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Mitochondrien sind die Kraftwerke unserer Zellen. In ihnen findet die Zellatmung statt, die unseren Körper mit lebenswichtiger Energie versorgt. Zusätzlich teilen sich die Zellorganellen und verschmelzen wieder miteinander im Minutentakt. Was aber passiert, wenn Teile dieses dynamischen Geflechts Defekte aufweisen? Die Antwort dazu könnte ein Protein sein, das auf zwei verschiedene Weisen in die Mitochondrien-Membranen eingebaut wird. Liegt keine kurze Form des Proteins vor, ist das ein Hinweis dafür, dass die Organellen defekt sind. Die Mitochondrien verbrennen die mit der Nahrung zugeführten Kohlenhydrate und Fette unter Verbrauch von Sauerstoff zu Kohlendioxid und Wasser. Bei diesem Vorgang, der Zellatmung, wird über eine Reihe von Proteinkomplexen ein elektrochemisches Potenzial aufgebaut, das zur Produktion des Energieträgers ATP (Adenosintriphosphat) genutzt wird. ATP kann aus den Mitochondrien abtransportiert werden und steht somit als eine Art Treibstoff für alle Stoffwechselprozesse zur Verfügung. Die Arbeit der Mitochondrien ist der Hauptgrund für unseren täglichen Sauerstoffbedarf. Außerdem tragen die Nano-Kraftwerke der Zelle dazu bei, unsere Körpertemperatur auf 37 °C aufrechtzuerhalten. Aufgrund dieser zentralen Funktionen ist es nicht verwunderlich, dass eine Reihe von Krankheiten beim Menschen durch den Funktionsverlust von Mitochondrien verursacht oder beeinflusst wird. Das sind in erster Linie neurologische oder muskuläre Erkrankungen, aber auch Diabetes, Fettleibigkeit, verschiedene Formen von Krebs und Alterungsprozesse. Folglich ist es von immenser Bedeutung zu verstehen, wie Mitochondrien funktionieren, wie sie ihre Funktionalität aufrechterhalten und gegebenenfalls repariert oder entsorgt werden können. Dem können wir am Wissenschaftsstandort Frankfurt hervorragend nachgehen, da sich einige international ausgewiesene Forschungsgruppen in den Fachbereichen Medizin, Biologie, Chemie und am Max-Planck-Institut für Biophysik mit verschiedenen Aspekten der mitochondrialen Biologie befassen. In zahlreichen interdisziplinären Kooperationen wird so versucht, dieses komplexe System besser zu verstehen.
The macrophage-inducible C-type lectin (mincle) is part of the innate immune system and acts as a pattern recognition receptor for pathogen-associated molecular patterns (PAMPS) and damage-associated molecular patterns (DAMPs). Ligand binding induces mincle activation which consequently interacts with the signaling adapter Fc receptor, SYK, and NF-kappa-B. There is also evidence that mincle expressed on macrophages promotes intestinal barrier integrity. However, little is known about the role of mincle in hepatic fibrosis, especially in more advanced disease stages. Mincle expression was measured in human liver samples from cirrhotic patients and donors collected at liver transplantation and in patients undergoing bariatric surgery. Human results were confirmed in rodent models of cirrhosis and acute-on-chronic liver failure (ACLF). In these models, the role of mincle was investigated in liver samples as well as in peripheral blood monocytes (PBMC), tissues from the kidney, spleen, small intestine, and heart. Additionally, mincle activation was stimulated in experimental non-alcoholic steatohepatitis (NASH) by treatment with mincle agonist trehalose-6,6-dibehenate (TDB). In human NASH, mincle is upregulated with increased collagen production. In ApoE deficient mice fed high-fat western diet (NASH model), mincle activation significantly increases hepatic collagen production. In human cirrhosis, mincle expression is also significantly upregulated. Furthermore, mincle expression is associated with the stage of chronic liver disease. This could be confirmed in rat models of cirrhosis and ACLF. ACLF was induced by LPS injection in cirrhotic rats. While mincle expression and downstream signaling via FC receptor gamma, SYK, and NF-kappa-B are upregulated in the liver, they are downregulated in PBMCs of these rats. Although mincle expressed on macrophages might be beneficial for intestinal barrier integrity, it seems to contribute to inflammation and fibrosis once the intestinal barrier becomes leaky in advanced stages of chronic liver disease.
