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Sonstige beteiligte Institutionen
- Center for Interdisciplinary Clinical Research, Würzburg University, Würzburg, Germany (2)
- Bavarian Center for Applied Energy Research (ZAE Bayern), 97074 Würzburg, Germany (1)
- Biomedizinische NMR Forschungs GmbH am Max-Planck-Institut fuer biophysikalische Chemie (1)
- Blindeninstitut, Ohmstr. 7, 97076, Wuerzburg, Germany (1)
- Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany (1)
- DNA Analytics Core Facility, Biocenter, University of Wuerzburg, Wuerzburg, Germany (1)
- Deakin University, Australia (1)
- Department of Pediatrics, Pediatrics I, Innsbruck Medical University, Anichstr. 35, 6020, Innsbruck, Austria (1)
- EMBL, Structural and Computational Biology Unit, Heidelberg, Germany (1)
- Genelux Corporation, San Diego Science Center, 3030 Bunker Hill Street, Suite 310, San Diego, California 92109, USA (1)
ResearcherID
- D-1250-2010 (1)
Serotonin (5-HT) has been implicated in the regulation of emotions as well as in its pathological states, such as anxiety disorders and depression. Mice with targeted deletion of genes encoding various mediators of central serotonergic neurotransmission therefore provides a powerful tool in understanding contributions of such mediators to homeostatic mechanisms as well as to the development of human emotional disorders. Within this thesis a battery of electrophysiological recordings were conducted in the dorsal raphe nucleus (DRN) and the hippocampus of two murine knockout lines with deficient serotonergic systems. Serotonin transporter knockout mice (5-Htt KO), which lack protein responsible for reuptake of 5-HT from the extracellular space and tryptophan hydroxylase 2 knockout (Tph2 KO) mice, which lack the gene encoding the neuronal 5-HT-synthesising enzyme. First, 5-HT1A receptor-mediated autoinhibition of serotonergic neuron firing in the DRN was assessed using the loose-seal cell-attached configuration. Stimulation of 5-HT1A receptors by a selective agonist, R-8-hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT), showed a mild sensitisation and a marked desensitisation of these receptors in Tph2 KO and 5-Htt KO mice, respectively. While application of tryptophan, a precursor of 5-HT and a substrate of Tph2, did not cause autoinhibition in Tph2 KO mice due to the lack of endogenously produced 5-HT, data from 5-Htt KO mice as well as heterozygous mice of both KO mice lines demonstrated the presence of autoinhibitory mechanisms as normal as seen in wildtype (WT) controls. When the Tph2-dependent step in the 5-HT synthesis pathway was bypassed by application of 5-hydroxytryptophan (5-HTP), serotonergic neurons of both Tph2 KO and 5-Htt KO mice showed decrease in firing rates at lower concentrations of 5-HTP than in WT controls. Elevated responsiveness of serotonergic neurons from Tph2 KO mice correspond to mild sensitisation of 5-HT1A receptors, while responses from 5-Htt KO mice suggest that excess levels of extracellular 5-HT, created by the lack of 5-Htt, stimulates 5-HT1A receptors strong enough to overcome desensitisation of these receptors. Second, the whole-cell patch clamp recording data from serotonergic neurons in the DRN showed no differences in basic electrophysiological properties between Tph2 KO and WT mice, except lower membrane resistances of neurons from KO mice. Moreover, the whole-cell patch clamp recording from CA1 pyramidal neurons in the hippocampus of 5-Htt KO mice showed increased conductance both at a steady state and at action potential generation. Lastly, magnitude of long-term potentiation (LTP) induced by the Schaffer collateral/commissural pathway stimulation in the ventral hippocampus showed no differences among Tph2 KO, 5-Htt KO, and WT counterparts. Taken together, lack and excess of extracellular 5-HT caused sensitisation and desensitisation of autoinhibitory 5-HT1A receptors, respectively. However, this may not directly translate to the level of autoinhibitory regulation of serotonergic neuron firing when these receptors are stimulated by endogenously synthesised 5-HT. In general, KO mice studied here showed an astonishing level of resilience to genetic manipulations of the central serotonergic system, maintaining overall electrophysiological properties and normal LTP inducibility. This may further suggest existence of as-yet-unknown compensatory mechanisms buffering potential alterations induced by genetic manipulations.
In the present work, the objective has been to analyse the compatibility of plant and human transcriptional machinery. The experiments revealed that nuclear import and export are conserved among plants and mammals. Further it has been shown that transactivation of a human promoter occurs by human transcription factor NF-\(\kappa\) B in plant cells, demonstrating that the transcriptional machinery is highly conserved in both kingdoms. Functionality was also seen for regulatory elements of NF-\(\kappa\) B such as its inhibitor I\(\kappa\)B isoform \(\alpha\) that negatively regulated the transactivation activity of the p50/RelA heterodimer by interaction with NF-\(\kappa\)B in plant cells. Nuclear export of RelA could be demonstrated by FRAP-measurements so that RelA shows nucleo-cytoplasmic shuttling as reported for RelA in mammalian cells. The data reveals the high level of compatibility of human transcriptional elements with the plant transcriptional machinery. Thus, Arabidopsis thaliana mesophyll protoplasts might provide a new heterologous expression system for the investigation of the human NF-\(\kappa\)B signaling pathways. The system successfully enabled the controlled manipulation of NF-\(\kappa\)B activity. We suggest the plant protoplast system as a tool for reconstitution and analyses of mammalian pathways and for direct observation of responses to e. g. pharmaceuticals. The major advantage of the system is the absence of interference with endogenous factors that affect and crosstalk with the pathway.
The work at hand studies problems from Loewner theory and is divided into two parts:
In part 1 (chapter 2) we present the basic notions of Loewner theory. Here we use a modern form which was developed by F. Bracci, M. Contreras, S. Díaz-Madrigal et al. and which can be applied to certain higher dimensional complex manifolds.
We look at two domains in more detail: the Euclidean unit ball and the polydisc. Here we consider two classes of biholomorphic mappings which were introduced by T. Poreda and G. Kohr as generalizations of the class S.
We prove a conjecture of G. Kohr about support points of these classes. The proof relies on the observation that the classes describe so called Runge domains, which follows from a result by L. Arosio, F. Bracci and E. F. Wold.
Furthermore, we prove a conjecture of G. Kohr about support points of a class of biholomorphic mappings that comes from applying the Roper-Suffridge extension operator to the class S.
In part 2 (chapter 3) we consider one special Loewner equation: the chordal multiple-slit equation in the upper half-plane.
After describing basic properties of this equation we look at the problem, whether one can choose the coefficient functions in this equation to be constant. D. Prokhorov proved this statement under the assumption that the slits are piecewise analytic. We use a completely different idea to solve the problem in its general form.
As the Loewner equation with constant coefficients holds everywhere (and not just almost everywhere), this result generalizes Loewner’s original idea to the multiple-slit case.
Moreover, we consider the following problems:
• The “simple-curve problem” asks which driving functions describe the growth of simple curves (in contrast to curves that touch itself). We discuss necessary and sufficient conditions, generalize a theorem of J. Lind, D. Marshall and S. Rohde to the multiple-slit equation and we give an example of a set of driving functions which generate simple curves because of a certain self-similarity property.
• We discuss properties of driving functions that generate slits which enclose a given angle with the real axis.
• A theorem by O. Roth gives an explicit description of the reachable set of one point in the radial Loewner equation. We prove the analog for the chordal equation.
