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Introduction: This study presents our online-teaching material within the k-MED project (Knowledge in Medical Education) at the university of Marburg. It is currently organized in five e-learning modules: cytogenetics, chromosomal aberrations, formal genetics, fundamentals of molecular diagnostics, and congenital abnormalities and syndromes. These are basic courses intended to do the educational groundwork, which will enable academic teachers to concentrate on more sophisticated topics during their lectures. Methods: The e-learning modules have been offered to a large group of about 3300 students during four years at the Faculty of Medicine in Marburg. The group consists of science students (human biology) and medical students in the preclinical or the clinical period, respectively. Participants were surveyed on acceptance by evaluating user-tracking data and questionnaires. Results and Conclusion: Analysis of the evaluation data proofs the broad acceptance of the e-learning modules during eight semesters. The courses are in stable or even increasing use from winter term 2005/06 until spring term 2009. Conclusion: Our e-learning-model is broadly accepted among students with different levels of knowledge at the Faculty of Medicine in Marburg. If the e-learning courses are maintained thoroughly, minor adaptations can increase acceptance and usage even furthermore. Their use should be extended to the medical education of technical assistances and nurses, who work in the field of human genetics. Keywords: Human genetics, e-Learning, evaluation, multimedia
Background: Due to the use of organophosphates (OP) as pesticides and the availability of OP-type nerve agents, an effective medical treatment for OP poisonings is still a challenging problem. The acute toxicity of an OP poisoning is mainly due to the inhibition of acetylcholinesterase (AChE) in the peripheral and central nervous systems (CNS). This results in an increase in the synaptic concentration of the neurotransmitter acetylcholine, overstimulation of cholinergic receptors and disorder of numerous body functions up to death. The standard treatment of OP poisoning includes a combination of a muscarinic antagonist and an AChE reactivator (oxime). However, these oximes can not cross the blood-brain barrier (BBB) sufficiently. Therefore, new strategies are needed to transport oximes over the BBB. Methodology/Principal Findings: In this study, we combined different oximes (obidoxime dichloride and two different HI 6 salts, HI 6 dichloride monohydrate and HI 6 dimethanesulfonate) with human serum albumin nanoparticles and could show an oxime transport over an in vitro BBB model. In general, the nanoparticulate transported oximes achieved a better reactivation of OP-inhibited AChE than free oximes. Conclusions/Significance: With these nanoparticles, for the first time, a tool exists that could enable a transport of oximes over the BBB. This is very important for survival after severe OP intoxication. Therefore, these nanoparticulate formulations are promising formulations for the treatment of the peripheral and the CNS after OP poisoning.
As important as the intrinsic properties of an individual nervous cell stands the network of neurons in which it is embedded and by virtue of which it acquires great part of its responsiveness and functionality. In this study we have explored how the topological properties and conduction delays of several classes of neural networks affect the capacity of their constituent cells to establish well-defined temporal relations among firing of their action potentials. This ability of a population of neurons to produce and maintain a millisecond-precise coordinated firing (either evoked by external stimuli or internally generated) is central to neural codes exploiting precise spike timing for the representation and communication of information. Our results, based on extensive simulations of conductance-based type of neurons in an oscillatory regime, indicate that only certain topologies of networks allow for a coordinated firing at a local and long-range scale simultaneously. Besides network architecture, axonal conduction delays are also observed to be another important factor in the generation of coherent spiking. We report that such communication latencies not only set the phase difference between the oscillatory activity of remote neural populations but determine whether the interconnected cells can set in any coherent firing at all. In this context, we have also investigated how the balance between the network synchronizing effects and the dispersive drift caused by inhomogeneities in natural firing frequencies across neurons is resolved. Finally, we show that the observed roles of conduction delays and frequency dispersion are not particular to canonical networks but experimentally measured anatomical networks such as the macaque cortical network can display the same type of behavior.
