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Diese Arbeit beschäftigt sich mit inversen Problemen für partielle Differentialgleichungen. Moderne Lösungsverfahren solcher inversen Probleme müssen die zugehörige partielle Differentialgleichung (PDGL) oft sehr häufig lösen. Mit Hinblick auf die Rechenzeit solcher Verfahren stellt das häufige Lösen der PDGL den Hauptanteil der benötigten Rechenzeit dar. Daraus resultiert die Grundidee dieser Arbeit: es sollen Lösungsverfahren von inversen Problemen beschleunigt werden, indem die für die Vorwärtslösung benötigte Rechenzeit verringert wird. Genauer gesagt soll anstatt der Vorwärtslösung eine Approximation an diese, welche kostengünstig zu berechnen ist, verwendet werden. Für die Bestimmung einer kostengünstigen Annäherung an die Vorwärtslösung wird die Reduzierte Basis Methode, eine Modellreduktionstechnik, verwendet.
Das Ziel der klassischen Reduzierten Basis Methode ist es einen globalen Reduzierte Basis Raum (RB-Raum) zu konstruieren. Dabei handelt es sich um einen niedrigdimensionalen Teilraum des Lösungsraumes der PDGL, welcher für jeden Parameter aus dem Parameterraum eine gute Näherung der PDGL-Lösung liefert. Eine beispielhafte Methode zur Konstruktion eines solchen Raumes ist es, geschickt Parameter auszuwählen und die dazu gehörigen PDGL-Lösungen als Basisvektoren des RB-Raumes zu verwenden. Die orthogonale Projektion der PDGL auf diesen RB-Raum liefert die entsprechenden Reduzierte Basis Lösungen. Das Besondere in dieser Arbeit ist, dass die betrachteten PDGLn einen sehr hochdimensionalen und unbeschränkten Parameterraum besitzen, und es ist bekannt, dass dies für die Reduzierte Basis Methode eine immense Schwierigkeit darstellt.
In Kapitel 1 wird ein schlechtgestelltes inverses Modellproblem, die Rekonstruktion der Wärmeleitfähigkeit eines Gegenstandes aus der Messung der Temperatur desselben, eingeführt und das nichtlineare Landweber-Verfahren als iteratives Regularisierungsverfahren zur Lösung dieses inversen Problems vorgestellt. Die Grundlagen der Reduzierten Basis Methode werden dargelegt und es wird erläutert, warum die klassische Variante der Methode in diesem Kontext der Bildrekonstruktion versagt. Daraufhin wird der neuartig Ansatz, ein adaptiver Reduzierte Basis Ansatz, entwickelt. Die folgenden Schritte bilden die Grundlage dieses adaptiven Reduzierte Basis Ansatzes:
1. Sei ein RB-Raum gegeben, so projiziere den Lösungsalgorithmus des inversen Problems auf diesen RB-Raum.
2. Generiere mit Hilfe dieses projizierten Verfahrens neue Iterierte bis entweder eine Iterierte das inverse Problem löst oder bis der RB-Raum erweitert werden muss.
3. Im ersten Fall wird das Verfahren beendet, im zweiten Fall wird die zur aktuellen Iterierten gehörige Vorwärtslösung verwendet um den RB-Raum zu verbessern. Danach wird mit dem ersten Schritt fortgefahren.
Es wird also nach und nach ein lokal approximierender RB-Raum konstruiert, indem Parameter für neue Basisvektoren mittels einer projizierten Variante des Lösungsalgorithmus des inversen Problems gefunden werden. Das neuartige Reduzierte Basis Landweber-Verfahren ist das Hauptresultat von Kapitel 1, wobei das Verfahren ausführlich numerisch untersucht und mit dem ursprünglichen Landweber-Verfahren verglichen wird.
In Kapitel 2 dieser Arbeit soll der zuvor entwickelte adaptive Reduzierte Basis Ansatz auf ein komplexes und praxisrelevantes Problem angewandt werden. Insbesondere soll die dadurch entstehende neue Methode mit Hinblick auf Konvergenz theoretisch ausführlich untersucht werden. Daher widmet sich der zweite Teil dieser Arbeit dem Problem der Magnet Resonanz Elektrischen Impedanztomographie (MREIT).