Background: Nicotine addiction is the most prevalent type of drug addiction that has been described as a cycle of spiraling dysregulation of the brain reward systems. Imaging studies have shown that nicotine addiction is associated with abnormal function in prefrontal brain regions that are important for cognitive emotion regulation. It was assumed that addicts may perform less well than healthy nonsmokers in cognitive emotion regulation tasks. The primary aims of this thesis were to investigate emotional responses to natural rewards among smokers and nonsmokers and to determine whether smokers differ from nonsmokers in cognitive regulation of positive and negative emotions. To address these aims, two forms of appraisal paradigms (i.e., appraisal frame and reappraisal) were applied to compare changes in emotional responses of smokers with that of nonsmokers as a function of appraisal strategies. Experiment 1: The aim of the first experiment was to evaluate whether and how appraisal frames preceding positive and negative picture stimuli affect emotional experience and facial expression of individuals. Twenty participants were exposed to 125 pairs of auditory appraisal frames (either neutral or emotional) followed by picture stimuli reflecting five conditions: unpleasant-negative, unpleasant-neutral, pleasant-positive, pleasant-neutral and neutral-neutral. Ratings of valence and arousal as well as facial EMG activity over the corrugator supercilii and the zygomaticus major were measured simultaneously. The results indicated that appraisal frames could alter both subjective emotional experience and facial expressions, irrespective of the valence of the pictorial stimuli. These results suggest and support that appraisal frame is an efficient paradigm in regulation of multi-level emotional responses. 8 Experiment 2: The second experiment applied the appraisal frame paradigm to investigate how smokers differ from nonsmokers on cognitive emotion regulation. Sixty participants (22 nonsmokers, 19 nondeprived smokers and 19 12-h deprived smokers) completed emotion regulation tasks as described in Experiment 1 while emotional responses were concurrently recorded as reflected by self-ratings and psychophysiological measures (i.e., facial EMG and EEG). The results indicated that there was no group difference on emotional responses to natural rewards. Moreover, nondeprived smokers and deprived smokers performed as well as nonsmokers on the emotion regulation task. The lack of group differences in multiple emotional responses (i.e., self-reports, facial EMG activity and brain EEG activity) suggests that nicotine addicts have no deficit in cognitive emotion regulation of natural rewards via appraisal frames. Experiment 3: The third experiment aimed to further evaluate smokers’ emotion regulation ability by comparing performances of smokers and nonsmokers in a more challenging cognitive task (i.e., reappraisal task). Sixty-five participants (23 nonsmokers, 22 nondeprived smokers and 20 12-h deprived smokers) were instructed to regulate emotions by imagining that the depicted negative or positive scenario would become less negative or less positive over time, respectively. The results showed that nondeprived smokers and deprived smokers responded similarly to emotional pictures and performed as well as nonsmokers in down-regulating positive and negative emotions via the reappraisal strategy. These results indicated that nicotine addicts do not have deficit in emotion regulation using cognitive appraisal strategies. In sum, the three studies consistently revealed that addicted smokers were capable to regulate emotions via appraisal strategies. This thesis establishes the groundwork for therapeutic use of appraisal instructions to cope with potential self-regulation failures in nicotine addicts.
Motivation moderately influences brain–computer interface (BCI) performance in healthy subjects when monetary reward is used to manipulate extrinsic motivation. However, the motivation of severely paralyzed patients, who are potentially in need for BCI, could mainly be internal and thus, an intrinsic motivator may be more powerful. Also healthy subjects who participate in BCI studies could be internally motivated as they may wish to contribute to research and thus extrinsic motivation by monetary reward would be less important than the content of the study. In this respect, motivation could be defined as “motivation-to-help.” The aim of this study was to investigate, whether subjects with high motivation for helping and who are highly empathic would perform better with a BCI controlled by event-related potentials (P300-BCI). We included N = 20 healthy young participants naïve to BCI and grouped them according to their motivation for participating in a BCI study in a low and highly motivated group. Motivation was further manipulated with interesting or boring presentations about BCI and the possibility to help patients. Motivation for helping did neither influence BCI performance nor the P300 amplitude. Post hoc, subjects were re-grouped according to their ability for perspective taking. We found significantly higher P300 amplitudes on parietal electrodes in participants with a low ability for perspective taking and therefore, lower empathy, as compared to participants with higher empathy. The lack of an effect of motivation on BCI performance contradicts previous findings and thus, requires further investigation. We speculate that subjects with higher empathy who are good perspective takers with regards to patients in potential need of BCI, may be more emotionally involved and therefore, less able to allocate attention on the BCI task at hand.
In the context of this thesis, the novel method soft X-ray energy-dispersive NEXAFS spectroscopy was explored and utilized to investigate intermolecular coupling and post-growth processes with a temporal resolution of seconds. 1,4,5,8- naphthalene tetracarboxylic acid dianhydride (NTCDA)multilayer films were the chosen model system for these investigations. The core hole-electron correlation in coherently coupled molecules was studied by means of energy-dispersive near-edge X-ray absorption fine-structure spectroscopy. A transient phase was found which exists during the transition between a disordered condensed phase and the bulk structure. This phase is characterized by distinct changes in the spectral line shape and energetic position of the X-ray absorption signal at the C K-edge. The findings were explained with the help of theoretical models based on the coupling of transition dipole moments, which are well established for optically excited systems. In consequence, the experimental results provides evidence for a core hole-electron pair delocalized over several molecules. Furthermore, the structure formation of NTCDA multilayer films on Ag(111) surfaces was investigated. With time-resolved and energy-dispersive NEXAFS experiments the intensity evolution in s- and p-polarization showed a very characteristic behavior. By combining these findings with the results of time-dependent photoemission measurements, several sub-processes were identified in the post- growth behavior. Upon annealing, the amorphous but preferentially flat-lying molecules flip into an upright orientation. After that follows a phase characterized by strong intermolecular coupling. Finally, three-dimensional islands are established. Employing the Kolmogorov-Johnson-Mehl-Avrami model, the activation energies of the sub-processes were determined.
Enhancing and reducing the Rashba-splitting at surfaces by adsorbates: Na and Xe on Bi/Cu(111)
(2013)
The surface alloy Bi/Cu(111) shows a paradigmatic free-electron-like surface state with a very large Rashba-type spin–orbit splitting. Using angle-resolved photoemission we investigate how adsorbates of different chemical nature influence the size of the spin splitting in this system. We find that the adsorption of small amounts of monovalent Na atoms leads to an enhancement of the spin splitting while an overlayer of the closed-shell rare gas Xe causes a reduction. The latter result is in contrast to the Au(111) surface for which an increased splitting size after Xe-adsorption was observed. We discuss these experimental findings in terms of the characteristic differences of the surface state wave functions and their spatial deformation in the presence of different types of adsorbates. Our results provide insight into the complex interplay of atomic and interface potential gradients governing the Rashba effect.
The tendency towards the exploitation of the resources of creation is the result of a long historical and cultural process. The modern African Communities have witnessed man’s growing capacity for environmental transformative intervention. The aspect of the conquest and exploitation of resources in rural communities such as in the Niger Delta of Nigeria has become predominant and invasive, and has even reached the point of threatening the environment’s hospitable function: the environment only as resource risks threatening the environment as home. In this respect, the ethical judgement of the social realities on ground is very decisive. And this is the very important aspect where the Catholic Social Ethics has a role to play. Because of the environmental crisis in this region through technological advancement, there is urgent need for a balance through the introduction of the model of a sustainable development.
The socio-ethical model of sustainability in this work is a framework so constructed that women, men, families and communities in the Niger Delta are to be the agents which determine what their developmental strategies are. Although their developmental opportunities and decisions are sometimes constrained by various factors, it remains the fact that they alone bear responsibility for their environment and must live with the consequences.
So if sustainable development in the Niger Delta region of Nigeria is to extend beyond narrow technical understanding, it must one that generally seek to embrace the cultural and social systems of the people. This will go a long way in reducing dependency and increase self-empowerment and will place more value on what the people understand and practice.
Bede Chinedum Nwadinobi, a native of Alike Obowo in Imo State (Nigeria), is a Catholic Priest of Okigwe Diocese (Nigeria). He studied Philosophy and Theology at St. Joseph Major Seminary Ikot-Ekpene. He also worked as a Vice-Principal of Queen of Apostles College Okigwe (Nigeria). At the University of Würzburg (Germany), he earned his doctorate in Catholic Theology specializing in Catholic Social Science.
Subacute sclerosing panencephalitis (SSPE) is a fatal long-term complication of measles infection. We performed an estimation of the total number of SSPE cases in Germany for the period 2003 to 2009 and calculated the risk of SSPE after an acute measles infection. SSPE cases were collected from the Surveillance Unit for Rare Paediatric Diseases in Germany and the Institute of Virology and Immunobiology at the University of Würzburg. The total number of SSPE cases was estimated by capture-recapture analysis. For the period 2003 to 2009, 31 children with SSPE who were treated at German hospitals were identified. The capture-recapture estimate was 39 cases (95% confidence interval: 29.2–48.0). The risk of developing SSPE for children contracting measles infection below 5 years of age was calculated as 1∶1700 to 1∶3300. This risk is in the same order of magnitude as the risk of a fatal acute measles infection.
The epidemic increase of type 2 diabetes and obesity in developed countries cannot be explained by overnutrition, physical inactivity and/or genetic factors alone. Epidemiologic evidence suggests that an adverse intrauterine environment, in particular a shortage or excess of nutrients is associated with increased risks for many complex diseases later in life. An impressive example for the ‘fetal origins of adult disease’ is gestational diabetes mellitus which usually presents in 1% to >10% of third trimester pregnancies. Intrauterine hyperglycemia is not only associated with increased perinatal morbidity and mortality, but also with increased lifelong risks of the exposed offspring for obesity, metabolic, cardiovascular and malignant diseases. Accumulating evidence suggests that fetal overnutrition (and similarly undernutrition) lead to persistent epigenetic changes in developmentally important genes, influencing neuroendocrine functions, energy homeostasis and metabolism. The concept of fetal programming has important implications for reproductive medicine. Because during early development the epigenome is much more vulnerable to environmental cues than later in life, avoiding adverse environmental factors in the periconceptional and intrauterine period may be much more important for the prevention of adult disease than any (i.e. dietetic) measures in infants and adults. A successful pregnancy should not primarily be defined by the outcome at birth but also by the health status in later life.
