapidity and transverse momentum gives access to the electromagnetic response of medium in all collision stages and in the different colliding systems. The highest influence of the electromagnetic fields is envisaged in the pre-equilibrium stage of the collision and therefore a significant imprint is left on the early-produced heavy quarks. The aim of this review is to discuss the current developments towards the understanding of the generation and relaxation time of the electromagnetic fields embedded in both large and small systems and their impact on the charge-odd directed flow of light and heavy particles, highlighting the experimental results and the different theoretical approaches. Since it is possible to perform realistic simulations of high-energy collisions that incorporate also the generated electromagnetic fields and vorticity, the study of the directed flow can provide unique insight into the early nonequilibrium phase and the ensuing QGP formation and transport properties.
This focus issue of the European Journal of Trauma and Emergency Surgery compiles a collection of outstanding clinical research using the immense dataset of the German TraumaRegister DGU® (TR-DGU). The TR-DGU of the German Trauma Society (Deutsche Gesellschaft für Unfallchirurgie, DGU) was founded in 1993. Currently, approximately 40,000 cases from more than 600 hospitals are entered into the database every year. The selected articles of this focus on issue highlight the immense value the TR-DGU constitutes for the current, but also for the future trauma research.
Shares of open-end real estate funds are typically traded directly between the investor and the fund management company. However, we provide empirical evidence for the growth of secondary market activities, i.e., the trading of shares on stock exchanges. We find high trading levels in situations where the fund management company suspends the issue or redemption of shares. Shares trade at a discount when the fund management company suspends the redemption, whereas shares trade at a premium when the fund management company suspends the issue. We also find evidence that secondary market trading activity is increasing since German regulation introduced a minimum holding period and a mandatory notice period for open-end real estate funds.