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Im Jahre 1891 entdeckte man bei Grabungsarbeiten in der Flur "Ob der Kaul" (heute Steinfelder Straße) in Nettersheim/Marcomagus (Kr. Euskirchen) in einem frühmittelalterlichen Gräberfeld eine fragmentarische Weihinschrift aus rötlichem Sandstein (Höhe 65,5 cm – Breite 40 cm – Tiefe 15 cm). Der in zwei Hälften gebrochene Stein diente in Zweitverwendung als Deckplatte für ein fränkisches Grab und wurde offenbar für diesen Zweck passend geschlagen,1 so dass die gesamte linke Hälfte der Inschrift und einige Buchstaben der rechten Seite verloren gingen. Obwohl die Inschrift teilweise stark verwittert ist, können die erhaltenen Buchstaben noch relativ sicher gelesen werden. Die Buchstabenhöhe beträgt in der ersten Zeile 4,5 cm, in den folgenden Zeilen 4 cm. Der Zeilenabstand misst 2 cm...
Contents:
Yuki Chiba, Santiago Escobar, Naoki Nishida, and David Sabel, and Manfred Schmidt-Schauß : Preface:
The Collection of all Abstracts of the Talks at WPTE 2015 xi
Brigitte Pientka : Mechanizing Meta-Theory in Beluga
Giulio Guerrieri : Head reduction and normalization in a call-by-value lambda-calculus
Adrián Palacios and Germán Vidal : Towards Modelling Actor-Based Concurrency in Term Rewriting
David Sabel and Manfred Schmidt-Schauß : Observing Success in the Pi-Calculus
Sjaak Smetsers, Ken Madlener, and Marko van Eekelen : Formalizing Bialgebraic Semantics in PVS 6.0
The calculus LRP is a polymorphically typed call-by-need lambda calculus extended by data constructors, case-expressions, seq-expressions and type abstraction and type application. This report is devoted to the extension LRPw of LRP by scoped sharing decorations. The extension cannot be properly encoded into LRP if improvements are defined w.r.t. the number of lbeta, case, and seq-reductions, which makes it necessary to reconsider the claims and proofs of properties. We show correctness of improvement properties of reduction and transformation rules and also of computation rules for decorations in the extended calculus LRPw. We conjecture that conservativity of the embedding of LRP in LRPw holds.
This report documents the extension LRPw of LRP by sharing decorations. We show correctness of improvement properties of reduction and transformation rules and also of computation rules for decorations in the extended calculus LRPw. We conjecture that conservativity of the embedding of LRP in LRPw holds.
An improvement is a correct program transformation that optimizes the program, where the criterion is that the number of computation steps until a value is obtained is decreased. This paper investigates improvements in both { an untyped and a polymorphically typed { call-by-need lambda-calculus with letrec, case, constructors and seq. Besides showing that several local optimizations are improvements, the main result of the paper is a proof that common subexpression elimination is correct and an improvement, which proves a conjecture and thus closes a gap in Moran and Sands' improvement theory. We also prove that several different length measures used for improvement in Moran and Sands' call-by-need calculus and our calculus are equivalent.
An improvement is a correct program transformation that optimizes the program, where the criterion is that the number of computation steps until a value is obtained is decreased. This paper investigates improvements in both { an untyped and a polymorphically typed { call-by-need lambda-calculus with letrec, case, constructors and seq. Besides showing that several local optimizations are improvements, the main result of the paper is a proof that common subexpression elimination is correct and an improvement, which proves a conjecture and thus closes a gap in Moran and Sands' improvement theory. We also prove that several different length measures used for improvement in Moran and Sands' call-by-need calculus and our calculus are equivalent.
