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Three-body nuclear forces play an important role in the structure of nuclei and hypernuclei and are also incorporated in models to describe the dynamics of dense baryonic matter, such as in neutron stars. So far, only indirect measurements anchored to the binding energies of nuclei can be used to constrain the three-nucleon force, and if hyperons are considered, the scarce data on hypernuclei impose only weak constraints on the three-body forces. In this work, we present the first direct measurement of the p−p−p and p−p−Λ systems in terms of three-particle mixed moments carried out for pp collisions at s√ = 13 TeV. Three-particle cumulants are extracted from the normalised mixed moments by applying the Kubo formalism, where the three-particle interaction contribution to these moments can be isolated after subtracting the known two-body interaction terms. A negative cumulant is found for the p−p−p system, hinting to the presence of a residual three-body effect while for p−p−Λ the cumulant is consistent with zero. This measurement demonstrates the accessibility of three-baryon correlations at the LHC.
Fungi play pivotal roles in ecosystem functioning, but little is known about their global patterns of diversity, endemicity, vulnerability to global change drivers and conservation priority areas. We applied the high-resolution PacBio sequencing technique to identify fungi based on a long DNA marker that revealed a high proportion of hitherto unknown fungal taxa. We used a Global Soil Mycobiome consortium dataset to test relative performance of various sequencing depth standardization methods (calculation of residuals, exclusion of singletons, traditional and SRS rarefaction, use of Shannon index of diversity) to find optimal protocols for statistical analyses. Altogether, we used six global surveys to infer these patterns for soil-inhabiting fungi and their functional groups. We found that residuals of log-transformed richness (including singletons) against log-transformed sequencing depth yields significantly better model estimates compared with most other standardization methods. With respect to global patterns, fungal functional groups differed in the patterns of diversity, endemicity and vulnerability to main global change predictors. Unlike α-diversity, endemicity and global-change vulnerability of fungi and most functional groups were greatest in the tropics. Fungi are vulnerable mostly to drought, heat, and land cover change. Fungal conservation areas of highest priority include wetlands and moist tropical ecosystems.
Background: MDM2 inhibitors are under investigation for the treatment of acute myeloid leukaemia (AML) patients in phase III clinical trials. To study resistance formation to MDM2 inhibitors in AML cells, we here established 45 sub-lines of the AML TP53 wild-type cell lines MV4-11 (15 sub-lines), OCI-AML-2 (10 sub-lines), OCI-AML-3 (12 sub-lines), and SIG-M5 (8 sub-lines) with resistance to the MDM2 inhibitor nutlin-3.
Methods: Nutlin-3-resistant sub-lines were established by continuous exposure to stepwise increasing drug concentrations. The TP53 status was determined by next generation sequencing, cell viability was measured by MTT assay, and p53 was depleted using lentiviral vectors encoding shRNA.
Results: All MV4-11 sub-lines harboured the same R248W mutation and all OCI-AML-2 sub-lines the same Y220C mutation, indicating the selection of pre-existing TP53-mutant subpopulations. In concordance, rare alleles harbouring the respective mutations could be detected in the parental MV4-11 and OCI-AML-2 cell lines. The OCI-AML-3 and SIG-M5 sub-lines were characterised by varying TP53 mutations or wild type TP53, indicating the induction of de novo TP53 mutations. Doxorubicin, etoposide, gemcitabine, cytarabine, and fludarabine resistance profiles revealed a noticeable heterogeneity among the sub-lines even of the same parental cell lines. Loss-of-p53 function was not generally associated with decreased sensitivity to cytotoxic drugs.
Conclusion: We introduce a substantial set of models of acquired MDM2 inhibitor resistance in AML. MDM2 inhibitors select, in dependence on the nature of a given AML cell population, pre-existing TP53-mutant subpopulations or induce de novo TP53 mutations. Although loss-of-p53 function has been associated with chemoresistance in AML, nutlin-3-adapted sub-lines displayed in the majority of experiments similar or increased drug sensitivity compared to the respective parental cells. Hence, chemotherapy may remain an option for AML patients after MDM2 inhibitor therapy failure. Even sub-lines of the same parental cancer cell line displayed considerable heterogeneity in their response to other anti-cancer drugs, indicating the need for the detailed understanding and monitoring of the evolutionary processes in cancer cell populations in response to therapy as part of future individualised treatment protocols.