Bei der MREIT handelt es sich um ein Bildgebungsverfahren, welches während der letzten drei Jahrzehnte entwickelt wurde. Dabei wird ein Gegenstand, an welchen Elektroden angeheftet sind, in einen Kernspintomographen gelegt und es ist das Ziel des Verfahrens die elektrische Leitfähigkeit des Gegenstandes zu bestimmen. Die dazu benötigten Daten werden folgendermaßen gewonnen: indem Strom an einer der Elektroden angelegt wird, wird ein Stromfluss erzeugt, welcher wiederum eine Änderung der Magnetflussdichte induziert. Diese kann mit Hilfe des Kernspintomographen gemessen werden, wodurch man einen vollen Satz innerer Daten zur Hand hat, sodass hoch aufgelöste Bilder der elektrischen Leitfähigkeit des Gegenstandes rekonstruiert werden können.
Als Lösungsalgorithmus für dieses praxisrelevante Problem wird der bereits bekannte Harmonische Bz Algorithmus vorgestellt. Das Problem und der Algorithmus werden mit Hinblick auf Konvergenz des Verfahrens untersucht und ein Konvergenzresultat, welches die bestehende Konvergenztheorie hin zu einem approximativen Harmonischen Bz Algorithmus erweitert, wird bewiesen. Dabei hängt das Resultat nicht davon ab welche Art von Approximation an die Vorwärtslösung der entsprechenden PDGL im approximativen Harmonischen Bz Algorithmus verwendet wird solange diese einer Regularitäts- und einer Qualitätsbedingung genügt. Damit folgt das zweite Hauptresultat dieser Arbeit: die numerische Konvergenz des Harmonischen Bz Algorithmus. Es soll dabei hervorgehoben werden, dass Konvergenzresultate im Bereich der inversen Probleme (sofern es sie gibt) meistens die Kenntnis der exakten Vorwärtslösung annehmen, sodass keine numerische Konvergenz des zugehörigen Verfahrens folgt (in einer numerischen Implementation wird stets eine Approximation an die Vorwärtslösung verwendet). Somit ist dieses Konvergenzresultat ein Schritt hin zur numerischen Konvergenz anderer Lösungsverfahren von inversen Problemen.
Da das theoretische Resultat von der Art der Approximation nicht abhängt, erhält man ebenfalls die Konvergenz des neuartigen Reduzierte Basis Harmonischen Bz Algorithmus, welcher die Kombination des in Kapitel 1 entwickelten adaptiven Reduzierte Basis Ansatzes und des Harmonischen Bz Algorithmus ist. In einer kurzen numerischen Untersuchung wird festgestellt, dass dieser Reduzierte Basis Harmonische Bz Algorithmus schneller als der Harmonische Bz Algorithmus ist, wobei die Qualität der Rekonstruktion gleichbleibend ist. Somit funktioniert der entwickelte adaptive Reduzierte Basis Ansatz auch angewandt auf dieses komplexe praxisrelevante inverse Problem der MREIT.
The Republic of Panama currently has 358 recorded species of Trichoptera. Herein we add 25 new country records for Panama. The newly recorded taxa increase Panama’s total known caddisfly fauna to 383 species, distributed among 15 families and 52 genera. These results are part of an ongoing effort to characterize the caddisfly fauna of Panama, and to evaluate that country’s major watersheds (cuencas).
There have been 136 species of microcaddisflies (Trichoptera: Hydroptilidae) recorded from the Republic of Panama. Herein we describe seven new species from the Mount Totumas Cloud Forest and Biological Reserve, in the upper reaches of the Río Chiriquí Viejo watershed (Costatrichia devestiva, C. dietrichi, Metrichia brocha, M. calla, Neotrichia atopa, Ochrotrichia anticheirion, and Rhyacopsyche totuma). These results are part of an ongoing effort to characterize the aquatic insect fauna of Panama, and to evaluate that country’s major watersheds.
Through this survey, four species of aphelinid, one species of encyrtid, and one species of signiphorid wasp (Hymenoptera: Chalcidoidea) were collected and identified as follows: Aphytis japonicus DeBach and Azim, Encarsia berlesei (Howard), Marietta carnesi (Howard), Pteroptrix sp. 2, Arrhenophagus chionaspidis Aurivillius, and Chartocerus subaenus (Förster). Among these, C. subaenus is recorded newly from the Korean parasitoid fauna. Also, three species of aphelinids and one species of signiphorid are newly added as parasitic wasps associated with Pseudaulacaspis cockerelli (Cooley) (Hemiptera: Coccoidea) from Korea. In this paper, the list of parasitoid species of P. cockerelli that occur in Korea is updated and a brief diagnosis and photographs of these species are provided.