Mitochondrial complex I, the largest and most complicated proton pump of the respiratory chain, links the electron transfer from NADH to ubiquinone to the pumping of four protons from the matrix into the intermembrane space. In humans, defects in complex I are involved in a wide range of degenerative disorders. Recent progress in the X-ray structural analysis of prokaryotic and eukaryotic complex I confirmed that the redox reactions are confined entirely to the hydrophilic peripheral arm of the L-shaped molecule and take place at a remarkable distance from the membrane domain. While this clearly implies that the proton pumping within the membrane arm of complex I is driven indirectly via long-range conformational coupling, the molecular mechanism and the number, identity, and localization of the pump-sites remains unclear. Here, we report that upon deletion of the gene for a small accessory subunit of the Yarrowia complex I, a stable subcomplex (nb8m delta) is formed that lacks the distal part of the membrane domain as revealed by single particle analysis. The analysis of the subunit composition of holo and subcomplex by three complementary proteomic approaches revealed that two (ND4 and ND5) of the three subunits with homology to bacterial Mrp-type Na+/H+ antiporters that have been discussed as prime candidates for harbouring the proton pumps were missing in nb8m delta. Nevertheless, nb8m delta still pumps protons at half the stoichiometry of the complete enzyme. Our results provide evidence that the membrane arm of complex I harbours two functionally distinct pump modules that are connected in series by the long helical transmission element recently identified by X-ray structural analysis.
Channelrhodopsin-2 (ChR2) is widely used for rapid photodepolarization of neurons, yet, as it requires high-intensity blue light for activation, it is not suited for long-term in vivo applications, e.g. for manipulations of behavior, or photoactivation of neurons during development. We used “slow” ChR2 variants with mutations in the C128 residue, that exhibit delayed off-kinetics and increased light sensitivity in Caenorhabditis elegans. Following a 1 s light pulse, we could photodepolarize neurons and muscles for minutes (and with repeated brief stimulation, up to days) with low-intensity light. Photoactivation of ChR2(C128S) in command interneurons elicited long-lasting alterations in locomotion. Finally, we could optically induce profound changes in animal development: Long-term photoactivation of ASJ neurons, which regulate larval growth, bypassed the constitutive entry into the “dauer” larval state in daf-11 mutants. These lack a guanylyl cyclase, which possibly renders ASJ neurons hyperpolarized. Furthermore, photostimulated ASJ neurons could acutely trigger dauer-exit. Thus, slow ChR2s can be employed to long-term photoactivate behavior and to trigger alternative animal development.
Effect sizes in experimental pain produced by gender, genetic variants and sensitization procedures
(2011)
Background: Various effects on pain have been reported with respect to their statistical significance, but a standardized measure of effect size has been rarely added. Such a measure would ease comparison of the magnitude of the effects across studies, for example the effect of gender on heat pain with the effect of a genetic variant on pressure pain. Methodology/Principal Findings: Effect sizes on pain thresholds to stimuli consisting of heat, cold, blunt pressure, punctuate pressure and electrical current, administered to 125 subjects, were analyzed for 29 common variants in eight human genes reportedly modulating pain, gender and sensitization procedures using capsaicin or menthol. The genotype explained 0–5.9% of the total interindividual variance in pain thresholds to various stimuli and produced mainly small effects (Cohen's d 0–1.8). The largest effect had the TRPA1 rs13255063T/rs11988795G haplotype explaining >5% of the variance in electrical pain thresholds and conferring lower pain sensitivity to homozygous carriers. Gender produced larger effect sizes than most variant alleles (1–14.8% explained variance, Cohen's d 0.2–0.8), with higher pain sensitivity in women than in men. Sensitization by capsaicin or menthol explained up to 63% of the total variance (4.7–62.8%) and produced largest effects according to Cohen's d (0.4–2.6), especially heat sensitization by capsaicin (Cohen's d = 2.6). Conclusions: Sensitization, gender and genetic variants produce effects on pain in the mentioned order of effect sizes. The present report may provide a basis for comparative discussions of factors influencing pain.