How is semantic information stored in the human mind and brain? Some philosophers and cognitive scientists argue for vectorial representations of concepts, where the meaning of a word is represented as its position in a high-dimensional neural state space. At the intersection of natural language processing and artificial intelligence, a class of very successful distributional word vector models has developed that can account for classic EEG findings of language, i.e., the ease vs. difficulty of integrating a word with its sentence context. However, models of semantics have to account not only for context-based word processing, but should also describe how word meaning is represented. Here, we investigate whether distributional vector representations of word meaning can model brain activity induced by words presented without context. Using EEG activity (event-related brain potentials) collected while participants in two experiments (English, German) read isolated words, we encode and decode word vectors taken from the family of prediction-based word2vec algorithms. We find that, first, the position of a word in vector space allows the prediction of the pattern of corresponding neural activity over time, in particular during a time window of 300 to 500 ms after word onset. Second, distributional models perform better than a human-created taxonomic baseline model (WordNet), and this holds for several distinct vector-based models. Third, multiple latent semantic dimensions of word meaning can be decoded from brain activity. Combined, these results suggest that empiricist, prediction-based vectorial representations of meaning are a viable candidate for the representational architecture of human semantic knowledge.
Tracking influenza a virus infection in the lung from hematological data with machine learning
(2022)
The tracking of pathogen burden and host responses with minimal-invasive methods during respiratory infections is central for monitoring disease development and guiding treatment decisions. Utilizing a standardized murine model of respiratory Influenza A virus (IAV) infection, we developed and tested different supervised machine learning models to predict viral burden and immune response markers, i.e. cytokines and leukocytes in the lung, from hematological data. We performed independently in vivo infection experiments to acquire extensive data for training and testing purposes of the models. We show here that lung viral load, neutrophil counts, cytokines like IFN-γ and IL-6, and other lung infection markers can be predicted from hematological data. Furthermore, feature analysis of the models shows that blood granulocytes and platelets play a crucial role in prediction and are highly involved in the immune response against IAV. The proposed in silico tools pave the path towards improved tracking and monitoring of influenza infections and possibly other respiratory infections based on minimal-invasively obtained hematological parameters.
The multistep PROTAC (PROteolysis TArgeting Chimeras) degradation process poses challenges for their rational development, as rate limiting steps determining PROTAC efficiency remain largely unknown. Moreover, the slow throughput of currently used endpoint assays does not allow the comprehensive analysis of larger series of PROTACs. Here we developed cell-based assays using NanoLuciferase and HaloTags, that allow measuring PROTAC induced degradation and ternary complex formation kinetics and stability in cells. Using PROTACs developed for degradation of WDR5, the characterization of the mode of action of these PROTACs in the early degradation cascade revealed a key role of ternary complex formation and stability. Comparing a series of ternary complex crystal structures highlighted the importance of an efficient E3-target interface for ternary complex stability. The developed assays outline a strategy for the rational optimization of PROTACs using a series of live cell assays monitoring key steps of the early PROTAC induced degradation pathway.
Significance The multistep PROTAC induced degradation process of a POI poses a significant challenge for the rational design of these bifunctional small molecules as critical steps that limit PROTAC efficacy cannot be easily assayed at required throughput. In addition, the cellular location of the POI may pose additional challenges as some cellular compartments, such as the nucleus, may not be easily reached by PROTAC molecules and the targeted E3 ligases may not be present in this cellular compartment. We propose therefore a comprehensive assay panel for PROTACs evaluation in cellular environments using a sensor system that allows continuous monitoring of the protein levels of the endogenous POI. We developed a cell line expressing WDR5 from its endogenous locus in fusion with a small sequence tag (HiBIT) that can be reconstituted to functional NanoLuciferase (NLuc). This system allowed continuous monitoring of endogenous WDR5 levels in cells and together with HaloTag system also the continuous monitoring of ternary complex (E3, WDR5 and PROTAC) formation. As this assay can be run at high throughput, we used this versatile system monitoring three diverse chemical series of WDR5 PROTACs that markedly differ in their degradation properties. Monitoring cell penetration, binary complex formation (PROTAC-WDR5 and PROTAC-VHL) as well as ternary complex formation we found that PROTAC efficiency highly correlated with synergy of ternary complex formation in cells. This study represents a first data set on diverse PROTACs studying this property in cellulo and it outlines a strategy for the rational optimization of PROTACs. It also provided kinetic data on ternary complex assembly and dissociation that may serve as a benchmark for future studies utilizing also kinetic properties for PROTAC development. Comparative structural studies revealed larger PROTAC mediated interaction surfaces for PROTACs that efficiently formed ternary complexes highlighting the utility of structure based optimization of PROTAC induced ternary complexes in the development process.
