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We develop a novel empirical approach to identify the effectiveness of policies against a pandemic. The essence of our approach is the insight that epidemic dynamics are best tracked over stages, rather than over time. We use a normalization procedure that makes the pre-policy paths of the epidemic identical across regions. The procedure uncovers regional variation in the stage of the epidemic at the time of policy implementation. This variation delivers clean identification of the policy effect based on the epidemic path of a leading region that serves as a counterfactual for other regions. We apply our method to evaluate the effectiveness of the nationwide stay-home policy enacted in Spain against the Covid-19 pandemic. We find that the policy saved 15.9% of lives relative to the number of deaths that would have occurred had it not been for the policy intervention. Its effectiveness evolves with the epidemic and is larger when implemented at earlier stages.
This essay argues for the philosophical standing of Walter Benjamin’s early work and posits a deeper continuity between this early work as a philosopher and the subsequent development of his work as a writer. When these fragments are read in proper relation to each other, they reveal for the first time many of the key innovations of Benjamin as a philosopher, as well as his points of influence on Horkheimer and Adorno. His early ‘Program’ critiques the Enlightenment conception of experience as a means for gaining empirical knowledge, and announces the need for a new concept of experience. Benjamin follows through on this program with a method of philosophical enquiry that is by turns fragmentary and constellational, developing a series of provisional notions of experience, which form a constellation with one another: perception, mimesis, language as a medium of experience, observation and memory.
Two main types of methods are used in gene therapy: integrating vectors and nuclease-based genome engineering. Nucleases are site-specific and are efficient for knock-outs, but inefficient at inserting long DNA sequences. Integrating vectors perform this task with high efficiency, but their insertion occurs at random genomic positions. This can result in transformation of target cells, which leads to severe adverse events in a gene therapy context. Thus, it is of great interest to develop novel genome engineering tools that combine the advantages of both technologies. The main focus of this thesis is on generating such a targetable integrating vector.
The integrating vector used in this project is the Sleeping Beauty (SB) transposon, a DNA transposon characterized by high activity across a wide range of cells. The SB transposase was combined with an RNA-guided Cas9 nuclease domain. This nuclease component was meant to direct transposase integration to specific targets defined by RNAs. The SB transposase was fused to cleavage-inactivated Cas9 (dCas9) to tether it to the target sites. In addition, adapter proteins consisting of dCas9 and domains non-covalently interacting with SB transposase or the SB transposon were generated. All constituent domains of these fusion proteins were tested in enzymatic assays and almost all enzymatic activities could be verified.
Combining the fusion protein dCas9-SB100X with a gRNA binding a sequence from the AluY repetitive element resulted in a weak, but statistically significant enrichment around sites bound by the gRNA. This enrichment was ca. 2-fold and occurred within a 300 bp window downstream of target sites, or within the AluY element.
Targeting with adapter proteins and targeting of other targets (L1 elements or single-copy targets) did not result in statistically significant effects. Single-copy targets tested included the HPRT gene and three specifically selected GSH targets that were known to be receptive to SB insertions. The combination with a more sequence-specific transposase mutant also failed to increase specificity to a level allowing targeting of single-copy loci. Genome-wide analysis of insertions however demonstrated, that dCas9-SB100X has a different insertion profile than SB100X, regardless of the gRNA used.
As low efficiency of retargeting is likely a consequence of the high background activity of the SB100X transposase in the fusion constructs, a SB mutant with reduced DNA affinity, SB(C42), was generated. For this mutant, transposition activity was partly dependent on a dCas9 domain being supplied with a multi-copy target gRNA, specifically a 2-fold increase in the presence of a AluY-directed gRNA. Whether using this mutant results in improved targeting remains to be determined.
In a side project, an attempt was made to direct SB insertions to ribosomal DNA by fusing the transposase to a nucleolar protein. This fusion transposase partially localized to nucleoli and insertions catalyzed by this transposase were found to be enriched in nucleolus organizer regions (NORs) and nucleolus-associated domains (NADs).
The aim of a second side project was increasing the ratio between homology-directed repair (HDR) and non-homologous end-joining (NHEJ) at Cas9-mediated double-strand breaks (DSBs). To achieve this, Cas9 was fused to DNA-interacting domains and corresponding binding sequences were fused to the homology donors. While an increased HDR/NHEJ ration could be observed for the fusion proteins, it was not dependent on the presence on the binding sequences in the donor molecules.
