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Scherer, Stefan ; Bass, Steffen A. ; Belkacem, Mohamed ; Bleicher, Marcus ; Brachmann, Jörg ; Dumitru, Adrian Bogdan ; Ernst, Christoph ; Gerland, Lars ; Hammon, Nils ; Hofmann, Markus ; Konopka, Jens ; Neise, Ludwig ; Reiter, Manuel ; Schramm, Stefan ; Soff, Sven ; Spieles, Christian ; Weber, Henning ; Zschiesche, Detlef ; Maruhn, Joachim ; Stöcker, Horst ; Greiner, Walter
Nonequilibrium models (three-fluid hydrodynamics, UrQMD, and quark molecular dynamics) are used to discuss the uniqueness of often proposed experimental signatures for quark matter formation in relativistic heavy ion collisions from the SPS via RHIC to LHC. It is demonstrated that these models - although they do treat the most interesting early phase of the collisions quite differently (thermalizing QGP vs. coherent color fields with virtual particles) -- all yield a reasonable agreement with a large variety of the available heavy ion data. Hadron/hyperon yields, including J/Psi meson production/suppression, strange matter formation, dileptons, and directed flow (bounce-off and squeeze-out) are investigated. Observations of interesting phenomena in dense matter are reported. However, we emphasize the need for systematic future measurements to search for simultaneous irregularities in the excitation functions of several observables in order to come close to pinning the properties of hot, dense QCD matter from data. The role of future experiments with the STAR and ALICE detectors is pointed out.
Scherer, Stefan ; Hofmann, Markus ; Bleicher, Marcus ; Neise, Ludwig ; Stöcker, Horst ; Greiner, Walter
The quark-molecular-dynamics model is used to study microscopically the dynamics of the coloured quark phase and the subsequent hadron formation in relativistic S+Au collisions at the CERN-SPS. Particle spectra and hadron ratios are compared to both data and the results of hadronic transport calculations. The non-equilibrium dynamics of hadronization and the loss of correlation among quarks are studied.
A microscopic model of deconfined matter based on color interactions between semi-classical quarks is studied. A hadronization mechanism is imposed to examine the properties and the disassembly of a thermalized quark plasma and to investigate the possible existence of a phase transition from quark matter to hadron matter.
Hofmann, Markus ; Eisenberg, Judah M. ; Scherer, Stefan ; Bleicher, Marcus ; Neise, Ludwig ; Stöcker, Horst ; Greiner, Walter
We investigate the hadronic cooling of a quark droplet within a microscopic model. The color flux tube approach is used to describe the hadronization of the quark phase. The model reproduces experimental particle ratios equally well compared to a static thermal hadronic source. Furthermore, the dynamics of the decomposition of a quark-gluon plasma is investigated and time dependent particle ratios are found.
Junghans, Arnd Rudolf ; Beyer, Roland ; Claußner, Jürgen ; Kögler, Toni ; Urlaß, Sebastian ; Bemmerer, Daniel ; Ferrari, Anna ; Schwengner, Ronald ; Wagner, Andreas ; Dietz, Mirco ; Frotscher, Axel ; Grieger, Marcel ; Hensel, Thomas ; Koppitz, Martina ; Ludwig, Felix ; Turkat, Steffen ; Nolte, Ralf ; Pirovano, Elisa ; Kopecky, Stefan ; Nyman, Markus ; Plompen, Arjan J. M. ; Schillebeeckx, Peter ; Borris, Erik ; Reifarth, René ; Veltum, Daniel ; Weigand, Mario ; Glorius, Jan ; Görres, Joachim ; Oberlack, Uwe ; Wenz, Daniel
Neutron total cross sections are an important source of experimental data in the evaluation of neutron-induced cross sections. The sum of all neutron-induced reaction cross sections can be determined with a precision of a few per cent in a relative measurement. The neutron spectrum of the photoneutron source nELBE extends in the fast region from about 100 keV to 10 MeV and has favourable conditions for transmission measurements due to the low instantaneous flux of neutrons and low gamma-flash background. Several materials of interest (in part included in the CIELO evaluation or on the HPRL of OECD/NEA) have been investigated: 197Au [1, 2], natFe [2], natW [2], 238U, natPt, 4He, natO, natNe, natXe. For gaseous targets high pressure gas cells with flat end-caps have been built that hold up to 200 bar pressure. The experimental setup will be presented including results from several transmission experiments and the data analysis leading to the total cross sections will be discussed.