Transfer RNA fragments replace microRNA regulators of the cholinergic post-stroke immune blockade
(2020)
Stroke is a leading cause of death and disability. Recovery depends on balance between inflammatory response and immune suppression, which can be CNS-protective but may worsen prognosis by increasing patients’ susceptibility to infections. Peripheral cholinergic blockade of immune reactions fine-tunes this immune response, but its molecular regulators are unknown. Therefore, we sought small RNA balancers of the cholinergic anti-inflammatory pathway in peripheral blood from ischemic stroke patients. Using RNA-sequencing and RT-qPCR, we discovered in patients’ blood on day 2 after stroke a “change of guards” reflected in massive decreases in microRNAs (miRs) and increases in transfer RNA fragments (tRFs) targeting cholinergic transcripts. Electrophoresis-based size-selection followed by RT-qPCR validated the top 6 upregulated tRFs in a separate cohort of stroke patients, and independent small RNA-sequencing datasets presented post-stroke enriched tRFs as originating from lymphocytes and monocytes. In these immune compartments, we found CD14+ monocytes to express the highest amounts of cholinergic transcripts. In-depth analysis of CD14+ regulatory circuits revealed minimally overlapping subsets of transcription factors carrying complementary motifs to miRs or tRFs, indicating different roles for the stroke-perturbed members of these small RNA species. Furthermore, LPS-stimulated murine RAW264.7 cells presented dexamethasone-suppressible upregulation of the top 6 tRFs identified in human patients, indicating an evolutionarily conserved and pharmaceutically treatable tRF response to inflammatory cues. Our findings identify tRF/miR subgroups which may co-modulate the homeostatic response to stroke in patients’ blood and open novel venues for establishing RNA-targeted concepts for post-stroke diagnosis and therapeutics.
Die Ressource "Wissen" rückte in den letzten Jahrzehnten als Quelle wissenschaftlicher Innovation immer stärker ins Zentrum des Interesses. Diese Fokussierung mündete in eine Selbstreflexion der Wissenschaft und der wissenschaftlichen Disziplinen: Thematisiert werden vor allem die Art und Weise, wie Wissen gewonnen wird, sowie die damit zusammenhängende Frage nach der Konstruktion von Wissenschaftlichkeit, womit das Bewusstsein gleichzeitig auf die mehr und mehr sich auflösende Abgrenzung zwischen den Disziplinen beziehungsweise zwischen den drei hauptsächlichen Wissenschaftskulturen, von Natur-, Geistes- und Kultur- sowie Sozialwissenschaften gelenkt wird. Innerhalb und außerhalb der Universitäten bildeten und bilden sich nicht immer klar verortbare "trading zones" (Gallison 1997), in denen neue Formen und Techniken der Wissensproduktion und Wissensvermittlung geprüft, geübt und teilweise auch institutionalisiert werden. ...
The equilibration of hot and dense nuclear matter produced in the central region in central Au+Au collisions at square root s = 200A GeV is studied within the microscopic transport model UrQMD. The pressure here becomes isotropic at t approx 5 fm/c. Within the next 15 fm/c the expansion of the matter proceeds almost isentropically with the entropy per baryon ratio S/A approx 150. During this period the equation of state in the (P, epsilon)-plane has a very simple form, P = 0.15 epsilon. Comparison with the statistical model (SM) of an ideal hadron gas reveals that the time of approx 20 fm/c may be too short to attain the fully equilibrated state. Particularly, the fractions of resonances are overpopulated in contrast to the SM values. The creation of such a long-lived resonance-rich state slows down the relaxation to chemical equilibrium and can be detected experimentally.
Ribosomes catalyze protein synthesis by cycling through various functional states. These states have been extensively characterized in vitro, yet their distribution in actively translating human cells remains elusive. Here, we optimized a cryo-electron tomography-based approach and resolved ribosome structures inside human cells with a local resolution of up to 2.5 angstroms. These structures revealed the distribution of functional states of the elongation cycle, a Z tRNA binding site and the dynamics of ribosome expansion segments. In addition, we visualized structures of Homoharringtonine, a drug for chronic myeloid leukemia treatment, within the active site of the ribosome and found that its binding reshaped the landscape of translation. Overall, our work demonstrates that structural dynamics and drug effects can be assessed at near-atomic detail within human cells.