Based on Foucault’s analysis of German Neoliberalism and his thesis of ambiguity, the following paper draws a two-level distinction between individual and regulatory ethics. The individual ethics level – which has received surprisingly little attention – contains the Christian foundation of values and the liberal-Kantian heritage of so called Ordoliberalism – as one variety of neoliberalism. The regulatory or formal-institutional ethics level on the contrary refers to the ordoliberal framework of a socio-economic order. By differentiating these two levels of ethics incorporated in German Neoliberalism, it is feasible to distinguish dissimilar varieties of neoliberalism and to link Ordoliberalism to modern economic ethics. Furthermore, it allows a revision of the dominant reception of Ordoliberalism which focuses solely on the formal-institutional level while mainly neglecting the individual ethics level.
Background: Microvolt T-wave alternans (MTWA) testing in many studies has proven to be a highly accurate predictor of ventricular tachyarrhythmic events (VTEs) in patients with risk factors for sudden cardiac death (SCD) but without a prior history of sustained VTEs (primary prevention patients). In some recent studies involving primary prevention patients with prophylactically implanted cardioverter-defibrillators (ICDs), MTWA has not performed as well.
Objective: This study examined the hypothesis that MTWA is an accurate predictor of VTEs in primary prevention patients without implanted ICDs, but not of appropriate ICD therapy in such patients with implanted ICDs.
Methods: This study identified prospective clinical trials evaluating MTWA measured using the spectral analytic method in primary prevention populations and analyzed studies in which: (1) few patients had implanted ICDs and as a result none or a small fraction (≤15%) of the reported end point VTEs were appropriate ICD therapies (low ICD group), or (2) many of the patients had implanted ICDs and the majority of the reported end point VTEs were appropriate ICD therapies (high ICD group).
Results: In the low ICD group comprising 3,682 patients, the hazard ratio associated with a nonnegative versus negative MTWA test was 13.6 (95% confidence interval [CI] 8.5 to 30.4) and the annual event rate among the MTWA-negative patients was 0.3% (95% CI: 0.1% to 0.5%). In contrast, in the high ICD group comprising 2,234 patients, the hazard ratio was only 1.6 (95% CI: 1.2 to 2.1) and the annual event rate among the MTWA-negative patients was elevated to 5.4% (95% CI: 4.1% to 6.7%). In support of these findings, we analyzed published data from the Multicenter Automatic Defibrillator Trial II (MADIT II) and Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) trials and determined that in those trials only 32% of patients who received appropriate ICD therapy averted an SCD.
Conclusion: This study found that MTWA testing using the spectral analytic method provides an accurate means of predicting VTEs in primary prevention patients without implanted ICDs; in particular, the event rate is very low among such patients with a negative MTWA test. In prospective trials of ICD therapy, the number of patients receiving appropriate ICD therapy greatly exceeds the number of patients who avert SCD as a result of ICD therapy. In trials involving patients with implanted ICDs, these excess appropriate ICD therapies seem to distribute randomly between MTWA-negative and MTWA-nonnegative patients, obscuring the predictive accuracy of MTWA for SCD. Appropriate ICD therapy is an unreliable surrogate end point for SCD.
Background: Endothelin-1 signalling plays an important role in pathogenesis of pulmonary hypertension. Although different endothelin-A receptor antagonists are developed, a novel therapeutic option to cure the disease is still needed. This study aims to investigate the therapeutic efficacy of the selective endothelin-A receptor antagonist TBC3711 in monocrotaline-induced pulmonary hypertension in rats.
Methods: Monocrotaline-injected male Sprague-Dawley rats were randomized and treated orally from day 21 to 35 either with TBC3711 (Dose: 30 mg/kg body weight/day) or placebo. Echocardiographic measurements of different hemodynamic and right-heart hypertrophy parameters were performed. After day 35, rats were sacrificed for invasive hemodynamic and right-heart hypertrophy measurements. Additionally, histologic assessment of pulmonary vascular and right-heart remodelling was performed.