The Scarabaeus subgenus Scarabaeolus Balthasar, 1965 (Scarabaeidae: Scarabaeinae: Scarabaeini) is defined and nine new species are described, six from the Republic of South Africa [S. (S.) fragilis sp. n., S. (S.) krugeri sp. n., S. (S.) lizleri sp. n., S. (S.) orientalis sp. n., S. (S.) rugosipennis sp. n., S. (S.) similis sp. n.] and one each from Angola [S. (S.) cunene sp. n.], Namibia [S. (S.) namibensis sp. n.] and Kenya [S. (S.) werneri sp. n.], bringing the number of recorded species up to 41. Species accounts listing original descriptions, subsequent accounts, type localities, type repositories, and geographic distributions are provided for all the species. The status of S. (S.) reichei Waterhouse, 1890 and of S. (S.) bohemani Harold, 1868, both formerly synonymized and reinstated, are discussed. It is concluded that S. (S.) reichei is synonymous with S. (S.) canaliculatus Fairmaire, 1888, whereas S. (S.) bohemani differs from S. (S.) palemo Olivier, 1789 in the color of antennal club and shape of paramere tips, and is upheld pending availability of molecular data.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers potential cure to acute myeloid leukemia (AML) patients. However, infections with commensal bacteria are an important cause for non-relapse mortality (NRM). We have previously described the impact of multidrug-resistant organism (MDRO) colonization on the survival of allo-HSCT patients. In the aforementioned publication, according to consensus, we there did not consider the opportunistic gram-negative bacterium Stenotrophomonas maltophilia (S. maltophilia) to be an MDRO. Since rate of S. maltophilia colonization is increasing, and it is not known whether this poses a risk for allo-HSCT patients, we here analyzed here its effect on the previously described and now extended patient cohort. We report on 291 AML patients undergoing allo-HSCT. Twenty of 291 patients (6.9%) were colonized with S. maltophilia. Colonized patients did not differ from non-colonized patients with respect to their age, remission status before allo-HSCT, donor type and HSCT-comorbidity index. S. maltophilia colonized patients had a worse overall survival (OS) from 6 months up to 60 months (85% vs. 88.1% and 24.7% vs. 59.7%; p = 0.007) due to a higher NRM after allo-HSCT (6 months: 15% vs. 4.8% and 60 months: 40.1% vs. 16.2% p = 0.003). The main cause of mortality in colonized patients was infection (46.2% of all deaths) and in non-colonized patients relapse (58.8% of all deaths). 5/20 colonized patients developed an invasive infection with S. maltophilia. The worse OS after allo-HSCT due to higher infection related mortality might implicate the screening of allo-HSCT patients for S. maltophilia and a closer observation of colonized patients as outpatients.
Background: Drugs used to treat gastrointestinal diseases (GI drugs) are widely used either as prescription or over23 the-counter (OTC) medications and belong to both the ten most prescribed and ten most sold OTC medications worldwide. Current clinical practice shows that in many cases, these drugs are administered concomitantly with other drug products. Due to their metabolic properties and mechanisms of action, the drugs used to treat gastrointestinal diseases can change the pharmacokinetics of some co27 administered drugs. In certain cases, these interactions can lead to failure of treatment or to the occurrence of serious adverse events. The mechanism of interaction depends highly on drug properties and differs among therapeutic categories. Understanding these interactions is essential to providing recommendations for optimal drug therapy.
Objective: To discuss the most frequent interactions between GI and other drugs, including identification of the mechanisms behind these interactions, where possible.
Conclusion: Interactions with GI drugs are numerous and can be highly significant clinically. Whilst alterations in bioavailability due to changes in solubility, dissolution rate and metabolic interactions can be (for the most part) easily identified, interactions that are mediated through other mechanisms, such as permeability or microbiota, are less well understood. Future work should focus on characterizing these aspects.