Mitochondrial matrix peptidase CLPP is crucial during cell stress. Its loss causes Perrault syndrome type 3 (PRLTS3) with infertility, neurodegeneration and growth deficit. Its target proteins are disaggregated by CLPX, which also regulates heme biosynthesis via unfolding ALAS enzyme, providing access of pyridoxal-5’-phosphate (PLP). Despite efforts in diverse organisms with multiple techniques, CLPXP substrates remain controversial. Here, avoiding recombinant overexpression, we employed complexomics in mitochondria from three mouse tissues to identify endogenous targets. CLPP absence caused accumulation and dispersion of CLPX-VWA8 as AAA+ unfoldases, and of PLPBP. Similar changes and CLPX-VWA8 comigration were evident for mitoribosomal central protuberance clusters, translation factors like GFM1-HARS2, RNA granule components LRPPRC-SLIRP, and enzymes OAT-ALDH18A1. Mitochondrially translated proteins in testis showed reductions to <30% for MTCO1-3, misassembly of complex-IV supercomplex, and accumulated metal-binding assembly factors COX15-SFXN4. Indeed, heavy metal levels were increased for iron, molybdenum, cobalt and manganese. RT-qPCR showed compensatory downregulation only for Clpx mRNA, most accumulated proteins appeared transcriptionally upregulated. Immunoblots validated VWA8, MRPL38, MRPL18, GFM1 and OAT accumulation. Coimmunoprecipitation confirmed CLPX binding to MRPL38, GFM1 and OAT, so excess CLPX and PLP may affect their activity. Our data elucidate mechanistically the mitochondrial translation fidelity deficits, which underlie progressive hearing impairment in PRLTS3.
We propose to use the hadron number fluctuations in the limited momentum regions to study the evolution of initial flows in high energy nuclear collisions. In this method by a proper preparation of a collision sample the projectile and target initial flows are marked in fluctuations in the number of colliding nucleons. We discuss three limiting cases of the evolution of flows, transparency, mixing and reflection, and present for them quantitative predictions obtained within several models. Finally, we apply the method to the NA49 results on fluctuations of the negatively charged hadron multiplicity in Pb+Pb interactions at 158A GeV and conclude that the data favor a hydrodynamical model with a significant degree of mixing of the initial flows at the early stage of collisions.
Dilepton spectra are calculated within the microscopic transport model UrQMD and compared to data from the CERES experiment. The invariant mass spectra in the region between 300 MeV and 600 MeV depend strongly on the mass dependence of the rho meson decay width which is not sufficiently determined by the Vector Meson Dominance model. A consistent explanation of both the recent Pb+Au data and the proton induced data can be given without additional medium effects.
The pion source as seen through HBT correlations at RHIC energies is investigated within the UrQMD approach. We find that the calculated transverse momentum, centrality, and system size dependence of the Pratt-HBT radii R_L and R_S are reasonably well in line with experimental data. The predicted R_O values in central heavy ion collisions are larger as compared to experimental data. The corresponding quantity sqrt R_O^2-R_S^2 of the pion emission source is somewhat larger than experimental estimates.
Based on the UrQMD transport model, the transverse momentum and the rapidity dependence of the Hanbury-Brown-Twiss (HBT) radii R_L, R_O, R_S as well as the cross term R_OL at SPS energies are investigated and compared with the experimental NA49 and CERES data. The rapidity dependence of the R_L, R_O, R_S is weak while the R_OL is significantly increased at large rapidities and small transverse momenta. The HBT "life-time" issue (the phenomenon that the calculated sqrt R_O^2-R_S^2 value is larger than the correspondingly extracted experimental data) is also present at SPS energies.
We compare multiplicities as well as rapidity and transverse momentum distributions of protons, pions and kaons calculated within presently available transport approaches for heavy ion collisions around 1 AGeV. For this purpose, three reactions have been selected: Au+Au at 1 and 1.48 AGeV and Ni+Ni at 1.93 AGeV.