Results: The novel endothelin-A receptor antagonist TBC3711 significantly attenuated monocrotaline-induced pulmonary hypertension, as evident from improved hemodynamics and right-heart hypertrophy in comparison with placebo group. In addition, muscularization and medial wall thickness of distal pulmonary vessels were ameliorated. The histologic evaluation of the right ventricle showed a significant reduction in fibrosis and cardiomyocyte size, suggesting an improvement in right-heart remodelling.
Conclusion: The results of this study suggest that the selective endothelin-A receptor antagonist TBC3711 demonstrates therapeutic benefit in rats with established pulmonary hypertension, thus representing a useful therapeutic approach for treatment of pulmonary hypertension.
Background: Chemotherapy of glioblastoma is largely ineffective as the blood-brain barrier (BBB) prevents entry of most anticancer agents into the brain. For an efficient treatment of glioblastomas it is necessary to deliver anti-cancer drugs across the intact BBB. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles coated with poloxamer 188 hold great promise as drug carriers for brain delivery after their intravenous injection. In the present study the anti-tumour efficacy of the surfactant-coated doxorubicin-loaded PLGA nanoparticles against rat glioblastoma 101/8 was investigated using histological and immunohistochemical methods. Methodology: The particles were prepared by a high-pressure solvent evaporation technique using 1% polyvinylalcohol (PLGA/PVA) or human serum albumin (PLGA/HSA) as stabilizers. Additionally, lecithin-containing PLGA/HSA particles (Dox-Lecithin-PLGA/HSA) were prepared. For evaluation of the antitumour efficacy the glioblastoma-bearing rats were treated intravenously with the doxorubicin-loaded nanoparticles coated with poloxamer 188 using the following treatment regimen: 3×2.5 mg/kg on day 2, 5 and 8 after tumour implantation; doxorubicin and poloxamer 188 solutions were used as controls. On day 18, the rats were sacrificed and the antitumour effect was determined by measurement of tumour size, necrotic areas, proliferation index, and expression of GFAP and VEGF as well as Isolectin B4, a marker for the vessel density. Conclusion: The results reveal a considerable anti-tumour effect of the doxorubicin-loaded nanoparticles. The overall best results were observed for Dox-Lecithin-PLGA/HSA. These data demonstrate that the poloxamer 188-coated PLGA nanoparticles enable delivery of doxorubicin across the blood-brain barrier in the therapeutically effective concentrations.
PAX2 regulates ADAM10 expression and mediates anchorage-independent cell growth of melanoma cells
(2011)
PAX transcription factors play an important role during development and carcinogenesis. In this study, we investigated PAX2 protein levels in melanocytes and melanoma cells by Western Blot and immunofluorescence analysis and characterized the role of PAX2 in the pathogenesis of melanoma. In vitro we found weak PAX2 protein expression in keratinocytes and melanocytes. Compared to melanocytes increased PAX2 protein levels were detectable in melanoma cell lines. Interestingly, in tissue sections of melanoma patients nuclear PAX2 expression strongly correlated with nuclear atypia and the degree of prominent nucleoli, indicating an association of PAX2 with a more atypical cellular phenotype. In addition, with chromatin immunoprecipitation assay, PAX2 overexpression and PAX2 siRNA we present compelling evidence that PAX2 can regulate ADAM10 expression, a metalloproteinase known to play important roles in melanoma metastasis. In human tissue samples we found co-expression of PAX2 and ADAM10 in melanocytes of benign nevi and in melanoma cells of patients with malignant melanoma. Importantly, the downregulation of PAX2 by specific siRNA inhibited the anchorage independent cell growth and decreased the migratory and invasive capacity of melanoma cells. Furthermore, the downregulation of PAX2 abrogated the chemoresistance of melanoma cells against cisplatin, indicating that PAX2 expression mediates cell survival and plays important roles during melanoma progression.