A Large Ion Collider Experiment (ALICE) is one of the four large experiments at the Large Hadron Collider (LHC) at the European Organization for Particle Physics (CERN). ALICE focuses on the physics of the strong interaction and in particular on the Quark-Gluon Plasma. This is a state of matter in which quarks are de-confined. It is believed that it existed in the earliest moments of the evolution of the universe. The ALICE detector studies the products of the collisions between heavy-nuclei, between protons, and between protons and heavy-nuclei. The sub-detector closest to the interaction point is the Inner Tracking System (ITS), which is used to measure the momentum and trajectory of the particles generated by the collisions and allows reconstructing primary and secondary interaction vertices. The ITS needs to have an accurate spatial resolution, together with a low material budget to limit the effect of multiple scattering on low-energetic particles to precisely reconstruct their trajectory. During the Long Shutdown 2 (2019-2020) of the LHC, the current ITS will be replaced by a completely redesigned sub-detector, which will improve readout rate and particle tracking performance especially at low-momentum.
The ALice PIxel DEtector (ALPIDE) chip was designed to meet the requirements of the upgraded ITS in terms of resolution, material budget, radiation hardness, and readout rate. The ALPIDE chip is a Monolithic Active Pixel Sensor (MAPS) realised in Complementary Metal-Oxide Semiconductor (CMOS) technology. Sensing element, analogue front-end, and its digital readout are integrated into the same silicon die. The readout architecture of the new ITS foresees that data is transmitted via a high-speed serial link directly from the ALPIDE to the off-detector electronics. The data is transmitted off-chip by a so-called Data Transmission Unit (DTU) which needs to be tolerant to Single-Event Effects induced by radiation, in order to guarantee reliable operation. The ALPIDE chip will operate in a radiation field with a High-Energy Hadron peak flux of 7.7·10^5 cm^-2s^-1.
The data are sent by the ALPIDE on copper cables to the readout system, which aggregates them and re-transmits them via optical fibres to the counting room. The position where the readout electronics will be placed is constrained by the maximum transmission distance reasonably achievable by the ALPIDE Data Transmission Unit and mechanical constraints of the ALICE experiment. The radiation field at that location is not negligible for its effects on electronics: the high-energy hadrons flux can reach 10^3 cm^-2s^-1. Static RAM (SRAM)-based Field Programmable Gate Arrays (FPGAs) are favoured over Application Specific Integrated Circuits (ASICs) or Radiation Hard by Design (RHBD) commercial devices because of cost effectiveness. Moreover, SRAM-based FPGAs are re-configurable and provide the data throughput required by the ITS. The main issue with SRAM-based FPGAs, for the intended application, is the susceptibility of their Configuration RAM (CRAM) to Single-Event Upsets: the number of CRAM bits is indeed much higher than the logic they configure. Total Ionizing Dose (TID) at the readout designed position is indeed still acceptable for Component Off The Shelf (COTS), provided that proper verification is carried out.
This dissertation focuses on two parts of the design of the readout system: the Data Transmission Unit of the ALPIDE chip and the design of fundamental modules for the SRAM-based FPGA of the readout electronics. In the first part, a module of the Data Transmission Unit is designed, optimising the trade-off between power consumption, radiation tolerance, and jitter performance. The design was tested and thoroughly characterised, including tests while under irradiation with a 30 MeV protons. Furthermore the Data Transmission Unit performance was validated after the integration into the first prototypes of ITS modules. In the second part, the problem of developing a radiation-tolerant SRAM-based FPGA design is investigated and a solution is provided. First, a general methodology for designing radiation-tolerant Finite State Machines in SRAM-based FPGAs is analysed, implemented, and verified. Later, the radiation-tolerant FPGA design for the ITS readout is described together with the radiation effects mitigation techniques that were selectively applied to the different modules. The design was tested with multiple irradiation tests and the results are stated below.
Proteine sind die Maschinen der Zellen. Um die Funktionalität von zahlreichen zellulären Prozessen zu gewährleisten, müssen Kommunikationssignale innerhalb von Proteinen weitergeleitet werden. Die Weiterleitung einer Störung an einem Ort im Protein zu einer entfernten Stelle, an welcher sie strukturelle und/oder dynamische Änderungen auslöst, wird Allosterie genannt. Zunächst wurde Allosterie hauptsächlich mit großräumigen Konformationsänderungen in Verbindung gebracht, aber später entwickelte sich ein dynamischerer Blickwinkel auf Allosterie in Abwesenheit dieser großräumigen Konformationsänderungen. Die Idee eines allosterischen Pfades bestehend aus konservierten und energetisch gekoppelten Aminosäuren, welche die Signalweiterleitung zwischen entfernten Stellen im Protein vermitteln, entstand. Diese allosterischen Pfade wurden durch zahlreiche theoretische Studien in Zusammenhang mit Pfaden effizienten anisotropen Energieflusses gebracht. Der Energiefluss entlang dieser Netzwerke verknüpft allosterische Signalübertragung mit Schwingungsenergietransfer (VET - vibrational energy transfer). Die Großzahl der Forschungsarbeiten über dynamische Allosterie basiert auf theoretischen Methoden, weil nur wenige geeignete experimentelle Verfahren existieren. Um diesen essentiellen biologischen Prozess der Informationsübertragung besser verstehen zu können, ist die Entwicklung neuer und leistungsstarker experimenteller Instrumente und Techniken daher dringend erforderlich. Die vorliegende Dissertation setzt sich dies zum Ziel.