Hepatitis B caused by infection with the hepatitis B virus (HBV) still ranks among the most challenging infectious diseases of our time. Despite the availability of an effective prophylactic vaccine, 240 million people worldwide are estimated to be chronically infected with HBV and are at risk of developing life-threatening liver diseases, including cirrhosis and liver cancer. The underlying pathogenic mechanisms of HBV-associated liver diseases are only incompletely understood. It is widely accepted that liver pathology results from long-term immune-mediated liver injury and inflammation as a consequence of inefficient viral elimination. This injury can be naturally compensated by liver regeneration. However, chronic liver damage and permanent inflammation debilitates the regenerative capacity of the liver and fosters fibrosis as well as accumulation of chromosomal aberrations, which both contribute to cirrhosis and liver cancer. Liver regeneration requires the presence of the redox-sensitive transcription factor Nrf2 and intact insulin receptor signaling. A lack of Nrf2 causes increased intracellular levels of reactive oxygen species (ROS) that inactivate insulin receptor signaling and induce insulin resistance. Interestingly, HBV was observed to activate Nrf2 and the expression of Nrf2-regulated genes. This argues against an inhibitory effect of HBV on insulin receptor signaling by increased ROS levels. However, chronic HBV infection is associated with dysregulation of hepatocyte proliferation and retardation of liver regeneration. Hence, the aim of this thesis was to investigate the influence of HBV on the process of liver regeneration with respect to the insulin receptor signaling pathway. After short-term carbon tetrachloride (CCl4)-induced liver damage, HBV transgenic mice present prolonged liver damage and impaired liver regeneration as reflected by reduced hepatocyte proliferation and increased apoptosis. Impaired hepatocyte proliferation in HBV transgenic mice correlates with diminished activation of the insulin receptor. It was further observed in vitro that the activation of Nrf2 by HBV induces increased levels of the insulin receptor mRNA and protein in HBV-expressing cells. Strikingly, stably HBV-expressing cells as well as primary mouse hepatocytes from HBV transgenic mice bind less insulin due to reduced amounts of insulin receptor on the cell surface. This is caused by intracellular retention of the insulin receptor in HBV-expressing cells as a consequence of increased amounts of the cellular trafficking factor α-taxilin. The reduced amounts of insulin receptor on the cell surface impair insulin sensitivity in HBV-expressing cells and inactivate downstream signaling cascades that initiate insulin-dependent gene expression and glucose uptake. As a consequence of impaired hepatocyte proliferation and liver regeneration, HBV transgenic mice exhibit increased development of fibrosis after long-term CCl4-induced liver damage. Taken together, in this thesis, a novel pathomechanism could be uncovered that includes inactivation of insulin receptor signaling by HBV via intracellular retention of the insulin receptor leading to impaired liver regeneration after liver damage and promotion of liver fibrosis. These findings significantly contribute to an enhanced understanding of HBV-associated liver pathogenesis.
Aus Wissen wird Gesundheit : das Magazin des Universitätsklinikums Frankfurt. Ausgabe 04/2015
(2015)
Aus Wissen wird Gesundheit : das Magazin des Universitätsklinikums Frankfurt. Ausgabe 03/2015
(2015)
Aus Wissen wird Gesundheit : das Magazin des Universitätsklinikums Frankfurt. Ausgabe 02/2015
(2015)
Aus Wissen wird Gesundheit : das Magazin des Universitätsklinikums Frankfurt. Ausgabe 01/2015
(2015)
Prehistoric dental treatments were extremely rare, and the few documented cases are known from the Neolithic, when the adoption of early farming culture caused an increase of carious lesions. Here we report the earliest evidence of dental caries intervention on a Late Upper Palaeolithic modern human specimen (Villabruna) from a burial in Northern Italy. Using Scanning Electron Microscopy we show the presence of striations deriving from the manipulation of a large occlusal carious cavity of the lower right third molar. The striations have a "V"-shaped transverse section and several parallel micro-scratches at their base, as typically displayed by cutmarks on teeth. Based on in vitro experimental replication and a complete functional reconstruction of the Villabruna dental arches, we confirm that the identified striations and the associated extensive enamel chipping on the mesial wall of the cavity were produced ante-mortem by pointed flint tools during scratching and levering activities. The Villabruna specimen is therefore the oldest known evidence of dental caries intervention, suggesting at least some knowledge of disease treatment well before the Neolithic. This study suggests that primitive forms of carious treatment in human evolution entail an adaptation of the well-known toothpicking for levering and scratching rather than drilling practices.
Cardiac arrhythmias are often associated with mutations in ion channels or other proteins. To enable drug development for distinct arrhythmias, model systems are required that allow implementing patient-specific mutations. We assessed a muscular pump in Caenorhabditis elegans. The pharynx utilizes homologues of most of the ion channels, pumps and transporters defining human cardiac physiology. To yield precise rhythmicity, we optically paced the pharynx using channelrhodopsin-2. We assessed pharynx pumping by extracellular recordings (electropharyngeograms--EPGs), and by a novel video-microscopy based method we developed, which allows analyzing multiple animals simultaneously. Mutations in the L-type VGCC (voltage-gated Ca(2+)-channel) EGL-19 caused prolonged pump duration, as found for analogous mutations in the Cav1.2 channel, associated with long QT syndrome. egl-19 mutations affected ability to pump at high frequency and induced arrhythmicity. The pharyngeal neurons did not influence these effects. We tested whether drugs could ameliorate arrhythmia in the optogenetically paced pharynx. The dihydropyridine analog Nemadipine A prolonged pump duration in wild type, and reduced or prolonged pump duration of distinct egl-19 alleles, thus indicating allele-specific effects. In sum, our model may allow screening of drug candidates affecting specific VGCCs mutations, and permit to better understand the effects of distinct mutations on a macroscopic level.