The indications for allogeneic stem cell transplantation (SCT) in Acute Myeloid Leukemia (AML) represent a real challenge due to the clinical and genetic heterogeneity of the disorder. Therefore, an optimized indication for SCT in AML first requires the determination of the individual relapse risk based on diverse chromosomal and molecular prognosis-defining aberrations. A broad panel of diagnostic methods is needed to allow such subclassification and prognostic stratification: cytomorphology, cytogenetics, molecular genetics, and immunophenotyping by multiparameter flow cytometry. These methods should not be seen as isolated techniques but as parts of an integral network with hierarchies and interactions. Examples for a poor risk constellation as a clear indication for allogeneic SCT are provided by anomalies of chromosome 7, complex aberrations, or FLT3-length mutations. In contrast, the favorable reciprocal translocations such as the t(15;17)/PML-RARA or t(8;21)/AML1-ETO are not indications for SCT in first remission due to the rather good prognosis after standard therapy. Further, the indication for SCT should include the results of minimal residual disease (MRD) diagnostics by polymerase chain reaction (PCR) or flow cytometry. New aspects for a safe and fast risk stratification as basis for an optimized indication for SCT in AML might be provided by novel technologies such as microarray-based gene expression profiling. Keywords: Acute Myeloid Leukemia (AML), Allogeneic Stem Cell Transplantation (SCT), Indication, Cytogenetics, Polymerase Chain Reaction (PCR)
In dyadic communication, both interlocutors adapt to each other linguistically, that is, they align interpersonally. In this article, we develop a framework for modeling interpersonal alignment in terms of the structural similarity of the interlocutors’ dialog lexica. This is done by means of so-called two-layer time-aligned network series, that is, a time-adjusted graph model. The graph model is partitioned into two layers, so that the interlocutors’ lexica are captured as subgraphs of an encompassing dialog graph. Each constituent network of the series is updated utterance-wise. Thus, both the inherent bipartition of dyadic conversations and their gradual development are modeled. The notion of alignment is then operationalized within a quantitative model of structure formation based on the mutual information of the subgraphs that represent the interlocutor’s dialog lexica. By adapting and further developing several models of complex network theory, we show that dialog lexica evolve as a novel class of graphs that have not been considered before in the area of complex (linguistic) networks. Additionally, we show that our framework allows for classifying dialogs according to their alignment status. To the best of our knowledge, this is the first approach to measuring alignment in communication that explores the similarities of graph-like cognitive representations. Keywords: alignment in communication; structural coupling; linguistic networks; graph distance measures; mutual information of graphs; quantitative network analysis
The Dagstuhl Perspectives Workshop "Online Privacy: Towards Informational Self-Determination on the Internet" (11061) has been held in February 6-11, 2011 at Schloss Dagstuhl. 30 participants from academia, public sector, and industry have identified the current status-of-the-art of and challenges for online privacy as well as derived recommendations for improving online privacy. Whereas the Dagstuhl Manifesto of this workshop concludes the results of the working groups and panel discussions, this article presents the talks of this workshop by their abstracts.
The article discusses current transformations in the education systems worldwide. Focusing on the European Union (EU) and the Organisation for Economic Cooperation and Development (OECD) as policy actors, it argues that these transformations imply a triple economization of education policy which can be observed at all levels of the education sector. The increasing importance of these organizations in educational issues marks a transition to a "postnational constellation" also in the education field insofar as the national educational sovereignty is being at least readjusted. The economization of education policy is however not restricted to bringing education closer to the needs of the economy and to turning its services into tradable goods. Rather, it also impinges on the operative level of education. A logics of production is being implemented in the self-description of the institutions of the education system, which are no longer bureaucratically administered establishments, but are rather conceived of as managerially conducted production business in which entrepreneurial action is needed. This new governance raises the problem of democratic legitimation of political decisions which ideally combines three elements: democratic, expertocratic, and ethico-professional. The article discusses the consequences of a shift in the balance of the three components with reference to Germany.