Macrophages are highly versatile cells, which acquire, depending on their microenvironment, pro- (M1-like), or antiinflammatory (M2-like) phenotypes. Here, we studied the role of the G-protein coupled receptor G2A (GPR132), in chemotactic migration and polarization of macrophages, using the zymosan-model of acute inflammation. G2A-deficient mice showed a reduced zymosan-induced thermal hyperalgesia, which was reversed after macrophage depletion. Fittingly, the number of M1-like macrophages was reduced in the inflamed tissue in G2A-deficient mice. However, G2A activation was not sufficient to promote M1-polarization in bone marrow-derived macrophages. While the number of monocyte-derived macrophages in the inflamed paw was not altered, G2A-deficient mice had less macrophages in the direct vicinity of the origin of inflammation, an area marked by the presence of zymosan, neutrophil accumulation and proinflammatory cytokines. Fittingly neutrophil efferocytosis was decreased in G2A-deficient mice and several lipids, which are released by neutrophils and promote G2A-mediated chemotaxis, were increased in the inflamed tissue. Taken together, G2A is necessary to position macrophages in the proinflammatory microenvironment surrounding the center of inflammation. In absence of G2A the macrophages are localized in an antiinflammatory microenvironment and macrophage polarization is shifted toward M2-like macrophages.
Endothelium-dependent vasodilation is thought to be mediated primarily by the NO/cGMP signaling pathway whereas cAMP-elevating vasodilators are considered to act independent of the endothelial cell layer. However, recent functional data suggest that cAMP-elevating vasodilators such as β-receptor agonists, adenosine or forskolin may also be endothelium-dependent. Here we used functional and biochemical assays to analyze endothelium-dependent, cGMP- and cAMP-mediated signaling in rat aorta. Acetylcholine and sodium nitroprusside (SNP) induced a concentration-dependent relaxation of phenylephrine-precontracted aorta. This response was reflected by the phosphorylation of the vasodilator-stimulated phosphoprotein (VASP), a validated substrate of cGMP- and cAMP-dependent protein kinases (cGK, cAK), on Ser157 and Ser239. As expected, the effects of acetylcholine were endothelium-dependent. However, relaxation induced by the β-receptor agonist isoproterenol was also almost completely impaired after endothelial denudation. At the biochemical level, acetylcholine- and isoproterenol-evoked cGK and cAK activation, respectively, as measured by VASP Ser239 and Ser157 phosphorylation, was strongly diminished. Furthermore, the effects of isoproterenol were repressed by eNOS inhibition when endothelium was present. We also observed that the relaxing and biochemical effects of forskolin were at least partially endothelium-dependent. We conclude that cAMP-elevating vasodilators, i.e. isoproterenol and to a lesser extent also forskolin, induce vasodilation and concomitant cyclic nucleotide protein kinase activation in the vessel wall in an endothelium-dependent way.
Streptococcus pneumoniae is the most frequent cause of community-acquired pneumonia. The infection process involves bacterial cell surface receptors, which interact with host extracellular matrix components to facilitate colonization and dissemination of bacteria. Here, we investigated the role of host-derived extracellular RNA (eRNA) in the process of pneumococcal alveolar epithelial cell infection. Our study demonstrates that eRNA dose-dependently increased S. pneumoniae invasion of alveolar epithelial cells. Extracellular enolase (Eno), a plasminogen (Plg) receptor, was identified as a novel eRNA-binding protein on S. pneumoniae surface, and six Eno eRNA-binding sites including a C-terminal 15 amino acid motif containing lysine residue 434 were characterized. Although the substitution of lysine 434 for glycine (K434G) markedly diminished the binding of eRNA to Eno, the adherence to and internalization into alveolar epithelial cells of S. pneumoniae strain carrying the C-terminal lysine deletion and the mutation of internal Plg-binding motif were only marginally impaired. Accordingly, using a mass spectrometric approach, we identified seven novel eRNA-binding proteins in pneumococcal cell wall. Given the high number of eRNA-interacting proteins on pneumococci, treatment with RNase1 completely inhibited eRNA-mediated pneumococcal alveolar epithelial cell infection. Our data support further efforts to employ RNAse1 as an antimicrobial agent to combat pneumococcal infectious diseases.
The function of the p53 transcription factor family is dependent on several folded domains. In addition to a DNA-binding domain, members of this family contain an oligomerization domain. p63 and p73 also contain a C-terminal Sterile α-motif domain. Inhibition of most transcription factors is difficult as most of them lack deep pockets that can be targeted by small organic molecules. Genetic knock-out procedures are powerful in identifying the overall function of a protein, but they do not easily allow one to investigate roles of individual domains. Here we describe the characterization of Designed Ankyrin Repeat Proteins (DARPins) that were selected as tight binders against all folded domains of p63. We determine binding affinities as well as specificities within the p53 protein family and show that DARPins can be used as intracellular inhibitors for the modulation of transcriptional activity. By selectively inhibiting DNA binding of the ΔNp63α isoform that competes with p53 for the same promoter sites, we show that p53 can be reactivated. We further show that inhibiting the DNA binding activity stabilizes p63, thus providing evidence for a transcriptionally regulated negative feedback loop. Furthermore, the ability of DARPins to bind to the DNA-binding domain and the Sterile α-motif domain within the dimeric-only and DNA-binding incompetent conformation of TAp63α suggests a high structural plasticity within this special conformation. In addition, the developed DARPins can also be used to specifically detect p63 in cell culture and in primary tissue and thus constitute a very versatile research tool for studying the function of p63.