Gutwein, Paul ; Schramme, Anja ; Abdel-Bakky, Mohamed Sadek ; Doberstein, Kai ; Hauser, Ingeborg A. ; Ludwig, Andreas ; Altevogt, Peter ; Gauer, Stefan ; Hillmann, Anja ; Weide, Thomas ; Jespersen, Christine ; Eberhardt, Wolfgang ; Pfeilschifter, Josef
Background: The importance of the Notch signaling in the development of glomerular diseases has been recently described. Therefore we analyzed in podocytes the expression and activity of ADAM10, one important component of the Notch signaling complex. Methods: By Western blot, immunofluorescence and immunohistochemistry analysis we characterized the expression of ADAM10 in human podocytes, human urine and human renal tissue. Results: We present evidence, that differentiated human podocytes possessed increased amounts of mature ADAM10 and released elevated levels of L1 adhesion molecule, one well known substrate of ADAM10. By using specific siRNA and metalloproteinase inhibitors we demonstrate that ADAM10 is involved in the cleavage of L1 in human podocytes. Injury of podocytes enhanced the ADAM10 mediated cleavage of L1. In addition, we detected ADAM10 in urinary podocytes from patients with kidney diseases and in tissue sections of normal human kidney. Finally, we found elevated levels of ADAM10 in urinary vesicles of patients with glomerular kidney diseases. Conclusions: The activity of ADAM10 in human podocytes may play an important role in the development of glomerular kidney diseases.
Hanauske, Matthias ; Steinheimer-Froschauer, Jan ; Motornenko, Anton ; Vovchenko, Volodymyr ; Bovard, Luke ; Most, Elias Roland ; Papenfort, Ludwig Jens ; Schramm, Stefan ; Stöcker, Horst
Gravitational waves, electromagnetic radiation, and the emission of high energy particles probe the phase structure of the equation of state of dense matter produced at the crossroad of the closely related relativistic collisions of heavy ions and of binary neutron stars mergers. 3 + 1 dimensional special- and general relativistic hydrodynamic simulation studies reveal a unique window of opportunity to observe phase transitions in compressed baryon matter by laboratory based experiments and by astrophysical multimessenger observations. The astrophysical consequences of a hadron-quark phase transition in the interior of a compact star will be focused within this article. Especially with a future detection of the post-merger gravitational wave emission emanated from a binary neutron star merger event, it would be possible to explore the phase structure of quantum chromodynamics. The astrophysical observables of a hadron-quark phase transition in a single compact star system and binary hybrid star merger scenario will be summarized within this article. The FAIR facility at GSI Helmholtzzentrum allows one to study the universe in the laboratory, and several astrophysical signatures of the quark-gluon plasma have been found in relativistic collisions of heavy ions and will be explored in future experiments.
Hanauske, Matthias ; Bovard, Luke ; Most, Elias Roland ; Papenfort, Ludwig Jens ; Steinheimer-Froschauer, Jan ; Motornenko, Anton ; Vovchenko, Volodymyr ; Dexheimer, Verônica Antocheviz ; Schramm, Stefan ; Stöcker, Horst
The long-awaited detection of a gravitational wave from the merger of a binary neutron star in August 2017 (GW170817) marks the beginning of the new field of multi-messenger gravitational wave astronomy. By exploiting the extracted tidal deformations of the two neutron stars from the late inspiral phase of GW170817, it is now possible to constrain several global properties of the equation of state of neutron star matter. However, the most interesting part of the high density and temperature regime of the equation of state is solely imprinted in the post-merger gravitational wave emission from the remnant hypermassive/supramassive neutron star. This regime was not observed in GW170817, but will possibly be detected in forthcoming events within the current observing run of the LIGO/VIRGO collaboration. Numerous numerical-relativity simulations of merging neutron star binaries have been performed during the last decades, and the emitted gravitational wave profiles and the interior structure of the generated remnants have been analysed in detail. The consequences of a potential appearance of a hadron-quark phase transition in the interior region of the produced hypermassive neutron star and the evolution of its underlying matter in the phase diagram of quantum cromo dynamics will be in the focus of this article. It will be shown that the different density/temperature regions of the equation of state can be severely constrained by a measurement of the spectral properties of the emitted post-merger gravitational wave signal from a future binary compact star merger event.