In this work we present a study of the influence of nucleus initializations on the event-by-event elliptic flow coefficient, v2. In most Monte-Carlo models, the initial positions of the nucleons in a nucleus are completely uncorrelated, which can lead to very high density regions. In a simple, yet more realistic model where overlapping of the nucleons is avoided, fluctuations in the initial conditions are reduced. However, v2 distributions are not very sensitive to the initialization choice.
Nusa Tenggara Timor, a south-eastern province of Indonesia, is populated mainly by Christians. The Alor-Pantar Archipelago has a majority of Protestant inhabitants who were baptized by Dutch Calvinists in the first half of the twentieth century. In addition, there are some coastal enclaves that have been inhabited by Muslims for centuries. In some areas, such as in the headland of Muna (Tanjung Muna) forming the northeast of Pantar Island, there is an even greater diversity of monotheistic religions, with some Catholic families living next to Protestants and Muslims. All adherers of the three religious faiths living at Tanjung Muna share core elements of the local adat, which consists of core rules relating to social behavior. It is believed that the ancestors will notice transgressions of these rules, and may use their supernatural power to punish their human descendants. In Indonesia, the term adat was first used by Muslims to distinguish the non-Islamic practices from Muslim faith (Keane 1997:260-261). This is definitely not the case in the village of Pandai at the coast of Tanjung Muna, where Islam tolerates ancestral worship. The same is true for the Catholics in the inland village of Helangdohi, who do not only tolerate but even support such customs. Some villagers from Helangdohi had become acquainted with this kind of Catholicism on the nearby island of Flores, where ancestral worship is encouraged by the missionaries of the Societas Verbi Divini (SVD). The attitude of Protestantism, at least in the Alor Archipelago, is quite the contrary of the permissive views held by Catholicism and Islam. In the 1930s the Protestant-Calvinist missionaries banned any kind of ancestral worship and destroyed most relics (Dalen 1928: Picture 1). These drastic measures demanded the disavowal of the ancestors, including the destruction of heirlooms and omitting of rituals.
The enzyme quinol:fumarate reductase (QFR) from the anaerobic epsilon-proteobacterium Wolinella succinogenes is a membrane protein complex that couples the catalysis of the oxidation of menaquinol to menaquinone to that of the reduction of fumarate to succinate. This is the terminal step in fumarate respiration, a form of anaerobic respiration in which oxygen is replaced by fumarate as the terminal electron acceptor in many anaerobic microorganisms. In QFR, both the heme groups (low-potential distal and high-potential proximal heme b group in transmembrane subunit C) are part of the electron transport chain between the two catalytic sites of the redox enzyme. Although the reduction of fumarate by menaquinol is exergonic, it is not exergonic enough to support the generation of a transmembrane electrochemical proton potential delta p. Evidence has previously shown that this reaction is catalysed by a novel mechanism, involving the facilitation of transmembrane electron transfer by transmembrane proton transfer via an essential compensatory transmembrane proton transfer pathway ("E-pathway") which is inactive in the oxidized state of the enzyme. The two key constitutents of the the pathway are the amino acid residue Glu C180 of the transmembrane helix V (located in subunit C) and the ring C propionate of the distal heme bD. The aim of the project was to obtain, by employing a combination of time-resolved as well as static spectroscopic approaches, a detailed insight of the transmembrane electron coupled proton transfer mechanism. Minute changes in both the oxidized and reduced states of a redox protein system can be selectively and sensitively monitored by static Fourier Transformed Infrared (FTIR) difference spectroscopy. The technique employed in this context, electrochemically induced FTIR difference spectroscopy, is complemented by computer-based electrostatic calculations. In order to elucidate the catalytic mechanism of the important reactions in QFR, it is necessary to investigate these in a time-resolved manner. Rapid scan FTIR difference spectroscopy is a suitable technique that allows the course of the reaction to be monitored in a time dependent fashion. The techniques employed in this context are time-resolved (tr-FTIR) and transient absorption spectroscopy. In the following, the details of individual sub-projects are discussed in brief. ...