This dissertation deals with certain business strategies that have become particularly relevant with the spread and development of new information technologies.
The introduction explains the motivation, discusses different ways of defining the term "two-sided market", and briefly summarizes the subsequent essays.
The first essay examines the effects of product information on the pricing and advertising decision of a seller who offers an experience good whose quality is unknown to consumers prior to purchase. It comprises of two theoretical models which differ with respect to their view on advertising. The analysis addresses the question how the availability of additional, potentially misleading information affects the seller's quality-dependent pricing and advertising decision.
In the first model, in which both advertising and product reviews make consumers aware about product existence, the seller's optimal price turns out to be increasing in product quality. However, under certain circumstances, also the seller of a low-quality product prefers setting a high price. Within the given framework, the relationship between product quality and advertising depends on the particular parameter constellation.
In the second model, some consumers are assumed to interpret price as a signal of quality, while others rely on information provided by product reviews. Consequently, and differently from the first part, pricing may indirectly inform consumers about product quality. On the one hand, in spite of asymmetric information on product quality, equilibria exist that feature full information pricing, which is in line with previous results presented by the signaling literature. On the other hand, potentially misleading product reviews may rationalize further pricing patterns. Moreover, assuming that firms can manipulate product reviews by investing in concealed marketing, equilibria can arise in which a high price signals low product quality. However, in these extreme cases, only a few (credulous) consumers consider buying the product.
The second essay deals with trade platforms whose operators not only allow sellers to offer their products to consumers, but also offer products themselves. In this context, the platform operator faces a hold-up problem if he sets classical two-part tariffs (on which previous literature on two-sided markets focussed) as potential competition between the platform operator and sellers reduces platform attractiveness. Since some sellers refuse to join the platform, products whose existence is not known to the platform operator in the first place and which can only be established by better informed sellers may not be offered at all. However, revenue-based fees lower the platform operator's incentives to compete with sellers, increasing platform attractiveness. Therefore, charging such proportional fees can be profitable, what may explain why several trade platforms indeed do charge proportional fees.
The third essay examines settings in which sellers can be active both on an intermediary's trade platform and in other sales channels. It explores the sellers' incentives to set different prices across sales channels within the given setup. Afterwards, it analyzes the intermediary's tariff decision, taking into account the implications on consumers' choice between different sales channels. The analysis particularly focusses on the effects of a no-discrimination rule which several intermediaries impose, but which appears to be controversial from a competition policy view. It identifies under which circumstances the intermediary prefers restricting sellers' pricing decisions by imposing a no-discrimination rule, attaining direct control over the split-up of customers on sales channels. Moreover, it illustrates that such rules can have both positive and negative effects on welfare within the given framework.
Background
Chronic heart failure requires a complex treatment regimen on a life-long basis. Therefore, self-care/self-management is an essential part of successful treatment and comprehensive patient education is warranted. However, specific information on program features and educational strategies enhancing treatment success is lacking. This trial aims to evaluate a patient-oriented and theory-based self-management educational group program as compared to usual care education during inpatient cardiac rehabilitation in Germany.
Methods/Design
The study is a multicenter cluster randomized controlled trial in four cardiac rehabilitation clinics. Clusters are patient education groups that comprise HF patients recruited within 2 weeks after commencement of inpatient cardiac rehabilitation. Cluster randomization was chosen for pragmatic reasons, i.e. to ensure a sufficient number of eligible patients to build large-enough educational groups and to prevent contamination by interaction of patients from different treatment allocations during rehabilitation. Rehabilitants with chronic systolic heart failure (n = 540) will be consecutively recruited for the study at the beginning of inpatient rehabilitation. Data will be assessed at admission, at discharge and after 6 and 12 months using patient questionnaires. In the intervention condition, patients receive the new patient-oriented self-management educational program, whereas in the control condition, patients receive a short lecture-based educational program (usual care). The primary outcome is patients’ self-reported self-management competence. Secondary outcomes include behavioral determinants and self-management health behavior (symptom monitoring, physical activity, medication adherence), health-related quality of life, and treatment satisfaction. Treatment effects will be evaluated separately for each follow-up time point using multilevel regression analysis, and adjusting for baseline values.
Discussion
This study evaluates the effectiveness of a comprehensive self-management educational program by a cluster randomized trial within inpatient cardiac rehabilitation in Germany. Furthermore, subgroup-related treatment effects will be explored. Study results will contribute to a better understanding of both the effectiveness and mechanisms of a self-management group program as part of cardiac rehabilitation.
The natural environment and livelihoods in the Lower Mekong Basin (LMB) are significantly affected by the annual hydrological cycle. Monitoring of soil moisture as a key variable in the hydrological cycle is of great interest in a number of Hydrological and agricultural applications. In this study we evaluated the quality and spatiotemporal variability of the soil moisture product retrieved from C-band scatterometers data across the LMB sub-catchments. The soil moisture retrieval algorithm showed reasonable performance in most areas of the LMB with the exception of a few sub-catchments in the eastern parts of Laos, where the land cover is characterized by dense vegetation. The best performance of the retrieval algorithm was obtained in agricultural regions. Comparison of the available in situ evaporation data in the LMB and the Basin Water Index (BWI), an indicator of the basin soil moisture condition, showed significant negative correlations up to R = −0.85. The inter-annual variation of the calculated BWI was also found corresponding to the reported extreme hydro-meteorological events in the Mekong region. The retrieved soil moisture data show high correlation (up to R = 0.92) with monthly anomalies of precipitation in non-irrigated regions. In general, the seasonal variability of soil moisture in the LMB was well captured by the retrieval method. The results of analysis also showed significant correlation between El Niño events and the monthly BWI anomaly measurements particularly for the month May with the maximum correlation of R = 0.88.
Background
Malignant hyperthermia (MH), a metabolic myopathy triggered by volatile anesthetics and depolarizing muscle relaxants, is a potentially lethal complication of general anesthesia in susceptible patients. The implementation of modern inhalation anesthetics that research indicates as less potent trigger substances and the recommended limitations of succinylcholine use, suggests there may be considerable decline of fulminant MH cases. In the presented study, the authors analyzed suspected MH episodes during general anesthesia of patients that were referred to the Wuerzburg MH unit between 2007 and 2011, assuming that MH is still a relevant anesthetic problem in our days.
Methods
With approval of the local ethics committee data of patients that underwent muscle biopsy and in vitro contracture test (IVCT) between 2007 and 2011 were analyzed. Only patients with a history of suspected MH crisis were included in the study. The incidents were evaluated retrospectively using anesthetic documentation and medical records.
Results
Between 2007 and 2011 a total of 124 patients were tested. 19 of them were referred because of suspected MH events; 7 patients were diagnosed MH-susceptible, 4 MH-equivocal and 8 MH-non-susceptible by IVCT. In a majority of cases masseter spasm after succinylcholine had been the primary symptom. Cardiac arrhythmias and hypercapnia frequently occurred early in the course of events. Interestingly, dantrolene treatment was initiated in a few cases only.
Conclusions
MH is still an important anesthetic complication. Every anesthetist must be aware of this life-threatening syndrome at any time. The rapid onset of adequate therapy is crucial to avoid major harm and possibly lethal outcome. Dantrolene must be readily available wherever MH triggering agents are used for anesthesia.
Recent evidence indicates that foamy viruses (FVs) are the oldest retroviruses (RVs) that we know and coevolved with their hosts for several hundred million years. This coevolution may have contributed to the non-pathogenicity of FVs, an important factor in development of foamy viral vectors in gene therapy. However, various questions on the molecular evolution of FVs remain still unanswered. The analysis of the spectrum of animal species infected by exogenous FVs or harboring endogenous FV elements in their genome is pivotal. Furthermore, animal studies might reveal important issues, such as the identification of the FV in vivo target cells, which than require a detailed characterization, to resolve the molecular basis of the accuracy with which FVs copy their genome. The issues of the extent of FV viremia and of the nature of the virion genome (RNA vs. DNA) also need to be experimentally addressed.