While interleukin (IL)-1β is a potent pro-inflammatory cytokine involved in host defense, high levels can cause life-threatening sterile inflammation including systemic inflammatory response syndrome. Hence, the control of IL-1β secretion is of outstanding biomedical importance. In response to a first inflammatory stimulus such as lipopolysaccharide, pro-IL-1β is synthesized as a cytoplasmic inactive pro-form. Extracellular ATP originating from injured cells is a prototypical second signal for inflammasome-dependent maturation and release of IL-1β. The human anti-protease alpha-1 antitrypsin (AAT) and IL-1β regulate each other via mechanisms that are only partially understood. Here, we demonstrate that physiological concentrations of AAT efficiently inhibit ATP-induced release of IL-1β from primary human blood mononuclear cells, monocytic U937 cells, and rat lung tissue, whereas ATP-independent IL-1β release is not impaired. Both, native and oxidized AAT are active, suggesting that the inhibition of IL-1β release is independent of the anti-elastase activity of AAT. Signaling of AAT in monocytic cells involves the lipid scavenger receptor CD36, calcium-independent phospholipase A2β, and the release of a small soluble mediator. This mediator leads to the activation of nicotinic acetylcholine receptors, which efficiently inhibit ATP-induced P2X7 receptor activation and inflammasome assembly. We suggest that AAT controls ATP-induced IL-1β release from human mononuclear blood cells by a novel triple-membrane-passing signaling pathway. This pathway may have clinical implications for the prevention of sterile pulmonary and systemic inflammation.
Bacterial pathogens exploit eukaryotic pathways for their own end. Upon ingestion, Salmonella enterica serovar Typhimurium passes through the stomach and then catalyzes its uptake across the intestinal epithelium. It survives and replicates in an acidic vacuole through the action of virulence factors secreted by a type three secretion system located on Salmonella pathogenicity island 2 (SPI-2). Two secreted effectors, SifA and SseJ, are sufficient for endosomal tubule formation, which modifies the vacuole and enables Salmonella to replicate within it. Two-color, superresolution imaging of the secreted virulence factor SseJ and tubulin revealed that SseJ formed clusters of conserved size at regular, periodic intervals in the host cytoplasm. Analysis of SseJ clustering indicated the presence of a pearling effect, which is a force-driven, osmotically sensitive process. The pearling transition is an instability driven by membranes under tension; it is induced by hypotonic or hypertonic buffer exchange and leads to the formation of beadlike structures of similar size and regular spacing. Reducing the osmolality of the fixation conditions using glutaraldehyde enabled visualization of continuous and intact tubules. Correlation analysis revealed that SseJ was colocalized with the motor protein kinesin. Tubulation of the endoplasmic reticulum is driven by microtubule motors, and in the present work, we describe how Salmonella has coopted the microtubule motor kinesin to drive the force-dependent process of endosomal tubulation. Thus, endosomal tubule formation is a force-driven process catalyzed by Salmonella virulence factors secreted into the host cytoplasm during infection.
Truffles (Tuber spp.) are the fruiting bodies of symbiotic fungi, which are prized food delicacies. The marked aroma variability observed among truffles of the same species has been attributed to a series of factors that are still debated. This is because factors (i.e. genetics, maturation, geographical location and the microbial community colonizing truffles) often co-vary in truffle orchards. Here, we removed the co-variance effect by investigating truffle flavour in axenic cultures of nine strains of the white truffle Tuber borchii. This allowed us to investigate the influence of genetics on truffle aroma. Specifically, we quantified aroma variability and explored whether strain selection could be used to improve human-sensed truffle flavour. Our results illustrate that aroma variability among strains is predominantly linked to amino acid catabolism through the Ehrlich pathway, as confirmed by 13C labelling experiments. We furthermore exemplified through sensory analysis that the human nose is able to distinguish among strains and that sulfur volatiles derived from the catabolism of methionine have the strongest influence on aroma characteristics. Overall, our results demonstrate that genetics influences truffle aroma much more deeply than previously thought and illustrate the usefulness of strain selection for improving truffle flavour.
Regulation of protein turnover allows cells to react to their environment and maintain homeostasis. Proteins can show different turnover rates in different tissue, but little is known about protein turnover in different brain cell types. We used dynamic SILAC to determine half-lives of over 5100 proteins in rat primary hippocampal cultures as well as in neuron-enriched and glia-enriched cultures ranging from <1 to >20 days. In contrast to synaptic proteins, membrane proteins were relatively shorter-lived and mitochondrial proteins were longer-lived compared to the population. Half-lives also correlate with protein functions and the dynamics of the complexes they are incorporated in. Proteins in glia possessed shorter half-lives than the same proteins in neurons. The presence of glia sped up or slowed down the turnover of neuronal proteins. Our results demonstrate that both the cell-type of origin as well as the nature of the extracellular environment have potent influences on protein turnover.