The ubiquinol:cytochrome c oxidoreductase is a key component of several aerobic respiratory chains in different organisms. It is an integral membrane protein complex, made up of three catalytic subunits (cytochrome b, cytochrome c1 and Rieske iron sulphur protein) and up to eight additional subunits in mitochondria. The complex oxidizes one quinol molecules and reduces two cytochrome c during the Q cycle, originally described by Peter Mitchell. Electrons are split between the low and the high potential chain and protons are released on the positive side of the membrane, increasing the protonmotive force needed by the ATP-synthase for energy transduction. The cytochrome bc1 complex from P. denitrificans is a perfect model for structural and functional studies. Bacteria are easy to grow and the genetic material is readily accessible for genetic manipulation. Moreover, the P. denitrificans aerobic respiratory chain is very close to the mitochondrial one: the complexes involved in electron transfer resemble the ones found in mitochondria, but lack most of the additional subunits. As a unique feature, P. denitrificans has a strongly acidic domain at the N-terminal region of the cytochrome c1, a sequence of 150 aminoacids which does not correlate with any known protein. An analogous composition can be found in the eukaryotic cytochrome bc1 complex as a part of an accessory subunit, proposed to be involved in facilitating electron transfer between the complex and the electron acceptor cytochrome c. In order to study the function of this domain in the P. denitrificans cytochrome bc1 complex, a deletion mutant has been previously cloned and modified with an affinity tag as a C-terminal extension of cytochrome b. The complex is purified by affinity chromatography and characterized by steady-state kinetics using not only horse heart cytochrome c but also the endogenous electron acceptor, the membrane bound cytochrome c552, employed here as a soluble fragment. Steady–state kinetics indicate that the deletion of the long acidic domain had effects neither on the turnover rate nor on the apparent affinity for the substrate. To understand wether the deletion affects the reaction between the cytochrome bc1 complex and the substrate, laser flash photolysis experiments are performed, showing that the interaction observed was not changed in the complex missing the acidic domain. The results presented in this work confirm the ones previously obtained by Julia Janzon using soluble fragments of the same interaction partners. The deletion, however, affected the oligomerization state of the complex, as shown by LILBID (Laser Induced Liquid Bead Ion Desorption) analysis. The wild type complex has a tetrameric structure, better described as a “dimer of dimers”. The deletion of the acidic domain on the cytochrome c1 results in the separation of the two dimers, yielding the canonical dimer. Therefore, the complex deleted in the acidic domain is used for cloning and expression of a heterodimeric complex, containing an inactivating mutation in the quinol oxidation site in only one monomer, thus allowing a selective switch-off for half the complex. Such a complex is needed for the verification of an internal regulation mechanism, the half-of-the-sites reactivity. According to it, the dimeric structure of the cytochrome bc1 complex has functional implications, since the two monomers can communicate and work in a coordinated manner. This approach confirms that substrate oxidation does effectively take place only in one of the two monomers constituting the dimer, and that the binding of substrate at the Qo and Qi site regulates the switch between active and inactive monomer. Moreover, this mechanism works also as an effective protection against the reaction of quinone intermediates with oxygen and the formation of reactive oxygen species (ROS), responsable for cellular aging. The motion of the ISP head domain is also addressed in this work; in particular the mechanism which regulates the movements towards the cytochrome c1 and the electron bifurcation at the quinol oxidation site. Laser flash kinetics in presence of several inhibitors and the substrate allow studying the response of the ISP to the binding of different species at the quinol oxidation site. The binding of ligand at the Qo site in the complex triggers the conformational switch in the ISP head domain, supporting the mechanism proposed in the literature according to which the Qo site is able to “sense” the presence of substrate and transfer the information to the ISP, regulating its mobility. The internal electron pathway between the ISP and the cytochrome c1 has been analyzed also by stopped-flow kinetics, in presence and absence of inhibitors. The results indicate that two kinetic phases describe the reduction of cytochrome c1 by the ISP, and a model for the simulation of the data is proposed.