We report a detailed experimental and theoretical study of the electronic structure of \(Mo_{1-x}Re_x\) random alloys. We have measured electronic band dispersions for clean and hydrogen-covered \(Mo_{1-x}Re_x\) ( 110) with x = 0-0.25 using angle-resolved photoemission spectroscopy. Our results suggest that the bulk and most surface electronic bands shift relative to the Fermi level systematically and approximately rigidly with Re concentration. We distinguish and quantify two contributions to these shifts: a raise of the Fermi energy and an increase of the overall bandwidth. Alloy bands calculated using the first-principles Korringa-Kohn-Rostoker coherent-potential-approximation method accurately predict both of these effects. As derived from the rigid band model, the Fermi energy shift is inversely related to the bulk density of states in this energy region. Using our results, we also characterize an electronic topological transition of the bulk Fermi surface and relate this to bulk transport properties. Finally, we distinguish effects beyond the rigid band approximation: a highly surface-localized state and a composition-dependent impact of the spin-orbit interaction.
Dirac particles, massless relativistic entities, obey linear energy dispersions and hold important implications in particle physics. The recent discovery of Dirac fermions in condensed matter systems including graphene and topological insulators has generated a great deal of interest in exploring the relativistic properties associated with Dirac physics in solid-state materials. In addition, there are stimulating research activities to engineer Dirac particles, elucidating their exotic physical properties in a controllable setting. One of the successful platforms is the ultracold atom-optical lattice system, whose dynamics can be manipulated and probed in a clean environment. A microcavity exciton-polariton-lattice system offers the advantage of forming high-orbital condensation in non-equilibrium conditions, which enables one to explore novel quantum orbital order in two dimensions. In this paper, we experimentally construct the band structures near Dirac points, the vertices of the first hexagonal Brillouin zone with exciton-polariton condensates trapped in a triangular lattice. Due to the finite spectral linewidth, the direct map of band structures at Dirac points is elusive; however, we identify the linear part above Dirac points and its associated velocity value is similar to ~0.9-2 x \(10^8 cm s^{-1}\), consistent with the theoretical estimate \(1 x 10^8 cm s^{-1}\) with a \(2 \mu m\) lattice constant. We envision that the exciton-polariton condensates in lattices would be a promising solid-state platform, where the system order parameter can be accessed in both real and momentum spaces.
Background: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factorinducible 14 (Fn14) are upregulated after myocardial infarction (MI) in both humans and mice. They modulate inflammation and the extracellular matrix, and could therefore be important for healing and remodeling after MI. However, the function of TWEAK after MI remains poorly defined.
Methods and results: Following ligation of the left coronary artery, mice were injected twice per week with a recombinant human serum albumin conjugated variant of TWEAK (HSA-Flag-TWEAK), mimicking the activity of soluble TWEAK. Treatment with HSA-Flag-TWEAK resulted in significantly increased mortality in comparison to the placebo group due to myocardial rupture. Infarct size, extracellular matrix remodeling, and apoptosis rates were not different after MI. However, HSA-Flag-TWEAK treatment increased infiltration of proinflammatory cells into the myocardium. Accordingly, depletion of neutrophils prevented cardiac ruptures without modulating all-cause mortality.
Conclusion: Treatment of mice with HSA-Flag-TWEAK induces myocardial healing defects after experimental MI. This is mediated by an exaggerated neutrophil infiltration into the myocardium.
Experimental Adaptation of Wild-Type Canine Distemper Virus (CDV) to the Human Entry Receptor CD150
(2013)
Canine distemper virus (CDV), a close relative of measles virus (MV), is widespread and well known for its broad host range. When the goal of measles eradication may be achieved, and when measles vaccination will be stopped, CDV might eventually cross the species barrier to humans and emerge as a new human pathogen. In order to get an impression how fast such alterations may occur, we characterized required adaptive mutations to the human entry receptors CD150 (SLAM) and nectin-4 as first step to infect human target cells. Recombinant wild-type CDV-A75/17red adapted quickly to growth in human H358 epithelial cells expressing human nectin-4. Sequencing of the viral attachment proteins (hemagglutinin, H, and fusion protein, F) genes revealed that no adaptive alteration was required to utilize human nectin-4. In contrast, the virus replicated only to low titres (102 pfu/ml) in Vero cells expressing human CD150 (Vero-hSLAM). After three passages using these cells virus was adapted to human CD150 and replicated to high titres (105 pfu/ml). Sequence analyses revealed that only one amino acid exchange in the H-protein at position 540 Asp→Gly (D540G) was required for functional adaptation to human CD150. Structural modelling suggests that the adaptive mutation D540G in H reflects the sequence alteration from canine to human CD150 at position 70 and 71 from Pro to Leu (P70L) and Gly to Glu (G71E), and compensates for the gain of a negative charge in the human CD150 molecule. Using this model system our data indicate that only a minimal alteration, in this case one adaptive mutation, is required for adaptation of CDV to the human entry receptors, and help to understand the molecular basis why this adaptive mutation occurs.
We use pump-repump-probe transient absorption spectroscopy to investigate the role of higher-lying electronic states in the photochemistry of a molecular switch. Moreover, replacing the pump pulse by a pulse-shaper-generated phase-stable double pulse, triggered-exchange two-dimensional (TE2D) electronic spectroscopy is established in the visible regime.
Background
Measles virus (MV) causes T cell suppression by interference with phosphatidylinositol-3-kinase (PI3K) activation. We previously found that this interference affected the activity of splice regulatory proteins and a T cell inhibitory protein isoform was produced from an alternatively spliced pre-mRNA.
Hypothesis
Differentially regulated and alternatively splice variant transcripts accumulating in response to PI3K abrogation in T cells potentially encode proteins involved in T cell silencing.
Methods
To test this hypothesis at the cellular level, we performed a Human Exon 1.0 ST Array on RNAs isolated from T cells stimulated only or stimulated after PI3K inhibition. We developed a simple algorithm based on a splicing index to detect genes that undergo alternative splicing (AS) or are differentially regulated (RG) upon T cell suppression.
Results
Applying our algorithm to the data, 9% of the genes were assigned as AS, while only 3% were attributed to RG. Though there are overlaps, AS and RG genes differed with regard to functional regulation, and were found to be enriched in different functional groups. AS genes targeted extracellular matrix (ECM)-receptor interaction and focal adhesion pathways, while RG genes were mainly enriched in cytokine-receptor interaction and Jak-STAT. When combined, AS/RG dependent alterations targeted pathways essential for T cell receptor signaling, cytoskeletal dynamics and cell cycle entry.
Conclusions
PI3K abrogation interferes with key T cell activation processes through both differential expression and alternative splicing, which together actively contribute to T cell suppression.
DHEA is a precursor for the male and female sex hormones testosterone and estradiol, which are mainly secreted from the testes and the ovary, respectively. In addition, epidemiological studies showed that low serum levels of DHEA and DHEAS correlate with the incidence of autoimmune disease, cancer and cardiovascular disease. In vitro, DHEA and DHEAS influenced glucose metabolism in a favourable manner. However, positive effects of DHEA substitution were only significant adrenal insufficiency in women.
Steroid sulphotransferase 2A1 (SULT2A1) is the responsible enzyme for sulphonation of DHEA to DHEAS which is thought to be the inactive form of DHEA. In this role, SULT2A1 acts as a central regulator of steroid synthesis because sulphonation of DHEA withdraws the substrate for further downstream conversion. Another essential cofactor for sulphonation is PAPS, which is produced by the enzyme PAPS synthase (PAPSS) from ATP and anorganic sulphate. PAPSS exists in the different isoforms PAPSS1 and PAPSS2 and splice variants PAPSS2a and PAPSS2b. Changes in PAPSS activity are thought to influence sulphonation of DHEA significantly. However, neither regulation of PAPSS nor its influence on SULT2A1 have been investigated in human cell lines or humans.
The main goal of this thesis was to analyze the enzyme expression of the DHEA/DHEA shuttle, i.e. mRNA and protein of SULT2A1, PAPSS1 and PAPSS2, in various human cell lines. Furthermore, I investigated which cell line could serve as a suitable model for further research regarding regulation of SULT2A1, PAPSS1 and PAPSS2.
Here, I could show that the enzymes of the DHEA/DHEAS shuttle were expressed in the human adrenal cell line NCI-h295R as both mRNA and protein. In enzyme assays, I was able to prove conversion of DHEA to DHEAS as well as to different other steroids. However, applying Trilostane, a potent inhibitor of CYP3B, effectively directed conversion of DHEA to DHEAS. Using these findings, future experiments can investigate for example the influence of certain cytokines or endocrine disruptors on expression and activity of PAPSS1/2 and on sulphonation of DHEA. In particular, the relatively equal expression of PAPSS1 and PAPSS2 will enable us to do knock down experiments with siRNA to elucidate how the activity of one enzyme changes when the other one fails.