This paper reports on Monte Carlo simulation results for future measurements of the moduli of time-like proton electromagnetic form factors, |GE | and |GM|, using the ¯pp → μ+μ− reaction at PANDA (FAIR). The electromagnetic form factors are fundamental quantities parameterizing the electric and magnetic structure of hadrons. This work estimates the statistical and total accuracy with which the form factors can be measured at PANDA, using an analysis of simulated data within the PandaRoot software framework. The most crucial background channel is ¯pp → π+π−,due to the very similar behavior of muons and pions in the detector. The suppression factors are evaluated for this and all other relevant background channels at different values of antiproton beam momentum. The signal/background separation is based on a multivariate analysis, using the Boosted Decision Trees method. An expected background subtraction is included in this study, based on realistic angular distribuations of the background contribution. Systematic uncertainties are considered and the relative total uncertainties of the form factor measurements are presented.
Using recent lattice data on the thermodynamics of QCD in the presence of a background magnetic field, we show that the ratio of transverse to longitudinal pressure exhibits, to good accuracy, a simple scaling behavior over a wide range of temperature and magnetic field, essentially depending only on the ratio T/B $$ T/\sqrt{B} $$. We compare this QCD response to the corresponding magnetoresponse in maximally supersymmetric Yang Mills theory. Given suitable calibrations defining the comparison, we find excellent agreement. This may be viewed as a further test of the applicability of holographic models for hot QCD.
Background: The approval of everolimus (EVE) for the treatment of angiomyolipoma (2013), subependymal giant cell astrocytoma (2013) and drug-refractory epilepsy (2017) in patients with tuberous sclerosis complex (TSC) represents the first disease-modifying treatment option available for this rare and complex genetic disorder. Objective: The objective of this study was to analyse the use, efficacy, tolerability and treatment retention of EVE in patients with TSC in Germany from the patient’s perspective. Methods: A structured cross-age survey was conducted at 26 specialised TSC centres in Germany and by the German TSC patient advocacy group between February and July 2019, enrolling children, adolescents and adult patients with TSC. Results: Of 365 participants, 36.7% (n = 134) reported the current or past intake of EVE, including 31.5% (n = 115) who were taking EVE at study entry. The mean EVE dosage was 6.1 ± 2.9 mg/m2 (median: 5.6 mg/m2, range 2.0–15.1 mg/m2) in children and adolescents and 4 ± 2.1 mg/m2 (median: 3.7 mg/m2, range 0.8–10.1 mg/m2) in adult patients. An early diagnosis of TSC, the presence of angiomyolipoma, drug-refractory epilepsy, neuropsychiatric manifestations, subependymal giant cell astrocytoma, cardiac rhabdomyoma and overall multi-organ involvement were associated with the use of EVE as a disease-modifying treatment. The reported efficacy was 64.0% for angiomyolipoma (75% in adult patients), 66.2% for drug-refractory epilepsy, and 54.4% for subependymal giant cell astrocytoma. The overall retention rate for EVE was 85.8%. The retention rates after 12 months of EVE therapy were higher among adults (93.7%) than among children and adolescents (88.7%; 90.5% vs 77.4% after 24 months; 87.3% vs 77.4% after 36 months). Tolerability was acceptable, with 70.9% of patients overall reporting adverse events, including stomatitis (47.0%), acne-like rash (7.7%), increased susceptibility to common infections and lymphoedema (each 6.0%), which were the most frequently reported symptoms. With a total score of 41.7 compared with 36.8 among patients not taking EVE, patients currently being treated with EVE showed an increased Liverpool Adverse Event Profile. Noticeable deviations in the sub-items ‘tiredness’, ‘skin problems’ and ‘mouth/gum problems’, which are likely related to EVE-typical adverse effects, were more frequently reported among patients taking EVE. Conclusions: From the patients’ perspective, EVE is an effective and relatively well-tolerated disease-modifying treatment option for children, adolescents and adults with TSC, associated with a high long-term retention rate that can be individually considered for each patient. Everolimus therapy should ideally be supervised by a centre experienced in the use of mechanistic target of rapamycin inhibitors, and adverse effects should be monitored on a regular basis.
We discuss the prospects for parity-nonconservation experiments with highly charged heavy ions. Energy levels and parity mixing for heavy ions with 2–5 electrons are calculated. We investigate two-photon transitions and the possibility of observing interference effects between weak-matrix elements and Stark matrix elements for periodic electric field configurations.