Dynamics of chaotic strings
(2011)
The main topic of this thesis is the investigation of dynamical properties of coupled Tchebycheff map networks. At every node of the network the dynamics is given by the iteration of a Tchebycheff map, which shows strongest possible chaotic behaviour. By applying a coupling between the various individual dynamics along the links of the network, a rich structure of complex dynamical patterns emerges. Accordingly, coupled chaotic map networks provide prototypical models for studying the interplay between local dynamics, network structure, and the emergent global dynamics. An exciting application of coupled Tchebycheff map lattices in quantum field theory has been proposed Beck in Spatio-temporal chaos and vacuum fluctuations of quantized fields' (2002). In this so-called chaotic string model, the coupled map lattice dynamics generates the noise needed for the Parisi-Wu approach of stochastic quantization. The remarkable obversation is that the respective dynamics seems to reproduce distinguished numerical values of coupling constants that coincide with those observed in the standard model of particle physic. The results of this thesis give insights into the chaotic string model and its network generalization from a dynamical point of view. This leads to a deeper understanding of the dynamics, which is essential for a critical discussion of possible physical embeddings. Apart from this specific application to particle physics, the investigated concepts like synchronization or a most random behaviour of the dynamics are of general interest for dynamical system theory and the science of complex networks. As a first approach, discrete symmetry transformations of the model are studied. These transformations are formulated in a general way in order to be also applicable to similar dynamics on bipartite network structures. An observable of main interest in the chaotic string model is the interaction energy. In Spatio-temporal chaos and vacuum fluctuations of quantized fields' (2002) it has been observed that certain chaotic string couplings, corresponding to a vanishing interaction energy, coincide with coupling constants of the standard model of elementary particle physics. Since the interaction energy is basically a spatial correlation measure, an interpretation of the respective dynamical states in terms of a most random behaviour is tempting. In order to distinguish certain states as most random', or evoke another dynamical principle, a deeper understanding of the dynamics essential. In the present thesis the dynamics is studied numerically via Lyapunov measures, spatial correlations, and ergodic properties. It is shown that the zeros of the interaction energy are distinguished only with respect to this specific observable, but not by a more general dynamical principle. The original chaotic string model is defined on a one-dimensional lattice (ring-network) as the underlying network topology. This thesis studies a modification of the model based on the introduction of tunable disorder. The effects of inhomogeneous coupling weights as well as small-world perturbations of the ring-network structure on the interaction energy are discussed. Synchronization properties of the chaotic string model and its network generalization are studied in later chapters of this thesis. The analysis is based on the master stability formalism, which relates the stability of the synchronized state to the spectral properties of the network. Apart from complete synchronization, where the dynamics at all nodes of the network coincide, also two-cluster synchronization on bipartite networks is studied. For both types of synchronization it is shown that depending on the type of coupling the synchronized dynamics can display chaotic as well as periodic or quasi-periodic behaviour. The semi-analytical calculations reveal that the respective synchronized states are often stable for a wide range of coupling values even for the ring-network, although the respective basins of attraction may inhabit only a small fraction of the phase space. To provide analytical results in closed form, for complete synchronization the stability of all fixed points and period-2 orbits of all chaotic string networks are determined analytically. The master stability formalism allows to treat the ring-network of the chaotic string model as a special case, but the results are valid for coupled Tchebycheff maps on arbitrary networks. For two-cluster synchronization on bipartite networks, selected fixed points and period-2 orbits are analyzed.