VET in Proteinen ist aufgrund der Proteingeometrie inhärent anisotrop. Alle globulären Proteine besitzen Kanäle effizienten Energieflusses, von denen vermutet wird, dass sie wichtig für Proteinfunktionen, wie die schnelle Ableitung von überschüssiger Wärme, Ligandenbindung und allosterische Signalweiterleitung, sind. VET kann mit zeitaufgelöster Infrarot (IR) Spektroskopie untersucht werden, bei welcher ein Femtosekunden Anregepuls eines Lasers Schwingungsenergie in ein molekulares System an einer bestimmten Stelle injiziert und ein, nach einem veränderbarem Zeitintervall folgender, IR Abfragepuls die Ausbreitung dieser Schwingungsenergie detektiert. Ein protein-kompatibler und universell einsetzbarer Chromophor, der die Energie eines sichtbaren Photons in Schwingungsenergie konvertiert, wird als Heizelement benötigt um langreichweitige VET Pfade in Proteinen kartieren zu können. Der Azulen (Azu) Chromophor eignet sich dafür, weil er nach Photoanregung des ersten elektronischen Zustandes durch ultraschnelle interne Konversion fast die gesamte injizierte Energie innerhalb von einer Picosekunde in Schwingungsenergie umwandelt. Eingebettet in die nicht-kanonische Aminosäure (ncAA - non-canonical amino acid) ß-(1-Azulenyl)-L-Alanine (AzAla), kann der Azu Rest in Proteine eingebaut werden. Die Ankunft der injizierten Schwingungsenergie an einer bestimmten Stelle im Protein kann mithilfe eines IR Sensors detektiert werden. Die Kombination aus Azu als VET Heizelement und Azidohomoalanine (Aha) als VET Sensor mit transienter IR (TRIR) Spektroskopie wurde schon erfolgreich an kleinen Peptiden in der Dissertation von H. M. Müller-Werkmeister getestet, die der vorliegenden Dissertation in den Laboren der Bredenbeck Gruppe vorausging.
Die Schwingungsfrequenz chemischer Bindungen ist hochempfindlich auf selbst kleine Änderungen der Konformation und Dynamik in der unmittelbaren Umgebung und kann mit IR Spektroskopie gemessen werden, z. B. mit Fourier Transform IR (FTIR) Spektroskopie. IR Spektroskopie bietet eine außergewöhnlich gute Zeitauflösung, die es ermöglicht, dynamische Prozesse in Molekülen auf einer Zeitskala von wenigen Picosekunden zu beobachten, wie z. B. die ultraschnelle Weiterleitung von Schwingungsenergie. Mit zweidimensionaler (2D)-IR Spektroskopie können die Relaxation von schwingungsangeregten Zuständen und strukturelle Fluktuationen um die schwingende Bindung untersucht werden. Allerdings geht die herausragende Zeitauflösung mit limitierter spektraler Auflösung einher. In größeren Molekülen mit zahlreichen Bindungen überlagern sich die Schwingungsbanden und die Ortsauflösung geht verloren. Um diese Limitierung zu überwinden, können IR Marker benutzt werden, chemische Gruppen, die in einer spektral durchsichtigen Region des Protein/Wasser Spektrums (1800 bis 2500 cm-1) absorbieren. Als ncAA können sie kotranslational in Proteine an einer gewünschten Stelle eingebaut werden und so ortsspezifische Informationen aus dem Proteininneren liefern. Aufgrund ihrer geringen Größe, eines relativ großen Extinktionskoeffizientens (350-400 M-1cm-1) und einer hohen Empfindlichkeit auf Änderungen in der lokalen Umgebung sind organische Azide (N3) wie zum Beispiel Aha besonders geeignete IR Marker. Aha kann als Methionin Analogon ins Protein eingebaut werden.