Parity mixing of electron states should be extremely strong for heliumlike uranium. We calculate its size and discuss whether it could be determined experimentally. We analyze one specific scheme for such an experiment. The required laser intensities for two-photon spectroscopy of the 23P0–2 1S0level splitting is of the order of 1017 W/cm2. A determination of parity mixing would require at least 1021 W/cm2.
The Gottfried sum-rule violation reported by the New Muon Collaboration was interpreted as an indication for a flavor asymmetry of the sea quark in the nucleon. We investigate the alternative possibility that isospin symmetry between the proton and the neutron is breaking. We examine systematically the consequences of this possibility for several processes, namely, neutrino deep inelastic scattering, the charged pion Drell-Yan process, the proton Drell-Yan process, and semi-inclusive deep inelastic scattering, and conclude that a decision between the two alternative explanations is possible.
A new spontaneous-symmetry-breaking mechanism is formulated for SU(3), which is used to describe the formation of bags around quarks. The Higgs field is replaced by the scalar product of two colored fermion fields. This model gives mass only to one gluon (equivalent to Aμ8) when spontaneously broken. The consequences of this scheme are discussed, and it is argued that it can explain several puzzling high-energy heavy-ion experiments.
Phenomenological consequences of a hypothetical light neutral particle in heavy ion collisions
(1986)
We discuss the possibility that the line structure observed in the spectrum of the positrons produced in heavy ion collisions is due to the decay of a new neutral elementary particle. We argue that this can be ruled out unless one is willing to accept fine tuning of parameters, or to assume the dominance of nonlinear effects.
We have investigated the channeling process of charged particles in a bent crystal. Invoking simple assumptions we derive a criterion, which determines whether channeling occurs or not. We obtain the same criterion using the Dirac equation. It is shown that the centrifugal force acting on the particle in the bent crystal significantly alters the effective transverse potential. The cases of axial and planar channeling are considered. The channeling probability and the dechanneling probability due to tunneling of the particle under the barrier in the effective transverse potential are estimated. These probabilities depend on the specific scaling parameter characterizing the process. Using the quasiclassical theory of synchrotron radiation we have calculated the contribution to the radiation spectrum, which arises due to the curvature of the channel. This contribution becomes significant to TeV electrons or positrons. Some practical consequences of our results are briefly discussed.
An alternative theoretical description of axial electron channeling in the multi-GeV region has been developed. We solve a kinetic equation to evaluate an electron distribution function in axially oriented single crystals. Based on the single-string model, the required matrix elements for radiation and scattering by lattice vibrations are calculated employing solutions of the Dirac equation in cylindrical coordinates. Results obtained for 150-GeV electrons propagating along the <110> axis of germanium are in good agreement with experimental observations.
We investigate the possibility that high-energy photons are channeled, when passing through an oriented single crystal, due to Delbrück scattering. For this purpose the exact electron propagator for the single-string model is constructed. Starting from a separation of variables, we solve the Dirac equation for a cylindrical electrostatic potential. The propagator for such external fields is constructed from solutions of the radial Dirac equation. This propagator is applied to a calculation of the S matrix for Delbrück scattering. We specify the conditions under which photon channeling takes place. Unfortunately these conditions are only matched for a very small fraction of those photons being produced by channeled electrons.
The electron-positron pairs observed in heavy-ion collisions at Gesellschaft für Schwerionen-forschung Darmstadt mbH have been interpreted as the decay products of yet unknown particles with masses around 1.8 MeV. The negative results of resonant Bhabha scattering experiments, however, do not support such an interpretation. Therefore we focus on a more complex decay scenario, where the e+e- lines result from a two-collision process. We discuss the induced decay of a metastable 1++ state into e+e- pairs. For most realizations of a 1++ state such a decay in leading order can only take place in the Coulomb field of a target atom. This fact has the attractive consequence that for such a state the Bhabha bounds are no longer valid. However, the absolute value of the e+e- production cross section turns out to be unacceptably small.
Hybrid robust deep and shallow semantic processing for creativity support in document production
(2004)
The research performed in the DeepThought project (http://www.project-deepthought.net) aims at demonstrating the potential of deep linguistic processing if added to existing shallow methods that ensure robustness. Classical information retrieval is extended by high precision concept indexing and relation detection. We use this approach to demonstrate the feasibility of three ambitious applications, one of which is a tool for creativity support in document production and collective brainstorming. This application is described in detail in this paper. Common to all three applications, and the basis for their development is a platform for integrated linguistic processing. This platform is based on a generic software architecture that combines multiple NLP components and on robust minimal recursive semantics (RMRS) as a uniform representation language.