Dexheimer, Verônica Antocheviz ; Constantinou, Constantinos ; Most, Elias Roland ; Papenfort, Ludwig Jens ; Hanauske, Matthias ; Schramm, Stefan ; Stöcker, Horst ; Rezzolla, Luciano
In this work, we discuss the dense matter equation of state (EOS) for the extreme range of conditions encountered in neutron stars and their mergers. The calculation of the properties of such an EOS involves modeling different degrees of freedom (such as nuclei, nucleons, hyperons, and quarks), taking into account different symmetries, and including finite density and temperature effects in a thermodynamically consistent manner. We begin by addressing subnuclear matter consisting of nucleons and a small admixture of light nuclei in the context of the excluded volume approach. We then turn our attention to supranuclear homogeneous matter as described by the Chiral Mean Field (CMF) formalism. Finally, we present results from realistic neutron-star-merger simulations performed using the CMF model that predict signatures for deconfinement to quark matter in gravitational wave signals.
Scherer, Stefan ; Bass, Steffen A. ; Bleicher, Marcus ; Belkacem, Mohamed ; Bravina, Larissa ; Brachmann, Jörg ; Dumitru, Adrian Bogdan ; Ernst, Christoph ; Gerland, Lars ; Hofmann, Markus ; Neise, Ludwig ; Reiter, Manuel ; Soff, Sven ; Spieles, Christian ; Weber, Henning ; Zabrodin, Eugene E. ; Zschiesche, Detlef ; Maruhn, Joachim ; Stöcker, Horst ; Greiner, Walter
Noneequilibrium models (three-fluid hydrodynamics and UrQMD) use to discuss the uniqueness of often proposed experimental signatures for quark matter formation in relativistic heavy ion collisions. It is demonstrated that these two models - although they do treat the most interesting early phase of the collisions quite differently(thermalizing QGP vs. coherent color fields with virtual particles) - both yields a reasonable agreement with a large variety of the available heavy ion data.
Horn, Tabea ; Ludwig, Michael ; Eickmeier, Olaf ; Neerinex, Anne H. ; Maitland-van der Zee, Anke Hilse ; Smaczny, Christina ; Wagner, Thomas O. F. ; Schubert, Ralf ; Zielen, Stefan ; Majoor, Christof ; Bos, Lieuwe D. ; Schmitt-Grohé, Sabina
Background: Lung disease phenotype varies widely even in the F508del (homozygous) genotype. Leukocyte-driven inflammation is important for pulmonary disease pathogenesis in cystic fibrosis (CF). Blood cytokines correlate negatively with pulmonary function in F508del homozygous patients, and gap junction proteins (GJA) might be related to the influx of blood cells into the lung and influence disease course. We aimed to assess the relationship between GJA1/GJA4 genotypes and the clinical disease phenotype. Methods: One-hundred-and-sixteen homozygous F508del patients (mean age 27 years, m/f 66/50) were recruited from the CF centers of Bonn, Frankfurt, and Amsterdam. Sequence analysis was performed for GJA1 and GJA4. The clinical disease course was assessed over 3 years using pulmonary function tests, body mass index, Pseudomonas aeruginosa colonization, diabetes mellitus, survival to end-stage lung disease, blood and sputum inflammatory markers. Results: Sequence analysis revealed one clinically relevant single nucleotide polymorphism. In this GJA4 variant (rs41266431), homozygous G variant carriers (n = 84/116; 72.4%) had poorer pulmonary function (FVC% pred: mean 78/86, p < 0.040) and survival to end-stage lung disease was lower (p < 0.029). The frequency of P. aeruginosa colonization was not influenced by the genotype, but in those chronically colonized, those with the G/G genotype had reduced pulmonary function (FVC% pred: mean 67/80, p < 0.049). Serum interleukin-8 (median: 12.4/6.7 pg/ml, p < 0.052) and sputum leukocytes (2305/437.5 pg/ml, p < 0.025) were higher for the G/G genotype. Conclusions: In carriers of the A allele (27.6%) the GJA4 variant is associated with significantly better protection against end-stage lung disease and superior pulmonary function test results in F508del homozygous patients. This SNP has the potential of a modifier gene for phenotyping severity of CF lung disease, in addition to the CFTR genotype.