Sulphonation of DHEA by SULT2A1 is thought to happen in the cytoplasm or more precisely in the Golgi apparatus. However, experiments in transfected cells have shown both a cytoplasmatic and a nuclear localisation when both enzymes were expressed at the same time. Immunocytochemistry revealed the same results in the adrenal cell line NCI-h295R, where both enzymes were expressed strongly in the nucleus. The physiological role is not clear and requires further research. Presumably, sulphate is activated in the nucleus. However, one could also speculate that a shift of PAPSS to the nucleus could generate a reservoir, which can be activated by re-localisation to the cytoplasm when more PAPS is needed.
Expression of SULT2A1 in some foetal tissues has been investigated earlier. Whilst in adult human cartilage PAPSS1 is predominant, in newly born hamsters PAPSS2 is more abundantly expressed. The expression of PAPSS isoforms in highly sulphonating tissue has not been investigated in humans, so far. This work demonstrated a differential expression of SULT2A1, PAPSS1 and PAPSS2 in adult and foetal liver, adrenal and foetal cartilage tissue. In adult and foetal adrenal expression was similar. However, foetal and adult liver differed in the expression of SULT2A1, which was expressed much more in adult tissue. Most importantly, in foetal cartilage there was only a low expression of SULT2A1 and PAPS seems to mostly provided by PAPSS1, which was considerably higher expressed in cartilage than in other tissues. In contrast, PAPSS2 was mainly expressed in adult and foetal adrenal.
Additionally, we reported a case of a female patient who had been investigated for hyperandrogenism. Two mutations in the PAPSS2 gene had led to massively reduced serum levels of DHEAS. One heterozygous mutation in the domain of the APS kinase of the PAPSS2 protein leads to substitution of one amino acid at position 48 (T48R). In vitro experiments showed a residual activity of 6% for this mutation. A second mutation in the ATP sulphurylase domain of PAPSS2 was found. The introduction of thymidine instead of cytidine leads to a stop codon, which is presumed to truncate the protein at position 329 (R329X). In vitro, no residual activity was seen for this mutation. The lack of PAPS reduces sulphonation of DHEA but also sulphonation of proteoglycanes, which leads to skeletal abnormalities. The abundance of DHEA enables massive downstream conversion to androgens leading to clinical features of hyperandrogenism. Regarding the bone abnormalities, it is interesting and surprising that activity of PAPSS1 compensated to a great extent in cartilage but was not able to keep up a more considerable sulphonation of DHEA. Possibly, the subcellular localisation might play a role in this scenario.
This thesis presents the detailed development of the fabrication process and the first observations of artificial magnetic atoms from the II-VI diluted magnetic semiconductor alloy (Zn,Cd,Be,Mn)Se. In order to manufacture the vertical quantum dot device which exhibits artificial atom behavior a number of development steps are conducted. First, the II-VI heterostructure is adjusted for the linear transport regime. Second, state of the art vertical quantum dot fabrication techniques in the III-V material system are investigated regarding their portability to the II-VI heterostructure. And third, new approaches to the fabrication process are developed, taking into account the complexity of the heterostructure and its physical properties. Finally a multi-step fabrication process is presented, which is built up from electron beam and optical lithography, dry and wet etching and insulator deposition. This process allows for the processing of pillars with diameters down to 200 nm with an insulating dielectric and gate. Preliminary transport data on the fabricated vertical quantum dots are presendted confirming the magnetic nature of the resulting artificial atoms.
Many plant secondary metabolites exhibit some degree of biological activity in humans. It is a common observation that individual plant-derived compounds in vivo are present in the nanomolar concentration range at which they usually fail to display measurable activity in vitro. While it is debatable that compounds detected in plasma are not the key effectors of bioactivity, an alternative hypothesis may take into consideration that measurable concentrations also reside in compartments other than plasma. We analysed the binding of constituents and the metabolite δ-(3,4-dihydroxy-phenyl)-γ-valerolactone (M1), that had been previously detected in plasma samples of human consumers of pine bark extract Pycnogenol, to human erythrocytes. We found that caffeic acid, taxifolin, and ferulic acid passively bind to red blood cells, but only the bioactive metabolite M1 revealed pronounced accumulation. The partitioning of M1 into erythrocytes was significantly diminished at higher concentrations of M1 and in the presence of glucose, suggesting a facilitated transport of M1 via GLUT-1 transporter. This concept was further supported by structural similarities between the natural substrate α-D-glucose and the S-isomer of M1. After cellular uptake, M1 underwent further metabolism by conjugation with glutathione. We present strong indication for a transporter-mediated accumulation of a flavonoid metabolite in human erythrocytes and subsequent formation of a novel glutathione adduct. The physiologic role of the adduct remains to be elucidated.
Background: We report on a patient with genetically confirmed overlapping diagnoses of CMT1A and FSHD. This case adds to the increasing number of unique patients presenting with atypical phenotypes, particularly in FSHD. Even if a mutation in one disease gene has been found, further genetic testing might be warranted in cases with unusual clinical presentation.
Case presentation: The reported 53 years old male patient suffered from walking difficulties and foot deformities first noticed at age 20. Later on, he developed scapuloperoneal and truncal muscle weakness, along with atrophy of the intrinsic hand and foot muscles, pes cavus, claw toes and a distal symmetric hypoesthesia. Motor nerve conduction velocities were reduced to 20 m/s in the upper extremities, and not educible in the lower extremities, sensory nerve conduction velocities were not attainable. Electromyography showed both, myopathic and neurogenic changes. A muscle biopsy taken from the tibialis anterior muscle showed a mild myopathy with some neurogenic findings and hypertrophic type 1 fibers. Whole-body muscle MRI revealed severe changes in the lower leg muscles, tibialis anterior and gastrocnemius muscles were highly replaced by fatty tissue. Additionally, fatty degeneration of shoulder girdle and straight back muscles, and atrophy of dorsal upper leg muscles were seen. Taken together, the presenting features suggested both, a neuropathy and a myopathy. Patient's family history suggested an autosomal dominant inheritance. Molecular testing revealed both, a hereditary motor and sensory neuropathy type 1A (HMSN1A, also called Charcot-Marie-Tooth neuropathy 1A, CMT1A) due to a PMP22 gene duplication and facioscapulohumeral muscular dystrophy (FSHD) due to a partial deletion of the D4Z4 locus (19 kb).
Conclusion: Molecular testing in hereditary neuromuscular disorders has led to the identification of an increasing number of atypical phenotypes. Nevertheless, finding the right diagnosis is crucial for the patient in order to obtain adequate medical care and appropriate genetic counseling, especially in the background of arising curative therapies.
Background
The aortic pulse-wave velocity (PWV) is an important indicator of cardiovascular risk. In recent studies MRI methods have been developed to measure this parameter noninvasively in mice. Present techniques require additional hardware for cardiac and respiratory gating. In this work a robust self-gated measurement of the local PWV in mice without the need of triggering probes is proposed.
Methods
The local PWV of 6-months-old wild-type C57BL/6J mice (n=6) was measured in the abdominal aorta with a retrospectively triggered radial Phase Contrast (PC) MR sequence using the flow-area (QA) method. A navigator signal was extracted from the CMR data of highly asymmetric radial projections with short repetition time (TR=3 ms) and post-processed with high-pass and low-pass filters for retrospective cardiac and respiratory gating. The self-gating signal was used for a reconstruction of high-resolution Cine frames of the aortic motion. To assess the local PWV the volume flow Q and the cross-sectional area A of the aorta were determined. The results were compared with the values measured with a triggered Cartesian and an undersampled triggered radial PC-Cine sequence.
Results
In all examined animals a self-gating signal could be extracted and used for retrospective breath-gating and PC-Cine reconstruction. With the non-triggered measurement PWV values of 2.3±0.2 m/s were determined. These values are in agreement with those measured with the triggered Cartesian (2.4±0.2 m/s) and the triggered radial (2.3±0.2 m/s) measurement. Due to the strong robustness of the radial trajectory against undersampling an acceleration of more than two relative to the prospectively triggered Cartesian sampling could be achieved with the retrospective method.
Conclusion
With the radial flow-encoding sequence the extraction of a self-gating signal is feasible. The retrospective method enables a robust and fast measurement of the local PWV without the need of additional trigger hardware.
