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The tumor suppressor p53 plays a crucial role in cellular growth control inducing a plethora of different response pathways. The molecular mechanisms that discriminate between the distinct p53-responses have remained largely elusive. Here, we have analyzed the p53-regulated pathways induced by Actinomycin D and Etoposide treatment resulting in more growth arrested versus apoptotic cells respectively. We found that the genome-wide p53 DNA-binding patterns are almost identical upon both treatments notwithstanding transcriptional differences that we observed in global transcriptome analysis. To assess the role of post-translational modifications in target gene choice and activation we investigated the genome-wide level of phosphorylation of Serine 46 of p53 bound to DNA (p53-pS46) and of Serine 15 (p53-pS15). Interestingly, the extent of S46 phosphorylation of p53 bound to DNA is considerably higher in cells directed towards apoptosis while the degree of phosphorylation at S15 remains highly similar. Moreover, our data suggest that following different chemotherapeutical treatments, the amount of chromatin-associated p53 phosphorylated at S46 but not at pS15 is higher on certain apoptosis related target genes. Our data provide evidence that cell fate decisions are not made primarily on the level of general p53 DNA-binding and that post-translationally modified p53 can have distinct DNA-binding characteristics.
Inter arma enim silent leges – im Krieg schweigen die Gesetze, so lautet ein berühmtes Zitat von Cicero, das über die Jahrtausende hinweg in Diskursen der Gewaltlegitimation bedeutsam geblieben ist. Thomas Hobbes und Immanuel Kant haben es übernommen, wobei Letzterer der Rechtfertigung von Krieg die Konzeption eines dreigliedrigen, "ewigen" Rechtszustandes entgegengestellt hat. Zwischen der von "Realisten" angenommenen Anarchie und der von "Idealisten" angestrebten Rechtsherrschaft in grenzübergreifenden politischen Beziehungen hat sich die moderne Völkerrechtswissenschaft insbesondere mit dem schwierigen, zuweilen paradoxen Verhältnis von Krieg und Recht beschäftigt: Das Kriegsrecht limitiert den Gebrauch von Gewalt (als violentia) nicht allein, es legitimiert ihn auch, indem es die Gewalt (als potestas) normativ ordnet und sie damit wiederum zur Rechtfertigungsressource macht. Mit dem Wiedererstarken der Völkerrechtsgeschichte sowie der aktuellen Brisanz kriegsrechtlicher Fragen (etwa angesichts des "war on terror") gehen erneut Forschungen zur Rolle des Rechts in Zeiten des Krieges, zu seiner Rechtfertigung und seiner rechtlichen Aufarbeitung einher. Isabel V. Hull und die AutorInnen im von Martin Löhnig, Mareike Preisner und Thomas Schlemmer herausgegebenen Sammelband leisten hierzu zwei sehr unterschiedliche Beiträge. ...
Dass die in den letzten Jahren stattfindende Ausweitung der Rechtsgeschichte(n) durch globale und transnationale Perspektiven gerade in der Völkerrechtsgeschichte auf besonders fruchtbaren Boden fällt, liegt auf der Hand. Denn Regulierung, Normierung und Legitimation überregionaler Beziehungen bieten sich wie kaum ein anderes Themenfeld für eine Horizonterweiterung über den Nationalstaat hinaus an. Aus einer vornehmlich europäischen Völkerrechtsgeschichte werden damit Völkerrechtsgeschichten in der Dialektik von lokalen und globalen Bezugspunkten. ...
In ihrer Dankesrede für den Friedenspreis des Deutschen Buchhandels argumentierte Susan Sontag 2003, der Gegensatz zwischen "alt" und "neu" stehe im Zentrum dessen, was wir unter Erfahrung verstünden. Mehr noch: "Alt" und "neu" seien die ewigen, unumstößlichen Pole aller Wahrnehmung und Orientierung in der Welt. Ohne das Alte kämen wir nicht aus, weil sich mit ihm unsere ganze Vergangenheit, unsere Weisheit, unsere Erinnerungen, unsere Traurigkeit, unser Realitätssinn verbinde. Ohne den Glauben an das Neue wiederum kämen wir nicht aus, weil sich mit dem Neuen unsere Tatkraft, unsere Fähigkeit zum Optimismus, unser blindes biologisches Sehnen, unsere Fähigkeit zu vergessen verbinde – diese heilsame Fähigkeit, ohne die Versöhnung nicht möglich sei. Mit anderen Worten: Erst eine noch so unpräzise und temporal begrenzte Unterscheidung zwischen "alt" und "neu" gestattet es uns, soziopolitische Phänomene historisch zu vergleichen, zu ordnen, zu periodisieren, und sie schließlich als Geschichte(n) zu erzählen. "Alt" und "neu" – diese mit dem Konzept des "Fortschritts" eng verbundene Dichotomie ist grundlegend nicht nur für Kants kosmopolitische Teleologie, für Hegels Dialektik, für den "alten" und "neuen" Marxismus, sondern auch für moderne Völker-Rechtsgeschichte(n). Das zeigt auch das gut lesbare und pointierte Buch von Oona A. Hathaway und Scott J. Shapiro. Und umso interessanter sind die teleologischen Verkürzungen, die die Autoren vornehmen, um ihr Narrativ vom Neuen zu bedienen. ...