Background Transposable elements (TEs) are an important source of genome plasticity across the tree of life. Accumulating evidence suggests that TEs may not be randomly distributed in the genome. Drift and natural selection are important forces shaping TE distribution and accumulation, acting directly on the TE element or indirectly on the host species. Fungi, with their multifaceted phenotypic diversity and relatively small genome size, are ideal models to study the role of TEs in genome evolution and their impact on the host’s ecological and life history traits. Here we present an account of all TEs found in a high-quality reference genome of the lichen-forming fungus Umbilicaria pustulata, a macrolichen species comprising two climatic ecotypes: Mediterranean and cold-temperate. We trace the occurrence of the newly identified TEs in populations along three replicated elevation gradients using a Pool-Seq approach, to identify TE insertions of potential adaptive significance.
Results We found that TEs cover 21.26 % of the 32.9 Mbp genome, with LTR Gypsy and Copia clades being the most common TEs. Out of a total of 182 TE copies we identified 28 insertions displaying consistent insertion frequency differences between the two host ecotypes across the elevation gradients. Most of the highly differentiated insertions were located near genes, indicating a putative function.
Conclusions This pioneering study into the content and climate niche-specific distribution of TEs in a lichen-forming fungus contributes to understanding the roles of TEs in fungal evolution. Particularly, it may serve as a foundation for assessing the impact of TE dynamics on fungal adaptation to the abiotic environment, and the impact of TE activity on the evolution and maintenance of a symbiotic lifestyle.
Transverse activity of kaons and the deconfinement phase transition in nucleus-nucleus collisions
(2003)
We found that the experimental results on transverse mass spectra of kaons produced in central Pb+Pb (Au+Au) interactions show an anomalous dependence on the collision energy. The inverse slopes of the spectra increase with energy in the low (AGS) and high (RHIC) energy domains, whereas they are constant in the intermediate (SPS) energy range. We argue that this anomaly is probably caused by a modification of the equation of state in the transition region between confined and deconfined matter. This observation may be considered as a new signal, in addition to the previously reported anomalies in the pion and strangeness production, of the onset of deconfinement located in the low SPS energy domain.
The production of prompt charmed mesons D0, D+ and D∗+, and their antiparticles, was measured with the ALICE detector in Pb-Pb collisions at the centre-of-mass energy per nucleon pair, sNN−−−√, of 2.76 TeV. The production yields for rapidity |y|<0.5 are presented as a function of transverse momentum, pT, in the interval 1-36 GeV/c for the centrality class 0-10% and in the interval 1-16 GeV/c for the centrality class 30-50%. The nuclear modification factor RAA was computed using a proton-proton reference at s√=2.76 TeV, based on measurements at s√=7 TeV and on theoretical calculations. A maximum suppression by a factor of 5-6 with respect to binary-scaled pp yields is observed for the most central collisions at pT of about 10 GeV/c. A suppression by a factor of about 2-3 persists at the highest pT covered by the measurements. At low pT (1-3 GeV/c), the RAA has large uncertainties that span the range 0.35 (factor of about 3 suppression) to 1 (no suppression). In all pT intervals, the RAA is larger in the 30-50% centrality class compared to central collisions. The D-meson RAA is also compared with that of charged pions and, at large pT, charged hadrons, and with model calculations.
The production of prompt charmed mesons D0, D+ and D∗+, and their antiparticles, was measured with the ALICE detector in Pb-Pb collisions at the centre-of-mass energy per nucleon pair, sNN−−−√, of 2.76 TeV. The production yields for rapidity |y|<0.5 are presented as a function of transverse momentum, pT, in the interval 1-36 GeV/c for the centrality class 0-10% and in the interval 1-16 GeV/c for the centrality class 30-50%. The nuclear modification factor RAA was computed using a proton-proton reference at s√=2.76 TeV, based on measurements at s√=7 TeV and on theoretical calculations. A maximum suppression by a factor of 5-6 with respect to binary-scaled pp yields is observed for the most central collisions at pT of about 10 GeV/c. A suppression by a factor of about 2-3 persists at the highest pT covered by the measurements. At low pT (1-3 GeV/c), the RAA has large uncertainties that span the range 0.35 (factor of about 3 suppression) to 1 (no suppression). In all pT intervals, the RAA is larger in the 30-50% centrality class compared to central collisions. The D-meson RAA is also compared with that of charged pions and, at large pT, charged hadrons, and with model calculations.