Introduction: Reversible posterior leukoencephalopathy syndrome – a reversible subacute global encephalopathy clinically presenting with headache, altered mental status, visual symptoms such as hemianopsia or cortical blindness, motor symptoms, and focal or generalized seizures – is characterized by a subcortical vasogenic edema symmetrically affecting posterior brain regions. Complete reversibility of both clinical signs and magnetic resonance imaging lesions is regarded as a defining feature of reversible posterior leukoencephalopathy syndrome. Reversible posterior leukoencephalopathy syndrome is almost exclusively seen in the setting of a predisposing clinical condition, such as pre-eclampsia, systemic infections, sepsis and shock, certain autoimmune diseases, various malignancies and cytotoxic chemotherapy, transplantation and concomitant immunosuppression (especially with calcineurin inhibitors) as well as episodes of abrupt hypertension. We describe for the first time clinical, radiological and histological findings in a case of reversible posterior leukoencephalopathy syndrome with an irreversible and fatal outcome occurring in the absence of any of the known predisposing clinical conditions except for a hypertensive episode.
Case presentation: A 58-year-old Caucasian woman presented with a two-week history of subacute and progressive occipital headache, blurred vision and imbalance of gait and with no evidence for raised arterial blood pressure during the two weeks previous to admission. Her past medical history was unremarkable except for controlled arterial hypertension. Cerebral magnetic resonance imaging demonstrated cortical and subcortical lesions with combined vasogenic and cytotoxic edema atypical for both venous congestion and arterial infarction. Routine laboratory and cerebrospinal fluid parameters were normal. The diagnosis of reversible posterior leukoencephalopathy syndrome was established.
Within hours after admission the patient showed a rapidly decreasing level of consciousness, extension and flexion synergisms, bilaterally extensor plantar responses and rapid cardiopulmonary decompensation requiring ventilatory and cardiocirculatory support. Follow-up cerebral imaging demonstrated widespread and confluent cytotoxic edematous lesions in different arterial territories, global cerebral swelling, and subsequent upper and lower brainstem herniation. Four days after admission, the patient was declared dead because of brain death.
Conclusion: This case demonstrates that fulminant and fatal reversible posterior leukoencephalopathy syndrome may occur spontaneously, that is, in the absence of any of the known predisposing systemic conditions.
Introduction: Reversible posterior leukoencephalopathy syndrome – a reversible subacute global encephalopathy clinically presenting with headache, altered mental status, visual symptoms such as hemianopsia or cortical blindness, motor symptoms, and focal or generalized seizures – is characterized by a subcortical vasogenic edema symmetrically affecting posterior brain regions. Complete reversibility of both clinical signs and magnetic resonance imaging lesions is regarded as a defining feature of reversible posterior leukoencephalopathy syndrome. Reversible posterior leukoencephalopathy syndrome is almost exclusively seen in the setting of a predisposing clinical condition, such as pre-eclampsia, systemic infections, sepsis and shock, certain autoimmune diseases, various malignancies and cytotoxic chemotherapy, transplantation and concomitant immunosuppression (especially with calcineurin inhibitors) as well as episodes of abrupt hypertension. We describe for the first time clinical, radiological and histological findings in a case of reversible posterior leukoencephalopathy syndrome with an irreversible and fatal outcome occurring in the absence of any of the known predisposing clinical conditions except for a hypertensive episode.
Case presentation: A 58-year-old Caucasian woman presented with a two-week history of subacute and progressive occipital headache, blurred vision and imbalance of gait and with no evidence for raised arterial blood pressure during the two weeks previous to admission. Her past medical history was unremarkable except for controlled arterial hypertension. Cerebral magnetic resonance imaging demonstrated cortical and subcortical lesions with combined vasogenic and cytotoxic edema atypical for both venous congestion and arterial infarction. Routine laboratory and cerebrospinal fluid parameters were normal. The diagnosis of reversible posterior leukoencephalopathy syndrome was established. Within hours after admission the patient showed a rapidly decreasing level of consciousness, extension and flexion synergisms, bilaterally extensor plantar responses and rapid cardiopulmonary decompensation requiring ventilatory and cardiocirculatory support. Follow-up cerebral imaging demonstrated widespread and confluent cytotoxic edematous lesions in different arterial territories, global cerebral swelling, and subsequent upper and lower brainstem herniation. Four days after admission, the patient was declared dead because of brain death.
Conclusion: This case demonstrates that fulminant and fatal reversible posterior leukoencephalopathy syndrome may occur spontaneously, that is, in the absence of any of the known predisposing systemic conditions.
Arterial embolism with lower limb ischemia is a rare manifestation of paraneoplastic hypercoagulability in cancer patients. We report a unique case of fatal thromboembolism involving both circulations associated with a poorly differentiated neuroendocrine tumor of the lung with rapid progress despite high doses of unfractioned heparin and review the current literature on anticoagulative regimen in tumour patients.
Introduction
Groin infections resulting in arterial bleeding due to bacterial vessel destruction are a severe challenge in vascular surgery. Patients with them most often present as emergencies and therefore need individualized reconstruction solutions.
Case presentation
Case 1 is a 67-year-old man with infectious bleeding after an autologous reconstruction of the femoral bifurcation with greater saphenous vein due to infection of a bovine pericard patch after thrombendarterectomy. Case 2 is a 35-year-old male drug addict and had severe femoral bleeding and infection after repeated intravenous and intra-arterial substance abuse. Both patients were treated with an autologous obturator bypass of the superficial femoral vein. We review the current literature and highlight our therapeutic concept of this clinical entity.
Conclusions
Treatment should include systemic antibiotic medication, surgical control of the infectious site, revascularization and soft tissue repair. An extra-anatomical obturator bypass with autologous superficial femoral vein should be considered as the safest revascularization procedure in infections caused by highly pathogenic bacteria.
Ultraviolet irradiation of CO-releasing molecules (CORMs) in water eventually leads to the loss of several carbon monoxide ligands.We show for an exemplary manganese tricarbonyl CORM that only one ligand is photolyzed off on an ultrafast timescale and that some molecules may undergo geminate recombination.
Fabry disease is a rare X-linked hereditary disease caused by mutations in the AGAL gene encoding the lysosomal enzyme alpha-galactosidase A. Enzyme replacement therapy (ERT) is the current cornerstone of Fabry disease management. Involvement of kidney, heart and the central nervous system shortens life span, and fibrosis of these organs is a hallmark of the disease. Fibrosis was initially thought to result from tissue ischemia secondary to endothelial accumulation of glycosphingolipids in the microvasculature. However, despite ready clearance of endothelial deposits, ERT is less effective in patients who have already developed fibrosis. Several potential explanations of this clinical observation may impact on the future management of Fabry disease. Alternative molecular pathways linking glycosphingolipids and fibrosis may be operative; tissue injury may recruit secondary molecular mediators of fibrosis that are unresponsive to ERT, or fibrosis may represent irreversible tissue injury that limits the therapeutic response to ERT. We provide an overview of Fabry disease, with a focus on the assessment of fibrosis, the clinical consequences of fibrosis, and recent advances in understanding the cellular and molecular mechanisms of fibrosis that may suggest novel therapeutic approaches to Fabry disease.
In the field of organic photovoltaics, one of the most intensely researched topics to date is the charge carrier photogeneration in organic bulk heterojunction solar cells whose thorough understanding is crucial for achieving higher power conversion efficiencies. In particular, the mechanism of singlet exciton dissociation at the polymer–fullerene interface is still controversially debated.
This work addresses the dissociation pathway via relaxed charge transfer states (CTS) by investigating its field dependence for reference material systems consisting of MDMO-PPV and one of the fullerene derivatives PC61BM, bisPCBM and PC71BM. Field dependent photoluminescence (PL(F)) and transient absorption (TA(F)) measurements give insight into the recombination of charge transfer excitons (CTE) and the generation of polarons, respectively. Optically detected magnetic resonance and atomic force microscopy are used to characterize the morphology of the samples.
The comparison of the experimental field dependent exciton recombination recorded by PL(F) and the theoretical exciton dissociation probability given by the Onsager–Braun model yields the exciton binding energy as one of the key parameters determining the dissociation efficiency. The binding energies of both the singlet exciton in neat MDMO-PPV and the CTE in MDMO-PPV:PC61BM 1:1 are extracted, the latter turning out to be significantly reduced with respect to the one of the singlet exciton.
Based on these results, the field dependence of CTE dissociation is evaluated for MDMO-PPV:PC61BM blends with varying fullerene loads by PL(F) and TA(F). For higher PC61BM contents, the CTE binding energies decrease notably. This behavior is ascribed to a larger effective dielectric constant for well-intermixed blends and to an interplay between dielectric constant and CTE delocalization length for phase separated morphologies, emphasizing the importance of high dielectric constants for the charge carrier photogeneration process.