Clinical Trial Registration: The study was registered with ClinicalTrials.gov, number NCT04242420, retrospectively on January 24th, 2020.
Maaser, Anna ; Forstner, Andreas Josef ; Strohmaier, Jana ; Hecker, Julian ; Ludwig, Kerstin ; Sivalingam, Sugirthan ; Streit, Fabian ; Degenhardt, Franziska ; Witt, Stephanie ; Reinbold, Céline S. ; Koller, Anna C. ; Raff, Ruth ; Heilmann-Heimbach, Stefanie ; Fischer, Sascha B. ; Herms, Stefan ; Hoffmann, Per ; Thiele, Holger ; Nürnberg, Peter ; Fier, Heide ; Orozco-Díaz, Guillermo ; Carmenate-Naranjo, Deinys ; Proenza-Barzaga, Niurka ; Auburger, Georg ; Andlauer, Till ; Cichon, Sven ; Marcheco-Teruel, Beatriz ; Mors, Ole ; Rietschel, Marcella ; Nöthen, Markus Maria
Bipolar disorder (BD) is a major psychiatric illness affecting around 1% of the global population. BD is characterized by recurrent manic and depressive episodes, and has an estimated heritability of around 70%. Research has identified the first BD susceptibility genes. However, the underlying pathways and regulatory networks remain largely unknown. Research suggests that the cumulative impact of common alleles with small effects explains only around 25–38% of the phenotypic variance for BD. A plausible hypothesis therefore is that rare, high penetrance variants may contribute to BD risk. The present study investigated the role of rare, nonsynonymous, and potentially functional variants via whole exome sequencing in 15 BD cases from two large, multiply affected families from Cuba. The high prevalence of BD in these pedigrees renders them promising in terms of the identification of genetic risk variants with large effect sizes. In addition, SNP array data were used to calculate polygenic risk scores for affected and unaffected family members. After correction for multiple testing, no significant increase in polygenic risk scores for common, BD-associated genetic variants was found in BD cases compared to healthy relatives. Exome sequencing identified a total of 17 rare and potentially damaging variants in 17 genes. The identified variants were shared by all investigated BD cases in the respective pedigree. The most promising variant was located in the gene SERPING1 (p.L349F), which has been reported previously as a genome-wide significant risk gene for schizophrenia. The present data suggest novel candidate genes for BD susceptibility, and may facilitate the discovery of disease-relevant pathways and regulatory networks.
Ludwig, Michael ; Eickmeier, Olaf ; Smaczny, Christina ; Schreiner, Felix ; Dubois, Wilma ; N'Gampolo, Doris ; Schubert, Ralf ; Zielen, Stefan ; Ganschow, Ralf ; Schmitt-Grohé, Sabina
Aims: We have provided evidence in former studies that cytokines (IL-8, TNF alpha, LBP, TGFß) measured in blood correlate negatively with lung function in deltaF508 homozygous patients. GAP junction proteins might be of importance for the influx of blood cells into the lung. Our aim was to assess the relationship between connexin genotypes and cytokines (IL-8, TNF-alpha, LBP, TGFß) in induced sputum and serum, and lung disease.
Methods: 36 patients homozygous for deltaF508 (median age 18 y, m/f 16/20, FEV1(%) 77) were examined. Sequence analysis was performed for genes encoding GAP junction protein alpha 1 (GJA1/connexin 43) and gap junction protein alpha 4 (GJA4/connexin 37). Cytokines were assessed in serum and induced sputum (IS) by chemiluminescence (DPC Biermann, Bad Homburg, Germany) as well as leukocyte counts.