Many cancers have the tumor suppressor p53 inactivated by mutation, making reactivation of mutant p53 with small molecules a promising strategy for the development of novel anticancer therapeutics. The oncogenic p53 mutation Y220C, which accounts for approximately 100,000 cancer cases per year, creates an extended surface crevice in the DNA-binding domain, which destabilizes p53 and causes denaturation and aggregation. Here, we describe the structure-guided design of a novel class of small-molecule Y220C stabilizers and the challenging synthetic routes developed in the process. The synthesized chemical probe MB710, an aminobenzothiazole derivative, binds tightly to the Y220C pocket and stabilizes p53-Y220C in vitro. MB725, an ethylamide analogue of MB710, induced selective viability reduction in several p53-Y220C cancer cell lines while being well tolerated in control cell lines. Reduction of viability correlated with increased and selective transcription of p53 target genes such as BTG2, p21, PUMA, FAS, TNF, and TNFRSF10B, which promote apoptosis and cell cycle arrest, suggesting compound-mediated transcriptional activation of the Y220C mutant. Our data provide a framework for the development of a class of potent, non-toxic compounds for reactivating the Y220C mutant in anticancer therapy.
In 1957, Craig Mooney published a set of human face stimuli to study perceptual closure: the formation of a coherent percept on the basis of minimal visual information. Images of this type, now known as “Mooney faces”, are widely used in cognitive psychology and neuroscience because they offer a means of inducing variable perception with constant visuo-spatial characteristics (they are often not perceived as faces if viewed upside down). Mooney’s original set of 40 stimuli has been employed in several studies. However, it is often necessary to use a much larger stimulus set. We created a new set of over 500 Mooney faces and tested them on a cohort of human observers. We present the results of our tests here, and make the stimuli freely available via the internet. Our test results can be used to select subsets of the stimuli that are most suited for a given experimental purpose.
Effect of progesterone on Smad signaling and TGF-β/Smad-regulated genes in lung epithelial cells
(2018)
The effect of endogenous progesterone and/or exogenous pre- or postnatal progesterone application on lung function of preterm infants is poorly defined. While prenatal progesterone substitution may prevent preterm birth, in vitro and in vivo data suggest a benefit of postnatal progesterone replacement on the incidence and severity of bronchopulmonary dysplasia (BPD). However, the molecular mechanisms responsible for progesterone’s effects are undefined. Numerous factors are involved in lung development, airway inflammation, and airway remodeling: the transforming growth factor beta (TGF-β)/mothers against decapentaplegic homolog (Smad) signaling pathway and TGF-β-regulated genes, such as connective tissue growth factor (CTGF), transgelin (TAGLN), and plasminogen activator inhibitor-1 (PAI-1). These processes contribute to the development of BPD. The aim of the present study was to clarify whether progesterone could affect TGF-β1-activated Smad signaling and CTGF/transgelin/PAI-1 expression in lung epithelial cells. The pharmacological effect of progesterone on Smad signaling was investigated using a TGF-β1-inducible luciferase reporter and western blotting analysis of phosphorylated Smad2/3 in A549 lung epithelial cells. The regulation of CTGF, transgelin, and PAI-1 expression by progesterone was studied using a promoter-based luciferase reporter, quantitative real-time PCR, and western blotting in the same cell line. While progesterone alone had no direct effect on Smad signaling in lung epithelial cells, it dose-dependently inhibited TGF-β1-induced Smad3 phosphorylation, as shown by luciferase assays and western blotting analysis. Progesterone also antagonized the TGF-β1/Smad-induced upregulation of CTGF, transgelin, and PAI-1 at the promoter, mRNA, and/or protein levels. The present study highlights possible new molecular mechanisms involving progesterone, including inhibition of TGF-β1-activated Smad signaling and TGF-β1-regulated genes involved in BPD pathogenesis, which are likely to attenuate the development of BPD by inhibiting TGF-β1-mediated airway remodeling. Understanding these mechanisms might help to explain the effects of pre- or postnatal application of progesterone on lung diseases of preterm infants.