Finally, the CTE binding energies are determined for MDMO-PPV blends with different fullerene derivatives, focusing on the influence of the acceptor LUMO energy. Here, the experimental results suggest the latter having no or at least no significant impact on the binding energy of the CTE. Variations of this binding energy are rather related to different trap levels in the acceptors which seem to be involved in CTS formation.
Members of the Diaphanous (Dia) protein family are key regulators of fundamental actin driven cellular processes, which are conserved from yeast to humans. Researchers have uncovered diverse physiological roles in cell morphology, cell motility, cell polarity, and cell division, which are involved in shaping cells into tissues and organs. The identification of numerous binding partners led to substantial progress in our understanding of the differential functions of Dia proteins. Genetic approaches and new microscopy techniques allow important new insights into their localization, activity, and molecular principles of regulation.
Community-acquired respiratory virus (CARV) infections have been recognized as a significant cause of morbidity and mortality in patients with leukemia and those undergoing hematopoietic stem cell transplantation (HSCT). Progression to lower respiratory tract infection with clinical and radiological signs of pneumonia and respiratory failure appears to depend on the intrinsic virulence of the specific CARV as well as factors specific to the patient, the underlying disease, and its treatment. To better define the current state of knowledge of CARVs in leukemia and HSCT patients, and to improve CARV diagnosis and management, a working group of the Fourth European Conference on Infections in Leukaemia (ECIL-4) 2011 reviewed the literature on CARVs, graded the available quality of evidence, and made recommendations according to the Infectious Diseases Society of America grading system. Owing to differences in screening, clinical presentation, and therapy for influenza and adenovirus, ECIL-4 recommendations are summarized for CARVs other than influenza and adenovirus.
We did not expect that research on the molecular mechanism of algal phototaxis or archaeal light‐driven ion transport might interest readers of a medical journal when we conceived and performed our experiments a decade ago. On the other hand, it did not escape our attention that channelrhodopsin is helping an ever‐increasing number of researchers to address their specific questions. For example, the channelrhodopsin approach is used to study the molecular events during the induction of synaptic plasticity or to map long‐range connections from one side of the brain to the other, and to map the spatial location of inputs on the dendritic tree of individual neurons. The current applications have been summarized in a number of recent reviews (Fenno et al, 2011; Yizhar et al, 2011; Zhang et al, 2011). Here, we give personal insight into the history of the discovery of channelrhodopsin and a biophysical perspective on this remarkable class of proteins that has been the main topic of our research since the 1990s.
The intrahelical salt bridge between \(E/D^{3.49}\) and \(R^{3.50}\) within the E/DRY motif on helix 3 (H3) and the interhelical hydrogen bonding between the E/DRY and residues on H6 are thought to be critical in stabilizing the class A G protein-coupled receptors in their inactive state. Removal of these interactions is expected to generate constitutively active receptors. This study examines how neutralization of \(E^{3.49/6.30}\) in the thromboxane prostanoid (TP) receptor alters ligand binding, basal, and agonist-induced activity and investigates the molecular mechanisms of G protein activation. We demonstrate here that a panel of full and partial agonists showed an increase in affinity and potency for E129V and E240V mutants. Yet, even augmenting the sensitivity to detect constitutive activity (CA) with overexpression of the receptor or the G protein revealed resistance to an increase in basal activity, while retaining fully the ability to cause agonist-induced signaling. However, direct G protein activation measured through bioluminescence resonance energy transfer (BRET) indicates that these mutants more efficiently communicate and/or activate their cognate G proteins. These results suggest the existence of additional constrains governing the shift of TP receptor to its active state, together with an increase propensity of these mutants to agonist-induced signaling, corroborating their definition as superactive mutants. The particular nature of the TP receptor as somehow "resistant" to CA should be examined in the context of its pathophysiological role in the cardiovascular system. Evolutionary forces may have favored regulation mechanisms leading to low basal activity and selected against more highly active phenotypes.
Polycomb group (PcG) proteins are chromatin modifiers involved in heritable gene repression. Two main PcG complexes have been characterized: Polycomb repressive complex (PRC) 2 is involved in the initiation of gene silencing, whereas PRC1 participates in the stable maintenance of gene repression. Pcgf4 (Polycomb group protein, Bmi1) is one of the most studied PRC1 members with essential functions for embryonic development and adult stem cell self renewal. In embryonic stem cells (ES cells), Pcgf4 is poorly expressed while its paralogs (Pcgf1, Pcgf2, Pcgf3, Pcgf5 and Pcgf6) are expressed at higher levels. The relevance of the Pcgf paralog Pcgf6 for the maintenance of ESC pluripotency has not been addressed so far. My analyses revealed that Pcgf6 was the most expressed Pcgf paralog in undifferentiated ES cells. When ES cells differentiated, gene expression of Pcgf6 strongly declined. To investigate the functions of Pcgf6 in ES cells, we established a doxycycline (dox) inducible shRNA-targeted knockdown system according to publications by Seibler et al. (Seibler et al. 2005; Seibler et al. 2007). Following dox-induced knockdown (KD) of Pcgf6, we observed decreased ES cell colony formation. In parallel, gene expression of pluripotency markers Oct4, Nanog and Sox2 was reduced upon dox-treatment, wheras the expression of mesoderm genes such as T (Brachyury) were up-regulated. Further, microarray analysis revealed de-repression of several spermatogenesis-specic genes upon Pcgf6-KD, suggesting that Pcgf6 may play a role during spermatogenesis. Upon in vitro differentiation, Pcgf6-KD ES cells showed increased hemangioblast formation, paralleled by increased hematopoietic development. In summary, results of this study suggest that Pcgf6 is involved in maintaining ES cell identity by repressing lineage-specific gene expression in undifferentiated ES cells.
Baclofen (1) is a potent and selective agonist for bicuculline-insensitive GABAB receptors and is used clinically as an antispastic and muscle relaxant agent. In the search for new bioactive chemical entities that bind specifically to GABAB receptors, we report here the synthesis of certain baclofen homologues, namely (R,S)-5-amino-3-arylpentanoic acid hydrochlorides (R,S)-1a–h as well as (R,S)-5-amino-3-methylpentanoic acid [(RS)-1i] to be evaluated as GABABR agonists. Compound 1a is an agonist to GABAB receptors with an EC50 value of 46 μM on tsA201 cells transfected with GABAB1b/GABAB2/Gqz5, being the most active congener among all the synthesized compounds.
Background: Plants have evolved an astonishing array of survival strategies. To defend against insects, for example, damaged plants emit volatile organic compounds that attract the herbivore’s natural enemies. So far, plant volatile responses have been studied extensively in conjunction with leaf chewing and sap sucking insects, yet little is known about the relationship between plant volatiles and gall-inducers, the most sophisticated herbivores. Here we describe a new role for volatiles as gall-insects were found to benefit from this plant defence.
Results: Chemical analyses of galls triggered by the gregarious aphid Slavum wertheimae on wild pistachio trees showed that these structures contained and emitted considerably higher quantities of plant terpenes than neighbouring leaves and fruits. Behavioural assays using goats as a generalist herbivore confirmed that the accumulated terpenes acted as olfactory signals and feeding deterrents, thus enabling the gall-inducers to escape from inadvertent predation by mammals.
Conclusions: Increased emission of plant volatiles in response to insect activity is commonly looked upon as a “cry for help” by the plant to attract the insect’s natural enemies. In contrast, we show that such volatiles can serve as a first line of insect defences that extends the ‘extended phenotype’ represented by galls, beyond physical boundaries. Our data support the Enemy hypothesis insofar that high levels of gall secondary metabolites confer protection against natural enemies.
Neisseria meningitidis is a facultative human pathogen that occasionally shows strong resistance against serum complement exposure. Previously described factors that mediate meningococcal serum resistance are for example the capsule, LPS sialylation, and expression of the factor H binding protein. I aimed for identification of novel serum resistance factors, thereby following two approaches, i) the analysis of the impact of global regulators of gene expression on serum resistance; and ii) a comparative analysis of closely related strains differing in serum resistance. (i) Of six meningococcal global regulators of gene expression studied, only mutation of the zinc uptake regulator Zur reduced complement deposition on meningococci. Little was known about meningococcal Zur and regulatory processes in response to zinc. I therefore elucidated the yet unidentified meningococcal Zur regulon comparing the transcriptional response of the N. meningitidis strain MC58 under zinc-rich and zinc-deficient conditions using a common reference design of microarray analysis. The meningococcal Zur regulon comprises 17 genes, of which 15 genes were repressed and two genes were activated at high zinc condition. Amongst the Zur-repressed genes were genes involved in zinc uptake, tRNA modification, and ribosomal assembly. A 23 bp meningococcal consensus Zur binding motif (Zur box) with a conserved central palindrome was established (TGTTATDNHATAACA) and detected in the promoter region of all regulated transcriptional units (genes/operons). In vitro binding of meningococcal Zur to the Zur box of three selected genes was shown for the first time using EMSAs. Binding of meningococcal Zur to DNA depended specifically on zinc, and mutations in the palindromic sequence constrained Zur binding to the DNA motif. ii) Three closely related strains of ST-41/44 cc from invasive disease and carriage which differed in their resistance to serum complement exposure were analysed to identify novel mediators of serum resistance. I compared the strains’ gene content by microarray analysis which revealed six genes being present in both carrier isolates, but absent in the invasive isolate. Four of them are part of two Islands of horizontally transferred DNA, i.e. IHT-B and –C. The working group furthermore applied a comprehensive screening assay, a transcriptome and a proteome analysis leading to identification of three target proteins. I contributed to establish the role of these three proteins in serum resistance: The adhesin Opc mediates serum resistance by binding of vitronectin, a negative regulator of the complement system; the hypothetical protein NMB0865 slightly contributes to serum resistance by a yet unknown mechanism; and NspA, recently identified to bind the negative complement regulator factor H, led to considerable reduced complement-mediated killing.
BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
Candida albicans and Candida dubliniensis are pathogenic fungi that are highly related but differ in virulence and in some phenotypic traits. During in vitro growth on certain nutrient-poor media, C. albicans and C. dubliniensis are the only yeast species which are able to produce chlamydospores, large thick-walled cells of unknown function. Interestingly, only C. dubliniensis forms pseudohyphae with abundant chlamydospores when grown on Staib medium, while C. albicans grows exclusively as a budding yeast. In order to further our understanding of chlamydospore development and assembly, we compared the global transcriptional profile of both species during growth in liquid Staib medium by RNA sequencing. We also included a C. albicans mutant in our study which lacks the morphogenetic transcriptional repressor Nrg1. This strain, which is characterized by its constitutive pseudohyphal growth, specifically produces masses of chlamydospores in Staib medium, similar to C. dubliniensis. This comparative approach identified a set of putatively chlamydospore-related genes. Two of the homologous C. albicans and C. dubliniensis genes (CSP1 and CSP2) which were most strongly upregulated during chlamydospore development were analysed in more detail. By use of the green fluorescent protein as a reporter, the encoded putative cell wall related proteins were found to exclusively localize to C. albicans and C. dubliniensis chlamydospores. Our findings uncover the first chlamydospore specific markers in Candida species and provide novel insights in the complex morphogenetic development of these important fungal pathogens.
Glucocorticoids (GCs) are steroid hormones that have inflammatory and immunosuppressive effects on a wide variety of cells. They are used as therapy for inflammatory disease and as a common agent against edema. The blood brain barrier (BBB), comprising microvascular endothelial cells, serves as a permeability screen between the blood and the brain. As such, it maintains homeostasis of the central nervous system (CNS). In many CNS disorders, BBB integrity is compromised. GC treatment has been demonstrated to improve the tightness of the BBB. The responses and effects of GCs are mediated by the ubiquitous GC receptor (GR). Ligand-bound GR recognizes and binds to the GC response element located within the promoter region of target genes. Transactivation of certain target genes leads to improved barrier properties of endothelial cells. In this review, we deal with the role of GCs in endothelial cell barrier function. First, we describe the mechanisms of GC action at the molecular level. Next, we discuss the regulation of the BBB by GCs, with emphasis on genes targeted by GCs such as occludin, claudins and VE-cadherin. Finally, we present currently available GC therapeutic strategies and their limitations.
An essential topic for synthetic biologists is to understand the structure and function of biological processes and involved proteins and plan experiments accordingly. Remarkable progress has been made in recent years towards this goal. However, efforts to collect and present all information on processes and functions are still cumbersome. The database tool GoSynthetic provides a new, simple and fast way to analyse biological processes applying a hierarchical database. Four different search modes are implemented. Furthermore, protein interaction data, cross-links to organism-specific databases (17 organisms including six model organisms and their interactions), COG/KOG, GO and IntAct are warehoused. The built in connection to technical and engineering terms enables a simple switching between biological concepts and concepts from engineering, electronics and synthetic biology. The current version of GoSynthetic covers more than one million processes, proteins, COGs and GOs. It is illustrated by various application examples probing process differences and designing modifications.
Silicene consists of a monolayer of silicon atoms in a buckled honeycomb structure. It was recently discovered that the symmetry of such a system allows for interesting Rashba spin–orbit effects. A perpendicular electric field is able to couple to the sublattice pseudospin, making it possible to electrically tune and close the band gap. Therefore, external electric fields may generate a topological phase transition from a topological insulator to a normal insulator (or semimetal) and vice versa. The contribution of the present paper to the study of silicene is twofold. Firstly, we perform a group theoretical analysis to systematically construct the Hamiltonian in the vicinity of the K points of the Brillouin zone and find an additional, electric field induced spin–orbit term, that is allowed by symmetry. Subsequently, we identify a tight-binding model that corresponds to the group theoretically derived Hamiltonian near the K points. Secondly, we start from this tight-binding model to analyze the topological phase diagram of silicene by an explicit calculation of the Z2 topological invariant of the band structure. To this end, we calculate the Z2 topological invariant of the honeycomb lattice in a manifestly gauge invariant way which allows us to include Sz symmetry breaking terms—like Rashba spin–orbit interaction—into the topological analysis. Interestingly, we find that the interplay of a Rashba and an intrinsic spin–orbit term can generate a non-trivial quantum spin Hall phase in silicene. This is in sharp contrast to the more extensively studied honeycomb system graphene where Rashba spin–orbit interaction is known to compete with the quantum spin Hall effect in a detrimental way.
Background: Despite availability of efficient treatment regimens for early stage colorectal cancer, treatment regimens for late stage colorectal cancer are generally not effective and thus need improvement. Oncolytic virotherapy using replication-competent vaccinia virus (VACV) strains is a promising new strategy for therapy of a variety of human cancers.
Methods: Oncolytic efficacy of replication-competent vaccinia virus GLV-1h68 was analyzed in both, cell cultures and subcutaneous xenograft tumor models.
Results: In this study we demonstrated for the first time that the replication-competent recombinant VACV GLV-1h68 efficiently infected, replicated in, and subsequently lysed various human colorectal cancer lines (Colo 205, HCT-15, HCT-116, HT-29, and SW-620) derived from patients at all four stages of disease. Additionally, in tumor xenograft models in athymic nude mice, a single injection of intravenously administered GLV-1h68 significantly inhibited tumor growth of two different human colorectal cell line tumors (Duke’s type A-stage HCT-116 and Duke’s type C-stage SW-620), significantly improving survival compared to untreated mice. Expression of the viral marker gene ruc-gfp allowed for real-time analysis of the virus infection in cell cultures and in mice. GLV-1h68 treatment was well-tolerated in all animals and viral replication was confined to the tumor. GLV-1h68 treatment elicited a significant up-regulation of murine immune-related antigens like IFN-γ, IP-10, MCP-1, MCP-3, MCP-5, RANTES and TNF-γ and a greater infiltration of macrophages and NK cells in tumors as compared to untreated controls.
Conclusion: The anti-tumor activity observed against colorectal cancer cells in these studies was a result of direct viral oncolysis by GLV-1h68 and inflammation-mediated innate immune responses. The therapeutic effects occurred in tumors regardless of the stage of disease from which the cells were derived. Thus, the recombinant vaccinia virus GLV-1h68 has the potential to treat colorectal cancers independently of the stage of progression.
Since the first description of a systematic mis-reaching by Balint in 1909, a reasonable number of patients showing a similar phenomenology, later termed optic ataxia (OA), has been described. However, there is surprising inconsistency regarding the behavioral measures that are used to detect OA in experimental and clinical reports, if the respective measures are reported at all. A typical screening method that was presumably used by most researchers and clinicians, reaching for a target object in the peripheral visual space, has never been evaluated. We developed a set of instructions and evaluation criteria for the scoring of a semi-standardized version of this reaching task. We tested 36 healthy participants, a group of 52 acute and chronic stroke patients, and 24 patients suffering from cerebellar ataxia. We found a high interrater reliability and a moderate test-retest reliability comparable to other clinical instruments in the stroke sample. The calculation of cut-off thresholds based on healthy control and cerebellar patient data showed an unexpected high number of false positives in these samples due to individual outliers that made a considerable number of errors in peripheral reaching. This study provides first empirical data from large control and patient groups for a screening procedure that seems to be widely used but rarely explicitly reported and prepares the grounds for its use as a standard tool for the description of patients who are included in single case or group studies addressing optic ataxia similar to the use of neglect, extinction, or apraxia screening tools.