Results: DNA analysis was performed in 35 patients. Whereas GJA1 showed only one rare heterozygous synonymous SNP (rs138386744) in one patient, four common SNPs were detected in GJA4. Two were synonymous changes, but the third variant (rs41266431) predicts an amino acid substitution (GTA → valine, ATA → isoleucine) as well as the fourth SNP (rs1764391: CCC→proline, TCC→serine). For rs41266431 patients with homozygosity for the G variant had higher IL-8 levels (median: 13.3/8.0 pg/ml, p=0.07) in serum as well as leukocytes in sputum (median: 2050/421 /µl p=0.041) than those showing heterozygosity (G/A). In individuals > 30 years lung function (FEV1 41.3/84.83 % predicted, p=0.07) was worse.
Conclusion: SNP rs41266431 seems a promising candidate for further investigations, suggesting GJA4 a potential disease modifying gene.
Ludwig, Jürgen ; Kerscher, Stefan ; Brandt, Ulrich ; Pfeiffer, Kathy ; Getlawi, Fariha ; Apps, David K. ; Schägger, Hermann
Vacuolar proton-translocating ATPase (holoATPase and free membrane sector) was isolated from bovine chromaffin granules by blue native polyacrylamide gel electrophoresis. A 5-fold excess of membrane sector over holoenzyme was determined in isolated chromaffin granule membranes. M9.2, a novel extremely hydrophobic 9.2-kDa protein comprising 80 amino acids, was detected in the membrane sector. It shows sequence and structural similarity to Vma21p, a yeast protein required for assembly of vacuolar ATPase. A second membrane sector-associated protein (M8-9) was identified and characterized by amino-terminal protein sequencing.
Zhang, Rong ; Gehlen, Jan ; Kawalia, Amit ; Melissari, Maria-Theodora ; Dakal, Tikam Chand ; Menon, Athira M. ; Höfele, Julia ; Riedhammer, Korbinian ; Waffenschmidt, Lea ; Fabian, Julia ; Breuer, Katinka ; Kalanithy, Jeshurun ; Hilger, Alina Christine ; Sharma, Amit ; Hölscher, Alice ; Boemers, Thomas M. ; Pauly, Markus ; Leutner, Andreas ; Fuchs, Jörg ; Seitz, Guido ; Ludwikowski, Barbara ; Gomez, Barbara ; Hubertus, Jochen ; Heydweiller, Andreas ; Kurz, Ralf ; Leonhardt, Johannes ; Kosch, Ferdinand ; Holland-Cunz, Stefan ; Münsterer, Oliver ; Ure, Beno ; Schmiedeke, Eberhard ; Neser, Jörg ; Degenhardt, Petra ; Märzheuser, Stefanie ; Kleine, Katharina ; Schäfer, Mattias ; Spychalski, Nicole ; Deffaa, Oliver J. ; Gosemann, Jan-Hendrik ; Lacher, Martin ; Heilmann-Heimbach, Stefanie ; Zwink, Nadine ; Jenetzky, Ekkehart ; Ludwig, Michael ; Grote, Phillip ; Schumacher, Johannes ; Thiele, Holger ; Reutter, Heiko
Introduction: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutational de novo events in genes involved in foregut development.
Methods: To identify mutational de novo events in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmed de novo variants were prioritized using in silico prediction tools. To investigate the embryonic role of genes harboring prioritized de novo variants we performed targeted analysis of mouse transcriptome data of esophageal tissue obtained at the embryonic day (E) E8.5, E12.5, and postnatal.
Results: In total we prioritized 14 novel de novo variants in 14 different genes (APOL2, EEF1D, CHD7, FANCB, GGT6, KIAA0556, NFX1, NPR2, PIGC, SLC5A2, TANC2, TRPS1, UBA3, and ZFHX3) and eight rare de novo variants in eight additional genes (CELSR1, CLP1, GPR133, HPS3, MTA3, PLEC, STAB1, and PPIP5K2). Through personal communication during the project, we identified an additional EA/TEF case-parent trio with a rare de novo variant in ZFHX3. In silico prediction analysis of the identified variants and comparative analysis of mouse transcriptome data of esophageal tissue obtained at E8.5, E12.5, and postnatal prioritized CHD7, TRPS1, and ZFHX3 as EA/TEF candidate genes. Re-sequencing of ZFHX3 in additional 192 EA/TEF patients did not identify further putative EA/TEF-associated variants.
Conclusion: Our study suggests that rare mutational de novo events in genes involved in foregut development contribute to the development of EA/TEF.