This study was designed to characterize morphologic stages during neuroma development post amputation with an eye toward developing better treatment strategies that intervene before neuromas are fully formed. Right forelimbs of 30 Sprague Dawley rats were amputated and limb stumps were collected at 3, 7, 28, 60 and 90 Days Post Amputation (DPA). Morphology of newly formed nerves and neuromas were assessed via general histology and neurofilament protein antibody staining. Analysis revealed six morphological characteristics during nerve and neuroma development; 1) normal nerve, 2) degenerating axons, 3) axonal sprouts, 4) unorganized bundles of axons, 5) unorganized axon growth into muscles, and 6) unorganized axon growth into fibrotic tissue (neuroma). At early stages (3 & 7 DPA) after amputation, normal nerves could be identified throughout the limb stump and small areas of axonal sprouts were present near the site of injury. Signs of degenerating axons were evident from 7 to 90 DPA. From day 28 on, variability of nerve characteristics with signs of unorganized axon growth into muscle and fibrotic tissue and neuroma formation became visible in multiple areas of stump tissue. These pathological features became more evident on days 60 and 90. At 90 DPA frank neuroma formation was present in all stump tissue. By following nerve regrowth and neuroma formation after amputation we were able to identify 6 separate histological stages of nerve regrowth and neuroma development. Axonal regrowth was observed as early as 3 DPA and signs of unorganized axonal growth and neuroma formation were evident by 28 DPA. Based on these observations we speculate that neuroma treatment and or prevention strategies might be more successful if targeted at the initial stages of development and not after 28 DPA.
Background and aims: Expression of carbonic anhydrase IX (CA9), an enzyme expressed in response to hypoxia, acidosis and oncogenic alterations, is reported to be a prognostic factor in HCC patients. Here we evaluated serum CA9 levels in HCC and cirrhosis patients.
Methods: HCC and cirrhosis patients were prospectively recruited and CA9 levels were determined. CA9 levels were compared to stages of cirrhosis and HCC stages. The association of the CA9 levels and overall survival (OS) was assessed. Furthermore, immunohistochemical CA9 expression in HCC and cirrhosis was evaluated.
Results: 215 patients with HCC were included. The median serum CA9 concentration in patients with HCC was 370 pg/ml and significantly higher than in a healthy cohort. Patients with advanced cancer stages (BCLC and ALBI score) had hid significant higher levels of CA9 in the serum. HCC patients with high serum CA9 concentrations (>400 pg/ml) had an increased mortality risk (hazard ratio (HR) 1.690, 95% confidence interval (CI) 1.017–2.809, P = 0.043). Serum CA9 concentration in cirrhotic patients did not differ significantly from HCC patients. Higher CA9 levels in cirrhotic patients correlated with portal hypertension and esophageal varices. Patients with ethanol induced cirrhosis had the highest CA9 levels in both cohorts. Levels of CA9 did not correlate with immunohistochemical expression.
Conclusions: We conclude that a high CA9 level is a possible prognostic indicator for a poor outcome in HCC patients. The high CA9 levels are probably mainly associated with portal hypertension. Ductular reactions might be a possible source of serum CA9.
Transmission of temporally correlated spike trains through synapses with short-term depression
(2018)
Short-term synaptic depression, caused by depletion of releasable neurotransmitter, modulates the strength of neuronal connections in a history-dependent manner. Quantifying the statistics of synaptic transmission requires stochastic models that link probabilistic neurotransmitter release with presynaptic spike-train statistics. Common approaches are to model the presynaptic spike train as either regular or a memory-less Poisson process: few analytical results are available that describe depressing synapses when the afferent spike train has more complex, temporally correlated statistics such as bursts. Here we present a series of analytical results—from vesicle release-site occupancy statistics, via neurotransmitter release, to the post-synaptic voltage mean and variance—for depressing synapses driven by correlated presynaptic spike trains. The class of presynaptic drive considered is that fully characterised by the inter-spike-interval distribution and encompasses a broad range of models used for neuronal circuit and network analyses, such as integrate-and-fire models with a complete post-spike reset and receiving sufficiently short-time correlated drive. We further demonstrate that the derived post-synaptic voltage mean and variance allow for a simple and accurate approximation of the firing rate of the post-synaptic neuron, using the exponential integrate-and-fire model as an example. These results extend the level of biological detail included in models of synaptic transmission and will allow for the incorporation of more complex and physiologically relevant firing patterns into future studies of neuronal networks.