The c-MYC proto-oncogene is a regulator of fundamental cellular processes such as cell cycle progression and apoptosis. The development of novel c-MYC inhibitors that can act by targeting the c-MYC DNA G-quadruplex at the level of transcription would provide potential insight into structure-based design of small molecules and lead to a promising arena for cancer therapy. Herein we report our finding that two simple bis-triazolylcarbazole derivatives can inhibit c-MYC transcription, possibly by stabilizing the c-MYC G-quadruplex. These compounds are prepared using a facile and modular approach based on Cu(I) catalysed azide and alkyne cycloaddition. A carbazole ligand with carboxamide side chains is found to be microenvironment-sensitive and highly selective for "turn-on" detection of c-MYC quadruplex over duplex DNA. This fluorescent probe is applicable to visualize the cellular nucleus in living cells. Interestingly, the ligand binds to c-MYC in an asymmetric fashion and selects the minor-populated conformer via conformational selection.
This thesis presents microstructural investigations of rock salt from the central part of the Gorleben salt dome (Northern Germany). The main emphasis was to characterize the rock salt microfabrics, to identify operating deformation mechanisms in halite and anhydrite and to decipher the macro- and microstructural distribution of hydrocarbons, which have been encountered during the underground exploration of the salt dome. The microfabrics of the Knäuel- and the Streifensalz formation indicate that strain-induced grain boundary migration has been active during deformation of halite. Crystal plastic deformation of halite is further documented by lattice bending, subgrain formation and minor subgrain rotation. Evidence for pressure solution of halite has not been found, but cannot be excluded because of the small grain size, the lack of LPO and the low differential stress (1.1 - 1.3 MPa) as deduced from subgrain-size piezometry. Solution precipitation creep was proven for intercalated anhydrite layers and clusters, which have been deformed in the brittle-ductile regime. Brittle deformation of anhydrite in terms of boudinage and fracturing was counteracted by viscous creep of halite which caused a re-sealing of fractures and a reestablishing of the characteristic sealing capacity of rock salt. Hydrocarbons are mainly located along cross cut 1 West of the Gorleben exploration mine and are heterogeneously distributed in the rock salt. They are incorporated in the rock salt foliation in the form of streaks, dispersed clouds, clusters and isolated patches. On the micro-scale, hydrocarbons are trapped along grain boundaries of halite and/or anhydrite, in micro-capillary tubes of anhydrite and in pore space of the rare rock salt with elevated porosity (< 1.26 vol.-%). Such elevated porosities correlate with elevated hydrocarbon concentrations of several hundred ppm. The overall concentrations of hydrocarbons, however, are very low (< 0.05 wt.-%). Elevated porosity is depicted to be a remnant originating from an early stage of salt uplift when fluid and hydrocarbons have migrated and spread from the Staßfurt Karbonat (z2SK) into the superjacent Gorleben Hauptsalz. During halokinesis and the strong reworking of the salt body hydrocarbons have been redistributed and dismembered resulting in the isolated present-day occurrences. The distribution of hydrocarbons shows no relation to local variations in the rock salt fabric. The microstructures of hydrocarbon-bearing and hydrocarbon-free Gorleben rock salt are not distinguishable from each other. Likewise, the presence of hydrocarbons should not have influenced the mechanical behavior or the rock salt as indicated by the microfabrics studied and by geomechanical data. The pure amounts of hydrocarbons are too low for any detectable impact on the barrier properties of this part of rock salt. Although hydrocarbons have migrated into the Gorleben Hauptsalz during an early stage of salt uplift when the sealing capacity of rock salt was diminished, the major implication of their isolated distribution patterns is that the Gorleben rock salt was able to regain its sealing capacity during subsequent deformation and re-equilibration. Former migration pathways for fluid and hydrocarbons have been healed and do not exist anymore. The application of X-ray computed tomography (CT) allows the 3D visualization and quantification of anhydrite, pore space and fluid phases located along grain-boundaries or trapped as intracrystalline inclusions. The 3D reconstruction of anhydrite clusters and pore space for the same sample reveals different spatial distribution patterns. This fact implies that anhydrite is not responsible for such elevated pore space in the rock salt studied, which has been largely closed during the polyphase deformation history of the Gorleben salt dome. High-resolution nanoCT scans (≤ 1 μm voxel size) of single intra- and intercrystalline fluid inclusions in rock salt enable a characterization of gaseous, solid and liquid phases inside single fluid inclusions and give exact information on morphology and shape. The 3D reconstruction of grain boundary fluid inclusions allows the amount, volumes, surface areas or diameters of various types to be determined. Non-destructive X-ray CT imaging is presented as very useful tool to characterize the structural inventory of rock salt. This non-destructive technique offers new perspectives for microstructural studies and for a wide range of research in structural geology, in general.