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The role of radiation therapy in the treatment of (colo)-rectal cancer has changed dramatically over the past decades. Introduced with the aim of reducing the high rates of local recurrences after conventional surgery, major developments in imaging, surgical technique, systemic therapy and radiation delivery have now created a much more complex environment leading to a more personalized approach. Functional aspects including reduction of acute or late treatment-related side effects, sphincter or even organ-preservation and the unsolved problem of still high distant failure rates have become more important while local recurrence rates can be kept low in the vast majority of patients. This review summarizes the actual role of radiation therapy in different subgroups of patients with rectal cancer, including the current standard approach in different subgroups as well as recent developments focusing on neoadjuvant treatment intensification and/or non-operative treatment approaches aiming at organ-preservation.
The novel coronavirus infection (COVID-19) is caused by the new coronavirus SARS-CoV-2 and is characterized by an exaggerated inflammatory response that can lead to severe manifestations such as adult respiratory syndrome, sepsis, coagulopathy, and death in a proportion of patients. Among other factors and direct viral effects, the increase in the vasoconstrictor angiotensin II, the decrease in the vasodilator angiotensin, and the sepsis-induced release of cytokines can trigger a coagulopathy in COVID-19. A coagulopathy has been reported in up to 50% of patients with severe COVID-19 manifestations. An increase in d-dimer is the most significant change in coagulation parameters in severe COVID-19 patients, and progressively increasing values can be used as a prognostic parameter indicating a worse outcome. Limited data suggest a high incidence of deep vein thrombosis and pulmonary embolism in up to 40% of patients, despite the use of a standard dose of low-molecular-weight heparin (LMWH) in most cases. In addition, pulmonary microvascular thrombosis has been reported and may play a role in progressive lung failure. Prophylactic LMWH has been recommended by the International Society on Thrombosis and Haemostasis (ISTH) and the American Society of Hematology (ASH), but the best effective dosage is uncertain. Adapted to the individual risk of thrombosis and the d-dimer value, higher doses can be considered, especially since bleeding events in COVID-19 are rare. Besides the anticoagulant effect of LMWH, nonanticoagulant properties such as the reduction in interleukin 6 release have been shown to improve the complex picture of coagulopathy in patients with COVID-19.
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.
Activations with neutrons in the keV energy range were routinely performed at the Karlsruhe Institute of Technology (KIT) in Germany in order to simulate stellar conditions for neutron-capture cross sections. A quasi-Maxwell-Boltzmann neutron spectrum of kT = 25 keV, being of interest for the astrophysical s-process, was produced by the 7Li(p,n) reaction utilizing a 1912 keV proton beam at the Karlsruhe Van de Graaff accelerator. Activated samples resulting in long-lived nuclear reaction products with half-lives in the order of yr 100 Myr were analyzed by Accelerator Mass Spectrometry (AMS). Comparison of the obtained reaction cross sections to literature data from previous Time-of-Flight (ToF) measurements showed that the selected AMS data are systematically lower than the ToF data. To investigate this discrepancy, 54Fe(n,γ)55Fe and 35Cl(n,γ)36Cl reaction cross sections were newly measured at the Frankfurt Neutron Source (FRANZ) in Germany. To complement the existing data, an additional neutron activation of 54Fe and 35Cl at a proton energy of 2 MeV was performed. The results will give implications for the stellar environment at kT = 90 keV, reaching the not yet experimentally explored high-energy s-process range. AMS measurements of the activated samples are scheduled.
Signaling pathways, depending on the second messenger molecule cAMP, modulate hippocampal cell signaling via influencing transcription factors like cAMP-regulated element-binding protein (CREB) or early growth response 1 EGR1/Krox24/zif268/ZENK (EGR1). Here, we investigated two reporter cell lines derived from an immortalized hippocampal neuronal cell line stably expressing a CRE- or EGR1-luciferase reporter gene (HT22CREluc and HT22EGR1luc, respectively). The cells were subjected to phosphodiesterase inhibitors and other cAMP-modulating agents to investigate dose- and time-dependent phosphodiesterase (PDE)-mediated fine-tuning of cAMP-dependent transcriptional signaling. The non-isoform-specific cyclic nucleotide phosphodiesterase (PDE) inhibitor isobutyl-methyl-xanthine (IBMX), as well as selective inhibitors of PDE3 (milrinone) and PDE4 (rolipram), were tested for their ability to elevate CRE- and EGR1-luciferase activity. Pharmacological parameters like onset of activity, maximum activity, and offset of activity were determined. In summary, phosphodiesterase inhibition appeared similarly potent in comparison to adenylate cyclase stimulation or direct activation of protein kinase A (PKA) via specific cAMP agonists and was at least partly mediated by PKA as shown by the selective PKA inhibitor <i>Rp</i>-8-Br-cAMPS. Moreover, transcriptional activation by PDE inhibition was also influenced by organic anion-exchanger action and interacted with fibroblast growth factor (FGF) receptor-mediated pathways.