This thesis is concerned with systematic investigations of electronic noise in novel condensed matter systems. Although fluctuations are frequently considered a nuisance, that is, a disturbance limiting the accuracy of scientific measurements, in many cases they can reveal fundamental information about the inherent system dynamics. During the past decades, the study of electronic fluctuations has evolved into an indispensable tool in condensed matter physics.
The focus of the present work lies both in a further development of the fluctuation spectroscopy technique and in the study of materials of current interest. In particular, a comprehensive study of the charge carrier dynamics in the archetypal diluted magnetic semiconductors (Ga,Mn)As and (Ga,Mn)P was performed. In spite of extensive research work carried out during the last years, there still exists no theoretical consensus on the precise mechanism of ferromagnetic order and the electronic structure in these materials. Moreover, disorder and correlation effects complicate the understanding of these compounds.
Fluctuation spectroscopy experiments presented in this work provide strong evidence that a percolation transition is observed in samples with localized charge carriers, since the normalized resistance noise magnitude displays a significant enhancement around the Curie temperature. In addition, this quantity exhibits a power law scaling behavior as a function of the resistance, which is in good agreement with theoretical models of percolating systems.
By contrast, it was found that the resistance noise in metallic samples is mainly dominated by the physics of defects such as manganese interstitials and arsenic antisites. Furthermore, first noise studies were carried out on hafnia- and yttria-based resistive random access memories. In these memristor devices, the rupture and re-formation of oxygen deficient conducting filaments caused by the electric field and Joule heating driven motion of mobile anions lead to an unusual resistance switching behavior. For the first time, comparative noise measurements on oxygen deficient and stoichiometric hafnium oxide devices, as well as on novel yttrium oxide based devices were performed in this work. Finally, new strategies for noise measurements of highly insulating and extremely low-resistive samples were developed and realized. In detail, an experimental setup for the measurements of dielectric polarization fluctuations in insulating systems was designed and successfully tested. Here, the polarization noise of a sample is measured as current or voltage fluctuations produced within a capacitance cell. The study of dielectric polarization noise allows for conclusions to be drawn regarding equilibrium structural dynamics in insulators such as relaxor ferroelectrics. On the other hand, as successfully demonstrated for a heavy-fermion compound, focused ion beam etching enables to introduce a meander-shaped geometry in single crystal platelets, in order to strongly enhance the sample resistance and thus make resistance noise measurements possible. First results indicate a connection of the noise properties with the Kondo effect in the investigated material.
Infections with the hepatitis B virus (HBV) or the hepatitis C virus (HCV) lead to complications like the development of cirrhosis or hepatocellular carcinoma. These complications end up in 887,000 and 500,000 deaths per year, respectively. Since the development of new direct acting antiviral agents for HCV in the past years a complete cure of an HCV infection can be achieved in the majority of the patients. In contrast, a complete cure of a chronic HBV infection still remains a challenging problem as current treatment regimens mainly suppress the viral replication and cccDNA as well as integrated DNA still persist in these patients. Several viral and host factors were described to impair the efficacy of treatment regimens or influence the course of the infection. Therefore, in this work viral factors as well as host factors were investigated in HBeAg negative chronic HBV infected patients and in chronic HCV infected patients. In the present study, it was demonstrated that mutations and/or deletions in the HBV basal core promoter (BCP), the precore and the preS domain occur in a genotype-specifc pattern in HBeAg negative HBV infected patients. While the BCP double mutation A1762T/G1764A was found with the highest prevalence in genotype E infected patients, the precore mutation G1896A occurred mostly in genotype B infected patients. Variants in the preS domain could be detected with the highest frequency in patients infected with genotype C. In patients, who had to start an antiviral therapy during the course of the disease, mutations in the precore region could be detected with a higher frequency in the samples right before treatment start in comparison to the baseline sample.
While different HBV genotypes and preS mutations were not associated with HBV-DNA serum levels, precore mutations as well as BCP mutations were significantly associated with HBV-DNA levels. Furthermore, precore mutations showed lower and preS mutations higher HBsAg levels. The HBsAg serum levels varied significantly among the different genotypes. Since HBsAg levels < 1000 IU/ml have been described as a prognostic marker in several studies, the prevalence of patients with HBsAg < 1000 IU/ml was analyzed among the genotypes A - E. While most of the patients infected with HBV genotype B had HBsAg < 1000 IU/ml, only a few patients infected HBV genotype E and A had HBsAg < 1000 IU/ml.