Viruses rely completely on the hosts' machinery for translation of viral transcripts. However, for most viruses infecting humans, codon usage preferences (CUPrefs) do not match those of the host. Human papillomaviruses (HPVs) are a showcase to tackle this paradox: they present a large genotypic diversity and a broad range of phenotypic presentations, from asymptomatic infections to productive lesions and cancer. By applying phylogenetic inference and dimensionality reduction methods, we demonstrate first that genes in HPVs are poorly adapted to the average human CUPrefs, the only exception being capsid genes in viruses causing productive lesions. Phylogenetic relationships between HPVs explained only a small proportion of CUPrefs variation. Instead, the most important explanatory factor for viral CUPrefs was infection phenotype, as orthologous genes in viruses with similar clinical presentation displayed similar CUPrefs. Moreover, viral genes with similar spatiotemporal expression patterns also showed similar CUPrefs. Our results suggest that CUPrefs in HPVs reflect either variations in the mutation bias or differential selection pressures depending on the clinical presentation and expression timing. We propose that poor viral CUPrefs may be central to a trade-off between strong viral gene expression and the potential for eliciting protective immune response.
BACKGROUND: Human SAMHD1 is a triphosphohydrolase that restricts the replication of retroviruses, retroelements and DNA viruses in noncycling cells. While modes of action have been extensively described for human SAMHD1, only little is known about the regulation of SAMHD1 in the mouse. Here, we characterize the antiviral activity of murine SAMHD1 with the help of knockout mice to shed light on the regulation and the mechanism of the SAMHD1 restriction and to validate the SAMHD1 knockout mouse model for the use in future infectivity studies.
RESULTS: We found that endogenous mouse SAMHD1 restricts not only HIV-1 but also MLV reporter virus infection at the level of reverse transcription in primary myeloid cells. Similar to the human protein, the antiviral activity of murine SAMHD1 is regulated through phosphorylation at threonine 603 and is limited to nondividing cells. Comparing the susceptibility to infection with intracellular dNTP levels and SAMHD1 phosphorylation in different cell types shows that both functions are important determinants of the antiviral activity of murine SAMHD1. In contrast, we found the proposed RNase activity of SAMHD1 to be less important and could not detect any effect of mouse or human SAMHD1 on the level of incoming viral RNA.
CONCLUSION: Our findings show that SAMHD1 in the mouse blocks retroviral infection at the level of reverse transcription and is regulated through cell cycle-dependent phosphorylation. We show that the antiviral restriction mediated by murine SAMHD1 is mechanistically similar to what is known for the human protein, making the SAMHD1 knockout mouse model a valuable tool to characterize the influence of SAMHD1 on the replication of different viruses in vivo.
Self-narratives of patients have received increasing interest in schizophrenia since they offer unique material to study patients’ subjective experience related to their illness, in particular the alteration of self that accompanies schizophrenia. In this study, we investigated the life narratives and the ability to integrate and bind memories of personal events into a coherent narrative in 27 patients with schizophrenia and 26 controls. Four aspects of life narratives were analyzed: coherence with cultural concept of biography, temporal coherence, causal-motivational coherence and thematic coherence. Results showed that in patients cultural biographical knowledge is preserved, whereas temporal coherence is partially impaired. Furthermore, causal-motivational and thematic coherence are significantly impaired: patients have difficulties explaining how events have modeled their identity, and integrating different events along thematic lines. Impairment of global causal-motivational and thematic coherence was significantly correlated with patients’ executive dysfunction, suggesting that cognitive impairment observed in patients could affect their ability to construct a coherent narrative of their life by binding important events to their self. This study provides new understanding of the cognitive deficits underlying self-disorders in patients with schizophrenia. Our findings suggest the potential usefulness of developing new therapeutic interventions to improve autobiographical reasoning skills.
Gallbladder cancer (GBC) is a highly malignant tumor characterized by a poor response to chemotherapy and radiotherapy. We evaluated the in vitro and in vivo antitumor efficacy of mTOR inhibitors, rapamycin and WYE-354. In vitro assays showed WYE-354 significantly reduced cell viability, migration and invasion and phospho-P70S6K expression in GBC cells. Mice harboring subcutaneous gallbladder tumors, treated with WYE-354 or rapamycin, exhibited a significant reduction in tumor mass. A short-term treatment with a higher dose of WYE-354 decreased the tumor size by 68.6% and 52.4%, in mice harboring G-415 or TGBC-2TKB tumors, respectively, compared to the control group. By contrast, treatment with a prolonged-low-dose regime of rapamycin almost abrogated tumor growth, exhibiting 92.7% and 97.1% reduction in tumor size, respectively, compared to control mice. These results were accompanied by a greater decrease in the phosphorylation status of P70S6K and a lower cell proliferation Ki67 index, compared to WYE-354 treated mice, suggesting a more effective mTOR pathway inhibition. These findings provide a proof of concept for the use of rapamycin or WYE-354 as potentially good candidates to be studied in clinical trials in GBC patients.