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.
Mapping cortical brain asymmetry in 17,141 healthy individuals worldwide via the ENIGMA Consortium
(2017)
The p53-family member p73 plays a role in various cellular signaling pathways during development and growth control and it can have tumor suppressor properties. Several isoforms of p73 exist with considerable differences in their function. Whereas the functions of the N-terminal isoforms (TA and delta Np73) and their opposing pro- and antiapoptotic roles have become evident, the functional differences of the distinct C-terminal splice forms of TAp73 have remained unclear. Here, we characterized the global genomic binding sites for TAp73alpha and TAp73beta by chromatin immunoprecipitation sequencing as well as the transcriptional responses by performing RNA sequencing. We identified a specific p73 consensus binding motif and found a strong enrichment of AP1 motifs in close proximity to binding sites for TAp73alpha. These AP1 motif-containing target genes are selectively upregulated by TAp73alpha, while their mRNA expression is repressed upon TAp73beta induction. We show that their expression is dependent on endogenous c-Jun and that recruitment of c-Jun to the respective AP1 sites was impaired upon TAp73beta expression, in part due to downregulation of c-Jun. Several of these AP1-site containing TAp73alpha-induced genes impinge on apoptosis induction, suggesting an underlying molecular mechanism for the observed functional differences between TAp73alpha and TAp73beta.
Background: Peritonitis is responsible for thousands of deaths annually in Germany alone. Even source control (SC) and antibiotic treatment often fail to prevent severe sepsis or septic shock, and this situation has hardly improved in the past two decades. Most experimental immunomodulatory therapeutics for sepsis have been aimed at blocking or dampening a specific pro-inflammatory immunological mediator. However, the patient collective is large and heterogeneous. There are therefore grounds for investigating the possibility of developing personalized therapies by classifying patients into groups according to biomarkers. This study aims to combine an assessment of the efficacy of treatment with a preparation of human immunoglobulins G, A, and M (IgGAM) with individual status of various biomarkers (immunoglobulin level, procalcitonin, interleukin 6, antigen D-related human leucocyte antigen (HLA-DR), transcription factor NF-κB1, adrenomedullin, and pathogen spectrum).
Methods/design: A total of 200 patients with sepsis or septic shock will receive standard-of-care treatment (SoC). Of these, 133 patients (selected by 1:2 randomization) will in addition receive infusions of IgGAM for 5 days. All patients will be followed for approximately 90 days and assessed by the multiple-organ failure (MOF) score, by the EQ QLQ 5D quality-of-life scale, and by measurement of vital signs, biomarkers (as above), and survival.
Discussion: This study is intended to provide further information on the efficacy and safety of treatment with IgGAM and to offer the possibility of correlating these with the biomarkers to be studied. Specifically, it will test (at a descriptive level) the hypothesis that patients receiving IgGAM who have higher inflammation status (IL-6) and poorer immune status (low HLA-DR, low immunoglobulin levels) have a better outcome than patients who do not receive IgGAM. It is expected to provide information that will help to close the knowledge gap concerning the association between the effect of IgGAM and the presence of various biomarkers, thus possibly opening the way to a personalized medicine.
Trial registration: EudraCT, 2016–001788-34; ClinicalTrials.gov, NCT03334006. Registered on 17 Nov 2017.
Trial sponsor: RWTH Aachen University, represented by the Center for Translational & Clinical Research Aachen (contact Dr. S. Isfort).
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.
Archaeological evidence indicates that pig domestication had begun by ∼10,500 y before the present (BP) in the Near East, and mitochondrial DNA (mtDNA) suggests that pigs arrived in Europe alongside farmers ∼8,500 y BP. A few thousand years after the introduction of Near Eastern pigs into Europe, however, their characteristic mtDNA signature disappeared and was replaced by haplotypes associated with European wild boars. This turnover could be accounted for by substantial gene flow from local European wild boars, although it is also possible that European wild boars were domesticated independently without any genetic contribution from the Near East. To test these hypotheses, we obtained mtDNA sequences from 2,099 modern and ancient pig samples and 63 nuclear ancient genomes from Near Eastern and European pigs. Our analyses revealed that European domestic pigs dating from 7,100 to 6,000 y BP possessed both Near Eastern and European nuclear ancestry, while later pigs possessed no more than 4% Near Eastern ancestry, indicating that gene flow from European wild boars resulted in a near-complete disappearance of Near East ancestry. In addition, we demonstrate that a variant at a locus encoding black coat color likely originated in the Near East and persisted in European pigs. Altogether, our results indicate that while pigs were not independently domesticated in Europe, the vast majority of human-mediated selection over the past 5,000 y focused on the genomic fraction derived from the European wild boars, and not on the fraction that was selected by early Neolithic farmers over the first 2,500 y of the domestication process.