Furthermore, HBV genotype A genomes derived from patients harboring a) A1762T/ G1764A (BCP), b) G1896A/G1899A (precore), c) 15 aa deletion in preS1, d) no mutation (reference genome) were cloned and analyzed in vitro. An enhanced expression but reduced secretion of viral genomes was found in the preS-deletion- and the precore-variant. No differences in the HBsAg production and secretion were observed in the cloned precore- or BCP-variant, while the preS-deletion-variant was characterized with an elevated HBsAg release.
Regarding the secretion of viral and subviral particles, a genotype-specifc pattern of the L/M/SHBs ratio was detected in the serum of patients infected with genotypes A - E. This pattern did not change in the serum of patients, who started antiviral treatment. Secreted HBsAg containing particles displayed a higher density as well as a higher filaments/spheres ratio in genotypes B and D compared to genotypes A, C and E. Population-based and deep sequencing revealed large deletions in the preS domain or preS2 start codon mutations in a certain number of the viral genomes. Theoretically, these mutations/deletions should influence the molecular weight of the expressed protein or abolish the expression of the protein at all. In contrast, LHBs/MHBs were detectable and appeared at the same molecular weight in these patient samples in comparison to patient samples without these mutations. Furthermore, in the in vitro analyses comparing the reference genome and the preS1-deletion genome, it was shown that the deletion indeed influenced the molecular weight of LHBs. Therefore, HBsAg might be expressed from a genetically different source than the released viral genomes, meaning the integrated DNA.
Additionally, in the present study the prevalence of resistance associated substitutions (RASs) in the viral genes NS3, NS5A and NS5B of chronic HCV infected patients was analyzed in correlation to single nucleotide polymorphisms (SNPs) in the interferon-λ4 (IFNL4) gene of the infected patients. No significant correlation was found between IFNL4 SNPs and RASs within NS3/NS5B in the present cohort. In contrast, the frequently detected NS5A RAS Y93H could be significantly associated with beneficial IFNL4 SNPs and a high baseline viral load in HCV genotype 1-infected patients.
Taken together, the present study demonstrated that viral genome mutations as well as the morphology of secreted particles occur in a genotype-dependent pattern in HBeAg negative HBV infected patients with no need of antiviral therapy. As the amount of serum qHBsAg levels varied among the different genotypes, the HBsAg cut-off < 1000 IU/ml should be adapted individually among the various genotypes. Because the composition of the secreted subviral particles varied between the different genotypes, a genotype-specific immune-response might be induced in these patients. Additionally, the results of the present study indicate that in HBeAg negative HBV infected patients with mutations or deletions in the preS domain MHBs and LHBs might be expressed from the integrated DNA and therefore from a genetically different source than the released viral genomes.
Aside from that, the finding of a significant association of the NS5A RAS Y93H with beneficial IFNL4 SNPs in chronic HCV infected patients may explain a lack of a correlation or an inverse correlation of treatment response with the IFNL4 genotype in some NS5A inhibitor-containing IFN-free regimens.
Evoked potentials (EPs) are well established in clinical practice for diagnosis and prognosis in multiple sclerosis (MS). However, their value is limited to the assessment of their respective functional systems. Here, we used transcranial magnetic stimulation (TMS) coupled with electroencephalography (TMS-EEG) to investigate cortical excitability and spatiotemporal dynamics of TMS-evoked neural activity in MS patients. Thirteen patients with early relapsing–remitting MS (RRMS) with a median Expanded Disability Status Scale (EDSS) of 1.0 (range 0–2.5) and 16 age- and gender-matched healthy controls received single-pulse TMS of left and right primary motor cortex (L-M1 and R-M1), respectively. Resting motor threshold for L-M1 and R-M1 was increased in MS patients. Latencies and amplitudes of N45, P70, N100, P180, and N280 TMS-evoked EEG potentials (TEPs) were not different between groups, except a significantly increased amplitude of the N280 TEP in the MS group, both for L-M1 and R-M1 stimulation. Interhemispheric signal propagation (ISP), estimated from the area under the curve of TEPs in the non-stimulated vs. stimulated M1, also did not differ between groups. In summary, findings show that ISP and TEPs were preserved in early-stage RRMS, except for an exaggerated N280 amplitude. Our findings indicate that TMS-EEG is feasible in testing excitability and connectivity in cortical neural networks in MS patients, complementary to conventional EPs. However, relevance and pathophysiological correlates of the enhanced N280 will need further study.